Purple Book IAP Guidebook On Immunization 2022-2023

Inhalt
1. Immunization in India: Past, Present,

and Future 1
M Indra Shekhar Rao, Shivananda S
2. General Aspects of Vaccination 9

2.1 Basic Immunology 9
Arun Wadhwa, Abhay Shah
2.2 Elementary Epidemiology 26
Shashi Kant Dhir, Sanjay Verma
2.3 Vaccine-preventable Disease Surveillance and IDsurv 32
Chandra Mohan Kumar, Sanjay Verma
2.4 Practical Aspects of Immunization 37
M Indra Shekhar Rao, Sanjay Srirampur
2.5 Vaccine Storage and Handling 49
Srinivas G Kasi, Sanjay Marathe
2.6 Adverse Events Following Immunization 73
M Indra Shekhar Rao, Harish Kumar Pemde
2.7 Scheduling of Vaccines 91
Arun Wadhwa, Harish Kumar Pemde
3. Licensed Vaccines 102

3.1 Bacillus Calmette–Guérin Vaccine 102
Kripasindhu Chatterjee, Shivananda S
3.2 Polio Vaccine 119
Bhaskar Shenoy, Sunil Kumar Agarwalla
3.3 Hepatitis B Vaccine 140
Srinivas Kalyani, Srinivas G Kasi
3.4 Diphtheria, Tetanus, and Pertussis Vaccines 159
Srinivas G Kasi, Abhay Shah
xxii Contents
3.5 Haemophilus Influenzae Type B Conjugate Vaccines 185

Sanjay Lalwani, Shivananda S
3.6 Pneumococcal Vaccines 193
Rajendra Khadke, Abhay Shah
3.7 Rotavirus Vaccines 221
Shashi Kant Dhir, Srinivas G Kasi
3.8 Measles, Mumps, and Rubella Vaccines 240
B Rajsekhar, Sanjay Verma
3.9 Varicella Vaccines 253
Rajendra Khadke, Sanjay Srirampur
3.10 Hepatitis A Vaccines 270
Chandra Mohan Kumar, Sanjay Marathe
3.11 Typhoid Vaccines 285
Kripasindhu Chatterjee, Srinivas G Kasi
3.12 Human Papillomavirus Vaccines 303
3.13 Influenza Vaccines 320
B Rajsekhar, Sunil Kumar Agarwalla
3.14 Japanese Encephalitis Vaccines 335
3.15 Meningococcal Vaccines 357
Ananda Kesavan TM, Harish Kumar Pemde
3.16 Rabies Vaccines 373
Bhaskar Shenoy, Sanjay Marathe
3.17 Cholera Vaccines 388
Ananda Kesavan TM, Sunil Kumar Aggarwalla
3.18 Yellow Fever Vaccine 394
3.19 COVID Vaccines 403
Srinivas G Kasi, Arun Wadhwa
4. Vaccination of Special Groups 421

4.1 Adolescent Vaccination 421
Contents xxiii
4.2 Immunization in Special Situations 434

Srinivas G Kasi, Sanjay Srirampur
4.3 Vaccination Strategies for Travelers 471
Srinivas G Kasi, Harish Kumar Pemde
5. Future Vaccines and Vaccine Hesitancy 483

5.1 Future Vaccines 483
Srinivas G Kasi, S Balasubramanium
5.2 Vaccine Hesitancy 500
M Indra Shekhar Rao, Srinivas Kalyani
Annexures
I. Immunization Schedule 2022 511
II. Internet Resources on Immunization Information 520
III. Ready Reckoner for Vaccines Currently Available in India 523
IV. AEFI Reporting Form 537
Index539
1 Immunization in India:
Past, Present, and Future
Chapter
M Indra Shekhar Rao, Shivananda S
INTRODUCTION
Immunization is one of the most cost-effective public health
interventions and largely responsible for reduction of under-5
mortality rate and indeed, is one of the strong pillars of child survival.
However, vaccine-preventable diseases (VPDs) are still responsible
for over 5 lakhs deaths annually in India.
STORY SO FAR
India and China were two countries where “some form of
inoculation” was practiced even before 16th century. However,
modern immunization developed in India in 19th century, parallel
to the Western world. The Compulsory Vaccination Act was passed
in India in 1892 to ensure higher coverage with smallpox.
In 1904–1905, Central Research Institute was set up in Kasauli,
Himachal Pradesh and then Pasteur Institute in Coonoor in 1907.
The Pasteur Institute of India produced neural tissue antirabies
vaccine in 1907, subsequently developed influenza vaccines,
trivalent oral polio vaccines (OPV) and first tissue culture, and then
Vero cell-derived rabies vaccine. As early as 1955–1956, the bacillus
Calmette–Guérin (BCG) vaccination mass campaign was initiated
in India.
In 1958, World Health Assembly (WHA) passed a resolution to
eradicate smallpox; India started National Smallpox Eradication
Programme (NSEP) in 1962, and universal vaccination of
entire population within 3 years was planned in two phases—
attack phase with 80% coverage of population followed by
maintenance phase to include all newborns, infants, and children.
2 Immunization in India: Past, Present, and Future
The last case was reported in 1975 from West Bengal, but surveillance
continued thereafter. The world was declared free from smallpox
on May 8, 1980 by the World Health Assembly.
The Pasteur Institute of India developed influenza vaccine in
1957, the beta-propiolactone (BPL) inactivated rabies vaccine, and
trivalent OPV in 1970. There were nearly 19 vaccine-manufacturing
units in public sector and 12 in private sector in 1971.
Universal Immunization Programme (UIP) is one of the largest
public health programs. Routine immunization (RI) targets to
vaccinate 29 million newborns each year, with all primary doses,
nearly 100 million children of 1–5 years of age with booster doses
of UIP vaccines and 30 million pregnant mothers are targeted for
tetanus toxoid (TT) vaccination each year.
Most of the immunization sessions are focused in rural areas.
89.8% of vaccination in India is provided through public sector,
while private sector contributed to only 8.7%. As per Coverage and
Evaluation Survey (2009), India has an annual birth cohort of ~2.67
crores (Table 1).
BACKGROUND NOTES AND PRESENT STATUS

OF IMMUNIZATION
In 1978, after the Alma-Ata declaration aimed at immunizing all,
the children Expanded Programme on Immunization (EPI) was
launched in 1978. It was renamed as UIP in 1985, when its reach
was expanded beyond urban areas. In 1992, it became part of Child
Survival and Safe Motherhood Programme and in 1997, it was
included in the ambit of National Reproductive and Child Health
Programme. Since the launch of National Rural Health Mission in
2005, UIP has always been an integral part of it.
The UIP is one of the largest public health programs targeting
close of 2.67 crore newborns and 2.9 crore pregnant women annually,
with all primary doses, nearly 100 million children of 1–5 years of age
with booster doses of UIP vaccines and 30 million pregnant mothers
are targeted for TT vaccination each year.
A child is said to be fully immunized if child receives all due
vaccine as per national immunization schedule within 1st year age
Immunization in India: Past, Present, and Future 3
TABLE 1: Vaccine milestones in India.

Year Vaccine Milestone remarks
1985 BCG; diphtheria, Universal Immunization
pertussis, and tetanus Programme (UIP) launched with
(DPT); OPV; and six antigens
measles-containing
vaccine (MCV)
2002 Hepatitis B—pilot Hepatitis B vaccine launched as a
pilot program in 33 districts and
14 metropolitan areas
2006–2010 Japanese encephalitis JE vaccine added to the UIP in
(JE) selected endemic districts in a
phased manner
2007–2011 Hepatitis B—scale up Hepatitis B vaccination scaled up
to cover 10 additional states of
Indien
2010 Measles-containing MCV2 (in the form of measles-
vaccine dose 2 rubella vaccine) added to the
(MCV2) + rubella UIP in 21 states (in the remaining
14 states, a catchup campaign was
initiated for children aged
9 months to 9 years)
2011 Haemophilus Hib vaccine introduced as the
influenzae type b pentavalent (DPT + Hib + HepB)
(Hib)-83 vaccine in two states (Tamil Nadu
and Kerala)
2016 Human Pilot program launched by state
papillomavirus-84 governments in Delhi and Punjab
2016–2018 Rotavirus-85 Introduced in two phases in nine
states (Andhra Pradesh, Haryana,
Himachal Pradesh, Odisha, Assam,
Madhya Pradesh, Rajasthan, Tamil
Nadu, and Tripura)
2017–2019 Pneumococcal PCV introduced in selected high-
conjugate vaccine burden districts in six states (Bihar,
(PCV)-86 Uttar Pradesh, Haryana,
Himachal Pradesh, Rajasthan, and
Madhya Pradesh)
(BCG: bacillus Calmette-Guérin; HepB: hepatitis B; OPV: oral polio vaccine)
of child. The two major milestones of UIP have been the elimination
of polio in 2014 and maternal and neonatal tetanus elimination in
2015.
The new vaccines introduced in recent years are:
■ Inactivated polio vaccine (IPV), November 2015–April 2016
■ Rotavirus vaccine (RVV): In March 2016 and expanded across the
country in 2019–20
■ Measles rubella (MR) vaccine: Introduced in the country
through a campaign mode in 2017, followed by two doses in RI
at 9–12 months and 16–24 months
■ Pneumococcal conjugate vaccine (PCV): Launched in May 2017
and now escalated to the entire country
■ Tetanus and adult diphtheria (Td) vaccine: Which replaced
the TT vaccine in UIP to limit the waning immunity against
diphtheria in older age groups. Td vaccine to be admini
stered to adolescents at 10 and 16 years of age and to pregnant
women.
Immunization Coverage in India

The immunization coverage in India is described in Table 2.
THE ROAD AHEAD AND THE FUTURE

Political and Bureaucratic Will
Such an elaborate National program obviously needs political
and bureaucratic support at all levels. “Inter Agency Coordination
Committee” (ICC) needs to increase its focus on RI. A public–
private partnership (PPP) between government of India (GoI),
National Technical Advisory Group on Immunization (NTAGI),
Indian Academy of Pediatrics (IAP), Indian Medical Association
(IMA), development partners, Integrated Child Development
Services, Ministries of Railways, Education and Defense, and
key nongovernmental organizations (NGOs) involved with
immunization and State representation should be strengthened and
monitored funds.
TABLE 2: The immunization coverage in India.

Coverage (%)
Antigens/vaccines 2000 2010 2018
BCG 58 79 89
DTP3 — 38 89
HepB3 56 82 90
MCV1 — — 80
MCV2 85 87 90
PAB 85 76 89
Pol3 — — 35
Rotavirus — — 89
Hib3 — — 6
(BCG: bacillus Calmette–Guérin; DTP: diphtheria; HepB: hepatitis B; MCV:
meningococcal vaccine; PAB: protection-at birth; Pol: polio; Hib: Haemophilus
influenzae type B)
Proper Monitoring of the Program

Vaccination is an essential preventive medical intervention;
the vaccination program is not simply a medical modality—it is a
management-dominant modality. The managerial, administrative,
and governance-related inadequacies need to be addressed on
a priority basis for successful flow of the program throughout the
country.
Develop Effective Surveillance Systems

Universal Immunization Programme is an opportunity to establish a
surveillance system for all important childhood infectious diseases
as has been demonstrated by the experience of acute flaccid paralysis
(AFP) surveillance network in India. Efficient surveillance systems
will work even in resource-poor settings, at quite low cost relative to
the cost of the intervention itself.
ADVERSE EFFECTS, DETECTION, REPORTING,

AND REDRESSAL SYSTEM
Having a functional real-time adverse events following immuni-
zation (AEFI) and post-marketing surveillance system will help in
generating national data and also will be useful to allow compen-
sation claims for vaccination-related injuries and serious adverse
events should the need arise, this will also provide sound basis for
decisions to modify or abandon certain vaccine preparations based
on reactogenicity profile.
REGULATORY AND ETHICAL ISSUES

The existing National Regulatory Authority (NRA) of the country
is reliable and properly functioning. Currently, the Indian NRA,
i.e., the Drug Controller General of India, though overburdened, is
performing many diverse tasks including marketing authorization
and licensing activities related to drugs, cosmetics, vaccines, etc.
There is need to have a vaccine-specific NRA to oversee different
issues related to vaccines such as licensing, postmarketing
surveillance including AEFI surveillance, batch release process,
laboratory support for vaccine testing, regulatory inspections of
Good Manufacturing Practices (GMPs), authorization and approval
of clinical trials, etc. Hence, the NRA has to be a more competent,
effective, independent, and transparent body.
We need single window system to avoid regulatory delays, and
strict guidelines for approval and cancellation of license must be
formulated and practiced. We need clear national guidelines on the
ethical conduct of clinical trials. Ethical concerns, skepticism, and
low vaccination rates persist despite India’s emergence as a global
manufacturing leader in vaccines.
SUPPORT TO INDIGENOUS VACCINE INDUSTRY,

RESEARCH AND DEVELOPMENT
Most low-cost traditional vaccines are now produced by vaccine
manufacturers in India. Currently, about 43% of the global UIP
vaccines come from India, and the Serum Institute is the world’s
leading producer of the UIP vaccines. Investment in research and
development is bound to pay rich dividends. A large number of

vaccine products are currently in the pipeline and are expected to
become available in near future. According to recent unpublished
data, more than 80 candidate vaccines are in the late stages of clinical
testing. About 30 of these candidate vaccines aim to protect against
major diseases for which no licensed vaccines exist, such as malaria
and dengue. Vaccines manufactured in India include—coronavirus
disease (COVID) vaccines, RVVs, PCV, Japanese Encephalitis
vaccines, and the 4HPV vaccine by the Serum Institute of India,
which recently received market authorization.
The current national vaccine policy is supportive of the Indian
vaccine industry with liberal support from government-owned
institutions such as Department of Biotechnology (DBT), National
Institute of Immunology (NII), and department of science, however,
there is need to further empower Indian vaccine sector to meet the
indigenous demand of vaccines. The time has come to develop a
more effective PPP and a shared responsibility of meeting demand
of local vaccine need is the need of the hour.
INTEGRATED DELIVERY OF HEALTH

INTERVENTIONS
Strengthening of immunization systems so that they support and
integrate with other preventive health services such as providing
vitamin A supplementation, deworming, growth monitoring, and
distribution of insecticide-treated bed nets offers the opportunity
to create synergies and facilitate the delivery of services to bolster
comprehensive disease prevention and control. Incorporating
immunization into integrated primary healthcare programs
may also facilitate social mobilization efforts, help to generate
community demand for services, and address equity issues. The
strategy of child health days, led by UNICEF, has also helped to
promote RI.
CONCLUSION
India is on strong path when it comes to promoting the health,
economic, and social well-being of its citizens. Indian government
will do well to dedicate itself to continue to expand its coverage,

expand the number of vaccines in UIP, and expand its manufacturing
industries. This must be done while managing Gavi transition and
avoiding backsliding as a result. Committing to sustained investment
in immunization will heap wonderful results in child health.
Funding: None.
Competing interests: None stated.
SUGGESTED READING
1. Bloom DE, Cadarette D, Ferranna M, Nandi A, Shet A. Value of
Vaccination in India: Past, Present and future Prospects. New Delhi:
Jaypee Brothers Medical Publishers; 2019.
2. John TJ, Vashishtha VM. Path to polio eradication in India: a major
milestone. Indian Pediatr. 2012;49:95-8.
3. Ministry of Health and Family Welfare, Government of India.
National Vaccine Policy. [online] Available from http://mohfw.nic.in/
WriteReadData/l892s/1084811197 NATIONALVACCINEPOLICY
BOOK.pdf. [Last accessed November, 2022].
4. Ploktin SA. Vaccines: Past, Present and future. Nat Med. 2005;11(4 Suppl):
S5-11.
5. The World Bank. Data Bank. Health Nutrition and Population Statistics.
[online] Available from http://databank.worldbank.org/Data/
Views/VariableSelection/SelectVariables.aspx?source=Health%20
Nutrition%20and%20Population%20Statistics. [Last accessed
November, 2022].
6. Vashishtha VM, Kumar P. 50 years of Immunization in India: Progress
and Future. Indian Paediatr. 2013:50:111-8.
7. World Health Organization (Regional Office for South-East Asia).
Coronavirus disease (COVID-19) pandemic. [online] Available from
https://www.searo.who.int/en/Section1226/Section2715.htm. [Last
accessed November, 2022].
8. World Health Organization. National Polio Surveillance Project.
[online] Available from http://www.npspindia.org. [Last accessed
November, 2022].
2 General Aspects
of Vaccination
Chapter
2.1 BASIC IMMUNOLOGY

Arun Wadhwa, Abhay Shah
IMMUNOLOGY OF VACCINATION
Vaccination: It is the act of introducing a vaccine into the body to
stimulate the immune system to induce protection against infection
or disease.
Immunization: It is a process by which a person becomes protected
against a disease, generally through vaccination.
INNATE AND ADAPTIVE IMMUNE RESPONSES

Immunity may be broadly classified as innate and adaptive. Innate
immunity comprises the skin and mucosal barriers, phagocytes
(neutrophils, monocytes, and macrophages), and the natural
killer (NK) cells. It comes into play immediately on entry of the
pathogen and is nonspecific. Adaptive immunity is provided by
the B lymphocytes (humoral/antibody-mediated immunity) and
T lymphocytes [(cellular/cell-mediated immunity (CMI)]. The innate
immune system triggers the development of adaptive immunity
by presenting antigens to the B lymphocytes and T lymphocytes.
Vaccines that stimulate innate immunity effectively are better
immunogens. This can be achieved by live vaccines, adjuvants,
toll-like receptor (TLR) agonists, live vectors, and deoxyribonucleic
acid (DNA) vaccines. Adaptive immunity takes time to evolve and is
pathogen specific (Table 1 and Fig. 1).1
10 General Aspects of Vaccination
TABLE 1: Differentiating features between innate and adaptive immunity.

Characteristic Innate Adaptive
Definition The resistance to infection The resistance that an
that an individual individual acquires in
possesses by virtue of response to exposure
genetic and constitutional to a foreign substance
makeup; i.e., by birth during their lifetime
Specificity Antigen independent Antigen specific
Time taken to Immediate—hours Late—days/weeks
respond
Memory response None Present
Cells involved Dendritic leukocyte, Predominantly
natural killer cells, mast lymphocytes: Killer CD8+
cell, granulocytes/ T cells, helper CD4+
macrophages, basophils, T cells, B cells, and
etc. antigen-presenting cells
Chemical Cytokines, complement, Antibodies, cytokines
mediators interferon, acute phase
reactants
Humoral immunity is conferred by B lymphocytes, which is the

principal defense mechanism against extracellular microbes and
their toxins. These activated B cells differentiate into antibody (Ab)
secreting plasma cells. For effective Ab production, B cells need help
from T helper cells.
B lymphocytes secrete Abs that act by neutralization, complement
activation, or by promoting opsonophagocytosis, which results
in early reduction of pathogen load and clearance of extracellular
pathogens. Also, humoral Abs prevent colonization, being the
first step in pathogenesis by encapsulated organisms such as Hib
(Haemophilus influenzae type b), pneumococcal, meningococcal,
and organisms such as diphtheria and pertussis. Abs are of several
different types [immunoglobulin G (IgG), IgM, IgA, IgD, and IgE]
and they differ in their structure, half-life, and site of action and
mechanism of action.
Cell-mediated immunity is mediated by T cells, which is the
principal defense mechanism against intracellular microbes. The
General Aspects of Vaccination 11
Fig. 1: Innate and adaptive immunity. (APC: antigen-presenting cell; NK cells:

natural killer cells)
Source: Adapted from Vashishtha VM, Kalra A, Thacker N. FAQ on Vaccines and
Immunization Practices. New Delhi: Jaypee Brothers Medical Publisher; 2011.
effectors of CMI and the T cells are of two types. The helper T cells
secrete proteins called cytokines that stimulate the proliferation
and differentiation of T cells as well as other cells including B
lymphocytes, macrophages, and NK cells. The cytotoxic T cells
act by lysing infected cells. Cellular immunity is essential for
clearance of intracellular pathogens. Bacillus Calmette–Guérin
(BCG) is the only currently used human vaccine for which there is
conclusive evidence that T cells are the main effectors. The T-cell
responses are more robust, long-lasting, and more cross-protective
than humoral responses; hence, modern vaccinology is being
directed in this direction. The inherent T-cell-mediated immune-
regulatory mechanisms prevent any vaccines causing autoimmune
diseases.2
CD4 T cells play critical roles in mediating adaptive immunity to
a variety of pathogens/antigens. Naïve CD4 T cells may differentiate
into one of several lineages of T helper (Th) cells, including Th1, Th2,
Th17, and iTreg, as defined by their pattern of cytokine production

and function.
■ Th1 cells produce interleukin-2 (IL-2) and interferon gamma and
are involved with intracellular organism such as mycobacteria
and induce T-cell response.
■ Th2 induces IL-4, IL-5, and IL-13 cytokine-induced humoral
response against extracellular organisms.
■ Th17 plays a crucial role at mucosal and epithelial surfaces.
Whole-cell pertussis (wP)-containing DPT (diphtheria, pertussis,
and tetanus) vaccines elicit Th1 and Th17 skewed response
whereas an aP containing vaccine induces Th2-skewed response.
■ iTreg cells are essential to the balance between pro- and anti-
inflammatory responses.
In addition to B cells and T cells, the antigen-presenting cells
(APCs) have a very important role to play, in the immune response.
APCs are a heterogeneous group of immune cells that mediate the
adaptive immune response, by processing and presenting antigens
for recognition by certain lymphocytes such as T cells. Classical
APCs include dendritic cells, macrophages, Langerhans cells, and
B cells.
Dendritic cells (DCs) are the only cells, capable of activating naïve
T cell and play a crucial role in the induction of T-cell response. They
act as messengers between the innate and the adaptive immune
systems. They capture antigen, process then into small peptides,
display them through major histocompatibility complex (MHC)
molecules, and provide costimulation signals to activate antigen-
specific T cells.
Active immunity is acquired through natural infection/
immunization and is long lasting, as it generally leads to development
of memory cells, and when antigen(s) enter(s) the body, strong
immune response is mounted. Passive immunity is conferred by
maternal Abs or immunoglobulin preparations given parenterally
and is short lasting depending on the half-life of immunoglobulins.
However, passive immunity provides instant protection required in
cases of exposure to certain pathogens, e.g., rabies virus, Clostridium
tetani, or hepatitis B virus (HBV).
TYPES OF VACCINES
Vaccines may be broadly classified as follows:
■ Live-attenuated vaccines (LAVs): BCG, oral polio, measles, MMR
(measles, mumps, and rubella), varicella, rotavirus, yellow fever,
live Influenza vaccine, and live hepatitis A
■ Inactivated vaccines:
y Whole-cell inactivated: Whole-cell pertussis vaccines, rabies,
inactivated poliovirus (IPV), and hepatitis A
y Toxoids: Tetanus and diphtheria
y Sub-unit vaccines: They differ from inactivated whole-cell
vaccines, by containing only the antigenic parts which are
necessary to elicit a protective immune response. They are
as under:
Protein vaccines: Subunit vaccines—acellular pertussis,
HBV, and some influenza
Pure polysaccharide vaccines: Typhoid, pneumococcal
polysaccharide vaccine (PPSV), and meningococcal
polysaccharide vaccine
Conjugated polysaccharide vaccines: Hib-CV, typhoid-CV,
PCV, and meningococcal-CV
Virus-like particle (VLP): HPV
DNA and RNA vaccines: COVID-19 vaccines.
HOW DO VACCINES WORK?

Vaccines play a crucial role in prevention, disease attenuation,
elimination, and eradication of vaccine-preventable diseases
(VPDs).
Early protective efficacy of currently available vaccines is
primarily conferred by the induction of antigen-specific Abs that are
capable of binding specifically to a toxin or a pathogen.
The role of CMI in currently used vaccines (that have T cell-
dependent antigens) is mainly by supporting Ab production. Other
important mechanisms by which CMI works are by cytotoxic CD8+
T lymphocytes (CTL) that may limit the spread of infectious agents
by recognizing and killing infected cells or secreting specific antiviral
cytokines. T cell-independent antigens (e.g., PS) do not stimulate
CMI and, therefore, do not produce long-lasting immunity.
T cell-independent antigens can be converted to T cell-dependent

antigens by conjugating them with proteins.
FIRST STEP AFTER IMMUNIZATION

Following vaccine injection, the vaccine antigens attract local
and systemic DCs, monocytes, and neutrophils. Innate immune
responses activate these cells by changing their surface receptors,
which migrate along lymphatic vessels, to the draining lymph nodes,
where the activation of T and B lymphocytes takes place. The type of
response elicited will depend upon the type of vaccine, its antigenic
type and content, and immune status of an individual. Vaccines
that stimulate innate immunity effectively are better immunogens.
This can be achieved by live vaccines, adjuvants: TLRs agonists, live
vectors, and DNA vaccines. Live vaccines are capable of activating
innate immunity in a better way, which is helpful for subsequent
induction of adaptive immune effectors. During their journey, the
attenuated organisms undergo dissemination and replication and
activate large number of DCs. The activated DCs migrate toward the
corresponding draining lymph nodes and launch multiple foci of
T- and B-cell activation. LAVs stimulate an excellent immune
response as they mimic a natural infection. Large number of DCs
take up vaccine antigen in multiple tissues and provide continual
antigenic stimulation giving sufficient time for memory cell
production.
In case of killed vaccines, there is only local and unilateral
lymph node activation. Consequently, the immunogenicity of killed
vaccines is lower than the live vaccines; killed vaccines require
adjuvants, which improve the immune response by producing local
inflammation and recruiting higher number of DCs/monocytes
to the injection site. Secondly, the site of administration of killed
vaccines is of importance; the intramuscular (IM) route which
is well vascularized and has a large number of patrolling DCs is
preferred over the subcutaneous route. Intradermal route recruits
the abundant DCs in the skin and offers the advantage of antigen
sparing and early and effective protection but the geometric mean
titers (GMTs) are lower than that achieved with IM and may wane
faster. The site of administration is usually of little significance for
live vaccines. Finally, due to focal lymph node activation, multiple

killed vaccines may be administered at different sites and at different
time intervals, with little immunologic interference. Immunologic
interference may occur with multiple live vaccines unless they are
given on the same day or at least 4 weeks apart or by different routes.
However, rotavirus vaccine and oral polio vaccine (OPV) can be
given simultaneously or at any interval before or after any inactivated
or live vaccine.
IMMUNE RESPONSES TO VACCINES

Immune Response to Polysaccharide Antigens
Bacterial (Streptococcus pneumoniae, Neisseria meningitidis,
Haemophilus influenzae, and Salmonella typhi) PS antigens are
T cell-independent antigens. On being released from the injection
site, they reach the marginal zone of the spleen/nodes and bind to
the specific Ig surface receptors of B cells. In the absence of help from
antigen specific T cells, B cells activate, proliferate, and differentiate
into plasma cells without undergoing affinity maturation in
germinal centers (GCs). The Ab response sets in 2–4 weeks following
immunization, and is predominantly IgM with low titers of low
affinity IgG. The half-life of the plasma cells is short and Ab titers
decline rapidly.
Additionally, the PS antigens are unable to evoke an immune
response in those aged <2 years due to immaturity of the marginal
zones. As PS antigens do not induce GCs, bona fide memory B cells
are not elicited. Consequently, subsequent re-exposure to the same
PS results in a repeat primary response that follows the same kinetics
in previously vaccinated as in naïve individuals.
Revaccination with certain bacterial PS, of which Group C
Meningococcus is a prototype, may even induce lower Ab
responses than the first immunization, a phenomenon referred
to as hyporesponsiveness. Due to this phenomenon, only a single
booster of either pneumococcal or meningococcal PS vaccine is
recommended even in patients who require lifelong protection.3,4
Immune Response to Protein Antigens or

T cell-dependent Antigens
Protein antigens are T cell-dependent antigens. The initial response
to these antigens is similar to PS antigens. However, the antigen-
specific helper T cells that have been activated by antigen bearing
DCs trigger some antigen-specific B cells to migrate toward follicular
dendritic cells (FDCs), initiating the GC reaction. In GCs, B cells
receive additional signals from FDCs and follicular T helper cells and
undergo massive clonal proliferation, switch from IgM toward IgG/
IgA, undergo affinity maturation, and differentiate into plasma cells
secreting large amounts of antigen-specific Abs. Most of the plasma
cells die at the end of GC reaction and thus decline in Ab levels is
noted 4–8 weeks after vaccination. However, a few plasma cells exit
in lymph nodes and spleen and migrate to survival niches mostly
located in the bone marrow, where they survive through signals
provided by supporting stromal cells and this results in prolonged
persistence of Abs in the serum. Memory B cells are generated in
response to T-dependent antigens, during the GC reaction, in parallel
to plasma cells. They persist there as resting cells until re-exposed to
their specific antigens when they readily proliferate and differentiate
into plasma cells, secreting large amounts of high-affinity Abs that
may be detected in the serum within a few days after boosting.2,5
Germinal Center Reaction (Fig. 2)

The development of this GC reaction requires a couple of weeks,
such that hypermutated IgG Abs to protein vaccine antigens first
appear in the blood 10–14 days after priming. It is the magnitude
of GC responses, i.e., the quality of DC, B cell, T cell, and FDC
interactions, which controls the intensity of B cell differentiation into
plasma cells, and thus the peak of IgG vaccine Ab reached within
4–6 weeks after primary immunization.
Immune Response to Live Vaccines

Live vaccines induce an immune response similar to that seen with
protein vaccines. However, the take of live vaccines is not 100%
with the first dose (primary failure). Hence, more than one dose is
Fig. 2: The germinal center reaction. (DC: dendritic cell)
recommended with most live vaccines. Once the vaccine has been
taken up, immunity is robust and lifelong or at least for several
decades. This is because of continuous replication of the organism
that is a constant source of the antigen. The second dose of the
vaccine is, therefore, mostly for primary vaccine failures (no uptake
of vaccine) and not for secondary vaccine failures (decline in Abs
over time). However, mumps does not follow this general principle
and waning Ab levels has been demonstrated, therefore, the need for
a subsequent doses.6,7
PRIMARY VERSUS SECONDARY

IMMUNE RESPONSES
When an antigen is introduced for the first time, the immune response
starts after a lag of 10 days or so. This is called primary response. In
primary immune response, the antigen exposure elicits an extrafol-
licular response that results in the rapid appearance of low IgG Ab
titers. As B cells proliferate in GCs and differentiate into plasma cells,
IgG Ab titers increase up to a peak value usually reached 4 weeks after
immunization. The short lifespan of these plasma cells results in a
rapid decline of Ab titers, which eventually return to baseline levels.2
Secondary immune responses start on subsequent exposure
(booster) to the same antigen. There is no lag phase, response
starts in <7 days, persists for a long time, mainly IgG type with high
Ab titers. In secondary immune responses, booster exposure to
antigen reactivates immune memory (memory B cells) and results
in a rapid (<7 days) increase of IgG Ab titer by a rapid proliferation
of memory B cells and their evolution into abundant Ab-secreting
plasma cells. Short-lived plasma cells maintain peak Ab levels
during a few weeks—after which serum Ab titers decline initially
with the same rapid kinetics as following primary immunization.
Long-lived plasma cells that have reached survival niches in the
bone marrow continue to produce antigen-specific Abs, which
then decline with slower kinetics. This generic pattern may not
apply to live vaccines triggering long-term IgG Abs for extended
periods of time.2
DETERMINANTS OF INTENSITY AND DURATION

OF IMMUNE RESPONSES
Primary Response
Primary immune responses after vaccination depend on various
factors such as vaccine type, nature of antigen, vaccination schedule,
genetic and environmental factors, and age at immunization.
Types of Vaccine
Broadly speaking, live vaccines are superior (exception BCG and
OPV) to protein antigens which in turn are superior to polysaccharide
vaccines:
■ Live versus inactivated: Higher intensity of innate responses,
higher antigen content following replication, and more prolonged
antigen persistence generally result into higher Abs responses to
live than inactivated vaccines.
■ Protein versus polysaccharide: Recruitment of T-cell help and
induction of GCs results into higher Ab responses to protein or
glycoconjugate than to PS vaccines. Hence, broadly speaking,
live vaccines are superior (exception BCG and OPV) to protein
antigens which in turn are superior to PS vaccines.
■ Adjuvants: Adjuvants improve immune responses to
inactivated vaccines by either modulation of antigen delivery
and persistence (depot or slow-release formulations) or

enhancement of Th responses (immunomodulator) which
may support or limit Ab responses.2 Thus, less amount of active
ingredient per dose is required for an immune response similar
to vaccines without adjuvant. However, adjuvants may cause
some side effects.
Antigen Nature
■ Polysaccharide antigens: Failure to induce GCs limits
immunogenicity.
■ Protein antigens: Inclusion of epitopes readily recognized by B
cells (B cell repertoire), inclusion of epitopes readily recognized
by follicular helper T cells, elicitation of efficient follicular
T-cell help, and the capacity of antigen to associate/persist in
association to FDCs result into higher Ab responses.
■ Antigen dose: As a rule, higher antigen doses increase the
availability of antigen for B/T cell binding and activation, as well
as for association with FDCs; however, there is a limiting dose for
each antigen.
Vaccination Schedule
The immune response improves with increasing number of doses
and increased spaces between doses.
Interval between doses: The immune response improves with proper
spacing of vaccine doses.
Traditionally, “0–1–6” month schedule (prime and boost) is
considered as a more immunogenic schedule than 6–10–14 week or
2–3–5 month or 2–4–6 month schedules for nonlive T cell-dependent
vaccines such as hepatitis-B vaccine. This is mainly due to adequate
time interval between first few doses which act by inducing immune
responses and last dose that works as boosters. Since, affinity
maturation of B cells in GCs and formation of adequate numbers of
memory B cells take at least 4–6 months, this schedule fulfils these
requirements (Fig. 3).
More than one dose is needed for better induction and
recruitment of a greater number of GCs in young age considering
young age limitations of immune system. A 4-week minimal interval
Fig. 3: Schematic presentation of various components of 0–1–6 months

immunization schedule at cellular level.
Source: Adapted from Vashishtha VM, Kalra A, Thacker N. FAQ on Vaccines and
Immunization Practices. New Delhi: Jaypee Brothers Medical Publisher; 2011.
between primary doses avoids competition between successive

waves of primary responses.2,6
Other Factors
■ Genetic factors: The capacity of antigen epitopes to associate
to a large panel of MHC molecules increases the likelihood of
responses in the population. MHC restriction may limit T-cell
responses. Gene polymorphisms in molecules critical for B and
T cell activation/differentiation are likely to affect Ab responses.
T-cell responses differ markedly between individuals and
populations because of genetic variability of MHC molecules
[human leukocyte antigen A2 (HLA-A2)].
■ Environmental factors: Mostly yet to be identified.
■ Age at immunization: Early life immune immaturity or age-
associated immune senescence impairs immune responses to
an administered vaccine.2
Secondary Immune Responses

Many factors that determine primary immune responses after
immunization also affect secondary immune responses.
■ Live versus inactivated: Live vaccines generally induce more
sustained Ab responses, presumably through prolonged antigen
persistence within the host. Secondary responses with inacti-
vated vaccines are highly pronounced (anamnestic response).
However, secondary responses are usually blunted with live
viral vaccines as preexisting Ab neutralizes the vaccine virus.
■ Polysaccharide antigens: Failure to generate GCs limits the
induction of memory responses and of high-affinity long-lived
plasma cells. Secondary immune response does not occur with
PS antigens.
■ Interval between primary doses: A minimal interval of 4 weeks
between primary doses allows development of successive waves
of antigen-specific primary responses without interference.
■ Interval before boosting: A minimal interval of 4 months between
priming and boosting allows affinity maturation of memory B
cells, and thus higher secondary responses.
■ Age at immunization: Early life immune immaturity and age-
associated immunosenescence limit the induction/persistence
of long-live plasma cells.2
IMMUNE MEMORY AND NEED FOR BOOSTERS

Immune memory allows one to complete an interrupted vaccine
schedule without restarting the schedule. Immune memory is seen
with live vaccines/protein antigens due to generation of memory B
cells which are activated on repeat vaccination/natural exposure.
Immune memory allows one to complete an interrupted vaccine
schedule without restarting the schedule. Activation of immune
memory and generation of protective Abs usually take 4–7 days.
Diseases which have incubation periods shorter than this period
such as Hib, tetanus, diphtheria, pertussis, and meningococcus
require regular boosters to maintain protective Ab levels. However,
diseases such as hepatitis A and hepatitis B do not need regular
boosters as the long incubation period of the disease allows for
activation of immune memory cells.
IMMUNE RESPONSES DURING EARLY

LIFE IMMUNIZATION
Limitations of Young Age Immunization
The two important factors negatively affect immune responses
during young age: maternal Abs and immaturity of immune system.
Young age limits Ab responses to most vaccine antigens since
maternal Abs inhibit Abs responses but not T-cell response, and due
to limitation of B-cell responses.8,9
Immunoglobulin G Abs are actively transferred through the
placenta, via the FcRn receptor, from the maternal to the fetal
circulation. Upon immunization, maternal Abs bind to their specific
epitopes at the antigen surface, competing with infant B cells and
thus limiting B-cell activation, proliferation, and differentiation.
The inhibitory influence of maternal Abs on infant B-cell responses
affects all vaccine types, although its influence is more marked for
live attenuated viral vaccines that may be neutralized by even minute
amounts of passive Abs. Hence, Ab responses elicited in early life
are short lasting. However, even during early life, induction of B
memory cells is not limited which is mediated through Th (CD4).
The extent and duration of the inhibitory influence of maternal Abs
increase with gestational age, e.g., with the amount of transferred
immunoglobulins, and decline with postnatal age as maternal Abs
wane.2,10
Early life immune responses are characterized by age-dependent
limitations of the magnitude of responses to all vaccines. Ab
responses to most PS antigens are not elicited during the first 2 years
of life, which is likely to reflect numerous factors including—the
slow maturation of the spleen marginal zone; limited expression
of CD21 on B cells; and limited availability of the complement
factors. Although this may be circumvented in part by the use of
glycoconjugate vaccines, even the most potent glycoconjugate
vaccines elicit markedly lower primary IgG responses in young
infants.
Although maternal Abs interfere with the induction of infant
Ab responses, they may allow a certain degree of priming, i.e., of
induction of memory B cells. This likely reflects the fact that limited
amount of unmasked vaccine antigens may be sufficient for priming

of memory B cells but not for full-blown GC activation, although
direct evidence is lacking. Importantly, however, Abs of maternal
origin do not exert their inhibitory influence on infant T-cell
responses, which remain largely unaffected or even enhanced.11
Limitations of young age immunization can be countered to a
certain extent by increasing the number of a vaccine doses for better
induction, use of adjuvants to improve immunogenicity of vaccines,
and by use of boosters at later age when immune system has shown
more maturity than at the time of induction. Increasing the dose of
vaccine antigen may also be sufficient to circumvent the inhibitory
influence of maternal Abs, as illustrated for hepatitis A or measles
vaccines.
Impact of Young Age Limitations on

Immunization Schedules
Disease epidemiology of VPDs in a country often determines a
particular vaccination schedule. Since, majority of childhood
infectious diseases causes morbidity and mortality at an early age
in developing countries, there is need to protect the children at
the earliest opportunity through immunizations. This is the reason
why early and accelerated schedules are practiced in developing
countries despite the known limitations of young age immunization.
Immunization schedules commencing at 2 months and having
2 months spacing between the doses are considered technically
appropriate. However, for operational reasons and for early
completion of immunization, the 6–10–14 week’s schedule is
chosen in developing countries. Such a schedule has shown to give
adequate protection in recipients. However, with the availability of
newer vaccines, an immunologically superior schedule of 2, 4, and
6 months may have to be considered for future.
For killed vaccines such as DPT (diphtheria, pertussis, and
tetanus), Hib, pneumococcal, and hepatitis B which are adminis
tered as early as birth/6 weeks, the first dose acts only as a priming
dose while subsequent doses provide an immune response even
in presence of maternal Abs. However, a booster at 15–18 months
is required for durable immunity. As the age of commencement

of vaccination advances, the number of doses reduces (two
doses at 6–12 months followed by a booster dose and one to
two doses between 12 and 23 months for Hib and pneumococcal
vaccines).
Live vaccines are even more susceptible to maternal Abs as
compared to killed vaccines. However, BCG may be given as the
maternal Abs actually enhance T-cell responses. OPV may be
given as there are no maternal IgA in the gut to neutralize the virus.
Furthermore, measles vaccine if given at the age of 6 months (in an
outbreak situation) may work by inducing T-cell immunity.2
CORRELATES OF VACCINE-MEDIATED IMMUNITY

A given marker that is measurable, whether the Ab or a cellular
component elicited in response to a vaccine that confers
protection against a disease is termed a “correlate of protection”.12
Conventionally, due to a relative ease of measurement, it is a specific
Ab in the serum of a vaccine. Measurement of cellular components
is difficult, invasive, and highly cost intensive. The correlate can
be absolute, e.g., Hib (0.15 mg/mL) and hepatitis B (10 mIU/mL),
which are directly protective or surrogates (indirect markers),
e.g., varicella (GP Elisa units) and ROTA (IgA). Diseases such as
pertussis and HPV, however, have no established correlates till
now. Correlates of protection are important to confirm immunity,
compare vaccines, and, therefore, need to be standardized and
replicable.
REFERENCES
1. Vashishtha VM, Kalra A, Thacker N. FAQ on Vaccines and Immunization
Practices. New Delhi: Jaypee Brothers Medical Publisher; 2011.
2. Siegrist CA. Vaccine immunology. In: Plotkin SA, Orenstein W, Offit P
(Eds). Vaccines, 5th edition. Philadelphia, PA: Saunders Elsevier; 2008.
3. Lee CJ, Lee LH, Lu CS, Wu A. Bacterial polysaccharides as vaccine
immunity and chemical characterization. Adv Exp Med Biol. 2001;
491:453-71.
4. Kobrynski LJ, Sousa AO, Nahmias AJ, Lee FK. Cutting edge: antibody
production to pneumococcal polysaccharides requires CD1 molecules
and CD8+ T cells. J Immunol. 2005;174:1787-90.
5. MacLennan IC, Toellner KM, Cunningham AF, Serre K, Sze DM,

Zúñiga E, et al. Extrafollicular antibody responses. Immunol Rev.
2003;194:8-18.
6. Plotkin SA. Vaccination against the major infectious diseases. CR Acad
Sci III. 1999;322:943-51.
7. Hong Kong Measles Vaccine Committee. Comparative trial of live
attenuated measles vaccine in Hong Kong by intramuscular and
intradermal injection. Bull World Health Organ. 1967;36:375-84.
8. Timens W, Boes A, Rozeboom-Uiterwijk T, Poppema S. Immaturity of
the human splenic marginal zone in infancy. Possible contribution to
the deficient infant immune response. J Immunol. 1989;143:3200-6.
9. Siegrist CA. Neonatal and early life vaccinology. Vaccine. 2001;
19:3331-6.
10. Siegrist CA. Mechanisms by which maternal antibodies influence
infant vaccine responses: Review of hypotheses and definition of main
determinants. Vaccine. 2003;21:3406-12.
11. Rowe J, Poolman JT, Macaubas C, Sly PD, Loh R, Holt PG. Enhancement
of vaccine-specific cellular immunity in infants by passively acquired
maternal antibody. Vaccine. 2004;22:3986-92.
12. Kamat D, Madhur A. Vaccine Immunology. In: Vashishtha VM (Ed). IAP
Textbook of Vaccines. New Delhi: Jaypee Brothers Medical Publisher;
2013.
2.2 ELEMENTARY EPIDEMIOLOGY

Shashi Kant Dhir, Sanjay Verma
EPIDEMIOLOGY OF VACCINATION
Basics of Epidemiology
Epidemiology is the study of the distribution and determinants of
disease frequency in man.1 It is the foundation science of public
health. It provides insights for applying intervention. It informs if
intervention is succeeding. It is the systematic study of the pathogen
amplification and transmission systems. Epidemiology can often
pinpoint the weak links in the chains of the source and transmission
pathways of the pathogen so that interventions can be directed at
those points. Vaccination is one such intervention.
Impact of Vaccinology on Disease Epidemiology

Vaccinology often perturbs the epidemiology of infectious diseases
(IDs). From vaccinology perspective, there are three reasons to
learn epidemiology. They include, the rational choice of vaccines for
vaccination programs, to design appropriate intervention program
including vaccinations, and to monitor and measure the progress
and impact of any vaccination program.
Knowledge of epidemiology helps in choosing the appropriate
vaccines for inclusion in public health programs after an
assessment of the disease burden and economic factors. It also
helps in designing disease-specific control/elimination/eradication
strategies after acquiring exact epidemiological data on prevalence,
incidence, and transmission characteristics of target pathogens,
and their transmission pathways. Finally, it also helps in monitoring
intervention success/failure in order to improve performance/
efficiency of the vaccination programs.2
INCIDENCE AND PREVALENCE OF DISEASES

Basic measures of disease frequency are done by incidence and
prevalence. Incidence relates to the number of new cases of the
disease, which occur during a particular period of time [e.g., new
tuberculosis (TB) cases]. Prevalence relates to total number of cases

of a disease in a specified period of time (includes both old and new
cases) usually during a survey. Often, it is expressed as a rate which is
a misnomer, as it is actually a proportion. In the long run, incidence
should be more than the deaths and recoveries, for prevalence to
accumulate. Prevalence of various diseases is a good indicator of the
load on health services.3
FORCE OF TRANSMISSION AND BASIC

REPRODUCTIVE NUMBER
The key determinant of incidence and prevalence of infection
depends on force of transmission which is determined by
“reproductive rate”. Reproductive rate is a simple concept in disease
epidemiology. Incidence and prevalence of infection depend on
reproductive rate.
“Basic reproductive number (Ro)” measures the average number
of secondary cases generated by one primary case in a susceptible
population. Suppose all others were susceptible—then how many
will be infected? That is Ro. Since population is a mix of susceptible
and immune persons, one case must attempt to infect more than
one person.4
In the long-term, pathogen can survive only if one “case”
reproduces another “case” (effective reproductive rate, Ro = 1). If Ro
<1, the disease is declining (e.g., herd effect). If Ro > 1, an outbreak is
occurring. For endemic diseases with periodic fluctuations, Ro may
swing from <1 to >1 but in the long-term, the average may remain 1.
Pathogen can survive if it reproduces. For all endemic IDs, Ro = 1 for
steady state or for long-term endemicity. The community benefit of
a vaccination program is to reduce Ro to <1 and sustain it for long
periods. Such beneficial effect, measured as the degree of disease
reduction due to a vaccination program, is sometimes called vaccine
effectiveness, to distinguish it from vaccine efficacy, which refers to
only the direct benefit of immunity in vaccinated individuals. Ro is
not a static entity and changes according to different time periods
even at a same geographic region.
The magnitude of Ro varies according to location and popula
tion. It is strongly influenced by birth rate, population density, and
behavioral factors. The magnitude of Ro can be ascertained by

cross-sectional surveys. Eradication is difficult when Ro is large and
population density plus net birth rate are high.
ENDEMIC, EPIDEMIC, AND PANDEMIC

PATTERNS OF DISEASES
“Endemic” refers to normal occurrence of disease in defined
population, e.g., cholera, malaria, TB, etc. Outbreaks/epidemics
are the occurrence of more cases of disease than expected in a
given area or among a specific group of people over a particular
period of time, e.g., measles, influenza, and meningococcal disease.
During epidemics, the disease spreads rapidly and extensively by
infection and affects many individuals in an area at the same time.
The difference between epidemic and outbreak is arbitrary. The
terms epidemic and outbreaks are often used similarly; however,
former usually indicates higher intensity, for example, epidemic
of Japanese encephalitis in a district or region and outbreak of
Salmonella in a neonatal unit. A community-based outbreak
meningococcal disease is defined as the occurrence of more than
three cases in <3 months in the same area, among those who are not
close contacts of each other, with a primary disease attack rate of >10
primary cases/100,000 persons. In terms of the flu, the difference
between an outbreak and an epidemic is the percentage of overall
deaths caused by the disease. “Pandemic” is a global epidemic.
Disease originates in one country and then spreads to a number of
countries, e.g., AIDS and H1N1.5
VACCINE CHARACTERISTICS AND DEVELOPMENT

VACCINE IMMUNOGENICITY
This is the ability of a vaccine to induce antibodies. These antibodies
may be protective or may not be protective to the vaccine. The
protective threshold for most vaccines is defined. However, there is
often controversy about the cutoffs [Pneumococcus/Haemophilus
influenzae type B (Hib)]. Levels below the limits may be protective
due to other reasons such as immune memory/T-cell immunity.
“Bridging studies” are those that look at vaccine immunogenicity
but not efficacy.6
VACCINE EFFICACY
This is the ability of the vaccine to protect an individual. It can
be assessed through clinical trials, cohort studies, or case control
studies. It is calculated as:
VE = ARU – ARV × 100
ARU
Where, ARU is attack rate in unvaccinated population, ARV is
attack rate in vaccinated population, and VE is vaccine efficacy.
VACCINE EFFECTIVENESS
This is the ability of the vaccine to protect the community and is
a sum of the vaccine efficacy and herd effect. It is revealed after a
vaccine is introduced in a program.
COST-EFFECTIVENESS
This is a method of economic evaluation which is carried out by
mathematical modeling usually prior to introduction of a vaccine
in a national program. It is expressed as cost per infections/deaths/
hospitalizations prevented/life years gained.
PHASES IN VACCINE DEVELOPMENT

■ Phase 1 trials are conducted on small number of healthy human
volunteers for assessing vaccine immunogenicity and safety.
■ Phase 2 trials are conducted with a similar objective in larger
number of subjects.
■ Phase 3 trials are randomized controlled trials in large number
of subjects for assessing vaccine efficacy and safety.
Cost-effectiveness analysis is conducted prior to introduction
of vaccines in a national program. Data on vaccine effectiveness
and more data on safety emerge following use of vaccines on a
widespread basis in programs.
HERD IMMUNITY, HERD EFFECT, HERD

PROTECTION, AND CONTACT IMMUNITY
The “herd immunity” refers to “the proportion of subjects with
immunity in a given population”, or in other words, it reflects the
“immunity of a population or a community” reflecting the literal
meaning of the word.7 It should not be confused with “herd effect”

which is defined as “the reduction of infection or disease in the
unimmunized segment as a result of immunizing a proportion
of the population”. Both “herd immunity” and “herd effect” can
be measured either by testing a sample of the population for the
presence of the chosen immune parameter, in the former or by
quantifying the decline in incidence in the unimmunized segment
of a population in which an immunization program is instituted,
in the latter. Herd effect is due to reduced carriage of the causative
microorganism by the vaccinated cohort and thus is seen only with
vaccines against those diseases where humans are the only source.
An effective vaccine is a prerequisite for good herd effect; tetanus
and bacillus Calmette–Guérin (BCG) vaccines have no herd effect.
Conjugated pneumococcal and Hib vaccines have good herd effect.8
Conventionally, “herd immunity” theory suggests that, in
contagious diseases that are transmitted from individual to individual,
chains of infection are likely to be disrupted when a large number of
population are immune or less susceptible to the disease. For example,
in Finland, when coverage with three doses inactivated polio vaccine
(IPV) reached 51%, poliomyelitis disappeared from the country. The
greater the proportion of individuals who are resistant, the smaller the
probability that a susceptible individual will come into contact with an
infectious individual. However, it does not apply to diseases such as
tetanus (which is infectious, but is not contagious), where the vaccine
protects only the vaccinated person from disease.
“Herd immunity” should not be confused with “contact
immunity”, a related concept wherein a vaccinated individual can
“pass on” the vaccine to another individual through contact. Not all
vaccines possess this virtue which is mainly the quality of certain live-
attenuated vaccines that shed very efficiently either through gut or
nasal mucosa though still producing “herd effect” and contributing
in generation of “herd immunity”. OPV has got this unique quality
and provides efficient “contact immunization”. Other live oral
vaccine such as rotavirus vaccines may theoretically also exhibit
this phenomenon; however, the evidence is lacking. On the other
hand, IPV despite providing “herd immunity” and “herd effect” does
not provide “contact immunity”. The greater the transmissibility,
the higher the contact immunization. “Herd protection” is another
term often used to describe a group of unimmunized individuals

that remain protected in a herd by virtue of protection rendered by
immunized individuals in a herd or population. However, when this
group of individuals moves out of that group/population, they again
become susceptible. In this situation, the unvaccinated individuals
are indirectly protected by vaccinated individuals, as the latter
will not contract and transmit the disease between infected and
susceptible individuals.
Herd immunity results from immunization or infection which is
transmitted human to human or otherwise. Herd effect results from
immunization or other health intervention/program in community
as such program(s) reduce the probability of transmission of
infection in the community.
EPIDEMIOLOGIC SHIFT
This refers to an upward shift in age of infection/disease in
communities with partial immunization coverage. Owing to
vaccination, the natural circulation of the pathogen decreases
and the age of acquisition of infection advances. This is especially
important for diseases such as rubella, varicella, and hepatitis A,
wherein severity of disease worsens with advancing age.
REFERENCES
1. Last JM. Dictionary of public health. Am J Prev Med. 2002;23(3):235.
2. Dowdle WR. The principles of disease elimination and eradication.
Bull World Health Organ. 1998;76(Suppl 2):23-5.
3. Park K. Park’s Textbook of Preventive and Social Medicine, 21st edition.
Jabalpur: Banarsidas Bhanot Publishers; 2011.
4. Dietz K. The estimation of the basic reproduction number for
infectious diseases. Stat Methods Med Res. 1993;2(1):23-41.
5. Porta M, Greenland S, Last JM. A Dictionary of Epidemiology, 5th
edition. New York: Oxford University Press; 2008.
6. Weinberg GA, Szilagyi PG. Vaccine epidemiology: efficacy,
effectiveness, and the translational research roadmap. J Infect Dis.
2010;201:1607-10.
7. Fine P. Herd immunity: history, theory, practice. Epidemiol Rev. 1993;
15(2):265-73.
8. John TJ, Samuel R. Herd immunity and herd effect: New insights and
definitions. Eur J Epidemiol. 2000;16:601-6.
2.3 VACCINE-PREVENTABLE DISEASE

SURVEILLANCE AND IDsurv
Chandra Mohan Kumar, Sanjay Verma
BACKGROUND
Disease surveillance is an essential component of public health
programs. The key objectives of an efficient surveillance system
are first to assess the burden of disease in the community, second
to monitor the progress of any ongoing interventions for disease
reduction, including the impact on disease epidemiology, and
finally, early detection of outbreaks to initiate investigations
and control measures. Surveillance of vaccine-preventable diseases
(VPDs) acquires a higher significance than all other surveillance
systems, such as surveillance of noncommunicable illnesses,
since most infectious diseases are now being prevented by highly
effective vaccines. The number of effective vaccines will go up
further in the coming time, considering the rapid advancements in
the field of vaccinology today.
WHY VACCINE-PREVENTABLE DISEASE

SURVEILLANCE IS NECESSARY?
The goals of an effective disease surveillance system should serve
the following functions:
■ To define the epidemiology of a disease
■ To identify high-risk populations and regions having high
transmission of the disease
■ To monitor the progress of a disease control program
■ To specify and monitor molecular epidemiology of infectious
disease, including identification of circulating strains of the
pathogen responsible for the infectious disease
■ To monitor the impact of the vaccination program on overall
disease epidemiology.
SURVEILLANCE: TERMINOLOGIES
■ Active surveillance, which is done actively by designated per
sons at any health institutions or community. For example,
acute flaccid paralysis (AFP) surveillance was done by National

Polio Surveillance Project (NPSP).
■ Passive surveillance, where suspected or confirmed cases of
a disease are reported routinely and passively from identified
health facilities, such as Integrated Disease Surveillance Project
(IDSP) and Infectious Disease Surveillance System (IDsurv).
■ Sentinel surveillance, where clinical syndromes after laboratory
confirmation are reported from selected health institutions, such
as Rotavirus (Indian National Rotavirus Surveillance Network)
and Haemophilus influenzae type b (Hib) surveillance.
■ Population-based surveillance is conducted for selected groups
with active diseases in a well-defined area/population.
■ Outbreak surveillance, where notification is done only whenever
there is a cluster of cases as per predefined norms, such as
measles surveillance and diseases reported through IDSP.
■ Case-based surveillance where any suspected case is immediately
notified for further investigations such as AFP and acute
encephalitis syndrome (AES) surveillance.
■ Zero reporting means reporting even when there is no case found
like AFP surveillance.
CURRENT STATUS OF VPD SURVEILLANCE IN INDIA

Vaccine-preventable diseases are still responsible for over 500,000
deaths annually in India.1 There is a lack of disease burden data on
many important VPDs in India in the perception that the disease is
not an important public health problem. Further, there is a scarcity
of diagnostic tools for certain VPDs. Lack of baseline surveillance
data also is a bottleneck in the introduction of many new vaccines
in the national immunization program (NIP) and also in monitoring
the impact of vaccination provided through Universal Immunization
Programme (UIP).2
VACCINE-PREVENTABLE DISEASE SURVEILLANCE

SYSTEMS EXISTING IN INDIA
Following are the key surveillance systems in India:
■ Integrated Disease Surveillance Project: Nationwide outbreak
surveillance system, including measles, diphtheria, pertussis,
AFP, hepatitis, and AES.
■ CBHI/SBHI (Central and State Bureaus of Health Intelligence):

Nationwide passive reporting system of suspected cases.
■ Measles—ICMR (Indian Council of Medical Research): Selected
practitioners and institutions provide clinical samples to National
Institute of Virology (NIV), Pune for measles virus isolation and
genotyping (Measles NetIndia).
■ AES/JE—NVBDCP (National Vector-borne Disease Control
Programme) and ICMR: Facility-based surveillance for AES
in endemic areas. It is run by the Government of India under
NVBDCP.
■ The WHO-NPSP played a critical role in strengthening
surveillance for polio that generated useful, timely, and accurate
data to guide policies, strategies, and interventions until
transmission of the poliovirus was interrupted in the country.
WHO-SUPPORTED SURVEILLANCE SYSTEMS

Motivated by the success of AFP surveillance, which has been active
surveillance done by designated persons at any health institution
or community, where the diagnosis was supported by laboratory
reports. Now, this nationwide WHO-supported surveillance network
will also provide surveillance for other VPDs in India.3
For VPD surveillance, efforts are being made to move from
a passive surveillance system that includes all the diseases
and conditions under national surveillance (IDSP) to active
surveillance (syndromic approach) supported by laboratory
investigations of each reported case on the framework of polio
surveillance. Currently, this is involved in the surveillance of six
diseases, which include:
1. Acute flaccid paralysis
2. Measles
3. Rubella
4. Neonatal tetanus
5. Pertussis
6. Diphtheria.
The WHO case definition for reporting of a suspected case include:
Measles/rubella:
Any person with fever and maculopapular rash (within last

3 months) with:
■ Cough
■ Coryza (running rose)
■ Conjunctivitis (red eyes)
■ Any person in whom a clinician suspects measles/rubella
infection.
Diphtheria:
Any illness of upper respiratory tract characterized by:
■ Laryngitis or pharyngitis or nasopharyngitis or tonsillitis
■ Adherent membranes of tonsils, pharynx, and/or nose.
Pertussis:
A person with a cough lasting at least 2 weeks with at least one of the
following:
■ Paroxysms (i.e., fits) of coughing
■ Inspiratory whooping
■ Posttussive vomiting
■ Apnea (only in <1 year of age)
■ A person in whom a clinician suspects pertussis without other
apparent cause.
All health facilities, including government, nongovernmental
organizations (NGOs), private clinics, hospitals, and laboratories,
should notify all cases under surveillance to District Surveillance
Officer every month.
IDSURV: AN INNOVATIVE PROJECT TO REPORT

INFECTIOUS DISEASES
Indian Academy of Pediatrics (IAP), in collaboration with its Kutch
branch, started an Infectious Disease Surveillance and AEFI (adverse
events following immunization) reporting system for reporting
severe AEFI, known as IDsurv.org.4
The “standard case definitions” for all the diseases covered
under this project were provided.3 The IAP members were motivated
to participate voluntarily to provide information on this website.
A provision is there to inform all users whenever a disease outbreak
is recorded.
The main objectives of the program were:3

■ To generate data on the burden of key VPDs in India
■ To develop an early warning system for pediatric VPDs in India
■ To sensitize pediatricians about serious AEFIs and generate data
on serious AEFI in India.
Ten key infectious diseases are targeted for surveillance under this
project, and they include:
■ Acute bacterial meningitis
■ Chickenpox
■ Diphtheria
■ Dengue
■ Enteric fever
■ Measles
■ Mumps
■ Pertussis
■ Pneumonia
■ Hepatitis.
REFERENCES
1. World Health Organization (Regional Office for South-East Asia).
Vaccine preventable disease (VPD) surveillance data. [online]
Available from https://www.who.int/southeastasia/health-topics/
immunization/vaccine-preventable-disease-(vpd)-surveillance-data.
[Last accessed November, 2022].
2. Vashishtha VM, Kumar P. 50 years of immunization in India: Progress
and future. Indian Pediatr. 2013;50(1):111-8.
3. Ministry of Health & Family Welfare, Government of India. (2011).
National Vaccine Policy. [online] Available from https://main.mohfw.
gov.in/sites/default/files/108481119000.pdf [Last accessed November,
2022].
4. IDsurv. [online] Available from http://www.idsurv.org./report.htm.
2.4 PRACTICAL ASPECTS OF IMMUNIZATION

M Indra Shekhar Rao, Sanjay Srirampur
COMMUNICATING WITH PARENTS/CAREGIVERS

With several new vaccines available for use, it is an arduous task for
pediatricians to offer appropriate advice to parents regarding pros
and cons of each vaccine. Most of these vaccines are included in
the Indian Academy of Pediatrics’ (IAP’s) recommendations. Thus,
pediatricians are required to communicate a balanced scientific
view, with clarity, to enable the parents to make the right decisions.
Unfortunately, most of the educated parents would leave the choice
to their pediatricians.
Prerequisite of one-to-one discussion is commitment on the part
of pediatrician to inform relevant facts about disease and vaccine. It
takes very little time if one uses structured format covering important
aspects in simple language. Following points need to be discussed
regarding each vaccine:
■ Risk of developing disease: It is not possible to evaluate risk of
disease in an individual child, but figures from literature may be
quoted, e.g., the risk of invasive pneumococcal disease (IPD) in
a healthy child aged <1 year is roughly 200 per 100,000 (as per
Western data). Some general statements are also helpful. Water-
or food-borne infections are preventable to some extent but not
airborne droplet infections. Risk of complications of disease is
higher in infants and younger children and in undernourished
population. Age prevalence of disease decides appropriate age of
vaccination as per the standard recommendations.
■ Efficacy of vaccine: No vaccine provides 100% protection though
most of the vaccines do offer high degree of protection. Vaccines
significantly decrease chance of disease and even partial
protection is useful to prevent complications. Occasional failure
of vaccine protection is no reason to consider against its use.
■ Safety of vaccine: Vaccines are very safe and serious adverse
reactions are extremely rare. Media outbursts of fatal reactions
to vaccines are mostly due to human error of administration and
not due to vaccine itself. Thus, benefits of vaccines outweigh the

risk of side effects caused by vaccines.
■ Cost of vaccine: Decision of affordability should be left to
parents. It is important to reiterate facts that all vaccines are
equally efficacious even though they may differ in their cost. For
example, DTwP (diphtheria, tetanus, and whole-cell pertussis)
and DTaP (diphtheria, tetanus, and acellular pertussis) are
equally efficacious though differ in reactogenicity. Similarly,
vaccines from different manufacturers are equally effective and
indigenously manufactured vaccines are usually as good as
imported ones.
■ Finally, it is important to emphasize that above discussion is
based on the current understanding of vaccine and its present
place in prevention of disease. With increasing experience
over time, there can be a change in the recommendations of
individual vaccine and it is necessary to adapt to such changes.
For example, three doses of measles, mumps, and rubella (MMR)
vaccine, are now recommended.
Many new vaccines are likely to be introduced over the next
few years. It would be a challenge for pediatricians to develop
communication skills to discuss pros and cons of all these vaccines.
But far more relevant is the need to keep updated on issues related
to vaccines and disease prevention. It is only then that “one-to-one
discussion” will become more meaningful.1,2
INJECTION PROCEDURE
Sterile Technique and Injection Safety
If the hands are visible dirty, they should be washed with soap and
water for 2 minutes using WHO’s 6-step technique. If hands are
not visibly dirty, alcohol-based waterless antiseptic hand rub can
be used, before every patient encounter. Gloves need not be worn
when administering vaccinations, unless the person administering
the vaccine has open lesions on hands or is likely to come in contact
with potentially infectious body fluids. Needles used for injections
must be sterile and disposable. Auto-disposable (AD) syringes
are single use, self-locking syringes designed in such a way that
these are rendered unusable after single use. Thus, they prevent
immediate/downstream reuse and their use is being promoted in

the national immunization program. A separate needle and syringe
should be used for each injection. Changing needles between
drawing vaccine from a vial and injecting it into a recipient are not
necessary.
If multidose vials are used, the septum should be swabbed with
alcohol prior to each withdrawal and the needle should not be left
in the stopper in-between uses. Different vaccines should never
be mixed in the same syringe unless specifically licensed for such
use, and no attempt should be made to transfer between syringes.
Prefilling of syringes should not be done because of the potential
for administration errors as the majority of vaccines have a similar
appearance after being drawn into a syringe. Thus, vaccine doses
should not be drawn into a syringe until immediately before
administration. To prevent inadvertent needlestick injury or reuse,
needles and syringes should be discarded immediately after use in
labeled, puncture-proof containers located in the same room where
the vaccine is administered. Needles should not be recapped before
being discarded.3-5 Box 1 summarizes a few key recommendations
on practical aspect of vaccination of a child.
INJECTION ROUTE, SITE, METHOD, AND

NEEDLE LENGTH
Vaccines are administered by oral, subcutaneous (SC), intradermal
(ID) or intramuscular (IM) routes. OPV and rotavirus vaccines
are administered orally, MMR, varicella, live-attenuated Japanese
encephalitis (JE), live-attenuated hepatitis A vaccine (HAV), and
yellow fever vaccines are administered SC, rest are administered
by the IM route. Generally, vaccines meant for SC administration
are valid if inadvertently administered IM. However, doses of
inactivated HAV vaccine and IPV, if inadvertently administered SC,
are considered valid. The IM route is crucial for HBV, HPV, and rabies
vaccines and the dose should be repeated, if given SC.
Generally, vaccines designated to be given IM should not be given
SC due to risk of side effects (as seen with aluminum adjuvanted
vaccines) or reduced efficacy (due to reduced blood supply in SC
tissue and hence reduced immunogenicity). The gluteal region
BOX 1: General instructions on immunization.

• Vaccination at birth means as early as possible within 24 hours after
birth or at least not later than 1 week after birth
• Whenever multiple vaccinations (including two live parenteral vaccines)
are to be given simultaneously, they should be administered in the
same sitting or they should be administered on the same clinic day
(conventionally a clinic day consists of 6 hours)
• The recommended age in weeks/months/years means completed
weeks/months/years
• Any dose not administered at the recommended age should be
administered at a subsequent visit, when indicated and feasible
• There is no recommendation to wait until a vaccine reaches room
temperature before administration. The vaccine should be administered
as soon as it is prepared
• Immediate administration after reconstitution of a vaccine implies the
reasonable time it takes to prepare, transport the vaccine to the patient
to be administered and the limited documentation that may be related
to this process. This interval should not exceed 30 minutes
• The use of a combination vaccine generally is preferred over separate
injections of its equivalent component vaccines
• When two or more live parenteral/intranasal vaccines are not
administered on the same day, they should be given at least 28 days
(4 weeks) apart; this rule does not apply to live oral vaccines
• If, given <4 weeks apart, the vaccine given second should be repeated
at least 4 weeks after the early dose
• The minimum interval between two doses of inactivated vaccines is
usually 4 weeks (exception rabies)
• Vaccine doses administered up to 4 days before the minimum interval
or age can be counted as valid (exception rabies). If the vaccine is
administered >5 days before minimum period, it is counted as invalid
dose and has to be repeated. This rule does not apply to live, parenteral
vaccines
• Any number of antigens can be given on the same day. Two or more
inactivated or inactivated and live vaccines can be administered at any
interval between them. Two or more live, parenteral vaccines, should be
administered on the same day or 4 weeks apart (Table 1)
• Changing needles between drawing vaccine into the syringe and
injecting it into the child is not necessary
• Different vaccines should not be mixed in the same syringe unless
specifically licensed and labeled for such use
• Patients should be observed for an allergic reaction (anaphylaxis) for
15–20 minutes after receiving immunization(s)
Contd...
Contd...
• If multiple vaccines are administered at a single visit, administration of
each preparation at a different anatomic site is desirable. For infants
and younger children, if more than two vaccines must be injected in a
single limb, the thigh is the preferred site because of the greater muscle
mass; the injections should be sufficiently separated (i.e., 1 inch or
more if possible) so that any local reactions do not overlap. For older
children and adults, the deltoid muscle can be used for more than one
IM injection (Table 2)
• If a vaccine and an immune globulin preparation are administered
simultaneously [e.g., Td/Tdap and tetanus immune globulin (TIg),
hepatitis B and hepatitis B immunoglobulin (HBIg)], separate
anatomic sites should be used for each injection. The location of each
injection should be documented in the patients’ medical record
(Figs. 1 to 4):
– If vaccine leaks during administration, it may be difficult to judge how
much vaccine the patient actually received. In general, it should be
treated as a nonstandard injectable dose and should be repeated. If it
is an inactivated vaccine, repeat the dose at the earliest
– If it was a live vaccine, repeat the dose on the same day or 4 weeks
later. If part of a dose of an oral vaccine (rotavirus) was spit out by an
infant, count the dose and do not administer a second dose
– If a person sneezes after live-attenuated influenza vaccine, the dose
can be counted as valid
– If an expired dose of a vaccine has been inadvertently administered,
the dose should be repeated. If the expired dose is a live virus vaccine,
it should be repeated at least 4 weeks after the previous (expired)
dose was given. If the expired dose is not a live vaccine, the dose
should be repeated as soon as possible. Although simply repeating
the dose is preferred, serologic testing to check for immunity after
certain vaccinations (e.g., measles, rubella, varicella, and hepatitis A)
may be accepted
• Diluents vary widely in composition, and therefore only the diluent
assigned by the manufacturer for the specific vaccine and presentation
should be used. The correct temperature for long-term storage of
diluents is +2°C to +8°C
• In case of space constraints in the ice-lined refrigerator (ILR)/fridge, the
diluents can be stored at room temperature and kept back in the ILR/
fridge, 24 hours before use
TABLE 1: Recommendations for spacing of vaccines.

Recommended interval between
Antigen combination doses
Two or more inactivated vaccines May be administered or at any
interval between doses
Inactivated and live vaccine May be administered or at any
interval between doses
Two or more live parenteral vaccines May be administered on same day
or at an interval of at least 28 days
Pneumococcal conjugate vaccine (PCV) 13 and Menactra (in children
with functional or anatomic asplenia) should not be administered at the
same visit; separate these vaccines by at least 4 weeks and administer
PCV first.
should never be used for administration of IM injections due to risk

of sciatic nerve injury and reduced efficacy (rabies and hepatitis B
vaccines). When used at the recommended sites, aspiration of
the syringe is not recommended. Moreover, aspiration makes the
injection procedure more painful. However, if on aspiration, blood
appears in the syringe, then the procedure is to withdraw the needle
and start over. The syringe, needle, and contaminated dose of
vaccine should be discarded in a sharps container, and a new syringe
and needle should be used to draw up and administer another dose
of vaccine. This is a waste of expensive vaccine that could be avoided
by simply not aspirating.
The needle should be withdrawn a few seconds after finishing
administration of the vaccine (to prevent backflow of vaccine into
the needle track), following which the injection site should be
pressed firmly for a few seconds with dry cotton. The injection site
should not be rubbed following injection.6,7
ALLEVIATION OF PAIN ASSOCIATED

WITH INJECTIONS
Comfort measures, such as distraction (e.g., playing music or
pretending to blow away the pain), ingestion of sweet liquids
(24% dextrose), breastfeeding, cooling of the injection site,
TABLE 2: Injection site, type of needle, and technique.

Site Type of needle Comments
Intramuscular injections (needle should enter at a 90° angle)
Preterms and Anterolateral 22–25 gauge, Skin should be
neonates thigh (junction 5/8 inch stretched between
of middle and thumb and
lower third) forefinger
Infants (1 to Anterolateral 22–25 gauge, Bunch the skin,
<12 months) thigh 1 inch subcutaneous
tissue, and muscle
to prevent striking
the bone
Toddlers and • Deltoid or • 22–25 gauge, • Skin should
older children 5/8 inch be stretched
(12 months to between thumb
10 years) and forefinger
• Anterolateral • 22–25 gauge, • Bunch the skin,
thigh 1 inch subcutaneous
tissue, and
muscle
Adolescents Deltoid or <60 kg 1 inch
and adults anterolateral >60 kg 1.5 inch
(11 years thigh
onward)
Intramuscular injections (needle should enter at a 45° to the skin)
Infants Thigh 22–25 gauge,
5/8 inch
>12 months Outer triceps 22–25 gauge,
5/8 inch
Intradermal injections
All ages Left deltoid 26/27 gauge, A 5-mm wheal
0.5 inch should be raised
and topical analgesia, can help infants or children cope with

the discomfort associated with vaccination. Pretreatment (30–
60 minutes before injection) with 5% topical lidocaine–prilocaine
emulsion can decrease the pain of vaccination by causing superficial
anesthesia.
Fig. 1: Intramuscular/subcutaneous site for administration:

Anterolateral thigh.
Fig. 2: Intramuscular site for administration: Deltoid muscle at upper arm.
Topical lidocaine–prilocaine emulsion should not be used

on infants aged <12 months who are receiving treatment with
methemoglobin-inducing agents because of the possible
development of methemoglobinemia.
Fig. 3: Intramuscular needle insertion.
Fig. 4: Subcutaneous needle insertion.
Use of a topical refrigerant (vapocoolant) spray immediately

before vaccination can reduce the short-term pain associated with
injections and can be as effective as lidocaine–prilocaine cream.
CONTRAINDICATIONS AND PRECAUTIONS

Contraindications
A condition in a recipient that greatly increases the chance of a
serious adverse reaction.7 It is a condition in the recipient of the
vaccine, not with the vaccine per se. If the vaccine was given in the
presence of that condition, the resulting adverse reaction could
seriously harm the recipient.
For instance, administering yellow fever to a person with a true

anaphylactic allergy to egg could cause serious illness or death in the
recipient. In general, vaccines should not be administered when a
contraindication is present.
The only true contraindication for any vaccine is the presence of
a known severe allergic reaction to a vaccine component or following
a prior dose of a vaccine.
Precautions
It is similar to a contraindication. A precaution is a condition in
a recipient that might increase the chance or severity of a serious
adverse reaction, or that might compromise the ability of the vaccine
to produce immunity (such as administering measles vaccine to a
person with passive immunity to measles from a blood transfusion).
Injury could result, but the chance of this happening is less than
with a contraindication (Flowchart 1).7 In general, vaccines are
deferred when a precaution condition is present (Flowchart 2).
For inactivated influenza vaccines (IIVs), egg allergy other than
hives, e.g., angioedema, respiratory distress, lightheadedness,
recurrent emesis, or required epinephrine or another emergency
medical intervention, is a precaution. IIV may be administered in an
inpatient or outpatient medical setting and under the supervision of
a healthcare provider who is able to recognize and manage severe
allergic conditions).
Flowchart 1: Contraindications—permanent and temporary.
(SCID: severe combined immunodeficiency)

Flowchart 2: Precautions—permanent and temporary.
(DTP: diphtheria, tetanus, and pertussis; HHE: hypotonic–hyporesponsive)
RECORDKEEPING
The vaccine administrator must record the type of vaccine, brand
name, and date of administration of the vaccine in the patient’s
file/immunization record. In addition, recording of the batch
number of the vaccine is also recommended. Recordkeeping is
very important as guidelines issued for reporting of adverse events
following immunization (AEFI) are also applicable to the private
practitioners.8
It is necessary to record combination the brand name, type of
combination [e.g., diphtheria tetanus whole-cell pertussis (DTwP)/
Haemophilus influenzae type B (Hib)/IPV], expiry date, date route,
and site of administration.
MEDICOLEGAL ASPECTS
The vaccine administrator must explain in detail the characteristics
and anticipated side effects of the vaccine in reasonable detail to
the caregivers prior to immunization. A verbal consent is usually
adequate. In any case, the recipient must be observed for any allergic
effects for at least 15 minutes after vaccination and all resuscitative
equipment must be kept standby for possible anaphylaxis. The
caregivers should also be counseled about possible side effects,
BOX 2: Minimum resuscitative equipment.

• Airway, self-inflating resuscitation bag, mask, intravenous (IV) access
(IV cannula of gauge 22, 24), oxygen cylinder, and oxygen mask with tubes
• Injection adrenaline (1:1,000 solution)
• IV hydrocortisone
• Normal saline
their management, and danger signs before the vaccine is sent

home.8,9 Box 2 provides the list of bare minimum equipment and
drugs needed to take care of any immediate AEFI, particularly any
hypersensitivity reaction to vaccine.
REFERENCES
1. Kimmel SR, Wolfe RM. Communicating the benefits and risks of
vaccines. J Family Practice. 2005;54:S51-7.
2. Healy MC, Pickering LK. How to communicate with vaccine-hesitant
parents. Pediatrics. 2011;127:S127-33.
3. Hutin Y, Hauri A, Chiarello L, Catlin M, Stilwell B, Ghebrehiwet T, et al.
Best infection control practices for intradermal, subcutaneous, and intra-
muscular needle injections. Bull World Health Organ. 2003;81:491-500.
4. World Health Organization. (2010). WHO best practices for injections
and related procedures toolkit. WHO/EHT/10.02. [online] Available
from http://whqlibdoc.who.int/publications/2010/9789241599252_
eng.pdf. [Last accessed November, 2022].
5. Atkinson WL, Kroger AL, Pickering LK. General immunization
practices. In: Plotkin SA, Orenstein WA, Offit PA (Eds). Vaccines, 5th
edition. Saunders Elsevier; 2008. pp. 83-109.
6. Nicoll LH, Hesby A. IM injection: An integrative research review and
guideline for evidence based practice. Appl Nurs Res. 2000;16:149-62.
7. National Center for Immunization and Respiratory Diseases. General
Recommendations on Immunization, Recommendations of the
Advisory Committee on Immunization Practices (ACIP). MMWR
Recomm Rep. 2011;60(2):1-64.
8. Ministry of Health and Family Welfare. (2010). AEFI Surveillance and
Response—Operational Guidelines. [online] Available from http://
www.cdsco.nic.in/AEFI%20Guidelines%20Print%20ready%202010.
pdf [Last accessed November, 2022].
9. Rajput M, Sharma L. Informed consent in vaccination in India:
Medicolegal aspects. Hum Vaccin. 2011;7:723-37.
2.5 VACCINE STORAGE AND HANDLING

Srinivas G Kasi, Sanjay Marathe
INTRODUCTION
By reducing the incidence of infectious diseases, immunization
programs have had a major impact on the health status of the
world population, especially in children. Proper vaccine storage
and handling is a key component of immunization programs and
is a shared responsibility from the time the vaccine is manufactured
until it is administered. The majority of vaccine storage and handling
errors are avoidable.
Cold chain breaches can occur even in well-designed and
well-managed systems as a result of technical malfunctions; but if
there are good procedures in place, problems will be detected and
effectively managed so that effective protection can be extended to
its recipients and vaccine losses can be prevented. Efficient vaccine
storage management is an essential quality assurance measure for
vaccine service providers.
WHAT IS THE COLD CHAIN?

The “cold chain” is the system of transporting and storing vaccines
within the recommended temperature range, from the place of
manufacture to the point of administration. It has three main
components:
1. Personnel
2. Equipment
3. Procedures (Flowchart 1)
Flowchart 1: Cold chain components.
Above three discussed components combine to ensure proper

vaccine transport, storage, and handling. The optimum temperature
for refrigerated vaccines is between +2 and +8°C. For frozen vaccines,
the optimum temperature is −15°C to −25°C. In addition, protection
from light is a necessary condition for some vaccines.
IMPORTANCE OF MAINTAINING THE COLD CHAIN

Vaccines and toxoids are made up of proteins, nucleic acids,
lipids, and carbohydrates, which may become less effective or even
destroyed, when exposed to temperatures outside the recommended
range. Cold-sensitive vaccines experience an immediate loss of
potency following freezing. Vaccines exposed to temperatures above
the recommended temperature range experience some loss of
potency with each episode of exposure. Repetitive exposure to heat
episodes results in a cumulative loss of potency that is not reversible.
There is no simple and cheap method that can be used in the field
to assess whether a vaccine exposed to ambient temperature has
retained at least the minimum required potency with exception of
vaccine-monitoring tool—vaccine vial monitors (VVMs), which is
provided with the WHO prequalified vaccines. VVM can indicate the
level of heat exposure of individual vials. It will be very difficult to
assess the potency of a mishandled vaccine because information on
vaccine degradation is sparse; multipoint stability studies on vaccines
are difficult to perform and information from manufacturers is not
always available (Table 1).
Maintaining the potency of vaccines is important for several
reasons:
■ Use of ineffective vaccine will lead to vaccine failures, which
ultimately leads to re-emergence of vaccine-preventable disease.
■ Vaccines are expensive and loss of vaccine will cause waste of
resource.
■ Loss of vaccines may result in short supply of vaccines, which
may lead to the cancellation of immunization sessions resulting
in lost opportunities to immunize.
■ Revaccination of people who have received an ineffective vaccine
is professionally uncomfortable and may cause a loss of public
confidence in vaccines and/or the healthcare system.
TABLE 1: Summary of vaccine sensitivities.

Storage
Exposure to heat/ temperature
Vaccine light Exposure to cold range
Heat- and light-sensitive vaccines:
BCG, freeze- Relatively heat stable, Not damaged by +2°C to +8°C
dried but sensitive to light freezing
OPV Heat sensitive Not damaged by +2°C to +8°C
freezing
MR/MMR Sensitive to heat and Not damaged by +2°C to +8°C
light freezing
Varicella Heat sensitive Not damaged by +2°C to +8°C
(lyophilized) freezing
RotavacTM Heat sensitive Not damaged by +2°C to +8°C
freezing
Yellow fever Heat sensitive Not damaged by +2°C to +8°C
freezing
JE:SA-14-14-2 Heat sensitive Not damaged by +2°C to +8°C
freezing
Live hepatitis A Heat sensitive Not damaged by +2°C to +8°C
freezing
Influenza: Heat sensitive Damaged by +2°C to +8°C
Inactivated freezing
Freeze-sensitive vaccines:
DPT/DT/Td/ Relatively heat stable Freezes at −0.5 to +2°C to +8°C
Tdap −3°C
Hepatitis B Relatively heat stable Freezes at −3°C +2°C to +8°C
TCV/MCV/ Relatively heat stable +2°C to +8°C
Hib-CV/PCV
HPV Relatively heat stable +2°C to +8°C
Rabies Relatively heat stable +2°C to +8°C
JE—Inactivated Relatively heat stable +2°C to +8°C
(BCG: bacillus Calmette–Guérin; DPT: diphtheria, pertussis, and tetanus;
Hib: Haemophilus influenzae type B; HPV: human papillomavirus vaccine; JE:
Japanese encephalitis; MCV: meningococcal vaccine; MMR: measles, mumps,
and rubella; OPV: oral poliovirus vaccine; PCV: pneumococcal conjugate vaccine;
TCV: typhoid conjugate vaccine; Tdap: tetanus, diphtheria, and pertussis)
■ Proper vaccine storage and management are the responsibility of

all those dealing with them right from manufacturer, transporter,
stockist, retailers to doctors, and end users.
■ Different surveys, studies, and site visits have found that about
17–37% of healthcare providers expose vaccines to improper
storage temperatures. Refrigerator temperatures are more
commonly kept too cold rather than too warm.
Bacillus Calmette–Guérin (BCG), measles, mumps, and rubella
(MMR), varicella DTaP (diphtheria, tetanus, and pertussis)-
containing vaccines, human papillomavirus (HPV) vaccines, and
rotavirus vaccines are sensitive to strong light, sunlight, ultraviolet,
fluorescents (neon), and exposure of these vaccines to light should
be avoided.
VACCINE STORAGE EQUIPMENT

Vaccine storage equipment can be classified into electrical and
nonelectrical equipment. Electrical equipment consists of walk-in
freezers, walk-in coolers, deep freezers, ice-lined refrigerators (ILRs),
and the domestic refrigerators. Nonelectrical equipment includes
the cold boxes and vaccine carriers.
Walk-in Freezers
Walk-in freezers (WIFs) are used for bulk storage of oral poliovirus
(OPV) vaccines and also for preparation and storage of frozen
ice packs at state stores. They maintain a temperature of −18°C
to −20°C.
Walk-in Coolers
Walk-in coolers (WICs) are made up of modular and prefabricated
polyurethane foam (PUF)-insulated panels with floor of either
stainless steel panels or modular floor panels with aluminum-
chequered plates. These cold rooms are typically controlled between
2 and 8°C. It has digital light-emitting device/light crystal device
(LED/LCD), temperature display, and temperature recorder. It
is fitted with an audio–video alarm system to warn of high or low
temperature. These are used for bulk storage of vaccines at state and
regional stores. Walk-in coolers/walk-in freezers stores 3 months of

requirement of vaccines and 25% buffer stock for the districts they
cater.
Deep Freezers
Deep freezers have either top-opening lid or front door. Deep freezers
supplied under immunization program have a top-opening lid. The
cabinet temperature is maintained between –18 and –20°C. This is
used for storing of OPV at district and also for freezing ice packs.
Ice-lined Refrigerator
These types of refrigerators are top opening and front opening. Inside
the ILR, there is a lining of water containers (ice packs or tubes) fitted
all around the walls and held in place by frame. While the refrigerator
is operating, the water in the containers freezes and if the electricity
supply fails, the ice lining keeps the temperature inside the refrigerator
at a safe level for vaccines. It can keep vaccine safe with as little as
8-hour continuous electricity supply in a 24-hour period.
Hence, it is suitable for use in the area with irregular power
supply. In the ILR, vaccines should be stored in baskets to avoid
direct contact with the sides and the bottom. Since the bottom of
the ILR is its coldest part, the most heat-sensitive vaccines should be
stored at the bottom and the most heat-resistant vaccines in the top
compartment. This is reverse of the domestic refrigerator.
■ Bottom: Measles, MR, MMR, BCG, OPV, yellow fever (YF), live
Japanese encephalitis (JE), varicella, rotavirus, live-attenuated
hepatitis A vaccine.
■ Middle and upper: All the pertussis containing combination
vaccines, inactivated hepatitis A vaccines, typhoid conjugate
vaccine (TCV), pneumococcal conjugate vaccine (PCV),
meningococcal vaccine (MCV), inactivated influenza vaccine,
HPV, rabies, and inactivated JE vaccines (Figs. 1 to 3).
Cold Boxes (Coolers)

Cold boxes are big insulated boxes with ice packs. They are
mainly used for transportation of vaccines from district store to the
Fig. 1: Ice-lined refrigerator.
Fig. 2: Vaccine storage in ice-lined refrigerator.
Fig. 3: Vaccine storage in cooler ice-lined refrigerator.

primary health center (PHC). In an emergency, they can also be

used to store vaccines and frozen ice packs. Before placing vaccines
in the cold boxes, conditioned ice packs are placed at the bottom and
sides of the cold box. The vials of diphtheria, pertussis, and tetanus
(DPT), diphtheria and tetanus (DT), hepatitis B, and tetanus toxoid
(TT) vaccines should not be placed in direct contact with ice packs,
they should be placed in a cartoon or plastic bag. Vaccines can be
kept in a 5-L cold box for 90 hours and a 20-L cold box for 6 days
when the ambient temperature is 43°C, provided that the boxes are
fully functional and not opened during this period.
Vaccine Carriers
It is used by health workers for carrying vaccines (16–20 vials) to
subcenters or to community outreach programs. They maintain the
cold chain during transport from the PHC for 1-day use in the field.
The inside temperature is maintained between +2 and −8°C with four
conditioned ice packs, for 1 day (if not opened frequently) (Table 2).
Icepacks
Icepacks are flat, leak-proof plastic containers, of standard
dimensions that should be filled with tap water to fill about 80% of the
capacity. They are kept in deep freezers at −25°C, till they are frozen.
When removed from the freezers, the temperature of the frozen
icepacks is −20°C, which can damage freeze-sensitive vaccines. The
frozen ice packs have to undergo a process known as “sweating” to
make it suitable for use. Sweating is done in the following way: the
icepacks are placed on a table. The icepacks are shaken every few
minutes till the ice is noted to move around in the icepacks. This may
take a few minutes to an hour. They are now ready for use in vaccine
carriers and cold boxes.
Domestic Refrigerator
Majority of the vaccination service providers in private sector use
domestic refrigerator to store the vaccines. The domestic refrigerator
is designed and built to store fresh or frozen food and drinks and
not for the special storage temperature need of vaccines. They do
TABLE 2: Summary of cold chain equipment used under expanded program

on immunization.
Equipment Temperature Storage capacity Holdover time
Electrical
Deep −15°C to −25°C 200 ice packs or • 43°C for 18 hours
freezer OPV stock for • 32°C for 22 hours
3 Monate
ILR +2°C to + 8°C BCG, DPT, DT, TT, • 43°C for 18 hours
measles, Hep B • 32°C for 22 hours
vaccine stock for
3 Monate
Nonelectrical
Cold box +2°C to + 8°C All vaccines stored • 43°C for 6.5 days
(large) for transport or in • 32°C for 10 hours
case of power
failure
Vaccine +2°C to + 8°C All vaccines carried • 43°C for 34 hours
carrier for 12 hours • 32°C for 51 hours
(BCG: bacillus Calmette–Guérin; OPV: oral poliovirus vaccine; DPT: diphtheria,
pertussis, and tetanus; DT: diphtheria and tetanus; Hep B: hepatitis B; TT: tetanus
toxoid; ILR: ice-lined refrigerator)
not have accurate temperature controlling system and hence it can

place the safety of vaccines at risk. For vaccine storage, the domestic
refrigerator has following drawbacks:
■ Temperature varies significantly every time the door is opened.
■ Temperature rises during defrosting in cycle in cyclic defrost and
frost-free refrigerator.
■ Cabinet temperature is easily affected by ambient temperature.
■ Temperature setting using dial is crude and inaccurate.
Direct cool refrigerators are to be avoided as there is uneven
temperature distribution and formation of ice from the water vapor
inside the refrigerator.
However, if domestic refrigerator is the only alternative to store the
vaccines, it is acceptable to store vaccines provided that the refrigerator
and freezer compartments have separate external doors. There are
two types of domestic refrigerators—(1) frost-free refrigerator, and
(2) manual and cyclic defrost refrigerator. The frost-free refrigerators

have no heating cycles but have low-level warming cycles and hence
it provides more uniform temperatures than manual and cyclic
defrost models and may be more suitable for vaccine storage. The
manual and cyclic defrost model refrigerator and bar refrigerator
(dormitory style) should not be used to store the vaccine as they have
wide fluctuations in the temperature in the internal compartment.
Safe vaccine storage is possible in domestic refrigerators, if following
points are observed:
■ Store vaccine in a dedicated refrigerator. Do not store food,
drinking water, or other medications in vaccine refrigerators.
■ The refrigerator compartment temperature is maintained
between 2 and 8°C and freezer compartment temperature
maintained at or below 5°F (−15°C).
■ The door seals are in good condition and are sealing tightly.
■ The door closes properly automatically on leaving it free.
■ The refrigerator has separate freezer compartment.
■ The refrigerator compressor is quiet.
■ The refrigerator is free from any coolant or water leak.
■ Vaccination clinic staff is well aware about vaccine storage plans.
If the above criteria cannot be met, with that, one should go for
purpose-built refrigerator for storing the vaccine.
Tips for Better Vaccine Storage in Domestic

Refrigerators (Table 3)
■ Placement of refrigerator:
y Should be placed away from direct sunlight and away from
doors and windows
TABLE 3: Periodic maintenance plan for vaccine refrigerator.

Daily Weekly Every fortnight
Check to make Check for ice buildup • Clean the coils and the motor
sure the doors in the freezer and • Defrost and clean the
are closed and defrost, if >0.5 cm refrigerator and freezer
sealed frost has accumulated compartments
• Adjust the thermostat, if
necessary
y A distance of 10 cm should be maintained all around to

permit air circulation.
y Should be placed on a stand at least 5 cm in height
y The electric socket should be switchless or the switch should
be taped to avoid accidental switching off.
■ Accessibility should be restricted only to the vaccination staff
so as to minimize unnecessary door opening and preventing
accidental switch off of power supply
■ A chart should be pasted on the door displaying the location of
the vaccines in the refrigerator
■ Stabilize the temperature of the new refrigerator before stocking:
y When the refrigerator is first installed, set the thermostat to
+2°C and +5°C. Once the daily temperature range remains
consistently between +2 and +8°C, the thermostat is correctly
adjusted and the setting should not be changed, even
if electrical power is lost. The thermostat should not be
readjusted if the temperature occasionally rises a degree or
so above +8°C after a power cut, or in very hot weather. In a
new refrigerator, allow 1 week of twice-daily refrigerator and
freezer temperature recordings before using the unit to store
vaccines. Once the temperature recorded on two consecutive
days of temperatures is within the recommended range, the
unit is stable and ready for use.
Avoid unnecessarily opening the refrigerator door. The WHO recom-
mends door openings be minimized to not more than four times a day.
■ Monitoring temperatures inside the refrigerators:
y Monitor internal temperature regularly with thermometer—
preferably Celsius digital minimum/maximum thermometer.
Place the thermometer in a central location within the storage
compartment (Fig. 4).
■ Safeguard the power source:
y Ensure the power source is marked clearly in a way to prevent
the refrigerator from being accidentally unplugged or turned
off (Fig. 5).
■ Increase cool mass:
y Place water bottles in the door or the lowest shelf of the
refrigerator and/or ice packs/gel packs in the freezer
Fig. 4: Temperature monitoring.
Fig. 5: Safeguard the power source.

Fig. 6: Water bottles to increase cool mass.
compartment to increase the cool mass; these will assist in

stabilizing the temperature in refrigerator compartment and
reduces warming periods when the refrigerator is opened.
This is also useful, if there is a short-time power cut or
refrigerator failure (Fig. 6).
■ Ideal storage method:
y Store vaccines in enclosed plastic-labeled containers or basket.
This will allow easy identification of vaccines and minimize the
time spent with the door opened searching for vaccines.
y Store vaccines in original packing as it can provide some
protection from very short-term fluctuations.
y Do not crowd the vaccines by overfilling the shelves. Allow
space between containers and gap of at least 4 cm from all
refrigerator walls to allow free air circulation.
y Never store any vaccine in the door of the refrigerator.
■ Place measles, MR, MMR, BCG, OPV, yellow fever, JE (SA-14-142),
meningococcal A conjugate, Rotavac and/or any other vaccines
not damaged by freezing on the top shelf (Figs. 7 and 8).
■ Put DTP, DT, Td, TT, Hep B, DTP/Hep B, DTP/Hep B/Hib, DTP/
Hep B/Hib/IPV Hib, PCV, HPV, rotavirus, and/or any other
freeze-sensitive vaccines in the middle shelf.
■ Store the diluents next to the freeze-dried vaccine with which
they are supplied, on the appropriate shelf. If there is not enough
space on the shelf, put the diluents on the bottom shelf, clearly
Fig. 7: Vaccine storage pattern.
Fig. 8: Storage protocol in domestic fridge. (BCG: bacillus Calmette–Guérin;

DPT: diphtheria, pertussis, and tetanus; HPV: human papillomavirus vaccine;
Hep: hepatitis; JE: Japanese encephalitis; MMR: measles, mumps, and rubella;
OPV: oral poliomyelitis vaccine; YF: yellow fever; IIV: inactivated influenza
vaccine; IPV: inactivated polio vaccine; PCV: pneumococcal conjugate vaccine;
TCV: typhoid conjugate vaccine)
labeled so they can be easily identified to their matching vaccine.

Heat-stable vaccines (PCV, HBV, TCV, HPV, and rabies) can be
stored in the lowest shelf for short periods.
■ Keep the door closed as much as possible:

y Reducing door opening helps to keep internal temperatures
stable.
y Vaccine refrigerators should have a sticker to remind staff of
avoiding unnecessary door opening.
y Stick a basic map of vaccine locations outside of the
refrigerator door so staff can go “straight” to the vaccine when
the door is opened.
y Do not open the door fully while using, keep it to minimum
sufficient for the need.
■ Training and assigning staff:
y Good vaccine storage and handling depends on knowledge
and habits of the staff.
y Training ensures that everyone handling vaccines knows how
to protect them.
y Ensure that one person is responsible for adjusting refrigerator
controls and the other person is responsible for cold chain
management to enable consistency.
■ Maintenance of the vaccine refrigerator:
y Report breakdowns immediately and arrange for alternative
storage for vaccines while the refrigerator is repaired
(see Table 3).
y When necessary, defrost refrigerator regularly. This also aids
in the efficient functioning of refrigerator.
■ Power failure:
y During a power failure of 4 hours or less, the refrigerator door
should be kept closed.
y If the backup generator facility is lacking, identify an available
unit at another nearby site.
y If a refrigerator with a backup generator has not been located
or is not working, and for power failures more than 4 hours,
store vaccines in a cold box with conditioned ice packs or gel
packs.
Purpose-built Vaccine Refrigerator

Purpose-built vaccine refrigerator is preferred refrigerator for
vaccine storage. It is used by hospitals, pharmacies, and larger
Fig. 9: Purpose-built vaccine refrigerator.
general practices. It has following advantages over the domestic

refrigerator (Fig. 9):
■ No need to modify for vaccine storage
■ Programmed to maintain an internal temperature between 2 and
8°C
■ Cabinet temperature is not affected by ambient temperature and
is stable and uniform
■ Evaporator operates at 2–8°C, preventing vaccine from freezing
■ Defrost cycle allowing defrosting without rise in cabinet
temperature
■ Even distribution of temperature because of ongoing air
circulation
■ Have external temperature reading display, maximum/
minimum temperature continuous display, and an out-of-range
temperature alarm
■ Good temperature recovery—when the fridge is open to access
the vaccines.
Automatic Voltage Stabilizer

The function of the voltage stabilizer is to control the range of
fluctuations in the main voltage of 220 volts (+10 volts). No electrical
cold chain equipment should be used or operated without a voltage

stabilizer.
COLD CHAIN TEMPERATURE MONITORING

Monitoring of temperature is a critical and integral part of any cold
chain system. The expensive equipment installed may become
meaningless unless a meticulous temperature record documents its
proper working. In every vaccine storage equipment, the temperature
should be monitored. Temperature should be recorded at least two
times in a day and plotted on a chart to show high/low excursions. To
measure the temperature during storage of vaccines, different type
of thermometer is used.
Minimum/Maximum Thermometer (Fig. 10)

It shows the current temperature and the minimum and maximum
temperatures achieved. Temperature fluctuations outside the
recommended range can also be detected. It is available in fluid-
filled and digital forms of which digital type with a probe is most
effective type. Place the probe directly in contact with a vaccine vial
or package.
Thermometer must be reset regularly; the thermometer battery
must be checked and replaced time to time.
Fig. 10: Minimum/maximum thermometer.

■ Digital thermometer: These are the most accurate constant

monitors and also offer alarm to safeguard against damage from
refrigerator malfunction. To get accurate reading, place the
temperature probe in proper location.
Data Loggers
This temperature chart recording system can record temperatures
over a long period of time as well as can provide visual and audio
alarms. Loggers use a similar measuring principle to chart as
recorders but record the data electronically.
The objective of data logging is to build up a “temperature
map” of the vaccine storage areas within the refrigerator to identify
the safest areas and the most dangerous areas for vaccine storage,
particularly looking for areas where vaccine could freeze.
Each logger is a self-contained miniature computer. Once
programmed via computer, loggers are disconnected from the
computer and placed in the vaccine refrigerator in close proximity to
the temperature probe. The logger then operates independently on
its own battery until the recording is downloaded to the computer.
Temperature of ILRs/freezers used for storage of vaccines must
be recorded twice daily, at 10 am and 4 pm. This should be recorded
in a logbook.
All cold chain temperature monitoring devices should be
calibrated once in 6 months or earlier, if necessary.
Vaccine Vial Monitor

A VVM is a label containing a heat-sensitive material, which is placed
on a vaccine vial to register cumulative heat exposure over time
(Fig. 11). A VVM enables the health worker to know whether vaccine
has been damaged by exposure to heat. The VVM is a circle with a
small square inside it, which is lighter in color than surroundings. The
inner square of VVM is made of heat-sensitive material that is lighter
in color at the starting point. The combined effect of time and tem-
perature causes the inner square of the VVM to darken gradually. The
color change is irreversible. A direct relationship exists between rate
of color change and temperature. Thus, lower the temperature, slower
the color change; and higher the temperature, faster the color change.
Fig. 11: Vaccine vial monitor.
Fig. 12: Decision to use vaccine(s) based on vaccine

vial monitor sensitivity.
Thus, VVM gives information about the heat exposure over

a period of time that affects vaccine potency. It does not give
information about other factors responsible for vaccine degradation
such as light. VVMs are not substitutes for expiry dates. If the inner
square is lighter than the outer ring, the vaccine can be used, whereas,
if inner-square matches has darker color than outer ring, then the
vaccine should be discarded (Fig. 12). The refrigerator temperature
needs to be stabilized before starting the use of refrigerator for
vaccine storage.
In multidose vials, where the VVM is attached over the label,

the vaccine vial once opened can be used for next 28 days (liquid or
freeze-dried). When the VVM is attached anywhere other than label
(cap or neck of ampoule), the vaccine vial, once opened, must be
discarded after immunization session or within 6 hours of opening,
whichever comes first.
Electronic freeze indicators: These are devices used to monitor
the exposure of vaccines to freezing and are used with freeze-
sensitive vaccines (DPT containing vaccines, Hep B, TT containing
vaccines).
The most commonly used type of freeze indicator is the freeze-
tag (Fig. 13). This consists of an electronic temperature measuring
circuit with a LCD. A small blinking dot of light in the corner of the
display shows that the freeze-tag is functioning correctly.
If the freeze-tag is exposed to a temperature below 0°C for more
than 60 minutes, the display will change from the “good status” (•)
to the “alarm status” (×).
Vaccines that have been exposed to freezing may have been
damaged and should be checked by using the shake test.
3MTM Freeze WatchTM indicators (Fig. 14) consist of a highly
sensitive indicating liquid inside a specially designed ampoule to
monitor exposure of temperature-sensitive products to freezing
temperatures.
Fig. 13: Freeze-tag.

Fig. 14: Freeze Watch.
When exposed to freezing temperatures, the ampule fractures,

releasing a liquid. The liquid irreversibly stains a paper behind the
ampule, indicating that product has been exposed to unacceptable
temperatures.
Vaccines that have been exposed to freezing may have been
damaged and should be checked by using the shake test.
VACCINE-HANDLING PERSONNEL
Designated Vaccine Coordinators Staff
Each vaccination clinic should designate one staff member to be the
primary vaccine coordinator and another staff member as a backup
in case the primary coordinator is unavailable. The designated
person will be responsible for ensuring that all vaccines are handled
correctly, that procedures are documented, and that all personnel
receive appropriate cold chain training. Designated vaccine
coordinators should be fully trained in routine and urgent vaccine
storage and handling protocols.
Other Staff
All staff members should be familiar with the policies and procedures
for vaccine storage and handling. This especially includes staff
members, such as receptionists who accept vaccine shipments.
Written policies and procedure documents should be available near

the vaccine storage units for easy reference.
Training Personnel
All staff that handle or administer vaccines should be trained in
proper vaccine storage and handling practices. All staff should
be trained to have an understanding of the importance of cold
chain maintenance and basic practices so that they are aware of
their responsibilities to the cold chain. Staff who monitor and
record vaccine storage unit temperatures should immediately
report inappropriate storage conditions (including exposure to
inappropriate temperature or light exposures) to the designated
vaccine coordinator.
EFFICIENT VACCINE MANAGEMENT PROTOCOLS

Routine Vaccine Storage and Handling Protocols
Routine protocols should include all aspects of day-to-day vaccine
management, from ordering vaccines, controlling inventory,
handling vaccines, and monitoring storage conditions. It should
include following four elements:
1. Ordering and accepting vaccine deliveries:
■ Order vaccines to maintain an adequate stock (about 1 month’s
requirement) to meet the needs of the vaccination unit
■ Ensure that the ordered vaccine stock is delivered when the
vaccination unit is open. Vaccines should be delivered when
staff is available to unpack and store.
■ Store vaccines at the recommended temperatures, immedi-
ately on arrival, refrigerated vaccines between 2 and 8°C
■ Maintain a vaccine inventory log including:
y Vaccine name and number of doses received
y Date vaccine received
y Condition of vaccine on arrival
y Vaccine manufacturer and lot number
y Vaccine expiration date
2. Storing and handling vaccines (as discussed above)
3. Managing inventory:
■ Rotate vaccine stock so vaccine and diluent with the shortest
expiration date are used first.
■ Place vaccine with the longest expiration date behind the
vaccine that has short expiry.
■ Remove expired vaccine and diluent from usable stock.
■ Keep vaccine stock well organized.
■ Stick a basic map of vaccine locations outside of the
refrigerator door so that staff can go “straight” to the vaccine
when the door is opened.
■ Inspect the storage unit daily. A physical inspection helps
to ensure that vaccines and thermometers are placed
appropriately within the unit.
■ Dispose of all vaccine materials using medical waste disposal
procedures.
4. Managing potentially compromised vaccines:
■ Identify and isolate all potentially compromised vaccines and
diluents
■ Label these vaccines “DO NOT USE” and store separately from
uncompromised vaccines and diluents in the recommended
temperature range
■ Contact vaccine manufacturers and/or state immunization
program for appropriate actions that should be followed for
all potentially compromised vaccines and diluents.
Emergency Vaccine Retrieval and Storage

Various situations such as equipment failures, power outages, or
natural disasters may compromise vaccine storage conditions. It is
important that all the staff involved in the immunization activity is
aware of the probable adverse effect of such situations on vaccine
storage conditions. Ensure that all staffs have appropriate training,
so that they understand the urgent vaccine storage and handling
protocols and their responsibility in maintaining the cold chain.
Emergency vaccine retrieval and storage plan should include the
following components:
■ Designate an alternate site where vaccines and diluents can

be safely stored. While choosing an alternate site, consider
availability of types of storage unit(s), temperature monitoring
capabilities, and backup generator.
■ Obtain and store an adequate packing containers and materials
(e.g., frozen or refrigerated gel packs, bubble wrap) in the facility
that will be needed to pack vaccines for safe transport.
■ Include written directions for packing vaccines and diluents for
transport. A calibrated thermometer should be placed in each
packing container near the vaccine.
■ Incorporate written procedures for managing potentially
compromised vaccines.
■ Include contact information for vaccine manufacturers and/or
the immunization program.
Electronic Vaccine Intelligence Network (eVIN): Electronic Vaccine
Intelligence Network is an IT-based system aimed at strengthening
vaccine supply chain systems across the country. First introduced
in 2015, eVIN enables real-time monitoring of vaccine stocks and
storage temperatures in multiple locations across the country.
All cold chain handlers are provided smartphones having an
application that allows for the digitization of vaccine inventory,
real-time stock and temperature vaccine requirement, emergency
management, consumption patterns, route planning and stock
reallocation. SIM-enabled temperature loggers are attached to
the cold chain equipment and capture temperature information
through digital sensors placed in the ILRs. Temperature data is
recorded every 10 minutes and updated at interval of 60 minutes
on the server via General Packet Radio Service (GPRS). In case
of a temperature breach, the logger alarms and sends mail and
SMS alerts to the concerned technicians and management
managers.
It has been implemented in all 36 states and 733 districts with
over 29,000 storage centers or cold chain points which are live on
eVIN. eVIN has achieved a vaccine availability rate of over 99% at
all cold chain points and over 80% reduction in instances of vaccine
stock-outs.
SUGGESTED READING
1. Centers for Disease Control and Prevention. Vaccine Storage and
Handling Toolkit. [online] Available from https://www.cdc.gov/vaccines/
hcp/admin/storage/toolkit/index.html. [Last accessed November, 2022].
2. Department of Health and Ageing; Australian Government. (2013).
National Vaccine Storage Guidelines, “Strive for 5”. [Online]. Available
from: https://www.health.gov.au/resources/publications/national-
vaccine-storage-guidelines-strive-for-5. [Last accessed November, 2022].
3. Galazka A, Milstien J, Zaffran M. (1998). Thermostability of Vaccines:
Global Programme for Vaccines and Immunization. [online]. Available
from https://apps.who.int/iris/bitstream/handle/10665/64980/
WHO_ GPV_98.07.pdf?sequence=1&isAllowed=y. [Last accessed
November, 2022].
4. Gupta SK, Shastri DD. Cold chain and vaccine storage. In: Shah NK,
Agrawal R, Sukumaran TU, Vashishtha VM (Eds). IAP Textbook of
Vaccines, 1st edition. New Delhi: Jaypee Brothers Medical Publishers;
2014. pp. 89-99.
5. Ketan B, Jariwala V, Kirit S. Target-5: Guide to Vaccine Storage and
Handling, 1st edition. Gujarat: IAP Surat publication; 2006.
6. National Health Portal. Electronic Vaccine Intelligence Network (eVIN).
[online] Available from https://www.nhp.gov.in/electronic-vaccine-
intelligence-network(evin)_pg#:~:text=Electronic%20Vaccine%20
Intelligence%20Network%20(eVIN)%20is%20an%20innovative
%20technological%20solution,chain%20systems%20across%20
the%20country. [Last accessed November, 2022].
7. Shastri DD. Vaccine storage and handling. In: Parthasarathy A (Ed).
IAP Textbook of Pediatrics Infectious Diseases, 1st edition. New Delhi:
Jaypee Brothers Medical Publishers; 2013. pp. 493-501.
8. Shastri DD. Vaccine storage and handling. In: Parthasarthy A (Ed).
IAP Textbook of Pediatrics, 5th edition. New Delhi: Jaypee Brothers
Medical Publishers; 2013. pp. 1-5.
9. Shastri DD. Vaccine storage and handling. In: Parthasarthy A (Ed).
IAP Textbook of Pediatrics, 7th edition. New Delhi: Jaypee Brothers
Medical Publishers; 2019.
10. World Health Organization. (2002). Getting started with VVMs. VVM for
all, Technical Session on Vaccine Vial Monitors. [online] Available from
https://apps.who.int/iris/bitstream/handle/10665/67806/WHO_
V-B_02.35_eng.pdf;jsessionid=0EBE0A30E560121C78C1A6FF62E7E8C4?
sequence=1 [Last accessed November, 2022].
11. World Health Organization. Immunization in Practice (WHO/EPI/
PHW/84.01 to 84.07). 2015 Geneva: WHO; https://apps.who.int/iris/
handle/10665/193412.
2.6 ADVERSE EVENTS

FOLLOWING IMMUNIZATION
M Indra Shekhar Rao, Harish Kumar Pemde
INTRODUCTION
Vaccines are among the safest medicines to use and these are
considered very effective tool for preventing infectious diseases.
Like any other drug, no vaccine is 100% effective or 100% safe,
100% of time. 1 As with other drugs, adverse events can occur
with vaccines too. In addition to the vaccines themselves, the
process of administration of vaccines is a potential source of
an adverse event following immunization (AEFI). As vaccine-
preventable infectious diseases continue to decline, the risks
associated with vaccines have become increasingly noticeable and
a matter of concern.
An AEFI surveillance system is usually a passive system to
enable spontaneous reporting of all adverse events. It is a part
of the National Regulatory Authority (NRA) for vaccines. The
primary purpose of spontaneous AEFI reporting is to monitor
the known adverse events associated with vaccine use, and to
identify the new adverse events, i.e., safety signals after a product
is marketed.2 India is a major vaccine producing and exporting
nation supplying 70% of UN vaccine requirements. A functional
NRA is a prerequisite for supplying vaccines to UN agencies.3
The Operational Guidelines for Surveillance and Response
to AEFI (2015) provides guidance for the AEFI surveillance system
in India.4
WHAT IS THE IMPORTANCE OF AEFI REPORTING?

■ It helps in identifying or better understanding the safety issues
relating to newly introduced vaccines.
■ It helps in monitoring AEFI rates and trends across the country.
■ It helps in identifying problems with manufacture, storage,
delivery, or administration.
TABLE 1: Some serious adverse events following immunizations with

commonly used vaccines.
Frequency per doses
Vaccine Reaction Onset interval given
BCG Fatal dissemination of 1–12 months 0.19–1.56/1,000,000
BCG infection
OPV Vaccine-associated 4–30 days 2–4/1,000,000
paralytic poliomyelitis
DTwP Prolonged crying and 0–24 hours <1/100
seizures
HHE 0–24 hours <1/1,000–2/1,000
Measles Febrile seizures 6–12 days 1/3,000
Thrombocytopenia 15–35 days 1/30,000
Anaphylaxis 1 hour 1/1000,000
(BCG: bacillus Calmette–Guérin; DTwP: diphtheria, tetanus, and whole cell
pertussis; HHE: hypotonic hypo‐responsive episode; OPV: oral poliovirus
vaccine)
ADVERSE EVENTS FOLLOWING IMMUNIZATION

An AEFI is any untoward medical occurrence, which follows
immunization and which does not necessarily have a causal
relationship with the usage of the vaccine, i.e., might have not been
caused by vaccine ingredients or the process of vaccination or
immunization but have a temporal relationship with administration
of vaccine (Table 1). It can be any unfavorable or unintended sign,
abnormal laboratory finding, symptom, or disease.5 Sometimes,
mass use of vaccines can cause anxiety in community and even such
responses can be considered as AEFI.
CAUSE-SPECIFIC TYPES OF ADVERSE EVENT

FOLLOWING IMMUNIZATION
■ Vaccine product-related reaction: An AEFI that is caused or
precipitated by a vaccine due to one or more of the inherent
properties of the vaccine product (or ingredients), e.g., extensive
limb swelling following diphtheria, tetanus, and pertussis (DTP)

vaccination. In this scenario, vaccine might have been used
correctly without compromising with manufacturing process,
transport, or storage. Thus, absolutely correct use of vaccine
may also cause this type of AEFI. In most cases, such events are
usually not serious in nature.
■ Vaccine quality defect-related reaction: An AEFI that is caused or
precipitated by a vaccine that is due to one or more quality defects
of the vaccine product including its administration device as
provided by the manufacturer, e.g., failure by the manufacturer
to completely inactivate a lot of inactivated poliovirus vaccine
(IPV) leads to cases of paralytic polio.
■ Immunization error-related reaction: An AEFI that is caused by
inappropriate vaccine handling, prescribing, or administration
and thus by its nature is preventable. These include:
y Transmission of infection by contaminated multidose vial or
reuse of disposable syringes and needles.
y Reconstitution error: Vaccine reconstituted with the incorrect
diluent.
y Injection administered at incorrect site: Bacillus Calmette–
Guérin (BCG) given subcutaneously (SC), rabies, or hepatitis
B vaccine given SC or DPT administered SC.
y Improper storage and transport of vaccine: Vaccines frozen
during storage and administered, can give rise to sterile
abscess. These vaccines are also ineffective.
y Contraindication is ignored: Live vaccine administered to an
immunosuppressed subject.
y Immunization anxiety-related reaction: An AEFI arising from
anxiety about the immunization, e.g., vasovagal syncope in
an adolescent following vaccination. The anxiety may spread
to community too, at times.
y Coincidental event: An AEFI that is caused by something
other than the vaccine product, immunization error, or
immunization anxiety, e.g., fever after vaccination (temporal
association) and malarial parasite isolated from blood.
TYPES OF ADVERSE EVENTS FOLLOWING

IMMUNIZATIONS BASED ON SEVERITY
■ Serious AEFI: An AEFI is considered serious if it—(1) results in
death, hospitalization, or persistent or significant disability/
incapacity, (2) occurs in clusters, (3) causes parental/community
concern, or (4) results in congenital anomaly/birth defect, (5)
where the vaccine quality is suspicious.
■ Severe AEFI: Severe AEFIs are minor AEFIs with increased
intensity/severity, e.g., high-grade fever following pentavalent
vaccination or post-DPT swelling extending beyond nearest
joint. They are caused when recipient’s immune system reacts
to antigens, adjuvants, stabilizers, preservatives contained
in the vaccine. They are very rarely life-threatening nor
do they cause any disability although there is some risk of
morbidity. The patient may not be hospitalized and will not
have sequelae.
■ Minor AEFI: Minor AEFIs usually occur within a few hours of
injection, resolve after short period of time, and pose little danger.
Minor AEFIs can be local reactions (pain, swelling, and redness)
or systemic reactions (fever > 38°C, irritability, malaise, etc.),
which can be managed with antipyretics and anti-inflammatory
and resolve within 2–3 days.
Cluster of AEFIs is considered serious AEFI. A cluster is defined as
two or more cases of the same AEFI related in time, place, or vaccine
administered. A cluster usually occurs with a particular healthcare
provider or a facility.
The following AEFIs should be reported:
■ All serious AEFI
■ Signals and events associated with a newly introduced vaccine
■ AEFI that may have been caused by an immunization error
■ Significant events of unexplained cause occurring within 30 days
after vaccination
■ Events causing significant parental or community concern.
The list of reportable AEFIs with timelines is shown in Table 2.
TABLE 2: Reportable adverse event following immunizations with timelines.

Timeline Event
Occurring within 24 • Anaphylactoid reaction (acute hypersensitivity
hours of immunization reaction)
• Anaphylaxis
• Persistent (more than 3 hours) inconsolable
screaming
• Hypotonic hypo‐responsive episode
• Toxic shock syndrome
Occurring within 5 days • Severe local reaction
of immunization • Sepsis
• Injection site abscess (bacterial/sterile)
Occurring within • Seizures, including febrile seizures (6–12 days
15 days of for measles/MMR; 0–2 days for DTP)
immunization • Encephalopathy (6–12 days for measles/MMR;
0–2 days for DTP)
Occurring within Acute flaccid paralysis (4–30 days for OPV
3 months of recipient; 4–75 days for contact)
immunization
Occurring between 1 • Lymphadenitis
and 12 months after • Disseminated BCG infection
BCG immunization • Osteitis/Osteomyelitis
No time limit Any death, hospitalization, or other severe
and unusual events that are thought by
health workers or the public to be related to
immunization
(BCG: bacillus Calmette–Guérin; DTP: diphtheria, tetanus, and pertussis; MMR:
measles, mumps, and rubella; OPV: oral poliovirus vaccine)
PROCESS OF REPORTING ADVERSE EVENTS

FOLLOWING IMMUNIZATIONS
Most vaccinations in India are given through the government system
through outreach sessions by auxiliary nurse midwives (ANMs)
and sessions in health facilities. To make reporting simple and to
get as many cases reported, health workers and medical personnel
are asked to notify serious and severe AEFIs immediately to the
nearest primary health center (PHC) medical officer (MO) or the
District Immunization Officer (DIO). Private practitioners are also
encouraged to notify AEFIs similarly to the DIO. The MO at the PHC

then reports the case in the case-reporting format (CRF) within
24 hours to the DIO who has another 24 hours to verify the case
and sends it to the State Immunization/Expanded Programme of
Immunization (EPI) Officer and the Immunization Division, Ministry
of Health and Family Welfare (MoHFW) simultaneously. The CRF
gives only the most basic details of the affected person, vaccines and
session details, and status of the patient (brief clinical summary) at
the time of filling the format (see Annexure).
INVESTIGATING ADVERSE EVENTS

FOLLOWING IMMUNIZATIONS
As soon as the AEFI is reported, case investigation begins. The
preliminary case investigation format (PCIF) acts as a checklist
and records the details of the investigations done with relation to
the case. The investigation involves verifying personal details,
vaccine and program details, a clinical examination, interviews with
the treating physicians, caregivers, service providers, volunteers,
etc. to understand the sequence of events. An epidemiological
investigation is also conducted. The cold chain and vaccine
transportation conditions are studied. Hospital records, laboratory
test reports, and other relevant documents are collected. In case
of death, postmortem is recommended. Verbal autopsies formats
have been designed specifically for finding the cause of AEFI deaths
(Fig. 1). These forms should be used whenever a death is alleged
to be associated with vaccine. These, along with the filled PCIF are
submitted simultaneously to the state and the national level within 10
days of notification. Whenever required, experts of the District/State
AEFI Committees are requested to participate in the investigation.
ADVERSE EVENTS FOLLOWING

IMMUNIZATIONS COMMITTEES
Adverse events following immunization committees have been
formed in all districts, states, and at the national level. The
responsibilities of the AEFI committees are to strengthen AEFI
reporting at all levels, ensure maintenance of national policy and
Fig. 1: The adverse event following immunization (AEFI)

reporting circle.
standards, ensure prompt and thorough investigation of serious/

severe AEFI, carry out periodic review of AEFI for trends of nonserious
AEFIs reported through the Health Management Information System
(HMIS)/routine immunization reporting, respond to the media and
community concerns to allay fears regarding vaccine safety, ensure
high standards of AEFI surveillance to ensure that no serious AEFI
are missed, and recommend changes to the immunization program
for ensuring vaccine safety. All AEFI committees at all levels meet at
least once a quarter.
The District AEFI Committee, when it meets, discusses all the case
reports and records, summarizes the findings of the investigation in
the final case investigation form (FCIF) and gives its opinion on the
probable diagnosis. The FCIF is sent to the State AEFI Committee
and the immunization division within 100 days of notification. At
the state level, the causality assessment experts of the State AEFI
Committee discusses all the reports available, gives a diagnosis, and
classifies the case as per WHO classification (Fig. 2). A proportion of
cases causally assessed by the states are further causally assessed by
the National AEFI Committee.
Fig. 2: Adverse event following immunization (AEFI) investigations timelines.
CAUSALITY ASSESSMENT
Causality assessment is the systematic evaluation of the information
obtained about an AEFI to determine the likelihood of the event
having been caused by the vaccines received. It should be noted
that causality assessment is not the responsibility of the reporting
pediatrician. The causality assessment is conducted at state and
national levels by trained experts in the AEFI committees within
a month of receipt of all records and reports of the AEFI case. The
criteria for causality in the causality assessment process include
proof of temporal relationship, biological plausibility, strength
of association, consistency of association, specificity, definitive
proof that the vaccine caused the event, consideration of alternate
explanations, and prior evidence that the vaccine in question could
cause a similar event.
Step 1: Eligibility for Causality Assessment

Eligibility for causality assessment considers whether the event
occurred following vaccination, all records, and reports of case
investigation are available including a diagnosis and the suspect
Flowchart 1: Eligibility for causality assessment.
vaccine is identified. Another requirement is the availability of

definitions for the event identified (Brighton’ or other standard
literature or national definition or other approved definition). This
is a critical step to identify the event as a diagnosis if possible, or a
well-defined abnormal symptom or laboratory test finding. A valid
diagnosis is the backbone of AEFI causality assessment and must
be arrived at before doing the causality assessment. This can be a
disease/symptom/sign/laboratory finding (Flowchart 1).
Once all information is available, a causality assessment question
is proposed in the following manner:
Create your question on causality here
Has the ______ vaccine/vaccination caused ________ (The event for review in
step 2—valid diagnosis)
Keeping this question in mind, a checklist is filled which collects

information and evidence relevant for causality assessment from the
available reports and records.
The Causality Assessment Checklist (Table 3)

The information collected in the above checklist is further processed
through an algorithm for decision making and conclusion related to
causality.
TABLE 3: Causality assessment checklist.

I. Is there strong evidence for other causes? Y N UK NA Remarks
1. In this patient, does the medical history,
clinical examination and/or investigations,
confirm another cause for the event?
II. Is there a known causal association with the
vaccine or vaccination?
Vaccine product
1. Is there evidence in published peer-reviewed
literature that this vaccine may cause such an
event if administered correctly?
2. Is there a biological plausibility that this
vaccine could cause such an event?
3. In this patient, did a specific test demonstrate
the causal role of the vaccine?
Vaccine quality
4. Could the vaccine given to this patient have a
quality defect or is substandard or falsified?
Immunization error
5. In this patient, was there an error in prescribing
or nonadherence to recommendations for
use of the vaccine (e.g., use beyond the expiry
date, wrong recipient, etc.)?
6. In this patient, was the vaccine (or diluent)
administered in an unsterile manner?
7. In this patient, was the vaccine’s physical
condition (e.g., color, turbidity, presence of
foreign substances, etc.) abnormal when
administered?
8. When this patient was vaccinated, was there
an error in vaccine constitution/preparation
by the vaccinator (e.g., wrong product, wrong
diluent, improper mixing, improper syringe
filling, etc.)?
9. In this patient, was there an error in vaccine
handling (e.g., a break in the cold chain during
transport, storage and/or immunization
session, etc.)?
Contd...
Contd...
Immunization anxiety (Immunization Triggered Stress Response - ITSR)
10. In this patient, was the vaccine administered
incorrectly (e.g., wrong dose, site or route of
administration; wrong needle size, etc.)?
11. In this patient, could this event be a stress
response triggered by immunization (e.g.,
acute stress response, vasovagal reaction,
hyperventilation or anxiety)?
II (time). If “yes” to any question in II, was the event within the time window of
increased risk?
12. In this patient, did the event occur within
a plausible time window after vaccine
administration?
III. Is there strong evidence against a causal association?
1. Is there a body of published evidence
(systematic reviews, GACVS reviews, Cochrane
reviews, etc.) against a causal association
between the vaccine and the event?
IV. Other qualifying factors for classification
1. In this patient did such an event occur in the
past after administration of a similar vaccine?
2. In this patient did such an event occur in the
past independent of vaccination?
3. Could the current event have occurred in this
patient without vaccination (background rate)?
4. Did this patient have an illness, pre-existing
condition or risk factor that could have
contributed to the event?
5. Was this patient taking any medication prior to
the vaccination?
6. Was this patient exposed to a potential factor
(other than vaccine) prior to the event (e.g.,
allergen, drug, herbal product, etc.)?
(Y: yes; N: no; UK: unknown; NA: not applicable; GACVS: Global Advisory
Committee on Vaccine Safety)
Flowchart 2: Causality assessment algorithm.
The Causality Assessment Algorithm

Flowchart 2 leads to classification of cause(s) of AEFI in the following
categories:
■ A: Consistent causal association to immunization:
y A1: Vaccine product-related reaction (as per published
literature)
y A2: Vaccine quality-defect related reaction
y A3: Immunization error-related reaction
y A4: Immunization anxiety-related reaction
■ B: Indeterminate:
y B1: Temporal relationship is consistent but there is insufficient
definitive evidence for the vaccine causing the event (may be
a new vaccine-linked event—a signal which requires further
analysis/studies)
y B2: Qualifying factors result in conflicting trends of consis
tency and inconsistency with causal association to
immunization
■ C: Inconsistent causal association to immunization—coincidental
■ D: Unclassifiable (in which the specific additional information
required for classification is asked for).
Fig. 3: Causality assessment classification.
Causality Assessment Classification (Fig. 3)

The causality assessment can also be done using a WHO software
(http://gvsi-aefi-tools.org/). This is an easy to learn software and
can be used even on a single adverse event. A screen shot of the first
window of this software is given in Figure 4.
Steps after Causality Assessment

After causality assessment, the results need to be shared with all
stakeholders for taking relevant action (Table 4). In case of vaccine
product-related reactions, these events are reviewed to see whether
these events are occurring at a rate higher than expected. In such
cases, the regulator needs to be informed. For vaccine quality-
defect related reactions, further analysis is needed to find out if a
particular vaccine brand or lot is involved and the regulator and
manufacturer needs to be informed. Training and capacity building
including intensification of supervision and monitoring is required
Fig. 4: WHO software for causality assessment.
for immunization error-related reactions. When immunization

anxiety-related reactions are identified, it should be ensured that
the immunizations take place in a nonstressful environment. All
cases in the indeterminate category in B1 should be maintained
in a database and reviewed to identify a signal suggesting a new
potential causal association of vaccine with a new adverse reaction
(sign/symptom/abnormal laboratory test). Cases in B2 are followed
up for additional information which can help in making a decision
to classify into vaccine/vaccination related or coincidental.
Confirmation of classification of coincidental cases is conveyed to
the informer and the patient and relatives. For unclassifiable cases,
the specific missing information to help in classifying is to be asked
for from the districts. Other actions which can be undertaken include
changes in policies and guidelines, research in indicated areas, and
communication activities.
Involvement of Healthcare Service Providers

Often healthcare professionals, relying on experience and intuition,
are the first to suspect a medical product problem and bring it to
TABLE 4: Follow-up action after causality assessment.

Type of AEFI Follow-up action
Vaccine- If a higher reaction rate than expected is observed from a
related specific vaccine or lot, inform the immunization division
reaction who can update drug regulators to consider:
• Withdrawing that lot
• Changing manufacturing specifications or quality
control
• Obtaining vaccine from a different manufacturer
Immunization- Correcting the cause of the error. This may mean one or
related errors more of the following:
• Change in logistics for supplying vaccine
• Change in procedures at the health facility
• Training of health workers
• Intensified supervision
Whatever action is taken, it is important to review it at a
later date to check that the immunization-related errors
have been corrected
Coincidental • The main objective is to present the evidence showing
that there is no indication that the AEFI is a vaccine-
related reaction or an immunization-related error and
that the most likely explanation is a coincidental event.
This communication can be challenging when there
is widespread belief that the event was caused by
immunization
• Sometimes, it may be useful to enlist further expert
investigation to convince/ensure that the event truly
was coincidental. The potential for coincidental events
to harm the immunization program through false
attribution is immense
Source: AEFI Surveillance and Response Operational Guidelines by Ministry of
Health and Family Welfare, Government of India. 2015.7
the attention of public health and regulatory officials.6 AEFIs are to

be reported following all vaccines used for preventive use including
vaccines given in private sector, travel vaccines, etc. Other than
reporting, pediatricians and other clinicians can be members of
the AEFI committees and contribute to investigations and causality
assessments. Representatives of professional bodies such as Indian
Academy of Pediatrics (IAP) and Indian Medical Association (IMA)
as AEFI Committee Members can also help in assisting the

immunization program manager to give correct messages to the
media in times of crisis. Medical colleges and large hospitals have
huge catchment areas and can contribute to AEFI surveillance by
reporting AEFI cases to the immunization program manager.
MANAGEMENT OF ANAPHYLAXIS
Although anaphylactic reactions are rare after vaccination, their
immediate onset and life-threatening nature require that all
personnel and facilities providing vaccinations have procedures in
place for anaphylaxis management. All vaccination providers should
be familiar with the office emergency plan and be currently certified
in cardiopulmonary resuscitation. Anaphylaxis usually begins
within minutes of vaccine administration.6 Rapid recognition and
initiation of treatment is required to prevent possible progression to
cardiovascular collapse. If flushing, facial edema, urticaria, itching,
swelling of the mouth or throat, wheezing, dyspnea, or other signs
or symptoms of anaphylaxis occur, the patient should be placed in a
recumbent position with the legs elevated if possible.6 Administration
of epinephrine is the management of choice. Additional drugs also
might be indicated (Box 1). Maintenance of the airway and oxygen
administration might be necessary. After the patient is stabilized,
arrangements should be made for immediate transfer to an
emergency facility for additional evaluation and treatment.
BOX 1: Emergency management of anaphylaxis.

• Administer epinephrine (1:1,000 solution) 0.01 mL/kg/dose (maximum
0.5 mL) intramuscular (IM) in anterolateral thigh
• Set up intravenous (IV) access
• Lay patient flat and elevate legs if tolerated. Give high flow oxygen and
airway/ventilation if needed
• If hypotensive, set up additional wide bore access and give IV normal
saline 20 mL/kg under pressure over 1–2 minutes
• IM adrenaline may be repeated after 3–5 minutes if required
• Oral antihistaminics may be given to ameliorate skin symptoms but IV
antihistaminics are not recommended. Oral or injectable corticosteroids
equivalent to prednisone 1–2 mg/kg may be given but benefit is yet
unproven
HOW TO REPORT ADVERSE EVENTS FOLLOWING

IMMUNIZATIONS FROM PRIVATE SECTOR?
The majority of children in India receive immunization through
public health facilities. However, it is estimated that approximately
10–20% of total immunization is provided through private sector and
by pediatricians.7 Moreover, the vaccines that are not included in
the Universal Immunization Programme (UIP) in India are provided
by the private sector only. AEFI reporting from private sector will
provide vital information on the safety of new vaccines in India. In
rural areas, serious AEFI occurring in the clinic of a pediatrician
should be immediately reported to the medical officer in-charge of
nearest PHC or other health facility. In the urban areas, it should
be reported to either the medical officer-in-charge of nearest urban
health center or to the DIO. By all channels, the information should
reach DIO as soon as possible.2
The private practitioners (including pediatricians) should use
the “Case Reporting Form” for reporting serious AEFI cases to the
district officials. Once an AEFI is reported from private sector, the DIO
and district AEFI committee members would then investigate the
reported AEFI case. The pediatricians should help the investigation
team in collection of all the related information.2
Online AEFI Reporting Platform for

Private Practitioners
IDsurv.org is an infectious disease surveillance and AEFI reporting
system developed by IAP.
The objectives of IDsurv are:
■ To develop an early warning system for pediatric vaccine-
preventable diseases in India
■ To generate data on burden of vaccine-preventable diseases in
Indien
■ To generate data on serious AEFI in India
Members have to register on the website and create an account
with a password.
When an AEFI case is reported on IDSurv, real-time notification
is sent to IAP AEFI surveillance committee, the State EPI officer, and
to the Nodal Person in MoHFW, Government of India. Subsequently,

the Government authorities will take over the investigation of the
case.
REFERENCES
1. World Health Organization. Surveillance of Adverse Events Following
Immunization, Field guide for managers of immunization programs.
Geneva: World Health Organization; 1997.
2. Chitkara AJ, Thacker N, Vashishtha VM, Bansal CP, Gupta SG.
Adverse event following immunization (AEFI) surveillance in India,
position paper of Indian Academy of Pediatrics, 2013. Indian Pediatr.
2013;50:739-41.
3. Chen RT, Rastogi SC, Mullen JR, Hayes SW, Cochi SL, Donlon JA,
et al. The vaccine adverse event reporting system (VAERS). Vaccine.
1994;12:542-50.
4. Government of India. Adverse Events Following Immunization:
Surveillance and Response Operational Guidelines. New Delhi:
Ministry of Health and Family Welfare, Government of India; 2010.
5. Government of India. Adverse Events Following Immunization:
Surveillance and Response Standard Operating Procedures. New
Delhi: Ministry of Health and Family Welfare, Government of India;
2010.
6. National Center for Immunization and Respiratory Diseases. General
Recommendations on Immunization, Recommendations of the
Recomm Rep. 2011;60(2):1-64.
7. Government of India. Multi Year Strategic Plan (MYP) for UIP of
India 2005–10. New Delhi: Ministry of Health and Family Welfare,
Government of India; 2010.
2.7 SCHEDULING OF VACCINES

Arun Wadhwa, Harish Kumar Pemde
INTRODUCTION
Main objectives of scheduling of vaccines are to achieve maximum
effectiveness using recommended vaccines for a country while
minimizing the number of healthcare system interactions.
Epidemiological, immunological, and programmatic aspects are
taken into account while scheduling vaccines. In past two decades,
many new vaccines have been developed, vaccination schedule is
undergoing changes, and has become more complex.1 Traditionally,
the public sector in developing countries, is slow to incorporate
newer vaccines, as compared to private sector, after the vaccine
is licensed for use. Cost-effectiveness, safety, and effectiveness
for a given region are important issues for introduction of newer
vaccines. As such, vaccination schedule in public sector has lesser
number of vaccines as compared to those in the private sector. It
often becomes a matter of debate what is the best schedule, but the
knowledge of principles that go behind making each schedule will
help pediatricians to build an informed opinion.
RATIONALE FOR IMMUNIZATION

Immunized individual gets protection from disease after exposure or
infection with organism against which vaccine has been given. When
many children in a community are immunized, even unimmunized
people get protection from disease due to reduction in transmission
of infection, which is known as herd immunity. Thus, disease control
or elimination requires the induction of protective immunity in a
sufficient proportion of population that would restrict the spread of
disease or even eradicate it, as has happened with smallpox.
IDEAL IMMUNIZATION SCHEDULE

An ideal immunization schedule is dictated by various considerations
foremost being appropriate immunologic response to vaccines and
epidemiologic consideration of the vaccine-preventable diseases
(VPDs). An optimal but not necessarily the best immunological
response may be considered appropriate in a situation where risk of

contracting infection at an early age is high. Immunization schedule
at individual level and community level often varies considerably
as safety and cost-effectiveness are taken into consideration. For
public sector programs, usually it is cost first, efficacy next followed
by safety. However, at individual level, it is safety first, efficacy next
followed by cost. An ideal immunization schedule depends on the
following considerations.2
■ Immunological: Minimum age at which vaccine elicits immune
response, number of doses required, and spacing of doses
(interval between primary series and boosters if multiple doses
are required)
■ Epidemiological: Susceptibility for infection and disease. Disease
severity and mortality
■ Programmatic: Opportunity to deliver with other scheduled
interventions.
MINIMUM AGE AT WHICH THE FIRST DOSE OF

VACCINE SHOULD BE GIVEN
The minimum age, at which a vaccine should be given, is dependent
on factors which include:
■ Disease epidemiology: Protective immune response must be
achieved prior to the most vulnerable age. Most vulnerable age
may depend on the disease burden in a country, earlier when the
burden is high and vice versa.
■ Immunological responsiveness: There is limitation of antibody
responses in early life due to the limited and delayed induction
of germinal centers (GCs) in which antigen-specific B cells
proliferate and differentiate. Therefore, later the age better is the
immunological response.
■ Maternal antibodies: Maternal antibodies may exert their
inhibitory influence on immune responses up to 1 year of age
and sometimes even beyond.
■ Booster doses: Immunological principle—after initial
immunization, a booster dose is intended to increase immunity
against that antigen back to protective levels.
PRINCIPLES OF ANTIBODY VACCINE

INTERACTIONS
Inactivated antigens are generally not affected by circulating
antibody, so they can be administered before, after, or at the same time
as the antibody. Simultaneous administration of passive antibodies
(in the form of immune globulin) and vaccine is recommended for
postexposure prophylaxis of certain diseases, such as hepatitis B,
rabies, and tetanus.
Live vaccines must replicate in order to cause an immune
response. Antibodies against the injected live vaccine may interfere
with replication. If a live-injectable vaccine [measles, mumps,
and rubella (MMR), varicella, or combination measles, mumps,
rubella, and varicella (MMRV)] must be given around the time that
immunoglobulins are given, the two must be separated by enough
time so that the antibodies do not interfere with viral replication.
If the live vaccine is given first, it is necessary to wait at least 2
weeks (i.e., an incubation period) before giving the antibody. If the
antibodies are given before a dose of MMR or varicella vaccine, it is
necessary to wait until the antibody has waned (degraded) before
giving the vaccine to reduce the chance of interference by their
specific antibodies. The necessary interval between an antibody-
containing product and MMR or varicella-containing vaccine
(except zoster vaccine) depends on the concentration of antibody in
the product, but is always 3 months or longer.3
COMBINATION VACCINES
As more effective vaccines are being developed, the question of the
number of needle pricks to which the young infants are subjected
to becomes important. More vaccines may also lead to more visits
to physicians. Combination vaccines represent one solution to
the issue of increased number of injections during a single visit.
Among the traditional vaccines, diphtheria, pertussis, and tetanus
(DPT) combination was a standard for a long time, so was MMR.
Logical additions to DPT were Haemophilus influenzae type B (Hib),
injectable polio, and hepatitis B. The preservation of efficacy needs
to be evaluated by trials and monitored by post-launch surveillance
as more such combinations are on the horizon.
FACTORS THAT AFFECT THE INCLUSION OF

A NEW VACCINE IN THE NATIONAL
IMMUNIZATION PROGRAM
■ Disease (burden, severity, mortality, national security, risk of
importation, and competing priorities)
■ Recipient (age, cohort size, and vulnerability)
■ Vaccine (local production, availability, cost, efficacy, safety, and
other vaccines).
In countries still having a high burden of natural disease, disease
prevention and controlling the morbidity and mortality is the most
important objective, therefore, vaccine with highest effectiveness is
chosen for inclusion in the national program. In a country with a
low burden of natural disease, the main concerns are low or no side
effects of a new vaccine which will decide acceptance of the vaccine.
Therefore, a vaccine with a high-safety level can only be included in
their immunization schedule. The National Immunization Schedule
(UIP) is shown in Table 1.
CATCH-UP IMMUNIZATION
Missed immunization does not require restarting of the entire
series or addition of doses to the series for any vaccine in the
recommended schedule. Two or more inactivated vaccines can
be given simultaneously or at any interval between doses without
affecting the immune response. An inactivated vaccine can similarly
be given simultaneously or at any interval with a live vaccine.
However, two live (intranasal/injectable) vaccines should either
be given simultaneously or at least 4 weeks apart. If a dose of DTP,
inactivated poliovirus vaccine (IPV), Hib, pneumococcal conjugate,
hepatitis A, hepatitis B, human papillomavirus (HPV), MMR, or
varicella vaccine is missed, subsequent immunization should be
given at the next visit as if the usual interval had elapsed. For Rota
vaccine, same principle can be followed, though upper age limit of
last dose should be maintained. Minimal interval recommendation
should be followed for administration of all doses.
ADOLESCENT IMMUNIZATION
Tdap and HPV are the vaccines prescribed for adolescent immuniza-
tion in India by Indian Academy of Pediatrics (IAP) (Table 2).4
TABLE 1: National Immunization Schedule.

National Immunization Schedule for pregnant women,
infants, and children (Vaccine-wise)
Vaccine When to give Dose Route Site
For pregnant women:
Tetanus Early in 0.5 mL Intramuscular Upper arm
and adult pregnancy
diphtheria (Td)
Td-2 4 weeks after 0.5 mL Intramuscular Upper arm
Td-1
Td-booster If received 0.5 mL Intramuscular Upper arm
2 TT/Td
doses in a
pregnancy
within the
last 3 years*
For infants:
Bacillus- At birth or 0.1 mL Intradermal Left upper
Calmette as early as (0.05 mL arm
Guérin (BCG) possible till until 1
1 year of age month age)
Hepatitis Β- At birth or 0.5 mL Intramuscular Anterolateral
birth dose as early as side of mid-
possible thigh
within 24
hours
Oral polio At birth or 2 drops Oral Oral
vaccine (OPV)- as early as
0 possible
within the
first 15 days
OPV-1, 2, and 3 At 6 weeks, 2 drops Oral Oral
10 weeks and
14 weeks
(OPV can be
given till 5
years of age)
Contd...
Contd...
Pentavalent 1,At 6 weeks, 0.5 mL Intramuscular Anterolateral
2, and 3 10 weeks, side of mid-
and 14 weeks thigh
(can be given
till 1 year of
age)
Pneumococcal Two primary 0.5 mL Intramuscular Anterolateral
conjugate doses at 6 side of mid-
vaccine (PCV) and 14 weeks thigh
followed
by booster
dose at 9–
12 months
Rotavirus At 6 weeks, 5 drops Oral Oral
(RVV) 10 weeks, (liquid
and 14 weeks vaccine)
(can be given 2.5 mL
till 1 year of (lyophilized
age) vaccine)
Inactivated Three 0.1 mL Intradermal Intradermal:
polio vaccine fractional two fractional Right upper
doses at 6–14 dose arm
weeks and
9 months
Measles- 9 completed 0.5 mL Subcutaneous Right upper
rubella (MR) months– arm
1-dose 12 months.
(Measles can
be given till 5
years of age)
Japanese 9 completed 0.5 mL • Subcutane- • Left upper
encephalitis months– ous (Live- Arm (Live-
(JE)-1 12 months attenuated attenuated
vaccine) vaccine)
• Intramus- • Antero-
cular (Killed lateral
vaccine) aspect of
mid-thigh
(Killed
vaccine)
Contd...
Contd...
Vitamin A (1- At 9 1 mL (1 lakh Oral Oral
dose) completed IU)
months with
MR
For children:
Diphtheria, 16–24 0.5 mL Intramuscular Anterolateral
pertussis, and months side of mid-
tetanus (DPT) thigh
booster-1
MR-2-dose 16–24 0.5 mL Subcutaneous Right upper
months arm
OPV booster 16–24 2 drops Oral Oral
months
JE-2 16–24 0.5 mL • Subcutane- • Left upper
months ous (Live- arm (Live-
attenuated attenuated
vaccine) vaccine)
• Intramus- • Antero-
cular (Killed lateral
vaccine) aspect of
mid-thigh
(Killed
vaccine)
Vitamin A (2nd 16–18 2 mL Oral Oral
to 9th dose) months. (2 lakh IU)
Then one
dose every 6
months up to
the age of 5
years
DPT booster-2 5–6 years 0.5 mL Intramuscular Upper arm
Td 10 years and 0.5 mL Intramuscular Upper arm
16 years
*One dose if previously vaccinated within 3 years.
Note:
• Japanese encephalitis vaccine is introduced in select endemic districts after
the campaign.
• The 2nd to 9th doses of vitamin A can be administered to children 1–5 years old
during biannual rounds, in collaboration with ICDS.
TABLE 2: Indian Academy of Pediatrics immunization schedule 2020–21.
Age in completed weeks/months/years
16–18 2–3 9–14 15–18
Vaccine Birth 6w 10 w 14 w 6m 7m 9m 12 m 13 m 15 m m 18–24 m y 4–6 y y y
BCG
Hepatitis B HB 1a HB 2 HB 3 HB 4b
c c
Polio OPV IPV 1 IPV 2 IPV 3c IPV c IPVc
B1 B2
DTwP/DTaP DPT 1 DPT 2 DPT 3 DPT B1 DPT B2
Hib Hib 1 Hib 2 Hib 3 Hib B1

PCV PCV 1 PCV 2 PCV 3 PCV B
d
Rotavirus RV 1 RV 2 RV 3
Influenza Dose Dose 2 Annual Vaccination
1e
MMR Dose Dose 2 Dose 3
1
TCV
Hepatitis A Dose Dose 2f

1
Varicella Dose 1 Dose 2g
Tdaph/Td
HPV 1 & 2i 1, 2 &
3j
Contd...
Contd...
Age in completed weeks/months/years
16–18 2–3 9–14 15–18
Vaccine Birth 6w 10 w 14 w 6m 7m 9m 12 m 13 m 15 m m 18–24 m y 4–6 y y y
Meningococcalk Dose Dose
1 2
JE Dose Dose 2
1
Cholera Dose Dose 2
1
PPSV 23
Rabies
Yellow Fever
Recommended age Vaccines in special situations Catch up age range
a
Fourth dose of hepatitis B permissible for combination vaccines only
b
In case IPV is not available or feasible, the child should be offered bOPV (3 doses). In such cases, give two fractional doses of IPV at 6 weeks and 14 weeks
c
b-OPV, if IPV booster (standalone or combination) not feasible
d
Third dose not required for RV1. Catch-up to 1 year of age in UIP schedule
e
Live-attenuated hepatitis A vaccine: single dose only
f
Begin influenza vaccination after 6 months of age, about 2–4 weeks before season; give 2 doses at the interval of 4 weeks during first year and then single dose yearly
till 5 years of age
g
2nd dose of varicella vaccine should be given 3–6 months of age after dose 1. However, it can be administered anytime 3 months after dose 1 or at 4–6 years
h
Tdap should not be administered as the second booster of DPT at 4–6 years. For delayed 2nd booster, Tdap can be given after 7 years of age. A dose of Tdap is necessary
at 10–12 years, irrespective of previous Tdap administration. If Tdap is unavailable/unaffordable, it can be substituted with Td
i
Before 14 completed years, HPV vaccines are recommended as a 2-dose schedule, 6 months apart
j
From 15th year onwards and the immunocompromised subjects at all ages, HPV vaccines are recommended as a 3-dose schedule, 0–2–6 (HPV4); HPV9 is licensed till 26 years.
k
Menactra is approved in a 2-dose schedule between 9 and 23 months. Minimum interval between two doses should be 3 months. Menveo is recommended as a single
dose schedule after 2 years of age
Meningococcal vaccine (MCV): 9 months through 23 months—2 doses, at least 3 months apart; 2 years through 55 years—single dose only
Japanese Encephalitis (JE): For individuals living in endemic areas and for travelers to JE endemic areas provided their expected stay is for a minimum period of 4 weeks
General Aspects of Vaccination
HPV: 2 doses at 6 months interval 9–14 years age; 3 doses (at 0, 1–2 and 6 months) 15 years or older and immunocompromised
Cholera vaccine: Two doses 2 weeks apart for >1 year old; for individuals living in high endemic areas and travelling to areas where risk of transmission is very high
TCV: typhoid conjugate vaccine; HPV: human papilloma virus
99
WORLD HEALTH ORGANIZATION

RECOMMENDATIONS
The World Health Organization (WHO) monitors vaccination
schedules across the world, noting what vaccines are included
in each country’s program, the coverage rates achieved, and
various auditing measures.5 WHO gives broad guidelines to help
different countries prepare their vaccination schedules according
to their epidemiological needs and cost-effectiveness. Summary
of WHO position papers on recommendations for routine
immunization is regularly updated.5 WHO further subclassifies
the vaccines as: (1) recommendations for all individuals (BCG,
hepatitis B, DPT, polio, Hib, PCV, rotavirus, measles, rubella,
HPV); (2) recommendations for individuals residing in certain
regions [Japanese encephalitis (JE), yellow fever, and tick-
borne encephalitis]; (3) recommendations for individuals in
some high-risk populations (typhoid, cholera, meningococcal,
hepatitis A, and rabies); and (4) recommendations for individuals
receiving vaccinations from immunization programs with certain
characteristics (mumps and influenza).6
REFERENCES
1. History of Vaccine Schedule. (2010). Children’s Hospital of
Philadelphia. [online] Available from Vaccine History: Developments
by Year. Available at https://www.chop.edu/centers-programs/
vaccine-education-center/vaccine-history/developments-by-year.
2. Choudhury P. Scheduling of vaccine. In: Vashishtha VM, Agarwal R,
Sukumaran T (Eds). IAP Textbook of Vaccines, Indian Academy of
Pediatrics. New Delhi: Jaypee Brothers Medical Publisher; 2013.
3. Kroger AT, Robinson CL (2020). Vaccination & Immunoprophylaxis:
General Recommendations. [online] Available from https://wwwnc.
cdc.gov/travel/yellowbook/2020/preparing-international-travelers/
vaccination-and-immunoprophylaxis-general-recommendations.
4. Indian Academy of Pediatrics Committee on Immunization (IAPCOI).
Consensus recommendation on Immunization and IAP Immunization
Timetable 2012. Indian Pediatr. 2012;49:560.
5. World Health Organization. (2013). WHO vaccine-preventable

diseases: Monitoring system. 2013 global summary. [online]
Available from http://apps.who.int/immunization_monitoring/
globalsummary/schedules. https://www.who.int/southeastasia/
our-work/vaccine-preventable-disease. [Last accessed November,
2022].
6. World Health Organization. (2013). Table 1: WHO recommendations
for routine immunization. Available at https://www.who.int/
publications/m/item/table-1-who-recommendations-for-routine-
immunization. [Last accessed November, 2022].
3
Licensed Vaccines
Chapter
3.1 BACILLUS CALMETTE–GUÉRIN VACCINE

Kripasindhu Chatterjee, Shivananda S
EPIDEMIOLOGY
Mycobacterium tuberculosis is the causative agent of human
tuberculosis (TB). Other species, which can also cause disease in
humans, include Mycobacterium bovis, Mycobacterium africanum,
Mycobacterium canettii, Mycobacterium caprae, Mycobacterium
microti, and Mycobacterium pinnipedii.
Tuberculosis occurs most commonly in children <5 years. While
pulmonary tuberculosis (PTB) is the predominant form of TB in
children, extrapulmonary TB is also common (around 30–40% of
cases). Children, who develop TB disease, usually do so within 1 year
following infection and childhood TB is, therefore, an indicator of
ongoing transmission of M. tuberculosis in the community.1 Infants
and young children (especially <2 years) are at risk of developing
severe disseminated disease associated with a high rate of mortality.
In infants, the time between infection and disease can be shorter
than in older children and the presentation may be more acute,
resembling severe recurrent or persistent pneumonia where in PTB
is suspected, if there is no response to usual antibiotics.
Adolescents are at increased risk of TB, in whom sputum positive
adult type of pulmonary disease is known. They may be the source of
transmission to others.
Globally, 1.7 billion people are estimated to be infected with
M. tuberculosis and 5–15% of these individuals will develop active
TB during their lifetime.
Licensed Vaccines 103
In 2016, an estimated 10.4 million people developed active

disease, of which, about 1 million were children. 10% of them
are human immunodeficiency virus (HIV) positive. In 2016, an
estimated 253,000 children died of TB and 52,000 of them are HIV-
infected children. Globally, there were 600,000 new cases in 2016
with resistance to rifampicin of which 490,000 had multidrug-
resistant TB (MDR-TB). Only 22% of them were enrolled and were
started on MDR-TB treatment and an estimated 6.2% of those with
MDR-TB had extensively drug-resistant TB (XDR-TB). XDR-TB
patients had a treatment success rate of 30% in 2016.2 TB continues
to spread mainly in poor, crowded, and poorly ventilated settings.
HIV infection and malnutrition are complementary factors.
Tuberculosis is preventable and curable but the majority of cases
are not diagnosed, 40% of the estimated 1 million children with
TB were notified to national TB programs. Diagnosis is difficult in
children as cough and sputum production is also less common and
disease is paucibacillary. In the 1st year of primary infection, 40–60%
of children are at risk of developing a progressive disease such as
meningitis and miliary TB.3,4
PREVENTION
The United Nations (UN) sustainable development goals include
ending TB epidemics by 2030 (Goal 3). To reach this goal in 2015,
the World Health Organization (WHO) member states endorsed the
End-TB Strategy, which aims to reduce the number of TB deaths by
95% by 2035 compared to that of 2015, suggested three strategies:5
1. Pillar 1, on integrated patient-centered care and prevention,
focuses on early detection and treatment for all TB patients and
prevention. One of the components of this pillar is vaccination
against TB.
2. Pillar 2 focuses on policies and supportive systems to strengthen
health and social sectors in order to prevent and end TB.
3. Pillar 3 calls for intensified research and innovation.
Bacillus Calmette–Guérin (BCG) vaccination of infants, at birth
or as soon as possible after birth, is one of the key components
of pillar 1 of the End-TB Strategy. It has been estimated that high
global coverage (90%) and widespread use of BCG in routine infant
104 Licensed Vaccines
vaccination programs could prevent over 115,000 TB deaths per birth

cohort in the first 15 years of life. BCG vaccination is recommended
in countries or settings with a high incidence [TB notification rate
>40 TB cases (all forms) per 100,000 population per year] of TB and/
or high leprosy burden.
VACCINE
Bacillus Calmette–Guérin vaccine is one of the oldest vaccines, first
used in humans in 1921. BCG vaccine is derived from the bovine
TB strain.6 It was the result of painstaking efforts by the French
microbiologist, Albert Calmette, and the veterinary surgeon, Camille
Guerin, who performed 231 repeated subcultures over 13 years.
It continues to be the only effective vaccine against TB. The two
common strains in use are Copenhagen (Danish 1331) and Pasteur,
of which the former was produced in India at the BCG Vaccine
Laboratory, Guindy, Tamil Nadu till recently.
The vaccine contains 0.1–0.4 million live viable bacilli per
dose. It is supplied as a lyophilized (freeze-dried) preparation in
vacuum-sealed, multi-dose, amber-colored ampoules or 2 mL
vials with normal saline as diluent. The vaccine is light sensitive
and deteriorates on exposure to ultraviolet rays. In lyophilized
form, it can be stored at 2–8°C for up to 12 months without losing
its potency. Diluent, supplied with the vaccine, should be used
for reconstitution. Sterile normal saline may be used, if diluent is
not available. As the vaccine contains no preservative, bacterial
contamination and consequent toxic shock syndrome may occur,
if kept for long after reconstitution. The reconstituted vaccine
should be stored at 2–8°C, protected from light, and discarded
within 4–6 hours of reconstitution. WHO recommends that all BCG
vaccines used in immunization programs adhere to WHO standards.
BCG is currently the only available TB vaccine. Even though BCG
has demonstrated significant effectiveness, protection has not been
consistent against all forms of TB and in all age groups. BCG is not
effective when used as postexposure prophylaxis.1,7 Several new
TB candidate vaccines are in development, some of which are in
advanced clinical trials. Some are designed to be used for booster
vaccination following neonatal BCG vaccination.
Vaccine Characteristics
Bacillus Calmette–Guérin vaccine is usually administered by
intradermal injection. Correct vaccine administration technique
by a trained health worker is important to ensure correct dosage
and optimal BCG vaccine efficacy and safety. Correct intradermal
administration can be verified by formation of a wheal of 5 mm.
BCG vaccine should be injected in a clean, healthy area of skin. The
vaccine should be given preferably in the lateral aspect of the left
upper arm. The injected site usually shows no visible change for
several days. Subsequently, a papule develops after 2–3 weeks, which
increases to a size of 4–8 mm by the end of 5–6 weeks. This papule
often heals with ulceration and results in a scar after 6–12 weeks. The
ulcer at vaccination site may persist for a few weeks before formation
of the final scar. No treatment is required for this condition.
There are no details related to efficacy/effectiveness and safety
for other anatomic sites of administration. BCG vaccination usually
causes a scar at the site of injection due to local inflammatory pro
cesses. Approximately, 10% of vaccine recipients do not develop a
scar. Absence of scar formation does not indicate a failure of take of
the vaccine. The standard dose of reconstituted vaccine is 0.05 mL for
infants aged <1 month and 0.1 mL for those aged >1 month. BCG is
given till 1 year of age as per National Immunization Schedule (NIS)
and till 5 years of age as per Indian Academy of Pediatrics–Advisory
Committee on Vaccines and Immunization Practices (IAP-ACVIP).
BCG vaccine is not available in combination with other vaccines.
IMMUNOGENICITY, EFFICACY,
AND EFFECTIVENESS
BCG Vaccine Efficacy and Effectiveness
against Pulmonary Tuberculosis
The efficacy and effectiveness of BCG vaccination against TB
have been found to differ considerably between studies and
populations. An extensive systematic review and meta-analysis of 18
randomized controlled trials (RCTs) compared the incidence of PTB
in BCG vaccinated and unvaccinated participants, and of different
subgroups. Among different variables studied included: age at
vaccination, prior tuberculin skin test (TST) positivity, distance from

the equator, and study quality. Among those vaccinated as neonates,
protection against PTB was 59% [RR: 0.41, 95% confidence interval
(CI): 0.29–0.58]. In studies where BCG was given in childhood and
with stringent TST screening, protection against PTB was 74% (RR:
0.26, 95% CI: 0.18–0.37). Protective efficacy was apparently higher
in settings further away from the equator. But this higher apparent
protection against PTB in settings further from the equator was
reduced in the multivariable analysis (p < 0.054). The authors
suggested the remaining persistence of a latitudinal effect could be
due to the fact that TST screening may not exclude exposure to all
environmental mycobacteria.8
In a systematic review and meta-analysis of 12 cohort studies,
protection against PTB was found to range from 44 to 99% in 11
studies, with no protection in one study. Protection was found to
vary by age, with neonatal vaccination providing 82% protection
against PTB (RR: 0.18, 95% CI: 0.15–0.21) as compared to 64% (RR:
0.36, 95% CI: 0.30–0.42) in TST-negative schoolchildren. The same
review also evaluated eight case–control studies which revealed 54%
neonatal BCG vaccine effectiveness (VE) from seven studies (OR:
0.46, 95% CI: 0.40–0.52), but found only one study in older children,
which reported minimal protection. These observational studies of
VE, therefore, support findings from RCTs of high protection against
PTB from BCG vaccination of neonates, and moderate protection of
school-age TST-negative children.9

against Meningeal and Miliary Tuberculosis
Evidence from a meta-analysis of six RCTs indicated a high degree
of vaccine efficacy, reducing severe TB in vaccinated individuals by
85% (RR: 0.15, 95% CI: 0.08–0.31). Protection was highest for those
immunized during the neonatal period, with 90% reduction of severe
TB (RR: 0.10, 95% CI: 0.01–0.77), and among school-age children
who were TST-negative, with 92% reduction of severe disease (RR:
0.08, 95% CI: 0.03–0.25).
Vaccination of school-age children or older individuals who were
not stringently TST screened revealed little evidence of protection
against severe disease. However, the numbers of severe TB cases

were very small (0–3 cases) to be statistically relevant.8
A systematic review and meta-analysis revealed that the
incidence of TB meningitis was reduced by 73% (95% CI: 67–87%),
with higher protection in the Latin American studies (VE: 87%, 95%
CI: 78–92%) compared to Asian settings (VE 69%, 95% CI: 60–76%).
Incidence of miliary TB was reduced by 77% (95% CI: 58–87%) as
reported in four of the studies in Asia and Latin America. These
studies confirm previous evidence of high degree of protection of
BCG vaccination against severe forms of TB.10
Emerging Evidence of BCG Vaccine Protection

against Primary Infection with M. Tuberculosis
A systematic review and meta-analysis,11 conducted to examine
protective effect of BCG against primary infection by interferon-
gamma release assay (IGRA) tests, showed that BCG-vaccinated
children exposed to persons with open PTB had 19% less infection
than unvaccinated children (95% CI: 8–29).

against Other Mycobacterial Diseases
Two recent systematic reviews,12 analyzing the efficacy and VE of
BCG against leprosy, revealed that BCG was effective in preventing
leprosy, with an overall pooled RR of 0.45 (95% CI: 0.34–0.56).
Systematic review13 on effect of BCG vaccination on Buruli ulcer
and other nontuberculous mycobacterial infections showed that
BCG vaccination has ~50% efficacy (RR: 0.5, 95% CI: 0.37–0.69) in
African settings against Buruli ulcer and that BCG is protective against
nontuberculous mycobacteria (NTM) lymphadenitis in children.13-15
Nonspecific Effects of BCG including COVID-19

In observational studies, it was observed that the severity of
COVID-19 and its mortality were lesser in the countries who had
long-term national BCG vaccination policy than those who did not
or those who previously used to give BCG but have discontinued
later.16-18
The nonspecific effects of BCG vaccination, “Trained Innate

Immunity”, result from metabolic and epigenetic changes expressing
genetic regions encoding for proinflammatory cytokines, leading to
more cytokine release such as interferon-γ (IFN-γ) and interleukin-1β
(IL-1β), that play vital role in prevention of viral infection against
heterologous diseases.19-21
A study from Guinea-Bissau22 and Spain23 has shown that BCG-
vaccinated children suffered less from neonatal sepsis, respiratory
infection, and fever than those who did not receive BCG. This
lower incidence of respiratory infection was not found in children
who received vaccines other than BCG proving that the infection-
lowering effect was due to BCG itself.22
DURATION OF PROTECTION
A systematic review concluded that protection after primary infant
BCG vaccination could last for up to 15 years in some populations.9
Longer duration of protection has been reported from some western
countries.24-26
BCG REVACCINATION IN ADOLESCENTS

AND ADULTS
Different studies have shown little or no evidence of an effect of
BCG revaccination in adolescents and adults after primary BCG
vaccination in infancy, either on protection against M. tuberculosis
infection or on TB disease.27-32 However, a study in Malawi30 found
that revaccination with BCG in both children and adults conferred
an additional 49% protection (95% CI: 0–75%). Such differences
between studies and populations may reflect different patterns of
natural exposure to a variety of mycobacterial species and other
confounding factors.
VACCINE SAFETY
In general, BCG vaccination is safe.
About 95% of BCG vaccine recipients experience a reaction at
the injection site characterized by a papule which may progress to
become ulcerated, with healing after 2–5 months leaving a superficial
scar. This is considered normal.
Mild reactions are mostly local with or without regional

manifestations. Local adverse effects include abscess, injection site
reaction, lymphadenopathy, and delayed healing of the ulcer at
site of vaccination.13,33 Batch-related variation in the adverse event
following immunization (AEFI) rates has been noted.34-36
The BCG lymphadenitis is diagnosed when ipsilateral axillary,
supraclavicular, or lower cervical lymph node enlargement develops
after BCG vaccination and is severe enough to arouse significant
concern from the child care provider to seek medical attention. The
incidence of suppurative lymphadenitis due to BCG vaccination is
100–1,000 per million doses administered.
There are two forms of BCG lymphadenitis—nonsuppurative
and suppurative. The nonsuppurative form has a benign clinical
course. Generally, the lymph node does not exceed 15 mm in size, is
firm in consistency, and the lesion resolves spontaneously without
any sequelae over a period of weeks. No treatment is indicated
except a periodic reassessment. The suppurative form is marked by
the progressive enlargement of the ipsilateral regional lymph nodes
with softening, fluctuation, and overlying skin changes of induration
and erythema. If untreated, the suppuration progresses to rupture,
persistent caseous discharge, and sinus formation. Wound healing
may take takes several months (Flowchart 1).
Flowchart 1: Algorithm for management of BCG lymphadenitis.
(BCG: bacillus Calmette–Guérin; TB: tuberculosis)

Other severe complications caused by BCG are osteitis/

osteomyelitis and disseminated BCG infection, with incidence rates
of 1–700 cases, and 2 cases per 1 million vaccinations, respectively.
Disseminated BCG infection is diagnosed definitively based on
the presence of the following features:
All three of the following conditions should be met:
1. BCG cultured and identified by culture, biochemical methods
2. Dissemination evidenced by either A or B:
A. Positive blood or bone marrow culture
B. Evidence of infection at two or more anatomic sites beyond
the region of vaccination
3. A systemic syndrome compatible with mycobacterial disease,
e.g., fever, weight loss, anemia, and death.
The occurrence of disseminated BCG infection warrants
investigations for immunodeficiency states including severe
combined immunodeficiencies (SCIDs), chronic granulomatous
disease (CGD), complete DiGeorge syndrome, and Mendelian
susceptibility to mycobacterial disease (MSMD) with underlying
genetic defects, NF-kappa B essential modulator (NEMO), tyrosine
kinase 2 (TYK2), and HIV.37,38
The BCG-induced osteitis or osteomyelitis is a serious AEFI
following BCG vaccination, usually affects the long bones and
the reported incidence varies from 0.01 to 30 per million doses,
varying by batch and has a good prognosis.39 Defects of the innate
immune response should be suspected in any infant with BCG
osteitis. There are no controlled studies regarding the treatment of
BCG osteitis. Apart from surgical management, which is necessary
in most cases, chemotherapy involves using three to four anti-TB
drugs selected from the group consisting of isoniazid, rifampicin,
ethambutol, streptomycin, and clarithromycin. Pyrazinamide is
not effective against Mycobacterium bovis, and is not included in
most regimes.40
SPECIAL POPULATIONS
HIV-infected Infants
In general, populations with high prevalence of HIV infection
also have high burden of TB; in such populations, the benefits of
preventing severe TB outweigh the risks associated with the use of

BCG vaccine.
Evidence shows that children who were HIV-infected at birth and
vaccinated with BCG at birth, and who later developed AIDS, were
at increased risk of developing disseminated BCG disease. Early
initiation of antiretroviral therapy (ART), before immunological and/
or clinical HIV progression, has been shown to substantially reduce
the risk of BCG-immune reconstitution inflammatory syndrome
(BCG-IRIS) regional adenitis. Observational data from a cohort study
in South Africa with 12,748 children receiving ART who developed
lymphadenitis following BCG confirmed a low risk: 0.6%.13,41 The risk
of TB in people living with HIV is 15–22 times higher than people
without HIV.42
The HIV-exposed infants, who are asymptomatic, like all
other infants, should be given BCG at birth. If BCG has not been
given at birth, or for neonates with HIV infection confirmed by
early virological testing, BCG vaccination should be delayed
until ART has been started and the infant confirmed to be
immunologically stable (CD4 > 25%). If HIV-infected individuals,
including children, are receiving ART, are clinically well and
immunologically stable (CD4% > 25% for children aged <5 years
or CD4 count ≥200 if aged >5 years), they should be vaccinated
with BCG.43
Preterm Infants and Low-birth Weight Infants

Bacillus Calmette–Guérin vaccination at birth in healthy preterm
infants born after 32–36 weeks of gestation was found to be safe and
effective.13,44-49 Evidence from three RCTs conducted in the same high
TB-endemic setting in West Africa found that early BCG vaccination
of low birth weight (LBW) infants weighing down to ~1,500 g has
a beneficial effect on overall infant mortality; however, safety and
efficacy studies were not reported.13,50-52 For BCG vaccination of very
LBW and extremely LBW infants, there are insufficient data to assess
safety, immunogenicity, and efficacy. Based on current evidence,
early BCG vaccination is recommended in stable infants who are
preterm and/or LBW.53,54
Neonates Born to Mothers with Pulmonary TB55

Asymptomatic neonates born to mothers with bacteriologically
confirmed PTB should receive preventive treatment, if TB disease
has been excluded, and should be regularly followed to verify
absence of TB. BCG vaccination should be given at birth.
ABSENCE OF SCAR FOLLOWING NEONATAL

BCG VACCINATION
Scar failure rate following BCG neonatal vaccination of 8.6%.56 and
10% has been reported in Indian studies. In a study of 655 children,
591 (90.2%) showed presence of scar. Of 64 children who failed to
develop a scar, positive in vitro response to PPD was demonstrated
in 88.2%, 94.7% and 80% of infants who received BCG at 0–1 day,
2–30 days and 31–90 days. Thus, failure of formation of BCG scar
at the site of BCG vaccination may not necessarily imply failure
of immunization because majority of them elicit positive in vitro
lymphocyte migration inhibition (LMI) response.57
The presence of BCG scar is the only simple way of determining
previous vaccination in clinical settings as well as in health surveys
to assess vaccine uptake in spite of studies indicating that scar
development is not a reliable indicator of the immunological
response to BCG. Hence, a single repeat dose of BCG may be
administered to infants who fail to demonstrate a scar beyond
6 months of vaccination. If there is a failure of scar formation after
the second vaccination, no further doses are warranted. Pre-BCG
Mantoux test is not necessary.
The BCG vaccine can be safely coadministered with diphtheria–
pertussis–tetanus (DPT), polio, hepatitis B, Haemophilus
influenzae type b (Hib), and measles and rubella vaccines.13 There
is no evidence to suggest reduced immunogenicity, and no safety
concerns have been reported.
CONTRAINDICATIONS FOR BCG VACCINE

■ Anaphylaxis after any component of a TB vaccine
■ Children with known or suspected HIV infection, who are symp-
tomatic or have laboratory evidence of immunosuppression
■ Children on corticosteroids or other immunosuppressive

therapy, including monoclonal antibodies against tumor
necrosis factor (TNF)-alpha, such as infliximab, etanercept, and
adalimumab
■ Infants born to mothers who were treated with biologic response
modifiers in the 3rd trimester of pregnancy. These medicines
include TNF-alpha-blocking monoclonal antibodies, rituximab
■ Children people with congenital cellular immunodeficiencies,
including specific deficiencies of the interferon-γ pathway
■ Children with malignancies involving bone marrow or lymphoid
systems.
Pregnant women: BCG vaccine has not been shown to harm the
fetus, but receiving live vaccines in pregnancy is not recommended.
PRECAUTIONS
Bacillus Calmette–Guérin vaccination should be deferred in the
following groups:
■ Neonates who are medically unstable, until the neonate is in
good medical condition and ready for discharge from hospital
■ Infants born to mothers who are suspected or known to be HIV-
positive, where testing facilities are available, until HIV infection
of the infant can be confidently excluded
■ People with active skin disease such as eczema, dermatitis, or
psoriasis at or near the site of vaccination
■ People can receive BCG vaccine at any time before or after
receiving immunoglobulins or any antibody-containing blood
product.
IAP/ACVIP RECOMMENDATIONS
A single dose of BCG vaccine should be given to all healthy neonates
at birth. If missed in the neonatal period, the vaccine should be
administered at the earliest opportunity.
Bacillus Calmette–Guérin should be administered intradermally,
on the left shoulder, at the insertion of the deltoid, in a dose of 0.05 mL
to those <1 month of age and 0.1 mL in those >1 month of age.
Bacillus Calmette–Guérin can be coadministered with hepatitis B
vaccine.
Catch up vaccination can be done till 5 years of age. Pre-BCG

Mantoux test is not recommended till this age.
REFERENCES
1. Marais BJ, Gie RP, Schaaf HS, Hesseling AC, Obihara CC, Nelson LJ,
et al. The clinical epidemiology of childhood pulmonary tuberculosis:
a critical review of literature from the pre-chemotherapy era. Int J
Tuberc Lung Dis. 2004;8(3):278-85.
2. World Health Organization (WHO). (2017). Global TB Report 2017.
[online] Available from http://www.who.int/tb/publications/global_
report/en/. [Last accessed November, 2022].
3. Plotkin S, Orenstein W, Offit P, Edwards KM. Tuberculosis (and
Leprosy). Plotkin’s Vaccines, 7th edition. USA: Elsevier; 2017.
4. World Health Organization (WHO). (2017). Compendium of
WHO guidelines and associated standards: ensuring optimum
delivery of the cascade of care for patients with tuberculosis
2017. [online] Available from http://apps.who.int/iris/
bitstream/10665/259180/1/9789241512572eng.pdf. [Last accessed
November, 2022].
5. World Health Organization (WHO). (2015). The End TB Strategy.
[online] Available from http://www.who.int/tb/strategy/endtb/en/.
6. World Health Organization (WHO). (2017). Recommendations to
assure the quality, safety and efficacy of BCG vaccines. [online]
Available from http://who.int/biologicals/areas/vaccines/TRS_979_
Annex_3.pdf?ua=1. [Last accessed November, 2022].
7. Hesseling AC, Johnson LF, Jaspan H, Cotton MF, Whitelaw A, Schaaf HS,
et al. Disseminated bacille Calmette–Guérin disease in HIV-infected
South African infants. Bull World Health Organ. 2009;87(7):505-11.
8. Mangtani P, Abubakar I, Ariti C, Beynon R, Pimpin L, Fine PE, et al.
Protection by BCG vaccine against tuberculosis: A systematic review of
randomized controlled trials. Clin Infect Dis. 2014;58(4):470-80.
9. Abubakar I, Pimpin L, Ariti C, Beynon R, Mangtani P, Sterne JA,
et al. Systematic review and metaanalysis of the current evidence on
the duration of protection by bacillus Calmette–Guérin vaccination
against tuberculosis. Health Technol Assess. 2013;17(37):1-372.
10. Trunz BB, Fine P, Dye C. Effect of BCG vaccination on childhood
tuberculous meningitis and miliary tuberculosis worldwide:
a meta-analysis and assessment of cost-effectiveness. Lancet.
2006;367(9517):1173-1.
11. Roy A, Eisenhut M, Harris RJ, Rodrigues LC, Sridhar S, Habermann S,
et al. Effect of BCG vaccination against Mycobacterium tuberculosis
infection in children: systematic review and meta-analysis. BMJ.

2014;349:g4643.
12. Merle CS, Cunha SS, Rodrigues LC. BCG vaccination and leprosy
protection: review of current evidence and status of BCG in leprosy
control. Expert Rev Vaccines. 2010;9(2):209-22.
13. WHO. (2017). BCG Working Group Report, SAGE meeting October
2017. [online] Available from http://www.who.int/entity/
immunization/sage/meetings/2017/october/1_BCG_report_revised_
version_online.pdf?ua=1.55. [Last accessed November, 2022].
14. Romanus V, Hallander HO, Wåhlén P, Olinder-Nielsen AM, Magnusson
PH, Juhlin I. Atypical mycobacteria in extrapulmonary disease among
children. Incidence in Sweden from 1969 to 1990, related to changing
BCG-vaccination coverage. Tuber Lung Dis. 1995;76(4):300-10.
15. Trnka L, Danková D, Svandová E. Six years’ experience with the
discontinuation of BCG vaccination. 4. Protective effect of BCG
vaccination against the Mycobacterium avium intracellulare complex.
Tuber Lung Dis. 1994;75(5):348-52.
16. Miller A, Reandelar MJ, Fasciglione K, Roumenova V, Li Y, Otazu GH.
(2020). Correlation between universal BCG vaccination policy and
reduced morbidity and mortality for COVID-19: an epidemiological
study. MedRxiv preprint. [online] Available from https://www.
medrxiv.org/content/10.1101/2020.03.24.20042937v1. [Last accessed
November, 2022].
17. Crisan-Dabija R, Grigorescu C, Pavel C, Artene B, Popa IV, Cernomaz A,
et al. Tuberculosis and COVID-19: Lessons from the past viral outbreaks
and possible future outcomes. Can Respir J. 2020;2020:1401053.
18. Sridhara SS, Chatterjee R, Pania S. BCG Vaccine Cross-protection from
COVID-19: Statistical Study through Data Science. Turk J Computer
Math Edu. 2021;12(11):5657-67.
19. Mathurin KS, Martens GW, Kornfeld H, Welsh RM. CD4 T-Cell-
Mediated C Heterologous Immunity between Mycobacteria and
Poxviruses. J Virol. 2009;83:3528-39.
20. Netea MG, Joosten LA, Latz E, Mills KH, Natoli G, Stunnenberg HG,
et al. Trained immunity: A program of innate immune memory in
health and disease. Science. 2016;352(6284):aaf1098.
21. Kleinnijenhuis J, Quintin J, Preijers F, Benn CS, Joosten LA, Jacobs C,
et al. Long-lasting effects of BCG vaccination on both heterologous
th1/th17 responses and innate trained immunity. J Innate Immun.
2014;6:152-8.
22. Kristensen I, Aaby P, Jensen H. Routine vaccinations and child
survival: Follow up study in Guinea-Bissau, West Africa. Br Med J.
2000;321:1435-9.
23. de Castro MJ, Pardo-Seco J, Martinón-Torres F. Nonspecific

(heterologous) protection of neonatal BCG vaccination against
hospitalization due to respiratory infection and sepsis. Clin Infect Dis.
2015;60:1611-9.
24. Aronson NE, Santosham M, Comstock GW, Howard RS, Moulton LH,
Rhoades ER, et al. Long-term Efficacy of BCG Vaccine in American
Indians and Alaska Natives: A 60-Year Follow-up Study. JAMA.
2004;291(17):2086-91.
25. Nguipdop-Djomo P, Heldal E, Rodrigues LC, Abubakar I, Mangtani P.
Duration of BCG protection against tuberculosis and change in
effectiveness with time since vaccination in Norway: a retrospective
population-based cohort study. Lancet Infect Dis. 2016;16:219-26.
26. Mangtani P, Nguipdop-Djomo P, Keogh RH, Sterne JAC, Abubakar I,
Smith PG, et al. The duration of protection of school-aged BCG
vaccination in England: a population – based case-control study. Int J
Epidemiol. 2017;47(1):193-201.
27. Leung CC, Yew WW, Au KF, Tam CM, Chang KC, Mak KY, et al. A strong
tuberculin reaction in primary school children predicts tuberculosis in
adolescence. Pediatr Infect Dis J. 2012;31(2):150-3.
28. Tala-Heikkila MM, Tuominen JE, Tala EO. Bacillus Calmette-Guerin
revaccination questionable with low tuberculosis incidence. Am J
Respir Crit Care Med. 1998;157(4 Pt 1):1324-7.
29. Sepulveda RL, Parcha C, Sorensen RU. Case-control study of the
efficacy of BCG immunization against pulmonary tuberculosis in
young adults in Santiago, Chile. Tuber Lung Dis. 1992;73(6):372-7.
30. Karonga Prevention Trial Group. Randomised controlled trial of single
BCG, repeated BCG, or combined BCG and killed Mycobacterium
leprae vaccine for prevention of leprosy and tuberculosis in Malawi.
Lancet. 1996;348(9019):17-24.
31. Rodrigues LC, Pereira SM, Cunha SS, Genser B, Ichihara MY, de Brito
SC, et al. Effect of BCG revaccination on incidence of tuberculosis in
school-aged children in Brazil: the BCG-REVAC cluster-randomised
trial. Lancet. 2005;366(9493):1290-5.
32. Barreto ML, Pereira SM, Pilger D, Cruz AA, Cunha SS, Sant’Anna C,
et al. Evidence of an effect of BCG revaccination on incidence of
tuberculosis in school-aged children in Brazil: Second report of
the BCG-REVAC cluster randomised trial. Vaccine. 2011;29(31):
4875-7.
33. Nissen TN, Birk NM, Kjærgaard J, Thøstesen LM, Pihl GT, Hoffmann T,
et al. Adverse reactions to the Bacillus Calmette-Guérin (BCG) vaccine
in new-born infants-an evaluation of the Danish strain 1331 SSI in a
randomized clinical trial. Vaccine. 2016;34(22):2477-82.
34. Alrabiaah AA, Alsubaie SS, Bukhari EI, Gad A, Alzamel FA. Outbreak
of bacille Calmette-Guérin-related lymphadenitis in Saudi children at
a university hospital after a change in the strain of vaccine. Ann Saudi
Med. 2012;32(1):4-8.
35. Engelis A, Kakar M, Meikšāns R, Petersons A. BCG-SSI() vaccine-
associated lymphadenitis: Incidence and management. Medicina
(Kaunas). 2016;52(3):187-91.
36. Soh SB, Han PY, Tam KT, Yung CF, Liew WK, Tan NW, et al. Investigations
into an outbreak of suppurative lymphadenitis with BCG vaccine
SSI() in Singapore. Vaccine. 2014;32(44):5809-15.
37. Hassanzad M, Valinejadi A, Darougar S, Hashemitari SK, Velayati AA.
Disseminated bacille Calmette-Guérin infection at a glance: a mini
review of the literature. Adv Respir Med. 2019;87(4):239-42.
38. Talbot EA, Perkins MD, Silva SF, Frothingham R. Disseminated bacille
Calmette-Guérin disease after vaccination: case report and review.
Clin Infect Dis. 1997;24(6):1139-46.
39. Lotte A, Wasz-Höckert O, Poisson N, Dumitrescu N, Verron M,
Couvet E. A bibliography of the complications of BCG vaccination. A
comprehensive list of the world literature since the introduction of BCG
up to July 1982, supplemented by over 100 personal communications.
Adv Tuberc Res. 1984;21:194-245.
40. Korppi M. The sixty-year story of Finnish Bacillus Calmette-Guérin
(BCG) osteitis. Acta Paediatr. 2021;110:1119-24.
41. Rabie H, Violari A, Duong T, Madhi SA, Josipovic D, Innes S, et al.
Early antiretroviral treatment reduces risk of bacille Calmette-
Guérin immune reconstitution adenitis. Int J Tuberc Lung Dis.
2011;15(9):1194-200.
42. Sharan R, Kaushal D. Vaccine strategies for the Mtb/HIV copandemic.
NPJ Vaccines. 2020;5:95.
43. National AIDS Control Organization. (2021). National Guidelines for
HIV Care and Treatment, 2021. New Delhi: NACO, Ministry of Health
and Family Welfare, Government of India. [online] Available from
http://naco.gov.in/sites/default/files/National_Guidelines_for_HIV_
Care_and_Treatment_2021.pdf. [Last accessed November, 2022].
44. Saroha M, Faridi MMA, Batra P, Kaur I, Dewan DK. Immunogenicity
and safety of early vs delayed BCG vaccination in moderately preterm
(31–33 weeks) infants. Hum Vaccin Immunother. 2015;11(12):2864-71.
45. Dawodu AH. Tuberculin conversion following BCG vaccination in
preterm infants. Acta Paediatr Scand. 1985;74(4):564-7.
46. Thayyil-Sudhan S, Kumar A, Singh M, Paul VK, Deorari AK. Safety and
effectiveness of BCG vaccination in preterm babies. Arch Dis Child
Fetal Neonatal Ed. 1999;81(1):F64-6.
47. Camargos P, Ribeiro Y, Teixeira A, Menezes L. Tuberculin skin reactivity

after neonatal BCG vaccination in preterm infants in Minas Gerais,
Brazil, 2001–2002. Rev Panam Salud Publica. 2006;19(6):403-7.
48. Sedaghatian MR, Kardouni K. Tuberculin response in preterm infants
after BCG vaccination at birth. Arch Dis Child. 1993;69:309-11.
49. Sedaghatian MR, Hashim F, Lakshmi VV, Santhosh A, Nagelkerke N.
BCG vaccination and immune response in preterm infants: The role of
gestational age. New Emirates Medical Journal. 2009;27(3):25-8.
50. Roth A, Jensen H, Garly ML, Djana Q, Martins CL, Sodemann M,
et al. Low birth weight infants and Calmette-Guérin bacillus
vaccination at birth: community study from Guinea-Bissau. Pediatr
Infect Dis J. 2004;23(6):544-50.
51. Biering-Sørensen S, Aaby P, Lund N, Monteiro I, Jensen KJ, Eriksen
HB, et al. Early BCG-Denmark and Neonatal Mortality Among Infants
Weighing <2500 g: A Randomized Controlled Trial. Clin Infect Dis.
2017;65(7):1183-90.
52. Biering-Sørensen S, Jensen KJ, Monterio I, Ravn H, Aaby P, Benn CS.
Rapid Protective Effects of Early BCG on Neonatal Mortality among
Low Birth Weight Boys: Observations from Randomized Trials. J Infect
Dis. 2018;217(5):759-66.
53. Sudhan ST, Paul VK. BCG Vaccination: Practical Dilemmas. Indian
Pediatr. 2000;37(6):687-9.
54. Badurdeen S, Marshall A, Daish H, Hatherill M, Berkley JA. Safety
and immunogenicity of early bacillus Calmette-Guérin vaccination in
infants who are preterm and/or have low birth weights: a systematic
review and meta-analysis. JAMA Pediatr. 2019;173(1):75-85.
55. Central TB Division Ministry of Health and Family Welfare
Government of India, New Delhi. (2021). Guidelines for Programmatic
Management of Tuberculosis Preventive Treatment in India. National
TB Elimination Program. [online] Available from https://tbcindia.gov.
in/WriteReadData/l892s/Guidelines%20for%20Programmatic%20
M a n a g e m e n t % 2 0 o f % 2 0 Tu b e r c u l o s i s % 2 0 P r e v e n t i v e % 2 0
Treatment%20in%20India.pdf. [Last accessed November, 2022].
56. Dhanawade SS, Kumbhar SG, Gore AD, Patil VN. Scar formation
and tuberculin conversion following BCG vaccination in infants:
A prospective cohort study. J Family Med Prim Care. 2015;4(3):384-7.
57. Rani SH, Vijayalakshmi V, Sunil K, Lakshmi KA, Suman LG, Murthy KJ.
Cell mediated immunity in children with scar-failure following BCG
vaccination. Indian Pediatr. 1998;35(2):123-7.
3.2 POLIO VACCINE

Bhaskar Shenoy, Sunil Kumar Agarwalla
INTRODUCTION
While polio cases have fallen 99.9% since 1988, polio remains a
Public Health Emergency of International Concern (PHEIC) and
persistent barriers in reaching every child with polio vaccines and
the pandemic have contributed to an increase in polio cases. In the
year 2022, 596 cases of all forms of polio were recorded compared to
698 in 2021.1,2
In 2014, India was officially declared “Polio Free” by the World
Health Organization (WHO). India is one of the 11 countries in the
Southeast Asian region which have been certified as being free of the
wild poliovirus (WPV). This achievement makes the South-East Asia
Region, the fourth WHO Region to be certified as polio free, after the
Region of the Americas in 1994, the Western Pacific Region in 2000
and the European Region in 2002.
EPIDEMIOLOGY
Poliomyelitis is an acute infection by three poliovirus serotypes—
types 1, 2, or 3, and was the leading cause of permanent disability
in children in the past. Almost all the children used to be infected
feco-orally or oro-orally, 0.5% of the infected, developing disability.
Most epidemic and endemic cases of poliomyelitis are caused by
poliovirus type 1, followed by type 3.
At one time, poliovirus infection occurred throughout the
world. Vaccination resulted in reduced circulation of WPV and its
elimination from the United States in 1979. A polio eradication
program conducted by the Pan American Health Organization led to
elimination of polio in the Western Hemisphere in 1991.
In 1988, more than 125 countries had WPV transmission with
350,000 of paralytic polio cases. This motivated the World Health
Assembly (WHA) to take a decision to eradicate poliomyelitis by the
year 2000, and the Global Polio Eradication Initiative (GPEI) was
established. Since then, sustained use of polio vaccines was given
an impetus, leading onto a precipitous fall of paralytic poliomyelitis

cases by 99% in 2015. Type 2 and 3 WPVs have been eradicated
worldwide and endemic circulation of type 1 WPV persists only in
two countries.
Polio remains endemic in two countries—Afghanistan and
Pakistan. Globally, as of December 27, 2022, 30 cases of confirmed
polio due to wild poliovirus type 1 (WPV1)1 and 566 cases due to
circulating vaccine-derived poliovirus (cVDPV),2 from AFP cases,
have been reported this year. Incidentally, both UK and USA have
reported one case each of cVDPV, from AFP cases.4 In 2022, cVDPV
cases have been reported in 23 countries, with 482 out of the 566
cases being cVDPV2.2 Until poliovirus transmission is interrupted
in these countries, all countries remain at risk of importation of
polio, especially vulnerable countries with weak public health and
immunization services and travel or trade links to endemic countries.
The Polio Eradication Strategy for 2022–2026 outlines measures
including increased government accountability and wider use of
novel oral poliovirus vaccine type 2 (nOPV2) that are needed to
avoid new emergences of cVDPV2 during outbreak responses.3 In
2021, approximately 136 million nOPV2 doses have been released
in eight countries approved for initial use (Benin, Chad, Congo,
Liberia, Niger, Nigeria, Sierra Leone, and Tajikistan). SIAs continue
to be affected by the COVID-19 pandemic in 2021. Gradually, nOPV2
is brought into wider use to ascertain whether it can replace mOPV2.
VIRUS
Polioviruses are single-stranded ribonucleic acid (RNA)
enteroviruses of the Picornaviridae family. Polioviruses share
most of their biochemical and biophysical properties with other
enteroviruses, and are resistant to inactivation by many common
detergents and disinfectants, including soaps, but are rapidly
inactivated by ultraviolet light. Viral infectivity is stable for months at
+4°C and for several days at +30°C.
DIAGNOSIS
World Health Organization guidelines rely on acute flaccid paralysis
(AFP) cases below 15 years to identify the cases of polio. All children
with AFP should be reported and tested for WPV within 48 hours of
onset.
To test for polio, fecal specimens are analyzed for the presence of
poliovirus. Because shedding of the virus is variable, two specimens,
taken 24–48 hours apart, are required.
Since the highest concentrations of poliovirus in the stools of
infected individuals are found during the first 2 weeks after onset
of paralysis, stools samples should be collected as soon as possible.
Stool specimens must be sealed in containers and stored immedi-
ately inside a refrigerator or packed between frozen ice packs at 4–8°C
in a cold box. Undue delays or prolonged exposure to heat on the way
to the laboratory may destroy the virus. Specimens should arrive at
the laboratory within 72 hours of collection. Otherwise, they must be
frozen (at −20°C), and then shipped frozen, ideally packed with dry
ice or cold packs. The procedure is known as the “reverse cold chain”.5
All cases of AFP are investigated and clinically examined,
and stools samples are collected and subjected to virological
investigations including molecular polymerase chain reaction (PCR)
done to differentiate WPV, cVDPV, and, in addition, all discordant
poliovirus isolates are partially sequenced to determine their origin
and relatedness to other isolates. According to the laboratory results
and review by national polio expert committees, cases are further
classified as confirmed, polio-compatible, or polio-negative.6
NATURAL IMMUNITY
Normal children infected by polioviruses develop immunity
through humoral (circulating antibody) and mucosal [secretory
immunoglobulin A (IgA)] immune responses. The presence in blood
of neutralizing antibody against polioviruses indicates protective
immunity; detectable antibody is an excellent correlate of protection
against paralytic disease.5
Mucosal immunity decreases the replication and viral shedding
and acts as a potential barrier to its transmission.
VACCINES
Inactivated polio vaccine (IPV), first developed and licensed in
1955, is given by injection and is available only in trivalent form
containing the three virus serotypes PV1, PV2, and PV3. OPV as a
monovalent (mOPV) vaccine was initially licensed in 1961 followed
by a trivalent version (tOPV) in 1963. Bivalent OPV (bOPV containing
types 1 and 3 Sabin viruses) has been licensed and used in some
settings since December 2009. Following the planned global switch
from tOPV to bOPV in April 2016, tOPV is now not available. mOPV
will be stockpiled for future outbreaks.5
Oral Polio Vaccine

Oral polio vaccine (OPV) is composed of live-attenuated polioviruses
derived of their parent WPV strains by passage in nonhuman cells
to obtain the three vaccine strains (Sabin 1, 2, and 3). Attenuation
reduces its neurovirulence and transmissibility. There are several
licensed formulations of OPV: (1) mOPV1, mOPV2, or mOPV3; and
(2) bOPV containing types 1 and 3. The tOPV containing types 1, 2,
and 3 has been discontinued globally.
Seroconversion with mOPV1 is approximately threefold higher
than that of the type 1 component of tOPV. A clinical trial in India
confirmed that the antibody response to types 1 and 3 with bOPV
was superior that induced by tOPV.
WPW2 was eradicated in 1999 and to reduce the repercussions
of neurovirulent cVDPV2 and vaccine-associated paralytic
poliomyelitis (VAPP); in 2016, Strategic Advisory Group of Experts
(SAGEs) recommended the cessation of use of type 2 OPV, switch
from tOPV to bOPV, and use of mOPV2 for outbreaks response.
Oral polio vaccine is administered as two drops (~0.1 mL) directly
into the mouth. It is highly heat-sensitive and must be kept frozen
for long-term storage or, after thawing, at temperatures between
+2 and +8°C for a maximum of 6 months. Vaccine vial monitor 2
(VVM2) gives a visual indication of whether the vaccine has been
kept at the correct temperature conditions. OPV is contraindicated
in immunodeficient children. OPV should not be given to a child
who is a member of a family in which there are immunocompromised
persons to avoid the possibilities of vaccine spread.6
Immunogenicity and Effectiveness

Until recently, tOPV was the vaccine of choice by GPEI and
demonstrated its effectiveness in eradicating WPW2 from the world.
Poliomyelitis cases have declined sharply.
The ability of OPV to infect contacts of vaccine recipients (i.e.,
contact spread) and “indirectly vaccinate” these contacts against
poliomyelitis is considered by many to be another advantage of OPV
compared with IPV.
By 4–6 weeks after the OPV is given, vaccine viral shedding takes
place from the gut and upper respiratory tract and this also occurs in
nonvaccinated contacts thereby transmission of vaccine virus and
herd intestinal immunity occurs in the community. This shedding
will stop with subsequent administration of OPV by 6–8 weeks.
In high-income countries, seroconversion rates in children following
administration of three doses of tOPV approach 100% for all
three poliovirus types. However, in some developing countries, the
same three-dose course of tOPV in children was found to induce
detectable antibodies in only 73%, 90%, and 70% to poliovirus type 1,
2, and 3, respectively.7,8 In lower-income settings, the response to
OPV appears to vary, e.g., in Northern India, seroconversion rates
were relatively as low as 17–34%.9,10 The reduced antibody response
to OPV in children in low-income settings is probably due to complex
interactions between the host, e.g., levels of maternal antibody, poor
intestinal immunity in malnourished children, diarrhea at the time
of vaccination, household exposure to other OPV recipients, zinc
deficiency, the vaccine and its delivery, and the environment (e.g.,
prevalence of other enteric infectious agents). Type 2 vaccine virus
interferes with immunological responses to vaccine virus types 1 and
3; consequently, type 2 virus induces seroconversion preferentially,
and children require multiple doses of OPV in order to respond to all
three serotypes.
A dose of OPV administered at birth, or as soon as possible
after birth, can significantly improve the seroconversion rates after
subsequent doses and induce mucosal protection before enteric
pathogens can interfere with the immune response. Giving the first
OPV dose at a time when the infant is still protected by maternally
derived antibodies does not carry the risk of inducing VAPP.
Studies from India demonstrated that the birth dose increases

the levels of poliovirus neutralizing antibodies and seroconversion
rates achieved after completion of the routine vaccination schedule.8
Mucosal Immunity
Intestinal mucosal immunity, primarily mediated by locally
produced secretory IgA after live poliovirus exposure, is measured
primarily by resistance to poliovirus replication and excretion in
the pharynx and intestine after challenge with mOPV or tOPV.5 In
developing countries with inadequate hygiene and great potential
for fecal–oral spread of enteric viruses, the clear increase in mucosal
(intestinal) immunity induced by OPV over IPV would seem to offer
a major advantage to OPV in reducing the circulation of polioviruses.
A recent study in India indicated that IPV compared to OPV can
more effectively boost mucosal immunity in infants and children
with a history of multiple doses of OPV.11
Persistence of Mucosal Immunity

Recent data reveals that mucosal immunity does not last >1 year.11
Several studies have assessed resistance to oral challenge by
vaccine viruses’ years after the initial administration of OPV. One
study reported that children were completely resistant to intestinal
infection 10 years after vaccination, unless prechallenge serum
antibodies were 1:8 or lower.10
Duration of Protection
After induction of active immunity either by vaccination or exposure
to poliovirus, usually measured by circulating antibody titer,
protection against paralytic polio is almost life-long and protective
immunity will not decrease even if the antibody titers decline over
time and fall below detectable levels. Seroconversion is a reliable
correlate of immunity against paralytic disease.
Coadministration with Other Vaccines

Oral polio vaccine is usually administered concurrently with
other vaccines including bacillus Calmette–Guérin (BCG),
diphtheria, pertussis, and tetanus (DPT), hepatitis B, measles, Hib,

pneumococcal conjugate vaccine (PCV), and/or rotavirus vaccines.
While some reduction in antibody response to rotavirus vaccine has
been demonstrated when administered simultaneously with OPV,
studies have shown no decrease in protective efficacy of rotavirus
vaccine in infants receiving concurrent OPV.
Immunocompromised Persons
In a small proportion of individuals with a primary immunodeficiency
disease, OPV immunization can lead to persistent iVDPV infections,
with chronic shedding of iVDPVs that show regained neurovirulence.
Safety Issues of OPV

The main safety issues of OPV are VAPP and cVDPV.
Vaccine-associated Paralytic Poliomyelitis

Vaccine-associated paralytic poliomyelitis is paralytic polio occurring
in a vaccinee or a close contact, which is caused by a strain of polio-
virus that has genetically changed in the intestine, from the original
attenuated vaccine strain contained in OPV. VAPP is defined as:
■ A case of AFP with residual paralysis (compatible with paralytic
poliomyelitis) lasting at least 60 days
■ Occurring in an OPV recipient between 4 and 40 days after the
dose of OPV was administered
■ In a person who has had known contact with a vaccine recipient
between 7 and 60–75 days after the dose of OPV was administered
■ Isolation of vaccine-related poliovirus from any stool samples
and no isolation of WPV was frequently used as criteria.
Vaccine-associated paralytic poliomyelitis is indistinguishable
from paralytic polio caused by the wild virus. The incidence of VAPP
is around 2–4 per million births per year and epidemiologically
different in different countries. In industrialized countries, VAPP
occurs mainly in early infancy associated with the first dose of OPV
and decreases sharply (>10-fold) with subsequent OPV doses. In
lower-income countries, which experience relatively lower rates
of vaccine seroconversion, this decline is more gradual and VAPP
may occur with second or subsequent doses of OPV, with the age
distribution concentrated among children aged 1–4 years.12,13 The
contributing factors to this difference are—(1) lower immune
responsiveness to OPV and (2) higher prevalence of maternally
derived antibody in populations in low-income settings. The risk of
VAPP is one case per 2.9 million doses of OPV for children receiving
the first doses of OPV. The risk of VAPP is highest after the first dose
of OPV. Recipients of a first dose and their contacts had a 6.6-fold
higher risk of VAPP than did recipients of subsequent doses and their
contacts. The risk of VAPP, however, is lesser in India due to maternal
antibodies, birth dose of OPV, early immunization with OPV, and
most importantly lower “take” of the vaccine. A recent review
reported that the majority of recipient VAPP cases were associated
with type 3 poliovirus (42%), followed by type 2 (26%), type 1 (20%),
and mixtures of more than one virus (15%). The exact burden of
VAPP in India is not known, as VAPP is classified as nonpolio AFP.
Vaccine-derived Poliovirus
The attenuated viruses in live OPV vaccines may reacquire
neurovirulence and transmission capacity through replication
and genetic divergence effect by >1% genetic divergence [or >10
nucleotide (nt) changes] for PV1 and PV3 and >0.6% (or >6 nt
changes) for PV2. Such mutated viruses can circulate in a community
for an extended period of time and cause paralysis, which is known
as cVDPV. 90% of reported cVDPV are due to type 2 polio virus.14
Key risk factors for cVDPV emergence and spread are: (1) devel
opment of immunity gaps arising from low-OPV coverage, (2) prior
elimination of the corresponding WPV serotype, (3) emphasis on
use of mOPV and bOPV in national immunization days (NIDs) and
subnational immunization days, leading to increasing susceptibility
to type 2 in the population, and (4) insensitive AFP surveillance.
These viruses are further subdivided into three categories:
1. Circulating VDPVs, when evidence of person-to-person
transmission in the community exists
2. Immunodeficiency-associated VDPVs (iVDPVs), which
are isolated from people with primary B-cell or combined
immunodeficiency disorders
3. Ambiguous VDPVs (aVDPVs), which are either clinical isolates

from persons with no known immunodeficiency, or sewage
isolates of unknown origin.14
If the circulation of cVDPV continues to circulate for >6 months
following detection, which represents programmatic failures to
contain the cVDPV, then they are known persistent cVDPVs.14
In July 2015, the GPEI revised the definition of cVDPV to
enhance its sensitivity. 14 In the new guidelines, cVDPVs are
defined as genetically linked VDPVs isolated from: (1) at least two
individuals—not necessarily AFP cases—who are not household
contacts; (2) one individual and one or more environmental
surveillance (ES) samples; or (3) at least two ES samples if they were
collected at more than one distinct ES collection site (no overlapping
of catchment areas), or from one site, if collection was >2 months
apart, cVDPVs have lost their attenuating characters, hence they
can cause paralysis in affected persons as well as transmissibility
can replicate at normal body temperature; the reasons for cVDPVs
outbreaks are low immunization coverage in the community and
poor sanitation.
Inactivated Polio Vaccine

Inactivated polio vaccine is made from selected WPV strains,
Mahoney or Brunhilde (type 1), MEF-1 (type 2), and Saukett (type
3), or from Sabin strains and is now grown in Vero cell culture or
in human diploid cells. IPV manufacturing relies on inactivation
of cell culture-derived polioviruses with formaldehyde, in a final
formulation containing sufficient antigen units for each serotype.
IPV may contain formaldehyde, as well as traces of streptomycin,
neomycin, or polymyxin B. Some formulations of IPV contain
2-phenoxyethanol (0.5%) as a preservative for multi-dose vials. IPV
formulations do not contain thiomersal, which is incompatible with
IPV antigenicity. The vaccine should be refrigerated to preserve
potency but not frozen as this could diminish potency. IPV is
available as 10-dose, 5-dose, and single dose vials; IPV vials can be
used up to 28 days after opening the vial. IPV is also available as a
component of combination vaccines.
Safety of Inactivated Polio Vaccine

Inactivated polio vaccine is very safe, whether given alone or in
combination with other vaccines. There may be transient minor local
erythema (0.5–1%), induration (3–11%), and tenderness (14–29%).
Immunogenicity, Efficacy, and Effectiveness

Inactivated polio vaccine has been shown to be highly effective in
eliciting humoral antibody responses to poliovirus in both high-
income and low-income settings. The immunogenicity of IPV
schedules depends on the age at administration and number of
doses antigenic properties, interval age at last dose between the
doses, and due to interference by maternal antibodies. A study of
immunogenicity of a three-dose schedule in Puerto Rico found sero
conversion rates of 85.8%, 86.2%, and 96.9% for serotypes 1, 2, and 3,
respectively, on a 6-, 10-, 14-week schedule, compared with 99.6%,
100%, and 99.1% on a 2-, 4-, 6-month schedule.15 At completion of
the two-dose immunization series, seroprotection rates ranged from
89 to 100% for poliovirus type 1, from 92 to 100% for poliovirus type 2,
and from 70 to 100% for poliovirus type 3. Seroprotection rates after
three doses are clearly higher than after two, particularly when the
schedule is 2–4–6 months. However, schedules of 3–4–5 and 2–3–4
months also give good responses, although lower than after 2–4–6
months, particularly with regard to geometric mean titers (GMTs).
The humoral immunogenicity of conventional inactivated
poliovirus vaccines (cIPV) in an Expanded Programme of
Immunization (EPI) schedule appears to be superior to the use of
OPV in such schedules in developing countries. After two or three
doses in the first 6 months of life, antibody levels fall although the
vaccines usually retain seroprotective titers until the first booster is
given during the 2nd year of life, and this third or fourth injection
gives a marked anamnestic response with booster dose.
Intradermal Inactivated Polio Vaccine

Fractional doses of IPV, one-fifth of a full dose, reduce the cost
and allow immunization of a larger number of persons with a
given vaccine supply. Studies have generally demonstrated that a
single fractional dose of IPV (one-fifth of the full dose) gives lower
seroconversion rates than a full dose but after two doses, the rates
are similar to those after two full doses (Fig. 1). The median antibody
titers induced by the two fractional doses, although high, were lower
than with the two full doses. In studies in Cuba (4 and 8 months)16
and in Bangladesh (6 and 14 weeks),17 two doses of fractional-
dose IPV induced seroconversion rates of 98% and 81% to type 2
poliovirus, respectively.
The results indicate that two fractional doses of IPV provide
higher seroconversion rates than a single full dose, as shown in Cuba
(63% when given at age of 4 months) and in Bangladesh (39% when
given at age of 6 weeks). This approach, using two fractional doses
instead of one full dose, increases the immunogenicity of IPV and
can extend coverage study in India by Jacob John who, in 1990, using
the modern cIPV, demonstrated that one-fifth of the intramuscular
(IM) dose is immunogenic in humans when delivered intradermally
(ID). Several trials have shown that two consecutive doses of
Fig. 1: Comparison of two fIPV doses with one full intramuscular dose
across five studies.
fractional ID IPV compared well to one dose of full IM dose of IPV

in infants regardless of whether they received tOPV or bOPV. Type
2 seroconversion, antibody levels, and priming were similar, if not
better, after two fractional IPV doses, each one-fifth of a full dose.16-18
These data will help the countries to propose this alternate use of
IPV as a way to maximize the available, but too limited, quantities
of IPV.
In early 2016, the WHO announced a global shortage of
inactivated poliovirus vaccine. In response, WHO’s Strategic Advisory
Group of Experts on Immunization recommended that countries with
good immunization systems and coverage consider administering
two fractional inactivated poliovirus vaccine doses of 0.1 mL each ID
instead of a single, IM, full dose of 0.5 mL.19
Coadministration of OPV and IPV or Sequential

Use of IPV and OPV
IPV followed by OPV
Sequential administration of IPV followed by OPV reduces or
prevents VAPP while maintaining the high levels of intestinal
mucosal immunity conferred by OPV.3 Sequential schedules of IPV
followed by two or more doses of OPV have been used or studied
in several countries including Israel, Oman, Pakistan, UK, Hungary,
and USA. Such schedules also reduce the number of doses of IPV.
Concurrent IPV and OPV

In developing country settings, the concurrent administration of OPV
and IPV has induced uniformly high antibody responses to all three
poliovirus types, as evidenced from the studies from Thailand and
Pakistan.20,21 A single dose of IPV will effectively close immunity gaps
to poliovirus type 2 (and types 1 and 3) in previously tOPV-vaccinated
children. Two recent studies in India found that single dose of IPV in
infants and children with a history of multiple doses of OPV boosted
intestinal mucosal immunity, and prevalence of excretion reduced
by 38–76%. Sequential schedule, IPV at 2 months followed by two
doses of bOPV at 4 and 6 months, results in seroconversion rates
of >98% to poliovirus type 1, >80% to type 2, and >98% to type 3,
respectively, indicating high immunogenicity with this schedule.11
OPV Followed by IPV

A recent study in India assessed a schedule with bOPV only at
birth, 6 and 10 weeks, and bOPV + IPV at 14 weeks. This schedule,
four doses of bOPV and one dose of IPV, resulted in excellent
seroconversion rates (>99% to poliovirus type 1, 69–78% to type 2,
and >98% to type 3).4
Mucosal Immunity/Protection
In a study done in India, 6–9-month-old infants who had previously
received multiple doses of tOPV and mOPV1, were given a single
dose of cIPV. Nearly, 100% of children who were seronegative to
types 2 and 3 at the time of the dose seroconverted. In addition,
the dose of cIPV was associated with a marked boost in intestinal
immunity as documented by decreased fecal shedding following an
OPV challenge.
The cIPV vaccinees could excrete poliovirus in stools and in
nasopharyngeal secretions after challenge, which was seen as an
important disadvantage of IPV versus OPV. Subsequent observations
made it clear that cIPV-induced nasopharyngeal immunity could
limit the virus shedding from this site after challenge.
No data is available on the long-term persistence of circulating
antibodies and waning of intestinal immunity conferred by a single
IPV dose to be administered per WHO recommendations (e.g., OPV
at 6, 10, and 14 weeks along with IPV at 14 weeks) whereas it has
been shown that intestinal immunity conferred by OPV can wane.
With the switch from tOPV to bOPV1 and 3, the single dose of IPV
will be the only exposure children on this schedule have to the type
2 antigen.
A single dose of cIPV demonstrated excellent immunogenicity
and led to higher increases in antibodies to all three polio types than
did an additional dose of bOPV. There is some suggestion that a cross
(heterotypic)-priming is induced by bOPV and that a one-dose cIPV
boost is able to achieve substantial humoral and intestinal responses
against type 2 poliovirus.20
WHO recently amended strategy stated that—“The national
choice of vaccines and vaccination schedules during the
preeradication period must include OPV or IPV, or a combination
of both, and should be based on assessments of the probabilities

and consequences of WPV importation. It is clear that after
eradication of the circulation of polioviruses, the use of OPV will
have to stop”.
Countries where poor sanitation and overcrowding facilitate
the fecal–oral spread of virus, OPV is critical, because OPV induces
higher levels of intestinal immunity than IPV. IPV has an important
role because it induces high levels of individual immunity with lesser
doses than OPV and overcomes the problems of OPV by bypassing
the intestines, which can impede OPV seroconversion in developing
countries. IPV also boosts intestinal and humoral immunity in prior
OPV vaccines who have not seroconverted, particularly against
type 2 after bOPV. Thus, IPV following OPV can improve protection
against the current circulating wild virus types because it improves
on both the systemic and mucosal immunity induced by OPV. IPV
also has a major role to play in preventing VAPP and emergence and
transmission of VDPVs.
It is not possible to say when IPV usage will cease. It is
recommended that countries have to continue administering at least
one dose of IPV in their immunization programs for at least 5 years
after bOPV cessation.22
WORLD HEALTH ORGANIZATION POSITION

Vaccination with OPV Plus IPV
For all countries using OPV in the National Immunization Program,
WHO continues to recommend the inclusion of at least one dose of
IPV in the vaccination schedule. The primary purpose of this IPV
dose is to induce an immunity base that could be rapidly boosted
if there is an outbreak of polio due to poliovirus type 2 after the
introduction of bOPV2. The inclusion of IPV may reduce risks of
VAPP and also boost both humoral and mucosal immunity against
poliovirus types 1 and 3 in vaccine recipients. For polio-endemic
countries and countries at high risk for importation and subsequent
spread of poliovirus, WHO recommends a bOPV birth dose (zero
dose) followed by a primary series of three bOPV doses and at least
one IPV dose. The zero dose of bOPV should be administered at
birth or as early as possible within 7 days.23
As discussed above, two doses of fIPV at 6 and 14 weeks results

in better seroconversion rates against type 2 as compared to a single
dose of IM-IPV at 14 weeks. Moreover, the fIPV schedule is dose
sparing.
Countries with insufficient routine vaccination coverage and
which rely on supplementary immunization activities (SIAs) to
increase population immunity should continue the SIAs using bOPV
until routine coverage improves or until the globally-coordinated
withdrawal of bOPV.
Inactivated Polio Vaccine-only Schedule

An IPV-only schedule may be considered in countries with sustained
high vaccination coverage and very low risk of both WPV importation
and transmission. In situations where combination vaccines are
used, a primary series of three doses of IPV should be administered
beginning 6 weeks at 4 weeks interval along with booster dose at
15–18 months (3+1 schedule).
Sequential IPV–OPV Schedule

In countries with high vaccination coverage (e.g., 90–95%)
and low importation risk (neighboring countries and major
population movement), an IPV–bOPV sequential schedule can
be used when VAPP is a significant concern. For sequential IPV–
bOPV schedules, WHO recommends that IPV should be given at
2 months of age (e.g., a three-dose IPV–bOPV–bOPV schedule),
or at 2 months and 3–4 months of age (e.g., a four-dose IPV–IPV–
OPV–OPV schedule).
To mitigate the risk of undetected transmission, WHO
recommends that endemic countries and countries with a high
risk of WPV importation should not switch to an IPV-only or a
sequential IPV–bOPV schedule at this time. The 3 bOPV + 1 IPV
schedule as currently recommended should be adopted and SIAs
should continue to support intensive efforts to eliminate poliovirus
transmission.
Studies, examining the long-term persistence of antibodies
following IPV vaccination in the absence of a booster vaccination
given after the first 2 years of life, are lacking. Persistence of

antibodies only up to the school-entry age has been demonstrated,
as all IPV using countries recommend a school age booster. All
infant and toddler schedules result in persistence of detectable polio
antibodies at least till the school age booster with the highest titers
with the 3+1 schedule.24
A study assessing the persistence of antibodies against
diphtheria, tetanus, pertussis, poliomyelitis, and Haemophilus
influenzae type b (Hib) in 5–6-year-old French children, after
primary vaccination and first booster with a pentavalent combined
aP/wP vaccine in the 2nd year, had shown persistence of SPR but a
significant fall in antibody titers just before the preschool booster. A
booster resulted in SPR rising to 100% and GMTs rising 32–55-fold
for all the three serotypes.
There are no studies regarding the long-term persistence of
antibodies with the schedule of 6–10–14 weeks or two fractional
doses intradermal inactivated polio vaccine (ID–IPV).
Mucosal immunity to polio vaccines is important for interruption
of poliovirus transmission. It is well established that IPV is less
effective than OPV in stimulating mucosal immunity.
Some studies have suggested an inverse correlation between
circulating levels of preexisting homotypic antibodies and excretion
of poliovirus types 1, 2, and 3 following the feeding of trivalent OPV.
This association was found to be strongest for type 1 and less for types
2 and 3. Reduced excretion of type 1 was demonstrated from the
stools, with titers <1:8 having the highest excretion rates and titers
>1:128 having the lowest excretion rates.25
Advisory Committee on Vaccines and Immunization

Practice Recommendations
The Advisory Committee on Vaccines and Immunization Practices
(ACVIP) recommends a birth dose of bOPV, followed by an all IPV
schedule at 6–10–14 weeks, an IPV booster at 15–18 months, and a
second booster of IPV at 4–6 years. The second booster dose can be
given as either standalone IPV or as a combination with DPT (DTwP/
DTaP) vaccines.
The Universal Immunization Programme (UIP) recommends

two dose of fIPV at 6 and 14 weeks, to be administrated ID at the
insertion of the deltoid, on the right arm and a booster dose of fIPV
at 9 months on the left arm.
Those who have received two doses of fIPV as part of the UIP
schedule may be offered a single dose of IM-IPV at least 8 weeks after
the last dose of fIPV.
For those who have received only bOPV, one dose of IM-IPV may
be offered followed by a second dose after 8 weeks.
All children <5 years of age should receive bOPV on all SIA days.
National Immunization Days

The objective of national immunization days (NIDs) is to reduce the
widespread transmission of wild polio in the endemic countries.
The NIDs are conducted once or twice annually for a period of
1–3 days when one dose of OPV is administered to all children
<5 years of age, regardless of prior vaccination history. A second
dose may be is repeated similarly after 4–6 weeks. The NIDs usually
take place during the low transmission season for both the polio and
enteroviruses—the optimal period to interrupt the few remaining
chains of poliovirus transmission.
Mopping-up Campaigns
Mopping-up campaigns usually target children <5 years of age
wherein two doses of OPV given with an interval of 4–6 weeks.
These campaigns include house-to-house administration of OPV
with an objective to eliminate the last potential or known reservoirs
of WPV circulation, critical component to achieve interruption of
the final chains of poliovirus transmission in all polio-endemic
areas.
IMPACT OF POLIO ERADICATION PROGRAM

Stopping all Poliovirus
Today, the two countries of focus are Afghanistan and Pakistan as
they have never stopped transmission of endemic WPV.
Surveillance
Polio surveillance underpins the entire polio eradication
initiative. Without surveillance, it would be impossible to pinpoint
where and how poliovirus is still circulating. Polio surveillance
identifies new cases and detects any circulation of poliovirus.
Preparing for a Polio-free World

A polio-free world requires updated vaccination policies, including
the phased withdrawal of OPV, appropriate containment of the
poliovirus in facilities, certification that polio has been eradicated,
and planning for the transition of knowledge and infrastructure to
serve other health goals.
Various strategies are being studied to make IPV more affordable.
These include:
■ Reduce the volume of each dose: ID delivery: discussed above.
■ Reduce the antigen content of each dose by use of adjuvants: An
investigational trivalent aluminium adjuvanted IPV (IPV-Al)
vaccine, containing approximately one-tenth of the amount of each
antigen in the IPV vaccine, adjuvanted to aluminum hydroxide
(0.5 mg aluminum), was shown to be noninferior to cIPV. This
vaccine was licensed in 2019 and WHO prequalified in 2020.
■ Reduce the number of IPV doses: Studies have shown that
administration of a 2-dose IPV schedule at 6 weeks to 9 months
or 14 weeks to 9 months had ≥99% cumulative immune response
to all three PV types. Schedules that provide two early doses with
DPT1 and DPT3 may achieve higher population coverage and
higher immune response for a younger age, but schedules that
provide a second dose at least 4 months after the first will overall
achieve a higher immune response though by a later age.
■ Sabin IPV (sIPV) to reduce the cost of vaccine manufacture: The
inherent safety of the attenuated Sabin strains used in OPV
vaccines has led to use of these strains for use in manufacturing
IPV. IPV manufacture needs BSL-IV levels and hence cannot be
manufactured by Developing Countries Vaccine Manufacturers
(DCVMs), thus increasing the cost of the vaccine. Since, sIPV does
not contain WPV, it requires BSL-I–II, for manufacture, which
is available with DCVMs, so its manufacture is less expensive.
IAP recommendations.
• Polio vaccine schedule: Birth OPV, IPV 6, 10, 14 weeks, booster 1 at
18 months, booster 2 at 4–6 years.
• OPV primed/incomplete fIPV vaccinated children must be given at least
1 IM IPV at least 8 weeks after the last fIPV dose.
• bOPV schedule at birth, 6–10–14 weeks without any IPV should be
strongly discouraged.
• No child should be left without at least 1 dose of IPV.
• All IAP/UIP immunized children should receive OPV on all SIA days till
5 years of age.
REFERENCES
1. Global Wild Poliovirus 2016–2022. Available at https ://
polioeradication.org/wp-content/uploads/2022/12/weekly-polio-
analyses-WPV-20221227.pdf. [Last accessed December, 2022].
2. Global Circulating Vaccine‐derived Poliovirus (cVDPV). Available at
https://polioeradication.org/wp-content/uploads/2022/12/weekly-
polio-analyses-cVDPV-20221227.pdf. [Last accessed December, 2022].
3. Global Polio Eradication Initiative. Delivering on a promise: GPEI
strategy 2022–2026. Geneva, Switzerland: World Health Organization;
2021. https://polioeradication.org/gpei-strategy-2022–2026/external
icon.
4. Rachlin A, Patel JC, Burns CC, Jorba J, Tallis G, O’Leary A, et al.
Progress toward polio eradication — Worldwide, January 2020–April
2022. MMWR Morb Mortal Wkly Rep. 2022;71:650-5.
5. Sutter RW, Kew OM, Cochi SL. Poliovirus vaccine-live. In: Plotkin
SA, Orenstein WA, Offit PA (Eds). Vaccines, 6th edition. Philadelphia:
Elsevier-Saunders; pp. 598-645.
6. World Health Organization. (2022). Polio vaccines: WHO position
paper – June 2022. Weekly Epidemiological Record, No 25, 24
June 2022. [online] Available from https://www.who.int/teams/
immunization-vaccines-and-biologicals/policies/position-papers/
polio. [Last accessed November, 2022].
7. Bernier R. Some observations on poliomyelitis lameness surveys. Rev
Infect Dis. 1984;6(Suppl 2):S371-5.
8. Bhaskaram P, Nair KM, Hemalatha P, Murthy N, Nair P. Systemic and
mucosal immune response to polio vaccination with additional dose
in newborn period. J Trop Paediatrics. 1997;43(4):232-4.
9. Estívariz CF, Jafari H, Sutter RW, John TJ, Jain V, Agarwal A, et al.
Immunogenicity of poliovirus vaccines administered at age 6–9
months in Moradabad District, India: A randomized controlled phase

3 trial. Lancet Inf Dis. 2012;12:128-35.
10. John TJ. Immunisation against polioviruses in developing countries.
Rev Med Virol. 1993;3:149-60.
11. John J, Giri S, Karthikeyan AS, Lata D, Jeyapaul S, Rajan AK, et al.
The Duration of Intestinal Immunity After an Inactivated Poliovirus
Vaccine Booster Dose in Children Immunized With Oral Vaccine: A
Randomized Controlled Trial. J Infect Dis. 2017;215(4):529-36.
12. Platt LR, Estívariz CF, Sutter RW. Vaccine-associated paralytic
poliomyelitis: a review of the epidemiology and estimation of the
global burden. J Infect Dis. 2014;210(Suppl 1):S380-9.
13. Kohler KA, Banerjee K, Gary Hlady W, Andrus JK, Sutter RW. Vaccine-
associated paralytic poliomyelitis in India during 1999: decreased risk
despite massive use of oral polio vaccine. Bull World Health Organ.
2002;80(3):210-6.
14. Global Polio Eradication Initiative. (2016). Classification and reporting
of vaccine-derived polioviruses (VDPV) GPEI guidelines August 2016.
[online] Available from https://polioeradication.org/wp-content/
uploads/2016/09/Reporting-and-Classification-of-VDPVs_Aug2016_
EN.pdf. [Last accessed November, 2022].
15. Dayan GH, Thorley M, Yamamura Y, Rodríguez N, McLaughlin S,
Torres LM, et al. Serologic response to inactivated polio vaccine: a
randomized clinical trial comparing 2 vaccination schedules in Puerto
Rico. J Inf Dis. 2007;195:12-20.
16. Resik S, Tejeda A, Diaz M, Okayasu H, Sein C, Molodecky NA, et al.
Boosting Immune Responses Following Fractional-Dose Inactivated
Poliovirus Vaccine: A Randomized, Controlled Trial. J Infect Dis. 2017;
215(2):175-82.
17. Anand A, Zaman K, Estívariz CF, Yunus M, Gary HE, Weldon WC,
et al. Early priming with inactivated poliovirus vaccine (IPV) and
intradermal fractional dose IPV administered by a microneedle device:
A randomized controlled trial. Vaccine. 2015;33(48):6816-22.
18. Mohammed AJ, AlAwaidy S, Bawikar S, Kurup PJ, Elamir E, Shaban
MM, et al. Fractional doses of inactivated poliovirus vaccine in Oman.
N Engl J Med. 2010;362:2351-9.
19. UNICEF. Inactivated Polio Vaccine (IPV): supply update; 201918.
World Health Organization. Polio Weekly Update 27 July 2022. [online]
Available from http://www.szu.cz/uploads/Epidemiologie/POLIO/
Polio_Weekly_Update/Polio_weekly_update_2022/30_Polio_Global_
update_27Jul2022_002_.pdf. [Last accessed November, 2022].
20. John TJ, Jain H, Ravishankar K, Amaresh A, Verma H, Deshpande J,
et al. Monovalent type 1 oral poliovirus vaccine among infants in
India: report of two randomized double-blind controlled clinical trials.

Vaccine. 2011;29(34):5793-801.
21. du Chatelet IP, Merchant AT, Fisher-Hoch S, Luby SP, Plotkin SA,
Moatter T, et al. Serological response and poliovirus excretion
following different combined oral and inactivated poliovirus vaccines
immunization schedules. Vaccine. 2003;21:1710-8.
22. Zipursky S, Patel M, Farrell M, Gonzalez AR, Kachra T, Folly Y, et al.
Lessons learned from managing the planning and implementation of
inactivated polio vaccine introduction in support of the polio endgame.
J Infect Dis. 2017;216:S15-23.
23. World Health Organization. Polio eradication & endgame strategic
plan 2013–2018. Glob Polio Erad Initiat Work Draft. 2013;23:1-99.
24. Kasi SG, Shivananda S, Marathe S, Chatterjee K, Agarwalla S, Dhir SK,
et al. Indian Academy of Pediatrics (IAP) Advisory Committee on
Vaccines and Immunization Practices (ACVIP): Recommended
Immunization Schedule (2020-21) and Update on Immunization for
Children Aged 0 Through 18 Years. Indian Pediatr. 2021;58:44-53.
25. Glezen WP, McCollough RH, Lamb GA, Chin TD. Quantitative
relationship of preexisting homotypic antibodies to excretion of
poliovirus types 1, 2, and 3 following the feeding of trivalent attenuated
poliovirus vaccine. Am J Epidemiol. 1969;90:146-56.
3.3 HEPATITIS B VACCINE

BACKGROUND
Hepatitis is the main manifestation of hepatitis viral infection in
humans, is caused by five virus species—(1) hepatitis A virus (HAV),
(2) hepatitis B virus (HBV), (3) hepatitis C virus (HCV), (4) hepatitis D
virus (HDV), and (5) hepatitis E virus (HEV). Together these viruses
caused 1.34 million deaths in 2015.1 All hepatitis viruses cause
acute hepatitis; HBV frequently causes chronic hepatitis. Chronic
hepatitis can lead to cirrhosis, which may progress to hepatocellular
carcinoma (HCC), the most common type of primary liver cancer.
In India, 2–4% of individuals are chronic carriers of HBV, thus
placing India in the intermediate endemicity zone.2 Infection with
HBV may occur perinatally (vertical transmission), during early
childhood (horizontal transmission), through sexual contact, or
nosocomially. In India, 1.6–4% of the populations carry this virus in
their blood. Chronic HBV infection in India is acquired in childhood,
presumably before 5 years of age, through horizontal transmission.
It should be noted that, in our country, horizontal route (e.g., child
to child) and the vertical route (i.e., mother to child) are the major
routes of transmission of hepatitis B (HepB). The seropositivity
of HepB was found to be 2.9% among pregnant women in India.3
The risk of infection in a child born to a HepB-positive mother ranges
from 10 to 85% depending on the mother’s hepatitis B e antigen
(HBeAg) status. Younger the age of acquisition of HBV infection,
higher the chances of becoming a chronic carrier. It is believed that
as many as 90% of those who are infected at birth go on to become
chronic carriers and up to 25% of chronic carriers will die of chronic
liver disease as adults. HBV genotypes A and D are prevalent in India,
which are similar to the HBV genotypes in the West.1
Infection with HBV is one of the most important causes of
chronic hepatitis, cirrhosis of liver, and HCC. These outcomes are
all preventable by early childhood immunization. It is for this reason
that the World Health Organization (WHO) has recommended
universal HepB vaccination.4
VACCINES
Hepatitis B virus immunization before HBV exposure is the most
effective means to prevent HBV transmission. The active substance
in the HepB vaccine is the viral surface protein HBsAg (hepatitis B
surface antigen). The currently available vaccine, containing the
surface antigen of HepB, is produced by recombinant technology
in yeast and adjuvanted with aluminum salts and preserved
with thimerosal (thimerosal-free vaccines are also available).
This vaccine is available since 1986. HepB vaccine is available
as single- and multidose vials and should be stored at 2–8°C. The
vaccine should not be frozen; frozen vaccine should be discarded.
HepB vaccines are relatively heat stable. 5 HepB vaccines are
available as monovalent formulations and in combination with
other vaccines including diphtheria, tetanus, and pertussis (DTP),
Haemophilus influenzae type b (Hib), and inactivated polio vaccine
(IPV).4,5
Hepatitis B vaccine is also available in combination with hepati
tis A vaccine. Each dose of this vaccine contains 20 µg of HbsAg
and 720 EU of hepatitis A vaccine. The schedule is 0–1–6 months
for those >18 years of age.
Immunogenicity, Efficacy, and Effectiveness

The protective efficacy of HepB vaccination is related to the
induction of antibody to hepatitis B surface antigen (anti-HBs)
antibodies and the induction of memory T-cells. An anti-HBs
concentration of 10 mIU/mL measured 1–3 months after admini
stration of the last dose of the primary vaccination series is
considered a reliable correlate of protection against infection. 6
The primary three-dose vaccine series induces protective antibody
concentrations in >95% of healthy infants, children, and young
adults.4 The WHO recommends a minimum interval of 4 weeks
between the three doses. Schedules with these minimum intervals
have seroconversion rates that are similar to schedules with longer
intervals between doses, but the antibody concentrations after
completion of the schedule are lower with schedules with shorter
intervals between doses.
Dosage and Administration

The dose in children and adolescents (aged <18 years) is 0.5 mL/10 μg
and in those 18 years and older, the dose is 1 mL/20 μg. It should be
injected intramuscularly in the deltoid/anterolateral thigh.
Hepatitis B vaccines are administered intramuscularly, in the
anterolateral thigh (for children <3 years) or deltoid (for children
≥3 years). HepB administered at any site other than the deltoid or
anterolateral thigh should not be counted as valid and should be
repeated.7,8 Injections in the gluteal region should be avoided due to
low immunogenicity.
Inadvertent administration of the adult dose to a child is safe.9
The vaccine is extremely safe and well tolerated.
Interchangeability
The same brand of vaccine should be used whenever it is feasible,
particularly for the first three doses in the series.10 However,
monovalent HepB vaccine brands may be interchanged within an
immunization series.
Till additional data is available, the primary series of an acellular
pertussis-containing HepB combination vaccine should not be
interchanged, as far as feasible and the same brand should be used
for completing the series.11
Immunization Schedules
Infants
The classical schedule is 0, 1, and 6 months. The vaccine is highly
immunogenic and seroconversion rates are >90% after a three-
dose schedule. However, seroprotection rates >90% are seen with
any schedule, consisting of three doses, given at an interval of at
least 4 weeks between doses. Seroconversion rates are lower in the
elderly, the immunocompromised, and those with chronic renal
failure. Four doses at 0, 1, 2, and 12 months of double dose may
be given in these patients, although there are no specific dosage
recommendations made for children.5 Four doses may be given
for programmatic reasons and the additional dose is not harmful.
It should be noted that delaying the administration of the birth
dose to infants of chronically infected mothers increases the risk of

perinatal HBV transmission. As of now, none of the above schedules
needs a booster.
Schedules with a birth dose are necessary in all areas of high and
moderate endemicity to prevent perinatal transmission. The birth
dose should be administered as soon as possible after birth, ideally
within 24 hours. If administration within 24 hours is not feasible,
a late birth dose has some effectiveness. Although effectiveness
declines progressively in the days after birth, after 7 days, a late birth
dose can still be effective in preventing horizontal transmission and,
therefore, remains beneficial.
Antibody titers >10 mIU/mL signify a response and are considered
protective.6
The HepB vaccine series does not need to be restarted, if it was
interrupted.10
Adverse Reactions
Hepatitis B vaccines are safe. The most frequently reported side
effects are pain at the injection site in 3–29%, erythema in 3%, and
fever >37.7°C (99°F) in 1–6%.1 Administration of the first dose during
the birth hospitalization has not been associated with increased
rates of newborn sepsis evaluations.12 In a large cohort, the risk of
anaphylaxis after a HepB-containing vaccine was 1 per 1.1 million
doses [95% confidence interval (CI): 0.1–3.9].13
Contraindications
The contraindication is severe allergic reaction (e.g., anaphylaxis)
after a previous dose or to a vaccine component (e.g., yeast).
Pregnancy and lactation are not contraindications for vaccination.
The standard three-dose HepB vaccine series consists of two
priming doses administered 1 month apart and a third doses
administered 6 months after the first dose. This schedule results
in very high-antibody concentrations. The higher the peak of anti-
HBs concentrations following immunization, the longer it takes for
antibody levels to decline to ≤10 mIU/mL.6
Several studies have documented the long-term protective

efficacy of this schedule in preventing HBsAg-carrier status or
clinical HBV-disease even when the anti-HBs concentrations
decline to ≤10 mIU/mL over time. Even an absent anamnestic
response following booster vaccination may not necessarily signify
susceptibility to HBV in such individuals.14 Furthermore, observa
tional studies have shown the effectiveness of a primary series of
HepB vaccine in preventing infection up to 22 years postvaccination
of infants.5,19 Studies have shown long-term protection against
developing primary liver cancer (efficacy 84%, 95% CI: 23–97), mortal
ity from infant fulminant hepatitis (efficacy 69%, 95% CI: 34–85), and
severe end-stage liver disease (efficacy 70%, 95% CI: 15–89).15
However, HepB vaccine is a T-cell-dependent vaccine and the
titers at the end of immunization schedule may not be important so
far as it is well above the protective level. An anamnestic response
would occur, with the titers going up, should there occur contact
with the virus again in future.
Need of Boosters
Routine boosters are not needed in healthy children and adults.
Studies have shown that individuals who had responded to the
vaccination series and had levels of 10 mIU/mL after vaccination
are protected against HepB disease for life even if the levels drop
to below protective levels or are undetectable later. This is due to
immune memory. In the immunocompromised and those with
comorbidities such as chronic renal disease, levels should be checked
yearly and booster vaccination given whenever levels drop to below
protective levels. Children with cystic fibrosis, liver disease, or celiac
disease should be managed as above, as they may not respond as
well to HepB vaccine.
Coadministration
Hepatitis B vaccines do not interfere with the immune response to
any other vaccine and vice versa. The immune responses and safety
of HepB-containing combination vaccines are comparable to those
observed when the vaccines are administered separately.5
HEPATITIS B IMMUNOGLOBULIN
Hepatitis B immunoglobulin (HBIG) provides passive immunity
and is indicated along with HepB vaccine in management of
perinatal/occupational/sexual exposures to HepB in susceptible
individuals.5 The dose of HBIG in adults is 0.06 mL/kg and in
neonates/infants, 0.5 mL. HBIG should be stored at 2–8°C and should
not be frozen. HepB vaccine and HBIG should be administered at
different anatomic sites and regardless of birth weight or maternal
antiviral therapy for high HepB viral loads during pregnancy. HBIG
provides temporary protection lasting 3–6 months. HBIG should
never be given intravenously.
The HBIG is also used alone following exposure to HepB in
patients who are nonresponders to HepB vaccination (genetic
reasons/immunocompromised status). In this situation, two doses
of HBIG, 1 month apart, are indicated.
Infants who receive appropriate immunoprophylaxis may be
breastfed immediately after birth.
Prevaccination Testing
Prevaccination serological testing is not advisable as routine
practice. The WHO HBV testing guidelines recommend offering
focused testing to individuals from populations most affected by
HBV infection.5
However, in patients at high risk of HBV infection, prevaccination
serology may identify acute or chronic HBV infection or immunity to
HBV infection, preventing unnecessary vaccination. In most cases,
the first dose of vaccine should be administered immediately after
blood is obtained for serology (i.e., without waiting for results).
When serologic testing and HepB vaccination are to be performed
on the same day, blood for serology should be obtained before
immunization. Transient HBsAg positivity (<21 days) has been
reported following HepB vaccination.16
Postvaccination Testing
Serologic testing to assess antibody response to HepB vaccine
usually is not necessary for immunocompetent children and
adolescents. However, it should be performed at least 1 month after

completion of the immunization schedule, in specific populations,
including:10
■ Patients on hemodialysis
■ People with HIV infection
■ Immunocompromised patients (e.g., hematopoietic stem-cell
transplant recipients or people receiving chemotherapy)
■ People at occupational risk of exposure from percutaneous
injuries or mucosal or nonintact skin exposures (e.g., certain
healthcare and public safety workers)
■ Sexual partners of HBsAg-positive people
■ Infants born to HBsAg-positive women.
Both HBsAg and antibody to HBsAg (anti-HBs) should be
obtained after receiving ≥3 doses of HepB vaccine, at least 4 weeks
after the last dose of the HepB vaccine. Levels of anti-HBs decreases
with increasing intervals from the last dose of HepB vaccine and
hence may result in unnecessary revaccination when serology is
obtained later that showed nonprotective titers.17-19
Older Children and Adolescents

Hemodialysis Patients
Serologic testing (anti-HBs) 1–2 months after administration of the
last dose of the primary HepB vaccine series is recommended to
determine the need for revaccination.10
Annual anti-HBs testing is recommended for hemodialysis
patients and administration of a booster dose of HepB
vaccine should be done, when the anti-HBs concentration is
<10 mIU/mL.10
Immunocompromised patients: The immune response to HepB
vaccine is reduced in children who are immunocompromised.20-22
Annual testing for anti-HBs and provision of a booster dose of
HepB vaccine when anti-HBs concentration is <10 mIU/mL
are a reasonable strategy for prevention of HBV infection in
immunocompromised children and adolescents with ongoing
risk of HBV exposure and is suggested by the Advisory Committee
on Immunization Practice (ACIP) and American Academy of
Pediatrics (AAP).10
Nonresponders
Vaccine recipients who do not develop a serum anti-HBs response
(≥10 mIU/mL) after a primary vaccine series should be tested
for HBsAg to rule out the possibility of a chronic infection as an
explanation of failure to respond to the vaccine. Such individuals
should receive a 2nd series of three doses in 0–1–6 months schedule
and retested for anti-HBs response, 1–2 months after the last dose.
A nonresponder is defined as a vaccine recipient who does not
develop a serum anti-HBs response (≥10 mIU/mL) after two series
of three doses of a HepB vaccine each, administered according to
recommendations.
Such individuals should be administered two doses of HBIG,
1 month apart, after every significant exposure to HepB.
Healthy individuals in whom the lack of response appears to be
genetically determined: Immunogenetic studies have demonstrated
that certain individuals lack a dominant response gene that controls
the production of anti-HBs. The absence of this gene may be marked
by two extended human leukocyte antigen (HLA) haplotypes.23 In a
study from the United States, an increased incidence of individuals
homozygous for the extended HLA haplotype B8, SC01, and DR3
was found among nonresponders.23
Among the responders, individuals homozygous for this
haplotype developed a lower antibody level compared with
heterozygotes.
In another study of 52 nonresponders from Sweden, the HLA
haplotype (DQB1*0604; DQA1*0102DRB1*1302) was more frequent
in nonresponders.24
VACCINE-INDUCED HBV S ESCAPE MUTANTS

Hepatitis B virus S gene mutants have been described in infants who
were infected with HBV despite an adequate anti-HBs response to
HepB vaccination. These mutants have been observed in many parts
of the world including China, Singapore, Taiwan, Japan, Italy, and
Africa.25
The most common mutation involves a glycine to arginine
substitution at codon 145 in the “a” determinant of HBsAg. This
mutation decreases binding of HBsAg to anti-HBs and may explain
why these infants develop “escape” infection.26,27
Most reports found that the HBV S mutations were not detected
in the maternal carriers, suggesting that the mutations were selected
by immune pressure (vaccine and/or HBIG).28
The benefits of conventional HepB vaccine far outweigh the
concerns of HBV S escape mutants, and vaccination programs
should not be deterred because of these concerns. There is clearly a
need for further research to develop vaccines that are more effective
and capable of circumventing these mutations.
Management of an Infant Born to

Hepatitis B-positive Mother29
The risk of perinatal transmission among infants born to HBsAg-
positive mothers is as high as 90% without immunoprophylaxis.29,30
Pregnant women should be counseled and encouraged to opt for
HBsAg screening. If the mother is known to be HBsAg negative,
HepB vaccine can be given in the recommended schedule. If the
mother’s HBsAg status is not known, it is important that HepB
vaccination should begin within a few hours of birth so that perinatal
transmission can be prevented.
If the mother is HBsAg positive (and especially HBeAg positive),
the baby should be given HBIG along with HepB vaccine within
12 hours of birth, using two separate syringes and separate sites
for injection at the same time (i.e., same day, same clinic visit).30
The injections may be administered in any order. There is no
minimum interval between administration of HepB vaccine and
HBIG, if they are not administered at the same time.
The dose of HBIG is 0.5 mL intramuscular. HBIG may be given
up to 7 days of birth but the efficacy of HBIG after 48 hours is not
known. Three more doses of HepB vaccine should be administered
at 6–10–14 weeks as part of combination vaccines.
If HBIG is not available (or is unaffordable), HepB vaccine may
be given at 0, 1, and 2 months with an additional dose between
9 months and 12 months. The efficacy of prophylaxis with both
HBIG and HepB vaccine is 85–95% and that with HepB vaccine alone
(first dose at birth) is 70–75%.31 All infants born to HBsAg-positive
mothers should be tested for HBsAg and anti-HBsAg antibodies
at the age of 9–15 months to identify carriers/nonresponders.32
Following neonatal administration of HBIG and HepB vaccination in
the first 4–6 months of age, the ideal time to perform serology is after
9 months of age, because HBIG may still be present in the blood, if
done earlier and may result in detection of HBIG and not the anti-
HBs produced by the baby. It should not be performed sooner than
4 weeks after the last dose of HepB vaccine because of the possibility
of transient (<21 days) HBsAg-positivity related to the vaccine.16
In case of infants born to HbsAg-positive mothers, who received
HBIG and the complete schedule of HepB vaccine, postvaccination
serology [both HBsAg and antibody to HBsAg (anti-HBs)] should be
obtained usually at 9–12 months of age, because HBIG may still be
present in the blood and, if done earlier, may result in detection of
HBIG and not the anti-HBs produced by the baby.10
Infants who are HBsAg-positive at any time during
postvaccination testing should be referred for evaluation of chronic
liver disease. Household contacts who have not been vaccinated
against HBV should be vaccinated.
Infants who are HBsAg-negative and have anti-HBs concentration
≥10 mIU/mL are immune to HBV. Additional doses of HepB vaccine
and serologic testing are not necessary.
Infants whose anti-HBs is <10 mIU/mL remain susceptible to
HBV. For infants who remain susceptible after the primary infant
series, the recommendation is to administer three doses of HepB
vaccine (at 0, 1–2, and 6 months) followed by measurement of anti-
HBs and HBsAg 1–2 months after the third dose.
The HBsAg-negative children whose anti-HBs levels remain
<10 mIU/mL after two complete series of HepB vaccines are
considered to be “nonresponders” and susceptible to HBV.
Available data do not suggest a benefit from additional doses of
HepB vaccine.19
Caregivers of nonresponders should receive information about
precautions to prevent HBV infection, and the nonresponders
should receive appropriate postexposure prophylaxis, if they are
exposed (HBIG: 0.06 mL/kg, to be given within 72 hours and a repeat
dose after 1 month).33
In a meta-analysis of three randomized trials, compared with
placebo/no intervention, the combination of HepB vaccine and
HBIG reduced HBV infection in infants born to HBsAg-positive
women [4% vs. 57%, relative risk (RR) 0.08, 95% CI: 0.03–0.17].34
IMMUNIZATION OF PRETERM INFANTS

Preterm infants and low-birth weight infants with birth weight
<2,000 g have a decreased response to HepB vaccines administered
before the age of 1 month. However, by the chronological age of
1 month, preterm babies irrespective of their initial birth weight
and gestational age are likely to respond as adequately as full-term
infants (Table 1).4,5,32
TABLE 1: Hepatitis B immunization management of preterm infants

weighing <2,000 g, by maternal hepatitis B surface antigen (HBsAg) status.
Maternal
HBsAg status Recommendation
Positive • Administer HBIG + single-antigen hepatitis B vaccine
within 12 hours of birth
• Do not count the birth dose as part of the vaccine
series
• Administer three additional hepatitis B vaccine doses at
6, 10, and 14 weeks
• Test for HBsAg and antibody to HBsAg 1–2 months
after completion of >3 doses of a licensed hepatitis B
vaccine series (i.e., at age 9–18 months, generally at the
next well-child visit). Testing should not be performed
before the age of 9 months nor within 4 weeks of the
most recent vaccine dose
Unknown • Administer HBIG + single-antigen hepatitis B vaccine
• Test mother for HBsAg
• Do not count the birth dose as part of the vaccine
series
• Administer three additional hepatitis B vaccine doses at
6, 10, and 14 weeks
Negative A birth dose of hepatitis B vaccine can be given to low
birth weight and premature infants. For these infants,
the birth dose should not be counted as part of the
primary three-dose series; the three doses of the standard
primary series should be given according to the national
vaccination schedule
(HBIG: hepatitis B immunoglobulin)
Recommendations for Preterm Infants

A birth dose of HepB vaccine can be given to low birth weight and
premature infants. For these infants, the birth dose should not be
counted as part of the primary three-dose series; the three doses
of the standard primary series should be given according to the
national vaccination schedule.
PATIENTS WITH CHRONIC RENAL FAILURE

Patients suffering from chronic renal failure are at particular risk
of infection with HBV, since they may need hemodialysis. These
patients have been offered schedules that include more than three
doses of the standard vaccine, or vaccine containing a higher dose of
HBsAg (e.g., double the usual adult dose) on each occasion, or both.5
HEALTHCARE WORKERS
Hepatitis B vaccination should be routinely offered to persons in
high-risk settings that include healthcare workers, public safety
workers, trainees in blood or blood-contaminated body fluid,
healthcare fields in schools of medicine, dentistry, nursing,
laboratory technology, and other allied health professions.35
Adults with risk factors for HBV infection can begin and should
be administered on a 0, 1, and 6 months schedule. An accelerated
schedule may be required as dose 1 of the series at any visit, dose 2 at
least 4 weeks after dose 1, and dose 3 at least 8 weeks after dose 2 and
at least 16 weeks after dose 1.
POSTEXPOSURE PROPHYLAXIS TO PREVENT

HEPATITIS B VIRUS INFECTION IN EXPOSED
HEALTHCARE PERSONNEL
Healthcare personnel (HCP) are defined as persons (including
nonmedical employees, students, medical personnel, public-safety
workers, or volunteers) whose occupational activities involve
contact with patients or with blood or other body fluids from
patients in a healthcare, laboratory, or public-safety setting. 32
HepB vaccine should be offered to all HCP who have a reasonable
expectation of being exposed to blood and body fluids on the job.
It is preferable that medical students and trainees be offered the

vaccine, as exposure is more common during the training period.
All HCP, including trainees, who have direct patient contact
or who draw, test, or handle blood specimens should have
postvaccination testing for anti-HBs. Postvaccination testing
should be done 1–2 months after the last dose of vaccine. For
immunocompetent HCP, periodic testing or periodic boosting is
not needed.
An exposure that might place HCP at risk for HBV infection
includes percutaneous injuries (e.g., a needlestick or cut with a
sharp object) or contact of mucous membrane or nonintact skin
with blood, tissue, or other body fluids that are potentially infectious.
In addition, HBV has been demonstrated to survive in dried
blood at room temperature on environmental surfaces for at least
1 week. The risk of HBV infection in the exposed HCP is primarily
related to the degree of contact with blood in the workplace and also
to the HBeAg status of the source person.
Following a percutaneous or mucosal exposure to blood,
three factors need to be considered when deciding the nature of
postexposure prophylaxis (PEP). These include:
■ HBsAg status of the source
■ Vaccination status of the exposed HCP
■ Vaccination response status of the HCP.
The PEP recommendations are given in Table 2.
TABLE 2: Recommendations for postexposure prophylaxis after per

cutaneous or mucosal exposure to HBV in HCP.
Vaccination Treatment
and antibody Source is
response status of Source is HBsAg HBsAg Source is unknown on
exposed persons* positive negative not tested
Unvaccinated HBIG† × 1 and Begin a If the source is suspec
begin a hepatitis hepatitis ted to be high risk, refer
B vaccine series B vaccine to the column “source
series is HBsAg positive.” If
not, begin a hepatitis B
vaccine series
Contd…
Contd…
Vaccination and Treatment

antibody response Source is
status of exposed Source is HBsAg Source is unknown on
persons* HBsAg positive negative not tested
Fully vaccinated No treatment No treatment No treatment
and known
responder‡
Vaccinated with HBIG† × 1 No treatment If the source is suspec
three doses and begin a ted to be high risk, refer
and known hepatitis B to the column “source
nonresponder‡ revaccination is HBsAg positive.” If
series§ not, begin a hepatitis B
revaccination series
Vaccinated with six HBIG†,|| × 2 No treatment Treat based on known
doses and known or suspected risk of
nonresponder source
Fully vaccinated Test for anti- No treatment • If the source is
with three doses HBs¶: suspected to be
but antibody titer • If adequate,‡ high risk, refer to
unknown no treatment the column “source
• If inade- is HBsAg positive.” If
quate, HBIG† not, test for anti-HBs¶
× 1 and • If adequate,‡ no treat-
hepatitis B ment, if inadequate,
vaccine give vaccine booster
booster and check anti-HBs
in 1–2 months
*
ersons known to have had HBV infection in the past or who are chronically
P
infected do not require HBIG or vaccine.
†
Hepatitis B immunoglobulin (0.06 mL/kg) administered IM.
‡
Adequate response is anti-HBs of at least 10 mIU/mL after vaccination.
§
Revaccination = additional three-dose series of hepatitis B vaccine administered
after the primary series.
||
First dose as soon as possible after exposure and the second dose 1 month later.
¶
Testing should be done as soon as possible after exposure.
(anti-HBs: antibody to hepatitis B surface antigen; HBIG: hepatitis B immuno
globulin; HBV: hepatitis B virus; HCP: healthcare personnel; IM: intramuscular)
Source: Adapted from Centers for Disease Control and Prevention. Updated U.S.
PHS Guidelines for the Management of Occupational Exposures to HBV, HCV,
and HIV and Recommendations for Postexposure Prophylaxis. MMWR. 2001;
50(RR-11):8.
IAP/ACVIP Recommendations for Use

Individual Use
All infants, irrespective of the birth weight or gestational age, should
be administered the first dose of HBV within 24 hours and three
more doses along with combination vaccines at 6–10–14 weeks.
The Indian Academy of Pediatrics (IAP) Advisory Committee
on Vaccines and Immunization Practices (ACVIP) committee
stresses the significance and need of a birth dose (within
12–24 hours). The birth dose can reduce perinatal transmission by
18–40%.
Catch-up Vaccination
Hepatitis B vaccine as a 0–1–6 schedule should be offered to all
children/adolescents who have not been previously vaccinated
with HepB vaccine or whose vaccination status is not known
or where the administration was inappropriate. Prevaccination
screening with anti-HBsAg antibody is not cost-effective and is not
recommended.
Catch-up vaccination is particularly important for contacts of
HBsAg-positive patient. Prevaccination screening for HBsAg should
be done in these contacts. All available brands of HepB vaccine are
equally safe and effective and any may be used.
All infants, irrespective of the birth weight or gestational age, of
HBsAg-positive mothers, should receive HBIG 0.5 mL IM followed
by the first dose of HepB vaccine, within 12 hours of birth (HBIG
and vaccine should be administered on different limbs), followed
by three doses of a HepB containing combination vaccine at
6–10–14 weeks. Postvaccination testing for HBsAg and anti-HBs
should be done at 9–12 months of age.
PUBLIC HEALTH PERSPECTIVES

Hepatitis B vaccination is great public health significance. Though
the Government of India (GoI) initiated HepB vaccination since
2002, the IAP–ACVIP believes that all infants should receive their
first dose of HepB vaccine as soon as possible after birth, preferably
within 24 hours. In countries where there is high disease endemicity

and where HBV is mainly spread from mother to infant at birth
or from child to child during early childhood, providing the first
dose at birth is particularly important, but even in countries where
there is intermediate endemicity or low endemicity, an important
proportion of chronic infections are acquired through early
transmission.4
Delivery of HepB vaccine within 24 hours of birth should be a
performance indicator for all immunization programs, and reporting
and monitoring systems should be strengthened to improve the
quality of data on the birth dose.
REFERENCES
1. Global Hepatitis Report, World Health Organization, Geneva: 2017.
Available from http://apps.who.int/iris/bitstream/10665/255016/1/
9789241565455-eng.pdf?ua=1, [Last accessed May, 2017].
2. Acharya SK, Madan K, Dattagupta S, Panda SK. Viral hepatitis in India.
Natl Med J India. 2006;19:203-17.
3. Mehta KD, Antala S, Mistry M, Goswami Y. Seropositivity of hepatitis B,
hepatitis C, syphilis, and HIV in antenatal women in India. J Infect Dev
Ctries. 2013;7:832-7.
4. Hepatitis B vaccines. WHO Position Paper. Weekly Epidemiological
Record, No 27. 2017.
5. Damme PV, Ward J, Shouval D, Zanetti A. Hepatitis B vaccines. In:
Plotkin SA, Orenstein WA, Offit PA (Eds). Vaccines, 6th edition,
Philadelphia: Saunders Elsevier; 2016.
6. Jack AD, Hall AJ, Maine N, Mendy M, Whittle HC. What level of hepatitis
B antibody is protective? J Infect Dis. 1999,179:489-92.
7. Shaw FE Jr, Guess HA, Roets JM, Mohr FE, Coleman PJ, Mandel EJ,
et al. Effect of anatomic injection site, age and smoking on the immune
response to hepatitis B vaccination. Vaccine. 1989;7:425.
8. Cook IF, Murtagh J. Comparative immunogenicity of hepatitis B
vaccine administered into the ventrogluteal area and anterolateral
thigh in infants. J Paediatr Child Health. 2002;38:393.
9. Immunization Action Coalition. Ask the Experts: Diseases & Vaccines.
Hepatitis B. http://www.immunize.org/askexperts/experts_hepb.
asp#recommendations. [Last accessed July, 2016].
10. Schillie S, Vellozzi C, Reingold A, Harris A, Haber P, Ward JW, et al.
Prevention of Hepatitis B Virus Infection in the United States:
Recommendations of the Advisory Committee on Immunization

Practices. MMWR Recomm Rep. 2018;67:1.
11. Langley JM, Halperin SA, Rubin E, White C, McNeil S, Mutch J, et al.
Safety and immunogenicity of 2 mixed primary infant immunization
schedules of pentavalent diphtheria, tetanus, acellular pertussis,
inactivated poliomyelitis, and Haemophilus influenzae Type B
vaccines at 2, 4, and 6 months of age: a randomized controlled trial.
Pediatr Infect Dis J. 2012;31:189.
12. Lewis E, Shinefield HR, Woodruff BA, Black SB, Destefano F, Chen RT,
et al. Safety of neonatal hepatitis B vaccine administration. Pediatr
Infect Dis J. 2001;20:1049.
13. Bohlke K, Davis RL, Marcy SM, Braun MM, DeStefano F, Black SB,
et al. Risk of anaphylaxis after vaccination of children and adolescents.
Pediatrics. 2003;112:815.
14. Schönberger K, Riedel C, Rückinger S, Mansmann U, Jilg W, Kries RV.
Determinants of Long-term protection after hepatitis B vaccination in
infancy: a meta-analysis. Pediatr Infect Dis J. 2013; 32:307.
15. Qu C, Chen T, Fan C, Zhan Q, Wang Y, Lu J, et al. Efficacy of neonatal
HBV vaccination on liver cancer and other liver diseases over 30-year
follow-up of the Qidong hepatitis B intervention study: a cluster
randomized controlled trial. PLoS Med. 2014;11:e1001774.
16. Kloster B, Kramer R, Eastlund T, Grossman B, Zarvan B. Hepatitis
B surface antigenemia in blood donors following vaccination.
Transfusion. 1995;35:475.
17. Euler GL, Copeland JR, Rangel MC, Williams WW. Antibody response
to postexposure prophylaxis in infants born to hepatitis B surface
antigen-positive women. Pediatr Infect Dis J. 2003;22:123.
18. Lolekha S, Warachit B, Hirunyachote A, Bowonkiratikachorn P, West
DJ, Poerschke G. Protective efficacy of hepatitis B vaccine without
HBIG in infants of HBeAg-positive carrier mothers in Thailand.
Vaccine. 2002;20:3739-43.
19. Centers for Disease Control and Prevention (CDC). Postvaccination
serologic testing results for infants aged ≤24 months exposed to
hepatitis B virus at birth: United States, 2008-2011. MMWR Morb
Mortal Wkly Rep. 2012;61:768.
20. Polychronopoulou-Androulakaki S, Panagiotou JP, Kostaridou S,
Kyratzopoulou A, Haidas S. Immune response of immunocompromised
children with malignancies toa recombinant hepatitis B vaccine.
Pediatr Hematol Oncol. 1996;13:425.
21. Zuin G, Principi N, Tornaghi R, Paccagnini S, Re M, Massironi E, et al.

Impaired response to hepatitis B vaccine in HIV infected children.
Vaccine. 1992;10:857.
22. Aljaberi N, Ghulam E, Smitherman EA, Favier L, Dykes DMH,
Danziger-Isakov LA, et al. Maintaining hepatitis B protection in
immunocompromised pediatric rheumatology and inflammatory
bowel disease patients. J Rheumatol. 2021;48(8):1314-21.
23. Alper CA, Kruskall MS, Marcus-Bagley D, Craven DE, Katz AJ, Brink SJ,
et al. Genetic prediction of nonresponse to hepatitis B vaccine. N Engl
J Med. 1989;321:708.
24. Langö-Warensjö A, Cardell K, Lindblom B. Haplotypes comprising
subtypes of the DQB1*06allele direct the antibody response after
immunisation with hepatitis B surface antigen. Tissue Antigens.
1998;52:374.
25. Zuckerman AJ. Effect of hepatitis B virus mutants on efficacy of
vaccination. Lancet. 2000;355(9213):1382-4.
26. Ghany MG, Ayola B, Villamil FG, Gish RG, Rojter S, Vierling JM,
et al. Hepatitis B virus S mutants in liver transplant recipients who
were reinfected despite hepatitis B immune globulin prophylaxis.
Hepatology. 1998;27:213.
27. Carman WF, Trautwein C, van Deursen FJ, Colman K, Dornan E,
McIntyre G, et al. Hepatitis B virus envelope variation after trans
plantation with and without hepatitis B immune globulin prophylaxis.
Hepatology. 1996;24:489.
28. Kajiwara E, Tanaka Y, Ohashi T, Uchimura K, Sadoshima S, Kinjo M,
et al. Hepatitis B caused by a hepatitis B surface antigen escape mutant.
J Gastroenterol. 2008;43:243.
29. Stevens CE, Beasley RP, Tsui J, Lee WC. Vertical transmission of
hepatitis B antigen in Taiwan. N Engl J Med. 1975;292:771.
30. Nelson NP, Jamieson DJ, Murphy TV. Prevention of Perinatal Hepatitis
B Virus Transmission. J Pediatric Infect Dis Soc. 2014;3 Suppl 1:S7.
31. Assateerawatt A, Tanphaichitr VS, Suvatte V, Yodthong S.
Immunogenicity and efficacy of a recombinant DNA hepatitis B
vaccine, GenHevac B Pasteur in high risk neonates, school children
and healthy adults. Asian Pac J Allergy Immunol. 1993;11:85.
32. CDC. Immunization of Health-Care Personnel; Recommendations of
the Advisory Committee on Immunization Practices, MMWR. 2011;
60(7):1-4.
33. Terrault NA, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM,
et al. Update on prevention, diagnosis, and treatment of chronic
hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018;

67:1560.
34. Lee C, Gong Y, Brok J, Boxall EH, Gluud C. Hepatitis B immunisation
for newborn infants of hepatitis B surface antigen-positive mothers.
Cochrane Database Syst Rev. 2006;(2):CD004790.
35. Centers for Disease Control and Prevention. A Comprehensive
Immunization Strategy to Eliminate Transmission of Hepatitis B Virus
Infection in the United States. Recommendations of the Advisory
Committee on Immunization Practices (ACIP). MMWR. 2005;54:RR16.
Available from http://www.cdc.gov/mmwr/PDF/rr/rr5416.pdf. [Last
accessed October, 2019].
3.4 DIPHTHERIA, TETANUS, AND

PERTUSSIS VACCINES
Srinivas G Kasi, Abhay Shah
BACKGROUND
Since the introduction of the whole-cell pertussis, diphtheria, and
tetanus vaccines in Expanded Programme for Immunization (EPI),
the morbidity and mortality due to diphtheria, tetanus, and pertussis
(DTP) have reduced significantly in India. The coverage with three
doses of the whole-cell vaccine, diphtheria, tetanus and whole cell
pertussis (DTwP) vaccine has increased over the years to 91% for
DTwP1 to 88% for DTwP3.1 It needs to be stressed that completion
of the primary schedule and boosters are necessary for complete
protection against the target diseases.
EPIDEMIOLOGY
Diphtheria
The use of DTP vaccines has had significant impact on the burden
of diphtheria. However, the disease is still persisting in India and
published reports of the disease indicate outbreaks, secular trends,
and a shifting epidemiology over the years.2-5 Outbreaks have been
reported in medical college hostels.6 Due to waning vaccine-induced
immunity and poor uptake of booster doses, majority of outbreaks
and cases are observed in schoolgoing children, adolescents, and
adults (Table 1).5
TABLE 1: Age distribution of cases of Diphtheria, in states of India with

case-based surveillance 2016.
State Total cases Under 5 years 5–10 years Over 10 years
Bihar 71 41% 34% 25%
Haryana 59 27% 53% 20%
Kerala 556 8% 18% 74%
Uttar Pradesh 844 25% 53% 22%
Total 1,530 20% 39% 41%
Diphtheria, however, remains endemic in countries in Africa,

Latin America, Asia, the Middle East, and parts of Europe, where
childhood immunization with diphtheria toxoid-containing
vaccines is suboptimal.7
Pertussis
In India, the incidence of pertussis declined sharply after launch
of Universal Immunization Programme (UIP). Prior to UIP, India
reported 200,932 cases and 106 deaths in the year 1970 with a mortality
rate of <0.001%. In 2020, 12,566 cases were reported, reflecting a
decline of >90%.8 Among different states, MP, Jharkhand, Assam, UP,
WB, and Dadra And Nagar Haveli reported the maximum cases in
2017, of which only 6 deaths were reported.9 A prospective multi
national serosurveillance study of Bordetella pertussis infection,
among 10–18 years subjects from 8 Asian countries, was carried
out, with 200 subjects from India. High titers of anti-PT immuno
globulin G (IgG) > 62.5 IU/mL (which is indicator for B petitions
infection within 12 months prior) were found in 18% of subjects.10
However, a large number of cases go unreported, and many
nonpertussis cases are reported and clubbed under the head
of “whooping-cough” cases. The actual number may be high
considering the low coverage with primary and booster doses
of DTP vaccine in the country. The data on pertussis disease and
infection in adolescents and adults is sorely lacking. Further, there is
no data on B. pertussis infection rates in the community that may be
responsible for appearance of typical pertussis disease in infants and
children.11
Tetanus
The incidence of tetanus in India has also declined sharply from
45,948 cases in 1980 and 23,356 cases in 1990 to only 4,702 cases
in 2017.8 In a sero-survey of schoolchildren, 7–17 years of age,
in Hyderabad, only 64% were immune to tetanus.12 In May 2015,
neonatal maternal tetanus was declared as eliminated in India based
on figures of incidence of <1 case per 1,000 live births in all districts
of the country for 2 consecutive years.8
DIPHTHERIA, TETANUS, AND PERTUSSIS VACCINES

Diphtheria, Tetanus, and Whole Cell Pertussis Vaccines
Popularly known as triple antigen, DTwP is composed of tetanus and
diphtheria toxoids as well as killed whole-cell pertussis (wP) bacilli
adsorbed on insoluble aluminum salts which act as adjuvants.
The content of diphtheria toxoid varies from 20 to 30 Lf that of
tetanus toxoid (TT) varies from 5 to 25 Lf per dose and whole cell
pertussis >4 IU per dose. The vaccines need to be stored at 2–8°C.
These vaccines should never be frozen, and if frozen accidentally,
should be discarded. The dose is 0.5 mL intramuscularly (IM)
and the preferred site is the anterolateral aspect of the thigh. The
immunogenicity (protective titer for diphtheria >0.1 IU/mL and
for tetanus >0.01 IU/mL) and effectiveness against diphtheria or
tetanus of three doses of the vaccine exceed 95%. There is no known
immune correlate of protection against pertussis. Disease may occur
in vaccinated individuals but is milder.
Efficacy
The efficacy of different wP products varies substantially not only
in different studies in different parts of the world but also varies
with the case definition of the disease employed.11,12 For higher
efficacy trials, the efficacy estimates vary from 83 to 98% and 36 to
48% in lower efficacy trials. According to a systematic review done
in 2003, the pooled-efficacy of wP vaccine against pertussis in
children was 78%.13 The efficacy of wP alone ranged from 61 to 89%,
and the efficacy of combination DTwP vaccines ranged from 46 to
92%.13 Immunity against all three components wanes over the next
6–12 years and thus regular boosting is needed.
Adverse Effects
Most adverse effects are due to the pertussis component. Minor
adverse effects such as pain, swelling, and redness at the local
site, fever, fussiness, anorexia, and vomiting are reported in almost
half the vaccines after any of the three primary doses. Serious
adverse effects have been reported with DTwP vaccines but are
rare. The frequency of these side effects/1,000 doses is 0.2–4.4 for
fever >40.5°C, 4–8.8 for persistent crying, 0.06–0.8 for hypotonic–

hyporesponsive episodes (HHEs), 0.16–0.39 for seizures, and 0.007
for encephalopathy.14 The frequency of systemic reactions reduces
and that of local reactions increases with increasing number
of doses. Serious adverse effects such as sudden infant death
syndrome (SIDS), autism, chronic neurologic damage, infantile
spasms, learning disorders, and Reye’s syndrome were attributed to
use of the wP vaccines in the past. It has now been proved beyond
doubt that the wP vaccine is not causally associated with any of
these adverse events. Absolute contraindications to any pertussis
vaccination (including DTwP vaccine) are history of anaphylaxis or
development of encephalopathy, without any other cause, within
7 days following previous DTwP vaccination. In case of anaphylaxis,
further immunization with any diphtheria or tetanus or pertussis
vaccine is contraindicated as it is uncertain which component caused
the event. For patients with history of encephalopathy following
vaccination, any pertussis vaccine is contraindicated and only
diphtheria and tetanus (DT) vaccines may be used. Events such as
persistent inconsolable crying of >3 hours duration or hyperpyrexia
(fever > 40.5°C) or HHE within 48 hours of DTwP administration
and seizures with or without fever within 72 hours of administration
of DTwP are considered as precautions but not contraindications
to future doses of DTwP because these events generally do not
recur with the next dose and they have not been proven to cause
permanent sequelae. Progressive or evolving neurological illnesses
are a relative contraindication to first dose of DTwP immunization.
However, DTwP can be safely given to children with stable neurologic
disorders.14
Recommendations for Use

The standard schedule is three primary doses at 6, 10, and 14 weeks
and two boosters at 15–18 months and 4–6 years. Early completion
of primary immunization is desirable as there is no maternal
antibody for protection against pertussis. The schedule for catch-up
vaccination is three doses at 0, 1, and 6 months. The second childhood
booster is not required, if the last dose has been given beyond the age
of 4 years. DTwP is not recommended in children aged 7 years and
older due to an increased reactogenicity. It is essential to immunize

even those recovering from DTP, as natural disease does not offer
complete protection.
Diphtheria, Tetanus, and Acellular Pertussis Vaccines

Background
The introduction of the whole-cell vaccines paid rich dividends
in terms of decline in disease morbidity and mortality. Once
disease rates declined, concerns about frequent local side effects,
as well as public anxiety about the safety of wP vaccines, led to the
development of acellular pertussis (aP) vaccines in Japan in 1981.
These were licensed in the US in 1996 and have now replaced the
whole-cell vaccines in most developed countries.
Vaccine
All aP vaccines are associated with significantly lesser side effects,
and thus the replacement of the wP vaccines was mainly driven by
the safety profile of these vaccines. The other important advantage of
the aP vaccines is the reproducible production process with its use of
purified antigens and the removal of lipopolysaccharides (LPS) and
other parts of the bacterial cell wall during the purification of soluble
antigenic material. These vaccines contain ≥1 of the separately
purified antigens pertussis toxin (PT), filamentous hemagglutinin
(FHA), pertactin (PRN), and fimbrial hemagglutinins 1, 2, and 3 (FIM
type 2 and type 3). Vaccines differ from one another not only in the
number and quantity of antigen components, but also with regard to
the bacterial clone used for primary antigen production, methods of
purification and detoxification, incorporated adjuvants, and the use
of preservatives, such as thiomersal (Table 2).15 Nearly 2-dozen aP
vaccines were designed, many were evaluated in immunogenicity
and reactogenicity trials, and the efficacy and safety of a number
were evaluated in field trials.
Efficacy and Preference of a Particular Acellular Pertussis

Vaccine Product
The efficacy and duration of protection with diphtheria, tetanus,
and acellular pertussis (DTaP) vaccines against diphtheria or
TABLE 2: Composition of available aP vaccines (in combination) brands

in India.
Infanrix
Product Hexa* Hexaxim* Pentaxim† Tetraxim‡ Adacel§ Boostrix§
Tetanus toxoid 40 IU 40 IU 40 IU 40 IU 20 IU 20 IU
Diphtheria 30 IU 20 IU 30 IU 30 IU 2 IU 2 IU
toxoid
Acellular pertussis
Pertussis 25 μg 25 μg 25 μg 25 μg 2.5 μg 8 μg
toxoid
Filamentous 25 μg 25 μg 25 μg 25 μg 5 μg 8 μg
hemagglutinin
Pertactin 8 μg – – 3 μg + 2.5 μg
5 μg
FIM 2
and 3
*Combination of DTaP, IPV, Hib, and hepatitis B
†
Combination of DTaP, IPV and Hib
‡
Combination of DTaP and IPV
§
Tdap vaccine
(DTaP: diphtheria, tetanus, acellular pertussis; IPV: inactivated polio vaccine;
Hib: Haemophilus influenzae type b; Tdap: tetanus toxoid and reduced quantity
diphtheria and acellular pertussis)
tetanus and pertussis are similar to that afforded by the whole-cell

vaccines. There is considerable controversy on the relative efficacy
of different aP vaccines with varying number of components.
Several randomized pertussis vaccine efficacy studies were
conducted in Europe and Africa to compare the safety and efficacy
of the aP and the wP vaccines for the prevention of laboratory-
confirmed pertussis disease in infants.11
Efficacy is influenced by both the choice of antigen and its
quantity. Thus, the monocomponent vaccine, with 50% more PT,
provides better protection against severe disease; while the two
component vaccines appear better in preventing mild-to-moderate
disease. The efficacies in these trials varied from 54 to 89%.11
However, a few countries such as Japan, Denmark, and Sweden have
shown consistent control of pertussis disease with aP vaccines in
their national immunization program.
There is as yet no consensus about the antigenic composition

of an ideal aP vaccine. The exact contribution of the different aP
antigens to protection is not clear. Current generation of aP available
from different manufacturers should be considered as different and
unique products because of the presence of one or more different
components in different concentrations, and with different degree of
adsorption to different adjuvants. Further, these individual antigens
may be derived from different strains of B. pertussis and have
been purified by different methods.15 This is the reason why direct
comparison of protective efficacy of different aP vaccines in human
is not possible.
Different researchers have studied the impact of number of
components in an aP vaccine on relative protective efficacy of
different aP products. In a recent retrospective study in the US
following a huge outbreak of pertussis in California, the researchers
found that five-component aP vaccine had an estimated efficacy
of 88.7% [95% confidence interval (CI): 79.4–93.8%].16 According
to a systematic review involving 49 randomized controlled trials
(RCTs), aP vaccines containing three or more components had
much higher absolute efficacy (80–84%) than those containing
only one- and two-components (67–70%).13 A Cochrane review
by Zhang et al.17 after studying six aP vaccine efficacy trials and
52 safety trials concluded that the efficacy of multicomponent
(≥3) aP vaccines varied from 84 to 85% in preventing “typical
whooping cough” and from 71 to 78% in preventing mild disease. In
contrast, the efficacy of one- and two-component vaccines varied
from 59 to 75% against typical whooping cough and from 13 to 54%
against mild disease. However, a few countries have demonstrated
high levels of effectiveness of mono- and bicomponent aP products
in preventing pertussis by employing them in their immunization
programs,14 the available evidence11 is not sufficient to establish any
significant difference in vaccine effectiveness of aP vaccines with
differing numbers of components.14
The effectiveness of vaccination programs on a national level
depends not only on the efficacy of the vaccine but also on other fac-
tors such as the vaccination schedule and adherence, transportation,
and storage of the vaccine, and herd immunity in the population.
Adverse Effects
The DTaP vaccines score over the whole-cell vaccines in terms of
adverse effects. Broadly speaking, the incidence of both minor and
major adverse effects is reduced by two-thirds with the acellular
vaccines. The incidence of adverse effects is similar with all currently
licensed DTaP vaccines. The absolute contraindications to DTaP
vaccines are same as those for whole-cell vaccines and include
history of anaphylaxis or encephalopathy following past pertussis
vaccination. Serious adverse events following previous pertussis
vaccination (listed in DTwP section) though less likely as compared
to DTwP may still occur with DTaP and are similarly considered as
precautions while using the vaccine. After the primary series, the rate
and severity of local reactions tend to increase with each successive
DTaP dose.
Correlate of Protection of Whole Cell Pertussis and

Acellular Pertussis Vaccines
Till date, there is no single absolute or surrogate correlate of
protection known for pertussis disease and vaccines. Antibody
levels against PT, PRN, and FIM can be used as markers of
protection, but no established protective antibody levels are known.
The mechanism of immunity against B. pertussis involves both
humoral and cellular immune responses which are not directed
against a single protective antigen. In addition to the PT, the vaccines
usually contain one or more attachment factors, which also may
be protective. Immune response to current wP vaccines mimics
the response to infection in animal models and differs from the
response to aP vaccines. The “murine intracerebral challenge test”
has been considered as a “gold standard” for wP vaccines and has
been used to standardize and assess the potency of wP vaccines.18
But until now, there has been no animal model in which protection
correlates with aP vaccines efficacy in children, and these vaccines
do not pass the original “murine intracerebral challenge test”.
The respiratory challenge by aerosol or intranasal of immunized
mice-model has been used to study pertussis pathogenesis and
immunity and can correlate with efficacy of aP vaccines, but not
yet accepted as a regulatory tool. In animal model, duration of

protection is longer after wP vaccines compared to aP vaccines,
suggesting a role for cell-mediated immunity for long-term
protection (see Table 2).

The vaccines should be stored at 2–8°C and the recommended dose
is 0.5 mL IM. DTaP vaccines are not more efficacious than DTwP
vaccines, but have fewer adverse effects. It must also be remembered
that serious adverse effects are rare phenomena even with the wP
vaccines unlike popular belief. The schedule is same as with DTwP
vaccines. Like DTwP vaccines, DTaP vaccines must not be used
in children 7 years or older because of increased reactogenicity.
All licensed DTaP vaccines are of similar efficacy and safety as of
currently available data and any one of them may be used. DTaP
combination vaccines will be discussed separately.
Recent Outbreaks of Pertussis and Choice of Whole

Cell Pertussis versus Acellular Pertussis Vaccines
Since 2009, large outbreaks of pertussis are regularly reported from
many countries such as USA, UK, Australia, Chile, Brazil, Colombia,
and Pakistan employing both aP and wP vaccines despite having
very high-vaccination coverage.14 Reasons for the resurgence of
pertussis were found to be complex and varied by country. Waning
of protective immunity is noted with both wP and aP vaccines, and
also after acquisition of immunity after natural infection. The shorter
duration of protection and probable lower impact of aP vaccines
on infection and transmission are likely to play critical roles. 14
Whereas little is known about the duration of protection following aP
vaccination in developing countries, many studies in industrialized
world documented faster waning with aP vaccines and showed that
protection waned after 4–12 years.16,17,19-22
The factors that have probably contributed to the increasing
numbers of recorded cases include higher disease awareness,
improved surveillance sensitivity, and the enhanced diagnostic
sensitivity of the now widely used polymerase chain reaction (PCR).14
World Health Organization (WHO) analyzed the epidemiology data

from 19 countries with high-vaccine coverage with history of good
disease control. True resurgence was seen only in five countries,
four using aP vaccines (Australia, Portugal, USA, and UK) and one
using wP vaccine (Chile).14 In Australia, the 18th-month booster
dose of DTaP was dropped in 2003 which was followed by resurgence
in 2008–2012. In Portugal, 6 years after aP introduction, there was
increased incidence in infants <1 year suggesting true resurgence,
though changes potentially magnified by increased PCR testing.
In England and Wales, increased incidence was noted in infants
<3 months (too young to be vaccinated). Data from the US suggest
waning of immunity following aP vaccine. In Chile, the resurgence
of pertussis observed in 2011 and 2012 was preceded by a drop in
vaccine coverage in under 4 years olds (from 91.3% in 2005 to 77.0%
in 2011). There are many countries (Norway, Finland, Denmark,
and Sweden) using aP vaccines for the last 10–20 years in their
national program with good control of pertussis and no evidence
of resurgence. There are some countries (e.g., Brazil and Columbia)
using wP with consistently high-vaccination coverage and recent
increase in pertussis incidence. This may be attributed to the changes
in the surveillance system and the natural cyclic disease trends.14
Several randomized trials conducted in the 1990s to document
efficacy of aP vaccines also compared their efficacy with wP vaccines.
Studies to date indicate that aP vaccines are more effective than
low-efficacy wP vaccines, but may be less effective than the highest
efficacy wP vaccines. At least five trials found that wP vaccines
had greater efficacy than aP vaccines.11 Many later trials have also
hinted that the efficacy of the aP vaccine may not be as robust as
reported in the initial studies.19-22 Studies after the outbreaks in US,
UK, and Australia have now concluded that the change from wP to
aP vaccines contributed to the increase in pertussis cases.24-26 Recent
data from US and Australia have suggested reduced durability of
vaccine-induced immunity after the aP vaccination in comparison
of wP vaccines.16,22 These findings suggest that priming with wP is
more effective at sustained prevention of pertussis disease than aP
vaccines. Witt and colleagues, after reviewing data from the Kaiser
Permanente, North California, concluded that “a wholly aP vaccine
series was significantly less effective and durable than one that
contains at least one dose of the traditional whole cell vaccine.”23
Original wP and aP priming generates comparable protective
immunity in the first few years after vaccination. However, wP/aP
priming induces different T cell phenotypes, which have been shown
to persist for at least 15 years. Adults who received a Tdap booster
and who had received either wP or aP priming followed by multiple
aP boosters, the aP primed group showed increased interleukin
4 (IL-4), IL-5, IL-13, IL-9, and transforming growth factor-β (TGF-β)
(Th2 response) and decreased interferon-γ (IFN-γ) and IL-17
production (Th1 and Th17 response), defective in their ex vivo
capacity to expand memory cells, and less capable of proliferating in
vitro. Pertussis-specific IgG4 antibodies were significantly elevated
in aP compared with wP individuals.24-31 While IgG1 antibodies are
potent neutralizing antibodies, IgG4 antibodies are less effective in
neutralization and are more tolerizing in nature.
The current evidence is tilted in favor of wP vaccines as far as
effectiveness of the pertussis vaccines is concerned.11 However,
the industrialized world would not take the risk of reverting to wP
vaccines considering the low acceptance of these vaccines by the
public in the past.11 Table 3 summarizes a few key differences in
different attributes related to wP and aP vaccines.
Tetanus Toxoid and Reduced Quantity Diphtheria and

Acellular Pertussis Vaccine
Vaccination of Adolescents and Adults
Pertussis in adolescents and adults is responsible for considerable
morbidity and also serves as a reservoir for disease transmission
to unvaccinated or partially vaccinated young infants.11 Pertussis is
increasingly reported from older children, adolescents, and adults.
According to one serological study from US, 21% (95% CI, 13–32%) of
adults with prolonged cough had pertussis.14 The pertussis burden is
believed to be substantially more than the number of reported cases;
approximately 600,000 cases are estimated to occur annually just
among adults.32 There is a paucity of robust data on the incidence
of adolescent and adult pertussis in India but is perceived to be
significant, especially in those states where childhood immunization
Table 3: Comparative evaluation of whole-cell pertussis (wP) and acellular

pertussis (aP) vaccines in terms of different attributes.
Characteristics wP vaccines aP vaccines
Mechanism of action Th-1 bias Th-2 bias
Correlate of protection Not known Not known
Animal model (for Known Not known
potency)
Immunogenicity data Available Available
(India)
Efficacy (global) Variable data Robust data
Efficacy (India) No trial No trial
Effectiveness (global) Well established Not established
universally
Effectiveness (India) Established No data
Priming Superior Inferior
Duration of Longer Shorter
protection/waning
Herd effect Documented No herd effect
Minor adverse effects 1 episode in Equal to control
2–10 injections
Serious adverse Very rare Very rare (at par with
effects wP)
Acceptance (global) Poor Good
Acceptance (India) Good (no Good
documentation of
resistance)
coverage is good and reduced natural circulation of pertussis leads

to infrequent adolescent boosting.11 In a study of pertussis infection
among 10–18 years subjects from 8 Asian countries, with 200 subjects
from India, high titers of anti-PT IgG > 62.5 IU/mL, indicative of B.
pertussis infection within the past 12 months, were found in 18% of
subjects.10
Objectives and rationale of adolescents and adult pertussis vaccina
tion: There are two main objectives—first, to protect vaccinated
persons against pertussis, and second, to reduce the reservoir of

pertussis in the population at large and thereby potentially decreases
exposure of persons at increased risk for complicated infection (e.g.,
infants).11 There is a definite need of protecting very young infants
not covered by current vaccination recommendations by vaccinating
adults and close contacts (cocooning).
Vaccines
Immunity against pertussis following primary or booster DTwP/
DTaP vaccination wanes over the next 6–12 years. Hence, several
developed countries have instituted routine booster immunization
of adolescents and adults with standard quantity tetanus toxoid, and
reduced quantity diphtheria and acellular pertussis (Tdap) vaccine
instead of tetanus and diphtheria (Td). The standard strength DTwP
and DTaP vaccines cannot be used for vaccination of children 7 years
and above due to increased reactogenicity.
Table 2 provides details of available Tdap vaccines in India.
The vaccine should be stored between 2 and 8°C, and must not be
frozen. The dose is 0.5 mL IM. Immunogenicity studies have shown
that antibody response to a single dose of Tdap booster in previously
vaccinated children/adolescents is similar to that following three
doses of full-strength DTwP or DTaP vaccines. Vaccine efficacy
against clinical disease exceeds 90%. The most common side effect
with Tdap is pain at the local injection site in about 70% of vaccines,
followed by redness and swelling. Systemic side effects such as fever,
headache, and fatigue are rarely seen. Serious adverse events have
not been reported. The contraindications are serious allergic reaction
to any component of the vaccine or history of encephalopathy not
attributable to an underlying cause within 7 days of administration
of a vaccine with pertussis component.
Global Experience with Tdap

Several developed countries have instituted routine booster
immunization of adolescents and adults with Tdap instead of Td in
their national immunization programs.14 The Indian Academy of
Pediatrics (IAP) has also recommended only a single one-time dose
of Tdap to adolescents aged 10–12 years of age.11 There is no data on
the coverage of Tdap in adolescents and adults in India since it is

being used exclusively in private health sector.
Efficacy and Effectiveness of Tdap

Wei et al. evaluated effectiveness of Tdap booster among adole
scents in the Virgin Islands in 2007, and found effectiveness of
61.3% (95% CI: −52.5–90.2) and 68.3% (95% CI: −126.4–95.6) against
probable and laboratory-confirmed pertussis, respectively. 28
A recent unpublished trial reported that Tdap was modestly
effective [vaccine effectiveness: 55.2% (95% CI: 44.1–64.1%,
p < 0.001)] at preventing PCR-confirmed pertussis among Kaiser
Permanente Northern California (KPNC) adolescents and adults.
According to Advisory Committee on Immunization Practices
(ACIP) data presented in February 2013 meeting, the Tdap
effectiveness was noticed ranging from 66 to 78% in field
observational studies. The preliminary data suggest effectiveness
wanes within 3–4 years among aP vaccine recipients and there was
no evidence of herd immunity.28-33
MATERNAL IMMUNIZATION TO PREVENT

INFANT PERTUSSIS
Immunization of adolescents and adults, and postpartum
administration of Tdap failed to have appreciable impact on
laboratory-confirmed pertussis in very young infants.11 Several
strategies such as maternal immunization including pregnant
women, cocooning, and neonatal immunization have been proposed
to reduce the burden of pertussis in those infants too young to have
been immunized. Among all these strategies, immunization during
pregnancy appears to be most effective strategy to have the most
impact on infantile pertussis, especially during the first few weeks
after birth. The effective transplacental transmission of maternal
pertussis antibodies would protect the infant against pertussis
during the first months of life. Though the transplacentally acquired
antibodies may be detectable at least up to first few weeks of life (at
6–8 weeks), the age at which the first pertussis-containing vaccine
is due, however, the concentration of antibodies required for
protection against pertussis in newborns is not known.11 In 2011, the
ACIP recommended a dose of Tdap to all pregnant women after 20

weeks of gestation to provide protection for both the mother and her
newborn during the infant’s earliest weeks of life.10
Safety of Tdap during pregnancy: There are limited safety data on
Tdap administration in pregnant women; however, existing
Tdap safety data from the CDC, United States Food and Drug
Administration (US FDA), and the pharmaceutical pregnancy
registries do not indicate any adverse safety effect.34 Even three to
six doses of wP vaccines were administered during single pregnancy
in five different clinical trials conducted in US and no serious
untoward local or systemic reactions were noted.35
There are a few concerns regarding maternal immunization,
they include ultimate titers achieved with a dose of Tdap during
pregnancy, the duration of maternal antibodies, and finally, the
interference with proper take of pertussis vaccines during primary
immunization due to high concentrations of maternal antibodies.11
However, a recent study demonstrated that infants whose mothers
had received Tdap vaccine during pregnancy had higher pertussis
antibody concentrations between birth and the first vaccine
dose than the cohort whose mothers did not receive the vaccine.
There was some blunting of the response to the infant series; but
the children did develop adequate antibodies by the end of the
complete series.36 The antibody titer to PT in acellular vaccine was,
however, not affected by the prevaccination antibody levels. Further
studies are needed to evaluate the impact of maternal antibody
levels to primary immunization in young children, if maternal
Tdap is to be routinely used where infants receive wP vaccines in
the primary series.19 The results of this study are quite reassuring
and add evidence to support the recommendation of vaccinating
pregnant mothers to protect their children against pertussis.
CURRENT STATUS OF PERTUSSIS

VACCINATION IN INDIA
Pertussis continues to be a serious public health problem in India.
India is employing only wP vaccines in their national immunization
program since the adoption of EPI in 1978. Though aP vaccines
are also licensed and available, they are mainly prescribed by the
private sector and coverage is still miniscule. Private health sector is
responsible for offering vaccination to only ~9% of the population in
India.1 Though the coverage of DTwP vaccine in India has increased,1
there is poor documentation of large-scale outbreaks of pertussis in
the country unlike the recent large-scale outbreaks reported in many
developed countries. Either many large-scale outbreaks are totally
ignored and go unreported or wP vaccines are providing adequate
protection. There are two scenarios of pertussis epidemiology in
a given population based on coverage of pertussis vaccine. Since
the overall coverage is not very high, pertussis in major parts of
the country continues mainly to be a problem of young children.
However, many states having very good immunization rates behave
like developed countries with high coverage in pediatric age group
with resultant more frequent disease in adolescents and adults.7
Regarding the safety of wP vaccines, there is still no report of higher
rates of serious adverse event following immunizations (AEFIs), and
public acceptance of the vaccine is still not a serious concern.11
INDIAN ACADEMY OF PEDIATRICS

RECOMMENDATIONS ON PERTUSSIS
VACCINATION
Public Health Perspectives
Pertussis is a highly prevalent pediatric illness having significant
morbidity and mortality in the country. There is an urgent
need of an effective surveillance to evaluate both the burden of
infection and the impact of immunization. The current status of
pertussis immunization, in the form of DTwP vaccination, is still
suboptimal in many states.1 The Advisory Committee on Vaccines
and Immunization Practices (ACVIPs) of the Indian Academy of
Pediatrics unambiguously supports the current immunization policy
of employing only wP vaccines (in the form of DTwP) in UIP because
of its proven efficacy, safety, adequate public acceptance, and
absence of documentation of significant waning. There is insufficient
marginal benefit to consider changing from wP-containing vaccine
to aP-containing vaccine.11
Individual Use: IAP Recommendations

Since there is scarcity of data on vaccine efficacies of both wP and
aP vaccines in India and other developing countries, most of the
recommendations of the academy in regard to pertussis vaccination
are based on the experience gained and data obtained from the
use of these vaccines in industrialized countries. However, the
continuous decline in reported pertussis cases in last few decades
has demonstrated good effectiveness of wP vaccine (of whatever
quality) in India. There is no data on the effectiveness of aP vaccines
in India.
Protection against severe pertussis in infants and early childhood
can be obtained with primary series of either wP or aP vaccine.14
Indian Academy of Pediatrics has issued following recommen-
dations on use of pertussis vaccines for office-practice in private
health sector:
■ Primary immunization: The primary series should be completed
with three doses of either wP or aP vaccines, irrespective of the
number of components. The schedule should begin at 6 weeks of
age, with three doses administered at an interval of 4 weeks. wP
vaccine is definitely superior to aP vaccine in terms of efficacy
and duration of protection but more reactogenic. In view of
parental anxiety and concerns for its reactogenicity, aP vaccine
can also be administered in the primary series. The primary aim
is to increase the vaccination coverage with either of the vaccines.
There is strong evidence of effectiveness and real-life performance
of wP vaccines from India where their widespread use has markedly
reduced the incidence of pertussis after the launch of UIP.
However, the aP vaccines may be preferred to wP vaccines in
those children with history of severe adverse effects after previous
dose/s of wP vaccines, children with progressive neurologic
disorders, if resources permit. There is no evidence of superiority
for any aP vaccines based on number of components. The schedule
is same as with wP (DTwP) vaccines. Like DTwP vaccines, DTaP
vaccines must not be used in children 7 years or older because of
increased reactogenicity. The contraindications are the same for
both the vaccines.
Boosters: The first and second booster doses of pertussis vaccines

should also be of wP or aP vaccines. However, considering the
higher reactogenicity, aP vaccine/combination (see Table 2) can be
considered for the boosters, if resources permit.
Administration and schedule: The standard dose of pertussis vaccine
is 0.5 mL; this is administered IM in the anterolateral thigh of children
aged <12 months and in the deltoid muscle in older age groups. The
standard primary vaccination schedule is three primary doses at 6,
10, and 14 weeks and two boosters at 16–18 months and 4–5 years.
Early completion of primary immunization is desirable as there is
no effective maternal antibody for protection against pertussis. The
booster should be given ≥6 months after the last primary dose. The
last dose of the recommended primary series should be completed
by the age of 6 months. All infants, including those who are human
immunodeficiency virus (HIV)-positive, should be immunized
against pertussis.
Schedule for catch up vaccination: If the series is started after 1 year
of age, three doses at 0, 1, and 6 months interval should be offered.
The second childhood booster is not required if the last dose has
been given beyond the age of 4 years. It is essential to immunize even
those recovering from pertussis as natural disease does not offer
complete protection.
Recommendations for adolescents and adults: Immunity against
pertussis following primary or booster wP or aP vaccination wanes
over the next 4–12 years. The Academy, therefore, recommends
offering Tdap vaccine instead of Td or TT vaccine to all children or
adolescents or adults in the schedule discussed below:
■ In those children who have received all three primary and the
two booster doses of DTwP/DTaP, Tdap should be administered
as a single dose at the age of 10–11 years.
■ Catch-up vaccination is recommended till the age of 18 years.
■ Persons aged 7 years through 10 years, who are not fully
immunized with the childhood DTwP/DTaP vaccine series,
should receive Tdap vaccine as the first dose in the catch-up
series; if additional doses are needed, Td vaccine should
be used.
■ For persons aged 7–10 years, who receive a dose of Tdap as part of
the catch-up series, an adolescent Tdap vaccine dose should be
administered at age 11–12 years.
■ A single dose of Tdap may also be used as replacement for
Td/TT booster in adults of any age, if they have not received Tdap
in the past.
■ Tdap can be given regardless of time elapsed since the last
vaccine containing TT or diphtheria toxoid.
■ There is no data at present to support repeat doses of Tdap.
■ Indian Academy of Pediatrics recommends decennial Td booster
for those who have received one dose of Tdap.
Only aP-containing vaccines should be used for vaccination in
those aged >7 years.
Tetanus toxoid, and reduced quantity diphtheria, and aP during
pregnancy: Immunization of pregnant women (maternal
immunization) is an effective approach to protect very young
infants and neonates. IAP recommends immunization of pregnant
women with a single dose of Tdap during the third trimester
(preferred during 27 weeks through 36 weeks of gestation) regardless
of number of years from prior Td or Tdap vaccination. Tdap has
to be repeated in every pregnancy irrespective of the status of
previous immunization (with Tdap).34-36
Interchangeability of brands: In principle, the same type of
wP-containing or aP-containing vaccines should be given throughout
the primary course of vaccination. However, if the previous type of
vaccine is unknown or unavailable, any wP vaccine or aP vaccine
may be used for subsequent doses, as it is unlikely to interfere with
the safety or immunogenicity of these vaccines.14
TETANUS AND DIPHTHERIA VACCINE

Background
Antibodies to tetanus and diphtheria decline over time, resulting
in increasing susceptibility of adolescents and adults to diphtheria.
Hence, regular boosting is needed to ensure adequate levels of
antibodies during any apparent or inapparent exposure to tetanus
bacilli/toxin.37
Good childhood vaccination coverage (at least 70%) provides

herd effect by reducing circulation of toxigenic strains and prevents
outbreaks in adults despite susceptibility. When childhood
vaccination programs break down as happened in the former Soviet
Union in the early 1990s, massive outbreaks of diphtheria involving
primarily adults have occurred. Thus, it is desirable to regularly
boost adult immunity against tetanus and diphtheria every 10 years.
Vaccine
Tetanus and diphtheria contain 5 Lf of TT and only two units of
diphtheria toxoid are stored at 2–8°C and are administered IM in
a dose of 0.5 mL. Administration of boosters more frequently than
indicated leads to increased frequency and severity of local and
systemic reactions as the preformed antitoxin binds with the toxoid
and leads to immune complex-mediated reactions (swollen limbs
and Arthus type 2 reactions).

This vaccine is indicated as replacement for DTwP/DTaP/DT for
catch-up vaccination in those aged above 7 years (along with Tdap),
and as replacement for TT in all situations where TT was previously
recommended. In individuals who have completed primary and
booster vaccination with DTwP/DTaP, Td boosters every 10 years
provide sufficient protection.
Tdap/Td in Pregnancy
The WHO has evolved exhaustive guidelines for administration of
Tdap/Td in pregnant women,38,39 which are endorsed by IAP.
■ Unimmunized: For pregnant women who have not been
previously immunized, one dose of Tdap/Td and another dose
of Td at least 1 month apart should be given during pregnancy
so that protective antibodies in adequate titers are transferred to
the newborn for prevention of neonatal tetanus. The first dose
should be administered at the time of first-contact/as early as
possible and the second dose of Td should be administered
1 month later and at least 2 weeks before delivery. A single dose of
Tdap/Td should be administered in each subsequent pregnancy.
■ Fully immunized: Five childhood doses (three primary doses

plus two boosters) and one adolescent booster Tdap: one dose of
Tdap is necessary in every pregnancy, in the schedule mentioned
earlier.
Tdap/Td in Wound Management

All patients presenting with skin wounds or infections should be
evaluated for tetanus prophylaxis. Cleaning of the wound, removal
of devitalized tissue, irrigation, and drainage are important to
prevent anaerobic environment which is conducive to tetanus
toxin production. The indications for Tdap/Td and tetanus
immunoglobulin (TIG) are as below (Table 4).
Evidence suggests that tetanus is highly unlikely in individuals
who have received three or more doses of the vaccine in the past and
who get a booster dose during wound prophylaxis, hence passive
protection with TIG is not indicated in these patients irrespective
of wound severity unless the patient is immunocompromised. For
children who are completely unimmunized, catch-up vaccination
should be provided by giving three doses of tetanus toxoid-containing
vaccine (DTwP/DTaP/Tdap/Td) at 0, 1, and 6 months depending
on the age of the child and nature of previous doses received for
TABLE 4: Tetanus prophylaxis in wound management.
Doses Clean and All other Given in

of TT minor wounds wounds# past
Td/Tdap TIG* Td/Tdap TIG*
Unknown, <3 Yes Yes Yes Yes
doses, and
immunodeficient
≥3 doses No† No No‡ No
#
Including, but not limited to, wounds contaminated with dirt, feces, soil,
and saliva; puncture wounds; avulsions; and wounds resulting from missiles,
crushing, burns, and frostbite.
*TIG: tetanus immunoglobulin (250–500 IU IM).
†
Yes, if >10 years since last dose.
‡
Yes, if >5 years since last dose.
(Tdap: tetanus toxoid and reduced quantity diphtheria and acellular pertussis;
TT: tetanus toxoid)
more comprehensive protection. For partially immunized children,

catch-up vaccination entails administration of at least three doses
of tetanus toxoid-containing vaccine including previous doses
received. Children with unknown or undocumented history should
be treated as unimmunized.
IAP recommendations: Diphtheria and tetanus toxoids and pertussis vaccine.
Routine vaccination:
• Recommended schedule: Three primary doses at 6, 10, and 14 weeks and
two boosters at 15–18 months and 4–5 years
• Minimum age: 6 weeks
• The first booster (4th dose) may be administered as early as age 12
months, provided at least 6 months have elapsed since the third dose
• DTaP or DTwP vaccine/combination may be used for the primary
immunization series
• DTaP may be preferred to DTwP in children with history of severe adverse
effects after previous dose/s of DTwP or children with neurologic disorders
• First and second boosters may also be of DTwP. However, considering a
higher reactogenicity, DTaP can be considered for the boosters
Catch-up vaccination:
• Catch-up schedule: The second childhood booster is not required if the
last dose has been given beyond the age of 4 years
• Catch-up below 7 years: DTwP/DTaP at 0, 1, and 6 months
• Catch-up above 7 years: Tdap, Td, and Td at 0, 1, and 6 months
(DTaP: diphtheria, tetanus, and acellular pertussis; DTwP: diphtheria, tetanus
and whole cell pertussis; Tdap: tetanus and diphtheria toxoids and acellular
pertussis)
I AP recommendations: Tetanus and diphtheria toxoids and acellular pertussis

(Tdap) vaccine.
• Recommended schedule: One dose of Tdap to all adolescents aged
10 years through 12 years
• Adacel™ is approved for use for 11–64 years
• Boostrix™ is approved for use >4 years of age
• The IAP/ACVIP does not recommend use of Tdap before the age of 7 years
• Tdap during pregnancy: One dose of Tdap vaccine to pregnant mothers/
adolescents during each pregnancy (preferred during 27 weeks through
36 weeks of gestation) regardless of number of years from prior Td or
Tdap vaccination
Contd…
Contd…
• Catch-up above 7 years: Tdap, Td, Td at 0, 1, and 6 months
• Persons aged 7 years through 10 years who are not fully immunized with
the childhood DTwP/DTaP vaccine series, should receive Tdap vaccine as
the first dose in the catch-up series; if additional doses are needed, use
Td vaccine
• If the last dose of Tdap has been administered >9 years, the adolescent
booster of Tdap is not necessary
• Persons aged 11 years through 18 years who have not received Tdap
vaccine should receive a dose followed by tetanus and diphtheria
toxoids (Tds) booster doses every 10 years thereafter
• Tdap vaccine can be administered regardless of the interval since the last
tetanus and diphtheria toxoid-containing vaccine
(DTaP: diphtheria, tetanus, and acellular pertussis; DTwP: diphtheria, tetanus and
whole cell pertussis)
REFERENCES
1. WHO; UNICEF. (2018). WHO and UNICEF estimates of immunization
coverage: 2017 revision [online]. Available from: http://www.who.int/
immunization/monitoring_surveillance/data/ind.pdf. [Last accessed
November, 2022].
2. Singhal T, Lodha R, Kapil A, Jain Y, Kabra SK. Diphtheria—down but
not out. Indian Pediatr. 2000;37:728-37.
3. Patel UV, Patel BH, Bhavsar BS, Dabhi HM, Doshi SK. A retrospective
study of diphtheria cases, Rajkot, Gujarat. Indian J Comm Med.
2004;24:161-3.
4. Khan N, Shastri J, Aigal U, Doctor B. Resurgence of diphtheria in the
vaccination era. Indian J Med Microbiol. 2007;25:434-7.
5. Murhekar M. Epidemiology of Diphtheria in India, 1996-2016: Implica
tions for Prevention and Control. Am J Trop Med Hyg. 2017;97(2):313-8.
6. Outbreak News Today. Diphtheria: Two dozen medical students in
Karnataka, India contract disease. [online] Available from: http://
outbreaknewstoday.com/diphtheria-two-dozen-medical-students-
in-karnataka-india-contract-disease-57913/. [Last accessed
November, 2022].
7. World Health Organization. (2017). Diphtheria vaccine: WHO position
paper – August 2017. 4 August 2017, No 31, 2017, 92, 417–436. [online]
Available from: https://www.who.int/publications/i/item/who-
wer9231. [Last accessed November, 2022].
8. WHO. (2019). WHO Vaccine-Preventable Diseases: Monitoring System

2018 Global Summary. [online] Available from: https://apps.who.int/
immunization_monitoring/globalsummary/countries?countrycriteria%
5Bcountry%5D%5B%5D=IND&commit=OK. [Last accessed November,
2022].
9. World Health Organization. (2015). Tetanus elimination in India. [online]
Available from: https://www.who.int/life-course/news/regional-
news/tetanus-elimination-in-India/en/#:~:text=AUGUST%202015%
20%2D%20India%20has%20achieved,births%20in%20the%20entire%20
country. [Last accessed November, 2022].
10. Son S, Thamlikitkul B, Chokephaibulkit K, Perera J, Jayatille ke K,
Hsueh PR, et al. Prospective multinational serosurveillance study of
Bordetella pertussis infection among 10- to 18-year-old Asian children
and adolescents. Clin Microbiol Infect. 2019;25:250.e1-e7.
11. Vashishtha VM, Bansal CP, Gupta SG. Pertussis vaccines: Position
paper of Indian Academy of Pediatrics (IAP). Indian Pediatr. 2013;50:
1001-9.
12. Murhekar MV, Bitragunta S, Hutin Y, Ckakravarty A, Sharma HJ, Gupte
MD. Immunization coverage and immunity to diphtheria and tetanus
among children in Hyderabad, India. J Infect. 2009;58(3):191-6.
13. Jefferson T, Rudin M, DiPietrantonj C. Systematic review of the effects
of pertussis vaccines in children. Vaccine. 2003;21:2003-14.
14. Pertussis vaccines: WHO position paper – August 2015. Available at
https://www.who.int/teams/immunization-vaccines-and-biologicals/
policies/position-papers/pertussis. [Last accessed November, 2022].
15. Recommendations to assure the quality, safety and efficacy of acellular
pertussis vaccines Replacement of Annex 2 of WHO Technical Report
Series, No. 878. Available at https://cdn.who.int/media/docs/default-
source/biologicals/vaccine-standardization/pertussis/trs_979_
annex_4.pdf?sfvrsn=59e0ecb1_3&download=true. [Last accessed
November 2022].
16. Misegades LK, Winter K, Harriman K, Talarico J, Messonnier NE, Clark
TA, et al. Association of childhood pertussis with receipt of 5 doses
of pertussis vaccine by time since last vaccine dose, California, 2010.
JAMA. 2012;308:2126-32.
17. Zhang L, Prietsch SO, Axelsson I, Halperin SA. Acellular vaccines for
preventing whooping cough in children. Cochrane Database Syst Rev.
2012;3:CD001478.
18. Kendrick PL, Eldering G, Dixon MK, Misner J. Mouse protection
tests in the study of pertussis vaccine; a comparative series using the
intracerebral route for challenge. Am J Public Health Nations Health.
1947;37:803-10.
19. Edwards KM, Decker MD. Pertussis Vaccines. In: Plotkin SA, Orenstein
WA, Offit P, Edwards KM (Eds). Plotkin’s Vaccines, 7th edition.
Netherlands: Elsevier; 2018. pp. 711-61.
20. Klein NP, Bartlett J, Rowhani-Rahbar A, Fireman B, Baxter R. Waning
protection after fifth dose of acellular pertussis vaccine in children.
N Engl J Med. 2012;367:1012-9.
21. Wendelboe AM, Van Rie A, Salmaso S, Englund JA. Duration of
immunity against pertussis after natural infection or vaccination.
Pediatr Infect Dis J. 2005;24:S58-61.
22. Witt MA, Katz PH, Witt DJ. Unexpectedly limited durability of
immunity following acellular pertussis vaccination in preadolescents
in a North American outbreak. Clin Infect Dis. 2012;54:1730-5.
23. da Silva Antunes R, Babor M, Carpenter C, Khalil N, Cortese M,
Mentzer AJ, et al. Th1/Th17 polarization persists following whole-cell
pertussis vaccination despite repeated acellular boosters. J Clin Invest.
2018;128(9):3853-65.
24. van der Lee S, Hendrikx LH, Sanders EAM, Berbers GAM, Buisman AM.
Whole-cell or acellular pertussis primary immunizations in infancy
determines adolescent cellular immune profiles. Front. Immunol.
2018;9:51.
25. WHO. (2014). SAGE pertussis working group. Background paper.
SAGE April 2014. [online] Available from: http://www.who.int/
immunization/sage/meetings/2014/april/1_Pertussis_background_
FINAL4_web.pda?ua=. [Last accessed November, 2022].
26. Rendi-Wagner P, Kundi M, Mikolasek A, Vécsei A, Frühwirth M,
Kollaritsch H. Hospital-based active surveillance of childhood
pertussis in Austria from 1996 to 2003: estimates of incidence and
vaccine effectiveness of whole-cell and acellular vaccine. Vaccine.
2006;24:5960-5.
27. Lacombe K, Yam A, Simondon K, Pinchinat S, Simondon F. Risk factors
for acellular and whole-cell pertussis vaccine failure in Senegalese
children. Vaccine. 2004;23:623-8.
28. Wei SC, Tatti K, Cushing K, Rosen J, Brown K, Cassiday P, et al.
Effectiveness of adolescent and adult tetanus, reduced-dose
diphtheria, and acellular pertussis vaccine against pertussis. Clin
Infect Dis. 2010;51:315-21.
29. Sheridan SL, Ware RS, Grimwood K, Lambert SB. Number and order of
whole cell pertussis vaccines in infancy and disease protection. JAMA.
2012;308:454-6.
30. Liko J, Robinson SG, Cieslak PR. Priming with whole-cell versus
acellular pertussis vaccine. N Engl J Med. 2013;368:581-2.
31. Witt MA, Arias L, Katz PH, Truong ET, Witt DJ. Reduced risk of pertussis
among persons ever vaccinated with whole cell pertussis vaccine
compared to recipients of acellular pertussis vaccine in a large US
cohort. Clin Infect Dis. 2013;561:1248-54.
32. Wright SW, Edwards KM, Decker MD, Zeldin MH. Pertussis infection
in adults with persistent cough. JAMA. 1995;273:1044-6.
33. CDC. (2006). Preventing tetanus, diphtheria, and pertussis among
adults: use of tetanus toxoid, reduced diphtheria toxoid and acellular
pertussis vaccine. [online] Available from: http://www.cdc.gov/
mmwr/preview/ mmwrhtml/rr5517a1.htm. [Last accessed November,
2022].
34. CDC. Updated recommendations for use of tetanus toxoid, reduced
diphtheria toxoid and acellular pertussis vaccine (Tdap) in pregnant
women and persons who have or anticipate having close contact with
an infant aged <12 months—Advisory Committee on Immunization
Practices (ACIP), 2011. Morb Mortal Weekly Rep. 2011;60:1424-6.
35. Gall SA, Myers J, Pichichero M. Maternal immunization with tetanus-
diphtheria-pertussis vaccine: effect on maternal and neonatal serum
antibody levels. Am J Obstet Gynecol. 2011;204:334.e1-5.
36. CDC. Prevention of pertussis, tetanus and diphtheria among pregnant
and postpartum women and their infants. MMWR Recomm Rep.
2008;57:1-51.
37. Hardy-Fairbanks AJ, Pan SJ, Decker MD, Johnson DR, Greenberg DP,
Kirkland KB, et al. Immune Responses in Infants Whose Mothers
received Tdap vaccine during pregnancy. Pediatr Infect Dis J.
2013;32(11):1257-60.
38. WHO. Diphtheria vaccine: WHO position paper. Weekly Epidemiol
Rec. 2017;92:417-36.
39. WHO. Tetanus vaccines: WHO position paper. Weekly Epidemiological
Rec. 2006;81:196-207.
3.5 HAEMOPHILUS INFLUENZAE TYPE B

CONJUGATE VACCINES
Sanjay Lalwani, Shivananda S
BACKGROUND
Haemophilus influenzae type b (Hib) organisms are divided into
capsulated and noncapsulated strains. Capsulated Haemophilus
influenzae has six serotypes of which type b is most important.
Hib is an important invasive pathogen causing diseases such as
meningitis, bacteremia, pneumonia, cellulitis, osteomyelitis, septic
arthritis, and epiglottitis. Most of invasive Hib disease occurs in
children in the first 2 years of life before natural protective immunity
is acquired by the age of 3–4 years. Noncapsulated (nontypeable
strain—NTHi) Hib causes bronchitis, otitis media, sinusitis, and
pneumonia, is not amenable to prevention at present, and can
occur at all ages. Haemophilus influenzae spread by respiratory
droplet infection and also by fomites contaminated with respiratory
secretions. Data from the Invasive Bacterial Infections Surveillance
(IBIS) Group from six referral hospitals in India show that Hib is a
common cause of pneumonia and meningitis in India.1
GLOBAL BURDEN OF Hib DISEASE

In spite of the availability of an effective vaccine against Hib for
more than a decade, Hib continues to be a leading cause of mortality
and morbidity worldwide, especially in developing countries.
It was estimated that there were 29,500 Hib deaths (18,400–40,700)
in HIV-uninfected children and an additional 1,000 deaths in HIV-
infected children aged 1–59 months in 2015. Hib deaths declined
by 90% (78–96) from 2000 to 2015. Most children who died of Hib
(76%) presented with pneumonia. India (15,600 deaths, 9,800–
21,500), Nigeria (3,600 deaths, 2,200–5,100), China (3,400 deaths,
2,300–4,600), and South Sudan (1,000 deaths, 600–1,400) had
the greatest number of Hib deaths in 2015. An estimated 340,000
episodes (196,000–669,000) of severe Hib occurred globally in
children in 2015.2
Global estimates of burden of disease caused by Hib in children

<5 years suggest that Hib caused about 8.13 million serious
illnesses worldwide in 2000 (uncertainty range 7.33–13.2 million)
and estimated that Hib caused 371,000 deaths (247,000–527,000)
in children aged 1–59 months. 3 In prospective, microbiology-
based studies in childhood pneumonia, the second most common
organism isolated in most studies is Hib (10–30%).4
In unvaccinated populations, Hib is the dominant cause of
nonepidemic bacterial meningitis during the 1st year of life. Even
with prompt and adequate antibiotic treatment, 3–20% of patients
with Hib meningitis die. Where medical resources are limited,
fatality rates for Hib meningitis may be much higher, and severe
neurological sequelae are frequently observed in survivors (in up to
30–40%).5
Hib Burden in India

The burden of Hib disease is underestimated in India as cultures
are often not sent, the organism is difficult to culture especially
when antibiotics have been administered and a large proportion of
pneumonia may be nonbacteremic. During 1993–1997, a prospective
surveillance was conducted in 5,798 patients aged 1 month to
50 years who had diseases likely to be caused by H. influenzae. Out
of a total of 125 H. influenzae infections detected, 97% of which
were caused by Hib, 108 (86%) isolates were from children aged
<5 years. The clinical spectrum of these children included meningitis
(70%), pneumonia (18%), and septicemia (5%). The case-fatality
rate was 11% overall and 20% in infants with Hib meningitis.1 In
1995, Bahl et al.6 conducted a hospital-based study on 110 children
<5 years on severe and very severe pneumonia, and it was found that
19% cases were due to Hib. Another hospital-based study conducted
in Delhi by Patwari et al.,7 in 1996, found 15% of 132 children
<12 years suffered from pneumonia due to Hib.
In a later cohort study of 17,951 children aged 0–18 months
enrolled from July 2005 to December 2006, the cohort population
presented with 227, 231, and 131 events of suspected pneumonia
and 164, 72, and 89 events of suspected meningitis at study
hospitals at Chandigarh, Kolkata, and Vellore, respectively. Among
hospitalized patients, 8–30% children had purulent meningitis and

Hib was detected in 20–29% of cases by culture or latex agglutination
test (LAT). Case fatality of pneumonia ranged from 0.77 to 2.35% and
that of meningitis ranged from 2.68 to 4.71% at these study centers.8
The World Health Organization (WHO) estimates for the year
2008 show that 1.828 million children under 5 years die annually in
India alone of which 20.3% mortality is due to pneumonia. These
statistics highlight the burden of Hib disease in the prevaccine era
in India.
VACCINES
All Hib vaccines are conjugated vaccines where the Hib capsular
polysaccharide (polyribosylribitol phosphate or PRP) is conjugated
with a protein carrier so as to provide protection in the early years
of life when it is most needed. Currently available vaccines include
HbOC (carrier CRM197 mutant Corynebacterium diphtheriae toxin
protein), PRP-OMP (carrier Neisseria meningitidis protein outer
membrane protein complex), and PRP-T (carrier tetanus toxoid).
PRP-D has been withdrawn due to relatively poor efficacy. HbOC
and PRP-T vaccines show only a marginal increase in antibody
levels after the first dose with a marked increase after the second
and even better response after the third dose. On the other hand,
PRP-OMP shows an increase in antibody level after the first dose
itself with only marginal increases after the second and third doses.
The onset of protection with PRP-OMP is thus faster. Additionally,
while three doses of HbOC and PRP-T are recommended for primary
vaccination, only two doses of PRP-OMP are recommended for this
purpose. Only PRP-T is currently available in India. The vaccines
should be stored at 2–8°C and the recommended dose is 0.5 mL
intramuscularly.
Serologic Correlate of Protection and Efficacy

Efficacy trials have demonstrated 90–100% efficacy against culture-
proven invasive Hib disease for 1 year after vaccination. A trial in
Gambian infants has shown 21% protection against episodes of
severe pneumonia. The serologic correlate of protection at the time
of exposure has been fixed at 0.15 μg/mL and that for long-term
protection as 1 μg/mL. Indirect protection to the unimmunized

susceptible children as a result of diminished Hib transmission
(∼50% of children exhibited anti-PRP titers ≥5 μg/mL; a level that
impedes Hib upper respiratory carriage) has also been observed
while conducting serological assessment of the Hib immunization
program in Mali.9
Effectiveness
Developed countries where the vaccine was introduced for
universal immunization have witnessed virtual elimination of Hib
disease with no serotype replacement. The vaccine has also been
shown to impart herd protection by reducing nasopharyngeal
carriage. A notable exception in the Hib success story was an
increased incidence of Hib disease in vaccinated children between
the years 1999 and 2003 in the UK occurring after a remarkable
initial decline in Hib disease in the early 1990s. Most of the cases
of invasive Hib disease occurred in the late second year of life.
The major factor responsible for this phenomenon was omission of
the 2nd year booster.
Waning of Immunity and Need of Boosters

Vaccine-induced immunity wanes over time and reduced carriage
of the organism in the environment compounds the problem by lack
of natural boosting. It is also recognized now that immunological
memory is insufficient for protection against Hib disease. Hence,
a booster dose is mandatory for sustained protection. Primary
immunization with either pentavalent vaccine is reported to
induce an excellent immunity lasting till the 2nd year of life.
A booster dose with diphtheria, tetanus, and whole-cell pertussis
(DTwP)-Hib vaccine effectuated a good anamnestic response to
all vaccine components, being especially strong for Hib in children
previously vaccinated with pentavalent vaccine.10
Safety
Side effects are mild and usually local. The committee reviewed
the postmarketing surveillance data on the safety of Hib and
Hib-containing combination vaccines in India and found a total

of 98 (46 serious and 49 nonserious) adverse event following
immunization (AEFI) episodes for 53.51 million doses (overall
frequency 1.83/million doses, and for serious AEFI 0.85/million)
from October 2004 through December 2011, suggesting that there
was no safety concern of Hib vaccines as reported frequently in
lay media. The committee strongly supports the Government of
India’s (GOI’s) efforts to introduce this vaccine in all the states in
the country.11
RECOMMENDATIONS FOR USE

Public Health Perspective
Following the recommendations of the Hib and pneumococcal
subcommittee of National Technical Advisory Group on Immuniza
tion (NTAGI) in India, in April 2008, Hib-CV as part of a pentavalent
combination vaccine was introduced in a phased manner in 2011,
in a three-dose schedule of 6–10–14 weeks, without any booster
dose and subsequently escalated to the rest of the country. All the
reported serious AEFIs were investigated by a special causality
subcommittee formed by the National AEFI Committee, which
concluded that these AEFIs were not causally related to pentavalent
vaccine. IAP had conducted a scientific study among around 1,000
pediatricians and found that >80% of them are using this Hib-
containing pentavalent vaccine in their clinical practice for more
than last 5–15 years. Majority of them had never encountered any
serious AEFI, including death.12
According to a meta-analysis, in 2000, there were almost 883,000
(517,000–1,750,000) cases of severe Hib disease in India. Following
the introduction of Hib in the UIP, the number of cases of severe Hib
estimated in 2015 had reduced to 236,000 (138,000–468,000) cases, a
significant reduction of over 75%. The estimated number of deaths
has dropped from 82,600 (52,300–112,000) in the year 2000 to 15,600
(9,800–21,500) in the year 2015.
Following introduction of pentavalent vaccine in the UIP,
significant reductions in the role of Hib as the causative pathogen in
cases of meningitis have been reported.13-15
INDIVIDUAL USE
Indian Academy of Pediatrics Advisory Committee on Vaccines and
Immunization Practices (ACVIP) recommends use of Hib vaccine
for all children below the age of 5 years.
SCHEDULE AND DOSES

Monovalent Hib-CV is no longer available. Hib-CV is available in
combination with DPT/HBV/IOPV as a quadrivalent or pentavalent
or hexavalent combinations.
The vaccination schedule for Hib is as follows:
■ <6 months: Three doses at an interval of at least 4 weeks and one
booster at 16–18 months
■ 6–12 months: Two doses at an interval of 4 weeks and 1 booster
at 16–18 months
■ 12–15 months: One dose and a booster at 16–18 months
■ >15 months: One dose only.
Catch-up vaccination is not recommended for healthy children
>5 years. However, the vaccine should be administered to all
individuals with functional or anatomic hyposplenia irrespective of
age. Hib vaccines are now used mostly as combination vaccines
with DTwP/DTaP/Hepatitis B/inactivated poliomyelitis vaccine
(IPV).
Haemophilus influenzae type B (Hib) conjugate vaccine.

• Minimum age: 6 weeks
• Primary series includes Hib conjugate vaccine at ages 6, 10, and 14
weeks with a booster at age 12 through 18 months
• Catch-up is recommended till 5 years of age
• 6–12 months: Two primary doses 4 weeks apart and one booster
• 12–15 months: One primary dose and one booster
• Above 15 months: Single dose
• If the first dose was administered at age 7 through 11 months,
administer the second dose at least 4 weeks later and a final dose at age
12–18 months at least 8 weeks after the second dose
REFERENCES
1. Invasive Bacterial Infections Surveillance (IBIS) Group of the
International Clinical Epidemiology Network. Are Haemophilus
influenzae infections a significant problem in India? A prospective
study and review. Clin Infect Dis. 2002;34:949-57.
2. Wahl B, O’Brien KL, Greenbaum A, Majumder A, Liu L, Chu Y, et al.
Burden of Streptococcus pneumoniae and Haemophilus influenzae
type b disease in children in the era of conjugate vaccines: global,
regional, and national estimates for 2000–15. Lancet Glob Health.
2018;6:e744-57.
3. Watt JP, Wolfson LJ, O’Brien KL, Henkle E, Deloria-Knoll M, McCall N,
et al. Burden of disease caused by Haemophilus influenzae type b
in children younger than 5 years: global estimates. Lancet.
2009;374:903-11.
4. Rudan I, Boschi-Pinto C, Biloglav Z, Mulholland K, Campbell H.
Epidemiology and etiology of childhood pneumonia. Bull World
Health Organ. 2008;86:408-16.
5. WHO Position Paper on Haemophilus influenzae type b conjugate
vaccines. Wkly Epidemiol Rec. 2006;81:445-52.
6. Bahl R, Mishra S, Sharma D, Singhal A, Kumari S. A bacteriological
study in hospitalized children with pneumonia. Ann Trop Paediatr.
1995;15(2):173-7.
7. Patwari AK, Bisht S, Srinivasan A, Deb M, Chattopadhya D. Aetiology
of pneumonia in hospitalized children. J Trop Pediatr. 1996;42:15-20.
8. Gupta M, Kumar R, Deb AK, Bhattacharya SK, Bose A, John J, et al.
Multi-center surveillance for pneumonia and meningitis among
children (<2 year) for Hib vaccine probe trial preparation in India.
Indian J Med Res. 2010;131:649-58.
9. Hutter J, Pasetti MF, Sanogo D, Tapia MD, Sow SO, Levine MM, et al.
Naturally acquired and conjugate vaccine-induced antibody to
Haemophilus influenzae type b (Hib) polysaccharide in Malian
children: Serological assessment of the Hib immunization program in
Mali. Am J Trop Med Hyg. 2012;86:1026-31.
10. Sharma H, Yadav S, Lalwani S, Kapre S, Jadhav S, Parekh S, et al.
Antibody persistence of two pentavalent DTwP-HB-Hib vaccines to
the age of 15–18 months, and response to the booster dose of quadri-
valent DTwP-Hib vaccine. Vaccine. 2013;31:444-7.
11. Indian Academy of Pediatrics Committee on Immunization. Consen
sus recommendations on Immunization and IAP Immunization
Timetable 2012. Indian Pediatr. 2012;49:549-64.
12. Vashishtha VM, Dogra V, Choudhury P, Thacker N, Gupta SG, Gupta

SK. Haemophilus influenzae type b disease and vaccination in India:
Knowledge, attitude and practices of pediatricians. WHO South East
Asia J Public Health. 2013;2:101-5.
13. Fitzwater SP, Ramachandran P, Kahn GD, Nedunchelian K, Suresh S,
Santosham M, et al. Impact of the introduction of the Haemophilus
influenzae type b conjugate vaccine in an urban setting in southern
India. Vaccine. 2019;37:1608-13.
14. Verghese VP, Friberg IK, Cherian T, Raghupathy P, Balaji V, Lalitha MK,
et al. Community effect of Haemophilus influenzae type b vaccination
in India. The Pediatric Infect Dis J. 2009;28(8):738-40.
15. Jayaraman Y, Veeraraghavan B, Kumar CPG, Sukumar B, Rajkumar P,
Kangusamy B, et al. Hospital-based sentinel surveillance for bacterial
meningitis in under-five children prior to the introduction of the
PCV13 in India. Vaccine. 2021;39:3737-44.
3.6 PNEUMOCOCCAL VACCINES

Rajendra Khadke, Abhay Shah
INTRODUCTION
As per the World Health Organization (WHO), pneumococcal
disease (PD) is the world’s number 1 vaccine-preventable cause of
death among infants and children <5 years of age. Furthermore, “the
recent development of widespread microbial resistance to essential
antibiotics underlines the urgent need for more efficient pneumococcal
vaccines.”1
EPIDEMIOLOGY
Pathogen
Streptococcus pneumoniae is gram-positive, catalase-negative,
facultatively anaerobic diplococci. The polysaccharide capsule
surrounding the cell wall is responsible for virulence, type-specific
identification, and stimulation of protective antibodies in the host.
Host
The causative agent, S. pneumoniae, frequently colonizes the
nasopharynx and is transmitted mainly through respiratory droplets.
Infants and young children are thought to be the main reservoir of
this agent with the prevalence of nasopharyngeal carriage ranging
from 27% in developed to 85% in developing countries.1
Disease Spectrum
Spectrum of disease ranges from asymptomatic nasopharyngeal
carriages to noninvasive and invasive pneumococcal disease (IPD).
Less common PDs include soft tissue infections, pyogenic arthritis,
osteomyelitis, primary peritonitis and salpingitis, and endocarditis.
Pneumococcal bacteremia in patients with compromised immune
status causes a rapidly progressive, fulminant course marked by
abrupt onset, progressive purpura, disseminated intravascular
coagulation, and death in 24–48 hours. The spectrum resembles
Fig. 1: Serotype distribution.15
Waterhouse–Frederickson syndrome. 2 Rare complications of

pneumococcal infection include hemolytic–uremic syndrome and
rhabdomyolysis.
A review of >70 studies has shown that out of >90 serogroups, only
10 serogroups are responsible for most pediatric infections (Fig. 1
and Table 1).3 After the introduction of pneumococcal conjugate
vaccine (PCV-7), surveillance studies from the United States showed
a decrease in cases of IPD due to vaccine serotypes and an increase in
cases due to nonvaccine serotypes, the “replacement phenomenon”.4
Burden of Pneumococcal Diseases

Disease occurs in all age groups, with the highest rates of disease in
children under 2 years of age and among the elderly. On average,
about 75% of IPD cases and 83% of pneumococcal meningitis
occur in children aged <2 years, but these incidences vary
considerably, as does the distribution of cases in age strata <2 years.
90% of bacteremia, 30–50% of severe pneumonia, are caused by
pneumococcus.12,13 Streptococcus pneumoniae is the leading cause
of pneumonia in children under 5 and it was responsible for 52% of
all fatal pneumonia cases in children in 2016.13
TABLE 1: Characteristics of different serotypes.5-11

Serotypes
1, 5, and • 28–34% of IPD
14 • 30% of IPD in 20 of the world’s poorest countries
• Serotype 14 is antibiotic resistant
3 • OM, pneumonia, especially complicated necrotizing pneumonia
• Usually causes noninvasive disease
6A • NP carriage, an important cause of IPD
• Antibiotic resistant
6B Antibiotic resistant
7F Important in India, increased case fatality rates
19A • Most prevalent in the US, in India (8–13%)
• IPD, AOM, mastoiditis
• Antibiotic resistant
19F and • Responsible for 9–18% cases globally
23F • Antibiotic resistant
(AOM: acute otitis media; IPD: invasive pneumococcal disease; NP: naso
pharyngeal carriage)
Global Burden
As per WHO (2018)11 of the estimated 5.83 million deaths among
children <5 years of age globally in 2015, 294,000 were estimated
to be caused by pneumococcal infections. Pneumonia accounts
for 14% of all deaths of children under 5 years old, killing 740,180
children in 2019.
Indian Scenario
Pneumococcal disease is also the number one vaccine-preventable
cause of death in children under 5 years, globally and in India.14
There is no robust data on the burden of milder pneumococcal
illnesses, such as sinusitis and otitis media.
The burden of pneumococcal diseases: There is no nationally
representative study of IPD incidence in the community. Most
of the available data on PDs is from hospitals and on meningitis.
According to a 2-year prospective study at three Bengaluru hospitals
in south India, the incidence of IPD in the 1st year of study among
less than 2-year-old children was found to be 28.28 cases per
100,000 population in which pneumonia contributed 15.91 and
acute bacterial meningitis (ABM) 6.82 cases per 100,000 population.
The same study has documented an overall estimated IPD incidence
of 17.78 cases per 100,000 1–59-month-old with highest burden
amongst 6–11-month-old population (49.85 cases per 100,000)
during the 2nd year of the study.15
Pneumonia burden: India accounts for 23% of global pneumonia
burden and 36% of total WHO regional burden. In 2010,
3.6 million episodes of severe pneumonia and 0.35 million all-cause
pneumonia deaths occurred in children under the age of 5 years
in India. Among those, 0.56 million episodes of severe pneumonia
(16%) and 0.10 million deaths (30%), respectively, were caused by
pneumococcal pneumonia.16-18
Meningitis burden: There is also a lack of community-based
incidence of ABM in India. A study from Vellore found an annual
incidence of “possible”, “probable”, and “proven” ABM as 86, 37.4,
and 15.9 per 100,000 children per year, respectively. Assuming
that the probable and proven cases were truly ABM, the burden of
disease was 53/100,000/year in under-five children.19 In a hospital-
based sentinel surveillance for bacterial meningitis in <5 years
children prior to the introduction of the PCV-13 in India, between
March 2012, and September 2016 in eleven hospitals, S. pneumoniae
accounted for 74.2%.20
Mortality Data
Global
World Health Organization estimates that pneumonia killed 740,180
children <5 years of age in 2019 out of estimated 5.3 million global
annual deaths with PD being the major cause of pneumonia.
India
Pneumonia causes an estimated 408,000 deaths among under-5
contributing to 19% of child mortality in India. Further, it was
estimated that 0.56 million (0.49–0.64 million) severe episodes

of pneumococcal pneumonia and 105,000 (92,000–119,000)
pneumococcal deaths occurred in India.21 These results highlight
the need to improve access to care and increase coverage and equity
of pneumonia-preventing vaccines.
Drug Resistance
Antimicrobial-resistant serotypes in S. pneumoniae have been
evolving with the widespread use of antibiotics. Particularly, among
various types of antimicrobial resistance, macrolide resistance
has most remarkably increased in many parts of the world, which
has been reported to be >70% among clinical isolates from Asian
countries. Penicillin resistance in pneumococci has complicated
its treatment and has increased the urgency for its prevention by
vaccination. About 85% resistant strains belong to six serotypes, i.e.,
6B, 23F, 14, 9V, 18A, and 18F. Multidrug resistance became a serious
concern in the treatment of IPDs, especially in Asian countries.22 After
PCV-7 vaccination, serotype 19A has emerged as an important cause
of IPDs, which was also associated with the increasing prevalence of
multidrug resistance in pneumococci.22 Penicillin-resistant isolates
may be cephalosporin-resistant and commonly exhibit resistance to
non-β-lactam antibiotics such as trimethoprim–sulfamethoxazole
and macrolides.
PNEUMOCOCCAL VACCINES
Currently, two types of vaccines are licensed for use:
1. Pneumococcal polysaccharide vaccine (PPSV)
2. Pneumococcal conjugate vaccines.
Pneumococcal Polysaccharide Vaccine

The unconjugated PPSV is a 23-valent vaccine (PPSV23) containing
25 µg per dose of the purified polysaccharide of the following 23
serotypes of pneumococcus—1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A,
12F, 14, 15B, 17F, 18C, 19F, 19A, 20, 22F, 23F, and 33F. These serotypes
account for over 80% of serotypes associated with serious diseases in
adults. It is a T-cell-independent vaccine that is poorly immunogenic
below the age of 2 years, has low immune memory, does not reduce
nasopharyngeal carriage, and does not provide herd immunity. The
vaccine is administered as a 0.5 mL dose either intramuscularly in
the deltoid muscle or subcutaneously. Each 0.5 mL dose contains
25 µg of each of the 23 polysaccharide antigens in a normal saline
solution with either phenol or thiomersal as a preservative. It is
stored at 2–8°C. Not more than two-lifetime doses are recommended,
as repeated doses may cause immunologic hyporesponsiveness to
subsequent doses.
Immunogenicity
A single dose of PPSV23 results in the induction of serotype-
specific immunoglobulin G (IgG), IgA, and IgM antibodies; the IgG
antibodies predominantly belong to the IgG2 subclass. Though the
total antibodies, as measured using the ELISA, are similar between
age groups, functional antibody responses are lower in the elderly
compared to young adults.
Efficacy and Effectiveness

Data on the efficacy and effectiveness of PPV23 is conflicting.23-25
A systematic review commissioned by WHO concluded that the
evidence was consistent with a protective effect against IPD and
pneumonia in healthy adults and against IPD in the elderly. There
was no evidence of efficacy against invasive disease or pneumonia
in other high-risk populations with underlying diseases or highly
immunosuppressed individuals in both adults and children.26 One
study in Uganda in HIV-infected adults showed an increased risk of
pneumonia among those vaccinated with PPSV23.26
Pneumococcal Conjugate Vaccines

In order to overcome the immunological limitations of PPSV, the
individual polysaccharides of a set of pneumococcal serotypes were
conjugated to carrier proteins in order to make them immunogenic
in infants, confer more long-lasting protection, and induce
immunological memory. Pharmaceutical companies developing
conjugate vaccines are using same protein carriers—cross-reactive
material (CRM197); a nontoxic mutant diphtheria toxin, diphtheria
toxoid, tetanus toxoid; or a meningococcal outer membrane

protein complex, which were used successfully to make conjugate
Haemophilus influenzae type B (Hib) vaccines.
Vaccines’ Composition
The serotypes and conjugating proteins in PCVs available in India
(Table 2).
Vaccine Immunogenicity and Efficacy

Serological correlates of protection: Any new PCV has to meet the
following criteria laid down by the WHO:1
■ Immunoglobulin G (IgG) (for all common serotypes collectively
and not individually) of ≥0.35 µg/mL measured by the WHO
reference assay (or an alternative)
■ The serotype-specific IgG geometric concentration ratios.
Immunogenicity
Comparisons of opsonophagocytic activity (OPA) antibody titers
of serotypes that are common to the new vaccine and the licensed
comparator should focus on serotype-specific geometric mean titer
(GMT) ratios rather than the previously used threshold functional
TABLE 2: Serotype composition and conjugating proteins of PCVs.

Serotypes
PCV-13 4 6B 9V 14 18C 19F 23F 1 5 7F 3 6A 19A
Conjugating CRM197
protein
PCV-10 4 6B 9V 14 18C 19F 23F 1 5 7F XX XX XX
GSK
Conjugating Protein D (NTHi) TT DT Protein D (NTHi)
protein/s
PCV-10v X 6B 9V 14 XX 19F 23F 1 5 7F XX 6A 19A
SII
Conjugating CRM197
protein
(CRM: cross-reactive material; PCV: pneumococcal conjugate vaccine)
titer ≥1:8. Both the vaccines have comparable immunogenicity in

terms of the proportion of subjects achieving serotype specific IgG
antibody levels ≥0.35 μg/mL in the dosage schedules indicated by
the manufacturer. The immunogenicity of the vaccines has also been
tested using different schedules.
Efficacy
■ Invasive pneumococcal disease: IPD was the primary outcome
for the pivotal clinical trials of PCV. While the trials used different
formulations of the vaccine administered in infants in either a 6-,
10-, and 14-week schedule or a 2-, 4-, and 6-month schedule, the
efficacy estimates were fairly consistent. In a systematic review
and meta-analysis from seven studies, a pooled vaccine efficacy
of 80% (95% CI: 58–90%, p < 0.0001) was observed against vaccine
type invasive disease and 58% (95% CI 29–75%, p = 0.001) against
total invasive disease (irrespective of serotype).27
■ Pneumonia: Since pneumococcal pneumonia is difficult to
diagnose, most trials opted to measure efficacy against pneumonia
from any cause that was associated with alveolar consolidation,
using a standardized WHO definition and process for interpreting
radiographs. Given the diversity in vaccine formulations and
vaccination schedules used and in the populations in which the
vaccines were tested, the results were remarkably consistent.
Based on the studies of PCV-7, PCV-9, and PCV-11, according
to Cochrane systemic review, the pooled estimate of vaccine
efficacy against radiologically defined pneumonia was found to
be 27% (95% CI: 15–36%, p < 0.0001).27-31 The impact of PCV was
observed in both WHO defined radiological pneumonias and the
pneumonias which do not satisfy the criteria for this definition.31
■ Otitis media: Two Cochrane database of systematic reviews
(CDSR), done in 2019 and revised in 2020, examined the effect
of PCVs on AOM.32,33 These studies did not include any data on
PCV-13.
For PCV-7 administered in early infancy, a relative risk reduction
(RRR) of −5% (95% CI: −25–12%) in high‐risk infants and 6% (95% CI:
4–9) in low‐risk infants, on all‐cause AOM was seen. A RRR of 20%
(95% CI: 7–31%) in pneumococcal AOM and 9% (95% CI: −12–27%)

to 10% (95% CI: 7–13%) reduction in recurrent AOM was also seen.
For PCV-10 (GSK), the RRR on all‐cause AOM varied from 6%
(95% CI: −6–17%) to 15% (95% CI: −1–28%) in healthy infants and
53% (95% CI: 16–74%) RRR in pneumococcal AOM was seen.
No beneficial effect was seen on all‐cause AOM, with PCV-7,
in children aged 1–7 years with a history of respiratory illness or
frequent AOM.
A systematic review of the efficacy, effectiveness, and impact of
high-valency pneumococcal conjugate vaccines on otitis media was
published recently.34
In children aged <2 years, impact studies reported reductions
of all-cause OM (primary care, outpatient, ambulatory, emergency
department visits) between 47–51% for PCV-13 and 34–43% for
PHiD-CV compared to periods before PCV introduction. These
studies were not conducted in comparable settings and the results
cannot be directly compared.
The RRR of PCV-13 and PHiD-CV on complex, complicated,
recurrent, and hospitalized otitis media (OM) varied from 9 to 62%,
with the highest impact seen in those <1 year. Greater RRR was seen
for hospitalized OM/complicated OM.
Only four studies allow some degree of direct comparison
between PCV-13 and PHiD-CV. These studies suggest PHiD-CV may
offer better protection against some OM outcomes than PCV-13, but
present data is inconclusive.
It is very difficult to establish the microbial diagnosis in AOM as it
is not ethical and feasible to do a middle ear tap for middle ear fluid
culture specimens. In a Finish study, the PCVs (PCV-7 and PCV-10
GSK) were efficacious in preventing AOM caused by the serotypes
of pneumococcus present in the vaccine, with very similar point
estimates of efficacy, ranging from 56 to 57.6%. In two of these trials
of two different formulations of PCV-7, increases in AOM due to other
serotypes of pneumococcus and other organisms increased, such
that the overall impact on otitis media was not significant.35,36 However,
the PCV-7-CRM197 was observed to protect against recurrent or more
severe forms of AOM, including otitis requiring tympanostomy
tube placement.37-39 In the third trial with PCV-10, the protection
against vaccine-type pneumococcal otitis was not completely offset
by increases in otitis by other serotypes of pneumococcus or other

bacteria; vaccine efficacy against all otitis media of 33.6% (95% CI:
21–44.3) was observed.40 In this trial, significant protection was also
observed against AOM caused by NTHi with observed efficacy of
35% (95% CI: 1.8–57.4); this protection was attributed to the immune
response to protein D of NTHi, which was the protein carrier in
this formulation of the vaccine.40 The Clinical Otitis Media and
Pneumonia Study (COMPAS) in Latin America showed that PCV-10
has a vaccine efficacy of 16.1% against otitis media. A prospective
study on AOM using PCV-13 in Israel showed a decrease in AOM
significantly from 12.2 per 1,000 to 6 per 1,000 children and that
caused by NTHi from 5.7 to 3.8 per 1,000 children.
Vaccine Effectiveness
Many countries in which PCVs were introduced as part of routine
immunization have shown a reduction in vaccine-type invasive
disease, not only in the targeted children but also in older populations
as a result of the indirect effects of the vaccine through a reduction
in nasopharyngeal carriage and transmission of the organism.40-42
Most of the available data on the effectiveness of PCV are with PCV-7.
But available data using the newer PCV-10 and -13 formulations
also show similar effectiveness, including against the additional
serotypes included in these formulations.43-46 After the introduction
of PCV-13 in the US, there was 90% decline in the 6 serotypes driven
predominantly by 19A and 7F.45 Following the introduction of PCV-13
into the national immunization programs of Australia,46,47 Uruguay,48
and United Kingdom,49 reductions in hospitalized chest X-ray-
confirmed pneumonia and empyema cases were noted. Similarly,
following PCV-13 introduction in Nicaragua—a low-to-middle
income country,50 a reduction in hospitalization and outpatient
visits for pneumonia was found in children 1 year of age. Finland
introduced PCV-10 in its national immunization program in 2010.
The vaccine efficacy was found to be 98% against vaccine serotypes.51
In South Africa, results of surveillance showed that 6.3 years after
vaccination with PCV-9, vaccine efficacy remained significant
against IPD (78%; 95% CI: 34–92%). This was consistent with
immunogenicity data showing that specific antibody concentrations
among HIV-uninfected children remained above the assumed
protective levels compared to unvaccinated HIV-uninfected controls
during this period.35
Effectiveness of Incomplete Series

Significant effectiveness against vaccine-type IPD in children
<5 years was reported for PCV-13 in 3+1 (86–96%) and 2+1 schedule
(67.2–86%) and for PCV-10 for 3+1 (72.8–100%) and 2+1 schedule (92–
97%). In pivotal clinical trials, the effectiveness of one dose of PCV-13
was estimated at 48%, two doses 87%, and 2+1 doses at 100%. One
dose catch-up for toddlers showed 83% effectiveness.36
Safety
The safety of PCV has been well studied and all formulations
are considered to have an excellent safety profile in various
studies.37,38 The main adverse events (AEs) observed are injection-
site reactions, fever, irritability, decreased appetite, and increased,
and/or decreased sleep which were reported in about 10% of the
vaccines. Fever with temperature >39°C was observed in 1/100 to
<1/10 vaccines, vomiting, and diarrhea in 1/1,000 to <1/100, and
hypersensitivity reactions and nervous system disorders (including
convulsions and hypotonic–hyporesponsive episodes) were reported
in 1/10,000 to <1/1,000 of the vaccines.1
PneumosilTM
Serum Institute of India has now introduced a new 10vPCV marked
at Pneumosil in India. This 10-valent PCV is focusing on the
serotypes prevalent in 70.4% of the affected population [Asia, Africa,
LAC (Latin America and the Caribbean), and India].
New 10vPCV (SIIPL-PCV) Clinical Data

Pneumosil (10-valent) has been extensively evaluated in five
randomized controlled trials (RCTs) and has demonstrated
comparable safety and immunogenicity against licensed
pneumococcal vaccines across diverse populations of India and

Africa when administered to adults, toddlers, and infants using
different vaccination schedules.
In the phase 1/2 study done in the Gambia, in infants,
seroprotection rates (SPRs) of >90% were observed for all serotypes
with PCV-13 following the primary immunization, whereas SPR
of >90% was observed for all serotypes except serotypes 6A and
6B, following SIIPL-PCV. Serotype-specific IgG geometric mean
concentrations (GMCs) estimates after the primary series were
above 1 mg/mL for all serotypes following both vaccines. The IgG
GMC was higher following PCV-13 for seven (6A, 6B, 7F, 9V, 19A, 19F,
and 23F) of the 10 serotypes.39
The serotype-specific OPA GMTs following the primary series
were comparable for the two vaccines for six (1, 5, 6B, 14, 19F, and
23F) of 10 serotypes, the responses were higher with PCV-13 for the
four remaining serotypes.
A substantial booster response was observed for all serotypes
following PCV-13 and for all serotypes except serotype 5 following
SIIPL-PCV.
The magnitude of the booster response was greater for five
serotypes (1, 6B, 9V, 19A, and 23F) following SIIPL-PCV and for
serotype 5 following PCV-13.
The persistence of antibodies was seen for all serotypes till 1 year
of follow-up.
The serotype-specific OPA GMTs following the primary series
were comparable for the two vaccines for six (1, 5, 6B, 14, 19F, and
23F) of 10 serotypes, while the responses were lower following
SIIPL-PCVTM for the remaining 4 serotypes. 52 A significant
booster response (except for type 5) was noted with both vaccines
in children primed at 6–10–14 weeks with the SIIPL-PCV and the
comparator vaccines. The magnitude of the booster response was
higher for 1, 6B, 9V, 19A, and 23F with SIIPL-PCVTM, while it was
higher for 5, 19A, and 19F with PCV-13. The OPA GMTs following
the booster vaccination in toddlers were generally comparable with
both vaccines. In comparison with Synflorix, both vaccines elicited
a significant booster immune response for all 10 serotypes except
serotype 5, while the OPA GMTs showed a booster response for all
10 serotypes. The persistence of antibodies was seen for all serotypes

till 1 year of follow-up.
A phase-3, randomized, double-blind study of the safety,
tolerability, lot-to-lot consistency, immunogenicity, and non-
interference with concomitant vaccinations of Serum Institute of
Pneumosil, was done in healthy infants (6–8 weeks of age) in The
Gambia, who received three doses of either Pneumosil (three groups
receiving vaccine from different lots) or Synflorix (one group) at 6,
10, and 14 weeks of age.53
Among the shared serotypes, the GMCs for serotypes 1, 5, 7F,
14, and 23F were higher after SIIPL-PCV than after PHiD-CV, while
the seroresponse for serotype 19F was higher after PHiD-CV. The
immune response to SIIPL-PCV compared with PHiD-CV was
confirmed. The seroresponse rates and GMCs to serotypes 6A and
19A in SIIPL-PCV were superior to the cross-reactive responses to
serotypes 6B and 19F generated by PHiD-CV.
Compared with after PHiD-CV, OPA GMTs after SIIPL-PCV
were higher for serotypes 1, 5, 6B, and 23F and lower for serotypes
9V and 19F.
In both groups, a significant booster response was demonstrated
for all serotypes except serotype 5 on the basis of IgG GMC ratios,
and for all serotypes, on the basis of OPA GMT ratios.
Post-booster IgG GMCs were higher in the SIIPL-PCV group for
serotypes 1, 5, 6B, 7F, 14, and 23F and were higher in the PHiD-CV
group for serotypes 9V and 19F. The OPA GMTs were higher in the
SIIPL-PCV group than in the PHiD-CV group for serotypes 1, 6B, 7F,
14, and 23F.
Safety and Side Effects

All injection-site AEs were mild (grade 1) to moderate (grade 2).
fever was the most frequent and was observed in more than half of
the participants. Altogether, five (0·7%) of 751 participants had any
grade 3 systemic reaction. The rates of local and systemic reactions
were lower after the booster.
The Drugs Controller General of India (DCGI) has approved it for
active immunization against invasive disease and pneumonia caused
by S. pneumoniae serotypes 1, 5, 6A, 6B, 7F, 9V, 14, 19A, 19F, and 23F
in infants from 6 weeks of the age group for three-dose regimen

(dosing schedule: 6, 10, and 14 weeks).54 The WHO has approved it
for active immunization against invasive disease, pneumonia, and
acute otitis media caused by S. pneumoniae serotypes 1, 5, 6A, 6B, 7F,
9V, 14, 19A, 19F, and 23F, till the age of 2 years.55
Serotype Replacement
Early observations, which showed that though PCV reduced
nasopharyngeal carriage with vaccine serotypes, a carriage with
nonvaccine serotypes increased, led to concerns about replacement
disease due to serotypes not contained in the vaccines. WHO
recommends that surveillance for replacement disease should
continue, especially in developing countries where the potential
for replacement may be different from that in industrialized
countries.1
PCV-10 versus PCV-13: Coverage of Serotypes

The recently published systematic review on serotype distribution
and antimicrobial susceptibility from India clearly shows the
serotype coverage difference between PCV-10 and PCV-13 (Fig. 2).
The vetted average difference is >11%.52
In the new 10vPCV from SII, there is no serotype 3 unlike PCV-13,
and it does not have serotypes 4 and 18C which are there in previous
PCVs. New 10vPCV also contains 6A and 19A serotypes like PCV-13.
This amounts to nearly 74% of Indian serotypes coverage presently
prevailing in India.
IAP/ACVIP RECOMMENDATIONS56
Pneumococcal Conjugate Vaccines
Individual Use
A. Healthy children
Indication: Both PCV-10 and PCV-13 are licensed for active
immunization for the prevention of PDs caused by the respective
vaccine serotypes in children from 6 weeks to 5 years of age. New
10vPCV (SII) is licensed for active immunization for the prevention
of PDs caused by the respective vaccine serotypes in children from
Fig. 2: Serotype coverage difference between PCV-10 and PCV-13 in

different studies.15,52,55 (PCV: pneumococcal conjugate vaccine)
6 weeks to 2 years of age only and not beyond. In addition, PCV-13 is

also licensed for the prevention of PD in healthy immunocompetent
children beyond 6 years and adults of all ages. PCV-13 has been
licensed by the DCGI for the age group of 6–17 years. However,
the disease burden in this age group is questionable and Advisory
Committee on Vaccines and Immunization Practices (ACVIP) does
not recommend it for this population (Table 3).
Interchangeability: When primary immunization is initiated with
one of these vaccines, the remaining doses should be administered
with the same product. However, if it is not possible to complete the
series with the same type of vaccine, the other PCV product should
be used.
The PCV-13 is administered intramuscularly as a 0.5 mL dose and
is available in latex-free, single-dose, and prefilled syringes. PCV-13
can be administered at the same time as other routine childhood
TABLE 3: Schedule for PCVs.

Primary Primary Primary
Age at first series series series Booster dose
dose PCV-13 PCV-10 10vPCV-10 All PCVs
6 weeks to 3 doses 3 doses 3 doses One dose*
6 months 12–15 months
7–11 months 2 doses* 2 doses* 2 doses* One dose* during
2nd year
12–23 months 2 doses† 2 doses† 2 doses† Not applicable
†
24–59 months 1 dose 2 doses Not applicable
*At least 6 months after the third dose.
†
At least 8 weeks apart.
Notes:
• Routine use of PCV-10/13 is not recommended for healthy children aged
>5 years.
• Minimum age for administering the first dose is 6 weeks.
• Minimum interval between two doses is 4 weeks for children vaccinated at age
<12 months, whereas, for those vaccinated at age >12 months, the minimum
interval between doses is 2 months (8 weeks).
• The DCGI has approved 10vPCV-10 SII for active immunization in infants from
6 weeks of the age group for three-dose regimen (dosing schedule: 6, 10, and
14 weeks). The WHO has approved it for active immunization, till the age of
2 years. ACVIP endorses WHO recommendation of its use till the age of 2 years.
(PCV: pneumococcal conjugate vaccine)
vaccinations if administered in a separate syringe at a separate

injection site. Concurrent administration of PCV-13 and PPV-23 is
not recommended.
B. High-risk group of children (Table 4)

Immunocompetent children (high risk):
■ Chronic heart disease (particularly cyanotic congenital heart
disease and cardiac failure)
■ Chronic lung disease (including asthma if treated with prolonged
high-dose oral corticosteroids)
■ Diabetes mellitus
■ Cerebrospinal fluid leaks
■ Cochlear implant.
TABLE 4: Recommendations for pneumococcal immunization with PCV13

and/or PPSV23 vaccine for children at high risk or presumed high risk of
pneumococcal disease.57
Previous dose of any
Age pneumococcal vaccine Recommendations
<23 Nil Age-appropriate recommendations
months
24–71 4 doses of PCV-13 • Dose 1 of PPSV23 at least 8 weeks
months after last dose of PCV13
• Dose 2 of PPSV23, 5 years after dose 1
24–71 3 previous doses • Dose 1 of PPSV23 at least 8 weeks
months of PCV13 before 24 after last dose of PCV13
months of age • Dose 2 of PPSV23, 5 years after dose 1
24–71 <3 doses of PCV 13 • 2 doses of PCV13 at least 8 weeks
months apart
• Dose 1 of PPSV23 at least 8 weeks
after last dose of PCV13
• Dose 2 of PPSV23, 5 years after dose 1
24–71 1 dose of PPSV23 • 2 doses of PCV13 at least 8 weeks
months apart and 8 weeks after last dose of
PPSV23
• 1 dose PPSV23, 5 years after dose 1
and 8 weeks after PCV13
6–18 Nil • 1 dose of PCV13
years with • Dose 1 of PPSV23, 8 weeks later
medical • Dose 2 of PPSV23, 5 years after dose 1
conditions
1 dose of PCV13 • 1 dose PPSV23
• 2nd dose PPSV23, 5 years later
>1 dose of PPSV23 • 1 dose PCV13, >8 weeks later
• 1 dose PPSV23, 5 years later
• A second dose of PPSV23, 5 years after the first dose is recommended
only for children who have functional or anatomic asplenia, HIV infection,
or other immunocompromising conditions.
• All other children with underlying medical conditions should receive one
dose of PPSV23.
• No more than two doses of PPSV23 are recommended.
(HIV: human immunodeficiency virus; PCV: pneumococcal conjugate vaccine;
PPSV: pneumococcal polysaccharide vaccine)
Children with functional or anatomic asplenia (very high risk):

■ Sickle cell disease and other hemoglobinopathies
■ Chronic or acquired asplenia
■ Splenic dysfunction.
Children with immunocompromising conditions (very high risk):
■ HIV infection
■ Chronic renal failure and nephrotic syndrome
■ Diseases associated with treatment with immunosuppressive drugs
or radiation therapy, including malignant neoplasms, leukemias,
lymphomas, and Hodgkin disease; or solid organ transplantation.
■ Congenital immunodeficiency [includes B- (humoral) or
T-lymphocyte deficiency; complement deficiencies, particularly
C1, C2, C3, and C4 deficiency; and phagocytic disorders
(excluding chronic granulomatous disease)].
When elective splenectomy, immunocompromising therapy, or
cochlear implant placement is being planned, PCV-13/PCV-10 and/
or PPSV23 vaccination should be completed at least 2 weeks before
surgery or initiation of therapy.
■ Prematurity (PT) and very low birth weight (VLBW) are
considered another high-risk category for pneumococcal
vaccination. These infants have up to ninefold higher incidence
of IPD in VLBW babies as compared to full-size babies.12 PCV-
13/-10 must be offered to these babies on a priority basis.6
Pneumococcal polysaccharide vaccine (PPSV23):
■ Minimum age: 2 years
■ Recommended only for the vaccination of persons with certain
high-risk conditions
■ Administer PPSV at least 8 weeks after the last dose of PCV to
children aged 2 years or older with certain underlying high-risk
medical conditions
■ An additional dose of PPSV should be administered after 5 years
to children with anatomic/functional asplenia or an immune
compromising condition
■ PPSV should never be used alone for the prevention of PDs
amongst high-risk individuals.
Direct versus cross-protection by PCVs: The direct protection rendered

by the serotype included in a vaccine formulation is definitely
superior to any cross-protection offered by the unrelated serotypes
even of the same group in any PCV formulation.58

As of March 2021, a total of 148 countries have introduced PCV into
their national immunization program (NIP), which includes 60 Gavi-
eligible countries. Majority (103) of the countries were using PCV-13,
whereas 31 countries use PCV-10 and 8 countries were using both
(PCV-10 and -13).59
On May 13th, 2017, PCV-13 was launched by the Union Health
Ministry of India under the Universal Immunization Programme
(UIP) and introduced in a phased manner and by November
2021, was rolled out in the entire country. The schedule consists
of two primary doses at weeks 6 and 14, followed with a booster
dose at 9 months.60 Presently, the SII-PCV-10 is being used in
the UIP.
Choice of Schedule
The WHO recommends a minimum of three doses of vaccine, given
in either a 3p + 0 or a 2p + 1 schedule. If a three-dose primary series
is used, the first dose may be given as early as 6 weeks of age with
a minimum of 4 weeks between doses. If 2p + 1 schedule is chosen,
the first dose may be given as early as 6 weeks of age, preferably with
an 8-week interval between the two primary doses, and the booster
dose administered between 9 months and 15 months. In countries
where disease incidence peaks before 32 weeks of age, the 2p + 1
schedule may leave some infants unprotected during the peak
period of risk, especially in the absence of herd effect.1 Catch-up
immunization of children >12 months of age at the time of vaccine
introduction may accelerate the impact of vaccination through
rapid induction of herd immunity. Older children with a high risk
of disease, e.g., those with asplenia, should also be targeted for
vaccination.61
RECENT UPDATES IN PNEUMOCOCCAL

VACCINES (TABLE 5)
BE 14v-PCV
On August 29, 2022, the Subject Expert Committee (SEC) of the
Central Drugs Standard Control Organization (CDSCO) has
recommended the grant of permission to Biological E Limited
to manufacture the 14-valent investigational vaccine against
S. pneumoniae infection.62
The BE’s PCV14 contains 14 serotypes, 12 of them the same as in
Prevnar. In addition, it contains serotypes 22F and 33F:
Each dose of 0.5 mL contains:63
■ Pneumococcal polysaccharide serotype 1……….3.0 μg
■ Pneumococcal polysaccharide serotypes 3, 4, 5, 7F, 9V, 14, 18C,
19A, 19F, 22F, 23F, and 33F ………2.2 μg
■ Pneumococcal polysaccharide serotype 6B……..4.4 μg
■ Adsorbed onto aluminum phosphate, as Al+++…….≤0.75 mg
■ Polysaccharide conjugated to…..20–50 µg of CRM197
■ Other ingredients: Polysorbate 20, succinic acid.
The single-dose vial is preservative free, while the multidose vial
has 2-phenoxyethanol as a preservative.
In phase-3 studies, BE 14v-PCV demonstrated noninferiority
to PCV-13 for the 12 common serotypes (1, 3, 4, 5, 6B, 7F, 9V, 14,
18C, 19A, 19F, and 23F) and noninferiority of 22F and 33F against
the lowest performing serotype 3, in PCV-13. Noninferiority was
demonstrated for OPA titers. The safety comparison shows that
BE-PCV-14 vaccine was well tolerated and found to be safe in
comparison with Prevenar 13 vaccine.
PCV-15: VaxneuvanceTM is indicated for active immunization
for the prevention of invasive disease caused by S. pneumoniae
serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, and 33F
in individuals 6 weeks of age and older. The schedule is the same as
PCV-13. It is not marketed in India.64,65
TABLE 5: Serotype composition of newly introduced PCVs compared to existing PCVs.
PCV-10 GSK 1 4 5 6A 6B 7F 9V 14 18C 19F 23F
PCV-10 SII 1 5 6A 6B 7F 9V 14 19A 19F 23F
PCV-13 1 3 4 5 6A 6B 7F 9V 14 18C 19A 19F 23F
PCV 14 (BE) 1 3 4 5 6B 7F 9V 14 18C 19A 19F 23F
22F 33F
PCV-15 (MSD) 1 3 4 5 6A 6B 7F 9V 14 18C 19A 19F 23F
22F 33F
PCV-20 (Pfizer) 1 3 4 5 6A 6B 7F 9V 14 18C 19A 19F 23F
22F 33F 8 10A 11A 12F 15B/C
(PCV: pneumococcal conjugate vaccine)
Licensed Vaccines
213
20-Valent Pneumococcal Vaccine

(20vPnC-Prevenar 20)66
PCV-20: Prevnar 20 is a vaccine indicated for active immunization
for the prevention of pneumonia and invasive disease caused by
S. pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F,
14, 15B, 18C, 19A, 19F, 22F, 23F, and 33F in adults 18 years of age
and older. For >19 years, it is indicated for those with certain chronic
conditions. It is preferred as a single 0.5 mL dose for those >65 years
of age.
REFERENCES
1. WHO Publication. Pneumococcal vaccines WHO position paper.
Vaccine. 2012;14(87):129-44.
2. Mufson MA. Pneumococcal Infections. JAMA. 1981;246:1942.
3. Balaji V, Jayaraman R, Verghese VP, Baliga PR, Kurien T. Pneumococcal
serotypes associated with invasive disease in under five children
in India & implications for vaccine policy. Indian J Med Res.
2015;142:286-92.
4. Byington CL, Samore MH, Stoddard GJ, Barlow S, Daly J, Korgenski K,
et al. Temporal trends of invasive disease due to Streptococcus
pneumoniae among children in the intermountain west: emergence of
nonvaccine serogroups. Clin Infect Dis. 2005;41:21-9.
5. Invasive Bacterial Infection Surveillance (IBIS) Group, International
Clinical Epidemiology Network (INCLEN). Prospective multi centre
hospital surveillance of Streptococcus pneumoniae disease in India.
Lancet. 1999;353:1216-21.
6. Le CF, Yusof MY, Shamala D. Current trends in pneumococcal serotype
distribution in Asia. J Vaccines Vaccin. 2011;S2:001.
7. Vashishtha VM, Choudhury P, Bansal CP, Yewale VN, Agarwal R.
Pneumococcal vaccines. IAP Guidebook on Immunization. New
Delhi: Jaypee Brothers Medical Publisher; 2013. p. 173.
8. Kaplan SL, Barson WJ, Lin PL, Stovall SH, Bradley JS, Tan TQ,
et al. Serotype 19A is the most common serotype causing invasive
pneumococcal infections in children. Pediatrics. 2010;125:429-36.
9. Reinert R, Jacobs MR, Kaplan SL. Pneumococcal disease caused by
serotype 19A: review of the literature and implications for future
vaccine development. Vaccine. 2010;28:4249-59.
10. Johnson HL, Deloria-Knoll M, Levine OS, Stoszek SK, Freimanis
Hance L, Reithinger R, et al. Systematic evaluation of serotypes causing
invasive pneumococcal disease among children under five: The

pneumococcal global serotype project. PLoS Med. 2010;7:pii:e1000348.
11. Manoharan A, Manchanda V, Balasubramanian S, Lalwani S, Modak M,
Bai S, et al. Invasive pneumococcal disease in children aged younger
than 5 years in India: a surveillance study. Lancet Infect Dis.
2017;17(3):305-12.
12. Global Burden of Disease Collaborative Network. Global Burden
of Disease Study 2017 (GBD 2017) Results Seattle, United States:
Institute for Health Metrics and Evaluation (IHME), 2018. [online]
Available from https://www.healthdata.org/sites/default/files/files/
policy_report/2019/GBD_2017_Booklet.pdf. [Last accessed November,
2022].
13. Troeger CE, GBD 2017 Lower Respiratory Infections Collaborators.
Quantifying risks and interventions that have affected the burden of
lower respiratory infections among children younger than 5 years: an
analysis for the Global Burden of Disease Study 2017. Lancet Infect Dis.
2020;20:60-79.
14. Johnson HL, Kahn GD, Anne M, Levine O, Santosham M. (2012).
Comprehensive review characterizing the epidemiology of
Streptococcus pneumoniae in India. The 8th International Symposium
on Pneumococci and Pneumococcal Diseases (ISPPD). Iguaçu Falls,
Brazil. 2012. [online] Available from https://www.jhsph.edu/ivac/
wp-content/uploads/2018/05/G_Kahn-Epidemiology_of_Strep_
pneumo_in_India.pdf. [Last accessed November, 2022].
15. Nisarga R, Premlatha R, Shivanada, Ravikumar KL, Shivappa U,
Gopi A, et al. Hospital-based surveillance of invasive pneumococcal
disease and pneumonia in South Bangalore, India. Indian Pediatr.
2015;52:205-11.
16. Rudan I, O’Brien KL, Nair H, Liu L, Theodoratou E, Qazi S, et al. Child
Health Epidemiology Reference Group (CHERG). Epidemiology and
etiology of childhood pneumonia in 2010: estimates of incidence,
severe morbidity, mortality, underlying risk factors and causative
pathogens for 192 countries. J Glob Health. 2013;3:010401.
17. Gupta M, Kumar R, Deb AK, Bhattacharya SK, Bose A, John J, et al.
Multicenter surveillance for pneumonia & meningitis among children
(<2 yr) for Hib vaccine probe trial preparation in India. Indian J Med
Res. 2010;131:649-65.
18. Broor S, Parveen S, Bharaj P, Prasad VS, Srinivasulu KN, Sumanth KM,
et al. A prospective three-year cohort study of the epidemiology and
virology of acute respiratory infections of children in rural India. PLoS
One. 2007;2:e491.
19. Minz S, Balraj V, Lalitha MK, Murali N, Cherian T, Manoharan G,

et al. Incidence of Haemophilus influenzae type b meningitis in India.
Indian J Med Res. 2008;128:57-64.
20. Jayaraman Y, Veeraraghavan B, Girish Kumar CP, Sukumar B,
Rajkumar P, Kangusamy B, et al. Hospital-based sentinel surveillance
for bacterial meningitis in under-five children prior to the introduction
of the PCV13 in India. Vaccine. 2021;39:3737-44.
21. Farooqui H, Jit M, Heymann DL, Zodpey S. Burden of Severe
Pneumonia, Pneumococcal Pneumonia and Pneumonia Deaths in
Indian States: Modelling Based Estimates. PLoS One. 2015;10(6):
e0129191.
22. Jaiswal N, Singh M, Das RR, Jindal I, Agarwal A, Thumburu KK,
et al. Distribution of serotypes, vaccine coverage, and antimicrobial
susceptibility pattern of Streptococcus pneumoniae in children living
in SAARC countries: A systematic review. PLoS One. 2014;9:e108617.
23. Moberley SA, Holden J, Tatham DP, Andrews RM. Vaccines for
preventing pneumococcal infection in adults. Cochrane Database Syst
Rev. 2008;(1):CD000422.
24. Huss A, Scott P, Stuck AE, Trotter C, Egger M. Efficacy of pneumococcal
vaccination in adults: a meta-analysis. CMAJ. 2009;180:48-58.
25. World Health Organization. 23-valent pneumococcal polysaccharide
vaccine: WHO position paper. Weekly Epidemiological Record.
2008;83:373-84.
26. French N, Nakiyingi J, Carpenter LM, Lugada E, Watera C, Moi K,
et al. 23-valent pneumococcal polysaccharide vaccine in HIV-1-
infected Ugandan adults: double-blind, randomized and placebo
controlled trial. Lancet. 2000;355:2106-11.
27. Lucero MG, Dulalia VE, Nillos LT, Williams G, Parreño RAN, Nohynek H,
et al. Pneumococcal conjugate vaccines for preventing vaccine‐
type invasive pneumococcal disease and X‐ray defined pneumonia
in children less than two years of age. Cochrane Database Syst Rev.
2009;(4):CD004977.
28. Klugman KP, Madhi SA, Huebner RE, Kohberger R, Mbelle N, Pierce N,
et al. A trial of a 9-valent pneumococcal conjugate vaccine in children
with and those without HIV infection. N Eng J Med. 2003;349:1341-8.
29. Cutts FT, Zaman SM, Enwere G, Jaffar S, Levine OS, Okoko JB, et al.
Efficacy of nine-valent pneumococcal conjugate vaccine against
pneumonia and invasive pneumococcal disease in the Gambia:
Randomised, double-blind, placebo-controlled trial. Lancet.
2005;365:1139-46.
30. Lucero MG, Nohynek H, Williams G, Tallo V, Simões EA, Lupisan S,
et al. Efficacy of an 11-valent pneumococcal conjugate vaccine against
radiologically confirmed pneumonia among children less than

2 years of age in the Philippines: A randomized, double-blind, placebo-
controlled trial. Pediatr Infect Dis J. 2009;28:455-62.
31. Hansen J, Black S, Shinefield H, Cherian T, Benson J, Fireman B,
et al. Effectiveness of hepta valent pneumococcal conjugate
vaccine in children younger than 5 years of age for prevention of
pneumonia: Updated analysis using World Health Organization
standardized interpretation of chest radiographs. Pediatr Infect Dis J.
2006;25(9):779-81.
32. Fortanier AC, Venekamp RP, Boonacker CW, Hak E, Schilder AG,
Sanders EA, et al. Pneumococcal conjugate vaccines for preventing
acute otitis media in children. Cochrane Database Syst Rev.
2019;5(5):CD001480.
33. de Sévaux JLH, Venekamp RP, Lutje V, Hak E, Schilder AGM,
Sanders EAM, et al. Pneumococcal conjugate vaccines for preventing
acute otitis media in children. Cochrane Database Syst Rev.
2020;11:CD001480.
34. Izurieta P, Scherbakov M, Guevara JN, Vetter V, Soumahoro L.
Systematic review of the efficacy, effectiveness and impact of high-
valency pneumococcal conjugate vaccines on otitis media. Hum
Vaccin Immunother. 2022;18(1):e2013693.
35. Madhi SA, Adrian P, Kuwanda L, Jassat W, Jones S, Little T, et al.
Long-term immunogenicity and efficacy of a 9-valent conjugate
pneumococcal vaccine in human immunodeficient virus infected
and non-infected children in the absence of a booster dose of vaccine.
Vaccine. 2007;25:2451-7.
36. Paradiso PR. Advances in pneumococcal disease prevention: 13-valent
pneumococcal conjugate vaccine for infants and children. Clin Infect
Dis. 2011;52:1241-7.
37. Dicko A, Odusanya OO, Diallo AI, Santara G, Barry A, Dolo A, et al.
Primary vaccination with the 10-valent pneumococcal non-typeable
Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) in
infants in Mali and Nigeria: A randomized controlled trial. BMC Public
Health. 2011;11:882.
38. Lalwani S, Chatterjee S, Chhatwal J, Verghese VP, Mehta S, Shafi F,
et al. Immunogenicity, safety, and reactogenicity of the 10-valent
pneumococcal non-typeable Haemophilus influenzae protein D
conjugate vaccine (PHiD-CV) when co-administered with the DTPw-
HBV/Hib vaccine in Indian infants: a single-blind, randomized,
controlled study. Hum Vaccines Immunother. 2012,8:612-22.
39. Clarke E, Bashorun AO, Okoye M, Umesi A, Badjie Hydara M,
Adigweme I, et al. Safety and immunogenicity of a novel 10-valent
pneumococcal conjugate vaccine candidate in adults, toddlers, and

infants in The Gambia—Results of a phase 1/2 randomized, double-
blinded, controlled trial. Vaccine. 2020;38(2):399-410.
40. Miller E, Andrews NJ, Waight PA, Slack MP, George RC. Herd immunity
and serotype replacement 4 years after seven-valent pneumococcal
conjugate vaccination in England and Wales: an observational cohort
study. Lancet Infect Dis. 2011;11:760-8.
41. Singleton RJ, Hennessy TW, Bulkow LR, Hammitt LL, Zulz T,
Hurlburt DA, et al. Invasive pneumococcal disease caused by
nonvaccine serotypes among Alaska native children with high
levels of 7-valent pneumococcal conjugate vaccine coverage. JAMA.
2007;29:1784-92.
42. Pilishvili T, Lexau C, Farley MM, Hadler J, Harrison LH, Bennett NM,
et al. Sustained reductions in invasive pneumococcal disease in the era
of conjugate vaccine. J Infect Dis. 2010;201:32-41.
43. Poehling KA, Talbot TR, Griffin MR, Craig AS, Whitney CG, Zell E,
et al. Invasive pneumococcal disease among infants before and
after introduction of pneumococcal conjugate vaccine. JAMA.
2006;295:1668-74.
44. Grijalva CG, Pelton SI. A second-generation pneumococcal conjugate
vaccine for prevention of pneumococcal diseases in children. Curr
Opin Pediatr. 2011;23(1):98-104.
45. Miller E, Andrews NJ, Waight PA, Slack MP, George RC. Effectiveness of
the new serotypes in the 13-valent pneumococcal conjugate vaccine.
Vaccine. 2011;29:9127-31.
46. Jardine A, Menzies RI, McIntyre PB. Reduction in hospitalizations
for pneumonia associated with the introduction of a pneumococcal
conjugate vaccination schedule without a booster dose in Australia.
Pediatr Infect Dis J. 2010;29:607-12.
47. O’Grady KF, Carlin JB, Chang AB, Torzillo PJ, Nolan TM, Ruben A,
et al. Effectiveness of 7-valent pneumococcal conjugate vaccine
against radiologically diagnosed pneumonia in indigenous infants in
Australia. Bull World Health Organ. 2010;88:139-46.
48. Gabarrot GG, Vega ML, Giffoni GP, Hernández S, Cardinal P, Félix V,
et al. Effect of pneumococcal conjugate vaccination in Uruguay, a
middle-income country. PLoS One. 2014;9(11):e112337.
49. Waight PA, Andrews NJ, Ladhani SN, Sheppard CL, Slack MPE,
Miller E. Effect of the 13-valent pneumococcal conjugate vaccine on
invasive pneumococcal disease in England and Wales 4 years after
its introduction: an observational cohort study. Lancet Infect Dis.
2015;15(5):535-43.
50. Becker-Dreps S, Blette B, Briceño R, Alemán J, Hudgens MG, Moreno G,

et al. Changes in the incidence of pneumonia, bacterial meningitis,
and infant mortality 5 years following introduction of the 13-valent
pneumococcal conjugate vaccine in a “3+0” schedule. PLoS One.
2017;12(8):e0183348.
51. Palmu AA, Jokinen J, Borys D, Teros-Jaakkola T, Waris M, Auranen K,
et al. Effectiveness of the ten-valent pneumococcal Haemophilus
influenzae protein D conjugate vaccine (PHiD-CV10) against
invasive pneumococcal disease: a cluster randomized trial. Lancet.
2013;381(9862):214-22.
52. Singh J, Sundaresan S, Manoharan A, Shet A. Serotype distribution
and antimicrobial susceptibility pattern in children ≤5 years with
invasive pneumococcal disease in India - A systematic review. Vaccine.
2017;35(35 Pt B):4501-4509.
53. Clarke E, Bashorun A, Adigweme I, Hydara MB, Umesi A, Futa A,
et al. Immunogenicity and safety of a novel ten-valent pneumococcal
conjugate vaccine in healthy infants in The Gambia: a phase 3,
randomised, double-blind, non-inferiority trial. Lancet Infect Dis.
2021;21:834-46.
54. Serum Institute of India. Pneumosil [DCGI Package insert]. Mumbai,
India: Serum Institute of India Pvt Ltd; 2020.
55. Serum Institute of India. Pneumosil [WHO Package insert]. Mumbai,
India: Serum Institute of India Pvt Ltd; 2020. [online] Available from
https://www.path.org/media-center/new-pneumococcal-vaccine-
serum-institute-india-achieves-who-prequalification/. [Last accessed
November, 2022].
56. Balasubramanian S. Pneumococcal vaccines. IAP Guidebook on
Immunization. New Delhi: Jaypee Brothers Medical Publisher; 2018-
19. p. 186.
57. American Academy of Pediatrics. Streptococcus Pneumoniae. In:
Kimberlin DW, Barnett ED, Lynfield R, Sawyer MH (Eds). Red Book:
2021 Report of the Committee on Infectious Diseases. Itasca, IL:
American Academy of Pediatrics: 2021. pp. 723-5.
58. Hausdorff WP, Hoet B, Schuerman L. Do pneumococcal conjugate
vaccines provide any cross-protection against serotype 19A? BMC
Pediatr. 2010;10:4.
59. Johns Hopkins Bloomberg School of Public Health International
Vaccine Access Center (IVAC). VIEW-hub Report: Global Vaccine
Introduction and Implementation. [online] Available from https://
www.jhsph.edu/ivac/wp-content/uploads/2021/05/VIEW-
hubReport_March2021.pdf. [Last accessed November, 2022].
60. Gavi, The Vaccine Alliance. India completes national introduction

of pneumococcal conjugate vaccine. [online] Available from https://
www.gavi.org/news/media-room/india-completes-national-
introduction-pneumococcal-conjugate-vaccine. [Last accessed
November, 2022].
61. World Health Organization. WHO position paper – February
2019. Pneumococcal conjugate vaccines in infants and children
under 5 years of age: Weekly epidemiological record. No 8,
2019, 94, 85-104. [online] Available from https://apps.who.
int/iris/bitstream/handle/10665/310970/WER9408-85-103.
pdf?sequence=2&isAllowed=y. [Last accessed November, 2022].
62. Biological E Limited. BE’S Corbevax Safe & Immunogenic in 5–18 age
Group. [online] Available from https://Www.Biologicale.Com/News.
Html. [Last accessed November, 2022].
63. BE vaccines PCV 14 clinical data. Personal communication. Dr
Siddalingiah, Medical advisor BE vaccines.
64. Greenberg D, Hoover PA, Vesikari T, Peltier C, Hurley DC,
McFetridge RD, et al. Safety and immunogenicity of 15-valent
pneumococcal conjugate vaccine (PCV15) in healthy infants. Vaccine.
2018;36(45):6883-91.
65. US Food and Drug Administration. Vaxneuvance. [online] Available
from https://www.fda.gov/media/150819/download. [Last accessed
November, 2022].
66. US Food and Drug Administration. Prevnar 20. [online] Available from
https://www.fda.gov/vaccines-blood-biologics/vaccines/prevnar-20.
3.7 ROTAVIRUS VACCINES

EPIDEMIOLOGY
Rotaviruses are globally the leading cause of severe, dehydrating
diarrhea in children aged <5 years. In low-income countries, 80%
of primary rotavirus infections occur among infants <1-year-old,
whereas in high-income countries, the first episode may occasionally
be delayed until the age of 2–5 years. According to Global Enteric
Multicenter Study (GEMS), the four most common pathogens
responsible for moderate-to-severe diarrhea among children in sub-
Saharan Africa and south Asia were Rotavirus, Cryptosporidium,
enterotoxigenic Escherichia coli, and Shigella.1
World Health Organization (WHO) estimates that in 2008,
approximately 453,000 (420,000–494,000) rotavirus gastroenteritis
(RVGE)-associated child deaths occurred worldwide. These fatalities
accounted for about 5% of all child deaths and cause-specific morta
lity rate of 86 deaths per 100,000 populations aged <5 years.2 More
than 80% of deaths due to rotavirus diarrhea occur in low-income
countries.3 Globally, the number of rotavirus deaths in children
<5 years of age declined from 528,000 (range: 465,000–591,000) in
2000 to 128,000 (range: 104,500–155,600) in 2016.4 The predicted
annual rotavirus detection rate declined slightly over time from
42.5% [95% confidence interval (CI): 37.4–47.5%] in 2000 to 37.3%
(95% CI: 34.2–40.5%) in 2013 globally.5
ROTAVIRUS MORBIDITY, MORTALITY, AND

BURDEN IN INDIA
National estimates of rotavirus attributable deaths among children
under 5 years of age ranged from 47,100 (India) to fewer than
5 deaths (79 countries). Twenty-two percent of all rotavirus deaths
under five years of age occurred in India. Four countries (India,
Nigeria, Pakistan, and the Democratic Republic of the Congo)
accounted approximately half (49%) of all rotavirus deaths under
age of 5 years in 2013. Indian Academy of Pediatrics (IAP) carried out
a systematic review of burden of rotavirus diarrhea in under-5 Indian

children. An analysis of 51 studies from all over India over last four
decades dealing with hospitalization with rotavirus diarrhea showed
a stool positivity rate of 22.1%. Stool positivity rate for rotavirus is
about 39% when studies year 2000 onward are only included. In
community settings, analysis of 16 studies with diarrhea showed
stool positivity for rotavirus at 18.6%. Rotavirus was identified as an
etiological agent in 16.1% cases of nosocomial diarrhea. Most cases
of rotavirus diarrhea were found to occur in the first 2 years of life.
The most commonly affected age group was 7–12 months both in
hospital and community settings. Highest numbers of cases were
recorded in winter months.6
It is difficult to estimate the impact of rotavirus diarrhea on
under-5 mortality in India. In the Million Death Study, 3,053 (13.2%)
of 23,152 deaths among children <5 years were due to diarrhea. This
corresponds to approximately 334,000 diarrheal deaths nationally
during 2005, or 1 in 82 Indian children dying from diarrhea before
the age of 5 years.7 The prevalence of rotaviral diarrhea among
Indian children aged <5 years included in ENRSN (September 2012
to December 2014) was 39.6%. This is in conformity with the findings
of the earlier round of NRSN (2005–2009).8 Taking together data from
the Million Death Study and the Indian Rotavirus Strain Surveillance
Network (IRSSN), it is estimated that in 2013, an estimated 47,100
deaths, 872,000 hospitalizations, over 3.2 million outpatient visits,
and 11.37 million diarrhea episodes occurred due to rotavirus
in children <5 years of age. In the Vellore birth cohort study, the
incidence of rotavirus diarrhea was 0.25 (95% CI: 0.22–0.29) per
child-year in children under 3 years and 0.49 (0.42, 0.58) per child-
year in children under 1 year. 48% of children experienced at least
one episode of rotavirus diarrhea by the age of 3 years. It is estimated
that India spends A2.0–3.4 billion (US$ 41–72 million) annually in
medical costs to treat rotavirus diarrhea.9
HEALTHCARE-ASSOCIATED ROTAVIRUS INFECTIONS

Rotavirus accounts for 31–87% of healthcare-associated
gastroenteritis out of which one-third is severe. The incidence is
0.3–4.8 per 1,000 hospital days.10
Seasonality of Rotavirus Infections

In temperate countries, there is a marked seasonal pattern with
peaks encompassing winter and spring months when the ambient
temperature and humidity is low. Such a marked seasonality is not
seen in the tropical countries but the activity is higher during winter
months. When minimal seasonality occurs, rotaviruses circulate at
a relatively higher level all year round, resulting in children exposed
at an early age and experiencing severe illness. According to data
generated by the extended IRSSN, most of the rotavirus cases occur in
the cooler months of September to February. The highest prevalence
is seen during December to February (56.4%).11
PATHOGEN
Rotavirus is an icosahedral ribonucleic acid virus and seven
serogroups have been described (A–G); Group A rotaviruses cause
most of the illness in humans. The viral outer capsid is made of VP7
and VP4 proteins. The VP7 protein determines the G serotypes and
the VP4 protein the P serotypes. Variability of genes coding for the
VP7 and VP4 proteins is the basis of classification into genotypes.
All G genotypes correspond with serotypes; there are more P
genotypes than serotypes. Each rotavirus strain is designated by
its G serotype number followed by P serotype number and then P
genotype number in square brackets, e.g., G1P1A[8]. The disease
spreads mostly through person-to-person contact rather than
poor hygienic or sanitary conditions. Transmission is by fecal-
oral spread, close person-to-person contact, and by fomites.
Rotaviruses are probably also transmitted by other modes such as
respiratory droplets. The increasing role of rotavirus in the etiology
of severe childhood diarrhea is likely attributable to the fact that this
pathogen is often transmitted from person to person and is difficult
to control through improvements in hygiene and sanitation, which
have had greater impact on the prevention of diarrhea caused
by bacterial and parasitic agents over the past two decades. The
universal occurrence of rotavirus infections even in settings with
high standards of hygiene testifies to the high transmissibility of
this virus.
In the systematic review carried out by IAP, a total of 51 studies

could be identified which dealt with serotyping of rotavirus.6
Overall, G1 was the most common serotype isolated in Indian studies
(32%), followed by G2 (24%), and G-untypeable (15%). Emergence
of G9 and G12 has been noticed in recent years. In P-serotyping,
P[4] was most prevalent (23%) all over India, followed by P[6] (20%)
and P-untypeable or others (13%). Several studies have reported
different G-P combinations, novel serotypes, group B and group
C rotavirus. Data from the extended IRSSN (2012–14) showed a
changing trend with G1P[8] accounting for 62.7% of isolates, G2P[4]
7.6%, G1P[4] 4.2%, G12P[6] 3.7%, G9P[8] 3.5%, G1P[6] 2.4%, G12P[8]
2.2%, and the rest being other G-P combinations, and untypeable
strains.11
Protective Immunity
Protection against rotavirus infection is mediated by both humoral
and cellular components of the immune system. Following the first
infection, the serological response is directed mainly against the
specific viral serotype (i.e., a homotypic response), whereas a broader,
heterotypic antibody response is elicited following ≥1 subsequent
rotavirus infections.12 A study from Mexico showed that children
with 1, 2, or 3 previous infections had progressively lower risk of
subsequent rotavirus infection (adjusted relative risk, 0.62, 0.40, and
0.34, respectively) or of diarrhea (adjusted relative risk, 0.23, 0.17,
and 0.08) than children who had no previous infections. Subsequent
infections were significantly less severe than first infections (p = 0.02)
and second infections were more likely to be caused by another G
type (p = 0.05).13 However, study from India reported that the risk
of severe disease continued after several reinfections. Levels of
reinfection were high, with only approximately 30% of all infections
identified being primary. Protection against moderate or severe
disease increased with the order of infection but was only 79% after
three infections.14 With G1P[8], the most common viral strain, there
was no evidence of homotypic protection.14
Vaccines
Currently, four live oral vaccines are licensed and marketed in India.
Human Monovalent Live Vaccine (RV1)

RotarixTM is a monovalent live rotavirus vaccine, which contains
a live-attenuated human strain 89-12 [type G1P1A(8)] rotavirus.
It is provided as a lyophilized power that is reconstituted before
administration. Each 1-mL dose of reconstituted vaccine contains
at least 106 median culture infective units of virus. The vaccine
contains amino acids, dextran, Dulbecco’s modified Eagle medium,
sorbitol, and sucrose. The diluents contain calcium carbonate, sterile
water, and dextran. The vaccine does not contain preservatives.
The vaccine and the diluents should be stored at 2–8°C and must
not be frozen. The vaccine should be administered promptly after
reconstitution as 1 mL orally.
Human Bovine Pentavalent Live Vaccine (RV5)

RotaTeqTM is a human bovine reassortant pentavalent vaccine
and consists of five reassortants between the bovine WC23 strain
and human G1, G2, G3, G4, and P1A[8] rotavirus strains grown
in Vero cells and administered orally. Each 2-mL vial of vaccine
contains approximately 2 × 106 infectious units of each of the five
reassortant strains. The vaccine viruses are suspended in the buffer
solution that contains sucrose, sodium citrate, sodium phosphate
monobasic monohydrate, sodium hydroxide, polysorbate 80,
and tissue culture media. The vaccine contains no preservatives
of thiomersal. The vaccine is available as a liquid virus mixed
with buffer and no reconstitution is needed. It should be stored at
2–8°C.
Indian Neonatal Rotavirus Live Vaccine (116E)

RotavacTM: This vaccine developed by Bharat Biotech of India is a
live, naturally attenuated vaccine containing monovalent, bovine-
human reassortant strain characterized as G9P[11], with the VP4 of
bovine rotavirus origin, and all other segments of human rotavirus
origin.
The vaccine strain was isolated from asymptomatic infants, with
mild diarrhea by Indian researchers in 1985 at All India Institute of
Medical Sciences, New Delhi. Follow-up of these infants indicated
that they were protected against severe rotavirus diarrhea for up to

2 years.15 This strain was sent for vaccine development to the
National Institute of Health (NIH) by Department of Biotechnology
India and later transferred to Bharat Biotech International Limited in
2001 for further development.
It is a liquid vaccine. A single human dose of this vaccine is
0.5 mL containing not less than 105 FFU (focus-forming unit) of live
rotavirus 116E.
In addition, it contains potassium phosphate, sucrose,
potassium L-glutamate monohydrate, neomycin sulfate,
kanamycin sulfate, and Dulbecco’s Modified Eagle Medium. The
commercial preparation does not contain any buffer. A recent
study has shown that administration of RotovacTM at a 0.5-mL dose
volume without buffering agent was shown to be well-tolerated
and immunogenic.16
It can be stored at −20°C till the expiry date. It can be stored up to
6 months at 5°C ± 3°C at any time during shelf-life. Rotavac 5D, can
be stored at 5°C ± 3°C till the expiry of the shelf life.
The same vaccine is also marketed by Abbott as Rotasure.
Bovine Rotavirus Pentavalent Vaccine

RotasiilTM is a pentavalent rotavirus vaccine (BRV-PV) developed
from five Bovine (UK) and Human Rotavirus Reassortant strains
(serotypes G1, G2, G3, G4, and G9) received from the US National
Institutes of Health (NIH) and further developed by the Serum
Institute of India. The viruses are propagated in Vero cells.17
The vaccine is supplied in a liquid, ready to use formulation, with
each dose of 2.0 mL containing NLT 105.6 FFU per serotype. A liquid,
ready to use formulation, is also marketed.
The liquid formulation is not heat-stable and needs to be stored
at 5°C ± 3°C till the expiry of the shelf life.14
The product insert states that the 3-dose regimen, of this vaccine,
can be completed by 1 year of age.
The comparative analysis of different rotavirus vaccines are given
in Table 1.
TABLE 1: Comparative analysis of rotavirus vaccines.

Rotavac Rotasiil RotaTeq Rotarix
Composition Monovalent: Pentavalent • G1, G2, G3, Monovalent:
116E (G9P11) G1, G2, G3, G4: Human, G1P8
G4, G9: P7: Bovine
Human P: • G6: Bovine,
UK bovine P1A[8]:
Human
Efficacy India: 53.6% India: 39.5% • USA and • Finland:
against Finland: 98% 85%
S-RVGE • Africa: 39.3% • Asia: 48.3%
Efficacy 54.4% 60.5%
against
VS-RVGE
Presentation Liquid Liquid Liquid Freezed
dried
Volume 0.5 mL 2.0 mL 2.0 mL 1 mL
Storage • Rotavac: Liquid: +2° +2° to +8°C +2° to
– –20°C till to +8°C till for 24 months +8°C for 26
expiry expiry date months
(5 years)
– +2° to
+8°C till
expiry of
VVM2
(6 m)
• Rotavac 5D:
– +2° to
+8°C for
3 Jahre
(RVGE: rotavirus gastroenteritis; S: severe; VS: very severe)
Rotavirus Vaccines’ Efficacy and Effectiveness

Although the composition of RV1 and RV5 is different, their efficacy
mechanism of action is largely similar.
Both prevent effectively severe rotavirus gastroenteritis (SRVGE)
but are less efficacious against mild RVGE or rotavirus infection.
Efficacy of these vaccines in Europe and the USA against SRVGE has
been above 90% and in Latin America around 80%. Trials in Africa
have yielded efficacy rates between 50 and 80%. In Malawi, the
effectiveness of RV1 was 49%, compared to about 77% in South Africa.
The study showed that a rotavirus vaccine significantly reduces the
episodes of SRVGE in African children during the 1st year of life.
The overall efficacy of the vaccine was lower than that observed in
European studies and Latin American studies. The possible reasons
include poor nutritional status, coinfections with other enteral
pathogens, interference by breastfeeding due to presence of high
levels anti-rotavirus neutralizing antibodies in breast milk, and
interference by maternal antibody or by coadministration of the oral
poliovirus vaccine, which may reduce rotavirus antibody levels.18
However, since the incidence of severe rotavirus disease is
significantly higher in high child mortality settings, the numbers of
severe disease cases and deaths averted by vaccines in these settings
are likely to be higher than in low-mortality settings, despite the
lower vaccine efficacy.
Rotavac TM: In a phase 3 randomized double-blind, placebo-
controlled, multicenter trial at three sites in Delhi (urban), Pune
(rural), and Vellore (urban and rural), infants aged 6–7 weeks were
randomly assigned (2:1), to receive either three doses of the 116E
vaccine or placebo at ages 6–7 weeks, 10 weeks, and 14 weeks (4
weeks interval). The primary outcome was incidence of SRVGE (≥11
on the Vesikari scale). Efficacy outcomes and adverse events were
ascertained through active surveillance.
Vaccine efficacy against SRVGE was overall, 53.6% (95% CI:
35.0–66.9; p = 0.0013), 56.4% (36.6–70.1; p < 0.0001) in the first year
of life and 48.9% (95% CI: 17.4–68.4; p = 0.0056) in the 2nd year of
life. Vaccine efficacy against severe gastroenteritis of any cause was
overall 18.6% (1.9–32.3, p = 0.0305), 24.1% (5.8–38.7, p = 0.0123) at
the end of the first year of life and 36.2% (20.5–48.7, p < 0.0001) in the
2nd year.19,20
RotasiilTM: Two phase-3 studies done in Niger and India have
established the immunogenicity, safety, and efficacy of this vaccine.
In the Indian study conducted across six centres, a total of 3,749
infants 6–8 weeks of age were randomized (1:1) to receive three oral
doses of BRV-PV or placebo (n = 3,751) at 6, 10, and 14 weeks of age

along with routine vaccines.
Vaccine efficacy against SRVGE, at the time of the primary
endpoint (when the minimum number of cases needed for analysis
were accrued), was 36% (95% CI: 11.7–53.6, p = 0.0067) in the per
protocol (PP) analysis and 39.5% (95% CI: 26.7–50, p < 0.0001) in
the intention to treat analysis over the entire follow-up period (until
children reached 2 years of age). Vaccine efficacy against the very
severe rotavirus cases (V-SRVGE, Vesikari score >16) was 60.5% (95%
CI: 17.7–81, p = 0.0131) at the time of the primary analysis and 54.7%
(95% CI: 29.7–70.8, p = 0.0004) for the complete follow-up period in
the PP population. Vaccine efficacy against severe gastroenteritis of
any etiology was negligible at 7.5% (−4.9–18.5, p = 0.2221).21
In the study done in Niger, the efficacy of three doses of vaccine
as compared with placebo against a first episode of laboratory-
confirmed SRVGE (Vesikari score, ≥11) beginning 28 days after dose
3 was 66.7% (49.9–7.9).22
Effectiveness of Rotavirus Vaccines

A systematic review of 48 peer-reviewed articles with postlicensure
data from 24 countries over the first decade of global postlicensure
(2006–2016) showed a greater vaccine effectiveness (VE) in low-
mortality countries (LMCs) and a lower VE in high-mortality
countries (HMCs) for both RV1 and RV5.23 VE tended to decline in the
2nd year of life, particularly in medium- and high-mortality settings,
and tended to be greater against more severe rotavirus disease. This
is in conformity with the findings in the recent Cochrane review.24
However, since the incidence of SRVGE is significantly higher in high
mortality settings, the numbers of severe disease cases and deaths
averted by vaccines in these settings are likely to be higher than in low-
mortality settings, despite the lower vaccine efficacy. Observational
studies in Mexico and Brazil after the introduction of RV1 reported a
reduction in diarrhea-related deaths in infants and young children.
The introduction of rotavirus vaccine has been shown to decrease the
rotavirus prevalence by 40% as shown by the data from 69 countries
participating in the Global rotavirus surveillance network. The mean
proportion of hospitalization also decreased from 38 to 23% in the
postvaccination epoch.25 Thus, introduction of the vaccine into

countries is likely to have a greater effect than that predicted on the
basis of the efficacy trials.
STUDIES IN INDIA
It was reported in a meta regression analysis of RCT’s that in low-
and medium-mortality settings, the pooled efficacy estimates
against severe RVGE were high at the 2-week time point (82–98%)
and provided durable protection at 12 months (77–94%) whereas,
in high-mortality settings, the pooled efficacy was lower at 2 weeks
(66%) and waned more rapidly to 44% by 12 months.26
There is no efficacy study of RV1 and RV5 conducted in India. In
2014, the results of the efficacy trial with 116E became available, and
at 55% efficacy, the performance of this vaccine was comparable to
that of RV1 and RV5 in Africa and other countries in Asia.
In the immunogenicity studies of RV1 and RV5 conducted in
India, the seroconversion rate was reported to be comparable with
the results obtained from other studies done in the developing
countries (i.e., Latin America, South Africa, and Bangladesh).
Studies show no interference between rotavirus vaccines and
other childhood vaccines including inactivated polio vaccine
(IPV), pneumococcal, Haemophilus influenzae type b (Hib),
diphtheria, tetanus, and acellular pertussis (DTaP), and hepatitis
B. Data is insufficient for pertussis immunity. Immunogenicity
studies about simultaneous administration of rotavirus vaccines
with oral poliovirus vaccines (OPV) are available for RV1 and
RV5, which show no reduction in immunogenicity against polio
and no clinically significant reduction in immunogenicity against
rotavirus.
Efficacy data of the Indian vaccines has been discussed above.
A multi-centric surveillance project for rotavirus VE assessment
is being carried out in 32 participating sites in nine states of India
over a period of 4 years. VE will be determined by a case–control
evaluation.27
SAFETY AND RISK OF ACUTE INTUSSUSCEPTIONS

OF ROTAVIRUS VACCINES
The available new generations of rotavirus vaccines are considered
quite safe and the risk of acute intussusception is very small in
comparison to previous vaccine.
Based on postmarketing surveillance data, the current
rotavirus vaccines have been associated with an increased risk of
intussusceptions (about 1–2/100,000 infants vaccinated) for a short
period after administration of the first dose in some populations.2
Although, a meta-analysis of intussusception risk following real
world Rotavirus vaccination in Australia, Brazil, England, Mexico,
Singapore and USA, found an increased risk of intussusception in
the first 21 days following the first dose of Rotarix or Rotateq, the
recent Cochrane Database of Systematic Reviews did not find any
increased risk of serious adverse events (moderate- to high-certainty
evidence) including intussusception.
Since the phase 3 study of Rotavac was not powered to assess the
risk of intussusception. A passive surveillance for intussusception
was set up in 35 sentinel health facilities covering 26.3 million
populations in three states. This was a self-controlled case-series
method. Intussusception was diagnosed using Brighton criteria. 151
intussusception cases were included in the analysis. The relative
incidence (incidence during the risk period compared to the control
period) 1–21 days after doses 1 and 2 combined was 1.56 (95% CI:
0.0–5.28) and that for three doses combined was 1.88 (95% CI: 0.76–
4.30) and the attributable risk after doses 1 and 2 combined was 0.11
(95% CI: 0.0–0.25) and that for three doses combined was 0.42 (95%
CI: 0.0–0.70) per 100,000 doses.
Thus, no increased risk of intussusception within 21 days of
receipt of the first two doses combined or all three doses combined
of Rotavac was detected.27
RotasiilTM: In the Indian study, adverse effects profile was similar
in both groups. 13 cases of intussusception were diagnosed; six
occurred in the BRV-PV arm and seven in the placebo arm. None
occurred within 28 days of receiving a dose of BRV-PV or placebo.21
So far, no data is available about the intussusception risk after its

introduction in the national immunization program (NIP).
Although the Global Advisory Committee on Vaccine Safety
(GACVS) in a report in 2017 concluded that there is a definite, albeit
a very small risk of acute following the use of the current rotavirus
vaccines, the recent Cochrane Database of Systematic Reviews did
not find any increased risk of serious adverse events (moderate- to
high-certainty evidence) including intussusception.24,28

The Advisory Committee on Vaccines and Immunization Practices
(ACVIP) acknowledges the morbidity and mortality burden of
rotavirus and need for effective rotavirus vaccines. Such vaccines
would be most needed in the NIP as the disease consequences are
the most serious in the underprivileged. Given the minimal impact
that water and sanitation measures have had on the burden of
rotavirus in developing areas, there is wide agreement that effective
vaccination represents the most promising prevention strategy
against the disease.
The vaccine has been rolled out in the NIP, all over the India.
Initially, WHO recommended lower age limits for vaccination
to minimize excess cases of intussusception. However, these
recommendations were changed as it excluded substantial
number of children from vaccination. A model was used to predict
the number of deaths prevented by rotavirus vaccination and the
number of intussusception deaths caused by rotavirus vaccination
when administered without any age restriction. The model
predicted that the restricted schedule would prevent 155,800
rotavirus deaths (5th–95th centiles, 83,300–217,700) while causing
253 intussusception deaths (76–689). As against it vaccination
without age restrictions would prevent 203,000 rotavirus deaths
(102,000–281,500) while causing 547 intussusception deaths (237–
1160) (i.e., 154 deaths averted for one death caused by the vaccine).29
WHO recommends administering rotavirus vaccine to children up
to 24 months of age concomitantly with diphtheria, tetanus, and

pertussis (DTP) vaccine.2
Schedule in Universal Immunization Programme (UIP): 30 The
rotavirus vaccine is to be administered in three doses at 6, 10, and
14 weeks along with the other UIP vaccines. The maximum upper
age limit for giving first dose of rotavirus vaccine is 1 year. If the child
has received first dose of rotavirus vaccine by 12 months of age, two
more doses of the vaccine should be given with an interval of 4 weeks
between two doses to complete the course.
Individual Use
Administration schedule: Vaccination should be strictly as per
schedule discussed below, as there is a potentially higher risk of
intussusceptions, if vaccines are given to older infants. Vaccination
should be avoided, if age of the infant is uncertain. There are no
restrictions on the infant’s consumption of food or liquid, including
breast milk, either before or after vaccination. Vaccines may be
administered during minor illnesses.
The risk of severe RV infection, with increased hospitalization
rates, increased intestinal dilatation, abdominal distension, and
mucoid stools are pronounced in preterm infants. Data exists about
the safety and efficacy of rotavirus vaccines in preterm infants.
Hence, rotavirus vaccines should be considered for these infants, if
they are clinically stable and at least 6 weeks of age.
Following the rollout of rotavirus vaccines in low- and middle-
income country (LMIC) of Africa and Asia, impact data against various
endpoints are now available. In general, the impact data have been
comparable to the efficacy data generated in phase-3 studies. These
include Ghana: Any-dose VE against rotavirus hospitalization was
estimated at 60% (95% CI: −2–84%; p = 0.056), Malawi: VE for two doses
of RV1 in rotavirus-negative individuals was 64% (95% CI: 24–83),
Zambia: VE against hospitalized children ≥6 months of age was 56%
(95% CI: −34–86%), South Africa: Adjusted VE using rotavirus-negative
controls was 57% (95% CI: 40–68) for two doses. A review of studies
from 38 populations found that all RVGE events occurred in 1%, 3%,
6%, 8%, 10%, 22%, and 32% children by age 6, 9, 13, 15, 17, 26, and
32 weeks, respectively. Mortality was mostly related to RVGE events

occurring before 32 weeks of age.31 The highest risk of mortality was
noted in the children having earliest exposure to rotavirus, living in
poor rural households, and having lowest level of vaccine coverage.32
It is ideal if immunization schedule is completed early in developing
countries where natural infection might occur early.2
Early administration of the first dose of rotavirus vaccine as
soon as possible after 6 weeks of age has been recommended by
WHO recently. The WHO position paper recommends that first
dose of rotavirus vaccination should be given with first dose of DPT
vaccination both for RV1 and RV5, which effectively means starting
the schedule at 6 weeks in India.
Upper limits of immunization: Immunization should not be initiated
in infants 15 weeks or older because of insufficient safety data for
vaccines use in older children. All the doses of the vaccines should be
completed within 8 months (32 weeks) of age. Programmatic errors
have been reported with use of this vaccine including parenteral
administration. ACVIP recommends to follow the manufacturers
recommendation. The vaccines should not be frozen. Large vaccine
volume requires full insertion of vial tip into infant’s mouth.
Contact with infant’s mouth contaminates the vial and has always
complicated the development of multidose vials.
Special Situations
Regurgitation of Vaccine
Readministration need not be done to an infant who regurgitates,
spits out, or vomits during or after administration of vaccine though
the manufacturers of RV1 recommend that the dose may be repeated
at the same visit, if the infant spits out or regurgitates the entire vaccine
dose. The infant should receive the remaining recommended doses
of rotavirus vaccine following the routine schedule (with a 4-week
minimum interval between doses).
Interchangeability of Rotavirus Vaccines

Ideally, the rotavirus vaccine series should be completed with
the same product. However, vaccination should not be deferred
because the product used for previous doses is unavailable. In

such cases, the series should be continued with the product that
is available. If any dose in the series was RV5, or if the product is
unknown for any dose in the series, a total of three doses should
be administered. Recent studies have shown the feasibility of
interchangeability between Rotateq and Rotarix and between
Rotavac and Rotasil.33,34
Delayed Doses
It is not necessary to restart the series or add doses because of a
prolonged interval between doses with either of the vaccines.
CONTRAINDICATIONS AND PRECAUTIONS

Contraindications:
■ Infants who have a history of a severe allergic reaction (e.g.,
anaphylaxis) after a previous dose of rotavirus vaccine or to a
vaccine component
■ History of intussusception in the past
■ Severe (anaphylactic) allergy to latex should not receive RV1
vaccine. The RV5 dosing tube is latex-free.
■ Severe combined immunodeficiency (SCID)
Precautions:
■ Altered immunocompetence (other than SCID, which is a
contraindication)
■ Moderate-to-severe illness, including gastroenteritis (vaccination
to be postponed)
■ Preexisting chronic intestinal tract disease
Rotavirus vaccine may be administered at any time before,
concurrent with, or after administration of any blood product,
including antibody-containing blood products.
IAP/ACVIP RECOMMENDATIONS
The first dose of all oral rotavirus vaccines should be administered
before 14 completed weeks.
The last dose should be completed before 32 completed weeks.
Interval between doses should be at least 4 weeks.
Except RV1, which is to be administered in a two-dose schedule,

the other vaccines are to be administered in a three-dose schedule.
Universal Immunization Programme Schedule

The first dose is to be administered at 6 weeks, with the 1st dose of
the Pentavalent vaccine, anytime up to 1 year of age.
Second and third doses are to be administered at an interval of
4 weeks.
If the first dose is administered around 1 year of age, the second
and third doses can be administered in the 2nd year.
Rotavirus Vaccination
■ Minimum age: 6 weeks for all available vaccines
■ An interval of 4 weeks should be maintained between doses
■ Only two doses of RV1 are recommended at present with the
first dose administered at 6 weeks of age and the second dose
administered 4 weeks later.
■ Other RV vaccines should be employed in a three-dose 6-, 10-,
and 14-week schedule.
■ Interchange between vaccine brands should be avoided. If
unavoidable or if vaccine product is unknown for any dose in the
series, a total of three doses of RV vaccine should be administered.
■ The maximum age for the first dose in the series is 14 weeks, 6 days.
■ Vaccination should not be initiated for infants aged 15 weeks,
0 days or older.
■ The maximum age for the final dose in the series is 8 months,
0 days.
REFERENCES
1. Kotloff KL, Nataro JP, Blackwelder WC, Nasrin D, Farag TH,
Panchalingam S, et al. Burden and aetiology of diarrhoeal disease in
infants and young children in developing countries (the Global Enteric
Multicenter Study, GEMS): a prospective, case-control study. Lancet.
2013;382:209-22.
2. Rotavirus vaccine. WHO Position Paper-July 2021. Weekly

epidemiological record. 2021;96:301-19.
3. Parashar UD, Gibson CJ, Bresse JS, Glass RI. Rotavirus and severe
childhood diarrhoea. Emerg Infect Dis. 2006;12:304-16.
4. Troeger C, Khalil IA, Rao PC, Cao S, Blacker BF, Ahmed T, et al. Rotavirus
vaccination and the global burden of rotavirus diarrhea among
children younger than 5 years. JAMA Pediatr. 2018;172(10):958-65.
5. Tate JE, Burton AH, Boschi-Pinto C, Parashar UD; World Health
Organization–Coordinated Global Rotavirus Surveillance Network.
Global, Regional, and National Estimates of Rotavirus Mortality in
Children <5 Years of Age, 2000–2013. Clin Infect Dis. 2016;62(Suppl
2):S96-S105. doi:10.1093/cid/civ1013.
6. Kumar A, Basu S, Vashishtha V, Choudhury P. Burden of
Rotavirus Diarrhea in Under five Indian Children. Indian Pediatr.
2016;53(7):607-17.
7. Morris SK, Awasthi S, Khera A, Bassani DG, Kang G, Parashar UD, et al.
The Million Death Study Collaborators. Rotavirus mortality in India:
estimates based on a nationally representative survey of diarrhoeal
deaths. Bull World Health Organ. 2012;90(10):720-7.
8. Kang G, Arora R, Chitambar SD, Deshpande J, Gupte MD, Kulkarni
M, et al. Multicenter, hospital-based surveillance of rotavirus disease
and strains among Indian children aged <5 years. J Infect Dis. 2009;200
(Suppl 1):S147-53.
9. Tate JE, Chitambar S, Esposito DH, Sarkar R, Gladstone B, Ramani S,
et al. Disease and economic burden of rotavirus diarrhoea in India.
Vaccine. 2009;27:F18-24.
10. Ramani S, Kang G. Burden of disease and molecular epidemiology
of group A rotavirus infections in India. Indian J Med Res.
2007;125(5):619-32.
11. Girish Kumar CP, Giri S, Chawla-Sarkar M, Gopalkrishna V,
Chitambar SD, Ray P, et al. Epidemiology of rotavirus diarrhea among
children less than 5 years hospitalized with acute gastroenteritis prior
to rotavirus vaccine introduction in India. Vaccine. 2020;38(51):8154-60.
12. Angel J, Franco MA, Greenberg HB. Rotavirus immune responses and
correlates of protection. Curr Opin Virol. 2012;2(4):419-25.
13. Velazquez FR, Matson DO, Calva JJ, Guerrero L, Morrow AL, Carter-
Campbell S, et al. Rotavirus infection in infants as protection against
subsequent infections. N Engl J Med. 1996;335:1022-8.
14. Gladstone BP, Ramani S, Mukhopadhya I, Muliyil J, Sarkar R,
Rehman AM, et al. Protective effect of natural rotavirus infection in an
Indian birth cohort. N Engl J Med. 2011;365:337-46.
15. Bhandari N, Sharma P, Taneja S, Kumar T, Rongsen-Chandola T,

Appaiahgari MB, et al. A dose-escalation safety and immunogenicity
study of live attenuated oral rotavirus vaccine 116E in infants: a
randomized, double blind, placebo-controlled trial. J Infect Dis.
2009;200:421-9.
16. Ella R, Bobba R, Muralidhar S, Babji S, Vadrevu KM, Bhan MK, et al.
A Phase 4, multicentre, randomized, single-blind clinical trial to
evaluate the immunogenicity of the live, attenuated, oral rotavirus
vaccine (116E), ROTAVAC, administered simultaneously with or
without the buffering agent in healthy infants in India. Hum Vaccin
Immunother. 2018;14(7):1791-9.
17. Zade JK, Kulkarni PS, Desai SA, Sabale RN, Naik SP, Dhere RM, et al.
Bovine rotavirus pentavalent vaccine development in India. Vaccine.
2014;32 Suppl 1:A124-8.
18. Vesikari T. Rotavirus vaccination: a concise review. Clin Microbiol
Infect. 2012;18(Suppl 5):57-63.
19. Bhandari N, Rongsen-Chandola T, Bavdekar A, John J, Antony K,
Taneja S, et al. Efficacy of a monovalent human-bovine (116E) rotavirus
vaccine in Indian infants: a randomised, double-blind, placebo-
controlled trial. Lancet. 2014;383:2136-43.
20. Bhandari N, Rongsen-Chandola T, Bavdekar A, John J, Antony K,
Taneja S, et al. Efficacy of a monovalent human-bovine (116E) rotavirus
vaccine in Indian children in the second year of life. Vaccine. 2014;32
Suppl 1:A110-6.
21. Kulkarni PS, Desai S, Tewari T, Kawade A, Goyal N, Garg BS, et al.
A randomized Phase III clinical trial to assess the efficacy of a bovine-
human reassortant pentavalent rotavirus vaccine in Indian infants.
Vaccine. 2017;35(45):6228-37.
22. Isanaka S, Guindo O, Langendorf C. Efficacy of a low-cost, heat-stable
oral rotavirus vaccine in Niger. N Engl J Med. 2017;376:1121-30.
23. Jonesteller CL, Burnett E, Yen C. Effectiveness of Rotavirus Vaccination:
A Systematic. Review of the First Decade of Global Postlicensure Data,
2006 -2016. Clin Infect Dis. 2017;65(5):840-50.
24. Bergman H, Henschke N, Hungerford D, Pitan F, Ndwandwe D,
Cunliffe N, et al. Vaccines for preventing rotavirus diarrhoea: vaccines
in use. Cochrane Database Syst Rev. 2021;17;11(11):CD008521.
25. Aliabadi N, Antoni S, Mwenda JM, Weldegebriel G, Biey JNM, Cheikh D,
et al. Global impact of rotavirus vaccine introduction on rotavirus
hospitalisations among children under 5 years of age, 2008–16:
findings from the Global Rotavirus Surveillance Network. Lancet Glob
Health. 2019;7(7):e893-e903.
26. Clark A, van Zandvoort K, Flasche S, Sanderson C, Bines J, Tate J,

et al. Efficacy of live oral rotavirus vaccines by duration of follow-up:
a meta-regression of randomised controlled trials. Lancet Infect Dis.
2019;19:717–27.
27. Nair NP, Reddy NS, Giri S, Mohan VR, Parashar U, Tate J, et al. Rotavirus
vaccine impact assessment surveillance in India: protocol and methods.
BMJ Open 2019;9:e024840. doi:10.1136/ bmjopen-2018-024840.
28. Reddy SN, Nair NP, Tate JE, Thiyagarajan V, Giri S, Praharaj I, et al.
Intussusception after rotavirus vaccine introduction in India. N Engl J
Med. 2020;383:1932-40.
29. Rotavirus vaccine safety update. Available at https://www.who.
int/groups/global-advisory-committee-on-vaccine-safety/topics/
rotavirus-vaccines/safety-vaccine. [Last accessed November, 2022].
30. Patel MM, Clark AD, Glass RI, Greenberg H, Tate J, Santosham M,
et al. Broadening the age restriction for initiating rotavirus vaccination
in regions with high rotavirus mortality: benefits of mortality reduction
versus risk of fatal intussusception. Vaccine. 2009;27(22):2916-22.
31. Operational guidelines. Introduction of Rotavirus vaccine in Universal
Immunization Program in India. Immunization division, Ministry of
Health and Family welfare, Government of India. December 2016.
32. Detailed Review Paper on Rotavirus Vaccines. Available at https://
www.nitag-resource.org/sites/default/files/333bf74ed2594625
b1c3c27f81409d418873f348_1.pdf. [Last accessed November, 2022].
33. Libster R, McNeal M, Walter EB, Shane AL, Winokur P, Gretchen Cress G,
et al. Safety and immunogenicity of sequential rotavirus vaccine
schedules. Pediatrics. 2016;137(2):e20152603.
34. Kanungo S, Chatterjee P, Bavdekar A, Murhekar M, Babji S, Garg R,
et al. Safety and immunogenicity of the Rotavac and Rotasiil
rotavirus vaccines administered in an interchangeable dosing
schedule among healthy Indian infants: a multicentre, open-label,
randomised, controlled, phase 4, non-inferiority trial. Lancet Infect
Dis. 2022;22(8):1191-9.
3.8 MEASLES, MUMPS, AND

RUBELLA VACCINES
B Rajsekhar, Sanjay Verma
MEASLES-RUBELLA: BURDEN OF DISEASE AND

GENERAL PERSPECTIVE
Measles elimination contributes significantly in achieving
Millennium Development Goal 4 (MDG-4). “One of the three
indicators for monitoring progress toward achieving MDG-4 is the
proportion of 1-year-old children immunized against measles”.1
Measles
While measles is now rare in many industrialized countries, it
remains a common illness in many developing countries. In countries
where measles has been largely eliminated, cases imported from
other countries and among the unvaccinated remain an important
source of infection. While India has made significant progress in
child survival, it continues to have the second-largest number of
children not vaccinated against measles. Since 2001, the Measles
Initiative has supported 80 countries to deliver >1 billion doses of
measles vaccine, helped to raise measles vaccination coverage to
85% globally, and reduced global measles deaths by 74%. These
efforts have contributed significantly to reduce child mortality as per
MDG-4.2
The Measles and Rubella Initiative is a global partnership
aimed at ensuring no child dies of measles or is born with
congenital rubella syndrome (CRS). Indian health ministry
launched a single dose measles–rubella (MR) vaccination
campaign in a phased manner in January 2017 to immunize
410 million children in the age group of 9 months to 15 years, all
over the country.3 The MR campaign led to a significant reduction
in measles cases in India, from 83,026 in 2015 to 10,695 in 2017.4
India still contributes to the fourth-largest measles caseload.
Studies have suggested that 47% of global measles-associated
deaths were reported from India alone.5
Mumps
In India, there is very limited data on the burden of mumps. Mumps
outbreaks have been reported from various states, at an interval of
every 5–10 years.6
Data on the seroprevalence of mumps in India is also limited.
In a study done on 321 serum samples to detect mumps-specific
antibodies in children <5 years, seropositivity for mumps was
53.3% in children aged <9 months, 20.3% in 9–12 months, and 40%
in 2 years old. Mean antibody levels for mumps were low between
9 months and 2 years with a slight rise by 5 years.7
In a study done on Health Sciences students from Manipal
University, 32% of them were susceptible to mumps.8 Among the
measles, mumps, and rubella (MMR)-vaccinated group, 34.7% were
susceptible to mumps. Generally, data suggests that seropositivity
for mumps among Indian population is low, and large group of
the population remains susceptible.
The complications of mumps are also many and can be
profound—aseptic meningitis, encephalitis, orchitis, oophoritis,
pancreatitis, deafness, transverse myelitis, facial palsy,
ascending polyradiculitis, and cerebellar ataxia. Mumps in a
pregnant woman can also give rise to fetal damage in the form of
aqueductal stenosis leading to congenital hydrocephalus.9
Rubella
Rubella per se is a mild exanthematous illness, but if acquired
in the first trimester of pregnancy, it can lead to disastrous
consequences in the fetus/newborn such as abortion, stillbirth,
mental retardation, congenital heart disease, blindness, and
cataract. Hence, the objective of vaccination against rubella is
protection against CRS. Developed countries have remarkably
reduced the burden of CRS by universal immunization against
rubella. It is essential that when immunization against rubella
is instituted, >80% coverage is achieved. Indiscriminate use of
rubella vaccine (monovalent or as a constituent of MR/MMR) in
young children through public health measures with suboptimal
coverage of the target population may be counterproductive as it
may shift the epidemiology of rubella to the right with more clinical
cases occurring in young adults leading to a paradoxical increase
in cases of CRS. This has been shown to occur using mathematical
models. Direct evidence from some Latin American countries
and Greece also corroborates these concerns. The incidence
of CRS increases when a significant proportion of women in the
reproductive age group are susceptible. Susceptibility to rubella
has been found to be high among adolescent girls in India. Studies
conducted in Amritsar, Maharashtra, and Jammu report rubella
susceptibility being 36%, 23.6%, and 32.7% in prepubertal girls,
adolescent females, and girls of 11–18 years, respectively. 10-12
Although the trend is changing, as shown by a recent serosurvey
conducted by Indian Council of Medical Research (ICMR) among
pregnant women attending antenatal clinics in various hospitals in
India, in which, 15.2% of them were seronegative for Rubella.13 A
systematic review done in India showed that 10–30% of adolescent
females and 12–30% of women in the reproductive age-group are
susceptible to rubella infection in India.14
Congenital Rubella Syndrome

Comprehensive evidence about the actual burden of CRS in India
is not available.14 The 2008 estimates suggest that the highest CRS
burden is in South East Asia (approximately 48%), India being
a major contributor and Africa (approximately 38%). 15 Other
developing countries have incidence rates of 0.6–4.1 per 1,000
livebirths.16 A sentinel surveillance done in India between 2016
and 2018, to study the epidemiology of CRS, had 645 suspected
CRS patients enrolled during 2 years, of which 137 (21.2%) were
classified as laboratory confirmed CRS and 8 (1.2%) as congenital
rubella infection. 17 A systematic review done in India showed
that 1–15% of all infants suspected to have intrauterine infection
were found to have laboratory evidence of CRS.14 About 3–10%
of suspected CRS cases are ultimately proven to have confirmed
CRS with the aid of laboratory tests. CRS accounts for 10–15% of
pediatric cataract. About 10–50% of children with congenital
anomalies have laboratory evidence of CRS. Thus, there is a
significant burden of CRS in India.14
M/MR/R VACCINES
Globally, most developed countries use MMR vaccines. For
reasons mentioned earlier, Advisory Committee on Vaccines and
Immunization Practices (ACVIP) feels that the combined MMR
vaccine is a better option than an MR vaccine. The burden of mumps
has been reduced in developed countries following use of MMR
vaccines. Like rubella, poor coverage of mumps vaccine, in early
childhood, can shift epidemiology to the right and increase infection
rates in adolescents and adults with greater complications.
Formulations from different manufacturers have different strains
of the vaccine virus. Mumps vaccine virus strains include Leningrad–
Zagreb, Leningrad-3, Jeryl Lynn, RIT 4385, Hoshini or Urabe AM9
strains and are grown in chick embryo/HDC cultures. In India, three
brands of MMR vaccines are available—Tresivac (SII), Priorix (GSK),
and ZyVac MMR (Zydus).
Tresivac contains live-attenuated strains of Edmonston–Zagreb
measles virus propagated on human diploid cell culture, L-Zagreb
mumps virus propagated on chick embryo fibroblast cells, and Wistar
RA 27/3 rubella virus propagated on human diploid cell culture. The
vaccine is freeze-dried and is provided with diluent. Each dose of the
reconstituted vaccine contains not <1,000 cell culture infective doses
(CCID50) of Measles virus, 5000 CCID50 of Mumps virus, and 1000
CCID50 of rubella virus. This vaccine does not contain preservatives.18
Storage:
■ Store between +2 and +8°C and protected from light
■ The diluent should not be frozen, but should be kept cool
■ The reconstituted vaccine must be kept between +2 and
+8°C, away from sunlight and must be discarded 4 hours after
reconstitution.
Priorix contains the Schwarz strain of live-attenuated measles virus,
the RIT 4385 strain of live-attenuated mumps virus (derived from the
Jeryl Lynn strain), both propagated in chick-embryo fibroblasts from
embryonated eggs of specific pathogen-free flocks and the Wistar
RA 27/3 strain of live-attenuated rubella virus propagated in MRC-5
human diploid cells.19
After reconstitution, each dose (0.5 mL) contains:

■ Live attenuated measles virus (Schwarz strain) not less than 103
CCID50
■ Live attenuated mumps virus (RIT 4385 strain), derived from
Jeryl Lynn strain), not less than 103.7 CCID50
■ Live attenuated rubella virus (Wistar RA 27/3 strain), not less
than 103 CCID50.
ZyVac MMR
Each 0.5 dose contains live-attenuated measles virus (Edmonston–
Zagreb strain) NLT 1000 CCID (propagated on human diploid cells),
live-attenuated mumps virus (Hoshino strain) NLT 5000 CCIDs
(propagated on chick fibroblast cells), and live-attenuated rubella
virus (RA27/13 strain) NLT 1000 CCIDs (propagated on human
diploid cells).
Storage:
■ Store at 2–8°C before and after reconstitution
■ Keep in carton to protect from light
■ The diluent should not be frozen
■ Single dose vials should be used immediately after
reconstitution
■ The multidose vials should be used within 6 hours after
reconstitution.
MR Vaccine
It is a freeze-dried vaccine, available as single-dose and multidose
vials, and is to be administered subcutaneously, over the upper arm/
anterolateral thigh. Each single dose of 0.5 mL, when reconstituted
contains not less than 1,000 median CCID50 of live measles virus
particles and 1,000 CCID50 of rubella virus.20
Its shelf life is 24 months at 2–8°C. WHO recommends that
opened vials of this vaccine should be discarded 6 hours after
opening or at the end of the immunization session, whichever comes
first.
Measles-containing vaccines vial can get contaminated when
the cap is punctured, leading to bacterial growth in the vial as it
does not contain any preservative. Bacterial contamination with

Staphylococci, which secrete several exotoxins, can cause severe
shock in recipients.21 Toxic shock syndrome (TSS) can be prevented
by adhering to injection safety, and if reconstituted, the multidose
MR vaccine should be used within 4–6 hours. Unused doses after
this period must be discarded.
Rubella Vaccine
Rubella (R) vaccine is currently derived from RA 27/3 vaccine strain
grown in human diploid/chick embryo cell cultures. The vaccine
is available in a freeze-dried form that should be stored frozen or
at 2–8°C and needs to be reconstituted with sterile diluent prior to
use. The reconstituted vaccine must be protected from light, stored
at 2–8°C, and used within 6 hours of reconstitution. The dose is
0.5 mL subcutaneously. A single dose of vaccine provides lifelong
protection in 95% of the vaccines. Apart from local side effects, a
mild rash may develop in 5% of the vaccines. Joint symptoms such as
arthralgia and arthritis may occur 1–3 weeks following vaccination,
especially in susceptible post-pubertal females but are usually mild.
Immune thrombocytopenic purpura may occur in a frequency of
1 per 30,000 vaccinated children. The vaccine is contraindicated in
the severely immunocompromised and in pregnancy. Pregnancy
should be avoided for 4 weeks after vaccination, but babies born
to women inadvertently vaccinated in pregnancy do not exhibit
an increased risk of congenital malformations. Hence, accidental
vaccination in pregnancy is not an indication for medical
termination of pregnancy.
IMMUNOGENICITY
Measles Vaccine
Due to interference by preexisting maternal antibodies,
immunogenicity depends on the age of administration.
Seroconversion rates are around 60% at the age of 6 months,
80–85% at the age of 9 months, and beyond 95% at the age of
12–15 months.22 While antibody titers wane over the years, measles-
specific cellular immunity persists and provides lifelong protection.
Secondary vaccine failures rarely occur. Immunogenicity is lower

in the immunocompromised, including human immunodeficiency
virus (HIV). In HIV-infected infants, superior seroconversion rates
are seen at 6 months as compared to 9 months due to progressive
immunodeficiency with age. Vaccine efficacy studies from India
have reported varying efficacies ranging from 60 to 80% when given
at the age of 9 months.22
Mumps Vaccine
Seroconversion rates against mumps are >90%, but clinical efficacy
and long-term protection with a single dose is 60–90%; outbreaks
have been noted in previously vaccinated populations.22 Hence,
two doses are needed for durable protection. When the first dose
is administered before the age of 1 year, two additional doses
are necessary, the second after the age of 1 year, and the third in the
preschool age.
Rubella Vaccine
A single dose of vaccine provides lifelong protection in >95% of the
vaccinees.22
ADVERSE EFFECTS
Measles Vaccine
Side effects are infrequent and usually mild.23 The measles vaccine
may cause within 24 hours of vaccination mild pain and tenderness
at the injection site. In most cases, they spontaneously resolve within
2–3 days without further medical attention. A mild fever can occur in
5–15% of vaccines 7–12 days after vaccination and last for 1–2 days.
The rash occurs in approximately 2% of recipients, usually starting
7–10 days after vaccination and lasting 2 days. The mild side effects
occur less frequently after the second dose of a measles-containing
vaccine and tend to occur only in a person not protected by the first
dose. Encephalitis has been reported following measles vaccination at
a frequency of approximately one case per million doses administered,
although a causal link is not proven. Apart from local pain and tender
ness, a mild measles-like illness appears 7–12 days after vaccination
in 2–5% of the vaccines. Thrombocytopenic purpura may occur at a

frequency of 1/30,000 vaccines. Though depression of cell-mediated
immunity may occur, it recovers within 4 weeks and is considered
harmless even for those with early HIV or latent/unrecognized tuber
culosis. There is no data supporting a causal relationship between the
measles vaccine and encephalitis, Guillain–Barré syndrome (GBS),
subacute sclerosing encephalitis, and autism. There is no transmission
of the vaccine virus from the vaccines to the contacts.23
Mumps Vaccine
About 5% of children can get fever more than 39°C 7–12 days following
vaccination, and febrile seizures may occur.23 Aseptic meningitis
can rarely occur 2–3 weeks following vaccination but is usually
mild. Transient parotitis may occur. The virus does not spread from
vaccine to contacts. There is now incontrovertible evidence that
there is no causal relationship between MMR vaccine and autism,
inflammatory bowel disease, GBS, and many other neurological
complications.
Rubella Vaccine
Apart from local side effects, a mild rash may develop in 5% of
the vaccinees.23 Joint symptoms such as arthralgia and arthritis
may occur 1–3 weeks following vaccination, especially in
susceptible postpubertal females but are usually mild. Immune
thrombocytopenic purpura may occur in a frequency of 1 per 30,000
vaccinated children.
CONTRAINDICATIONS FOR MMR VACCINE24-26

■ Severe allergic reaction to vaccine component or following a
prior dose of MMR vaccine
■ Severe immunocompromised state including systemic high-
dose corticosteroid therapy for 14 days or more, HIV infection
with severe immunosuppression, family history of congenital or
heredity immunodeficiency in first-degree relatives
■ Pregnancy.
PRECAUTIONS FOR MMR VACCINE24-26

■ Moderate or severe acute illness
■ Receipt of antibody-containing blood products, in the past
3–11 months
■ History of thrombocytopenic purpura or thrombocytopenia
■ If pregnancy is planned, then an interval of 1 month should be
observed after MR vaccination.
ACVIP RECOMMENDATIONS27
Indian Academy of Pediatrics (IAP)/ACVIP recommends a 3-dose
schedule of MMR vaccine as follows:
■ Dose 1: Completion of 9 months
■ Dose 2: 15–18 months
■ Dose 3: 4–5 years of age.
UNIVERSAL IMMUNIZATION PROGRAMME

RECOMMENDATIONS
The National Technical Advisory Group on Immunization (NTAGI)
observed that since the “disability component” of mumps is not a
serious public health problem and since the addition of mumps
component to Universal Immunization Programme (UIP) would
result in a substantial increase (more than twice than that of rubella
vaccine) in cost without commensurate public health benefits, MR
vaccine should be introduced instead of MMR. Immediately after
the completion of the campaign, the MR vaccine was introduced in
RI, replacing the two doses of measles vaccine—at 9–12 months and
16–24 months.
■ Dose 1: 9–12 months
■ Dose 2: 16–24 months.
In case of an outbreak, the vaccine can be given to infants as
young as completed 6 months, but this early dose is not to be counted
and the usual dose at 9 months is to be administered.
The MMR vaccine, if administered within 72 hours after
exposure, to susceptible individuals, may prevent or modify
measles disease and is the intervention of choice for postexposure
prophylaxis in immunocompetent hosts. Postexposure prophylaxis

is not of much benefit against mumps and rubella.
The Global Measles and Rubella Strategic Plan 2012–2020
(MRSP 2012–2020) resulted in measles elimination in 82 countries
and rubella elimination in 81 countries (by the end of 2018).28
There was a sizable reduction in the measles and rubella disease
burden, a steep increase in the introduction of the MCV2 and
rubella-containing vaccine, and improvements in the surveillance.
Now, the Measles and Rubella Strategic Framework 2021–2030 aims
for a world free of measles and rubella, although the timeline and
targets for eradication will be set when the necessary conditions for
eradication are met. This also allows the individual WHO regions to
set their regional measles and rubella elimination goals and develop
strategies to achieve them.28
Member countries of the WHO South-East Asia region, including
India, set a regional goal to eliminate measles and rubella by 2023.
Measles elimination and rubella control have been a regional
flagship priority since 2014. Five countries have already eliminated
measles—Bhutan, DPR Korea, Maldives, Sri Lanka, Timor-Leste,
and six countries have controlled rubella—Bangladesh, Bhutan,
Maldives, Nepal, Sri Lanka, and Timor-Leste. Member countries
adopted a “Strategic Plan for Measles and Rubella Elimination 2020–
2024” that lays down the roadmap and focus areas on achieving the
elimination targets in the region.29
Measles, mumps, and rubella (MMR) vaccine, IAP/ACVIP.

• Minimum age: 9 months
• Administer the first dose of MMR vaccine at 9 months of age, second
dose at 15 months, and third dose at age 4 through 6 years
• Ensure that all school-aged children and adolescents have had two doses
of MMR vaccine; the minimum interval between the two doses is 4 weeks
• One dose if previously vaccinated with one dose
• In campaign mode, MMR vaccine can be administered irrespective of the
administration of previous doses
(ACVIP: Advisory Committee on Vaccines and Immunization Practices; IAP:
Indian Academy of Pediatrics)
MR vaccine.
Routine vaccination: Universal Immunization Programme:
• Dose 1 is administered at minimum age of 9 months or 270 completed
days
• Dose 2 is administered at 16–24 months
• Catch-up vaccination up to 5 years
• For catch-up vaccination, minimum interval between dose 1 and dose 2
should be at least 4 weeks
• Measles-containing vaccine can be administered to infants aged 6
through 11 months during outbreaks. These children should be revacci-
nated with two doses of measles-containing vaccines; the first at ages
12 through 15 months and at least 4 weeks after the previous dose, and
the second dose at ages 4 through 6 years
REFERENCES
1. WHO SEARO. Measles Elimination and Rubella Control 2013. [online]
Available from http://www.searo.who.int/mediacentre/events/
governance/rc/66/9.pdf. [Last accessed November, 2022].
2. Measles Key Facts. Available at https://www.who.int/news-room/
fact-sheets/detail/measles?gclid=Cj0KCQiA7bucBhCeARIsAIOwr--
cl5okfe4_KMRuH_FO6ZaAfCrooWxShZnl1Fp0w-nN4rtGqGDLi7
AaAi4eEALw_wcB. [Last accessed November, 2022].
3. Singh KP. India’s measles-rubella vaccination campaign a big step
towards reducing childhood mortality, addressing birth defects.
[online] Available from https://www.who.int/southeastasia/news/
detail/05-02-2017-india-s-measles-rubella-vaccination-campaign-
a-big-step-towards-reducing-childhood-mortality-addressing-birth-
defects. [Last accessed November, 2022].
4. Panda BK, Mishra S, Awofeso N. Socio-demographic correlates of first
dose of measles (MCV1) vaccination coverage in India. BMC Public
Health. 2020;20:1221.
5. Sinha K. (2012). Times of India report: 47% of global measles deaths in
India, 2012. [online] Available from https://timesofindia.indiatimes.
com/home/science/47-of-global-measles-deaths-in-india/
articleshow/12843053.cms. [Last accessed November, 2022].
6. World Health Organization. Position paper. Mumps virus vaccines.
Wkly Epidemiol Rec. 2007;7:51-60.
7. Chakravarti A, Yadav S, Berry N, Rastogi A, Mathur MD. Evaluation of
serological status of rubella and mumps in children below five years.
Indian J Med Res. 1999;110:1-3.
8. Arunkumar G, Vandana KE, Sathiakumar N. Prevalence of Measles,

Mumps, Rubella and Varicella Susceptibility among Health
Science Students in a University in India. Am J Ind Med. 2013;56(1):
58-64.
9. Mumps virus vaccines: WHO position paper, 2007. Available at https://
www.who.int/teams/immunization-vaccines-and-biologicals/
policies/position-papers/mumps. [Last accessed November, 2022].
10. Singla N, Jindal N, Aggarwal A. The seroepidemiology of rubella in
Amritsar (Punjab). Indian J Med Microbiol. 2004;22:61-3.
11. Sharma HJ, Padbidri VS, Kapre SV, Jadhav SS, Dhere RM, Parekh
SS, et al. Seroprevalence of rubella and immunogenicity following
rubella vaccination in adolescent girls in India. J Infect Dev Ctries.
2011;5:74-81.
12. Sharma H, Chowdhari S, Raina TR, Bhardwaj S, Namjoshi G,
Parekh S, et al. Serosurveillance to assess immunity to rubella
and assessment of immunogenicity and safety of a single dose of
rubella vaccine in school girls. Indian J Community Med. 2010;35:
134-7.
13. Muliyil DE, Singh P, Jois SK, Otiv S, Suri V, Verma S. Seroprevalence
of rubella among pregnant women in India, 2017. Vaccine.
2018;36(52):7909-12.
14. Dewan P, Gupta P. Burden of Congenital Rubella Syndrome (CRS) in
India: a systematic review. Indian Pediatr. 2012;49(5):377-99.
15. Cutts FT, Robertson SE, Diaz-Ortega JL, Samuel R. Control of rubella
and congenital rubella syndrome (CRS) in developing countries,
Part 1: Burden of disease from CRS. Bull World Health Organ.
1997;75(1):55-68.
16. WHO. Global Measles and Rubella. Strategic Plan 2012–2020. [online]
Available from https://apps.who.int/iris/bitstream/handle/10665/448
55/9789241503396_eng.pdf. [Last accessed November, 2022].
17. Murhekar M, Verma S, Singh K, Bavdekar A, Benakappa N, Santhanam
S, et al. Epidemiology of Congenital Rubella Syndrome (CRS) in India,
2016-18, based on data from sentinel surveillance. PLoSNegl Trop Dis.
2020;14(2):e0007982.
18. Serum Institute of India Ltd. Tresivac Product insert. [online] Available
from https://www.seruminstitute.com/product_ind_tresivac.php.
[Last accessed December, 2022].
19. Priorix Product insert. [online] Available from https://india-pharma.
gsk.com/media/6402/priorix.pdf. [Last accessed November, 2022].
20. Serum Institute of India Ltd. MR vaccine product insert. [online]
Available from https://www.seruminstitute.com/product_ind_mrvac.
php. [Last accessed November, 2022].
21. Sood DK, Kumar S, Singh S, Sokhey J. Adverse reactions after measles
vaccination in India. Natl Med J India. 1995;8(5):208-10.
22. Lalwani S, Chatterjee S, Balasubramanian S, Bavdekar A, Mehta S,
Datta S, et al. Immunogenicity and safety of early vaccination with
two doses of a combined measles-mumps-rubellavaricella vaccine in
healthy Indian children from 9 months of age: a phase III, randomised,
non-inferiority trial. BMJ Open. 2015;5:e007202.
23. Vaccine Knowledge Project. Adverse effects of MMR vaccine. [online]
Available from https://vk.ovg.ox.ac.uk/vk/mmr-vaccine. [Last
24. Center for Disease Control and Prevention. (2021). Measles. [online]
Available from https://www.cdc.gov/vaccines/pubs/pinkbook/meas.
html. [Last accessed November, 2022].
25. Center for Disease Control and Prevention. (2021). Mumps. [online]
Available from https://www.cdc.gov/vaccines/pubs/pinkbook/
mumps.html. [Last accessed November, 2022].
26. Center for Disease Control and Prevention. Rubella. https://www.cdc.
gov/vaccines/pubs/pinkbook/rubella.html. [Last accessed November,
2022].
27. Kasi SG, Shivananda S, Marathe S, Chatterjee K, Agarwalla S, Dhir
SK, et al. Indian Academy of Pediatrics (IAP) Advisory Committee
on Vaccines and Immunization Practices (ACVIP): Recommended
Children Aged 0 Through 18 Years. Indian Pediatr. 2021;58(1):44-53.
28. WHO. Measles and Rubella Strategic Framework 2021-2030.
[online] Available from https://s3.amazonaws.com/wp-agility2/
measles/wp-content/uploads/2021/02/Measles-Rubella-Strategic-
Framework-Updated.pdf. [Last accessed November, 2022].
29. WHO. WHO South-East Asia Region sets 2023 target to eliminate
measles, rubella. [online] Available from https://www.who.int/
southeastasia/news/detail/05-09-2019-accelerate-efforts-to-
eliminate-cervical-cancer-who. [Last accessed November, 2022].
3.9 VARICELLA VACCINES

Rajendra Khadke, Sanjay Srirampur
INTRODUCTION
Varicella-zoster virus (VZV) is a highly contagious virus, which
causes both varicella (chickenpox), usually during childhood, and
herpes zoster (HZ) (shingles), usually much later in adult life. VZV
is present worldwide and, in the absence of a varicella vaccination
program, most people become infected by mid-adulthood.1
Varicella (chickenpox) is a febrile rash illness resulting from
primary infection with the VZV. Humans are the only source of
infection for this virus. Varicella severity and complications are
increased among immunocompromised persons, infants, and
adults. In otherwise healthy children, varicella is usually self-
limiting. However, healthy children and adults may also develop
serious complications and rarely mortality may occur from varicella.2
The most common complications in children are secondary
bacterial infections. Pneumonia, usually viral, is the most
common complication in adults. Groups at higher risk for severe
complications are neonates, infants, pregnant women, adults, and
immunocompromised persons. In neonates, varicella can be life-
threatening, especially if the mother develops varicella within 5 days
before or 2 days after delivery. Central nervous system complication
seen includes cerebellar ataxia and encephalitis.
MODE OF TRANSMISSION
Varicella-zoster virus is a double-stranded deoxyribonucleic acid
(DNA) virus belonging to the Herpesviridae family. The virus is
transmitted from person to person by direct contact with the varicella
or HZ rash, inhalation of aerosolized droplets from respiratory tract
secretions of patients with varicella, or rarely from the inhalation of
aerosolized droplets from vesicular fluid of skin lesions of patients
with varicella or disseminated HZ. The virus enters the host through
the upper respiratory tract or the conjunctiva. After primary infection
with VZV, the virus remains dormant in the sensory nerve ganglia
and can reactivate later in life, causing HZ.3,4
DISEASE BURDEN
The epidemiology of varicella differs between temperate and
tropical climates. In tropical climates, VZV seroprevalence peaks at
a higher mean age and higher susceptibility among adults is seen, as
compared to temperate climates. There is a little data on the health
burden of varicella in developing countries. However, as in tropical
climates, higher proportion of varicella cases may occur among
adults, varicella morbidity and mortality may be higher than that
described in developed countries.5 Seropositivity is lower in adults
from tropical and subtropical areas.6 A seroprevalence study from
West Bengal reported only 42% rural adults were immune.7
Seroprevalence studies in healthcare workers or students have
demonstrated seronegative prevalence ranging from <5% in USA,
14–19% in Saudi Arabia, 25% in India, and 50% in Sri Lanka.1 Varicella
shows a strong seasonality in temperate settings and in most tropical
settings, with peak incidence during winter and spring, or in the
coolest, driest months in the tropics. Periodic large outbreaks occur
with an interepidemic cycle of 2–5 years.
A study from South India found that healthcare workers in the
tropics may be vulnerable to hospital-acquired varicella infection
and may further transmit infection to susceptible hospitalized
patients, as well as to other susceptible children and adults.8 Based
on conservative estimates, the global annual varicella disease
burden would include 4.2 million severe complications leading to
hospitalization and 4,200 deaths.9
Infectious Disease Surveillance Data

According to the academy’s passive reporting system of 10 infectious
diseases by the pediatricians (www.idsurv.org), a total of 816 (7.7%)
cases of varicella were reported out of total 10,580 cases from
December 2010 to December 11, 2013. Out of these 816 cases, 58.2%
were between 5 and 18 years, 18.6% between 3 and 5 years, and 15.4%
between 1 and 3 years of age. 63 (7.7%) cases were below 1 year of
age. Only 12% were fully immunized while 74% were not immunized
at all. 3% had severe disease, needed hospitalization, and there was
no mortality.10
PREVENTION OF VARICELLA: NATURAL IMMUNITY

Varicella-zoster virus infection stimulates both humoral and cell-
mediated immune response. Although commercially available
enzyme-linked immunosorbent assay (ELISA) tests are designed
to detect immunoglobulin G (IgG) antibodies formed in response
to natural infection, they are less sensitive than glycoprotein ELISA
(gp-ELISA). The antibody titers peak at around 4–8 weeks and usually
remain high for 6–8 months. Thereafter, the titers decline steadily.9,10
Primary VZV infection induces cell-mediated immunity (CMI) by
the proliferation of VZV-specific CD4+ and CD8+ T cells. The IgG
antibodies against VZV persist lifelong. Although CMI responses
also last for a long time, they usually start waning at around 50 years
of age and this is the time individuals become prone to develop
zoster.11
VACCINE
A vaccine based on live-attenuated VZV (Oka strain)12 was developed
and clinically tested in the 1970s and 1980s. It was first licensed in
Germany and Sweden in 1984. The vaccines are available either
as monovalent (varicella only), or in combination with measles,
mumps, and rubella (MMR) vaccine.13
Takahashi et al. developed a live-attenuated vaccine from the
Oka strain in Japan in the early 70s.14 Varicella vaccines, in use today,
are all derived from the original Oka strain but the virus contents may
vary from one manufacturer to another. They differ in the number
of passages in human diploid cells, the virus dose, antibiotics used,
stabilizers, and other minor components incorporated. Vaccination
induces both humoral and cellular immunity.
Monovalent varicella vaccines available in India currently are as
under:
■ Variped (MSD)
■ Varilrix (GSK)
■ Nexipox (Mf. China, Mkt-NovoMedi Sciences).
All vaccines are approved by Central Drugs Standard Control
Organization (CDSCO) after phase II and III immunogenicity
and safety studies. All varicella vaccines are freeze-dried and
TABLE 1: Stabilizers in varicella vaccines.

Monosodium Human Trehalose
L-glutamate— serum as a Stability
stabilizer Gelatin albumin stabilizer at 2–8°C
VARIPED Yes Yes 24 months
VARILIX Yes Yes 24 months
NEXIPOX Yes Yes Yes 36 months
lyophilized. They are licensed for use in persons aged >12 months.
All of them employ live-attenuated VZV (Oka strain). They do
differ in the number of plaque-forming units (PFUs) from 1,300
to 2,500 PFUs—though a dose of 200 PFU is immunogenic. WHO
does not specify a minimum number of PFUs per vaccine dose, but
is important for national regulatory authority, which licenses the
vaccine.14
Stabilizers are added to vaccine to ensure that the vaccine
remains unchanged when it is exposed to heat, light, acidity, or
humidity. It is necessary to have a look at these ingredients because
the vaccines differ in their use and often claims are made based on
these ingredients (Table 1). WHO has not offered any guideline
regarding choice of stabilizer.
IMMUNOGENICITY11,12
The gp-ELISA was the first test used to assess the immunogenicity
of the vaccine. Prelicensure studies showed that seroconversion
(any detectable varicella antibodies >0.3 gp-ELISA units/mL) was
seen in 95–98% of susceptible children aged 1–12 years after a
single dose of the vaccine. Later, a gp-ELISA cutoff of 5 units/mL
was seen to correlate better with protection against clinical disease
as compared to seroconversion and this level was achieved in
86% of children following a single dose. Subsequent studies used
fluorescent antibody to membrane antigen (FAMA) titers of >1:4 at
16 weeks of vaccination as a correlate of protection; 76% children
achieved this cutoff following receipt of single dose of the vaccine.
Follow-up studies indicate persistence of antibodies for 7–10 years
and even 20 years following vaccination. Since immunity to varicella
is also cell-mediated, T lymphocyte proliferation responses have

been studied and found to be present in 87–90% of children for up to
5 years postvaccination.
The immunogenicity improves with a second dose of the
vaccine in all respects; percentage seroconversion and those with
antibody levels above the serologic correlate of protection both by
gp-ELISA and FAMA is higher (99.6% vs. 85.7%), the geometric mean
titers (GMTs) achieved are higher with two doses as compared to a
single dose and the lymphocyte proliferation responses are better.
The immunogenicity is similar whether the second dose is given
3 months or 4–6 years after the first dose. Immunogenicity is better
when the second dose is given 8–12 weeks after the first dose as
compared to 4 weeks.
The immunogenicity of the vaccine is lower in adolescents
and adults and studies have demonstrated seroconversion rates of
72–94% following a single dose of the vaccine and 94–99% after two
doses of the vaccine administered 4–8 weeks apart. However, other
studies indicate that 25–31% of adults lose their detectable antibodies
by FAMA at multiple intervals (1–11 years) following vaccination.
The immunogenicity of the MMR plus varicella (MMRV) vaccine
is similar to that of MMR and varicella vaccine administered on the
same day at different sites.
EFFICACY
Prelicensure efficacy and postlicensure effectiveness studies
have shown the efficacy of a single dose of the vaccine to range
from 70 to 90% against any disease and >95% against combined
moderate and severe disease for 7–10 years after vaccination.15-17
Administration of two doses 3 months/4–6 years apart improves
seroprotection rates to 99% and results in higher GMTs by at
least 10-fold. This translates to superior efficacy of 98.3% against
any disease/100% against moderate/severe disease and reduces
incidence of breakthrough varicella as compared to single dose by
3.3-fold (Table 2). A 10-year follow-up after vaccination comparing
1 versus 2 doses (2900–9000 PFUs) estimated vaccine efficacy
(VE) to be 94.4% and 98.3% respectively (p < 0.001). There was no
breakthrough varicella till 7–10 years after two doses.
TABLE 2: Seroconversion and efficacy of one and two doses of varicella

vaccine.
Parameter One dose Two doses
Seroconversion 86% 99%
Efficacy—mild disease 70–90% 98.3%
Efficacy—moderate to severe disease >95% 100%
Vaccine Effectiveness (Table 2)

Most postlicensure studies were done in the United States. Hence,
most data are available for Variped. Varilrix, Okavax, and other
vaccines were studied in other countries. SAGE Working Group
of WHO did systemic review of both Variped and Varilrix with
substantial data available. There have been few studies on Chinese
vaccine. A systemic review concludes that VE appears similar across
all products amounting to 80–92%.
INDIAN STUDIES
All the Indian studies are immunogenicity studies with Varilrix/
Variped as comparator vaccines. There are no efficacy studies from
India.
Population Impact Data

Till 2021, 49 countries have introduced varicella in National
Immunization Schedule, 6 in western Pacific region, 24 in the
European region, 6 in the Eastern Mediterranean region, and 13 in
the Americas. The impact studies have been published from several
countries, which are using either Variped, Varilrix, or both. Overall,
a reduction >80% in the incidence of disease and hospitalizations
has been reported in most of the studies. The second dose has
conferred additional benefits as well as the induction of some herd
immunity. Any increase in the incidence of HZ in older individuals
has not been confirmed in most of the studies. Universal VV has been
shown to be cost-effective. Most data are reported from high- and
middle-income countries, and the impact in low-income countries

may not be the same.18
Breakthrough varicella: It is defined as varicella developing >42 days

after immunization and usually occurs 2–5 years following vaccina
tion. It occurs in about 1–4% of vaccines per year. Breakthrough
varicella was observed to have the highest rate in the first 4–5 years
after vaccination.9 Breakthrough disease in 70% of instances is
typically mild, with <50 skin lesions, predominantly maculopapular
rather than vesicular rash, low or no fever, and shorter (4–6 days)
duration of illness.19 It may go unnoticed/undiagnosed resulting
in more opportunities to infect others due to failure to isolate these
cases. Nevertheless, breakthrough varicella is contagious, may
be severe, can result in outbreaks, and has occasionally caused
deaths in the immunocompromised. Some of the risk factors
for vaccine failure and breakthrough disease include young age
at vaccination (<15 months), increasing time since vaccination,
receipt of steroids within 3 months of breakthrough disease,
initiation of vaccination in older children and adolescents, and
administration of vaccine within 28 days of MMR vaccine but not on
the same day.
Vaccine Failure and Breakthrough Varicella

Vaccine failure with single dose is mainly “primary” as most cases
of breakthrough disease happen within 5 years of vaccination and
efficacy of single dose or two doses are similar at 10 years following
vaccination. The observed vaccine failure after one dose of vaccine
may be explained in most probability as that immunized children
either do not develop humoral immunity to VZV at all or that there
is an initial immune “burst” of immunity that is enough to generate
a positive gp-ELISA result but is inadequate to generate a sustained
memory T-cell response leading to waning of immunity over a period
of time. This logically explains that second dose given 3 months after
the first dose is more protective to protect an individual against
breakthrough varicella.
SAFETY
There is a strong evidence for safety of all varicella vaccines. Only
minor adverse events are reported. Postmarketing survey and other
data are available only for Variped and Varilrix.
Adverse reactions, documented carefully in prelicensure/post
licensure studies, include local reactions such as pain, redness, and
swelling at vaccination site, injection site rash, fever, and a systemic
varicella-like rash in around 5%. Transmission of the vaccine virus
from vaccines to contacts is rare, especially in the absence of a
vaccine-related rash in the vaccines. However, vaccine recipients
who develop a rash should avoid contact with persons without
“evidence of immunity” who are at high risk for severe complications.
The side effect profile is similar with the two-dose schedule.
There is no increased incidence of zoster after vaccination.
Contraindication for varicella vaccines:
■ Known severe allergic reaction to vaccine component or
following a prior dose
■ Immunosuppression due to malignancies, immune deficiency
disease, or immunosuppressive therapy
■ Family history of congenital or heredity immunodeficiency in
first-degree relatives
■ Pregnancy
■ Hematopoietic stem cell transplantation (HSCT)—may be given
after 24 months.
Precautions for varicella vaccines:
■ Receipt of antibody-containing blood products (wait 3–11 months
to vaccinate)
■ Receipt of specific antiviral drugs 24 hours before vaccination
■ Child on aspirin or aspirin-containing products, salicylates to be
discontinued for 6 weeks after vaccination.
Risk of HZ among Immunized Individual

Herpes zoster in vaccine recipients is known to occur due to both
the vaccine virus and the wild virus; however, the overall incidence
of HZ in vaccinated children was noted to be much lower than

unvaccinated children in prelicensure trials.

Individual Use
Advisory Committee on Vaccines and Immunization Practices
(ACVIP) recommends the following:
■ To all healthy children with no prior history of varicella.
With special emphasis in all children belonging to certain high-
risk groups as enumerated below:
■ Children with humoral immunodeficiencies
■ Children with HIV infection but with CD4 counts 15% and above
the age-related cutoff
■ Leukemia in remission and off chemotherapy for at least
3–6 months
■ Children on long-term salicylates. Salicylates should be avoided
for at least 6 weeks after vaccination.
■ Children likely to be on long-term steroid therapy. The vaccine
may be given at any time if the children are on low-dose steroids/
alternate day steroids but only 4 weeks after stopping steroids
if the patients have received high-dose steroids (>2 mg/kg) for
14 days or more.
■ In household contacts of immunocompromised children
■ Adolescents who have not had varicella in past and are known to
be varicella IgG negative, especially if they are leaving home for
studies in a residential school/college.
■ Children with chronic lung/heart disease
■ Seronegative adolescents and adults if they are inmates of or
working in the institutional setup, e.g., school teachers, day-care
center workers, military personnel, and healthcare professionals.
Varicella vaccine in children with acute lymphatic leukemia
(ALL), with no evidence of immunity:
■ Since varicella is a devastating illness in the immunocompro-
mised especially ALL, exclusive recommendations exist for
administration in ALL.
In children between 12 months and 17 years of age with a

negative history of varicella in whom leukemia is in remission
for at least 12 months, the peripheral blood lymphocyte count
≥700 cells/mm3 and the platelet count is ≥100,000/mm 3, two
doses of varicella vaccine may be administered. Maintenance
chemotherapy should be withheld for 7 days before and after at least
the first dose.
Varicella vaccine for postexposure prophylaxis in susceptible
healthy nonpregnant contacts:
■ Among children, protective efficacy was reported as ≥90% when
vaccination occurred within 3 days of exposure.
■ Protective efficacy in preventing any type of disease was 62.3%
[confidence interval (CI) 95%: 47.8–74.9] and 79.4% (CI 95%:
66.4–88.9) in preventing moderate and severe disease, up to
5 days after exposure.
■ Vaccination still recommended for those with no other evidence
of immunity even after 5 days of exposure because it will help to
provide protection against future exposures.
The following groups are at high risk for varicella complications:
■ Infants born to mothers who develop varicella within 5 days
before delivery to 2 days after delivery. The risk of varicella-
related death in these infants as per older estimates is likely to be
30% but may be lower. Other full-term healthy newborns are not
at increased risk for complications and do not merit prophylaxis
if exposed to varicella.
■ Exposure to varicella in:
y Preterms >28 weeks GA, no maternal immunity
y Preterm <28 weeks GA or <1,000 g, irrespective of maternal
immunity
y Immunocompromised without e/o immunity. All immuno
compromised children especially neoplastic disease,
congenital or acquired immunodeficiency or those receiving
immunosuppressive therapies. Immunosuppressed
children, who received intravenous immunoglobulin (IVIg)
at a dose of 400 mg/kg in the past 3 weeks are deemed
protected.
y Pregnant women without e/o immunity.
Varicella zoster immunoglobulin (VZIg) provides passive

immunity against varicella and is indicated for postexposure
prophylaxis in susceptible individuals with significant contact with
varicella/HZ who are at high risk for severe disease. Susceptible
individual is defined as:
■ All unvaccinated children who do not have a clinical history of
varicella in the past
■ All unvaccinated adults who are seronegative for antivaricella
IgG.
Bone marrow transplant recipients are considered suscep-
tible even if they had disease or received vaccinations prior to
transplantation.
A “significant contact” is defined as any face-to-face contact or
stays within the same room for a period greater than 1 hour with a
patient with infectious varicella (defined as 1–2 days before the rash
till all lesions have crusted) or disseminated HZ. Patients meeting
these two criteria and who are at high risk of developing severe
disease as enumerated below merit prophylaxis with VZIg:
Management of exposure in a high-risk contact:
■ VZIg: as soon after exposure, up to 10 days. Dose: 125 IU/10 kg
BW to a maximum of 625 IU, minimum is 62.5 IU, in a neonate.
The currently available VZIg is for intravenous use (Varitect) and
is administered at a dose of 0.2–1 mL/kg diluted in normal saline
over 1 hour.
If VZIg is unavailable: IVIg: 400 mg/kg, single dose.
If VZIg and IVIg is unavailable: Oral acyclovir, beginning 7 days after
exposure, given for 7–10 days in a dose of 20 mg/kg/dose 6 hourly.
Administration of VZIg/IVIg is recommended as soon as possible,
within 10 days, to immunocompromised children without evidence
of immunity.
Following the above-mentioned postexposure prophylaxis, the
child should be under observation, for a month, for development of
varicella, as delayed appearance has been noted after administration
of VZIg/IVIg. If clinical Varicella is noted, the high-risk contact
should be treated with IV acyclovir for 10 days.
VACCINE STORAGE AND HANDLING

Vaccine is available in a lyophilized form. The vaccine should be
reconstituted using the diluent provided and as per the instructions
issued by the manufacturer in the product insert. Each 0.5 mL of
the reconstituted vaccine contains over 1,350–3,000 PFUs. Some
brands contain hydrolyzed gelatin, trace amounts of neomycin
and fetal bovine serum, sucrose, and trace residual components of
MRC-5 cells (including DNA and protein). To maintain potency, the
lyophilized vaccine must be stored frozen at 2–8°C in the refrigerator
in the clinic. The diluent should be stored separately either at room
temperature or in refrigerator at 2–8°C. The unreconstituted form of
the vaccine has a shelf life of 2/3 years, if stored as per manufacturer’s
guidelines. The reconstituted vaccine should be used immediately
after reconstitution. It should be protected from light and needs to
be used within 30 minutes of reconstitution.
DOSAGE AND SCHEDULE

The recommended dose is 0.5 mL to be administered sub
cutaneously. The vaccine may be given simultaneously with all other
childhood vaccines.
The vaccines are licensed for age 12 months and above. However,
the risk of breakthrough varicella is lower if given 15 months onward.
Hence, ACVIP recommends administration of varicella vaccine in
children aged 15 months or older. After a single dose of varicella
vaccine, approximately 15% of vaccines remain at risk of developing
a breakthrough varicella disease. These varicella infections in
immunized population may raise concern regarding VE and a
misunderstanding by physicians or parents who may lose faith in
vaccination. Two doses of varicella vaccine offer superior individual
protection as compared to a single dose. The ACVIP now recommends
two doses of varicella vaccine for children of all age groups.
For primary immunization, the first dose is best administered at
15 months and the second dose should be given 3–6 months after
the first dose. However, during an outbreak, the first dose may be
administered at 12 months of age if it is ensured that the two-dose
schedule will be completed by the individual child. The second
dose may be administered anytime 3 months after the first dose.

For catch-up vaccination, children below the age of 13 years should
receive two doses 3 months apart and those aged 13 years or more
should receive two doses at an interval of 4–8 weeks.
All high-risk children should, however, receive two doses
4–8 weeks apart irrespective of age. Susceptible household contacts
of immunocompromised individuals can safely receive the varicella
vaccine since there is no evidence of transmission of the vaccine
virus from the vaccine to the contact and even if it was to occur, the
disease is likely to be very mild. If the vaccine develops a vaccine-
related rash, he/she should avoid contact with a susceptible
immunocompromised contact.
Two vaccines, ZostavaxTM (live attenuated) and Shingrix TM
(recombinant) are available in the global market, for protection
against HZ. Presently, they are not available in India.
Zostavax
Zostavax zoster vaccine live (ZVL) is a lyophilized preparation of
live, attenuated VZV (Oka/Merck), propagated in human diploid
cell cultures. The reconstituted single dose suspension contains a
minimum of 19,400 PFUs when stored at room temperature for up
to 30 minutes.
The VE was 70% (95% CI = 54–81) (median follow-up time
was 1.3 years), in persons aged 50–59 years, 64% (95% CI = 56–71)
in persons aged 60–69 years and 38% (95% CI = 25–48) in persons
aged ≥70 (median follow-up time was 3.1 years). The VE reduces
substantially following the first year after receipt of ZVL, and, by 6
years postvaccination, vaccine effectiveness against HZ is <35%.
The incidence of serious adverse events were similar in
vaccinated and placebo groups. Rarely, disseminated rash as
well as HZ has been reported in immunocompetent recipients,
and life-threatening and fatal complications in immunocompromised
recipients.
Schedule: Single dose of HZ vaccine for people 50 years of age or
older, irrespective of prior history of HZ, administered SC.
Contraindications: Life-threatening or severe allergic reaction to

gelatin, the antibiotic neomycin or any other component of HZ
vaccine, immunocompromised persons, pregnancy. Women should
not become pregnant until at least 4 weeks after getting zoster
vaccine.
Shingrix
Shingrix recombinant zoster vaccine (RZV) is a lyophilized
preparation of sterile suspension for intramuscular injection of
lyophilized recombinant VZV surface glycoprotein E (gE) antigen
component, which must be reconstituted with the accompanying
vial of AS01B adjuvant suspension component.
Vaccine efficacy against HZ was 96.6% [95% confidence interval
(CI) = 89.6–99.3] in persons aged 50–59 years, 97.4% (95% CI = 90.1–
99.7) in persons aged 60–69 years and [91.3% (95% CI = 86.8–94.5) in
participants aged ≥70 years]. VE was 97.6% (95% CI = 90.9–99.8) in
the first year after vaccination and was 84.7% (95% CI = 69.0–93.4)
or higher for the remaining 3 years of the study in persons aged
≥70 years. Efficacy for prevention of postherpetic neuralgia was
91.2% (95% CI = 75.9–97.7) in adults aged ≥50 years and 88.8% (95%
CI = 68.7–97.1) in those aged ≥70 years.
The incidence of serious adverse events were similar in vaccinated
and placebo groups. The most common solicited adverse reactions
(grade 1–3) were pain (78%), myalgia (45%), and fatigue (45%).
Schedule: Two doses administered IM, 2–6 months apart, in adults
aged 50 years and older and for adults aged 18 years and older who
are immunosuppressed.
Contraindications: History of severe allergic reaction (e.g.,
anaphylaxis) to any component of the vaccine or after a previous
dose of the vaccine.
This vaccine is safe in the immunocompromised.
Recommendations for use of HZ vaccines (Advisory Committee
on Immunization Practices—ACIP (USA):
■ Recombinant zoster vaccine is recommended for the prevention
of HZ and related complications for immunocompetent adults
aged ≥50 years.
■ RZV is recommended for the prevention of HZ and related

complications for immunocompetent adults who previously
received ZVL.
■ RZV is preferred over ZVL for the prevention of HZ and related
complications.
■ ZVL is preferred for those with a history of severe allergic
reactions to any component of the RZV.20

The varicella vaccine is not recommended for universal
immunization in India in children as the disease is generally mild
and as the vaccine is expensive at the current market prices and there
are other health-related priorities that rank higher than varicella
vaccine. WHO continues to mention that countries where varicella
is an important public health burden could consider introducing
varicella vaccination in the routine childhood immunization
program. However, resources should be sufficient to ensure reaching
and sustaining vaccine coverage ≥80%. Vaccine coverage that
remains <80% will result into shift in epidemiology.
Extensive use of varicella vaccine as a routine vaccine in children
will have a significant impact on the epidemiology of the disease.21
If sustained high coverage can be achieved, the disease may
virtually disappear. If only partial coverage can be obtained, the
epidemiology may shift, leading to an increase in the number
of cases in older children and adults. Hence, routine childhood
varicella immunization programs should emphasize high, sustained
coverage.
MMRV VACCINE: PRIORIX-TETRA BY GSK

VACCINES LTD.
Measles, mumps, and rubella plus varicella is a live-attenuated
virus vaccine against measles, mumps, rubella, and varicella. It is
a sterile lyophilized mixed preparation of the attenuated Schwarz
measles, RIT 4385 mumps (derived from Jeryl Lynn strain),
Wistar RA 27/3 rubella, and Oka varicella strains of viruses.
This vaccine is no longer marketed in India.
REFERENCES
1. World Health Organization. Varicella and herpes zoster vaccines:
WHO position paper, June 2014. Wkly Epidemiol Rec. 2014;89:265-87.
2. CDC. (2011). Chapter 17: Varicella. Surveillance of Varicella. Manual
for the Surveillance of Vaccine-Preventable Diseases, 5th edition.
[online] Available from http://www.cdc.gov/vaccines/pubs/surv-
manual/chpt17-varicella.html. [Last accessed November, 2022].
3. Gershon AA, Marin M, Seward JF. Varicella vaccine. In: Plotkin
S, Orenstein W, Offit P (Eds). Vaccines, 7th edition. Philadelphia:
Saunders Elsevier; 2018. pp. 1145-80.
4. Varicella and herpes zoster vaccines: WHO position paper, June 2014.
Available at https://www.who.int/teams/immunization-vaccines-
and-biologicals/policies/position-papers/varicella [Last accessed
November, 2022].
5. WHO. Varicella Vaccine. [online] Available from https://www.who.int/
teams/health-product-policy-and-standards/standards-and-
specifications/vaccine-standardization/var icella#:~:text=
Varicella%20Vaccines&text=Reconstituted%20vaccine%20is%20
injected%20subcutaneously,of%20shingles%20in%20the%20elderly.
6. Ooi PL, Goh KT, Doraisingham S, Ling AE. Prevalence of varicella-
zoster virus infection in Singapore. Southeast Asian J Trop Med Public
Health. 1992;23:22-5.
7. Mandal BK, Mukherjee PP, Murphy C, Mukherjee R, Naik T. Adult
susceptibility to varicella in the tropics is rural phenomenon due to
lack of previous exposure. J Infect Dis. 1998;178(Suppl 1):S52-54.
8. Richard VS, John TJ, Kenneth J, Ramaprabha P, Kuruvilla PJ,
Chandy GM. Should health care workers in the tropics be immunized
against varicella? J Hosp Infect. 2001;47:243-5.
9. Baxter R, Ray P, Tran TN, Black S, Shinefield HR, Coplan PM, et al.
Long-term effectiveness of varicella vaccine: a 14-Year, prospective
cohort study. Pediatrics. 2013;131:e1389-96.
10. Recommendations of Advisory Committee on Immunization Practices.
Prevention of varicella. MMWR. 2007;56:1-40.
11. Infectious Disease Surveillance. Surveillance Data. http://idsurv.org/
mapcomplete/map.php?maincat=Chicken+pox&age=0&age1=
500&sex=&pv=&outcome=&state=&district=&city=&from=&to=&B1=
Search+%26+Show+Now. [Last accessed November, 2022].
12. Chartrand SA. Varicella vaccine. Pediatr Clin North Am. 2000;47:
373-95.
13. Lokeshvar MR, Singhal T. Immunization against varicella.

Immunization in Clinical Practice, 2nd edition. New Delhi: Jaypee
Brothers Medical Publisher; 2017.
14. World Health Organization. Requirements for varicella vaccine
(live), WHO Technical Report Series, No. 848, 1994. [online] Available
from: https://cdn.who.int/media/docs/default-source/biologicals/
vaccine-standardization/varicella/who_trs_848_a1.pdf?sfvrsn=
8850d145_3&download=true. [Last accessed November, 2022].
15. Takahashi M. The varicella vaccine. Vaccine development. Infect Dis
Clin North Am. 1996;10(3):469-88.
16. Kuter BJ, Weibel RE, Guess HA, Matthews H, Morton DH, Neff BJ, et al.
Oka/Merck varicella vaccine in healthy children: final report of a 2-year
efficacy study and 7-year follow-up studies. Vaccine. 1991;9:643-7.
17. Skull SA, Wang EEL. Varicella vaccination—a critical review of the
evidence. Arch Dis Child. 2001;85:83-90.
18. WHO. Varicella vaccines. WHO Position Paper. Wkly Epidemiol Rec.
1998;73:241-8.
19. Varela FH, Pinto LA, Scotta MC. Global impact of varicella vaccination
programs. Hum Vaccin Immunother. 2019:15:3,645-57.
20. Dooling KL, Guo A, Patel M, Lee GM, Belongia EA, Harpaz R.
Practices for Use of Herpes Zoster Vaccines. MMWR Morb Mortal Wkly
Rep. 2018;67(3):103-8.
21. Bialek SR, Perella D, Zhang J, Mascola L, Viner K, Jackson C, et al.
Impact of a routine two-dose varicella vaccination program on
varicella epidemiology. Pediatrics. 2013;132:e1134-40.
3.10 HEPATITIS A VACCINES

Chandra Mohan Kumar, Sanjay Marathe
INTRODUCTION
Hepatitis A virus (HAV) is a common hepatotropic virus causing
inflammation of liver. The virus primarily spreads through feco-oral
route and is closely associated with unsafe water and food as well
as poor sanitation and hygiene practices. It is a relatively benign
infection in young children. As many as 85% of children below
2 years and 50% of those between 2 and 5 years infected with HAV are
anicteric and may have no symptoms at all or just have nonspecific
symptoms such as fever, malaise, diarrhea, vomiting, cough, etc.
like any other viral infection. On the contrary, 70–95% of adults with
hepatitis A are symptomatic with a mortality of 1%. The disease
severity increases irrespective of age, in those with underlying
chronic liver disease.
However, infection rates are low in high income countries with
good sanitary and hygienic conditions.
BURDEN OF DISEASE
Global Burden
Based on an ongoing reassessment of the global burden of hepatitis
A, preliminary World Health Organization (WHO) estimates suggest
an increase in the number of acute hepatitis A cases from 117 million
in 1990 to 126 million in 2005 (and increase in deaths due to hepatitis
A from 30,283 in 1990 to 35,245 in 2005).1 Increased number of cases
were estimated to occur in the age groups 2–14 years and more than
30 years.2
Hepatitis A virus infection occurs worldwide but mostly in low/
middle income group countries. Globally 1.4 million cases occur
every year.3
In high-income regions, the prevalence of anti-HAV antibody
is very low (<50% are immune by age 30 years), there is almost no
circulation of the virus and therefore the risk of acquiring HAV
infection is low. In contrast, in countries with high endemicity,
most individuals acquire natural infection in childhood and
therefore burden of disease including incidence of outbreaks is

also low. As a shift occurs toward intermediate endemicity due to
improvements in hygiene and sanitation, the population stands
at a higher risk because a certain proportion of children remains
susceptible till adulthood and the risk of HAV transmission
continues to be high due to overall suboptimal access to clean water
and sanitation. Thus, burden of symptomatic disease and incidence
of outbreaks paradoxically increase despite some improvements in
socioeconomic indicators.
In several Asian countries, the age at first infection by hepatitis A
seems to be increasing (Figs. 1A to H).4
Indian Burden
India, earlier a highly endemic country, is now shifting to
intermediate endemicity in some areas in cities and in higher
Figs. 1A and B: (A) Thailand; and (B) Japan.

Figs. 1C to E: (C) Taiwan; (D) India; and (E) Korea.

Figs. 1F to H: (F) China; (G) Singapore; and (H) Indonesia. Age-specific

hepatitis A seroprevalence in: (A) Thailand (n = 17); (B) Japan (n = 4); (C) Taiwan
(n = 10); (D) India (n = 14); (E) Korea (n = 18); (F) China (n = 3); (G) Singapore
(n = 2); (H) Indonesia (n = 2). N represents number of studies included in the
review. Each line of the same color represents results from a single study.
Source: Gripenberg M, Aloysia D’Cor N, L’Azou M, Marsh G, Druelles S, Nealon J.
et al. Changing sero-epidemiology of hepatitis A in Asia Pacific countries:
A systematic review. Int J Infect Dis. 2018;68:13-17.
socioeconomic strata of community.5 Seroprevalence studies show

susceptibility in 30–40% of adolescents and adults belonging to the
high socioeconomic class with regional differences (seropositivity in
Kerala being lower than other states). Studies also show a reduction
in cord blood seropositivity (indicative of young adult seronegativity)
for HAV over the years. Several outbreaks of hepatitis A in various
parts of India have been recorded in the past; children from rural
and semiurban areas of the state of Maharashtra (2002–2004), an
explosive outbreak among adults from Kerala involving 1,137 cases
(2004) and over 450 cases in children and adults in Shimla (2007).
An increasing contribution of hepatitis A to fulminant hepatic failure
(FHF) has also been noted, especially in children. In a study from
Pune, 18–50% of pediatric patients admitted for FHF either had
hepatitis A alone or along with other hepatitis viruses.6 According
to the academy’s passive reporting system of 10 infectious diseases
by the pediatricians (www.idsurv.org), a total of 1,690 (16%) cases of
hepatitis A were reported out of total 10,554 cases from December
2010 to December 10, 2013, signifying it’s relatively higher burden.
The epidemiology of viral hepatitis A is changing in India too.
Arankalle et al. in their study on 928 children aged between 18 months
and 10 years found that out of the 348 children who tested positive
for anti-HAV, 50.3% were in the age group of 6–10 years and 30.3%
were in the 18 months to 6 years age group (Fig. 2). They also found
linkages between the seropositivity of HAV and the educational and
socioeconomic status of the parents. Children who used a private
toilet within the house were less often seropositive (33.1%) when
compared to the children and their parents who used an open field
for excreta disposal (75%).7
VACCINES (TABLE 1)
Inactivated Vaccines
Inactivated vaccines available in India:
■ Havrix-GSK
■ Avaxim-Sanofi
■ HapiBEV and HAVshield.
Most of the currently available vaccines are derived from HM
175/GBM strains and grown on MRC-5 human diploid cell lines.
Fig. 2: Age-specific prevalence of hepatitis A in all centers in Kolkata, Pune,

Chennai, and Delhi. (HAV: Hepatitis A virus)
Source: Arankalle V, Mitra M, Bhave S, Balasubramanian S, Chatterjee S,
Choudhury J, et al. Changing epidemiology of hepatitis A virus in Indian
children. Dovepress. 2014;4:7-13.
TABLE 1: Comparison of inactivated (two doses) and live-attenuated

hepatitis A vaccines (single dose).
Inactivated Live attenuated
Source HM-175 strain H2 strain
Schedule and 2 doses at 6–12 months 1 dose, SC >12 months
route interval, IM >12 months of age of age
SCR 100% SCR with 1 dose by 100% SCR with 1 dose
19 days postvaccination by 3–4 weeks post
vaccination
Ab response Higher titers Lower titers
Immuno- Can be used Cannot be used
compromised
Long-term Based on Ab titers at 15 years, SCR of 81.3% after
protection expected >85% protected at 15 years
50 years Modeling: Protection
lasts at least 30 years
(IM: intramuscular; SC: subcutaneous; SCR: seroconversion rates)
Recently, BE vaccines, has introduced an inactivated vaccine derived

from the TZ84 strain of HealiveTM. It is available in our country as
Hapibev (BE) and HAVshield (Abbott). Both, Havrix (GSK) and
Healive (Sinovac) are WHO prequalified. The virus is formalin
inactivated and adjuvanted with aluminum hydroxide. The vaccine
is stored at 2–8°C. The serologic correlate of protection is 20 mIU/mL.
All hepatitis A vaccines are licensed for use in children aged 1 year
or older.
A liposomal adjuvanted hepatitis A vaccine derived from
the RG-SB strain, harvested from disrupted MRC-5 cells and
inactivated by formalin is now available. The liposome adjuvant
is immune-potentiating reconstituted influenza virosome (IRIV)
composed of phosphatidylcholine, phosphatidylethanolamine, and
hemagglutinin from an H1N1 strain of influenza virus. The efficacy
and safety profile is nearly similar to the other inactivated vaccines.
Currently, this vaccine is not marketed in India.
Combination of hepatitis A and hepatitis B vaccines is also
available to be used in those who have not been vaccinated for
hepatitis B previously. These are available in both adult and pediatric
formulations and are discussed separately under combination
vaccines (Both are not available in India). Similarly, combinations
of hepatitis A vaccine with Vi-polysaccharide vaccines are available
internationally though not in India.

Protective antibody concentrations are elicited in >95% of healthy
children, adolescents, and adults when measured 1 month after
receipt of the first dose and in >99% 1 month after a second
dose. The median predicted duration of protection has been
estimated at 45.0 years.8 The vaccine efficacy is lower in the
elderly, immunocompromised, those with chronic liver disease,
in transplant recipients and those with pre-existing maternal
antibodies. Immunity is life-long due to anamnestic response and
no boosters are recommended at present in the immunocompetent.
A higher geometric mean concentration (GMC) of anti-HAV
IgG was induced in the two-dose inactivated than in the one-dose
inactivated and the attenuated vaccines at 12 months.9 Compared
to the classical two-dose schedule, one single dose of inactivated
hepatitis A vaccines is similarly efficacious, less expensive and easier

to implement. High efficacy of postexposure prophylaxis against
hepatitis A using one single dose of inactivated vaccine within
2 weeks of exposure is also documented. However, in risk groups for
hepatitis A, a two-dose vaccination schedule is preferred.8
Safety
Adverse reactions are minor and usually include local pain and
swelling. Cumulative global experience from the use of several
hundred million doses of inactivated hepatitis A vaccines testify
to their excellent overall safety profile.8 The vaccine may be safely
given with other childhood vaccines and interchange of brands is
permitted though not routinely recommended.
Dosage Schedule
Indian Academy of Pediatrics (IAP) Advisory Committee on
Vaccines and Immunization Practices (ACVIP) recommends two
doses of inactivated hepatitis A vaccine given intramuscularly,
with the second dose administered 6–18 months after the first
dose.10 Minimum age for giving hepatitis A vaccine is 12 months. All
the inactivated vaccines are safe and efficacious and can be used
interchangeably if supply of a vaccine given earlier is not available.
Live-attenuated Vaccine
Only one brand, BioVac A is marketed in India.
This vaccine is derived from the H2 strain of the virus
attenuated after serial passage in Human Diploid Cell (KMB 17
cell line). It has been in use in China since the 1990s in mass
vaccination programs. The vaccine meets WHO requirements and
is now licensed and available in India. Controlled trials conducted
among large numbers of children 1–15 years of age have shown
up to 100% efficacy for preexposure prophylaxis and 95% efficacy
for postexposure prophylaxis. Anti-HAV antibodies were detected
in 72–88% of the vaccines 15 years after vaccination.9 Studies in
China have demonstrated that live-attenuated hepatitis A vaccine
provide postexposure protection against HAV infection during
outbreaks.11
Data on Immunogenicity and Safety of a Single Dose

of the Live-attenuated Vaccine
A study involving 11,451 subjects was conducted to assess its
immunogenicity. A seroprotection level of >20 mIU/mL was
achieved in 92.9% of subjects within 2–5 weeks of vaccination.12 In a
randomized controlled trial, Biovac-A was compared to inactivated
international vaccine from GSK and also a domestic inactivated
vaccine. The assessment was in terms of immunogenicity. There
was a comparable immune response seen between Biovac-A and
international inactivated hepatitis A vaccine within 7–28 days.13
In another study evaluating Biovac-A vaccine effectiveness and
its long-term immunogenicity, there was a significant reduction
in Hepatitis A cases reported (98%) in the vaccinated group.
Additionally, there was reduction incidence of hepatitis A in the
entire population by 90% because of herd immunity. Certain
subjects in this group were regularly followed up for immuno
genicity parameters up to 15 years.
It was found that >80% subjects remain seroconverted above the
protection criteria of 20 mIU/mL. The GMT graph also confirmed
that the rate at which there is a fall in the titers over all these years is
very slow.14
Indian Data
The vaccine was brought to India in 2004 and has undergone
studies in Indian subjects as well. Of 143 children vaccinated in
2004, 121 children were evaluated in 2014, clinically and for anti-
HAV antibodies. About 106 (98%) of 108 remaining children had
seroprotective levels with a geometric mean titer of 100.5 mIU/mL.
On analysis of all 121 children, the immunogenicity was 87.6%.15
In a multicentric single arm study conducted in four metros of
the country, children of 18–60 months were followed up for 5 years.
It was noted that the seroprotection criteria was maintained 97.3% in
these 5 years of follow-up with high GMT levels. While the GMT was
81.4 mIU/mL at 6 weeks, there was a rise in GMT seen at 6 months.
This rise is attributed to the live-attenuated property of the vaccine.
The seroconversion rates considering seroprotection levels

of anti-HAV antibody titer >20 mIU/mL, following vaccination
starting from 6 weeks, 6 months, 12 months, 24 months, 36 months,
48 months, and 60 months were 95.1%, 97.9%, 98.3%, 96.2%, 97.8%,
92.6%, and 97.3%, respectively. The GMC over the years increased
from 64.9 mIU/mL at 6 weeks to 38.1 mIU/mL and 135.2 mIU/mL
at 6 months and 12 months, respectively and was maintained at
127.1 mIU/mL at 60 months.16 In conclusion, the result of this 5-year
follow-up study showed that the single dose of live-attenuated
vaccine is well tolerated and provides long-term immunogenicity in
healthy Indian children. As per WHO position paper, both inactivated
and live-attenuated hepatitis A vaccines are highly immunogenic
and immunization will generate long-lasting, possibly life-long,
protection against hepatitis A in children as well as in adults.
Currently, inactivated HAV vaccines are licensed for intramuscular
administration in a two-dose schedule with the first dose given at
the age 1 year, or older. The interval between the first (primary) dose
and the second (booster) dose is 6–18 months. The live-attenuated
vaccine is administered as a single subcutaneous dose.
The IAP ACVIP committee has already recommended a single
dose of this vaccine at 12 months of age.17 IAP ACVIP (2018–19) also
recommends a single dose of live Hepatitis A vaccine. Second dose
of live-attenuated hepatitis A vaccine is not recommended.18
Safety
No substantial safety concerns have been identified during vaccine
trials8 and no horizontal transmission or serious adverse effects have
been noted with the live vaccine.
Hepatitis A Vaccines for Postexposure Prophylaxis

Hepatitis A vaccines are preferred for PEP, as vaccines have several
advantages compared with IGIM, including the induction of active
immunity, longer duration of protection, ease of administration, and
greater availability. A single dose of Hepatitis A should be offered,
within 2 weeks of exposure, to those between 1 and 40 years of age.
This is as effective as IMIg, in preventing clinical hepatitis A disease.
For those <1 year or >40 years, IMIg in a dose of 0.1 mL/kg may be
offered. This offers protection for 1 month.
World Health Organization concludes that both inactivated
and live-attenuated hepatitis A vaccines are safe and highly
immunogenic and that in most cases, these vaccines will generate
long-lasting, possibly life-long protection against hepatitis A both
in children and adults.8 Immunocompromised subjects can receive
only the inactivated vaccines.
Age at Vaccination
Based on data suggesting a decline in the adult seropositivity rates
especially in those belonging to the high socioeconomic status, it is
likely that babies may be born with no maternal antibodies, thereby
making a case for vaccination for hepatitis A at an earlier age.
Immunogenicity studies also show that antibody titers achieved with
vaccination at 12 months are comparable to those achieved at 18
months to 2 years. In light of these facts, the IAP-ACVIP recommends
initiating hepatitis A vaccine at the age of 12 months.
Catch-up Vaccination and Screening for

Hepatitis A Antibodies
In India, a very rapid socioeconomic development has taken place
in the last few years; many high endemicity areas for HAV infection
coexist with others, making a transition to intermediate endemicity.
Some studies have demonstrated an epidemiological shift of the
age of acquisition of the HAV infection in the community, even if
the current available data do not confirm a consistent decline in
childhood HAV seroprevalence rates and increased susceptibility to
HAV in young adults.19 A study from Hyderabad observed that 25%
of children <15 years remain susceptible to HAV infection.20 Another
study from Bijapur observed seropositivity in 54.4% children
between 5 and 15 years.21 Since the cost of screening to identify
those susceptible to get hepatitis A infection is lower than the cost
of vaccine, IAP-ACVIP recommends prevaccination screening for
hepatitis A antibody in children >10 years of age.
IAP/ACVIP RECOMMENDATIONS FOR

INDIVIDUAL USE
The hepatitis A vaccine may be offered to all healthy children.
Special emphasis in risk groups as enumerated below:
■ Patients with chronic liver disease
■ Carriers of hepatitis B and hepatitis C
■ Congenital or acquired immunodeficiency
■ Transplant recipients
■ Adolescents seronegative for HAV who are leaving home for
residential schools
■ Travelers to countries with high endemicity for hepatitis A.
Inactivated vaccines: For >12 months, two doses administered IM at
0 and 6–18 months.
Live vaccines: For >12 months, one dose administered SC.

According to the WHO, in countries transitioning from high to inter-
mediate endemicity, as is the case in India, large-scale hepatitis A
vaccination is likely to be cost-effective and is therefore encour-
aged. The effectiveness of vaccination of pediatric populations at
risk of hepatitis A has been demonstrated in a number of geographic
regions worldwide compared to the classical two-dose schedule, one
single dose of inactivated hepatitis A vaccines is similarly efficacious,
less expensive and easier to implement.
Single-dose Immunization
Within 2–4 weeks of the first dose of inactivated hepatitis A vaccine,
up to 100% of immunocompetent children and young adults achieve
anti-HAV IgG titers over 20 mIU/mL.22 Furthermore, a single dose
of this vaccine may successfully control outbreaks of hepatitis A.8
In 2003, a randomized, double-blind trial of a single dose of
inactivated hepatitis A vaccine was conducted in Nicaragua among
239 children. Protective efficacy within those 6 weeks was 85% (95%
CI: 55–96%) and after 6 weeks, 100% (79.8–100%).23
Effectiveness of Single Dose in National

Immunization Program
Argentina began a Universal Immunization Programme (UIP)
in 12-month-old children based on a single dose schedule of
inactivated hepatitis A vaccine in 2005. In 2007, with vaccination
coverage of 95%, the incidence of symptomatic viral hepatitis A
had dropped by more than 80% in all age groups.24 Six years after
implementation of this countrywide single-dose program, no
hepatitis A cases have been detected among vaccinated individuals,
whereas among the unvaccinated a number of cases have
occurred, confirming continued circulation of hepatitis A virus in
the Argentinian population.8,24 The above studies demonstrate
effectiveness of even a single dose of inactivated vaccine when used
in large-scale programs.
Considering the uniformly high burden of the disease and
effectiveness of hepatitis vaccine even in single dose, the IAP-ACVIP
recommends that vaccination against hepatitis A be integrated into
the UIP for children aged ≥1 year. However, it should be part of a
comprehensive plan for the prevention and control of viral hepatitis
including measures to improve hygiene and sanitation and measures
for outbreak prevention.
IAP recommendations: Hepatitis A vaccine schedule.

• Inactivated vaccines: >12 months: Two doses administered intramuscular
(IM) at 0 and 6–18 months
• Live vaccines: >12 months: Single dose administered subcutaneous (SC)
• Inactivated vaccines: Two doses administered IM at 0 and 6–18 months
• Live vaccines: single dose administered SC
• For catch-up vaccination, prevaccination screening for hepatitis A
antibody is recommended in children >10 years, as at this age the
estimated seropositive rates exceed 50%
REFERENCES
1. Jacobsen KH, Wiersma ST. Hepatitis A virus seroprevalence by age and
world region, 1990 and 2005. Vaccine. 2010;28(41):6653-7.
2. Foster MA, Hofmeister MG, Kupronis BA, Lin Y, Xia GL, Yin S, et al.
Increase in hepatitis A virus infections—United States, 2013-2018.
Morb Mortal Wkly Rep (MMWR). 2019;68(18):413-5.
3. World Health Organization. Global Alert and Response (GAR): Hepatitis
A. http://www.who.int/csr/disease/hepatitis/whocdscsredc2007/en/
index4.html#estimated. [Last accessed May, 2022].
4. Gripenberg M, Aloysia D’Cor N, L’Azou M, Marsh G, Druelles S,
Nealon J. Changing sero-epidemiology of hepatitis A in Asia Pacific
countries: a systematic review. Int J Infect Dis. 2018;68:13-7.
5. Mathur P, Arora NK. Epidemiological transition of hepatitis A in India:
issues for vaccination in developing countries. Indian J Med Res.
2008;128(6):699-704.
6. Bendre SV, Bavdekar AR, Bhave SA, Pandit AN, Chitambar SD,
Arankalle VA. Fulminant hepatic failure: etiology, viral markers and
outcome. Indian Pediatr. 1999;36(11):1107-12.
7. Arankalle V, Mitra M, Bhave S, Ghosh A, Balasubramanian S,
Chatterjee S, et al. Changing epidemiology of hepatitis A virus in
Indian children. Dovepress. 2014;4:7-13.
8. World Health Organization. Hepatitis A Vaccine—WHO Position Paper
2012. Wkly Epidemiol Rec. 2012;87:261-76.
9. Liu XE, Wushouer F, Gou A, Kuerban M, Li X, Sun Y, et al. Comparison
of immunogenicity between inactivated and live attenuated hepatitis
A vaccines: a single-blind, randomized, parallel-group clinical trial
among children in Xinjiang Uighur Autonomous Region, China. Hum
Vaccine Immunother. 2013;9(7):1460-5.
10. Balasubramanian S, Shah A, Pemde HK, Chatterjee P, Shivananda S,
Guduru VK, et al. Indian Academy of Pediatrics (IAP) Advisory
Committee on Vaccines and Immunization Practices (ACVIP)
recommended immunization schedule (2018-19) and update on
immunization for children aged 0 through 18 years. Indian Pediatr.
2018;55(12):1066-74.
11. Wang X, Ma J, Xu Z, Liu H, Zhang Y, Han C, et al. [Effectiveness of
postexposure prophylaxis using live attenuated hepatitis Alpha
vaccine (H(2) strain) among schoolchildren]. Zhonghua Yi Xue Za Zhi.
2002;82(14):955-7.
12. Cheng NL. [Immunological effects of live attenuated hepatitis A
vaccine]. Zhonghua Yi Xue Za Zhi. 1992;72(10):581-3, 638.
13. Zheng H, Chen Y, Wang F, Gong X, Wu Z, Miao N, et al. Comparing live-

attenuated and inactivated hepatitis A vaccines: an immunogenicity
study after one single dose. Vaccine. 2011;29:9098-103.
14. Zhuang FC, Mao ZA, Jiang LM, Wu J, Chen YQ, Jiang Q, et al. Long-
term immunogenicity and effectiveness of live attenuated hepatitis
A vaccine (H2-strain): a study on the result of 15 years’ follow up.
Zhonghua Liu Xing Bing Xue Za Zhi. 2010;31:1332-5.
15. Bhave S, Sapru A, Bavdekar A, Jain R, Debnath K, Kapatkar V. Long-
term immunogenicity of single dose of live attenuated hepatitis A
vaccine in Indian children. J Ind Ped. 2015;52:687-90.
16. Mitra M, Shah N, Faridi M, Ghosh A, Sankaranarayanan VS, Aggarwal
A, et al. Long term follow-up study to evaluate immunogenicity and
safety of a single dose of live attenuated hepatitis a vaccine in children.
Hum VaccinImmunother. 2015;11(5):1147-52.
17. Vashishtha VM, Choudhury P, Kalra A, Bose A, Thacker N, Yewale VN,
et al. Indian Academy of Pediatrics (IAP) Recommended Immunization
Schedule for Children Aged 0 through 18 years, India, 2014 and
Updates on Immunization. Indian Pediatr. 2014;51(10):785-800.
18. Balasubramanian S, Shah A, Pemde HK, Chatterjee P, Shivananda S,
Guduru VK, et al. Immunization schedule (2018–19) for children
birth through 18 years—Immunization Update. Indian Pediatr.
2018;55:1066-74.
19. Franco E, Meleleo C, Serino L, Sorbara D, Zaratti L. Hepatitis A:
epidemiology and prevention in developing countries. World J
Hepatol. 2012;4(3):68-73.
20. Joshi N, Yr NK, Kumar A. Age related seroprevalence of antibodies
to hepatitis A virus in Hyderabad, India. Trop Gastroenterol.
2000;21(2):63-5.
21. Rath CP, Akki A, Patil SV, Kalyanshettar SS. Seroprevalence of hepatitis
A virus antibody in Bijapur, Karnataka. Indian Pediatr. 2011;48(1):71-3.
22. Schmidtke P, Habermehl P, Knuf M, Meyer CU, Sänger R, Zepp F. Cell
mediated and antibody immune response to inactivated hepatitis A
vaccine. Vaccine. 2005;23(44):5127-32.
23. Mayorga Pérez O, Herzog C, Zellmeyer M, Loáisiga A, Frösner G,
Egger M. Efficacy of virosome hepatitis A vaccine in young children
in Nicaragua: randomized placebo-controlled trial. J Infect Dis.
2003;188(5):671-7.
24. Vacchino MN. Incidence of Hepatitis A in Argentina after vaccination.
J Viral Hepat. 2008;15(Suppl 2):47-50.
3.11 TYPHOID VACCINES

BACKGROUND
Typhoid fever is a disease of developing countries associated with
poor public health and low socioeconomic indices. Cases of enteric
fever occurring in travelers returning to the US and the UK suggest
that it is present across the developing world but that the Indian
subcontinent represents a hotspot of disease activity.
Typhoid fever is an acute generalized infection, caused by the
invasive enteric bacterium, Salmonella enterica serovar typhi,
generally termed Salmonella typhi (S. typhi). Typhoid fever primarily
effects mononuclear phagocyte system, intestinal lymphoid tissue,
and gallbladder. Typhoid fever is an important public health problem
in many low- and middle-income countries (LMICs). The Indian
subcontinent and recently Pakistan raising alarms of extensively
drug-resistant (XDR) typhoid represent a hotspot of disease activity
raising global concerns.
BURDEN OF DISEASE
Global
Global estimates of typhoid fever burden range between 11 and
21 million cases and approximately 128,000 to 161,000 deaths
annually.1 Children are disproportionately affected by typhoid
fever, with peak incidence known to occur in individuals aged 5 to
<15 years of age.
Based on the Global Burden of Disease Study 2017, it is estimated
that globally, 14.3 million [95% uncertainty interval (UI) 12.5–16.3]
cases of typhoid and paratyphoid fevers occurred in 2017.2 The
estimated global case fatality was 0.95% (0.54–1.53) in 2017, with
an estimated 135.9 thousand (76.9–218.9) deaths from typhoid and
paratyphoid fever globally in 2017. There has been a significant
decline from the 1990 estimates.
Typhoid fever is one of the most common etiological sources of
bacteremia in many developing countries, with most of the cases
Fig. 1: Global burden with study sites.9
originating in the Indian subcontinent of South Asia, followed by

sub-Saharan Africa (Fig. 1).3-5
GEOGRAPHICAL DISTRIBUTION
Asia and the Indian Subcontinent
Typhoid fever incidence varies substantially in Asia. Very high
typhoid fever incidence has been found in India and Pakistan. In
comparison, typhoid fever frequency was moderate in Vietnam
and China and intermediate in Indonesia. 6 However, it is the
Indian subcontinent which has the highest incidence of the disease
worldwide.7
In a multicentric study in five Asian countries—China, India,
Indonesia, Pakistan, and Vietnam—it was estimated that the
incidence of typhoid ranged from 15.3 per 100,000 persons/year in
China to 451.7 per 100,000/year in Pakistan.7 In India, the overall
incidence was 214.2/100,000.
Extensively drug-resistant typhoid fever in Pakistan 2016, resistant to
five groups of antibiotics: An ongoing outbreak of XDR typhoid fever
was reported by health officials in Karachi, Pakistan in November
2016. The strain of S. typhi resistant to five types of antibiotics is
feared to disseminate globally. Several deaths have been reported. In
2018, three cases of XDR typhoid fever were reported in travellers—

one who returned to the United Kingdom, and two who returned to
the United States. Seventy-six cases of XDR and XDR variant Typhi
infections have been identified by the CDC between February 6,
2018, and March 27, 2021, in the US residents. Sixty-seven (88%)
reported travel to or from Pakistan, and 9 (12%) denied having
traveled internationally in the 30 days before their illness.8
Age Distribution
Children are disproportionately affected by typhoid fever, with
peak incidence in individuals aged 5 to <15 years of age.9 Ochiai et
al. reported that the mean age of typhoid was significantly lower in
the South Asian sites (Pakistan and India) than in the South East
and North East Asian sites. In India, the incidence of Typhoid in the
0–1 year age group was 89.2/100,000, which was the highest among
the countries studied. In the same study the overall incidence
of Typhoid was 214.2/100,000, with the highest incidence of
493.5/100/000 in the 5–15 years age group.7
There is a significant burden of typhoid and paratyphoid fevers
in India.10-13 Typhoid fever in pregnancy can result in a range of
maternal complications as well as miscarriage, fetal death, and
neonatal infection.14
CASE FATALITY RATES

Estimates of case fatality rates in typhoid fever range from 1 to 4%;
fatality rates in children younger than 4 years of age are 10 times
higher than in older children. In untreated cases, the fatality rates
may rise to 10–20%.11
PATHOGEN, ANTIGENS RELEVANT TO VACCINE

Salmonella is a genus of the family Enterobacteriaceae. Salmonellae
are rod-shaped, gram-negative, facultative anaerobic bacteria, most
of which are motile by peritrichous flagella which bear the H antigens.
In addition to the H antigen(s), two polysaccharide surface antigens
aid in the further characterization of S. enterica, namely the somatic
O antigen and the capsular Vi (virulence) antigen. The Vi antigen is
associated with resistance to complement-mediated bacterial lysis

and resistance to complement activation by the alternate pathway.
Salmonella enterica serovars paratyphi A and paratyphi B (and
uncommonly paratyphi C) cause a disease (paratyphoid fever) that
is clinically indistinguishable from typhoid fever, particularly in
parts of Asia. Typhoid fever and paratyphoid fever are collectively
termed enteric fever. While S. typhi and S. paratyphi C express Vi, the
Vi locus is absent from S. paratyphi A and B.
DISEASE
Ingested S. typhi, following a silent primary bacteremia, reaches
the reticuloendothelial system and multiplies intracellularly
within macrophages. After an incubation period of 7–14 days on
average (ranging from 3 to 60 days), patients experience an illness
with a wide range of clinical severity, more severe forms being
characterized by persistent high fever, abdominal discomfort,
malaise, and headache. Constipation or diarrhea may occur in
older children and adults, and younger children more often suffer
from diarrhea. Complications are estimated to occur in 10–15%
of hospitalized patients and are more frequent among untreated
patients whose illness has persisted for 2 weeks or more. The most
common life-threatening complications are intestinal hemorrhage,
intestinal perforation, and encephalopathy with hemodynamic
shock. Intestinal perforation has been reported in some
outbreaks at unexpectedly high rates (>40%) and associated with
high mortality (18–43%).
Infectious Disease Surveillance (IDsurv) Data

According to the Academy’s passive reporting system of 10 infec
tious diseases by the pediatricians, a total of 2,302 (22%) cases of
enteric fever were reported out of total 10,478 cases of 10 infectious
diseases from December 2010 to till December 6, 2013.15-17
There were 2,261 cases of typhoid and 41 were paratyphoid cases,
10.7% were below 2 years of age and 44.6% were below 5 years,
20% cases were hospitalized, 17% were immunized with typhoid
vaccine, and microbial diagnosis was established in 25% cases.15
VACCINES AGAINST TYPHOID FEVER

Typhoid vaccination was part of India’s National Immunization
Program till 1985 when measles vaccine was added by the
Government as part of Universal Immunization Programme (UIP).
There have been several vaccines against typhoid till quite recently.
Historically, different vaccine preparations have been developed
against typhoid fever, many preparations are obsolete and not
available now. Typhoid fever vaccines have been used for more
than a century. Clinical trials, some conducted decades ago, have
demonstrated efficacy of a range of typhoid vaccines which include:
■ Whole cell inactivated vaccines
■ Virulence capsular polysaccharide vaccines
■ Live-attenuated vaccines; and more recently
■ Virulence conjugate vaccines (TCVs).
The World Health Organization (WHO) has recommended that
countries consider the use of typhoid vaccines for high-risk groups
and populations, and for outbreak control. Despite this, typhoid
vaccines have not been widely applied in typhoid endemic areas or
are often used in outbreaks.12
NEW GENERATION TYPHOID VACCINES

The new generation current typhoid fever vaccines include oral
live-attenuated Ty21a vaccine, parenteral Vi polysaccharide and
Vi-polysaccharide (Vi-PS) capsular conjugate vaccines. Oral live-
attenuated Ty21a vaccine is not available in the country, hence will
not be discussed further.
Vi Capsular Polysaccharide Vaccine

The vaccine contains highly purified antigenic fraction of Vi-PS
antigen of S. typhi, which is a virulence factor of the bacteria. Each
dose contains 25 μg of purified polysaccharide in 0.5 mL of phenolic
isotonic buffer for intramuscular or subcutaneous use. The vaccine
should be stored at 2–8°C and should not be frozen. The vaccine
is stable for 6 months at 37°C and for 2 years at 22°C. Since it is a
pure polysaccharide vaccine, it is not immunogenic in children
below 2 years of age and has no immune memory.
A single dose of Vi polysaccharide vaccine prevents around

two-thirds of typhoid cases in the first year after vaccination (year
1: 69%, 95% CI: 63–74%; 3 trials, 99,979 participants; high-certainty
evidence). The 3 years cumulative efficacy of the vaccine may be
around 55% (95% CI: 30–70%; 11,384 participants, 1 trial; low-
certainty evidence).16
Re-vaccination with Vi-PS vaccine is advised every 3 years. With
more safe and effective conjugate vaccines with long-term protection
potential, the Advisory Committee on Vaccines and Immunization
Practices (ACVIP) prefers the use of Vi conjugate vaccines.
Efficacy
The biological marker is anti-Vi antibodies and 1 μg/mL is proposed
as the serologic correlate of protection (CoP). The vaccine does not
interfere with the interpretation of the Widal test. Efficacy drops
over time and the cumulative efficacy at 3 years against culture
confirmed typhoid fever is reported as 55%. In a recently published
cluster randomized effectiveness trial conducted in over 40,000
subjects in urban slums of Kolkata, the overall effectiveness of the
vaccine at 2 years follow-up was 61%, and in children below 5 years
was 80%.18 Interestingly the herd protection of 44% was noted in
unvaccinated children in the vaccinated cluster as compared to the
control cluster.17
Safety
The adverse effects are mild and include pain and swelling at injection
site. The vaccine is contraindicated only in those with previous
history of hypersensitivity to the vaccine and can be safely given
in the immunocompromised including human immunodeficiency
virus (HIV) infected.
Dosage
The Vi polysaccharide vaccine is recommended for use as a single
dose in children aged 2 years and above and can safely be given with
all other childhood vaccines. Revaccination is recommended every
3 years.
Currently there are at least three manufacturers exporting the

vaccine [Sanofi Pasteur, GlaxoSmithKline Biologicals, and Bharat
Biotech (India)] and many other companies producing for local use
[e.g., Lanzhou Institute (China), Chengdu Institute (China), Finlay
Institute (Cuba), and DAVAC (Vietnam)]. Out of these vaccines, the
one from Sanofi Pasteur is now prequalified by WHO.
Vi Capsular Polysaccharide Conjugate Vaccines

To overcome the limitations of polysaccharide vaccine, Vi capsular
PS [derived either from Salmonella enterica subspecies enterica
serovar Typhi (S. typhi), or from Citrobacter freundii sensu lato
(C. freundii s. l.)] is conjugated to carrier proteins, TT or CRM197,
converting T-independent PS to T-dependent antigen.18
Different TCVs, like Typbar-TCV, Zyvac TCV and Typhibev
contain 25 μg whereas PedaTyph contain 5 μg of Vi-PS. The dose
of 25 μg was selected on the basis of the amount of PS present in
the licensed Vi-PS vaccine.18 The issue of the exact dose of Vi-PS
in a TCV is still unsettled. Most of the manufacturers of TCVs have
adopted a high-end dose, 25 μg of Vi-PS, in their upcoming products
(Table 1).
The TCVs demonstrate (i) superior efficacy and effectiveness
than unconjugated Vi-PS vaccines; (ii) longer duration of protection;
(iii) immunogenicity among younger children, including infants;
(iv) reasonably good herd immunity; and (v) induction of immune
memory.18
The WHO-SAGE Working Group on Typhoid Vaccines has
recommended only a single dose of the TCV at any time between
6 and 23 months of age in the endemic countries.1,12 This has been
further corroborated by the published 7-year follow-up data of
Typbar-TCV.19-25
Immune Correlate of Protection

No internationally agreed correlates or surrogates of protection
have yet been identified for Vi-conjugate vaccines.19 The study
to evaluate Vi-TT in Nepal found that higher anti-Vi IgG levels
are associated with greater protection against typhoid infection,
TABLE 1: Licensed typhoid conjugate vaccines (TCVs) in India.

Name Manufacturer Composition Comments
Typbar- Bharat Biotech 25 µg purified Vi-PS Robust evidence
TCV International Ltd. of S. typhi (strain 2) to regarding safety
tetanus toxoid and efficacy. Human
challenge study
proved efficacy,
long-term efficacy
and safety data up to
5 years available. DCGI
approved August 2013.
WHO prequalification
January 2018
Zyvac Cadila 25 µg purified Vi-PS 1 trial. Licensed based
TCV Healthcare Pvt. of S. typhi (strain 2) of noninferiority to
Ltd. to tetanus toxoid. Typbar-TCV. DCGI
2-phenoxyethanol as approved
preservative
Typhibev Biological E 25 µg purified Vi-PS DCGI approved in
vaccines conjugated to 16.7 μg February 2020. WHO
to 100 μg of CRM-197 prequalification
December, 2020
Entero- Abbott 25 µg purified Vi-PS As in Typbar-TCV
shield of S. typhi (strain 2) to above
tetanus toxoid
Typbar Bharat Biotech 25 µg purified Vi-PS Above 2 years up to
of S. typhi (strain 2) adults, recommended
unconjugated every 3 years
Zyvac Cadila Vi-PS unconjugated Few studies
Gesundheitswesen
Pvt. Ltd.
(DCGI: Drug Controller General of India; Vi-PS: virulence polysaccharide)
no threshold level could be identified at which the probability of

infection becomes negligible within the range of antibody levels
induced by vaccination. It is possible that multiple immunological
parameters, including cell mediated immune responses, may
be responsible for protection against S. typhi infection. Thus, all
second generation TCVs will be licensed on basis on noninferiority

to existing licensed vaccines.
Virulence-polysaccharide Conjugate Typhoid

Vaccines in India
Different Vi-PS conjugate vaccines have been licensed in India in
last 8 years. Conjugate vaccines have solved the issue of able to
administer below 2 years, incorporate in programmatic schedules
of nations with high endemicity and high incidence of typhoid
fever below 4 years of age. India fits in to this situation along with
Southeast Asia and parts of Africa.
VI-POLYSACCHARIDE CONJUGATE VACCINE

CONJUGATED WITH TETANUS TOXOID FROM
BHARAT BIOTECH (TYPBAR-TCV®)
Typbar-TCV is a Vi-PS conjugate typhoid vaccine conjugated with
TT, was the first licensed TCV in India, in 2013, for intramuscular
administration of a single dose (0.5 mL) in children aged 6 months
and older and in adults up to 45 years of age. It is available in single-
dose vials or prefilled syringes, and five-dose vials.
Each vaccine dose comprises 25 µg of purified Vi-PS conjugated
to TT. In the multidose formulation, each dose also contains 5 mg of
2-phenoxyethanol as preservative. The manufacturer-recommended
storage temperature is 2–8°C. The vaccine has a vaccine vial monitor
(VVM30).20
A phase III, randomized, multicentric, controlled trial was
conducted to evaluate the immunogenicity and safety of this vaccine,
Typbar-TCV in a total of 981 healthy subjects and compared with
the typhoid Vi-PS vaccine of the same manufacturer (Typbar) having
similar amount of antigen per dose.21
The study group receiving the test vaccine (Typbar-TCV) was
divided into two cohorts, i.e., ≥6 months to ≤2 years (327 subjects)
and >2 years to <45 years (654 subjects). Cohort-I was single arm
open label and all the 327 subjects received single dose of the
test vaccine. Cohort-II was randomized double-blind trial and
the subjects were recruited into two groups—one who received

single dose of either test vaccine (340 subjects) or reference vaccine
(314 subjects).
Among subjects 2–45 years of age, Typbar-TCV elicits
significantly higher titers of immunoglobulin (IgG) Vi antibody
than unconjugated Typbar at 6 weeks after a primary immunization
[1292.5 (95% CI: 1152.9, 1448.9), N = 332 vs. 411.1 (95% CI: 358.9,
470.9), N = 305] and 6 weeks after a second immunization [1680.6
(95% CI: 1498.3, 1885.1), N = 174 vs. 475.0 (95% CI: 339.9, 663.6)],
N = 50. At 3 and 5 years after a single immunization, the anti-Vi GMTs
and the proportion of individuals with titers more than fourfold over
their baseline were significantly higher among recipients of the
TCV. In infants 6–11 months old and toddlers 12–23 months old, a
single dose of Typbar TCV elicited high titers of IgG anti-Vi antibody
[1937.4 (95% CI: 1785.0, 2102.9), N = 307] that endured up to 5 years
in a proportion of young children.12,26-29
Data on antibody avidity and IgG subclasses provide further
confidence in the quality of the antibody response, and that the
vaccine-induced immune response is boostable.
The 7-year follow-up data in Table 2 of the 6–23 months cohort
shows nonsignificant differences in the titers in the boosted and
nonboosted groups at the end of 7 years.22
Coadministration with Other Vaccines

Measles and MMR
Compatibility and efficacy of Typbar-TCV with measles vaccine
alone at 9 months and measles, mumps, and rubella (MMR) at
15 months were studied.
No significant differences were detected among the groups at
any time relevant points including days 56, 180, 360, and 720. The
anti-Vi GMT and antimeasles antibodies were similar in all five
groups. The anti-Vi antibodies and IgG antimeasles antibodies
were similar when the vaccines were given either in combination
or alone.
TABLE 2: Anti-Vi titers in the boosted and unboosted 6–23 months cohort till 7 years followup.
ELIZA Day 1095 Day 1825 Day 2555
method Boosted Measure Day 0 Day 42 Day 720 Day 762 (3 Y) (5 Y) (7 Y)
Szu-NIH Boosted Persisting 100% 98.8% 100% 100% 100% 92%
(N = 86) SCR (98.8, 100) (93.7, 99.9) (98.8, 100) (98.8, 100) (98.8, 100) (84.0, 96.7)
GMT 0.7 105.4 20.7 50 40.4 33.7 13.9

(0.6, 0.8) (90.9, 122.3) (19.4, 22.1) (47.2, 53) (33.3, 49) (28.8, 39.4) (12.2, 15.9)
Non Persisting 0.9 100% 96.0% 92.0% 92% 96%
boosted SCR (98.8, 100) (79.7, 99.9) (74.0, 99.0) (74.0, 99.0) (79.7, 99.9)
(N = 25)
GMT 119.9 22.5 40.3 35.6 14.7
(95.2, 151.3) (21.3, 23.8) (31.0, 52.4) (28.4, 44.5) (10.1, 21.5)
Vacczyme Boosted Persisting 96.5% 65.1% 97.6% 90.7% 84.8% 70.9%
(N = 86) SCR (90.1, 99.3) (54.1, 75.1) (91.9, 99.7) (82.5, 95.9) (75.5, 91.7) (60.1, 80.2)
GMT 9.4” 1902.7 53.8 1700.2 319.2 132.3 111.0
(8.2, 10.8) (1670.0, (44.6, 64.7) (1500.2, (266.7, (109.1, (77.3, 159.5)
2167.8) 1927.0) 381.9) 160.4)
Contd…
Licensed Vaccines
295
Contd…
ELIZA Day 1095 Day 1825 Day 2555

method Boosted Measure Day 0 Day 42 Day 720 Day 762 (3 Y) (5 Y) (7 Y)
Non- Persisting 100% 56% 72% 72% 44%

boosted SCR (89.7, 100) (34.9, 75.6) (50.6, 87.9) (50.6, 87.9) (24.4, 65.1)
(N = 25)
GMT 10.9 1445.7 57.9 255.8 79.4 51.5
(7.2, 16.6) (986.2, (35.7, 94.1) (138.5, (48.6, 129.7) (22.8, 116.1)
2119.5) 368.1)
NIBSC Boosted Persisting 100% 100% 100% 100% 100% 98.8%
(IU/mL) (N = 86) SCR (95.8, 100) (95.8, 100) (95.8, 100) (95.8, 100) (95.8, 100) (93.7, 100)
GMT 1.7 224.9 13.7 326.6 35.9 33.9 25.9
(0.8, 3.6) (221.1, (4.20, 44.8) (275.4, (26.3, 49) (25.4, 45.2) (19.7, 33.9)
228.9) 387.2)
Non- Persisting 100% 100% 96% 100% 100%
boosted SCR (89.7, 100) (89.7, 100) (79.7, 99.9) (89.7, 100) (89.7, 100)
(N = 25)
GMT 1.2 109.3 9.3 23.6 34.2 23.4
(0.7, 2.1) (90.3, 132.2) (6.9, 12.3) (20.1, 27.6) (26.3, 44.6) (10.1, 54.3)
Effectiveness/Efficacy Studies
In the seroefficacy study, vaccine seroefficacy was 85% (95% CI:
80–88%).23
When Typbar-TCV was evaluated in a human challenge model in
a population of immunologically naïve adult volunteers (16–80 years
of age), efficacy of 87.1% (95% CI: 47.2–96.9%) was estimated based
on an endpoint of persistent fever followed by positive blood culture,
thus reflecting clinical and surveillance parameters under which a
typhoid fever case would be confirmed.24
In a phase 3 study, conducted in Lalitpur, at the end of 1 year,
vaccine efficacy was 81.6% (95% CI: 58.8–91.8). The vaccine
efficacy of TCV fever at 2 years was 79.0% (95% CI: 61.9–88.5;
p < 0.0001) with no significant waning of immunity over 2 years.
The adverse effects profile was similar in the vaccine and control
groups, with fever developing in 5.0% of participants in the TCV
group and 5.4% in the MenA vaccine group in the first week after
vaccination.25
In a study done in Dhaka, Bangladesh, in children, between
9 months and 16 years, the overall VE was (81%; 95% CI: 39–94,
p = 0.0052), including children vaccinated at ages under 2 years.
Fever (5.3%), a general feeling of unwellness (4.3%), diarrhea
(2.1%), and pain at the injection site (1.6%) were the common
adverse events reported which were similar in the two vaccine
groups. The risk of serious adverse effects was similar in the vaccine
and control groups. None of the reported deaths in both groups,
were judged to be related to vaccination.26
In a phase 3, double-blind trial conducted in Blantyre, Malawi,
the efficacy of Vi-TCV was 80.7% [95% confidence interval (CI),
64.2–89.6] in the intention-to-treat analysis and 83.7% (95% CI:
68.1–91.6) in the per-protocol analysis. The estimated efficacy of
Vi-TCV was 84.6% (95% CI: 50.0–94.4) at 12 months, 82.9% (95% CI:
58.1–92.5) at 18 months, and 78.7% (95% CI: 52.8–91.7) at 24 months
after vaccination. No serious adverse events were considered by the
investigators to be related to vaccination.27
Navi Mumbai Municipal Corporation (NMMC) launched the
world’s first public sector TCV introduction aimed at vaccinating
approximately 320,000 children aged 9 months to under 15 years in

two phases.
ZYVAC TCV: TYPHOID CONJUGATE VACCINE WITH

TT FROM CADILA HEALTH CARE LIMITED
Single dose: 0.5 mL vial; Vi polysaccharide of S. typhi 25 µg,
2-phenoxyethanol 2.50 mg as preservative and buffer solution. A
Phase II/III study to demonstrate the noninferiority of ZyVac-TCV
to Typbar TCV in healthy individuals aged 6 months to 45 years
was initiated in 2016. The seroconversion rate among ZyVac-TCV
recipients was 94.8% (96.6% in adults and 93.1% in children),
compared with 91.6% (91.7% in adults and 91.5% in children) for
Typbar TCV recipients. The GMT of anti-Vi antibodies among
ZyVac-TCV recipients was 1,121 EU/mL (adults, 1,411; children,
891.1), compared with 1,104 EU/mL (adults, 1,199; children, 1,014)
among Typbar TCV recipients. ZyVac-TCV was deemed noninferior
to Typbar TCV and received marketing authorization in India
in 2017.29
TYPHIBEV: VI-PS CRM197 TCV FROM

BIOLOGICAL E VACCINES
TYPHIBEV (Biological E vaccines) is a typhoid conjugate vaccine
where the source of the Vi antigen is C. frenundii, which is in
conformity with WHO specifications. Each dose of 0.5 mL contains
typhoid Vi polysaccharide (produced from C. Freundii sensu lato
3056): 25 μg conjugated to 16.7–100 μg of CRM197. Typhibev was
licensed for use in India by DCGI in February 2020 and WHO
prequalified in December 2020, approved for those aged older than
6 months to 45 years, to be given in 0.5 mL single dose, intramuscular
injection.30
A multicentric phase II/III study showed that seroconversion
(anti-Vi IgG > 2 μg/mL) was obtained in 99% subjects (95% CI:
97.06, 99.79) in Typhibev compared to 99.4% in comparator group
Typbar-TCV (Bharat Biotech India Limited). Noninferiority was
established with comparator TCV. Anti-Vi IgG > 4.3 µg/mL (criteria
defined for having sustained protection for at least 4 years) also
fulfilled predefined noninferiority criteria. The side-effect profile
was comparable with the comparator vaccine.31

Individual Use
IAP/ACVIP Recommendation Typhoid Vaccines32,33
Primary schedule:
■ A single dose of TCV 25 µg is recommended from the age of
6 months onward routinely.
■ TCV can be administered simultaneously with measles-containing
vaccine when it is offered at age of 9 months or beyond.
■ For a child who has received only typhoid polysaccharide
vaccine, a single dose of TCV is recommended at least 4 weeks
following the receipt of polysaccharide vaccine. Routine booster
for TCV at 2 years is not recommended as of now.
The WHO position paper in 2018 has remarked that the body of
evidence for the 5 µg vaccine is very limited.
Vi-polysaccharide vaccine: IAP-ACVIP recommends the adminis-
tration of the currently available Vi-polysaccharide vaccine 0.5 mL
intramuscularly (IM) every 3 years beginning at the age of 2 years.
A child with history of suspected or confirmed enteric fever may be
vaccinated 4 weeks after recovery if he/she has not received the vac-
cine in the past 3 years.
Among the available typhoid vaccines, TCV is preferred at all ages
in view of its improved immunological properties, use in younger
children and expected longer duration of protection.
The IAP strongly urges the government to include typhoid vaccina-
tion in the UIP considering the enormous burden of the disease (Box 1).
BOX 1: IAP recommendations: Typhoid vaccines.

• Both Vi-PS (polysaccharide) and Vi-PS conjugate vaccines are available
• Minimum ages:
– Vi-PS (Typbar-TCV®): 6 months
– Vi-PS (polysaccharide) vaccines: 2 years
• Vaccination schedule:
– Vi-PS (polysaccharide) vaccines: Single dose at 2 years; revaccination
every 3 years (no evidence of hyporesponsiveness on repeated
revaccination so far)
– Vi-PS conjugate (Typbar-TCV®): Single dose at 9–12 months
• Catch-up vaccination:
– Recommended throughout the adolescent period, i.e., till 18 years
– IAP prefers the use of Vi-PS conjugate vaccine
(Vi-PS: virulence polysaccharide; TCV: typhoid conjugate vaccines)
REFERENCES
1. World Health Organization. Typhoid vaccines: WHO position paper –
March 2018. Wkly Epidemiol Rec. 2018;93:153-72.
2. GBD 2017 Typhoid and Paratyphoid Collaborators. The global burden
of typhoid and paratyphoid fevers: a systematic analysis for the
Global Burden of Disease Study 2017. Lancet Infect Dis. 2019;19(4):
369-81.
3. Kothari A, Pruthi A, Chugh TD. The burden of enteric fever. J Infect Dev
Ctries. 2008;2:253-9.
4. Kanungo S, Dutta S, Sur D. Epidemiology of typhoid and paratyphoid
fever in India. J Infect Dev Ctries. 2008;2:454-60.
5. Date KA, Bentsi-Enchill AD, Fox KK, Abeysinghe N, Mintz ED,
Khan MI, et al. Typhoid Fever surveillance and vaccine use—South-
East Asia and Western Pacific regions, 2009-2013. MMWR Morb Mortal
Wkly Rep. 2014;63:855-60.
6. Garrett DO, Longley AT, Aiemjoy K, Yousafzai MT, Hemlock C, Yu AT,
et al. Incidence of typhoid and paratyphoid fever in Bangladesh,
Nepal, and Pakistan: results of the Surveillance for Enteric Fever in
Asia Project. Lancet Glob Health. 2022;10:e978-88.
7. Ochiai RL, Acosta CJ, Danovaro-Holliday MC, Baiqing D, Bhattacharya
SK, Agtini MD, et al. A study of typhoid fever in five Asian countries:
disease burden and implications for controls. Bull World Health
Organ. 2008;86:260-8.
8. Hughes MJ, Birhane MG, Dorough L, Reynolds JL, Caidi H, Tagg KA,
et al. Extensively Drug-Resistant Typhoid Fever in the United States.
Open Forum Infect Dis. 2021;8(12):ofab572.
9. Crump JA, Luby SP, Mintz ED. The global burden of typhoid fever. Bull
World Health Organ. 2004;82:346-53.
10. John J, Van Aart CJ, Grassly NC. The Burden of Typhoid and Paratyphoid
in India: Systematic Review and Meta-analysis. PLoS Negl Trop Dis.
2016;10(4):e0004616.
11. Sinha A, Sazawal S, Kumar R, Sood S, Reddaiah VP, Singh B, et al.
Typhoid fever in children aged less than 5 years. Lancet. 1999;354:734-7.
12. WHO. (2017). Background Paper on Typhoid Vaccines for SAGE
Meeting (October 2017). [online] Available from https://www.who.
int/immunization/sage/meetings/2017/october/1_Typhoid_SAGE_
background_paper_Final_v3B.pdf. [Last accessed December, 2022].
13. Touchan F, Hall JD, Lee RV. Typhoid fever during pregnancy: case
report and review. Obstet Med. 2009;2:161-3.
14. Ochiai RL, Wang X, von Seidlein L, Yang J, Bhutta ZA, Bhattacharya SK,
et al. Salmonella paratyphi A rates, Asia. Emerg Infect Dis. 2005;11:
1764-6.
15. IAP. (2019). Infectious disease surveillance. [online] Available from

www.idsurv.org. [Last accessed December, 2022].
16. Milligan R, Paul M, Richardson M, Neuberger A. Vaccines for
preventing typhoid fever. Cochrane Database Syst Rev. 2018;5:
CD001261.
17. Sur D, Ochiai RL, Bhattacharya SK, Ganguly NK, Ali M, Manna B, et al.
A cluster-randomized effectiveness trial of Vi typhoid vaccine in India.
N Engl J Med. 2009;361:335-44.
18. Szu SC. Development of Vi conjugate—A new generation of typhoid
vaccine. Expert Rev Vaccines. 2013;12:1273-86.
19. Acharya IL, Lowe CU, Thapa R, Gurubacharya VL, Shrestha MB,
Cadoz M, et al. Prevention of typhoid fever in Nepal with the Vi
capsular polysaccharide of Salmonella Typhi. A preliminary report.
N Engl J Med. 1987;317:1101-4.
20. Bharatbiotech.com. Typbar-TCV product insert. [online] Available
from https://www.bharatbiotech.com/images/typbartcv/Typbar-
TCV-Package-Insert.pdf. [Last accessed December, 2022].
21. Mohan VK, Varanasi V, Singh A, Pasetti MF, Levine MM, Venkatesan R,
et al. Safety and immunogenicity of a Vi polysaccharide-tetanus toxoid
conjugate vaccine (Typbar-TCV) in healthy infants, children, and
adults in typhoid endemic areas: a multicenter, 2-cohort, open-label,
double-blind, randomized controlled phase 3 study. Clin Infect Dis.
2015;61:393-402.
22. Vadrevu KM, Raju D, Rani S, Reddy S, Sarangi V, Ella R, et al. Persisting
antibody responses to Vi polysaccharide–tetanus toxoid conjugate
(Typbar TCV) vaccine up to 7 years following primary vaccination
of children < 2 years of age with, or without, a booster vaccination.
Vaccine. 2021;39(45):6682-90.
23. Voysey M, Pollard AJ. Seroefficacy of Vi polysaccharidetetanus toxoid
typhoid conjugate vaccine (Typbar TCV). Clin Infect Dis. 2018;67:
18-24.
24. Jin C, Gibani MM, Moore M, Juel HB, Jones E, Meiring J, et al. Efficacy
and immunogenicity of a Vi-tetanus toxoid conjugate vaccine in the
prevention of typhoid fever using a controlled human infection model
of Salmonella Typhi: a randomised controlled, phase 2b trial. Lancet.
2017;390:2472-80.
25. Shakya M, Voysey M, Theiss-Nyland K, Colin-Jones R, Pant D, Adhikari A,
et al. Efficacy of typhoid conjugate vaccine in Nepal: final results
of a phase 3, randomised, controlled trial. Lancet Glob Health.
2021;9:e1561-8.
26. Qadri F, Khanam F, Liu X, Theiss-Nyland K, Biswas PK, Bhuiyan AI, et al.
Protection by vaccination of children against typhoid fever with a
Vi-tetanus toxoid conjugate vaccine in urban Bangladesh: a cluster-

randomised trial. Lancet. 2021;398:675-84.
27. Patel PD, Patel P, Liang Y, Meiring JE, Misiri T, Mwakiseghile F, et al.
Safety and Efficacy of a Typhoid Conjugate Vaccine in Malawian
Children. N Engl J Med. 2021;385:1104-15.
28. Navi Mumbai Municipal Corporation launches the world’s first public-
sector typhoid conjugate vaccine campaign. Available at https://www.
coalitionagainsttyphoid.org/navi-mumbai-municipal-corporation-
launches-the-worlds-first-public-sector-typhoid-conjugate-vaccine-
campaign/. [Last accessed December, 2022].
29. Kundu R, Kandulna AK, Nayak U, Jangid SK, Babu TR, Vukkala R, et al.
Immunogenicity and Safety of Typhoid Conjugate Vaccine in Healthy
Indian Subjects: A Randomized, Active-controlled, Comparative
Clinical Trial. Indian Pediatr. 2020;57(7):625-30.
30. Typhibev Product Insert. [online] Available from https://www.
biologicale.com/pdf/Product_VB_International_Marketing.pdf. [Last
accessed December, 2022].
31. Thuluva S, Paradkar V, Matur R, Turaga K, Subba Reddy GV. A multi
center, single-blind, randomized, phase-2/3 study to evaluate
immunogenicity and safety of a single intramuscular dose of
biological E’s Vi-capsular polysaccharide-CRM 197 conjugate typhoid
vaccine (TyphiBEV TM) in healthy infants, children, and adults in
comparison with a licensed comparator. Hum Vaccin Immunother.
2022;18(5):2043103.
32. Vashishtha VM, Kalra A, Bose A, Choudhury P, Yewale VN, Bansal CP,
et al. Indian Academy of Pediatrics (IAP) recommended immunization
schedule for children aged 0 through 18 years—India, 2013 and
updates on immunization. Indian Pediatr. 2013;50:1095-108.
33. Kasi SG, Shivananda S, Marathe S, Chatterjee K, Agarwalla S, Dhir SK,
et al. Indian Academy of Pediatrics (IAP) Advisory Committee
on Vaccines and Immunization Practices (ACVIP): Recommended
Immunization Schedule (2020-21) and Update on Immunization
for Children Aged 0 Through 18 Years. Indian Pediatr. 2021;58(1):
44-53.
3.12 HUMAN PAPILLOMAVIRUS VACCINES

EPIDEMIOLOGY
Human papillomavirus (HPV) is a member of the family
Papillomaviridae. They are small and nonenveloped
deoxyribonucleic acid (DNA) viruses. These infections are highly
transmissible and are primarily transmitted by sexual contact.
Whereas most HPV infections are transient, self-regressing and
benign, persistent genital infection with certain viral genotypes can
lead to the development of anogenital precancers and cancers.
Over 200 serotypes of HPV have been discovered, of which
15–20 are oncogenic. Presence of oncogenic HPV-DNA has been
demonstrated in 99.7% of all cervical cancer cases, the highest
attributable fraction so far reported for a specific cause of major
human cancer. The lag period between the oncogenic HPV infection
and the invasive cervical cancer is 15–20 years. 1 Based on the
association with cervical cancer, genital HPVs are further grouped
into high-risk types, probable high-risk types and low-risk types.
In Indian women, the most common prevalent genotypes are
HPV-16 and -18. Nononcogenic HPV serotypes-6 and -11 contribute
to over 90% of benign genital infections such as genital warts. In
addition, HPV has been implicated in anal, penile, vulvar, vaginal,
and oropharyngeal cancers.
CERVICAL CANCER MORBIDITY AND

MORTALITY IN INDIA
Globally cancer of the cervix uteri is the second most common
cancer among women with an estimated 604,127 new cases and
341,831 deaths in 2020. About 86% of the cases occur in developing
countries, representing 13% of female cancers.2 In many countries
in sub-Saharan Africa, Central and South America, South and
Southeast Asia, age-standardized incidence rates of cervical cancer
exceed 25 per 100,000.3
In India, cancer of the cervix uteri is the second most important
cancer in women.2 Globally, age-standardized rate (ASR) of cervical
cancer is 13.3 per 100,000, and for Indian women it is 18 per 100,000.
It is estimated that 123,907 cases of cervical cancer cases occur in
India and of these 77,348 die every year2 and this has come down
from earlier very high rates even without a control program.4 The
urban population-based cancer registries (PBCRs) at Bengaluru,
Bhopal, Chennai, Delhi, and Mumbai have shown a significant
decrease in the AARs of cervical cancer (16.9 in 2001 to 15.3 in 2012
in Bengaluru, 18.6 to 13.8 in Bhopal, 29.1 to 15.7 in Chennai, 19.7 to
15.5 in Delhi, and 14.1 to 9 in Mumbai).5,6
The cumulative risk of cervical cancer at 75 years is 2%.
PREVENTION OF CERVICAL CANCER:

SCREENING OR VACCINATION
Cervical cancer is essentially a preventable cancer as it has a long
preinvasive stage. Countries with well-organized programs to detect
and treat precancerous abnormalities and early stage cervical cancer
can prevent up to 80% of these cancers.7 It has been shown that it
is possible to screen and treat cervical cancer in early stages with
high success even in rural India.8 However, information on screening
behaviors of Indian women related to cervical cancer is very little.
In a study from Kolkata, most women reported “limited” to “no”
knowledge of cervical cancer (84%) and the Pap smear test (95%).9
Further, to implement national screening program, large investment
has to be made in terms of logistics and training of healthcare
personnel.
Human papillomavirus vaccines are necessary to significantly
reduce the health care burden currently required for cervical cancer
prevention. In addition, cervical cancer screening is necessary
due to the limitations of current HPV vaccines both in their lack
of therapeutic effect (thus not protecting women with an ongoing
neoplastic processes) and in their limited number of HPV types.10
Human Papillomavirus Prevalence in Men

A multicenter clinical trial examined the baseline prevalence of
penile, scrotal, and perineal/perianal HPV infection in heterosexual
men. The prevalence of any HPV type was 18.7% at the penis, 13.1%
at the scrotum, 7.9% at the perineal/perianal region, and 21.0% at

any site.7
PATHOGEN
Human papillomaviruses are nonenveloped and double-stranded
DNA viruses in the family of Papillomaviridae. The HPV genome
is enclosed in a capsid shell comprising major (L1) and minor
(L2) structural proteins. More than 200 HPV genotypes are known.
Certain HPV genotypes are associated with cell immortalization and
transformation related to carcinogenesis. Of these, at least 14 may
cause cervical cancer or are associated with other anogenital and
oropharyngeal cancers.
Human papillomavirus types 16 and 18 cause about 70% of all
cases of invasive cervical cancer worldwide, with type 16 having the
greatest oncogenic potential. The distribution of HPV types varies
among geographical regions, but the dominant oncogenic type in all
regions is HPV-16.11 The low-risk HPV types 6 and 11 are responsible
for about 90% of anogenital warts and almost all recurrent respiratory
papillomatosis.
In India, high-risk HPV types were found in 97% of cervical
cancers.12 According to data updated on 11th June 2019, in India,
HPV-16 was found in 69.7% of invasive cervical cancers (ICC),
HPV-18 in 13.5%, and HPV-16/18 in 83.2%.2 HPV-16/18 was found
in 62.8% (56.7–68.6) of high-grade lesions, 28.2% (22.1–35.3) of low-
grade lesions and 5.0% (4.6–5.5) in women with normal cytology.2
There was no difference in overall HPV prevalence in cervical
cancer between North and South India. However, HPV-16 and
HPV-45 appeared to be more prevalent in North India while HPV-35
appeared to be more prevalent in South India. It is estimated that
HPV-16/18 vaccines will provide over 80.3% protection against ICC
in South Asia.13
Globally, 69.4% (69–69.8) of all ICC are caused by HPV-16/18.
HPV-31 accounts for 3.5%, HPV-33 for 4.2%, HPV-45 for 5.0%,
HPV-52 for 3.5%, and HPV-58 for 3.9% of cervical cancer cases.2
Approximately 89.5% of the squamous cell carcinomas which are
positive for HPV-DNA are related to HPV types-16, 18, 45, 31, 33, 52,
and 58.2,14
PROTECTIVE IMMUNITY
Natural HPV infections do not induce a vigorous immune response
as they are restricted to the intraepithelial basement layers of the
mucosa. Approximately half of all women infected with HPV develop
detectable serum antibodies, but these antibodies do not necessarily
protect against subsequent infection by the same HPV type. They are
known as “non-neutralizing” antibodies. The neutralizing antibodies
are best characterized and most type-specific HPV antibodies which
are those directed against the L1 protein of the virus, which is the
main capsid protein. The other L2 protein is minor and is responsible
for nononcogenic genital warts.
Human Papillomavirus Vaccines

The quadrivalent and nonavalent vaccines have been licensed
globally (Table 1). The bivalent vaccine has been withdrawn from
the Indian market. Both vaccines are manufactured by recombinant
DNA technology that produces noninfectious virus-like particles
(VLPs) comprising the HPV-L1 protein. The mechanisms by which
these vaccines induce protection have not been well-defined,
but seem to involve both cellular immunity and neutralizing
immunoglobulin G antibodies. Clinical trials with these vaccines
have used efficacy against cervical intraepithelial neoplasia (CIN)-
2/3 and adenocarcinoma in situ (AIS) caused by HPV strains
contained in the concerned vaccine as primary endpoints. Regulatory
authorities have accepted the use of CIN grade 2 or 3 (CIN-2/3) and
AIS as clinical endpoints in vaccine efficacy trials instead of invasive
cervical cancer.15
These vaccines do not protect against the serotype with which
infection has already occurred before vaccination. Higher immune
response is seen in preadolescents through 9–13 years as compared
to adolescents and young adults. All the three vaccines have been
licensed in several countries world over.
These vaccines are equally safe and have shown nearly complete
protection against precancerous and other anogenital lesions caused
by the respective vaccine related HPV-types during the 10–14 years
of observation so far. The consistency of these observations strongly
TABLE 1: Human papillomavirus (HPV) vaccines: A comparison.

Gardasil 4 Gardasil 9 Cervavac
HPV types in 6, 11, 16, and 18 6, 11, 16, 18, 6, 11, 16, and
vaccine 31, 33, 45, 52, 18
and 58
Adjuvant 225 µg of 500 µg of Al+++ ≤ 1.25
amorphous AAHS mg
aluminum
hydroxyphosphate
sulfate (AAHS)
Composition • 20 µg of virus-like • 20 µg of VLP • 20 µg of VLP
particle of 6, and of 31, 33, 45, of 6, and 18
18 52, and 58 • 40 µg of VLP
• 40 µg of VLP of • 30 µg of VLP of 11, and 16
11, and 16 of 6
• 40 µg of VLP
of 11, and 18
• 60 µg of VLP
of 16
Age Females: 9–45 years • Females: Males and
recommendations 9–26 years females: 9–26
• Males: 9–14 years
years
suggests that similar high rates of protection can be expected also

against cervical cancer. However, the immune protective correlates
are not known and the level of antibody titers which will be translated
into clinical efficacy are ill understood.15
Quadrivalent Vaccine
Quadrivalent vaccine (4vHPV) available in India is a mixture of L1
proteins of HPV serotypes 6, 11, 16, and 18 with aluminum containing
adjuvant.
Each 0.5 mL dose of this vaccine contains:
■ 20 μg of HPV-6 L1 protein
■ 20 μg of HPV-18 L1 protein adsorbed onto 225 μg of the aluminum

hydroxide.
Efficacy
The safety and efficacy of quadrivalent vaccine was assessed in a
large study named FUTURE (Females United to Unilaterally Reduce
Endo/Ectocervical Disease) in 17,622 women aged 15–26 years
who were enrolled in one of two randomized, placebo-controlled,
efficacy trials for the HPV-6/11/16/18 vaccine.
Clinical trials with three doses at 0, 2, and 6 months have shown
99% efficacy at a median follow-up of 3.9 years against types 16,
18 related CIN-2/3, and AIS in per protocol analysis (women who
received all three doses of the vaccine and who remained uninfected
with vaccine HPV type at onset and for 1 month after completion
of the vaccine schedule). Additionally, 99–100% efficacy was seen
against vaccine type related genital warts, vaginal intraepithelial
neoplasia (VaIN), and vulvar intraepithelial neoplasia (VIN).
Reduction in HPV-16 related lesions and HPV-18 related lesions are
98% and 100%, respectively when CIN-2/3 is taken into consideration
and AIS as endpoints.
Data from two international, double-blind, placebo-controlled,
randomized efficacy trials of quadrivalent HPV vaccine (FUTURE I)
and (FUTURE II) showed persistent protection in participants over
5 years.16,17 The targeted long-term follow-up studies for 14 years
have been published and show sustained protection.
Nine Valent Human Papillomavirus Vaccine

Nine valent HPV (9vHPV) vaccine contains HPV-6, 11, 16, 18, 31, 33,
45, 52, and 58 VLPs. Studies have found that 9vHPV is an efficacious
vaccine.
Phase III studies in ~10,000 women aged 16–26 years have
demonstrated that 9vHPV is safe and highly efficacious against
HPV infection and anogenital precancer lesions in both men and
women with a VE of 96.7% (80.9–99.8) against high-grade cervical,
vulvar, or vaginal disease as well as 6-month persistent infection
caused by HPV-31, 33, 45, 52, and 58 in women not previously
infected with HPV following three doses of 9vHPV. This high efficacy
(90–98%) of 9vHPV in preventing certain HPV-related precancers
was sustained for >8 years.
All participants who received 9vHPV, seroconverted to the
additional five HPV types (HPV-31, 33, 45, 52, and 58) 1-month
following the last dose, and the levels of these five additional HPV
types were significantly higher than in 4vHPV recipients. Antibody
responses to HPV-6, 11, 16, and 18 were noninferior to those
generated by the qHPV vaccine.18-24
Adverse events related to injection site were more common in
the 9HPV group than in the qHPV group.25
In a Latin American study, GMTs for HPV types 6, 11, 16, 18, 31,
33, 45, 52, and 58 at month 7 were higher in girls and boys 9–15 years
of age than in young women 16–26 years of age.26
Around 77.5–100% of individuals who received three doses of
9vHPV remained seropositive to all 9vHPV after 5 years.27 When a
fourth dose of 9vHPV was given to this group of individuals, antibody
responses were 1.25–4.10- and 1.65–4.88-fold higher at 1 week and
1 month after the fourth dose, respectively, when compared to the
levels at 1 month after the third dose, suggesting the induction of
immunological memory to all nine HPV types following the three-
dose primary series.28
9-valent HPV Vaccine after Quadrivalent HPV Vaccine

9-valent HPV is also immunogenic to all nine HPV types in young
women previously vaccinated with three doses of 4vHPV. Women
who were naïve to any HPV vaccination and received three doses
of 9vHPV had higher antibody responses to HPV-31/33/45/52/58
when compared with women who previously received three doses
of 4vHPV and received three doses of 9vHPV. Nevertheless, the
antibody level to these types was still several-fold higher than
natural infection and the study demonstrated that it was safe to give
9vHPV to individuals previously vaccinated with 4vHPV or 2vHPV
after 12 months.29 However, there is no recommendation to give
a 9vHPV to females who have received a full course of 2/4vHPV
vaccine.
Adverse Events Following Nonavalent Vaccine

The most common adverse event from seven Phase III clinical trials
was injection-site pain, swelling, and redness, which was more
common for 9vHPV than 4vHPV with increasing number of doses. It
is important to note that the adjuvant content in 9vHPV is more than
double that of 4vHPV (0.5 vs. 0.225 mg), and also has a higher VLP
antigen content. Nevertheless, most adverse events were mild to
moderate in intensity.30
Coadministration with Other Adolescent Vaccines

Coadministration of 9vHPV and other adolescent vaccines (i.e.,
Neisseria meningitidis serotypes A/C/Y/W-135, diphtheria/tetanus/
acellular pertussis, or diphtheria/tetanus/acellular pertussis/
inactivated poliomyelitis vaccine) to boys and girls aged 9–14 years
was also found to be safe and immunogenic when compared with
those who received the vaccines nonconcomitantly.31,32
4vHPV Vaccine of Serum Institute of India (CervavacTM)

Recently, the 4vHPV vaccine of Serum Institute of India (CervavacTM)
has been granted market authorization.
CERVAVACTM is a quadrivalent HPV vaccine developed by the
Serum Institute of India.33
Each dose of 0.5 mL contains:
■ HPV type 6 L1 protein ≥ 20 µg
■ Al+++ ≤ 1.25 mg.
It is produced from Hansenula polymorpha.
In a pivotal, phase 2/3 trial, done in 9–26 years aged popula-
tion, CERVAVACTM—induced IgG geometric mean titers (GMT)
were >1,000 times higher than the baseline titers against all targeted
HPV types. Postvaccination, at 7-month timepoint (1 month after
the last dose), a 100% seroconversion was reported across all four
vaccine types (Serotypes 6, 11, 16, and 18) in initially seronegative
populations.
The vaccine has demonstrated comparable immunogenicity

against licensed quadrivalent vaccine when administered to female
and male aged 9–26 years.
Safety Profile
The most common adverse events noted were injection site pain and
headache. The majority of adverse events were mild to moderate in
severity and usually resolved within a few days of vaccination. All
resolved without sequelae.
Indications
In girls and women 9 through 26 years of age for the prevention
of the following diseases caused by HPV types, included in the
vaccine:
■ Cervical, vulvar, vaginal, and anal cancer caused by HPV types
16 and 18
■ Genital warts (condyloma acuminata) caused by HPV types 6
and 11
■ CIN grade 2/3 and cervical AIS, and
■ CIN grade 1 caused by types 6, 11, 16, and 18
■ VIN grades 2 and 3
■ VaIN grades 2 and 3
■ Anal intraepithelial neoplasia (AIN) grades 1, 2, and 3.
In boys and men 9 through 26 years of age for the prevention of the
following diseases caused by HPV types included in the vaccine:
■ Anal cancer caused by HPV types 16 and 18
■ Genital warts (condyloma acuminata) caused by HPV types 6
and 11
■ AIN grades 1, 2, and 3 caused by 6, 11, 16, and 18.
Contraindications
Hypersensitivity to the active substances or to any of the excipients
of the vaccine. Hypersensitivity, including severe allergic reactions
to yeast (a vaccine component), or after a previous dose of the
vaccine.
Schedule
Individuals 9–14 years of age (boys and girls): Two-dose schedule
(0.5 mL at 0 and 6 months). The interval between the 1st and 2nd
dose should not be <5 months.
Individuals 15–26 years of age (females and males): 3-dose (0.5 mL
at 0, 2, and 6 months) schedule. The second dose should be
administered at least 1 month after the first dose and the third dose
should be administered at least 3 months after the second dose. All
three doses should be given within a 1-year period.
Safety of Human Papillomavirus Vaccines

Local adverse effects with quadrivalent vaccines reported were pain
at the injection site in 83% of vaccines (mainly mild and moderate
intensity) and swelling and erythema in 25%. Systemic adverse
effects such as fever reported in 4% of vaccines. They are all minor
adverse effects and no serious vaccine-related adverse events have
been reported either in trials or post-marketing surveillance studies.
Local side-effects with bivalent vaccines reported were pain (mild
and moderate intensity) in 90% and swelling and erythema in 40%.
Systemic side-effects such as fever were seen in 12%. No serious
vaccine-related adverse effects were observed. Both the vaccines
have very good safety record.
More than 175 million doses have been distributed worldwide
and more countries offering the vaccine through national
immunization programs. WHO’s Global Advisory Committee on
Vaccine Safety (GACVS) continues to be reassured by the safety
profile of the available products.25 Centers for Disease Control and
Prevention (CDC) monitors HPV vaccine safety and states that there
are no new or unusual patterns of adverse events to suggest the
HPV vaccine safety concern. However, the CDC states that syncope
(fainting) can occur among adolescents following vaccination.
To decrease the risk of falls and other injuries that might follow
syncope, CDC’s Advisory Committee on Immunization Practices
(ACIP) recommends that clinicians consider observing patients for
15 minutes after vaccination.34
Analysis from the Vaccine Adverse Event Reporting System

(VAERS) and the Vaccine Safety Datalink (VSD), published in 2019,
did not reveal any unexpected safety problems with Gardasil 9. This
included multiple years of data.34

The HPV vaccines are of public health importance. WHO states
that HPV vaccine should be included in national immunization
programs.27 This is especially so in countries like India having
considerable disease burden but without a screening program.
All three licensed HPV vaccines (bivalent, quadrivalent, and
nonavalent) have excellent safety, efficacy, and effectiveness
profiles.7
However, introduction of vaccine in program needs to take
into account public awareness and programmatic feasibility. The
production capacity of HPV vaccine is also limited and may not
serve the need of India, if it decides to give it to all eligible girls during
adolescence. WHO recommends introduction of HPV vaccine in
national immunization programs.7
Efforts are being made to scale up HPV vaccination for
adolescent girls in India. Since 2016, HPV vaccination was
introduced in the immunization programs in Punjab, Sikkim, and
Delhi. With the current thinking of the feasibility of a single dose of
HPV vaccination and the availability of an affordable Indian vaccine
in the near future, HPV vaccination in the national immunization
program is not too far off.35
Individual Use
The ACVIP recommends offering HPV vaccine to all females and
boys 9–14 years, in the schedules discussed below. Since protection
is seen only when the vaccine is given before infection with HPV, the
vaccine should preferably be given prior to sexual debut. The vaccine
should preferably be introduced to parents as a cervical cancer and
warts preventing vaccine and not as a vaccine against a sexually
transmitted infection (STI). Vaccines are not 100% protective against
cervical cancer and not a replacement for periodic screening. Hence,

screening programs should continue as per recommendations.
All the available vaccines are equally efficacious and safe for
protection against cervical cancer and precancerous lesions as of
currently available data. The quadrivalent and nonavalent vaccine
additionally protect against anogenital warts.
Currently, only the 9-valent HPV vaccine is licensed in India for
use in males.
Storage: The vaccines should be stored at 2–8°C and must not be
frozen.
Dose: The dose is 0.5 mL intramuscular in deltoid.
Human papillomavirus vaccines can be given simultaneously
with other vaccines such as hepatitis B and Tdap. As a precaution
against syncope following any vaccine in adolescents, the vaccinee
should be counseled prior to vaccination, vaccine is administered in
a sitting/lying down position and the patient should be observed for
15 minutes postvaccination.
Human papillomavirus vaccines are contraindicated in those
with history of previous hypersensitivity to any vaccine component
and should be avoided in pregnancy. The vaccines may be adminis
tered in the immunocompromised, but immunogenicity and efficacy
may be lower. At present, there is no data to support use of boosters.
Breastfeeding is not a contraindication for HPV vaccination.
Available evidence does not indicate an increased risk of adverse
events linked to the vaccine in either the mothers or their babies
after administration of HPV vaccine to lactating females.7
In April 2022, the WHO Strategic Advisory Group of Experts
(SAGE) on immunization recommended updating the dose
schedules for HPV vaccines in national immunization programs.36,37
The new dose schedules suggested are as follows:
■ One or two-dose schedule for the primary target of girls aged
9–14 years
■ One or two-dose schedule for young women aged 15–20 years
■ Two doses with a 6-month interval for women older than 21 years.
Immunocompromised individuals, including those with HIV,
should receive three doses if feasible, and if not, at least two doses. There
is limited evidence regarding the efficacy of a single dose in this group.
Till date, this recommendation is not endorsed by the

Government of India or IAP.
IAP Recommendations: Human Papillomavirus Vaccines

Routine vaccination in India:
■ Both, 4vHPV and 9vHPV are currently available in India.
■ Minimum age: 9 years.
■ 9–14 years girls: 4vHPV and 9vHPV are recommended in two-
dose series with a minimum gap of 6 months between the
doses.
■ 9–14 years boys: 9vHPV is recommended in a 2-dose series, with
a minimum interval of 6 months between the doses (0–6 months).
■ 15–45 years girls and women: Three-dose schedule:
y 4vHPV: (0, 2, and 6 months)
y 9vHPV: (0, 2, and 6 months) till 26 years of age
■ For immunocompromised individuals, three-dose series is
recommended.
■ In a two-dose schedule, the minimum interval between doses
should not be <5 months. If the second dose is administered
after a shorter interval, a third dose should be administered a
minimum of 5 months after the first dose and a minimum of
12 weeks after the second dose.
■ In a three-dose schedule, the minimum interval between dose
1 and 2 should not be <4 weeks, the minimum interval between
dose 2 and 3 should not be <12 weeks, and the minimum interval
between dose 1 and 3 should not be <5 months.
■ If a vaccine dose is administered after a shorter interval, it should
be re-administered after another minimum interval has elapsed
since the most recent dose.
Catch-up Vaccination
■ Administer the vaccine series to females (4vHPV) at age 13
through 45 years and 9vHPV till 26 years (in females), if not
previously vaccinated.
■ Use recommended routine dosing intervals (see above) for
vaccine series catch-up.
REFERENCES
1. Walboomers JM, Jacobs MV, Manos MM, Bosch FX, Kummer JA,
Shah KV, et al. Human papillomavirus is a necessary cause of invasive
cervical cancer worldwide. J Pathol. 1999;189(1):12-9.
2. Bruni L, Albero G, Serrano B, Mena M, Gómez D, Muñoz J, et al. ICO/
IARC Information Centre on HPV and Cancer (HPV Information
Centre). Hum Papilloma Relat Dis World Sum Report. 2021.
3. Curado MP, Edwards B, Shin HR. Cancer incidence in five continents,
Vol. IX. IARC Scientific Publications No. 160. Lyon: IARC; 2007.
4. Nandakumar A, Ramnath T, Chaturvedi M. The magnitude of cancer
cervix in India. Indian J Med Res. 2009;130(3):219-21.
5. Takiar R. Status of breast and cervix cancer in selected registries of
India. Ann Women’s Health. 2018;2(1):1012.
6. ICMR, NCDIR. (2014). National Cancer Registry Program. Three-
year report of population-based cancer registries: 2012–14. [online]
Available from http://ncdirindia.org/NCRP/all_ncrp_reports/pbcr_
report_2012_2014/all_content/Printed_Version.htm [Last accessed
December, 2022].
7. WHO. Human Papillomavirus Vaccines: WHO position paper. Wkly
Epidemiol Rec. 2017;92(9):241-68.
8. Bhatla N, Gulati A, Mathur SR, Rani S, Anand K, Muwonge R, et al.
Evaluation of cervical screening in rural North India. Int J Gynecol
Obstet. 2009;105(2):145-9.
9. Roy B, Tang TS. Cervical cancer screening in Kolkata, India:
beliefs and predictors of cervical cancer screening among women
attending a women’s health clinic in Kolkata, India. J Cancer Educ.
2008;23(4):253-9.
10. Bosch FX, Castellsague X, Sanjose SD. HPV and cervical cancer:
screening or vaccination? Br J Cancer. 2008;98(1):15-21.
11. Smith JS, Melendy A, Rana RK, Pimenta JM. Age-specific prevalence
of infection with human papillomavirus in females: a global review.
J Adolesc Health. 2008;43(4 Suppl):S5-25, S25.e1-41.
12. Sankaranarayanan R, Bhatla N, Gravitt PE, Basu P, Esmy PO,
Ashrafunnessa KS, et al. Human papillomavirus infection and cervical
cancer prevention in India, Bangladesh, Sri Lanka and Nepal. Vaccine.
2008;26(Suppl 12):M43-52.
13. Bhatla N, Lal N, Bao YP, Ng T, Qiao YL. A meta-analysis of human
papillomavirus type-distribution in women from South Asia:
Implications for vaccination. Vaccine. 2008;26(23):2811-7.
14. Serrano B, de Sanjosé S, Tous S, Quiros B, Muñoz N, Bosch X,
Alemany L. Human papillomavirus genotype attribution for HPVs
6, 11, 16, 18, 31, 33, 45, 52 and 58 in female anogenital lesions. Eur J
Cancer. 2015;51(13):1732-41.
15. WHO. (2016). HPV vaccine background document. [online] Available
from http://www.who.int/immunization/sage/meetings/2016/
october/1_HPV_vaccine_background_document_27Sept2016.
pdf?ua=1 [Last accessed December, 2022].
16. Garland SM, Hernandez-Avila M, Wheeler CM, Perez G, Harper DM,
Leodolter S, et al. Quadrivalent vaccine against human papillomavirus
to prevent anogenital diseases. N Engl J Med. 2007;356(19):1928-43.
17. Dillner J, Kjaer SK, Wheeler CM, Sigurdsson K, Iversen OE, Hernandez-
Avila M, et al. Four year efficacy of prophylactic human papillomavirus
quadrivalent vaccine against low grade cervical, vulvar, and vaginal
intraepithelial neoplasia and anogenital warts: Randomized controlled
trial. BMJ. 2010;341:c3493.
18. Paavonen J, Naud P, Salmeron J, Wheeler CM, Chow SN, Apter D,
et al. Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted
vaccine against cervical infection and precancer caused by oncogenic
HPV types (PATRICIA): final analysis of a double-blind, randomized
study in young women. Lancet. 2009;374(9686):301-14.
19. Szarewski A, Poppe WA, Skinner SR, Wheeler CM, Paavonen J,
Naud P, et al. Efficacy of the human papillomavirus (HPV)-16/18 AS04-
adjuvanted vaccine in women aged 15–25 years with and without
serological evidence of previous exposure to HPV-16/18. Int J Cancer.
2012;131(1):106-16.
20. Hildesheima A, Wacholdera S, Catteaub G, Struyfb F, Dubinc G,
Herrerod R, For the CVT Group. Efficacy of the HPV-16/18 vaccine: Final
according to protocol results from the blinded phase of the randomized
Costa Rica HPV-16/18 vaccine trial. Vaccine.2014;32:5087-97.
21. Porras C, Tsang SH, Herrero R, Guillén D, Darragh TM, Stoler MH,
et al. Costa Rica Vaccine Trial Group. Efficacy of the bivalent
HPV vaccine against HPV 16/18-associated precancer: long-term
follow-up results from the Costa Rica Vaccine Trial. Lancet Oncol.
2020;21(12):1643-52.
22. Howell-Jones R, Soldan K, Wetten S, Mesher D, Williams T, Gill ON,
et al. Declining genital Warts in young women in England associated
with HPV 16/18 vaccination: An ecological study. J Infect Dis.
2013;208(9):1397-403.
23. Szarewski A, Skinner SR, Graland SM, Romanowski B, Schwarz TF,
Apter D, et al. Efficacy of the HPV-16/18 AS04-adjuvanted vaccine
against low-risk HPV types (PATRICIA randomized trial): an
unexpected observation. J Infect Dis. 2013;208(9):1391-6.
24. Giuliano AR, Palefsky JM, Goldstone S, Moreira ED Jr, Penny ME,
Aranda C, et al. Efficacy of quadrivalent HPV vaccine against HPV
infection and disease in males. N Engl J Med. 2011;364(5):401-11.
25. Joura EA, Giuliano AR, Iversen OE, Bouchard C, Mao C, Mehlsen J,
et al. A 9-Valent HPV Vaccine against Infection and Intraepithelial
Neoplasia in Women. N Engl J Med. 2015;372:711-23.
26. Ruiz-Sternberga AM, Moreira ED Jr, Restrepoc JA, Lazcano-Ponced E,
Cabelloe R, Silvaf A, et al. Efficacy, immunogenicity, and safety of a
9-valent human papillomavirus T vaccine in Latin American girls,
boys, and young women. Papillomavirus Res. 2018;5:63-74.
27. Huh WK, Joura EA, Giuliano AR, Iversen OE, de Andrade RP, Ault KA,
et al. Final efficacy, immunogenicity, and safety analyses of a nine-
valent human papillomavirus vaccine in women aged 16-26 years:
a randomised, double-blind trial. Lancet. 2017;390(10108):2143-59.
28. Guevara A, Cabello R, Woelber L, Moreira ED Jr, Joura E, Reich O,
et al. Antibody persistence and evidence of immune memory at
5 years following administration of the 9-valent HPV vaccine. Vaccine.
2017;35(37):5050-7.
29. Garland SM, Cheung TH, McNeill S, Petersen LK, Romaguera J,
Vazquez-Narvaez J, et al. Safety and immunogenicity of a 9-valent
HPV vaccine in females 12–26 years of age who previously received the
quadrivalent HPV vaccine. Vaccine. 2015;33(48):6855-64.
30. Moreira ED Jr, Block SL, Ferris D, Giuliano AR, Iversen OE, Joura EA,
et al. Safety Profile of the 9-Valent HPV Vaccine: A Combined Analysis
of 7 Phase III Clinical Trials. Pediatrics. 2016;138(2):e20154387.
31. Kosalaraksa P, Mehlsen J, Vesikari T, Forstén A, Helm K, Van Damme P,
et al. An open-label, randomized study of a 9-valent human
papillomavirus vaccine given concomitantly with diphtheria,
tetanus, pertussis and poliomyelitis vaccines to healthy adolescents
11–15 years of age. Pediatr Infect Dis J. 2015;34(6):627-34.
32. Schilling A, Parra MM, Gutierrez M, Restrepo J, Ucros S, Herrera T,
et al. Coadministration of a 9-valent human papillomavirus vaccine
with meningococcal and Tdap vaccines. Pediatrics. 2015;136(3):
E563-72.
33. Wadhwa M, Serum Institute of India. Cervavac PI text SmPC_qHPV.
Personal communication.
34. CDC. Human Papilloma virus vaccine safety. [online] Available from
https://www.cdc.gov/vaccinesafety/vaccines/hpv-vaccine.html. [Last
35. Sankaranarayanan R, Basu P, Kaur P, Bhaskar R, Singh GB, Denzongpa P,
et al. Current status of human papillomavirus vaccination in India’s
cervical cancer prevention efforts. Lancet Oncol. 2019;20(11):e637-44.
36. WHO. (2022). One-dose Human Papillomavirus (HPV) vaccine offers

solid protection against cervical cancer. [online] Available from
https://www.who.int/news/item/11-04-2022-one-dose-human-
papillomavirus-(hpv)-vaccine-offers-solid-protection-against-
cervical-cancer. [Last accessed December, 2022].
37. Basu P, Malvi SG, Joshi S, Bhatla N, Muwonge R, Lucas E, et al. Vaccine
efficacy against persistent human papillomavirus (HPV) 16/18
infection at 10 years after one, two, and three doses of quadrivalent
HPV vaccine in girls in India: a multicentre, prospective, cohort study.
Lancet Oncol. 2021;22:1518-29.
3.13 INFLUENZA VACCINES

B Rajsekhar, Sunil Kumar Agarwalla
BACKGROUND
Pathogen
The influenza virus, an orthomyxovirus, is a single-stranded RNA
virus. It is capable of causing disease in humans, birds, and animals.
There are three types of influenza viruses A, B, and C. The subtypes
of type A influenza virus are determined by hemagglutinin (HA)
and neuraminidase. The influenza type A causes moderate-to-
severe illness in all age groups in humans and other animals. The
illness caused by type B is usually a milder disease in humans only
and primarily affects children. The illness by type C influenza virus
is rarely reported in humans and it does not cause epidemics. The
nomenclature of influenza virus is in order of virus type, geographic
origin, strain number, year of isolation, and virus subtype.
Therefore, the nomenclature of the pandemic influenza virus is A/
California/7/2009/H1N1.
Influenza virus is characterized by frequent mutations—
antigenic drifts (minor antigenic change, both A and B) and antigenic
shifts (major antigenic change, only A). The human pandemic A/
H1N1 is an example of antigenic shift. Vaccines elicit a relatively
strain-specific humoral response, have reduced efficacy against
antigenically drifted viruses, and are ineffective against unrelated
strains. It is of utmost importance, therefore, that vaccine should
incorporate the current strain prevalent during that time.1
Influenza vaccine is most effective when circulating viruses are
well-matched with viruses contained in vaccines. Due to the constant
evolving nature of influenza viruses, the WHO Global Influenza
Surveillance and Response System (GISRS)—a system of 142
National Influenza Centres in 115 countries, 6 WHO Collaborating
Centres around the world, 4 WHO essential regulatory laboratories,
and 13 WHO H5 reference laboratories continuously monitors the
influenza viruses circulating in humans and updates the composition
of influenza vaccines twice a year, for the Northern (February)
and Southern (September) hemisphere influenza seasons and the

hemispheric specific vaccines are generally available 4–6 months
later (April–May for SH and September–October for NH vaccines).1
HISTORICAL PERSPECTIVES
The 20th century pandemics were in 1918 due to H1N1 (Spanish flu),
1957 due to H2N2 (Asian flu), and 1968 due to H3N2 (Hong Kong
flu). Of these pandemics, the 1918 pandemic was the most severe
causing an estimated 20–40 million or more deaths worldwide.
The new virus tends to replace endemic/seasonal influenza
viruses and postpandemic, it continues to co-circulate as the new
seasonal virus. Thereafter, it would exhibit antigenic drift; thus, more
than one drifted variant may co-circulate.
In India, the first positive case of pdmH1N1 was reported in May
2009 and by end of the year 2010, 20,604 cases with 1,763 deaths were
reported. The country experienced three waves during the period
of pandemic of 2009–2010, first one in 2009 September, followed by
second wave in December, and the third peak in August 2010 when
the end of pandemic was declared.2 pdmH1N1 now circulates as a
seasonal influenza strain.
DISEASE BURDEN
Global: Influenza occurs globally with an annual attack rate estimated
at 5–10% in adults and 20–30% in children.1 Children, particularly
below 2 years of age, have a high burden of influenza. In 2017,
deaths attributable to influenza accounted for 0·26% (95% UI 0.2–0-
32) of all deaths. 5·6% (95% UI: 4.3–7.1) of global lower respiratory
tract infections (LRTI) deaths were attributable to influenza, which
corresponded to 145,000 (98,000–200,000) deaths across all ages.
Nearly one-third of all influenza LRTI deaths occurred in India
[26,000 (95% UI: 16,000–37,000)].3
The incidence of influenza episodes and associated acute lower
respiratory infection (ALRI) is significantly higher in developing
countries as compared to developed countries. 4 A recent
systemic review5 found that influenza was associated with 10%
(95% CI: 8–11%) of respiratory hospitalizations in children
<18 years worldwide and it ranged from 5% (95% CI: 3–7%) among
children <6 months to 16% (95% CI: 14–20%) among children

5–17 years. According to the authors’ estimates, influenza results in
approximately 374,000 (95% CI: 264,000–539,000) hospitalizations
in children <1 year of which 228,000 (95% CI: 150,000–344,000) occur
in children <6 months and 870,000 (95% CI: 610,000–1,237,000)
hospitalizations in children <5 years annually. They also found
influenza-associated hospitalization rates more than three times
higher in developing countries than in industrialized countries
(150/100,000 children/year versus 48/100,000 children/year).
India: Adequate data on the prevalence and burden of influenza
in India is lacking. According to published data, it contributes to
around 5–10% of all acute respiratory infections (ARIs). The reported
incidence of influenza upper respiratory infection (URI) was found
to be 10/100 child years and that of ALRI to be only 0.4/100 child
years. According to an Indian review, influenza virus was responsible
for about 1.5–14.5% of all ARIs episodes.6
A community-based study from north India estimated incidence
of influenza episodes among children with ARI around 180 and 178
per 1,000 children per year, among children below 1 and 2 years,
respectively. Similarly, the incidence of influenza-associated ALRI
was calculated as 33 and 44 per 1,000 children per year.7
According to the GBD 2017 study,3 the figures in India have been
shown in Table 1.
Influenza Network in India is comprised of 10 sentinel sites
strategically located to cover major areas of India. Of the 44,127 nasal
swabs collected from influenza-like illness (ILI)/SARI cases between
2009 and 2013, 6,193 (14.0%) were positive for influenza virus.8
TABLE 1: Mortality, morbidity, and hospitalisations due to influenza lower

respiratory tract infections, 2017.
Episodes Hospitalizations Deaths
Numbers 13,966,000 588,000 26,000
(95% UI) (9,449,000– (196,000–1,611,000) (16,000–37,000)
19,552,000)
Per 100,000 1,011.6 42.6 1.8
(95% UI) (684.4–1,416) (14.2–116.7) (1.2–1.7)
Source: Global Burden of Disease 2017.
TABLE 2: Year-wise number of cases and deaths from 2017 to 2022 (As on
30.11.2022).
Year Cases Deaths
2017 38,811 2,270
2018 15,266 1,128
2019 28,798 1,218
2020 2,572 44
2021 778 12
2022 12,881 399
Source: Seasonal Influenza A (H1N1): State/UT: Yearwise number of cases and
deaths from 2017 to 2022* (As on 30.11.2022). Available at https://ncdc.gov.in/
showfile.php?lid=280.
SWINE FLU OR A H1N1 PANDEMIC (TABLE 2)

Globally, between 151,700 people and 575,400 people died from 2009
H1N1 virus infection during the 1st year, the virus was circulated
according to a new study from the Centers for Disease Control and
Prevention (CDC) Influenza Division.9 A disproportionate number
of deaths occurred in Southeast Asia and Africa, where access to
prevention and treatment resources are more likely to be limited.8
According to the data from Government of India, 22.8% of the samples
out of the total samples from 202,790 persons who had been tested
have been found positive for A (H1N1). In the majority, the illness was
self-limited with recovery within a week. Among those tested, 94%
cases were recovered and 2,728 deaths were reported till December
2010.10 In India, in 2015 (up to March 17), 30,766 patients were reported
to have H1N1 influenza and out of which 1,809 died; 17% of deaths
occurred in the age group of 18–30 years while 12% of deaths were in
the 60 and above age category, 4% in 0–12 years and 1% in 12–18 years
of age.11 In 2015, outbreak of influenza A (H1N1) pdm09 occurred in
India causing 42,592 laboratory confirmed cases with 2,991 deaths.
Rajasthan, Gujarat, Delhi, Jammu and Kashmir, Maharashtra, Madhya
Pradesh, Telangana, Karnataka, and Tamil Nadu reported most cases.12
SEASONALITY OF INFLUENZA
Influenza occurs throughout the year, but its incidence has distinct
peaks in most geographical areas. Whereas, in temperate regions,
influenza epidemics occur in the winter in tropical regions, influenza

occurs throughout the year with peaks in winter or monsoons.
Every season’s epidemic or outbreak lasts for 6–8 weeks or
longer. Reasons for seasonality may include effects of humidity and
temperature on virus survival and crowding inside home in winters.
The onset, peak, duration, and size of outbreak in a season may vary
with the virus’s antigenic variation, virulence, transmissibility and
population immunity.
Globally, since September 2020, influenza activity was mostly
reported from countries located in the tropics and subtropics
as well as some countries present in the temperate zone of the
northern hemisphere. India was among the tropical Asian countries
that reported the greatest detection of influenza.
Due to the diverse climate across India, there are vast variations
in the impact of influenza from the northern to southern regions. In
India, influenza season differs in various parts of country. In India, the
disease is observed to have two peaks: one during the winter (January
to March) and the second during the post-monsoon season (August
to October). However, it may vary from state to state. The month-wise
trend of pan India for year 2014–2019 is described in Figure 1.
In northern part of India, influenza peak is in January to March
which is similar to Northern hemisphere. In central India (e.g., Delhi,
Fig. 1: Monthwise trend of cases reported in India since 2014–2019

(data up to 23rd June, 2019).
Lucknow, Nagpur, and Pune), influenza peak is in July to September

and in southern part of India (e.g., Chennai and Vellore), it occurs in
September to November. Thus, it is a mixture of both Northern and
Southern hemisphere seasons.
Peaks of influenza were observed during July–September coin-
ciding with monsoon in cities (north, west, southwest, central, and
east) and northeast parts of India, whereas Chennai and southeast
revealed peaks in October–November, coinciding with the monsoon
months in these cities. In Srinagar, the northern most city at 34°N
latitude influenza circulation peaked in January–March in winter
months.8
The patterns of circulating strains also vary from year to year. In
2009 and 2010, co-circulation of A/H1N1pdm09 and type B was seen,
H3N2 was the predominant circulating strain in 2011, co-circulation
of A/H1N1pdm09 and influenza B in 2012 and return of A/H3N2 in
2013. In 2019, H1N1pdm09 predominated, in 2021: H3N2 followed
by B-Victoria and in 2022, H1N1pdm09 predominated.8
INFLUENZA VACCINES
The influenza vaccine, popularly known as the “flu shot”, is the first
protective step against the virus. With changes in the major influenza
strains year-on-year, it remains essential to take the latest influenza
vaccine, comprising an updated composition to provide adequate
and relevant immunity.6
Most of the current seasonal influenza vaccines include two
influenza A strains and two influenza B strain (quadrivalent).
The trivalent vaccines are not in use, in most countries. Globally,
quadrivalent inactivated vaccines (QIVs3) and live-attenuated
influenza vaccines (LAIVs) are available. In order to enhance
immunogenicity, some current formulations of trivalent vaccines
include adjuvants such as oil-in water adjuvants or virosomes.
Adjuvanted trivalent influenza vaccines (aTIVs3) show enhanced
priming and boosting, although the need for two doses remains.
Quadrivalent inactivated influenza vaccine (QIIV4) formulation
for seasonal influenza aims in providing more comprehensive
protection against influenza B viruses.
Inactivated Influenza Vaccines

The IIVs are produced from virus growth in embryonated hen’s
eggs and are of three types: (1) Whole virus, (2) Split product, and
(3) Subunit surface—antigen formulations. Whole virus vaccines are
associated with increased adverse reactions, especially in children
and are currently not in use. Most influenza vaccines are split-product
vaccines, produced from detergent treated, highly-purified influenza
virus, or surface antigen vaccines containing purified HA and
neuraminidase. All currently available quadrivalent vaccines now
have the influenza strain that is antigenically similar to 2009 pandemic
swine flu strain, i.e., A (H1N1) pdm09. Hence, there is no need to
go for separate “swine flu” vaccine. The trivalent and quadrivalent
vaccines contain 15 µg HA of each of WHO recommended two
influenza A strains (H1N1 and H3N2) and one/two influenza B strain.
Quadrivalent vaccines contain two influenza B strains. Vaccines are
licensed for use in children aged 6 months and older.
Influenza vaccine is most effective when circulating viruses
are well-matched with viruses contained in vaccines. Due to the
constant evolving nature of influenza viruses, the WHO Global
Influenza Surveillance and Response System (GISRS)—a system of
National Influenza Centres and WHO Collaborating Centres around
the world—continuously monitors the influenza viruses circulating
in humans and updates the composition of influenza vaccines
twice a year, for the Northern Hemisphere in February and for the
Southern Hemisphere in September every year.
There are occasions when the compositions of the NH and SH
vaccines may be similar.
Influenza vaccination is recommended every year, for children
of 6 months to 5 years of age and for the high-risk groups, beyond
5 years. IIV is administered intramuscularly.
Efficacy and Effectiveness of Inactivated

Influenza Vaccines
The reported efficacy/effectiveness of influenza vaccines varies
substantially with factors such as the case definition (e.g., laboratory
confirmed influenza disease or the less specific ILI), the “match”
between the vaccine strains and prevailing influenza strains, vaccine

preparation, dose, prior antigenic experience, and age or underlying
disease conditions of an individual.1
Inactivated vaccines have efficacy of 59% (95% CI: 41–71%) and
effectiveness at 36% (95% CI: 24–46%).13 There is no published data
on efficacy/effectiveness of influenza vaccines from India.
Quadrivalent demonstrated 63.2% efficacy against moderate‑
to‑severe influenza and 49.8% efficacy against influenza of any
severity in children 6 months through 35 months of age.
Following vaccination, anti-HA antibody titers peak 2–4 weeks
postvaccination in primed individuals but may peak 4 weeks or later
in unprimed individuals or older adults. Serum antibody titers may
fall by 50% or more by 6 months after vaccination, with the degree
of reduction being proportional to the peak titers achieved. Vaccine
induced serum antibody titers and then remains stable for 2–3 years.
Evidence from clinical trials suggests that protection against viruses
that are similar antigenically to those contained in the vaccine
extends for at least 6–8 months.14
Safety of Inactivated Influenza Vaccines

Transient local reactions at the injection site occur frequently
(>1/100), and fever, malaise, myalgia, and other systemic
adverse events may affect persons without previous exposure to
the influenza vaccine antigens, trivalent influenza vaccines are
generally considered safe.1 During some influenza seasons, IIV has
been associated with a slight increase in the risk of Guillain–Barré
syndrome (GBS). However, time-series analysis demonstrated no
evidence of seasonality and revealed no statistically significant
increase in hospital admissions because of GBS after the
introduction of the Universal Influenza Immunization Program.
However, the vaccine should preferably be avoided in patients
with history of GBS and who are not at high risk of severe influenza-
related complications. The vaccine should be administered with
caution in patients with history of severe egg allergy. Severe allergic
reaction to vaccine component or following a prior dose, is a

contraindication for IIV.
Contraindication: Severe allergic reaction to vaccine component or
following a prior dose.
Precaution:
■ History of GBS within 6 weeks of receipt of influenza vaccine
■ History of egg-allergy.
Those who report having had reactions to egg involving symptoms
other than urticaria (e.g., angioedema or swelling, respiratory distress,
light-headedness, sweating, palpitations or recurrent vomiting) or
who required adrenaline or another emergency medical intervention
should be vaccinated in an inpatient or outpatient medical setting.
The should be administered by a healthcare provider who is able to
recognize and manage severe allergic reactions.
Uniform Dosing for Inactivated Influenza Vaccines

The whole virion vaccines were administered at half the standard
dose (7.5 µg) to reduce reactogenicity and febrile convulsions
observed with the full dose (15 µg). However, the immune response
in young children was very variable, especially against the B strains
in the vaccine. This was particularly significant in children younger
than 3 years of age, who were vaccine-naïve.
Studies with the modern split-virus and subunit vaccines, have
generally shown comparable reactogenicity and non-inferior
immunogenicity with the full dose, in comparison with the half dose,
in children 6–35 months of age. Superior GMTs were demonstrated
against both vaccine B strains in children 6–17 months of age and
unprimed children 6–35 months of age. In children 6–35 months of
age, the quadrivalent vaccine in a dose of 0.5 mL, demonstrated an
efficacy of 63% (97.5% CI: 52–72) against moderate-severe influenza,
in a season when there was a 68% mismatch between the vaccine
strains and the strains isolated in the study.15 Several countries
including USA, Finland, Australia, UK, New Zealand, Canada, have
adopted a uniform dosage schedule for all age groups.
Dosage and Schedule

■ 0.5 mL (15 µg) > 6 months of age
■ From 6 months to 8 years for the first time, 2 doses of IIV to be
given 4 weeks apart.
■ >8 years: Single dose
■ Revaccination is recommended with a single annual dose, till the
age of 5 years. In those at high risk of influenza complications,
annual revaccination may be continued beyond the age of
5 years.
Live‑attenuated Influenza Vaccines

Live-attenuated influenza vaccine provides broader and higher
levels of protection than trivalent inactivated vaccines in healthy
children aged 2–5 years of age. A Cochrane review of randomized
controlled trials (RCTs) evaluating live vaccines in healthy children
aged >2 years found an overall efficacy against laboratory confirmed
influenza of 82% (95% CI: 71–89%) and an effectiveness against ILI of
33% (95% CI: 28–38%).
A quadrivalent live-attenuated vaccine for intranasal application
containing two influenza A strains and two influenza B strains,
Nasovac S4, is marketed in India. A single intranasal dose of
0.25 mL in each nostril, is recommended above the age of 2 years.1
Live-attenuated vaccine is not recommended below 2 years of age,
in high-risk individuals, and in pregnant women. Nonpregnant
individuals aged 2–49 years may receive either TIV or LAIV in
accordance with national policy.
Contraindications:
■ Severe allergic reaction to vaccine component or following a
prior dose
■ Concomitant aspirin- or salicylate-containing therapy in children
and adolescents
■ Children aged 2 through 5 years who have had a wheezing
episode in the past 12 months
■ Children who are immunosuppressed
■ Close contacts and caregivers of severely immunosuppressed
persons
■ Pregnancy
■ Receipt of influenza antiviral medication (oseltamivir and
zanamivir) within the previous 48 hours.
Precautions:
■ Moderate or severe acute illness with or without fever
■ History of GBS within 6 weeks of receipt of influenza vaccine
■ Asthma in persons aged ≥5 years
■ Other underlying medical conditions that might predispose to
complications after wild-type influenza infection [e.g., chronic
pulmonary, cardiovascular (except isolated hypertension),
renal, hepatic, neurologic, hematologic, or metabolic disorders
(including diabetes mellitus)].
Advisory Committee on Vaccines and Immunization

Practices Recommendation
Advisory Committee on Vaccines and Immunization Practices
(ACVIP) endorses the use of a uniform dosing schedule of inacti-
vated influenza vaccines (15 µg/0.5 mL) for all children older than
6 months.

Individual Use
Whom to Give?
Influenza vaccines are recommended for:
■ Children 6 months to 5 years of age.
■ The “high-risk children” aged >5 years including the following:
y Chronic cardiac, pulmonary (excluding asthma), hematologic
and renal (including nephritic syndrome) condition, chronic
liver diseases, and diabetes mellitus.
y Congenital or acquired immunodeficiency [including human
immunodeficiency virus (HIV) infection]
y Children on long-term salicylates therapy
y Laboratory personnel and healthcare workers.
Target group prioritization for seasonal influenza vaccination: The
prioritization is based on following attributes: Contribution of risk
group to the overall influenza disease burden in population, disease

severity within individual risk group, and vaccine effectiveness in
different age groups and categories.
Prioritization of target groups: (1-Highest priority, 4-Lowest priority)
1. Elderly individuals (>65 years) and nursing-home residents (the
elderly or disabled)
2. Individuals with chronic medical conditions including
individuals with HIV/AIDS, and pregnant women (especially to
protect infants 0–6 months)
3. Other groups: Healthcare workers including professionals,
individuals with asthma, and children from aged 6 months to
2 years.
4. Children aged 6–18 years, and healthy young adults.
Inactivated Influenza Vaccine in Pregnancy

Pregnant women have increased risk of severe disease and death
from influenza; the infection may also lead to complications such
as stillbirth, neonatal death, preterm delivery, and decreased birth
weight.1 Pregnant women should be vaccinated with IIV at any
stage of pregnancy. This recommendation is based on evidence of
a substantial risk of severe disease in this group and evidence that
seasonal influenza vaccine is safe throughout pregnancy and effective
in preventing influenza in the women as well as in their young infants,
in whom the disease burden is also high.
Which Vaccine to Give?

In those who with underlying risk factors, only the inactivated
vaccines should be used. In healthy individuals aged 2–49 years,
either the inactivated or live-attenuated vaccines may be used.
When to Give?
The WHO guidelines recommend that the latest strain of influenza
vaccine should be taken 2 weeks prior to the onset of the influenza
season for a particular region.
As far as the influenza virus circulation in India is concerned,
influenza viruses remain active throughout the year in a low grade
(3–8%). The peaks have been noted during rainy seasons throughout
India. In northern India (Delhi), peaks have also been noted during
winters.
The evidence of antigenic drifts of circulating influenza viruses
in India, together with the temporal peaks in seasonality of influenza
in different parts of the country, illustrate the need for a staggered
approach in vaccination timing. This is to be noted that the WHO
convenes two meetings to provide recommendations for the usage
of influenza vaccine in February and September each year. The
vaccine for the February recommendations (Northern hemisphere)
and September recommendations (Southern hemisphere) becomes
available after 6 months of each recommendation. In addition to this,
the WHO classifies India under the “South Asia” transmission zone
of influenza circulation. This strongly points India’s alignment with
the availability of Southern hemisphere vaccine (March–April) to
ensure that we have the latest available strains for early vaccination
to prevent the peak of circulation of influenza in the rainy season
across the country.16
Hence, there is a need for a staggered approach in vaccination
timing, April–May for the entire country, except Tamil Nadu and
southern Kerala (October–December), and northern parts (Jammu
and Kashmir in October–December).
IAP recommendations.
• Risk groups for severe influenza include pregnant women, children aged
<5 years, elderly and individuals with comorbids like HIV/PID, chronic
lung, cardiac disease, etc.
• Minimum age: 6 months for IIV, 2 years for live attenuated influenza
vaccination.
• First-time vaccination: 6 months to 8 years: Two doses 4 weeks apart,
9 years and above: single dose
• Annual revaccination with single dose
• Universal dose 0.5 mL IM
• Quadrivalent influenza vaccine is preferred over trivalent influenza vaccine
• There is no much difference in efficacy between split virion versus
subunit vaccine
• Apart from known severe allergy to vaccine components or to a previous
dose of IIV, there are no contraindications
• Use the most recent strains containing vaccine, in the premonsoon period
Which Hemispheric Strain should be Administered?

World Health Organization classifies India under the “South Asia”
transmission zone of influenza circulation and reviews strain
circulation in the country during both the meetings, i.e., February (for
northern hemisphere) and September (southern hemisphere). India
extends from 8° to 37° N latitudes, with climatic conditions varying
from temperate to tropical types. A major part of the country has year-
long circulation of influenza, with a smaller peak in winter months,
whereas, northern India experiences another peak during winter just
like northern hemisphere pattern. However, there is a tendency for
strains to “spill” from one to another. Hence, hemispheric-specific
vaccine recommendations will not be applicable, and one should
use the vaccine that has the “most recent strains” irrespective of the
hemisphere-specific formulations.
REFERENCES
1. World Health Organization. (2022). Vaccines against influenza: WHO
position paper – May 2022. Weekly epidemiological record. No 19,
2022, 97, 185–208. [online] Available from http://www.who.int/wer
2. Choudhry A, Singh S, Khare S, Rai A, Rawat DS, Aggarwal RK, et al.
Emergence of pandemic 2009 influenza A H1N1, India. Indian J Med
Res. 2012;135(4):534-7.
3. GBD 2017 Influenza Collaborators. Mortality, morbidity, and
hospitalisations due to influenza lower respiratory tract infections,
2017: an analysis for the Global Burden of Disease Study 2017. Lancet
Respir Med. 2019;7(1):69-89.
4. Nair H, Brooks WA, Katz M, Roca A, Berkley JA, Madhi SA, et al.
Global burden of respiratory infections due to seasonal influenza
in young children: a systematic review and meta-analysis. Lancet.
2011;378(9807):1917-30.
5. Lafond KE, Nair H, Rasooly MH, Valente F, Booy R, Rahman M,
et al. Global Role and Burden of Influenza in Pediatric Respiratory
Hospitalizations, 1982-2012: A Systematic Analysis. PLoS Med.
2016;13(3):e1001977.
6. Mathew JL. Influenza vaccination of children in India. Indian Pediatr.
2009;46(4):304-7.
7. Broor S, Parveen S, Bharaj P, Prasad VS, Srinivasulu KN, Sumanth KM,

et al. A Prospective Three-year Cohort Study of the Epidemiology and
Virology of Acute Respiratory Infections of Children in Rural India.
PLoS One. 2007;2(6):e491.
8. Chadha MS, Potdar VA, Saha S, Koul PA, Broor S, Dar L, et al.
Dynamics of Influenza Seasonality at Sub-Regional Levels in India and
Implications for Vaccination Timing. PLoS One. 2015;10(5):e0124122.
9. Centers for Disease Control and Prevention (CDC). (2012). First
Global Estimates of 2009 H1N1 Pandemic Mortality Released by CDC-
Led Collaboration. [online] Available from http://www.cdc. gov/flu/
spotlights/pandemic-global-estimates.htm. [Last accessed November,
2022].
10. Ministry of Health and Family Welfare. (2013). Pandemic influenza
A H1N1: Clinical Management Protocols and Infection Control
Guidelines. [online] Available from https://mohfw.gov.in/sites/
default/files/2366426352.pdf. [Last accessed November, 2022].
11. The New Indian Express. (2015). People in 30-45 Age Group
Worst Affected by Swine Flu. [online] Available from http://www.
newindianexpress.com/nation/People-in-30-45-Age-Group-Worst-
Affected-by-Swine-Flu/2015/03/18/article2719779.ece. [Last accessed
November, 2022].
12. Press Information Bureau (PIB). (2015). Preventive Measures for Swine
Flu. [online] Available from https://pib.gov.in/newsite/PrintRelease.
aspx?relid=115710 [Last accessed November, 2022].
13. Jefferson T, Rivetti A, Di Pietrantonj C, Demicheli V. Vaccines for
preventing influenza in healthy children. Cochrane Database Syst Rev.
2008;(16):CD004879.
14. Saha S, Chadha M, Shu Y; Group of Asian Researchers on Influenza
(GARI). Divergent seasonal patterns of influenza types A and B across
latitude gradient in Tropical Asia. Influenza Other Respir Viruses.
2016;10(3):176-84.
15. Kasi SG, Shivananda S, Marathe S, Chatterjee KS, Agarwalla S, Dhir SK,
et al. Indian Academy of Pediatrics (IAP) Advisory Committee on
Vaccines and Immunization Practices (ACVIP): Recommended
Children Aged 0 Through 18 Years. Indian Pediatr. 2021;58(1):44-53.
16. Ampofo WK, Azziz-Baumgartner E, Bashir U, Cox NJ, Fasce R,
Giovanni M, et al. Strengthening the influenza vaccine virus
selection and development process. Report of the 3rd WHO Informal
Consultation for Improving Influenza Vaccine Virus Selection held
at WHO headquarters, Geneva, Switzerland, 1–3 April 2014. Vaccine.
2015;33:4368-82.
3.14 JAPANESE ENCEPHALITIS VACCINES

BACKGROUND
Japanese encephalitis virus (JEV), a mosquito-borne flavivirus, is
the most important cause of viral encephalitis in Asia based on its
frequency and severity. The JEV has shown a tendency to extend
to other geographic regions. Case fatality rates (CFR) averages 30%
and a high percentage of the survivors are left with permanent
neuropsychiatric sequelae.1
Currently, an estimated 3 billion people live in the 24 countries,
mainly in the South-East Asia and Western Pacific Regions, considered
at risk of JE.2 JE is endemic throughout most of Asia and parts of the
western Pacific. Map of JE endemic countries is shown in Figure 1.
For travelers to Asia, the risk of JE is very low but varies based
on season, destination, duration, and activities.3 Risk is likely to be
Fig. 1: Japanese encephalitis endemic countries.

Source: Hills SL, Lindsey NP, Fischer M. Japanese encephalitis. In: CDC Yellow
Book 2020: health information for international travel. New York, NY: Oxford
University Press. 2019:248-57.
higher for expatriates or travelers with longer duration of travel or

whose plans include extensive outdoor activities in rural areas.
ACUTE ENCEPHALITIS SYNDROME

Clinically, a case of acute encephalitis syndrome (AES) is defined
as a person of any age, at any time of year with the acute onset of
fever and a change in mental status (including symptoms such as
confusion, disorientation, coma, or inability to talk) and/or new
onset of seizures (excluding simple febrile seizures).
Acute encephalitis syndrome has heterogeneous etiology and JE
remains an important contributing agent (5–40%) to AES in India.4
GLOBAL BURDEN
Japanese encephalitis is one of the most important causes of viral
encephalitis in Asia.
According to WHO, nearly 50,000 cases of JE occur worldwide
per year and 15,000 of them die.5 In endemic areas, the annual
incidence of disease ranges from 10 to 100 per 100,000 population. It
is postulated that the actual incidence of JE is nearly 10 times higher
than reflected in recent reports to WHO.6,7
A recent systematic review of the literature estimates 67,900
cases of JE each year, with approximately 13,600–20,400 deaths, and
an overall incidence rate of 1.8/100,000.
The majority (75%) of JE cases occur in children aged <15 years.
Although most JE cases are asymptomatic, the CFR among patients
with encephalitis approaches 30%, and approximately 30–50% of
survivors have long-term neurologic sequelae.
Vaccination is the cornerstone of JE control and prevention
measures. A 2011 systematic review of JE disease burden estimated
that approximately 68,000 cases occur globally each year; only about
10% of these cases are reported to WHO.
INDIAN BURDEN
Presently, 368 districts across 22 states have been identified as JE
endemic districts. The JEV has shown a tendency to extend to other
geographic regions. Inapparent infections tend to outnumber the
clinical cases with a ratio ranging from 1:250 to 1:1000. Inapparent

infections confer lifelong immunity. Spread of JE is documented
in newer states, newer districts in endemic states due to increased
surveillance efforts including laboratory confirmation by national
agencies. The risk is highest in children aged 1–15 years in rural areas
and in the monsoon or postmonsoon season.
SEASONALITY
Within the JE-endemic region, there are two typical patterns of
transmission:
1. In areas with temperate climates (including China, Japan, South
Korea, Nepal, northern Vietnam, and northern India), most
cases occur over a period of several months when the weather
is warmest, usually after the monsoons begin or associated with
heavy rainfall.8,9 The peak months of transmission and the length
of the season vary from place to place. There are sometimes
large, explosive outbreaks.
2. In areas with tropical climates (including Cambodia, Indonesia,
southern Vietnam, and southern Thailand), there is year-round
transmission. An increase in cases may be observed during the
rainy season.10,11 In endemic areas, JE typically affects children,
15 years of age, and by early adulthood, the majority of the
population has protective immunity following natural exposure
to JEV as a result of ongoing environmental transmission.
Transmission
Japanese encephalitis virus is transmitted in an enzootic cycle
involving mosquitoes and vertebrate amplifying hosts, primarily
pigs and wading birds. Humans are incidental and dead-end hosts
in the JEV transmission cycle as they do not develop sufficiently high
viremia to infect feeding mosquitoes. Therefore, mosquitoes do not
transmit the virus directly from one person to another person.
Mosquitoes of the Culex vishnui subgroup, particularly Culex
tritaeniorhynchus, are the major vectors of JEV, although JEV has
been isolated from over 30 mosquito species. C. tritaeniorhynchus
commonly breeds in rice fields, marshes, and other shallow pools
of water. It is an evening and night-time biting mosquito and mainly

feeds outdoors, preferentially on large animals and birds and only
infrequently on humans.
Pigs and wading birds, such as herons and egrets, are the most
important hosts for maintenance and amplification of JEV. Pigs are
key host as they develop high levels of viremia, and in Asia, large
numbers of pigs are frequently kept near human dwellings.
JE cases are more frequently in rural areas, however, Japanese
encephalitis cases are occasionally reported from urban or
periurban areas.4 Transmission via infected blood products has
been reported.12
Age Distribution
However, when the virus enters new geographic areas where there
is no immunity, JE affects both adults and children.10 In regions
where childhood immunization programs have been introduced,
the age distribution of disease shifts to older ages. 9,13 Among
immunologically naïve travelers visiting JEV-endemic regions, the
disease can affect individuals at any age.14
Annual incidences vary by age group and have been estimated
to be in the range of 5.4 per 100,000 in the 0–14 years age group, and
0.6 per 100,000 in the ≥15 years age group.15 ICMR and NIV, Pune
investigated adult AES epidemic in West Bengal and Assam in 2014.
The study revealed JEV as causative agent in 49.4% of AES. 70.8% were
adults with case fatality ratio of 28.9%. JEV infection was detected in
134 (49.4%) among 271 AES cases tested and most of them (79.1%,
106/134) were adults.16
OUTBREAKS OF JAPANESE ENCEPHALITIS

IN INDIA
In India, JE was first diagnosed in Vellore in 1955 and the first
major outbreak took place in West Bengal in 1973. Presently highly
endemic areas are Andhra Pradesh, Tamil Nadu, Karnataka, and
Uttar Pradesh.17
In 2005, Uttar Pradesh faced a devastating epidemic of JE
mostly confined to Gorakhpur district affecting 6,061 cases with
1,500 deaths followed by another outbreak in 2006 with 2,320 cases
Fig. 2: Percentage distribution of mortality reported in communicable

diseases in 2017.
Source: National Health Profile 2018, 13th issue, Central Bureau of Health
Intelligence, DGHS, MoH and FW, GOI, p. 75.
and 528 deaths. Similarly, JE cases in Uttar Pradesh were confined

predominantly in Gorakhpur during 2007 reporting 3,024 cases
and 645 deaths.18 The reported mortality rate varies between 8.5
and 72%.19,20
The CFR due to AES or JE in India has been around 17% with
wide variations in states (Fig. 2).
Acute encephalitis syndrome or encephalitis contributed to 11%
of mortality due to communicable diseases in 2017 (Fig. 3).21
Reasons for increase in JE cases while major epidemics are
not reported since 2015 are presumably due to spread of JE
to previously nonendemic states and spread to new districts
within endemic states, increase in adult cases, and increased
surveillance efforts.
VACCINES
World over, following vaccines were available for use against JE
(Fig. 4):
■ Mouse brain-derived inactivated JE vaccine (JE-VAX): This
vaccine is no longer in clinical usage.
Fig. 3: Confirmed cases of Japanese encephalitis (JE) in India.

Source: Directorate of National Vector Borne Disease Control Programme,
Delhi. [online] Available from http://nvbdcp.gov.in/Doc/je-aes.pdf. [Last
Fig. 4: Operational Guide, Japanese encephalitis (JE) vaccination in India.

TABLE 1: Japanese encephalitis (JE) vaccines available in India.

Manufacturer Commercial Pharmaceutical No. of
Vaccine type (country) name form Presentation doses
JE vaccine Biological E. JEEV Liquid: Ready Vial 1
(inactivated) Limited (India) to use
JE vaccine Biological E. JEEV Pediatric Liquid: Ready Vial 1
(inactivated) Limited (India) to use
JE vaccine Chengdu JE live, Lyophilized Two vial set 1
(live, Institute of attenuated active (active +
attenuated) Biological (SA14-14–2) component to excipient)
Products Co., be reconstituted
Ltd. (People’s with excipient
Republic of diluent before
China) use
Public sector Two vial set 5
only (active +
excipient)
JE vaccine Bharat Biotech JENVAC Liquid: Ready Vial 1
(inactivated) to use
■ Inactivated primary hamster kidney cells with P3—China.

■ Live attenuated, cell culture-derived SA 14-14-2.
y Newer JE vaccines:
Inactivated SA 14-14-2 vaccine (IC51; IXIARO by Intercell
and JEEV by Biological Evans India Ltd.) (Table 1).
Inactivated Vero cell culture-derived Kolar strain,
821564XY, JE vaccine (JENVAC by Bharat Biotech).
Live attenuated recombinant SA 14-14-2 chimeric vaccine
(JE-CV, IMOJEV by Sanofi Pasteur).
Inactivated Vero cell-derived JE vaccine (Beijing-1
JE strain by Biken and Kaketsuken, Japan) not available in
India.
Owing to many drawbacks (high cost, complicated dosing
schedule, requirement of numerous doses and boosters, concerns
about side effects and reliance neurological tissue for production)
and availability of better vaccines, the first two vaccines, i.e.,
mouse brain-derived and primary hamster kidney cells with
P3 are no longer being produced, hence will not be discussed
further.
LIVE-ATTENUATED CELL CULTURE-DERIVED

SA 14-14-2 VACCINE
This vaccine is based on the genetically stable, neuro-attenuated
SA 14-14-2 strain of the JEV, which elicits broad immunity against
heterologous JEVs. Reversion to neurovirulence is considered highly
unlikely. WHO technical specifications have been established for
the vaccine production.22 Chengdu Institute of Biological Products
is the only manufacturer authorized to export this vaccine from
China. The live-attenuated vaccine was licensed in China in 1989.
Since then, more than 200 million children have been vaccinated.17
Extensive use of this and other vaccines has significantly contributed
to reducing the burden of JE in China from 2.5/100,000 in 1990 to
<0.5/100,000 in 2004. This vaccine is also licensed for use in Nepal
(since 1999); South Korea (since 2001); India (since 2006); Thailand
(since 2007); and Sri Lanka.17 The price per dose of the vaccine is
comparable to the EPI measles vaccine.

In China, the vaccine is licensed for 0.5 mL dose to be administered
subcutaneously to children at 8 months of age and a second
opportunity again at 2 years. In some areas, a booster dose is
given at 7 years. Measles has been given concurrently.23 It can also
be offered to all susceptible children up to 15 years as catch-up
vaccination.18
Stability
The infectious titer of the vaccine is not appreciably changed after
storage at 37°C for 7–10 days, at room temperature for 4 months, or
at 2–8°C for at least 1.5 years.23
Immunogenicity and Correlate of Protection

After a single dose, antibody responses are produced in 85–100% of
nonimmune 1–12 years old children. A neutralization antibody titer
of more than 1:10 is generally accepted as evidence of protection and
postvaccination seroconversion.23

Five major efficacy trials of SA 14-14-2 vaccine, completed in China
from 1988 to 1999 in 1–10 years old, consistently yielded high
protection rates, above 98%.23-25 Case control studies and numerous
large-scale field trials in China have consistently shown an efficacy
of at least 95% following two doses administered at an interval of
1 year.6
Efficacy in Nepal
A field trial in Nepal in 1999 reported efficacy of a single dose of 99.3%
in the same year and 98.5% 1 year later.26,27 At 5 years, the protective
efficacy was 96.2%.28 Vaccine, in this study, contained 105.8 plaque
forming unit (PFU) per 0.5 mL. The study provides evidence that SA
14-14-2 will be useful to combat epidemics.
Indian Experience
In India, one dose of SA 14-14-2 imported from China is being used
since 2006 and children between the age group of 1 and 15 years were
vaccinated with a single dose of the vaccine, followed by integration
in UIP in a 2-dose schedule, at 9 months and 16–24 months.29,30
A small case-control study from Lucknow, India found an
efficacy of 94.5% (95% CI, 81.5‒98.9) after a single dose of this vaccine
within 6 months after its administration.31 However, data from
postmarketing surveillance (PMS) in India showed that protective
efficacy of the vaccine in India is not as high as that seen in Nepal.
PMS study showed that virus neutralizing antibodies were seen in
45.7% of children before vaccination.
Seroconversion against Indian strains 28 days after vaccination
was 73.9% and 67.2% in all individuals and in those who were
nonimmune prevaccination, respectively.
The protective efficacy of the vaccine at 1 year was 43.1%
overall and 35% for those who were nonimmune prevaccination,
respectively.32
Preliminary results of a recent case control study carried out
by ICMR on impact of JE vaccine shows an unadjusted protective
effect of 62.5% in those with any report of vaccination. According
to this report, the JE vaccine efficacy has been around 60% in Uttar
Pradesh and around 70% in Assam. Following this report, the ICMR
has recommended a study on the impact of two doses versus single
dose of SA 14-14-2 vaccine in Assam.32
A recent study in children, demonstrated a vaccination
effectiveness of 86.7% (95% CI: 30.8–94.7).33
A study done in adults in Assam, demonstrated a VE of 77.0 (95%
CI: 67.0-83.0) over 7 years. Vaccine effectiveness decreased from
91% (95% CI: 73.0-97.0) in first year of vaccination to 71% (95% CI:
21.0–90.0) at 6 years post-vaccination.34
Safety
An estimated 300 million children have been immunized with
this vaccine without apparent complication.23 WHO’s Global
Advisory Committee on Vaccine Safety acknowledged the vaccine’s
“excellent” safety profile. Transient fever may occur in 5–10%, local
reactions, rash, or irritability in 1–3%. Neither acute encephalitis nor
hypersensitivity reactions have been associated with the use of this
vaccine.35
INACTIVATED VERO CELL CULTURE-DERIVED

SA 14-14-2 JE VACCINE (JE-VC), IXIARO BY
INTERCELL AND JEEV BY BIOLOGICAL E LTD.
IXIARO by Intercell AG
This is an inactivated vaccine (JE-VC) derived from the attenuated
SA 14-14-2 JEV strain propagated in Vero cells. This vaccine has been
evaluated in several clinical trials conducted in India and abroad
in both adults and children.36-38 IXIARO has now been approved
by the US-FDA and EU for use in children from the age of 2 months
onward.39 There is no efficacy data for IXIARO, and the vaccine
has been licensed in pediatric age group especially for travelers to
Asian countries on the basis of a phase III RCT conducted in the
Philippines,40 and favorable interim data from a second Phase III
trial in EU, US, and Australia.40 The safety profile of the test vaccine
was good, and its local tolerability profile was more favorable than
that of the mouse brain vaccines.
A phase 3 uncontrolled study conducted on neutralizing

antibody persistence in pediatric travelers from non-JE-endemic
countries following vaccination with IXIARO. Results showed
SPRs remained high but declined from 100% 1 month after primary
immunization to 91.3% at month 7 and 89.5% at month 36. GMTs
declined considerably from 384.1 by day 56 to 60.8 at month 36. The
decline in GMT observed in this study, together with previous data
with IXIARO support the recommendation for a booster dose in
children who remain at risk of JE from 1 year after the primary series
of IXIARO, consistent with the recommendation for adults. No
long-term safety concerns were identified.40,41
Indian Trial
A half-dose given to young children (1–3 years of age) had excellent
immunogenicity and the safety profile comparable to that of adults
taking the full adult dosage.
A phase II trial investigated the safety and immunogenicity
of JE-VC in healthy children aged 1 and 2 years in India, using a
standard (6 μg) or half (3 μg) dose.36 Children in both groups received
two doses of JE-VC administered 28 days apart. A third group of
children received three doses of a JE-MB vaccine (JenceVac) on days
0, 7, and 28. At 56 days after the vaccination series was complete,
seroconversion rates in the 6 μg (n = 21) and 3 μg (n = 23) JE-VC
recipient groups and the JE-MB vaccine group (n = 11) were 95%,
96%, and 91%, and plaque reduction neutralization test (PRNT50)
geometric mean titers (GMTs) were 218 (95% CI, 121–395), 201
(95% CI, 106–380), and 230 (95% CI, 68–784), respectively. The
corresponding figures at 28 days were 71.4% (15/21), 65.2% (15/23),
and 63.6% (7/11). None of the differences in seroconversion rates or
GMTs was statistically significant.36
JEEV—the Indian Variant of IC51, IXIARO by

Biological E Ltd.
Biological E Ltd. has a vaccine for the endemic markets under
the trade name JEEV based on Intercell’s technology and has
already been WHO prequalified. In 2011, the Biological E Ltd. India
conducted a multicentric open label randomized controlled phase

II/III study to evaluate safety and immunogenicity of JEEV vaccine
in ~450 children (≥1 to <3 years old) and compared to control Korean
Green Cross Mouse Brain Inactivated (KGCC) vaccine.42,43
This study demonstrated seroconversion (SCR) of 56.28% on
day 28 and 92.42% on day 56 in JEEV  vaccinated group.
Noninferiority of JEEV established against control in terms of
proportion of subjects seroconverted.
Geometric mean titers in JEEV group were significantly higher
than GMTs achieved in KGCC-JE vaccine group (218 vs. 126). There
was no significant difference between the groups in proportion of
subjects’ seroprotected, and in proportion of subjects reporting
adverse events between groups.
JEEV has been licensed by Drug Controller General of India
(DCGI) for use in prevention of JEV infection in children and adult
population on the basis of its ability to induce JEV neutralizing
antibodies as a surrogate for protection.44
INACTIVATED VERO CELL CULTURE-DERIVED

KOLAR STRAIN, 821564XY, JE VACCINE (JENVAC)
JENVAC is a Vero cell culture derived, inactivated, adjuvanted,
and thiomersal-containing vaccine developed by Bharat Biotech
International Ltd. (BBIL). The original virus strain used in the
vaccine was isolated from a patient in the endemic zone in Kolar,
Karnataka, India by NIV, Pune, and later transferred to BBIL for
vaccine development.
A phase II/III, randomized, single-blinded, active controlled
study to evaluate the immunogenicity and safety of the vaccine
was conducted among 644 healthy subjects. Out of 644 subjects,
212 were between the age of ≤50 years and >18 years, 201
subjects were between the age of ≤18 years and >6 years and
231 subjects were between the age of ≤6 years and >1 years. Subjects
received two doses of the test vaccine or a single dose of a reference
vaccine (live attenuated, SA 14-14-2 Chinese vaccine) as the first
dose and a placebo as the second dose.
On 28th day, the subjects who had received a single dose were
98.67% seroprotected and 93.14% seroconverted (four fold) for
≤50 to ≥1 years, whereas the corresponding figures for the reference
vaccine were 77.56% and 57.69%, respectively (p-value < 0.001).
There was no statistically significant difference in all the
three groups. The seroconversion (93.14% and 96.90%) and
seroprotection (98.67% and 99.78%) percentages on the 28th
and 56th day were not significantly different and similarly, no
statistically significant difference in these rates was noted among
different age groups.
Higher GMTs were achieved in younger age groups. After the
second dose of the test vaccine, the GMTs increased exponentially
from day 28 (145) to day 56 (460.5) in ≤50 to ≥1 years. However,
there was waning of both seroconversion and GMTs in both the test
vaccine and reference vaccine groups at 18 months. All the subjects
were followed up for 56 ± 2 days. There was no serious adverse event
or adverse event of any special interest noted in the study.
Immunogenicity assessment in some subjects who withdrew
after the first dose showed that the seroprotection rates were 81.82%,
with GMTs of 40.90, after 12 months.
In a phase 4 study, in which participants received a single dose of
the vaccine. At day 360 (postvaccination), GMTs were 33.7 (95% CI,
27.9–40.77) and SPR was 81.7% (95% CI, 74.9–87.3). GMTs at most
time points in the JENVAC group were significantly higher than the
comparator, SA 14-14-2 group. The results of this study led to the
DCGI licensure of a single dose of JenvacTM.
Live-attenuated Recombinant SA14-14-2 Chimeric

Vaccine (JE-CV, Imojev By Sanofi Pasteur)
A promising new genetic approach is adopted in the construction
of a chimeric live-attenuated vaccine comprising neutralizing
antigen-coding sequences of the SA 14-14-2 strain of the JEV
inserted into the genome of the 17D yellow fever vaccine strain. The
resulting recombinant virus is cultivated on Vero cells.37 This novel,
live, recombinant vaccine, was previously known as ChimeriVax-JE
and developed initially by Acambis. It is a safe, highly immuno
genic and capable of inducing long-lasting immunity in both
preclinical and clinical trials. 43 A single dose was sufficient to

induce protective immunity, similar to that induced in adults by
three doses of JE-VAX with a seroconversion rate of >97% (after
single dose).6 This vaccine has been licensed in Australia and is
under review in Thailand. 44 The clinical development of this
vaccine (IMOJEV) is currently on hold in India due to delay in
authorization of the phase III study.

Individual Use
The vaccination against JE is not recommended for routine use,
but only for individuals living in endemic areas. Though occasional
cases have been reported from urban areas in a few districts, JE
is predominantly a disease of rural areas. Presently, 368 districts
across 22 states have been identified as JE endemic districts.
Of these, JE vaccine has been introduced in RI in 297 districts
across 21 states.
JE vaccine is also recommended for travelers to JE endemic areas
provided they are expected to stay for a minimum of 4 weeks in rural
areas in the JE season.
Live-attenuated SA 14-14-2 Vaccine

Two doses are given in UIP in endemic districts of India. First dose of
the vaccine can be administered at 9 months along with measles and
rubella (MR) vaccine and second at 16–18 months at the time of 1st
booster of DTP vaccine.
JEEV by Biological E Ltd

The primary schedule consists of two doses of 3 μg/0.5 mL for
children aged ≥1 to ≤3 years and two doses of 6 μg/0.5 mL for child
ren >3 years, adolescents, and adults administered intramuscularly
on days 0 and 28. However, the long-term persistence of protective
efficacy in endemic areas and need of boosters are still undeter
mined.42 In February 2011, US ACIP approved recommendations
for a booster dose of JE-VC (IXIARO) in adults.
JENVAC by BBIL
The primary schedule consists of two doses of the vaccine
(0.5 mL each) administered intramuscularly at 4 weeks interval
for the primary immunization series for office practice starting
from 1 year of age. Since appreciable waning was noted in both
seroconversion and seroprotection rates, and GMTs were also waned
significantly, there is definitely a need of booster dose at later stage.
The exact timing of the booster along with feasibility of single dose
for primary series can be determined only after obtaining the long-
term follow-up data.42

Vaccination of humans is the method of choice for prevention of
JE. The consensus statement from all the Global JE meetings over
the years (1995, 1998, and 2002) has been that human vaccination
is the only effective long-term control measure against JE. All at-risk
population should receive a safe and efficacious vaccine as part of
their national immunization program.
JE vaccination via national campaign followed by national
routine delivery was the most cost-effective strategy.45
Any of the three available JE vaccines can be used in
“routine immunization”, in a 2-dose schedule: the 1st dose at 9–
12 months and the 2nd at the age of 16–24 months in the JE-endemic
areas.
The Scientific and Technical Subcommittee recommended
interchangeability on use of three JE vaccines.
A single dose of any of the three vaccines formulations (JenVaC,
LAJEV or 6-μg Jeev) may be used in children (1–15 years of age)
as well as adults (above 15 years) during JE vaccine campaigns in
endemic areas.
IAP ACVIP supports the government’s decision to include JE
vaccine in its UIP in endemic districts only. Large scale JE vaccination
is required because there is a large population which is susceptible
to JE, ratio of asymptomatic to symptomatic infection is high, disease
has a high mortality and morbidity and other control measures are
not effective.
Vaccination of the susceptible population has been demonstrated

to be cost-effective strategy in China, Nepal, Japan, and Thailand.
After introduction of mass vaccination in high-risk areas of
Andhra Pradesh (population of 75 million) cases of JE decreased
from 300 cases in 2002 to 25 in 2003. However, there is need to
undertake periodic assessment of the effectiveness of the employed
JE vaccine.
Japanese Encephalitis Campaigns in India

In India, though JE is primarily a disease that affects children living
in rural areas, there have also been reports of cases from urban areas.
Therefore, a decision has been made to vaccinate all target children
in both rural and urban areas of the operational districts to have the
maximum impact of the program.
Following the massive outbreak of JE in 2005 in the districts
of Eastern Uttar Pradesh and the adjoining districts of Bihar and
Telangana districts, vaccination campaigns were carried out in 11 of
the highest risk districts of the country in 2006, 27 districts in 2007, 22
districts in 2008, and 30 districts in 2009.
Children between the age group of 1 year and 15 years
were vaccinated with a single dose of SA 14-14-2 vaccine. Mass
vaccinations will continue to cover all the 109 endemic districts.
Following the mass campaign, the vaccination will continue in
the routine immunization program to cover the new cohort. The
Government of India has identified around 231 districts to be
endemic for JE. More districts are identified in 2018 and 268 districts
are considered JE endemic.
Campaigns in Adults
Following mass vaccination of campaigns with Chinese SA 14-14-2
vaccine among pediatric age group, adult JE cases have outnumbered
pediatric cases in some JE endemic states including Assam. This has
become a cause of concern for public health program, researchers,
and medical practitioners in India. This led Government of Assam
to conduct supplementary immunization activities (SIAs) of JE
vaccines in adults (>15 years) in the most affected districts like
Sivasagar in Assam. The exact reason behind this shift in age group
is not well understood.
A study was done for effectiveness of JE vaccine SA 14-14-2
and impact of immunization among adults in Assam. Vaccine
effectiveness among adults was 90% in 2012; it declined to 82% in
2013. Following the second round in 2014, a marginal increase in
vaccine effectiveness was noted (84%). Subsequently (2015–2018),
VE stabilized at 70%. Incidence rate during the prevaccination period
was 11.5 that came down and maintained at 5 (postvaccination). In
Japanese encephalitis (JE) vaccines: IAP recommendations.

• Recommended only for individuals living in endemic districts. Both rural
and urban children in a district should be vaccinated.
• Three types of new generation JE vaccines are licensed in India:
1. Live-attenuated, cell culture-derived SA 14-14-2
2. Inactivated JE vaccines, namely “Vero cell culture-derived SA 14-14-2
JE vaccine” (JEEV by BE India)
3. “Vero cell culture-derived, 821564XY, JE vaccine” (JENVAC by Bharat
Biotech)
• Live-attenuated, cell culture-derived SA-14-14-2:
– Minimum age: 8 months
– Two-dose schedule, first dose at 9 months along with MR vaccine and
– Second dose at 16–18 months along with DTP booster
– Not available in private market for office use
• Inactivated cell culture-derived SA 14-14-2 (JEEV by BE India)
– Minimum age: 1 year (US-FDA: 2 months)
– Primary immunization schedule: Two doses of 3 µg mL each
administered intramuscularly on days 0 and 28 for children aged ≥1
to ≤3 years
– Two doses of 0.5 mL for children >3 years and adults aged ≥18 years
– Need of boosters still undetermined
• Inactivated Vero cell culture-derived Kolar strain, 821564XY, JE vaccine
(JENVAC by Bharat Biotech):
– Minimum age: 1 year
– Primary immunization schedule: Two doses of 0.5 mL each
administered intramuscularly at 4 weeks interval
– Need of boosters still undetermined
Catch-up vaccination: All susceptible children up to 15 years should be
administered during disease outbreak or ahead of anticipated outbreak in
campaigns.
Nepal, the same vaccine showed 96.2% VE among children (5 years’

postvaccination) with coverage of above 70% that brought down
incidence rate <1. Therefore, high vaccine coverage (at least 70%)
seems to be a prerequisite for achieving the desired results.46
JE vaccine should not be used as an “outbreak response vaccine”.
With the availability of two quality inactivated vaccines in India, the
academy urges the government to introduce one of these products in
the UIP program of affected districts based on cost-effective analysis.
The performance of the current live-attenuated Chinese vaccine, SA
14-14-2 has not been very satisfactory in high burden states.
A severe allergic reaction after a previous dose of JE-VC, any
other JE vaccine, or any component of JE-VC is a contraindication
to administration of a subsequent dose. JE-VC contains protamine
sulfate, which is known to cause hypersensitivity reactions in some
individuals; it does not contain gelatin or murine proteins.47-49
Pregnancy is a precaution for the use of JE-VC. Vaccination
with JE vaccine usually should be deferred because of a theoretical
risk for the developing fetus. However, pregnant women who must
travel to an area in which risk for JE is high should be vaccinated
if the benefits outweigh the risks of vaccination to the mother and
developing fetus.
Concomitant administration of JE-VC with other vaccines,
inactivated hepatitis A, rabies and meningococcal vaccines has been
found to be safe and immunogenic.50
REFERENCES
1. Tiwari S, Singh RK, Tiwari R, Dhole TN. Japanese encephalitis: a review
of the Indian perspective. Braz J Infect Dis. 2012;16:564-73.
2. Mackenzie JS, Williams DT, Smith DW. Japanese encephalitis virus:
The geographic distribution, incidence, and spread of a virus with a
propensity to emerge in new areas. In: Tabor E (Ed). Emerging Viruses
in Human Populations. Amsterdam, Netherlands: Elsevier; 2007.
3. Hills SL, Walter EB, Atmar RL, Fischer M; ACIP Japanese
Encephalitis Vaccine Work Group. Japanese Encephalitis Vaccine:
Practices. MMWR Recomm Rep. 2019;68:1-33.
4. Lincoln AF, Sivertson SE. Acute phase of Japanese B encephalitis; two
hundred and one cases in American soldiers, Korea, 1950. J Am Med
Assoc. 1952;150:268.
5. World Health Organization. Japanese encephalitis vaccines. Wkly

Epidemiol Rec. 2006;81:331-40.
6. Campbell GL, Hills SL, Fischer M, Jacobson JA, Hoke CH, Hombach JM,
et al. Estimated global incidence of Japanese encephalitis: a systematic
review. Bull World Health Organ. 2011;89:766-74.
7. Heffelfinger JD, Li X, Batmunkh N, Grabovac V, Diorditsa S, Liyanage JB,
et al. Japanese Encephalitis Surveillance and Immunization—Asia
and Western Pacific Regions, 2016. MMWR Morb Mortal Wkly Rep.
2017;66:579-83.
8. Endy TP, Nisalak A. Japanese encephalitis virus: ecology and
epidemiology. Curr Top Microbiol Immunol. 2002;267:11.
9. Arai S, Matsunaga Y, Takasaki T, Tanaka-Taya K, Taniguchi K, Okabe N,
et al. Japanese encephalitis: surveillance and elimination effort in
Japan from 1982 to 2004. Jpn J Infect Dis. 2008;61:333-8.
10. Vaughn DW, Hoke CH Jr. The epidemiology of Japanese encephalitis:
prospects for prevention. Epidemiol Rev. 1992;14:197-221.
11. Ompusunggu S, Hills SL, Maha MS, Moniaga VA, Susilarini NK,
Widjaya A, et al. Confirmation of Japanese encephalitis as an endemic
human disease through sentinel surveillance in Indonesia. Am J Trop
Med Hyg. 2008;79:963-70.
12. Solomon T, Dung NM, Kneen R, Thao le TT, Gainsborough M, Nisalak
A, et al. Seizures and raised intracranial pressure in Vietnamese
patients with Japanese encephalitis. Brain. 2002;125:1084-93.
13. Wu YC, Huang YS, Chien LJ, Lin TL, Yueh YY, Tseng WL, et al. The
epidemiology of Japanese encephalitis on Taiwan during 1966-1997.
Am J Trop Med Hyg. 1999;61:78-84.
14. Centers for Disease Control and Prevention. (2020). Japanese
Encephalitis. [online] Available from https://wwwnc.cdc.gov/travel/
yellowbook/2020/travel-related-infectious-diseases/japanese-
encephalitis [Last accessed November, 2022].
15. Background Paper on Japanese Encephalitis vaccines. (2014). SAGE
Working Group on Japanese encephalitis vaccines. [online] Available
from http://www.who.int/immunization/sage/meetings/2014/
october/1_JE_Vaccine_Background_Paper.pdf.
16. Gurav YK, Bondre VP, Tandale BV, Damle RG, Mallick S, Ghosh US,
et al. A large outbreak of Japanese encephalitis predominantly
among adults in northern region of West Bengal, India. J Med Virol.
2016;88(11):2004-11.
17. Tiroumourougane SV, Raghava P, Srinivasan S. Japanese viral
encephalitis. Postgrad Med J. 2002;78:205-15.
18. Arunachalam N, Samuel PP, Paramasivan R, Balasubramanian A,
Tyagi BK. Japanese encephalitis in Gorakhpur Division, Uttar Pradesh.
Indian J Med Res. 2008;128:775-7.
19. Gourie-Devi M. Clinical aspects and experience in the management

of Japanese encephalitis patients. Proceedings of the National
Conference on Japanese Encephalitis. New Delhi: Indian Council of
Medical Research; 1984. pp. 25-9.
20. Kumar R, Mathur A, Kumar A. Clinical features and prognostic
indicators of Japanese encephalitis in children in Lucknow (India).
Indian J Med Res. 1990;91:321-7.
21. National Health Profile. (2018). Health status indicators in India
3.1.4(B) state/UT wise cases and deaths due to Japanese encephalitis,
2013-2017. [online] Available from http://www.cbhidghs.nic.in/
WriteReadData/l892s/Chapter%203.pdf. [Last accessed October, 2019].
22. World Health Organization. (2002). WHO Expert Committee on
Biological Standardization. Fifty-first report. WHO Technical Report
Series No. 910. [online] Available from http://www.who.int/biologicals/
publications/trs/51/en/index.html. [Last accessed October, 2019].
23. Halstead SB, Jacobson J. Japanese encephalitis vaccines. In: Plotkins
SA, Orenstein WA, Offit PA (Eds). Vaccines, 5th edition. Philadelphia:
Saunders Elsevier; 2008. pp. 311-52.
24. Hennessy S, Zhengle L, Tsai TF, Strom BL, Wan CM, Liu HL, et al.
Effectiveness of live-attenuated Japanese encephalitis vaccine (SA
14-14-2): a case control study. Lancet. 1996;347:1583-6.
25. Responsible Party: Mingbo Sun, Director, WHO Prequalification
Department, Chinese Academy of Medical Sciences. ClinicalTrials.gov
Identifier:NCT04223037.
26. Bista MB, Banerjee MK, Shin SH, Tandan JB, Kim MH, Sohn YM,
et al. Efficacy of single-dose SA 14-142 vaccine against Japanese
encephalitis: a case control study. Lancet. 2001;358:791-5.
27. Ohrr H, Tandan JB, Sohn YM, Shin SH, Pradhan DP, Halstead SB.
Effect of single dose of SA 14-14-2 vaccine 1 year after immunisation
in Nepalese children with Japanese encephalitis: a case-control study.
Lancet. 2005;366:1375-8.
28. Andan JB, Ohrr HC, Sohn YM, Yoksan S, Ji M, Nam CM, et al. Single
dose of SA14-14-2 vaccine provides long-term protection against
Japanese encephalitis: a case control study in Nepalese children five
years after immunization. Vaccine. 2007;25:5041-5.
29. Immunization Division Department of Family Welfare Ministry of
Health and Family Welfare, Government of India. Control of Japanese
Encephalitis. Operational Guide Japanese Encephalitis Vaccination in
India. 2010. pp. 13-5.
30. Ministry of Health and Family Welfare, Government of India. (2011).
Immunization Handbook for Medical Officers. [online] Available
from http://www.searo.who.int/india/topics/routine_immunization/
Immunization_Handbook_for_Health_Workers_English_2011.pdf.
31. Kumar R, Tripathi P, Rizvi A. Effectiveness of one dose of SA 14-14-2
vaccine against Japanese encephalitis. N Engl J Med. 2009;360:1465-6.
32. Indian Council of Medical Research. Minutes of the meeting of the
Core Committee on Vaccines. [online] Available from http://www.
icmr.nic.in/minutes/Minutes%20Core%20Committee%20on%20
Vaccines.pdf. [Last accessed October, 2019].
33. Tandale BV, Khude PM, Deshmukh PS, Narang R, Qazi MS, Padmaja GV,
et al. Japanese Encephalitis Epidemiology Study Group. Effectiveness
of Japanese encephalitis vaccination among children in central India. J
Med Virol. 2023;95(1):e28399.
34. Khan SA, Choudhury P, Kakati S, Doley R, Barman MP, Murhekar MV,
et al. Effectiveness of a single dose of Japanese encephalitis vaccine
among adults, Assam, India, 2012–2018. Vaccine. 2021;39(35):
4973-8.
35. WHO. Global Advisory Committee on Vaccine Safety, 9–10 June 2005.
36. Kaltenbock A, Dubischar-Kastner K, Schuller E, Datla M, Klade CS,
Kishore TS. Immunogenicity and safety of IXIARO (IC51) in a Phase II
study in healthy Indian children between 1 and 3 years of age. Vaccine.
2010;28:834-9.
37. Schuller E, Jilma B, Voicu V, Golor G, Kollaritsch H, Kaltenböck A,
et al. Long-term immunogenicity of the new Vero cell-derived,
inactivated Japanese encephalitis virus vaccine IC51 Six and 12 month
results of a multicenter follow-up phase 3 study. Vaccine. 2008;
26:4382-6.
38. Dubischar-Kastner K, Eder S, Kaltenboeck A, Buerger V, Gartner-
Woelfl G, Schuller E, et al. Long-term immunity following vaccination
with the inactivated Japanese encephalitis vaccine IXIARO and
neutralizing antibody response to a booster dose. 11th Conference
of the International Society of Travel Medicine; May 24–28, 2009,
Budapest, Hungary.
39. ACIP unanimously votes to extend the recommendations for use of
IXIARO(R) vaccine. [online] Available from http://www.reuters.com/
article/2013/06/21/idUSnHUGd8N0+72+ONE201306. [Last accessed
October 2019].
40. Jelinek T, Cromer MA, Jakob P, Cramer JP, Deborah J, Mills DJ,
et al. Safety and immunogenicity of an inactivated Vero cell_derived
Japanese encephalitis vaccine (IXIARO, JESPECT) in a pediatric
population in JE non-endemic countries: An uncontrolled, open-label
phase 3 study. Travel Med Infect Dis. 2018;22:18-24.
41. Rodriguez-Morales AJ, Cardona-Ospina JA, Gutiérrez-Ocampo E,

Villamizar-Peña R, Holguin-Rivera Y, Escalera-Antezana JP, et al.
Clinical, laboratory and imaging features of COVID-19: a systematic
review and meta-analysis. Travel Med Infect Dis. 2020;34:101616.
42. Vashishtha VM, Kalra A, Bose A, Choudhury P, Thacker N, Yewale VN,
et al. Indian Academy of Pediatrics (IAP) recommended immunization
schedule for children aged 0 through 18 years—India, 2013 and
updates on immunization. Indian Pediatr. 2013;50:1095-108.
43. Appaiahgari MB, Vrati S. IMOJEV: a Yellow fever virus-based novel
Japanese encephalitis vaccine. Expert Rev Vaccines. 2010;9:1371-84.
44. Halstead SB, Thomas SJ. New Japanese encephalitis vaccines:
Alternatives to production in mouse brain. Expert Rev Vaccines.
2011;10:355-64.
45. Vodicka E, Zimmermann M, Lopez AL, Silva MW, Gorgolon L, Kohei T,
et al. Japanese encephalitis vaccination in the Philippines: a cost-
effectiveness analysis comparing alternative delivery strategies.
Vaccine. 2020;38(13):2833-40.
46. Khan SA, Choudhury P, Kaur H. Effectiveness of Japanese encephalitis
vaccine SA 14-14-2 and impact of immunization among adults in
Assam, India. Int J Infect Dis. 2020;101:482.
47. US Food and Drug Administration. (2009). Product approval
information [package insert]. Ixiaro (Japanese encephalitis virus
vaccine inactivated). Intercell Biomedical, Livingston, United
Kingdom. [online] Available from http://www.fda.gov/cber/label/
ixiarocommercialLB.pdf [Last accessed November, 2022].
48. Kaltenböck A, Dubischar-Kastner K, Eder G, Jilg W, Klade C, Kollaritsch
H, et al. Safety and immunogenicity of concomitant vaccination with
the cell-culture based Japanese Encephalitis vaccine IC51 and the
hepatitis A vaccine HAVRIX1440 in healthy subjects: a single-blind,
randomized, controlled Phase 3 study. Vaccine. 2009;27(33):4483-9.
49. Jelinek T, Cramer JP, Dieckmann S, Hatz C, Paulke-Korinek M,
Alberer M, et al. Evaluation of rabies immunogenicity and tolerability
following a purified chick embryo cell rabies vaccine administered
concomitantly with a Japanese encephalitis vaccine. Travel Med Infect
Dis. 2015;13(3):241-50.
50. Alberer M, Burchard G, Jelinek T, Reisinger E, Beran J, Meyer S, et al.
Co-administration of a meningococcal glycoconjugate ACWY vaccine
with travel vaccines: a randomized, open-label, multi-center study.
Travel Med Infect Dis. 2014;12:485-93.
3.15 MENINGOCOCCAL VACCINES

Ananda Kesavan TM, Harish Kumar Pemde
BACKGROUND
Meningococcal disease is caused by gram-negative bacterium
Neisseria meningitidis, which is a diplococcus and appears
bean-shaped lying with flat surfaces adjacent to each other in a
polysaccharide capsule. The meningococci are usually found as
commensal organisms in the upper respiratory tract of about 10%
of the population at any one time. Humans are the only natural
reservoir. Meningococcal disease generally manifests as acute
illness but chronic course with a mean duration of 6–8 weeks is also
known.1 The disease spectrum includes meningitis, septicemia,
pneumonia, myocarditis, pericarditis, arthritis, and conjunctivitis,
and occasionally may present as shock referred to as Waterhouse–
Friderichsen syndrome with high risk of mortality.
There are 13 known serogroups but 90% of the disease causing
isolates belongs to serogroups A, B, C, Y, and W-135. The burden of
meningococcal disease is greatest in the African meningitis belt. In
these areas, disease occurs endemically in the dry season and also
as epidemics every 7–14 years and is usually due to serogroups A
and W-135. Disease outbreaks in Hajj pilgrims have been attributed
to A and W-135. Disease in industrialized countries is primarily due
to B, C, and Y.2 There is lack of information of serogroup responsible
for endemic meningococcal disease in India. In one study from
Postgraduate Institute of Medical Education and Research in
Chandigarh, out of 12 isolates, eight were found to be serogroup A
and four were serogroup C. However, Group A Meningococcus is the
cause of all the major investigated epidemics.
EPIDEMIOLOGY OF MENINGOCOCCAL DISEASE

Global
In most countries, Neisseria meningitidis is recognized as a leading
cause of meningitis and fulminant septicemia and a significant
public health problem. Endemic disease mostly afflicts young
children. Older children, adolescents, and young adults mainly

suffer during epidemics. In developing countries, the background
incidence of meningococcal disease is 15–20 cases per 100,000
peoples per year. When three or more cases of meningococcal
disease occur in a 3-month period in the same locality, amounting
to at least 10 cases per 100,000 persons suffering from the disease,
the situation is referred as outbreak. However, in sub-Saharan Africa
disease is hyperendemic due to unknown reasons and is considered
to have the highest annual incidence (10–25/100,000 population) of
meningococcal disease in the world.
In the African meningitis belt, the World Health Organization
(WHO) definition of a meningococcal epidemic is >100 cases/100,000
population/year. In endemic regions, an incidence of >10 cases, 2–10
cases, and <2 cases per 100,000 population in a year characterizes
high, moderate, and low endemicity, respectively.3 However, the
situation has changed after the introduction of monovalent MenA
vaccine in the year 2010, and meningococcal group A disease has
reduced sharply. However, the meningococcal disease by strains
with other capsular groups such as C, W, or X has emerged (Fig. 1).
A low-cost pentavalent vaccine MenACWXY is under development
and may replace the monovalent vaccine.
Fig. 1: Serogroups (>25% of the total cases) of N. meningitidis reported from

various countries between 2010 and 2016.
Source: From the Reference #4.
A recent global systemic review and survey found that different

serotypes are prevalent in different parts of the world.4 In India,
serotype A has been reported in studies.
India
The data available on the background incidence of meningo
coccal disease in India are suggestive of low incidence of
meningococcal disease. Hence, routine childhood vaccination with
meningococcal vaccine is unlikely to be a priority. As per the review
by Sinclair et al.4 which is a comprehensive study of epidemiology
of meningococcal disease in India, prevalence of meningitis is 1.5–
3.3% of all acute hospital admissions in children. N. meningitidis
is the third most common cause of bacterial meningitis in India in
children <5 years of age and is responsible for an estimated 1.9% of
all cases regardless of age.5 Prevalence of septicemia according to
one study is 2.8% of all hospital admissions.
In India, outbreaks of meningococcal meningitis were reported
in 1883–1884.6 Confirmed outbreaks occurred in 1961–61, 1966–67,
1985–86, 2005–2006 in New Delhi, and 2008–2009 in Meghalaya and
Tripura.5 Serogroup A was found in these outbreaks.
Outbreaks have been reported more in temperate northern than
tropical southern regions of the country. Large cities of North and
coastal areas such as Mumbai and Kolkata are being affected sparing
the southern and central regions. The important contributing
factors in major outbreaks may be overcrowding or vulnerability to
importation of new strain or a suitable climatic condition.
The epidemic period coincides with dry season of November–
March and the cases reduce with onset of monsoon and again
increase November onward. The outbreaks occur when season is
dry and temperature is low. The seasonal cycle is similar to that seen
in Africa where outbreaks peak in hot dry season and subside during
monsoon. The mechanism of this seasonal association is not exactly
known. This happens probably because during dry period there is
damage to natural mucosal barrier of the nasopharynx increasing
the chance of invasion of viral infection. Most of the epidemics in
India are reported from the drier northern parts of the country than
the more humid south is supportive of the current view of seasonal
effect of the disease.
The existence of endemic disease is recognized, but much of

the epidemiological data that are available are collected during
outbreaks. Unlike Haemophilus influenzae type b (Hib), N.
meningitidis affects adults as well as children. Endemic disease
occurs primarily in infants and children with the highest attack rates
in infants aged 3–12 months. The disease is found more in males
than females. During an epidemic condition, the disease is found in
children; however, shift is noted from young children to adolescents
and young adults later. Overall carriage rates are lower in India
than other similar settings. High carriage rates are found in close
household contacts which justifies chemoprophylaxis. High carrier
rates are also found among the military recruits.
Severe meningococcal disease is associated with high case
fatality rates (5–15%) even where adequate medical facilities are
available and permanent disability occurs in about 19% survivors.
Chemoprophylactic measures are in general insufficient for the
control of epidemics because secondary cases comprise only 1–2%
of all meningococcal cases.
Hospital-based sentinel surveillance of meningitis in 10 hospitals
(one each in Shimla and Bhubaneswar and 8 in Southern parts of
India) in 2012 found that out of 257 confirmed cases of meningitis
2.7% (7 of 257) were caused by N. meningitidis, 14.4% (37 of 257)
by H. influenzae type B and the remaining 82.9% (213 of 257) were
caused by S. pneumoniae.7 A recently published systematic review
and meta-analysis of bacterial meningitis among children between
1 month and 59 months of age in South Asia (including studies from
India) found that meningococcus contributed for only 1% (95% CI:
0–2%) of the all reported cases of meningitis.8
VACCINES
Two types of meningococcal vaccines have been developed but all
are not available everywhere in the world (Table 1). They include:
■ Meningococcal polysaccharide vaccines (MPSV)
■ Meningococcal polysaccharide-protein conjugate vaccines (MCV).
Meningococcal Polysaccharide Vaccines

These are either bivalent (A + C) or quadrivalent (A, C, Y, and
W-135) and contain 50 μg of each of the individual polysaccharides,
TABLE 1: Licensed meningococcal vaccines in India.
Type Valency/strains covered Brand/manufacturer Nature and diluent Dose and schedule
Polysaccharide Quadrivalent (Serogroups A, C, • Mencevax( GSK) Lyophilized, sterile 0.5 mL by SC or IM,
(MPSV: W-135 and Y; contains individual • Quadri Meningo distilled water recommended in children
Meningococcal capsular polysaccharides 50 μg (BioMed) >2 years, revaccination
polysaccharide each) • Menomune after 3–5 years in high-risk
vaccine) • (Sanofi Pasteur children and adolescents
Presently, these Bivalent (Serogroups A and C Bi Meningo, BioMed 0.5 mL, IM
vaccines are not contains individual capsular
marketed in India polysaccharides 50 μg each)
MCV: Quadrivalent (Serogroups A, • Menactra Lyophilized, sterile • >24 m: 0.5 mL by deep
Meningococcal C, W-135 and Y; contains 4 • Sanofi Pasteur distilled water IM, revaccination after
conjugate μg each of A, C, Y and W-135 3–5 years in high-risk
vaccine polysaccharide conjugated to children and adolescents
48 μg of diphtheria toxoid) • 9 m–23 m: 2 doses
12 weeks apart
Meningococcal (Groups A, C, • Menveo MenA powder and • >2 years: 0.5 mL, IM
Y, and W-135) oligosaccharide • Glaxo SmithKline MenCWY solution that • Revaccination after 3–5
diphtheria CRM197 conjugate must be combined years in high-risk children
vaccine prior to administration and adolescents
Monovalent (Serogroup A: 10 μg Serum Institute of Lyophilized vaccine 0.5 mL IM single
of group A polysaccharide con India Ltd. administration for
jugated to 10–33 μg tetanus individuals 1–29 years of
toxoid, with alum as adjuvant age
Licensed Vaccines
and thiomersal as preservative).

Licensed but not marketed in India
361
available in lyophilized form, reconstituted with sterile water

and stored at 2–8°C. These “T cell independent” vaccines do not
induce immunological memory and the response in children
younger than 2 years is poor. Hence, these are indicated for adults
and children older than 2 years (only under special circumstances
in children 3 months to 2 years of age). Presently, these vaccines are
not marketed in India.
Immunogenicity and Efficacy

The antibody responses to each of the four polysaccharides in the
quadrivalent vaccine are serogroup-specific and independent.
Protective antibody levels are usually achieved within 10–14 days
of vaccination. The serogroup A polysaccharide induces antibody
in some children as young as 3 months of age, although a response
comparable with that occurring in adults is not achieved until age
4–5 years. The serogroup C component is poorly immunogenic
in children <2 years. The serogroup A and C vaccines have good
immunogenicity with clinical efficacy rates of 85% or higher among
children 5 years of age or older and adults. Serogroup Y and W-135
polysaccharides are safe and immunogenic in older children and
adults; although clinical protection has not been documented.
In infants and young children aged <5 years, measurable levels
of antibodies against serogroup A and C polysaccharides, as
well as clinical efficacy, decrease substantially during the first
3 years after a single dose of the vaccine administration. Antibody
levels also decrease in healthy adults, but antibodies are still
detectable up to 10 years after immunization. Multiple doses
of serogroups A and C polysaccharides are known to cause
immunologic hyporesponsiveness (impact on clinical efficacy has
not been demonstrated). Vaccines are safe and most common side
effects are local pain and redness at site of injection.
Quadri MeningoTM [Meningococcal polysaccharide vaccine
(Group A, C, Y, and W-135) IP] by Bio-Med is available in India.
Vaccination is recommended in regions of endemic infection, trav-
elers to countries with epidemic meningococcal disease (Hajj
pilgrims), household or institutional contacts, military recruits. It also
recommended for subjects living in closed communities and close

contact of patients/carriers of meningococcal group A, C, Y, and
W-135.
Meningococcal Conjugate Vaccines

Currently, two different types of MCVs are licensed in India. The
quadrivalent conjugate vaccines include Menactra from Sanofi
Pasteur and Menveo from Glaxo SmithKline. The monovalent
vaccine is MenAfriVac from Serum Institute of India (SII).
Quadrivalent Meningococcal Polysaccharide-

protein Conjugate Vaccine (MenACWY-D, Menactra®,
Manufactured by Sanofi Pasteur)
This is a quadrivalent (A, C, W-135, and Y) meningococcal conjugate
vaccine using diphtheria toxin as carrier protein (A, C, W-135, and
Y-D), and was licensed in the US in 2005. However, it is licensed
in India only in 2012 for use among persons aged 2–55 years. In
2011, the Advisory Committee on Immunization Practices (ACIP)
recommended a two-dose series of this vaccine for use in children
aged 9–23 months and the IAP/ACVIP has endorsed a similar
schedule. This vaccine contains 4 μg each of A, C, Y, and W-135
polysaccharide conjugated to 48 μg of diphtheria toxoid. A single
dose of 0.5 mL intramuscular (IM) is recommended beyond 24
months of age. This vaccine had comparable immunogenicity to the
previously used polysaccharide vaccine.
Recent estimates of the effectiveness of MenACWY-D, the first
licensed quadrivalent vaccine suggests that within 3–4 years after vac-
cination, effectiveness is 80–85%.9,10 There is higher level of evidence
for protection of children against meningococcal disease in children
>12 months to <5 years of age than in individuals aged ≥5 years.10
It is associated with minor local side effects such as pain and
swelling. Guillain-Barré syndrome (GBS) was noted as a possible
but unproven risk in some adolescents following immunization with
quadrivalent MCV. As a precaution, people who have previously been
diagnosed with GBS should not receive this vaccine unless they are
at increased risk of meningococcal disease. Interference with PCV-13
immune responses was noted when MenACWY-D and PCV13 were
administered simultaneously in patients with asplenia. Hence, CDC
ACIP has now recommended that at least 1 month interval should

be kept between PCV-13 and MenACWY-D, and PCV-13 should be
administered first.11
A safety and immunogenicity open label nonrandomized
multicentric phase III trial of the MenACYW-DT vaccine among
Indian children, adolescents and adults, found a robust and protective
immune response 30 days postvaccination against meningococcal
serogroups A, C, Y, and W-135 in nearly all (96.9–100%) of the Indian
study participants aged 2–55 years and it was well tolerated.12
Quadrivalent Meningococcal Polysaccharide-

protein Conjugate Vaccine (MenACW-135Y Menveo®,
Manufactured by GlaxoSmithKline)
Menveo is meningococcal group A, C, W-135, and Y conjugate
vaccine where CRM-197 is used as the conjugating protein. This
vaccine contains meningococcal group A capsular oligosaccharide
10 µg in a lyophilized form, and meningococcal group C, W-135,
and Y capsular oligosaccharides 5 µg each in a liquid form. All the
antigens are conjugated to Corynebacterium diphtheriae CRM-
197 protein. The volume for a single dose is 0.5 mL. This vaccine is
supplied in two vials; the lyophilized MenA component which is to
be dissolved in the liquid component containing MenCWY.
MenACWY-CRM-197 was studied in children and youth (2–
5 years, 6–10, and 11–18 years age groups). It showed noninferiority
to all serogroups in 11–18 age group. Noninferiority could not be
established in other groups. However, pooled estimates in age groups
2–10 years and 11–18 years were noninferior to MenACWY-DT.
Antibodies persist up to 5 years postvaccination. This can be
coadministered with other vaccines.
The seroresponse rates at 1 month following vaccination
were 72%, 88%, 55%, and 71% for serogroups A, C, W, and Y,
respectively. No safety concerns were there and the vaccine was
well tolerated. This vaccine is licensed for use as a single IM dose in
>2 years of age in India. In the USA, this vaccine is licensed for use in
2 months through 55 years. The safety and efficacy of this vaccine has
not yet been established below 2 years of age in India.
A quadrivalent vaccine MenACWY-TT (MenQuadfi) has also
been licensed in the USA in April 2020 for age 2 years or older. This
vaccine is licensed in Europe for use in children as young as 6 weeks

of age. This vaccine is not available in India.
Pentavalent Meningococcal Vaccine

A single pentavalent vaccine against meningococcal A, B, C, Y, and W
is being tested in different phases. In an ongoing phase 2 randomized
controlled trial in healthy adolescents and young adults, preliminary
results found MenABCWY noninferior to separate administration of
MenACWY and MenB vaccines. There was more than fourfold rise in
serum bactericidal human complement (hSBA) against each of the
4MenB strains. The vaccine was found safe and well tolerated.1
Monovalent Serogroup A Conjugate Vaccine (PsA–TT,

MenAfriVac®, Manufactured by Serum Institute of India)
Meningococcal group A conjugate vaccine (PsA-TT) is a lyophilized
vaccine of purified meningococcal A polysaccharide covalently
bound to tetanus toxoid (TT) which acts as a carrier protein. It
contains 10 μg of group A polysaccharide conjugated to 10–33 μg
tetanus toxoid, with alum as adjuvant and thiomersal as preservative.3
The vaccine is licensed in India since 2009 and prequalified by the
WHO in 2010, but the company has not launched this inexpensive
vaccine (costing around half a cent to African nations) in India so
far. It has been used in large campaigns in Burkina Faso, Mali, and
Niger and is being progressively introduced in other countries of the
African meningitis belt.3
It should be administered as a single IM injection of 0.5 mL to
individuals 1–29 years of age.3 The possible need for a booster dose
has not yet been established. Persons who have previously received
a meningococcal A polysaccharide-containing vaccine can be
vaccinated with the conjugate vaccine.
The single IM dose induces functional antibody titers against
meningococcal serogroup A which are significantly higher and more
persistent than those induced by a corresponding polysaccharide
vaccine.13-15 The immune response seems to persist for a long time. The
vaccine has also got a very good safety profile. There is moderate level
of evidence for protection of children against group A meningococcal
disease in both children >12 months to <5 years, and in individuals
≥5 years old.11 Furthermore, the vaccine has demonstrated a great

effectiveness when used in Africa in campaigns.
Three characteristics of conjugate vaccines are believed to be
important for establishing long-term protection against a bacterial
pathogen: (1) Memory response, (2) herd immunity, and (3)
circulating antibody. Recent data from the United Kingdom indicate
that although vaccination primes the immune system, the memory
response after exposure might not be rapid enough to protect against
meningococcal disease. After initial priming with a serogroup C
meningococcal conjugate vaccine, a memory response after a booster
dose was not measurable until 5–7 days later. The incubation period
for meningococcal disease usually is <3 days. In the UK, to date no
evidence of herd immunity has been observed. Therefore, circulating
bactericidal antibody is critical for protection against meningococcal
disease.
There is sufficient evidence to indicate that approximately 50%
of persons vaccinated 5 years earlier had bactericidal antibody
levels protective against meningococcal disease. Therefore,
>50% of persons immunized at age 11 or 12 years might not be
protected when they are at higher risk at ages 16–21 years. This is
the reason why ACIP has now recommended revaccination with
MCV in individual previously vaccinated with either conjugated or
polysaccharide vaccine who are at increased risk for meningococcal
disease. Those who are vaccinated at age older than 7 years should
be vaccinated 5 years after their previous meningococcal vaccine
and those vaccinated at ages 2–6 years should be revaccinated 3 years
after their previous meningococcal vaccine. Persons who remain in
one of these increase risk group indefinitely should continue to be
revaccinated at 5 years interval.

Individual Use
The current epidemiology and burden of meningococcal diseases
in India do not justify routine use of meningococcal vaccines.
Meningococcal vaccines are recommended only for certain high-
risk conditions and situations as enumerated below in children aged
2 years or more (3 months or older if risk of meningococcal disease is
high, e.g., outbreaks/close household contact). Conjugate vaccines

are preferred over polysaccharide vaccines due to their potential for
herd protection and their increased immunogenicity, particularly in
children <2 years of age.
INDIAN ACADEMY OF PEDIATRICS

RECOMMENDATIONS ON DOSAGE IN
DIFFERENT CATEGORIES12
Indian Academy of Pediatrics (IAP) now recommends the use of
MCVs in different categories as per following description:
■ During disease outbreaks: Due to the limited efficacy of poly-
saccharide vaccines in children <2 years of age, conjugate
vaccines should be used for protection of those aged 12–
24 months, particularly for MenA disease. Since majority of
documented outbreaks in India are caused by MenA, monova-
lent MCV, like PsATT should be employed in mass vaccination.
■ Vaccination of persons with high-risk conditions/situations:
y Children with terminal complement component deficiencies:
A two-dose primary series of MCV administered 8–12 weeks
apart is recommended for persons aged 24 months through
55 years with persistent deficiencies of the late complement
component pathway. A booster dose should be administered
every 5 years. Children who receive the primary series before
their seventh birthday should receive the first booster dose in
3 years and subsequent doses every 5 years.
y Children with functional/anatomic asplenia/hyposplenia
(including sickle-cell disease): Administer two primary
doses of either MCV with at least 8 weeks between doses for
individuals aged 24 months through 55 years. Vaccination
should ideally be started 2 weeks prior to splenectomy.
y Persons with human immunodeficiency virus: Administer two
doses at least 8 weeks interval.
y Laboratory personnel and healthcare workers: Who are
exposed routinely to N. meningitidis in solutions that may
be aerosolized should be considered for vaccination. A single
dose of MCV is recommended. A booster dose should be
administered every 5 years if exposure is ongoing.
y Adjunct to chemoprophylaxis: In close contacts of patients

with meningococcal disease (healthcare workers in contact
with secretions, household contacts, and daycare contacts)
single dose of appropriate group MCV is recommended.
■ International travelers: Students going for study abroad:
Some institutions have policies requiring vaccination against
meningococcal disease as a condition of enrolment (mandatory
in most universities in the USA). Persons aged ≤21 years should
have documentation of receipt of a MCV not >5 years before
enrolment. In the US, ACIP recommends routine vaccination of
all adolescents with single dose of MCV4 at age 11–12 years with
a booster dose at age 16 years (available online at http:// www.
cdc.gov/vaccines/pubs/acip-list.htm). For further details, follow
the catch-up recommendations for meningococcal vaccination
of the destination country.
■ Hajj pilgrims: Vaccination in the 3 years before the date of travel
is required for all travelers to Mecca during the annual Hajj.
The quadrivalent vaccine is preferred for Hajj pilgrims and
international travelers as it provides added protection against
emerging W-135 and Y disease in these areas. A single dose 0.5
mL IM is recommended in age group 2–55 years. Single dose of
polysaccharide vaccine also useful.
■ Travelers to countries in the African meningitis belt: A single
dose of monovalent or quadrivalent vaccine is recommended.
Conjugate vaccine is preferred to polysaccharide vaccine. A
booster dose of MCV is needed if the last dose was administered
5 or more years previously.

Sporadic outbreaks of meningococcal disease have been recorded
for last many decades in India. These outbreaks, particularly
the larger epidemics have almost universally been caused
by serogroup A meningococci. 5 The committee believes that
the new affordable serogroup A containing monovalent conjugate
vaccine manufactured by Serum Institute of India should have
a critical role in containing future epidemics. The Academy
urges the Indian manufacturer to make this vaccine available
in the country also. The quadrivalent MenACWY-D should

be employed in individuals having certain high-risk conditions and
situations and among international travelers (mentioned earlier).
Conjugated meningococcal vaccines are more expensive than
polysaccharide vaccines. Based on results on the cost-effectiveness
of use of MCVs in Australia, Canada, Netherlands, Portugal,
Switzerland, and United Kingdom, it was found that one dose in
the second year of life was more cost-effective than a 3-dose infant
schedule. The most cost-effective strategy was routine vaccination
of children at 12 months of age combined with a catch-up
campaign for all children and adolescents <18 years of age.16
No studies on the cost-effectiveness of meningococcal vaccination
have yet been reported from India.
Decision to Vaccinate
If ≥3 cases of meningococcal disease have occurred in either an
organization or a community-based outbreak during <3 months
(starting at the time of the first confirmed or probable case), a
primary attack rate should be calculated. Attack rate per 100,000 =
(number of primary confirmed or probable cases during a 3-months
period)/(number of population at risk) × 100,000.
If the attack rate of the meningococcal disease exceeds 10 cases
per 100,000 persons, then vaccination of the population at risk
should be considered keeping following factors in sight.2
OUTBREAK IDENTIFICATION AND MANAGEMENT

A decision to carry out mass vaccination is based on following
conditions:
■ Completeness of case reporting and number of possible cases of
meningococcal disease for which bacteriologic confirmation or
serogroup data are not available.
■ Occurrence of additional cases of meningococcal disease after
recognition of a suspected outbreak (e.g., if the outbreak occurred
2 months before and if no additional cases have occurred, in
which case vaccination might be unlikely to prevent additional
cases of meningococcal disease).
■ Logistic and financial considerations. Because available vaccines

are not effective against N. meningitidis serogroup B, vaccination
should not be given during serogroup B outbreaks.
■ Age consideration: Meningococcal disease outbreaks
occur predominantly among persons aged <30 years. If the
calculated attack rate remains >10 cases/100,000 persons,
then vaccination should be considered for part or all of the
population at risk.
■ In infants aged 3 months to 2 years, meningococcal conjugate
vaccine is preferred.
■ If MCVs are not available, two doses of MPSV given 3 months
apart may be administered if the risk for meningococcal disease
is high, e.g., outbreaks/close household contacts.
■ Close child contacts of a patient with invasive meningococcal
disease are at increased risk of secondary disease. Most
secondary cases occur within the first 72 hours after presentation
of the index case; risk of secondary disease decreases to near
baseline by 10–14 days.9 Meningococcal vaccines may be given
to pregnant women during epidemics.
When there is an outbreak, immediate action is taken by
the government. However, in remote areas of the country, more
time may be needed before remedial action can be expected. A
rapid response team typically composed of an epidemiologist,
medical professionals, and a microbiologist is deployed to identify
individuals exposed to meningococcal disease and to assist in
the management of those who are ill. If diagnostic facilities are
not available locally, as is typical for remote areas of the country,
patient samples are sent to the NCDC for diagnostic testing.
During the recent outbreaks, microscopy, culture, and latex
agglutination tests were employed for diagnosis. Polymerase chain
reaction (PCR) was also used to investigate the epidemic in
New Delhi.
OUTBREAK PREVENTION AND CONTROL

ACTIONS IN INDIA
Following actions should be urgently taken after confirmation of an
outbreak (Box 1):
BOX 1: Use of meningococcal vaccine.

• Recommended only for certain high-risk group of children, during
outbreaks, and international travelers, including students going for
study abroad and travelers to Hajj and sub-Sahara Africa.
• Both meningococcal conjugate vaccines (Quadrivalent MenACWY-D,
Menactra® by Sanofi Pasteur and MenACWY-CRM197 by GSK and
monovalent group A vaccine (PsA-TT, MenAfriVac® by Serum Institute of
India) and polysaccharide vaccines (bi- and quadrivalent) are licensed in
India. PsA-TT is not freely available in market.
• Conjugate vaccines are preferred over polysaccharide vaccines due to
their potential for herd protection and their increased immunogenicity,
particularly in children <2 years of age.
• As of today, quadrivalent conjugate and polysaccharide vaccines are
recommended only for children 2 years and above.
• Monovalent group A conjugate vaccine, PsA-TT can be used in children
above 1 year of age.
■ Active case surveillance

■ Early diagnosis and prompt treatment
■ Chemoprophylaxis of close contacts (household members and
healthcare professionals)
■ Fostering disease awareness within the community, including
the need to seek medical help and to avoid crowded places
■ Respiratory isolation of patients for 72 hours
■ Reactive vaccination of high-risk groups.
REFERENCES
1. Granoff DM, Gilsdorf JR. Neisseria meningitidis. In: Kliegman RM,
Stanton BF, St Geme JW, Schor NF, Behrman RE (Eds). Nelson textbook of
Pediatrics, 19th edition. Philadelphia: Elsevier Saunders; 2012. pp. 929-33.
2. Centers for Disease Control and Prevention. (2014). Meningococcal
disease. [online] Available from http://wwwnc.cdc.gov/travel/
yellowbook/2014/chapter-3-infectious- diseases-related-to-travel/
meningococcaldisease. [Last accessed November, 2022].
3. WHO. Meningococcal vaccines: WHO position paper, November 2011.
4. Peterson ME, Li Y, Bita A, Moureau A, Nair H, Kyaw MH, et al.
Meningococcal serogroups and surveillance: a systematic review and
survey. J Glob Health. 2019;9(1):010409.
5. Sinclair D, Preziosi MP, Jacob John T, Greenwood B. The epidemiology

of meningococcal disease in India. Trop Med Int Health.
2010;15:1421-35.
6. Patel PT. Cerebrospinal fever in Bombay. A study of 170 consecutive
cases during the years 1921-24. Lancet. 1926;11:539-41. [Meningococcal
meningitis was known as cerebrospinal fever at that time.]
7. Jayaraman Y, Veeraraghavan B, Chethrapilly Purushothaman GK,
Sukumar B, Kangusamy B, Nair Kapoor A, et al. Burden of bacterial
meningitis in India: Preliminary data from a hospital based sentinel
surveillance network. PLoS One. 2018;13(5):e0197198.
8. Ali M, Chang BA, Johnson KW, Morris SK. Incidence and aetiology of
bacterial meningitis among children aged 1-59 months in South Asia:
systematic review and meta-analysis. Vaccine. 2018;36(39):5846-57.
9. Jayaraman Y, Veeraraghavan B, Girish Kumar CP, Sukumar B,
Rajkumar P, Kangusamy B, et al. Hospital-based sentinel surveillance
for bacterial meningitis in under-five children prior to the introduction
of the PCV13 in India. Vaccine. 2021;39(28):3737-44.
10. Dutta AK, Swaminathan S, Abitbol V, Kolhapure S, Sathyanarayanan S.
A comprehensive review of meningococcal disease burden in
India. Infect Dis Ther. 2020;9:537-59.
11. Macneil JR, Cohn AC, Zell ER, Schmink S, Miller E, Clark T, et al. Early
estimate of the effectiveness of quadrivalent meningococcal conjugate
vaccine. Pediatr Infect Dis J. 2011;30:451-5.
12. WHO. (2019). Grading of scientific evidence– Table VIa and b (efficacy
of quadrivalentmeningococcal conjugate vaccines). [online] Available
from http://www.who.int/entity/immunization/meningococcal_
grad_ efficacy.pdf. [Last accessed November, 2022].
13. Kroger A. General Recommendations on Immunization. ACIP
Presentation Slides: February 2013 Meeting. Atlanta: CDC; 2013.
14. Yadav S, Manglani MV, Narayan DA, Sharma S, Ravish HS, Arora R,
et al. Safety and immunogenicity of a quadrivalent meningococcal
conjugate vaccine (MenACYW-DT): a multicenter, open-label, non-
randomized, phase III clinical trial. Indian Pediatr. 2014;51(6):451-6.
15. Kshirsagar N, Mur N, Thatte U, Gogtay N, Viviani S, Préziosi MP,
et al. Safety, immunogenicity, and antibody persistence of a new
meningococcal group A conjugate vaccine in healthy Indian adults.
Vaccine. 2007;25(Suppl 1):A101-7.
16. Sow SO, Okoko BJ, Diallo A, Viviani S, Borrow R, Carlone G, et al.
Immunogenicity and safety of a meningococcal A conjugate vaccine in
Africans. N Engl J Med. 2011;364:2293-304.
3.16 RABIES VACCINES

Bhaskar Shenoy, Sanjay Marathe
BACKGROUND
Rabies is a neglected zoonotic disease responsible for an estimated
59,000 human deaths annually, of which 18,000–20,000 deaths
occur in India (Fig. 1). Rural populations in Africa and Asia are
predominantly affected, and approximately 40% of cases occur in
children under the age of 15 years. As per the national multicentric
rabies survey done in 2003,1 about 17 million animal bites occur
annually out of which about 35% of these are in children. 2 One-
third of the national rabies deaths were found in Uttar Pradesh
(4,300) and nearly three-quarters (8,900) were in seven central and
south-eastern states: Chhattisgarh, Uttar Pradesh, Odisha, Andhra
Pradesh, Bihar, Assam, and Madhya Pradesh.3 Rabies is transmitted
through bites and scratches from infected animals. Human-to-
human transmission occurs almost exclusively as a result of organ
or tissue transplantation (including cornea). Dogs are responsible
for up to 99% of human rabies cases. The incubation period for
rabies is typically 2–3 months but may vary from 1 week to few years,
dependent upon factors such as the location of virus entry and viral
load. Although fatal once clinical signs appear, rabies is preventable
Fig. 1: Global distribution of deaths occurred due to rabies.

Fig. 2: category of wounds. (ERIG: equine rabies immunoglobulin; HRIG:

human rabies immunoglobulin)
Source: World Health Organization (WHO) Expert Consultation on Rabies, third report:
WHO Technical Series Report No. 1012, Geneva, 2018 (ISBN 978-92-4-121021-8).4
through (i) mass dog vaccination to control disease at its source;

(ii) awareness of rabies and the need to seek treatment if exposed;
(iii) timely post-exposure prophylaxis (PEP) for people potentially
exposed to rabies; and (iv) preexposure prophylaxis (PrEP) for those
at high risk of rabies virus exposure.
CATEGORY OF WOUNDS (FIG. 2)

The following categories describe the risk of a rabies virus (RABV)
exposure according to the type of contact with the animal suspected
of having rabies. The category of exposure determines the indicated
PEP procedure.
INITIAL CARE OF ANIMAL-BITE WOUNDS

■ The first step is thorough cleansing of the wound with soap and
flushing under running water for 10 minutes.
■ This should be followed by application on the sites of exposure, a
virucidal agent such as 70% alcohol or povidone iodine.
■ Antimicrobials and tetanus toxoid should be given if indicated.
■ Any suturing of wound should be avoided. When suturing is
unavoidable for purpose of hemostasis, it must be ensured that
rabies immunoglobulin (RIG) has been infiltrated in the wound
prior to suturing.
Proper wound care will reduce the viral load by at least 50%.
MANAGEMENT
World Health Organization recommends two main immunization
strategies for the prevention of human rabies:
1. Postexposure prophylaxis which includes extensive and thorough
wound washing at the RABV-exposure site, together with RIG/
Mab administration if indicated, and the administration of a
course of several doses of rabies vaccine.
2. Preexposure prophylaxis which is the administration of several
doses of rabies vaccine before exposure to RABV.
Passive Immunization
Monoclonal Antibodies
■ Rabishield (Serum Institute of India) is a recombinant
human immunoglobulin G1 (IgG1), antirabies monoclonal
antibody (SII RMab), which binds to the ectodomain of G
glycoprotein (Fig. 3).
Rabies human monoclonal antibody (HuMAb) (Rabishield)
neutralizes 25 different wild-type or street RABV isolates.
Efficacy is proved in an animal model of PEP in Syrian hamsters
challenged with wild virus. HuMAb 17C7 was the most promising
antibody identified because it neutralized all RABV isolates
tested. HuMAb 17C7 recognizes a conformational epitope
on the RABV glycoprotein, which includes antigenic site III.
HuMAb 17C7 protected hamsters from a lethal dose of RABV in
Fig. 3: Various rabies viral proteins.

a well-established in vivo model of PEP.5 Advantages of RMab

include easier to produce in bulk and adverse reactions of blood
born products are avoided. Skin tests are not necessary before
administration of Mabs.
Dose: 3.33 IU/kg.
Post-marketing surveillance following the use of 50,000 vials
has not reported any serious adverse events. RMab can be
administered till 7 days after the first dose of vaccine.
Presentation: 100 IU/2.5 mL (40 IU/mL) vial and 250 IU/2.5 mL
(100 IU/mL) vial.
■ Twinrab (Zydus Cadila): Twinrab is a combination of two
murine monoclonal antibodies, docaravimab (62-71-3) and
miromavimab (M777-16-3). They bind to two different epitopes
on the G protein expressed on the surface of rabies virus. The
two monoclonal antibodies bind to and neutralize both, rabies
and rabies-like viruses, preventing their infection into the
neighboring cells. The cocktail of antibodies was also found to
neutralize rabies virus strains isolated from dog, canine, human,
and bovine sources from southern parts of India.6
Composition, dosage, and indication: Twinrab is a sterile
preservative free clear colorless liquid solution for infiltration.
Twinrab is available in two different strengths, viz.:
1. 2.5 mL vial containing 1500 IU (600 IU/mL) of twinrab
2. 1 mL vial containing 600 IU (600 IU/mL) of twinrab.
The recommended dose of twinrab is 40 IU/kg of bodyweight.
Twinrab is indicated for postexposure prophylaxis in individuals
with suspected rabies exposure. Twinrab must always be used in
combination with rabies vaccine as part of postexposure prophylaxis
in line with the recommendation of WHO.7
Recommendations for monoclonal antibodies: ACVIP strongly
recommends the use of MRabs over RIGs in the management of
category 3 bites.
Human monoclonal rabies antibody (Rabishield) and murine
cocktail, monoclonal rabies antibodies (TWINRAB), both are avail-
able in India and recommended for the postexposure management
of suspected rabies exposure.
Rabies Immunoglobulin
Dosage: It contains specific antirabies antibodies that neutralize
the RABV and provide passive protection till active immunity is
generated. There are two types of RIG:
1. Human rabies immunoglobulin (HRIG)—dose is 20 U/kg
bodyweight, maximum dose 1,500 IU
2. Equine rabies immunoglobulin (ERIG)—dose is 40 U/kg,
maximum dose 3,000 IU.
Human rabies immunoglobulin is preferred, but if not
available/unaffordable, ERIG may be used. Most of the new ERIG
preparations are potent, safe, highly purified, and less expensive as
compared to HRIG, but do carry a small risk of anaphylaxis. As per
latest recommendations from the WHO, skin testing prior to ERIG
administration is not recommended as skin tests do not accurately
predict anaphylaxis risk and ERIG should be given whatever the
result of the test.7
Indications for RIG/Mabs: All category III bites, all wild animal bites,
and class II bites in immunocompromised should be given RIG
or MAbs. RIG/MAb is not necessary if the patient has received a
complete course of PEP or PrEP previously. Since rabies has a long
incubation period, PEP, including RIG/Mabs and vaccine, may be
administered weeks, months, or even a few years after a category III
exposure, if no PEP was administered earlier.
While RIG/Mabs are recommended only locally at the sites of
exposure, full dose IM may be administered for aerosol exposures.
Flushing of conjunctive for conjunctival exposure and rinsing of
mouth with RIG/Mabs, for oral mucosal exposure, without bleeding,
is recommended.
Administration: RIG/Mabs should be infiltrated thoroughly into and
around the wounds. For small wounds, the maximal quantity that
is anatomically feasible should be administered. It is important to
avoid the compartment syndrome which occurs if large volumes of
RIG are injected into a small body area with limited tissue. It is no
longer recommended to give remaining part of RIG intramuscularly.
Therefore, if the volume of the calculated RIG dose1 is likely to be too
large for local wound infiltration, it can be fractionated into smaller,
individual syringes and the residual unused RIG can be used that
same day for other patients, if stored and handled aseptically.
Unused, fractionated RIG should be discarded at the end of the day.
If the wounds are large or multiple, the maximum calculated
volume of RIG can be diluted with physiological buffered saline to
allow sufficient volume for complete wound infiltration. Regardless
of RIG availability, all category III exposed patients should receive
rabies vaccines immediately. RIG should be administered only once,
preferably at initiation of PEP and not >7 days following the first
rabies vaccine dose.8
If a limited amount of RIG is available, its allocation should
be prioritized for patients with high risk, category III exposures:
multiple bites; those with deep wounds, or bites to highly innervated
parts of the body, such as the head, neck and hands; patients with
severe immunodeficiency; and cases where the biting animal is a
confirmed or probable rabies case, or where bites, scratches or
exposure of a mucous membrane were caused by a bat.
It is essential that the entire body should be examined for small bites,
especially in smaller children and every site should be infiltrated with
RIG/Mabs.
Active Immunization
Rabies Vaccines
Vaccines are the mainstay for prevention of development of
rabies. The nerve tissue vaccines, used earlier, are no longer
available due to poor efficacy and life-threatening adverse effect of
neuroparalytic reactions. Rabies vaccines are highly effective, safe,
and well-tolerated.
The currently available vaccines are:
■ The cell culture vaccines (CCVs) include purified chick embryo
cell vaccine (PCECV), human diploid cell vaccine (HDCV),
purified vero cell rabies vaccine (PVRV)
■ Purified duck embryo vaccine (PDEV).
It is to be noted that all CCVs and PDEV should have potency
(antigen content) >2.5 IU per intramuscular dose irrespective of
whether it is 0.5 mL or 1.0 mL vaccine by volume.
Efficacy and effectiveness: The vaccines are available in lyophilized

form with sterile water as diluent, are stable for 3 years at 2–8°C and
should be used within 6 hours of reconstitution. All CCVs have almost
equal efficacy and any one of these can be used. These vaccines
induce protective antibodies in >99% of vaccinees following PrEP
or PEP. Prompt postexposure use of CCVs combined with proper
wound management and simultaneous administration of RIG/Mabs
is almost invariably effective in preventing rabies, even following
high-risk exposure. However, delays in starting or failure to complete
correct prophylaxis may result in death, particularly following bites
in highly innervated regions, such as the head, neck, or hands, or
following multiple wounds.
Duration of immunity: The current CCVs possess immunological
memory after vaccination, and individuals who had received their
primary series 5–21 years previously showed good anamnestic
response after booster vaccination even when antibodies are no
longer detectable.2
Adverse effects: The main adverse effects are local pain, swelling,
and redness and less commonly fever, headache, dizziness, and
gastrointestinal side effects. Intradermal vaccination may cause
more local irritation as compared to the intramuscular route.2
Postexposure prophylaxis: Postexposure prophylaxis is a medical
urgency. It should be initiated as soon as possible and should not
be delayed till results of lab tests or animal observation is available.
Which exposures warrant PEP?
■ All mammalian bites need PEP (dogs, cats, cows, buffaloes, sheep,
goats, pigs, donkeys, horses, camels, foxes, jackals, monkeys,
mongoose, bears, and others).
■ Bites by small domestic rodents do not warrant PEP.
■ Exposure to bats does not warrant PEP for rabies in India.
■ All bites that occur in wild warrant PEP and should be managed
as a category 3 exposure.
■ Bites by unknown animals warrant PEP.
The comparatively long incubation period provides an opportunity
for highly effective PEP. PEP consists of:
■ Thorough washing and flushing of the wound

■ A series of rabies vaccine administrations promptly started after
an exposure, and if indicated
■ RIG infiltration into and around the wound, promptly after exposure.
Thorough wound washing with soap or detergent and water and/
or virucidal agents reduces the viral inoculum at the wound site.
Antibodies induced by postexposure vaccination lower the risk of
RABV entering peripheral nerves after a bite from a rabid animal.
Additionally, timely administration of RIG neutralizes RABV at the
wound site. Rabies deaths occur mainly in those who cannot access
timely and effective PEP. Prompt PEP following severe exposures is
100% effective in preventing rabies. However, delay in seeking PEP,
improper wound care, unnoticed wounds, direct nerve inoculation,
and lack of patient compliance with vaccination schedules among
other factors contribute to PEP failure and subsequent death.
Because rabies is a lethal disease, there are no contraindications
for PEP including infants, and pregnant and lactating women.
Persons presenting several days/months/years after the bite
should be managed in a similar manner as a person who has been
bitten recently (with RIG if indicated) as rabies may have a long
incubation period and the window of opportunity for prevention
remains.
Schedule of Vaccination
The Essen protocol consists of five doses on days 0, 3, 7, 14, and
28, with day “0” being the day of commencement of vaccination. A
regimen of five doses of HDCV or PCECV should be administered IM
to previously unvaccinated persons. The first dose of the five-dose
course should be administered as soon as possible after exposure.
This date is then considered day 0 of the PEP series. Additional doses
should then be administered on days 3, 7, 14, and 28 after the first
vaccination. This schedule is recommended by the National Center
for Disease Control (NCDC) of the Govt of India.9
If any doses are delayed, vaccination should be resumed, not
restarted.
A change in the route of administration or in vaccine product

during a PEP or PrEP course is acceptable if such a change is
unavoidable. Vaccination should continue according to the schedule
for the new route of administration.
Shortened Schedules
A shortened Essen regimen, consisting of one dose on each of days
0, 3, 7, and between 14 and 28th day, is recommended, for immune
competent, exposed people provided that they receive wound care
plus rabies immunoglobulin in category III and a WHO-prequalified
rabies vaccine.10
The IAP/ACVIP has endorsed this four-dose PEP schedule and
two-dose PrEP schedule recommended by the WHO in 2018.
Most interruptions in the vaccine schedule do not require re-
initiation of the entire series. For most minor deviations from the
schedule, vaccination can be resumed as though the patient was on
schedule. For example, if a patient misses the dose scheduled for day
7 and presents for vaccination on day 10, the day 7 dose should be
administered that day and the schedule resumed, maintaining the
same interval between doses. In this scenario, the remaining dose
would be administered between day 17 and 31st. The dose is same at
all ages and is 1 mL IM for HDCV, PCEV, PDEV, and 0.5 mL for PVRV.
Re-exposure prophylaxis: If an individual has a repeat exposure
<3 months after a complete PEP schedule, then only wound care
is needed, neither ARV nor RIG is needed. For repeat exposures
occurring >3 months after the last PEP, the PEP schedule for
previously immunized individuals should be followed, two IM doses
on days 0 and 3. RIG is not indicated. (WHO position paper 2018).
Post-vaccination serological testing: Routine estimation of serological
response following the completion of preexposure or postexposure
prophylaxis is not necessary.
It is necessary if:
■ The person is immunosuppressed
■ Significant deviations of the prophylaxis schedule have occurred
■ The person’s antibody status is being monitored routinely due to
occupational exposure to rabies virus.
Concurrent Chloroquine and Hydroxychloroquine Use

Lower VNA titers have been reported in individuals who received
ID PrEP during chloroquine treatment. The difference in observed
VNA titers was small, above the 0.5 IU/mL threshold, and unlikely
to be clinically significant. Based on pharmacovigilance, since 1983
there have been no additional reports of rabies cases among persons
who received PEP, with or without PrEP, and who were concurrently
taking chloroquine or hydroxychlorine.
There is no contraindication for individuals receiving treatment
with chloroquine or hydroxychloroquine; both ID and IM route
of vaccine administration can be used. However, if possible, PrEP
should be completed before chloroquine or hydroxychloroquine
treatment is initiated. (WHO Position Paper 2018).
Any of the CCVs may be used intramuscularly in anterolateral
thigh or the deltoid. Rabies vaccine should never be injected in the
gluteal region. Interchange of vaccines is permitted only in special
circumstances but should not be done routinely. If RIG is not
available, then two doses of the vaccine may be given on day 0 (this
is, however, not a substitute for RIG).
Intradermal Vaccination
A systematic review of vaccine potency has shown that current
vaccines (>2.5 IU/IM dose), when administered by the ID route for
either PEP or PrEP, have efficacy equivalent to or higher than that
of the same vaccine administered by the IM route. For the ID route
one dose is 0.1 mL of CCEEV (irrespective of the vaccine brand).
The vaccine in one vial can therefore be fractionated to provide 5–10
doses for ID administration, depending on the vial size (0.5 mL or
1.0 mL). For the IM route, one dose is one vial of vaccine per patient.
The higher concentration of antigen-presenting cells in the dermis
is responsible for the strong immunologic response to vaccine
administered ID, despite the lower amount of antigen injected.
ID administration of rabies vaccines provides a cost-saving and
dose-sparing alternative to IM vaccination. ID PEP regimens use at
least 25% less vaccine vials than IM PEP regimens. As numbers of
patients seen in clinics increase, ID regimens become increasingly
cost-effective, using up to 85% less vaccine vials.
WHO/IAP recommended PEP by ID route: 2-sites ID on days 0, 3, and

7 for the immunologically naïve individual.
NCDC (Govt. of India) recommended PEP by ID route: Updated Thai
Red Cross Schedule: 2-sites ID on days 0, 3, 7, and 28 days.
Re-exposure prophylaxis:
■ <3 months since completion of PEP: No intervention except
wound hygiene.
■ >3 months since completion of PEP: 1-site IM on days 0–3 OR
1-site ID on days 0 and 3 or 4-site ID on day 1.
Reduced Three-dose Schedule

ThRabis: Cadila Pharmaceuticals has developed a novel three-
dose recombinant nano-particle-based rabies G protein vaccine,
ThRabis, based on virus-like particle (VLP) technology. The vaccine
generates antibodies against rabies G protein, which leads to virus
neutralization and prevents virus attachment to the cell to confer
protection against rabies.
Cadila Pharmaceuticals successfully tested immunogenicity
and safety of three doses, i.e., 50 µg (microgram) on days 0, 3, and
7 of the novel vaccine in Phase-I/II and Phase-III clinical trials in
healthy volunteers as well as preclinical models. The safety and
immunogenicity of the vaccine were established in the trials.11
ThRabis is an intramuscular vaccine and less painful for
the recipients, and does not require reconstitution prior to use.
Since it is three-dose vaccine, it will improve compliance to
complete the vaccine course. This vaccine has been licensed by the
Drug Controller General of India (DCGI) for use >18 years of age.
However, the NCDC, WHO, and IAP have not made any statement
on the use of this vaccine.
Postexposure Prophylaxis of Immunocompromised

Patients (Box 1)
Several studies of patients with human immunodeficiency virus/
acquired immunodeficiency syndrome have reported that those
with low CD4 (<200 counts) will mount a significantly lower or
BOX 1: Rabies vaccines.

• Only modern tissue culture vaccines (MTCVs) and intramuscular (IM)
routes are recommended for both “postexposure” and “preexposure”
prophylaxis in office practice.
• Postexposure prophylaxis is recommended following a significant
contact with dogs, cats, cows, buffaloes, sheep, goats, pigs, donkeys,
horses, camels, foxes, jackals, monkeys, mongoose, bears, and others.
Rodent bites do not require postexposure prophylaxis in India.
• Postexposure prophylaxis:
– Modern tissue culture vaccines are recommended for all category II
and III bites.
– Dose: 1.0 mL IM in anterolateral thigh or deltoid (never in gluteal
region) for human diploid cell vaccine (HDCV), purified chick
embryo cell (PCEC) vaccine, purified duck embryo vaccine (PDEV);
0.5 mL for purified Vero cell rabies vaccine (PVRV). Intradermal (ID)
administration is not recommended in individual practice yet.
– 4 dose schedule: 0, 3, 7, and between 14- and 28th day with day “0”
being the day of commencement of vaccination.
– Monoclonal Rabies antibodies/Rabies immunoglobulin (RIG) along
with rabies vaccines are recommended in all category III bites.
– Rabishied 3.33 IU/kg, Twinrab 40 IU/kg, HRIG 20 mg/kg or equine
rabies immunoglobulin (ERIG) (dose 40 U/kg) can be used.
Monoclonal rabies antibodies to be preferred over RIG.
• Preexposure prophylaxis:
– Two doses are given intramuscularly in deltoid/anterolateral thigh on
days 0, 7, OR 2-site ID on day 0 and 7.
– For re-exposure occurring 3 or more months after completed (and
documented) pre- or postexposure prophylaxis, two doses are given
on days 0 and 3.
– Rabies immunoglobulin should not be used during re-exposure
therapy.
no detectable neutralizing antibody response to rabies. In such

patients and those in whom the presence of immunological
memory is no longer assured as a result of other causes, proper
and thorough wound management and antisepsis accompanied
by local infiltration of RIG followed by antirabies vaccination
are of utmost importance. Even immune-compromised patients
with category II exposures should receive RIG in addition to a full
postexposure vaccination. Preferably, if the facilities are available,
antirabies antibody estimation should be done 14 days after

the completion of course of vaccination, to assess the need for
additional doses of vaccine.
Preexposure Prophylaxis (see Box 1)

Preexposure prophylaxis consists of a series of rabies vaccination
administered prior to a potential exposure. PrEP is recommended
for certain high-risk groups enumerated as follows:
■ Continuous exposure: Laboratory personnel involved with rabies
research and production of rabies biologics. Source and exposure
may be unrecognized.
■ Frequent exposure: Veterinarians, laboratory personnel involved
with rabies diagnosis, medical, and paramedical staff treating
rabies patients, dog catchers, zoo keepers, and forest staff.
■ Infrequent exposure:
y Postmen, policemen, and courier boys
y Travelers to rabies endemic countries particularly those who
intend to backpack/trek.
Although PEP and PrEP can be administered intramuscularly
(IM) or intradermally (ID), ID vaccination is both dose and cost-
sparing. Modern purified cell-culture and embryonated egg-based
rabies vaccines are highly immunogenic, effective, and safe to use in
people of all ages.
Individuals with documented evidence of previous PrEP are
considered previously immunized and benefit from an abridged PEP
without RIG in case of exposure.
Preexposure prophylaxis eliminates the need for RIG (awareness,
cost, and availability of RIG is a problem). It also reduces the number
of vaccine doses.
PrEP schedules:
■ WHO/IAP: (a) 2-site ID on days 0 and 7, or (b) 1-site IM on days
0 and 7
■ NCDC: IM-days 0-7-21 to 28. ID-1-site ID on days 0-7-21 to 28.
Most Indian children are at risk for rabies. The Advisory
Committee on Vaccines and Immunization Practices (ACVIP)
recommends offering preexposure prophylaxis to children at high
risk of rabies exposure after discussion with parents.
Individuals who are immunocompromised should receive a

3-visit ID or IM PrEP regimen on days 0, 7 and between days 21 and
28, and should be managed with full PEP in the case of a potential
rabies exposure with particular emphasis on rigorous wound
washing. (SAGE Working group on Rabies vaccine WHO 2017).
Routine assessment of antirabies antibody titer after
completion of vaccination is not recommended unless the person
is immunocompromised. It is desirable to monitor antibody titers
every 6 months in those with continuous exposure and every year in
those with frequent exposure. A booster is recommended if antibody
levels fall below 0.5 IU/mL. When serologic testing is not available
booster vaccination every 5 years is an acceptable alternative. For
re-exposure at any point of time after completed (and documented)
preexposure prophylaxis or PEP, two doses are given on days 0
and 3. RIG should not be used as it may inhibit the relative strength
or rapidity of an expected anamnestic response.
REFERENCES
1. Assessing Burden of Rabies in India, WHO sponsored national
multicentric rabies survey. Association for Prevention and Control of
Rabies in India. May 2004. [online] Available from http://rabies.org.in/
rabies/ wp-content/uploads/2009/11/whosurvey.pdf. [Last accessed
November, 2022].
2. Rabies vaccines. WHO position paper. Wkly Epidemiol Record.
2010;85:309-20.
3. Suraweera W, Morris SK, Kumar R, Warrell DA, Warrell MJ, Jha P,
et al. Deaths from symptomatically identifiable furious rabies in India:
a nationally representative mortality survey. PLoS Negl Trop Dis.
2012;6(10):e1847.
4. WHO Expert Consultation on Rabies, third report: WHO Technical
Series Report No. 1012, Geneva, 2018 (ISBN 978-92-4-121021-8).
5. Gogtay NJ, Munshi R, Ashwath Narayana DH, Mahendra BJ,
Kshirsagar V, Gunale B, et al. Comparison of a novel human
rabies monoclonal antibody to human rabies immunoglobulin for
postexposure prophylaxis: a phase 2/3, randomized, single-blind,
noninferiority, controlled study. Clin Infect Dis. 2018;66(3):387-95.
6. Kansagra K, Parmar D, Mendiratta SK, Patel J, Joshi S, Sharma N,
et al. A Phase 3, Randomized, Open-label, Noninferiority Trial
Evaluating Anti-Rabies Monoclonal Antibody Cocktail (TwinrabTM)
Against Human Rabies Immunoglobulin (HRIG). Clin Infect Dis.

2021;73(9):e2722-e2728.
7. TwinRab. Available at https://twinrab.com/.
8. Association for prevention and control of rabies in India. (2009).
Manual on RIG administration. [online] Available from http://
rabies.org.in/rabies/wp-content/uploads/2009/11/Manual-on-
RabiesImmunoglobulin-Administratio.pdf. [Last accessed November,
2022].
9. National Guidelines for Rabies prophylaxis, National rabies control
programme. Published by Division of Zoonosis Disease Programme,
National Centre for Disease Control, Directorate General of Health
Services, 22, Sham Nath Marg, Delhi, 110054. www.ncdc.gov.in.
10. Rupprecht CE, Briggs D, Brown CM, Franka R, Katz SL, Kerr HD,
et al. Use of a reduced (4-dose) vaccine schedule for postexposure
prophylaxis to prevent human rabies: recommendations of the
advisory committee on immunization practices. MMWR Recomm
Rep. 2010;59(RR-2):1-9.
11. Ravish HS, Khobragade A, Satapathy D, Gupta M, Kumar S, Bhomia V,
et al. Safety and immunogenicity of a novel three-dose recombinant
nanoparticle rabies G protein vaccine administered as simulated
post exposure immunization: a randomized, comparator controlled,
multicenter, phase III clinical study. Hum Vaccin Immunother. 2021;
17(11):4239-45.
3.17 CHOLERA VACCINES

Ananda Kesavan TM, Sunil Kumar Aggarwalla
BACKGROUND
Cholera is an important public health problem in developing
countries, with poor sanitation and hygiene, as well as in displaced
populations. It occurs over a wider geographic area in India than was
previously recognized.
The predominant strain is Vibrio cholerae (V. cholerae) O1
(classical and El Tor biotype). V. cholerae O139 is an emerging
strain. Cholera is an extremely virulent disease that can cause severe
acute watery diarrhea. Incubation period after ingestion of cholera
organisms by contaminated food or water is 12 hours to 5 days.
Cholera affects both children and adults and can kill within hours
if untreated.
GLOBAL BURDEN
Cholera remains a global threat to public health and an indicator of
inequity and lack of social development. Researchers have estimated
that every year, there are roughly 1.3–4.0 million cases, and 21,000–
143,000 deaths worldwide due to cholera.1
After penetrating the mucus layer, V. cholerae colonizes the
epithelial lining of the gut. Cholera toxin, which is secreted by
toxigenic V. cholerae O1 or O139, affects the small intestine. The
toxin depends on a specific receptor: the monosialosyl ganglioside
GM-1. The binding (B) subunit of the toxin attaches to GM-1 and
releases the active (A) subunit, which enters the host cell. This
activation results in massive loss of intravascular and extracellular
fluids and electrolytes.2 Cholera is endemic in India where only 25%
of the population has access to piped water supply and sanitation.
A recent meta-analysis reports 22,000 cases a year in India
(probably a gross underestimate) of which most is V. cholerae O1 El
Tor biotype.3
In a longitudinal community-based surveillance study in urban
slums of Kolkata, the overall incidence was around 1.6/1,000
person years with the highest incidence seen in children below the
age of 2 years (8.6/1,000 per year) followed by 6.2 in the age group
2–5 years and 1.2 in those aged above 5 years.4
As the World Health Organization (WHO) collaborating Centre
for Diarrhoeal Disease Research and Training, the National Institute
of Cholera and Enteric Diseases (NICED) received during 1990–
2007, a total of 16,624 strains of V. cholerae from 24 states, of which
7,225 strains of V. cholerae were included for phage typing study. Of
the total strains received, 96.5% strains were serotyped as Ogawa and
the remaining 3.5% were Inaba. Periodic shifts in the occurrence of
Ogawa and Inaba serotypes in a given area are usual phenomenon
and are thought to be a consequence of population-level immunity
patterns.5
Young children living in endemic areas are most affected by the
disease, but any age group may suffer. In a prospective study, cholera
surveillance was conducted in selected slums in Kolkata, India,
Beira, Mozambique, and North Jakarta, Indonesia.1 Children aged
2–4 years had annualized incidence rates of 8.8/1,000 in Beira,
6.2/1,000 in Kolkata, and 1.2/1,000 in North Jakarta. Although
these rates were 2–4 times higher than those found in the overall
population, children aged <2 years had highest incidence rates of
8.6/1,000 in Kolkata and 3.2/1,000 in Jakarta.2
Endemic cholera: Exogenous reintroduction of the pathogen is not
required. Endemic disease happens in younger age groups, three of
last 5 years suffer from cholera.
Epidemic cholera happens due to exogenous introduction of
V. cholerae, not recurrent, clinically more severe, and all age groups
suffer.6
VACCINES
The parenteral killed vaccine which had a 3-month efficacy of 45%
is no longer recommended. The killed whole cells of V. cholerae
O1 and recombinant cholera toxin B subunit (WC-rBS) vaccine
available internationally as Dukoral oral vaccine and widely
used in travelers is a vaccine comprising of killed V. cholerae
O1 with recombinant B subunit of cholera toxoid. Because of
similarity in the structure and functions of the cholera toxin B,

this vaccine provides cross-protection against enterotoxigenic
Escherichia coli (E. coli). However, this vaccine is not marketed in
India.7
The variant WC-rBS vaccine first developed and licensed in
Vietnam comprises only killed whole-cell V. cholerae O1 (classical
and El Tor) and V. cholerae O139. There is no recombinant
β-subunit toxoid and will therefore not protect against entero
toxigenic E. coli.
Shancol is the only Cholera vaccine available in India.
Shancol composition is shown in Table 1.
This vaccine (Shanchol) is now manufactured and licensed in
India for children above the age of 1 year. It is provided in a single
dose vials and does not require a buffer or water for administration,
although water may be given. The vaccine has a shelf-life of 2 years
at 2–8°C. The vaccine has a good safety profile.8
This vaccine is available as mORCVAX in Vietnam and Euvichol
in Korea.
Shanchol, as programmatic vaccine to control stable endemic
cholera disease in rural India, has conferred efficacy of 69% and 53%
in Bangladesh.6
TABLE 1: Composition of Shancol.

Active ingredient Quantity
V. Cholerae O1 Inaba El Tor 600 Eliza units (EU) of
Formaldehyde killed lipopolysaccharide (LPS)
V. Cholerae O1 Ogawa, Classical strain. 300 EU of LPS
Heat killed
V. Cholerae O1 Ogawa, Classical strain, 300 EU of LPS
formaldehyde killed
V. Cholerae O1 Inaba, Classical strain. 300 EU of LPS
Heat killed
V. Cholerae O139, Formaldehyde killed 600 EU of LPS
Excipients
Thiomersal Not >0.02% w/v
Buffer qs to 1.5 mL
TABLE 2: Shancol: Vaccine efficacy (VE) at 2 years and 5 years follow up (FU).
VE (%)
Age group 2 years FU 5 years FU
1–4 years 49 42
5–14 years 87 68
>15 years 63 74
Overall 67 65

A randomized double-blind immunogenicity trial with this vaccine
in Kolkata demonstrated fourfold rise in titers in 53% of adults
and 80% of children with response to O139 being lesser than
O1. Subsequently, a very large cluster randomized double-blind
placebo-controlled trial in Kolkata demonstrated that the average
per protocol efficacy of the vaccine to be 67% across all ages for up
to 2 years after vaccination and 3 years efficacy is 65%. Subsequent
study by the same authors has also shown that the cumulative
efficacy at 5 years is also 65% (Table 2).9 No adverse effects were
noted.
Parenteral vaccines are under development.

The ideal method for cholera control is improvement in water
supply and sanitation. As recommended by the WHO, cholera
vaccines should be used preemptively in endemic areas and in crises
situations and not as outbreak control measure. Vaccination should
not disrupt the provision of other high priority health interventions
to control or prevent cholera outbreaks. The inclusion of new killed
whole-cell oral cholera vaccine in the national immunization
schedule is being considered by the policy makers in those areas
where cholera is highly endemic, particularly the states of West
Bengal and Orissa. In a study done of a single dose of OCV in an
endemic setting, in Bangladesh, the vaccine efficacy (VE) was
BOX 1: Recommendations for use of cholera vaccine.

• Minimum age: One year [killed whole cell Vibrio cholerae (Shanchol™)]
• Not recommended for routine use in healthy individuals; recommended
only for the vaccination of persons residing in highly endemic areas and
travelling to areas where risk of transmission is very high like Kumbh
Mela, etc.
• Two doses 2 weeks apart for >1 year old.
• For continued risk of exposure, a booster may be administered after 3 years.
40% (95% CI: 11–60%); against all cholera episodes, 63% (95% CI:
24–82%) against severely dehydrating cholera episodes, and 16%
(95% CI: −49–53%) in 1–4 years, 63% (95% CI: −39–90%) in the age
of 5–14 years and 56% (95% CI: 16–77%) in 15 or more years, against
all cholera episodes, although the differences according to age
were not significant (P = 0.25).10 Adverse events occurred at similar
frequencies in the two groups. Thus, a single dose of the oral cholera
vaccine was efficacious in older children (≥5 years of age) and in
adults in a setting with a high level of cholera endemicity.10
Cost-effectiveness analysis studies have demonstrated that
vaccination of the 1–14 years old population would be highly
cost-effective.
Individual Use
The Indian Academy of Pediatrics-Advisory Committee on Vaccines
and Immunization Practices (IAP-ACVIP) has included the cholera
vaccine in the category of vaccines to be used under special
circumstances only. These include travel to or residence in a highly
endemic area and circumstances where there is risk of an outbreak
such as during pilgrimages like Kumbh Mela, etc. Protection
starts 2 weeks after receipt of the second dose (Box 1).
REFERENCES
1. Ali M, Nelson AR, Lopez AL, Sack DA. Updated global burden of
cholera in endemic countries. PLoS Negl Trop Dis. 2015;9:e0003832.
2. Cholera vaccines: WHO position paper. Wkly Epidemiol Rec.
2010;85:117-28.
3. Verma R, Khanna P, Chawla S. Cholera vaccine: new preventive tool for
endemic countries. Hum Vaccin Immunother. 2012;8:682-4.
4. Deen JL, von Seidlein L, Sur D, Agtini M, Lucas ME, Lopez AL, et al.
The high burden of cholera in children: comparison of incidence
from endemic areas in Asia and Africa. PLoS Negl Trop Dis. 2008;
2:e173.
5. Sarkar BL, Kanungo S, Nair GB. How endemic is cholera in India?
Indian J Med Res. 2012;135:246-8.
6. Clemens JD, Desai SN, Quadri F. Cholera vaccines. In: Plotkin S,
Orenstein W, Offit P, Edwards KM (Eds). Plotkin’s Vaccines, 7th edition.
New York: Elsevier; 2017. pp. 185-6.
7. Lopez AL, Clemens JD, Deen J, Jodar L. Cholera vaccines for the
developing world. Hum Vaccine. 2008;4:165-9.
8. Mahalanabis D, Lopez AL, Sur D, Deen J, Manna B, Kanungo S, et al.
A randomized, placebo-controlled trial of the bivalent killed, whole-
cell, oral cholera vaccine in adults and children in a cholera endemic
area in Kolkata, India. PLoS One. 2008;3:e2323.
9. Bhattacharya SK, Sur D, Ali M, Kanungo S, You YA, Manna B, et al.
5 year efficacy of a bivalent killed whole-cell oral cholera vaccine
in Kolkata, India: a cluster-randomised, double-blind, placebo-
controlled trial. Lancet Infect Dis. 2013;13:1050-6.
10. Qadri F, Ali M, Lynch J, Chowdhury F, Khan AI, Wierzba TF, et al. Efficacy
of a single-dose, inactivated oral cholera vaccine in Bangladesh.
N Engl J Med. 2016;374:1723-32.
3.18 YELLOW FEVER VACCINE

BACKGROUND
Yellow fever (YF) is caused by yellow fever virus (YFV), a single-
stranded ribonucleic acid (RNA) virus that belongs to the genus
Flavivirus. Vector-borne transmission occurs via the bite of an
infected mosquito Aedes or Haemagogus spp. Humans infected with
YFV experience the highest levels of viremia and can transmit the
virus to mosquitoes shortly before onset of fever and for the first
3–5 days of illness.
Yellow fever is confined to certain countries in sub-Saharan Africa
and Central/South America and varies in severity from influenza-
like illness to severe hepatitis and hemorrhagic fever. Though YF
does not exist in India, conditions are conducive for its spread in
the country due to the widespread presence of the mosquito vector
Aedes aegypti and favorable environmental conditions. Therefore,
the Government of India has strict regulations in place to restrict the
entry of susceptible and unvaccinated individuals from YF endemic
countries.
EPIDEMIOLOGY AND RISK FOR TRAVELERS

Yellow fever is endemic and intermittently epidemic in sub-
Saharan Africa and tropical South America. The growth of air travel
has diminished the barriers to the spread of YF, posing a threat to
regions that have not previously been reached by the disease but are
considered receptive, including the Middle East, coastal East Africa,
the Indian subcontinent, Asia, and Australia. The risk for travelers to
endemic areas of Africa has been estimated as 23.8/100,000/week, in
epidemic areas 357/100,000/week.1
Data from the US travelers produced an estimate of 0.4–4.3
cases/million travelers to YF endemic areas. 2 Each year,
approximately 9 million tourists travel to countries where YF is
endemic.3 A traveler’s risk for acquiring YF is determined by various
factors, including immunization status, location of travel, season,
duration of exposure, occupational and recreational activities while
traveling, and local rate of virus transmission at the time of travel.

For a 2-week stay, the risks for illness and death due to YF for an
unvaccinated traveler traveling to an endemic area are as follows:4
■ West Africa area 50 per 100,000 and 10 per 100,000, respectively
■ South America area 5 per 100,000 and 1 per 100,000, respectively.
The Centers for Disease Control and Prevention (CDC), the
World Health Organization (WHO), and other YF experts recently
completed a comprehensive review of available data and revised the
criteria and global maps designating the risk of YFV transmission.
The new criteria establish four categories of risk for YFV transmission
that apply to all geographic areas:
1. Endemic
2. Transitional
3. Low potential for exposure
4. No risk.
Yellow fever vaccination is recommended for travel to endemic
and transitional areas. Although vaccination is generally not recom-
mended for travel to areas with low potential for exposure, it might be
considered for a small subset of travelers whose itinerary could place
them at increased risk for exposure to YFV (such as prolonged travel,
heavy exposure to mosquitoes, or inability to avoid mosquito bites).
Based on the revised criteria for YF risk classification, the current
maps and country-specific information (YF and malaria information,
by country) designate three levels of YF vaccine recommendations:
(1) recommended, (2) generally not recommended, (3) and not
recommended.5
VACCINE
It is a live-attenuated vaccine derived from 17D strain of the virus
grown in chick 140 embryo cells. The 17D live YF vaccine has been
widely acknowledged as one of the most effective and safe vaccines
in use and is the only commercially available YF vaccine.6
The vaccine is available as a freeze-dried preparation in single/
multidose vials that should be stored at 2–8°C (must not be frozen)
along with sterile saline as diluent. The reconstituted vaccine is
heat labile, must be stored at 2–8°C, and discarded within 1 hour of
reconstitution.
The dose is 0.5 mL subcutaneously. It can be safely given along

with all other childhood vaccines.
Immunogenicity and efficacy are >90%. Immunogenicity is lower
in pregnancy and immunocompromised.
Vaccine Safety and Adverse Reactions

About 10–30% of vaccines report mild systemic adverse events like
low-grade fever, headache, and myalgias that begin within days after
vaccination and last 5–10 days. Severe adverse reactions are rare and
include immediate hypersensitivity reactions, characterized by rash,
urticaria, bronchospasm, or a combination of these. Anaphylaxis
after YF vaccine is reported to occur at a rate of 0.8 cases per 100,000
doses administered.
Serious adverse events following immunization (AEFI) with YF
vaccine fall into three categories:
1. Immediate severe hypersensitivity or anaphylactic reactions:
Anaphylactic reactions have been estimated to occur in 0.8 per
100,000 vaccinations, most commonly in people with allergies to
eggs or gelatin.
2. Yellow fever vaccine-associated neurologic disease (YEL-AND):
YEL-AND represents a conglomerate of different clinical
syndromes, including meningoencephalitis, Guillain-Barré
syndrome, acute disseminated encephalomyelitis, bulbar palsy,
and Bell’s palsy. The onset of illness for documented cases is
3–28 days after vaccination, and almost all cases were in first-
time vaccine recipients. YEL-AND is rarely fatal. The incidence
of YEL-AND in the United States is 0.8 per 100,000 doses
administered. The rate is higher in people aged ≥60 years, with
a rate of 1.6 per 100,000 doses in people aged 60–69 years and
2.3 per 100,000 doses in people aged ≥70 years.
3. Yellow fever vaccine-associated viscerotropic disease (YEL-AVD):
YEL-AVD is a severe illness similar to wild-type disease, with
vaccine virus proliferating in multiple organs and often leading
to multisystem organ failure and death. Since the initial cases of
YEL-AVD were published in 2001, >50 confirmed and suspected
cases have been reported throughout the world. YEL-AVD
appears to occur after the first dose of YF vaccine, rather than with
booster doses. The onset of illness for YEL-AVD cases averaged
3 days (range 1–8 days) after vaccination. The case-fatality ratio
for reported YEL-AVD cases is 65%. The incidence of YEL-AVD
in the United States is 0.4 cases per 100,000 doses of vaccine
administered. The rate is higher for people aged ≥60 years,
with a rate of 1.0 per 100,000 doses in people aged 60–69 years
and 2.3 per 100,000 doses in people aged ≥70 years.5,7,8
The risk of neurologic and viscerotropic disease is higher
and hence the vaccine is contraindicated in infants below the
age of 6 months, those with history of thymus disease, and
the severely immunocompromised including HIV with severe
immunosuppression (CD4 count < 15% of age-related cutoff ) and
those with history of serious egg allergy. The vaccine is preferably
avoided in infants aged 6–9 months, individuals aged >65 years,
and in pregnant and lactating women. The contraindications and
precautions to YF vaccine are given in Table 1.

The vaccine is mandatory for all travelers to YF endemic zones as
per the International Health Regulations (IHR). All vaccinees receive
TABLE 1: Contraindications and precautions to yellow fever vaccine

administration.
Contraindications Precautions
• Allergy to vaccine component • Age 6–8 months
• Age <6 months • Age ≥60 years
• Symptomatic human immunodeficiency • Asymptomatic HIV
virus (HIV) infection or CD4 infection and CD4
T-lymphocytes <200 cells/mm3 (or <15% T-lymphocytes 200–499
of total in children aged <6 years)1 cells/mm3 (or 15–24% of
• Thymus disorder associated with total in children aged
abnormal immune-cell function <6 years)1
• Primary immunodeficiencies • Pregnancy
• Malignant neoplasms • Breastfeeding
• Transplantation
• Immunosuppressive and
immunomodulatory therapies
an international certificate for vaccination duly dated, stamped, and

signed by the center administering the vaccine. The vaccine should
be administered only at authorized centers.

Yellow fever vaccines are given as a single dose (0.5 mL) and the
manufacturers recommend that the vaccine can be injected either
subcutaneously or intramuscularly. The vaccination site is usually
the lateral aspect of the upper part of the arm or the anterolateral
aspect of the thigh in babies and very young children.9
Endemic countries: In these countries, YF vaccine is given to children

at age of 9–12 months at the same time as the measles vaccine.
Vaccination should be provided to all >9 months in any area with
reported cases.
Travelers to endemic countries: Vaccine should be offered to all

unvaccinated travelers aged >9 months, traveling to and from at-risk
areas, unless they belong to the group of individuals for whom YF
vaccination is contraindicated.9
The vaccine is contraindicated in children aged <6 months
and is not recommended for those aged 6–8 months, except during
epidemics when the risk of infection with the YF virus may be very
high.9
International Certificate of Vaccination or Prophylaxis

New yellow fever vaccination requirements for travelers:10,11 Travelers
need to check with the destination country’s embassy or consulate
before departure.
From 11th July 2016, the certificate of vaccination against YF
is valid for the life of the person vaccinated. This lifetime validity
applies automatically to all existing and new certificates, beginning
10 days after the date of vaccination.
Yellow fever is the only disease specified in the IHR for which
countries may require proof of vaccination from travelers as a
condition of entry under certain circumstances. Likewise, countries
may take certain measures if an arriving traveler is not in possession

of such a certificate.
The current advice by the WHO for international travelers going
to areas deemed to be at risk is the following:
■ Vaccination against YF at least 10 days prior to the travel.
Travelers with contraindications for YF vaccine (children below
9 months, pregnant or breastfeeding women, people with severe
hypersensitivity to egg antigens, and severe immunodeficiency)
or over 60 years of age should consult their health professional
for advice.
■ Adoption of measures to avoid mosquito bites.
■ Awareness of symptoms and signs of YF.
■ Seeking care in case of symptoms and signs of YF, while traveling
and upon return from areas at risk for YF transmission.
For 2017, updates on country requirements for the International
Certificate of Vaccination or Prophylaxis (ICVP), with proof of
vaccination against YF, and the WHO vaccination recommendations
for international travelers, are available on the WHO International
Travel and Health website: Annexure 1 and country list. More
specific information about requirements for the ICVP, with proof
of vaccination against YF, implemented by member states related
to the current situation in Brazil in the Region of the Americas
is available on the Pan American Health Organization (PAHO)
YF website.
India
Any traveler (except infants <9 months old) arriving by air or sea
without a certificate is detained in isolation for up to 6 days if that
person:
■ Arrives within 6 days of departure from an area with risk of YFV
transmission.
■ Has been in such an area in transit (except those passengers and
members of flight crews who, while in transit through an airport
in an area with risk of YFV transmission, remained in the airport
during their entire stay and the health officer agrees to such an
exemption).
■ Arrives on a ship that started from or touched at any port in an

area with risk of YFV transmission up to 30 days before its arrival
in India, unless such a ship has been disinfected in accordance
with the procedure recommended by WHO.
■ Arrives on an aircraft that has been in an area with risk of YFV
transmission and has not been disinfected in accordance with
the Indian Aircraft Public Health Rules, 1954, or as recommended
by the WHO (Box 1).
BOX 1: Yellow fever (YF) vaccine.

• Not for routine vaccination in India.
• Only needed for those individuals traveling to sub-Saharan Africa and few
tropical South American countries.
• A single dose of YF vaccine is sufficient to confer sustained life
long protective immunity against YF disease; a booster dose is not
necessary.
• It is recommended that YF vaccine be given to children at age 9–12 months
at the same time as the measles vaccine.
• The vaccine is contraindicated in children aged <6 months and is not
recommended for those aged 6–8 months, except during epidemics when
the risk of infection with the YF virus is very high. Other contraindications
for YF vaccination are severe hypersensitivity to egg antigens and severe
immunodeficiency.
• Preventive mass vaccination campaigns are recommended for inhabitants
of areas at risk of YF where there is low vaccination coverage.
• Vaccination should be provided to everyone aged ≥9 months, in any
area with reported cases. Noting that YF is a live vaccine, a risk-benefit
assessment should be undertaken for all pregnant and lactating
women.
• Vaccine should be offered to all unvaccinated travelers aged ≥9 months,
traveling to and from at-risk areas, unless they belong to the group of
individuals for whom YF vaccination is contraindicated.
• Yellow fever vaccine may be administered simultaneously with other
vaccines.
• Live-attenuated, single-dose vaccine sufficient to confer sustained
lifelong protection.
• Dose: 0.5 mL subcutaneously or intramuscularly in lateral aspect of the
upper arm or the anterolateral thigh.
• Minimum age: 9 months.
The following countries and areas are regarded as having risk of

YFV transmission:
■ Africa: Angola, Bénin, Burkina Faso, Burundi, Cameroon, Central
African Republic, Chad, Congo, Côte d’Ivoire, Democratic
Republic of the Congo, Equatorial Guinea, Ethiopia, Gabon, The
Gambia, Ghana, Guinea, Guinea-Bissau, Kenya, Liberia, Mali,
Niger, Nigeria, Rwanda, Senegal, Sierra Leone, Sudan, Togo, and
Uganda.
■ Americas: Bolivia, Brazil, Colombia, Ecuador, French Guiana,
Guyana, Panama, Peru, Suriname, Trinidad and Tobago, and
Venezuela.
REFERENCES
1. Khromava AY, Eidex RB, Weld LH, Kohl KS, Bradshaw RD,
Chen RT, et al. Yellow fever vaccine: an updated assessment of
advanced age as a risk factor for serious adverse events. Vaccine.
2005;23:3256-63.
2. Centers for Disease Control and Prevention. Health information for
international travel 2003–2004. Atlanta: US Department of Health and
Human Services, Public Health Service; 2003.
3. Barnett ED, Wilder-Smith A, Wilson ME. Yellow fever vaccines and
international travelers. Expert Rev Vaccines. 2008;7:579-87.
4. Staples JE, Gershman M, Fischer M; Centers for Disease Control and
Prevention (CDC). Yellow fever vaccine: recommendations of the
Recomm Rep. 2010;59:1-27.
5. Centers for Disease Control and Prevention (CDC). (2014). Infectious
disease related to travel. [online] Available from: http://wwwnc.cdc.
gov/travel/yellowbook/2014/chapter-3-infectious-diseases-related-
totravel/yellow-fever [Last accessed November, 2022].
6. Kay A, Chen LH, Sisti M, Monath TP. Yellow fever vaccine seroconver-
sion in travelers. Am J Trop Med Hyg. 2011;85:748-9.
7. Thomas RE, Lorenzetti DL, Spragins W, Jackson D, Williamson T.
Reporting rates of yellow fever vaccine 17D or 17DD-associated
serious adverse events in pharmacovigilance data bases: systematic
review. Curr Drug Saf. 2011;6:145-54.
8. Silva ML, Espírito-Santo LR, Martins MA, Silveira-Lemos D, Peruhype-
Magalhães V, Caminha RC, et al. Clinical and immunological insights
on severe, adverse neurotropic and viscerotropic disease following
17D yellow fever vaccination. Clin Vaccine Immunol. 2010;17:

118-26.
9. Vaccines and vaccination against yellow fever. WHO position paper—
June 2013. Wkly Epidemiol Rec. 2013;88:269-83.
10. World Health Organization (WHO). (2016). New yellow fever
vaccination requirements for travelers. [online] Available from: https://
www.who.int/ ith/updates/20160727/en/[Last accessed November,
2022].
11. World Health Organization (WHO). (2019). Yellow fever Brazil. [online]
Available from: https://www.who.int/csr/don/11-february-2019-
yellowfever-brazil/en/ [Last accessed November, 2022].
3.19 COVID VACCINES

Srinivas G Kasi, Arun Wadhwa
INTRODUCTION
The first human cases of coronavirus disease 2019 (COVID-19) were
identified in Wuhan, People’s Republic of China, in December 2019.
The World Health Organization (WHO) declared the COVID-19
outbreak a Public Health Emergency of International Concern on
January 30, 2020, and a pandemic on March 11, 2020.
COVID-19 IN CHILDREN
Although the brunt of the disease has been born by the elderly,
immunocompromised, and the adult population, children of all
ages are as susceptible to COVID-19 as adults. Surveillance data
from various countries reveal that children account for up to 25%
of laboratory-confirmed cases.1 The National Center for Disease
Control data of February 26, 2021 revealed that 3.9% of cases occurred
in the 0–10 year age group and 7.99% in the 11–20 years age group.2
While ~70% of severe acute respiratory syndrome–coronavirus
2 (SARS-CoV-2) infections in children are asymptomatic, critical
illness and hospitalizations are extremely rare, except in the
children with risk factors. Children account for ~1.5% of all COVID
hospitalizations. The morbidity and mortality of COVID-19 in
children are much lower than that seen in adults and the elderly.3 In
the initial phase of the pandemic, a systematic review of fatality and
intensive care unit (ICU) admission in children worldwide revealed
that 91.5% of deaths were reported from low- and middle-income
countries (LMIC).4,5 The pediatric deaths/1,000,000 children, the
case fatality rate (CFR), and the ICU admission/1,000,000 children
were significantly higher in LMIC than in high-income countries
(HIC). The highest deaths/1,000,000 children and CFR were in
infants <1 years old, with the highest figures from LICs and LMICs.
Severity of disease may be related to the variant.6 In observational
studies in children and adolescents, the rates of admission to the ICU
and mechanical ventilation were lower with the Omicron than the
Delta variant. Deaths in children and adolescents, due to COVID-19,

are rare. Children and adolescents accounted for 0.4% of all COVID-
related deaths.1
Risk factors for severe disease and death include genetic
conditions, neurologic and metabolic conditions, congenital heart
disease and cardiovascular disease, obesity [body mass index (BMI)]
>95th percentile for age and sex, diabetes mellitus, asthma or other
chronic pulmonary diseases, sickle cell disease, immunosuppressed
state, age <1 year, Down syndrome and prematurity (gestational age
<37 weeks).
MULTISYSTEM INFLAMMATORY SYNDROME

IN CHILDREN
A clinical presentation in children similar to incomplete Kawasaki
disease (KD) or toxic shock syndrome was first reported from South
England, in April 2020. Subsequently, similar cases were reported
from all over the world. Although rare, the incidence, in New York,
has been reported as 2 per 100,000, when the incidence of laboratory
confirmed COVID-19 was 322/100,000. Generally, it occurs in <1% of
children with confirmed SARS-CoV-2 infection.7 Several case reports
and case series have appeared from India. Multisystem inflammatory
syndrome in children (MIS-C) may need hospitalization and ICU
care in addition to expensive medications.
LONG COVID IN CHILDREN

Post-COVID syndrome (or long COVID) by consensus is defined
as signs and symptoms that develop during or after an infection
consistent with COVID-19 which continue for more than 12 weeks
and are not explained by alternative diagnosis. Evidence for long
COVID evidence in children is limited and heterogeneous. The
psychosocial consequences of lockdown are difficult to distinguish
from long COVID symptoms. It can include a wide range of ongoing
health problems; these conditions can last weeks, months, or
years. Symptoms include involvement of the cardiovascular,
gastrointestinal, respiratory, and nervous systems. A systematic
review reported a prevalence varying from 1.6 to 70%. The most
frequently reported symptoms were fatigue (2–87%), headache

(3.5–80%), musculoskeletal issues (5.4–66%), chest tightness or pain
(1.4–51%), and dyspnea (2–57.1%). Five studies reported limitations
in daily function due to long COVID.8
INDIRECT EFFECTS OF COVID-19 PANDEMIC

Children are not the face of this pandemic. But, they are the biggest
victims of this pandemic. Children’s lives have changed in profound
ways. Children, of all ages, and in all countries, have been affected
by the socioeconomic impacts and the mitigation measures, such
as nationwide lockdown, school closures, online lectures, and
quarantines, have resulted in significant adverse psychological
effects on children, and adolescents and a loss of learning
and developmental opportunities. Suspension of nutritional and
immunization activities has aggravated nutritional deficiencies
and increased susceptibility to disease outbreaks.9,10
CHILDREN AND COVID-19 TRANSMISSION

Studies done in the initial stages of the pandemic suggested that
children do not participate significantly in the chain of transmission.
Uncertainty exists in role of children in various age groups, in the
transmission of COVID-19. Variable factors include socioeconomic,
environmental factors and the adoption of risk mitigation strategies
by the community. However, older children and adolescents transmit
SARS-CoV-2 effectively in household and community settings.9
COVID VACCINES AVAILABLE FOR PEDIATRIC

POPULATION IN INDIA
Four vaccines have received emergency use authorization (EUA) for
the pediatric population in India. These are:
1. CovaxinTM
2. CorbevaxTM
3. CovovaxTM
4. ZyCoV-DTM
CovaxinTM
This is a whole virion inactivated vaccine from the NIV-2020-770
strain developed by Bharat Biotech India and the Indian Council
of Medical Research. The live virus has been inactivated by the use
of beta-propiolactone. The vaccine is adjuvanted with alum and
imidazoquinolinone, which is a toll-like receptor (TLR) 7/8 agonist.
The vaccine received the EUA in India on January 3, 2021.11
Each 0.5-mL dose of the vaccine contains:
■ Whole virion inactivated antigen: 6 µg
■ Aluminum hydroxide equivalent to aluminum: 0.25 mg
■ TLR 7/8 agonist: 15 µg
■ 2-phenoxyethanol: 2.5 mg.
The vaccine is to be stored at +2°C to +8°C. It should not be
frozen. If frozen, the vaccine should be discarded. The vaccine is to
be protected from light.
The multidose vials are eligible for the WHO Multi-Dose Vaccine
Policy.
The vaccine is administered in a two-dose schedule on 0–28 days.
Known hypersensitivity to vaccine constituents is a
contraindication.
In the phase 3 study, the vaccine demonstrated an efficacy of
77.8% [95% confidence interval (CI) 65.2–86.4] against symptomatic
COVID-19, 93.4% (57.1–99.8) against severe symptomatic COVID-19,
79.4% (66.0–88.2) against symptomatic COVID-19 in participants
aged 18–59 years and 67.8% (8.0–90.0) against symptomatic
COVID-19 in participants aged >65 years. The vaccine demonstrated
an efficacy of 65.2% (33.1–80.0) against the Delta variant.12
The vaccine demonstrated a good reactogenicity profile with
similar proportions of participants reporting solicited, unsolicited,
and serious adverse events (AEs) and AEs of special interest in the
vaccine and placebo groups. Local injection pain was reported
in >1% of participants after the first or second dose of vaccine
or placebo. The most frequent solicited systemic AE overall was
headache, followed by pyrexia (fever), fatigue, and myalgia, but in
<1% of participants in either group.11
Covaxin Study in Children

A total of 526 children were enrolled into three groups: Group 1
(12–18 years, n = 176), Group 2 (6–12 years, n = 175), Group 3
(2–6 years, n = 175). Two 0.5-mL doses of BBV152 (Covaxin), which
is the same formulation indicated in adults, were administered at an
interval of 28 days.13
Mild injection site pain was reported by <35% after the first dose,
and <25% after the second dose; there were no cases of severe pain.
The most frequent systemic AE, after dose 1, was mild-to-moderate
fever in 5–13% of participants. No case of severe fever was reported,
and rates were all 4% or less after dose 2. This vaccine was well
tolerated with no statistical difference in the incidence of adverse
effects between groups.
Neutralizing antibody (Nab) responses, measured as MNT
antibody titers, were similar in all three age groups. On day 56, the
SCR (% age) was 100% for group 3 versus 89.8 (84.0–94.1) for Group
2 and 90.3 (84.9–94.2) for Group 3. Geometric mean titer (GMT)
ratio comparing all children to adults was 0.98 (95% CI: 0.80–1.19).
The GMTs by Plaque Reduction Neutralization Test (PRNT50) were
higher in children as against adults with a ratio of 1.76 (1.32–2.33).
Binding IgG antibody responses against S-protein, receptor-
binding domain (RBD), and N-protein were comparable in all the
three age groups. Lower GMTs at day 56 were observed for N-protein
in Group 3. The immunoglobulin G1 (IgG1)/IgG4 ratio at day 56 was
substantially above 1 for all vaccinated groups, indicative of a Th1 bias.
Th1:Th2 index as GMT ratios of IgG1:IgG4, on day 56, were 79.6
(304–1,164) for Group 1, 49.4 (21.8–112) for Group 2, and 38.1 (7.67–
188) for Group 3. These ratios indicate a Th1 bias.13
CorbevaxTM
Corbevax is a protein subunit vaccine containing RBD of S-protein
produced through recombinant technology utilizing the Pichia
Pastoris expression system. This vaccine contains the protein
antigen adjuvanted to CpG1018 and aluminum hydroxide. CpG1018
is a short (22-mer) oligonucleotide sequence containing CpG
motifs which are active in both rodents and primates, to induce
both cell-mediated and antibody-mediated immunity. CpG 1018,

a potent TLR9 agonist, stimulates antibody production, stimulates
helper (CD4+) and cytotoxic (CD8+) T cell populations and generates
robust T- and B-cell memory responses. Additionally, CpG 1018
strongly favors development of the Th1 subset of helper T cells. CpG
is in use in HeplisavTM which is a hepatitis B vaccine.14
Each dose of 0.5 mL contains:
■ RBD antigen: 25 µg
■ Aluminum hydroxide: 750 µg
■ CpG 1018: 750 µg
■ Buffer: qs to 0.5 mL
■ The schedule is two doses administered 28 days apart through
intramuscular (IM) route
■ It is stored between 2 and 8°C
■ The vaccine does not contain any preservatives or stabilizers.
Contraindications: Hypersensitivity to any of the components
of the vaccine, pregnant and lactating women, during fever and
severe infection, children <12 years of age, previous receipt of
another COVID-19 vaccine, bleeding disorder or on blood thinner,
immunocompromised persons or on a immunosuppressive
medications.
In the phase 3 clinical study, all the adverse effects noted
were mild to moderate in intensity and no severe adverse effects
were reported.
Phase 1 and 2 trial assessed the immune response and safety
of four different antigens and adjuvants strengthens to select the
optimum dose for the phase 3 trial. At 12 months of follow-up, phase
1 and 2 trial subjects demonstrated good retention of Nabs.15
The phase 2/3 clinical trial (BECT069) was done in a cohort
of 1,268 subjects, from 18 to 80 years of age. The immunogenicity
cohort consisted of 100 individuals in subjects 18–55 years of age in
the phase 2 trial and a subset of individuals >45 years of age in the
phase 3 trial.16
The safety profile in both pediatric cohorts was comparable to
the placebo-control group. Majority of reported AEs were mild in
nature and all reported AEs resolved without any sequelae.
TABLE 1: CORBEVAX: Summary of anti-RBD IgG and neutralizing antibody

(nAb) titers against Wuhan from phase II/III study.
Neutralizing antibody (nAb)
Anti-RBD IgG titers against Wuhan
Time % %
point Parameter CORBEVAX® SCR Parameter CORBEVAX® SCR
Phase II:
Baseline N 98 N 98
GMC 945, 95% GMT 67, 95%
(EU/mL) CI: 788–1134 CI: 52–58
Day 42 N 98 N 98
GMC 26,448, 95% 95 GMT 1,338, 95%
(EU/mL) CI: 19,858– CI: 917–1,954
35,223
Phase III:
Baseline N 65 N 65
GMC 4,287, 95% GMT 470, 95%
(EU/mL) CI: 3,137– CI: 330–670
5,857
Day 42 N 65 N 65
GMC 61,138, 95% 89 GMT 5,166, 95% 86%
(EU/mL) CI: 47,485– CI: 3,830–
78,715 6,967
(CI: confidence interval; GMT: geometric mean titer; N: number of subjects; SCR:
seroconversion rate)
Immune response in terms of increase in anti-RBD IgG

concentrations and neutralizing antibody titers post-vaccination,
was observed in both younger population (18–45 years) and elderly
population (45–80 years). Table 1 significant nAb titers were
observed against Wuhan, Delta and Beta strains.
In the superiority phase 3 trial, wherein, Corbevax was compared
to Covishield, Corbevax demonstrated superior immune response
and safety with respect to the anti-RBD, i.e., G antibodies, Nabs
against Wuhan strain and Delta strain.
TABLE 2: CORBEVAX: Comparison of IgG responses in pediatric age group

versus adults (from other study).
Age group Day 0 GMC; Day 42 GMC;
(in years) EU/mL EU/mL GMFR %SCR post-vaccine
12–18 939 18,049 19 91%
5–12 969 26,802 28 96%
18–55 945 26,448 28 94%
(GMC; geometric mean concentration; EU/mL: ELISA units/mL; GMFR: geometric
mean fold rise: SCR: seroconversion rate)
The phase 2/3 clinical study (BECT072) was conducted in 624

subjects in 2 age cohorts 5–12 years and 12–18 years.17
The safety profile was similar to that seen with the adult cohort.
The responses in the two pediatric age groups were noninferior
to that seen in the adult cohort (Table 2).
Corbevax has been granted EUA initially in December 2021 for
adults, for 12–18 years in February 2022 and for 5–12 years in April
2022.
Covovax
NVX-CoV2373, the COVID-19 vaccine by Novavax, will be
manufactured and marketed in Europe as NuvaxovidTM (approved by
EMA) and in India as CovovaxTM, manufactured by Serum Institute
of India (approved by the Drugs Controller General of India). This is
a “recombinant nanoparticle vaccine”.
The gene for the SARS-CoV-2 spike protein, which is modified
by incorporating two proline amino acids in order to stabilize the
prefusion form of the protein, is engineered into a baculovirus,
which infects a culture of Sf9 moth cells, which then create the
spike protein and display it on their cell membranes. The spike
proteins are harvested and assembled onto a synthetic lipid
nanoparticle about 50 nanometers across, each displaying up to
14 spike proteins. The adjuvant used is Matrix-M1 (Fraction-A42.5
micrograms and Fraction-C7.5 micrograms of Quillaja Saponaria
Molina extract).
Each 0.5 mL dose consists of:

■ 5 micrograms of SARS-CoV-2 spike protein
■ Adjuvant matrix-M1: Fraction-A (42.5 micrograms) and
Fraction-C (7.5 micrograms) of Quillaja Saponaria Molina
extract.18
■ Schedule: Two doses of 0.5 mL administered IM on days 0–21
■ To be stored in a refrigerator (+2°C to +8°C). Should not be frozen
■ Contraindications: Hypersensitivity to the active substance or to
any of the excipients.
All opened (punctured) multidose vials of Covovax should be
discarded at the end of immunization session or 6 hours after the
first needle puncture, whichever comes first.18
In the phase 3 trial, adults between the ages of 18 and 84 years,
in UK, were administered two doses of 5-μg doses of NVX-CoV2373
or placebo at an interval of 21 days. The primary efficacy endpoint
was virologically confirmed mild, moderate, or severe SARS-CoV-2
infection with an onset at least 7 days after the second injection in
participants who were serologically negative at baseline. The vaccine
efficacy (VE) was 89.7% (95% CI: 80.2–94.6) against a symptom onset
of at least 7 days after the second injection, VE against hospitalization
and death was 100%. VE of 86.3% (95% CI: 71.3–93.5) was observed
against the B.1.1.7 (or alpha) variant and 96.4% (95% CI: 73.8–99.5)
against non-B.1.1.7 variants. There was no significant differences
in VE according to age group or the presence of coexisting medical
illnesses.19
In the phase 3 trial in USA and Mexico, VE against reverse
transcription-polymerase chain reaction (RT-PCR) confirmed
COVID-19 occurring at least 7 days after the second dose was 90.4%
(95% CI: 82.9–94.6). VE against moderate-to-severe disease was
100% (95% CI: 87.0–100). There were no significant differences in the
VE as regard to age, sex, presence or absence of co-existing illnesses
or those who were at high risk for complications of COVID-19. VE
against the alpha variant was 93.6% (95% CI: 81.7–97.8), and against
any variant of concern or interest was 92.6% (95% CI: 83.6–96.7).
The most common solicited systemic AEs were headache,
myalgia, fatigue, and malaise, which were slightly more frequent
among NVX-CoV2373 recipients than among placebo recipients.20
The Technical Advisory Group for Emergency Use Listing (of

WHO) listed Nuvaxovid (NVX-CoV2373) vaccine against COVID-
19 and Covovax (NVX-CoV2373) vaccine against COVID-19 for
emergency use on December 20, 2021 and December 17, 2021,
respectively.
The pediatric expansion of phase 3 study in USA of NVX-CoV2373
was conducted in 2,247 adolescent participants 12 to <18 years of
age who received two IM injections of Nuvaxovid or placebo (normal
saline) 21 days apart. The observed VE of Nuvaxovid against PCR-
confirmed, symptomatic mild, moderate, or severe COVID-19 in the
per-protocol efficacy population was 79.54% (95% CI: 46.83–92.13).
VE against the delta variant was 82.0% (95% CI: 32.4–95.2). IgG
responses against spike proteins of several variants (including alpha,
beta, delta, gamma, Mu, and Omicron) were twofold to threefold
higher than in adults, with 100% seroconversion against all variants
following a two-dose series of vaccinations. Nab responses in
adolescents functional against these variants were 2.4–4-fold higher
than in adults against all evaluated variants.21
The pediatric trial of Covovax was conducted in Indian children,
2–17 years of age, to evaluate the safety and immunogenicity of
Covovax. 460 children received at least one dose of the study vaccine.
None of the participants had any comorbid condition.
The anti-S IgG antibody titers measured as the geometric mean
Eliza units (GMEUs) were comparable between the groups at
baseline—day 1. They increased substantially after each dose of the
vaccine in the Covovax group with no response seen in the placebo
group.
More than 98% seroconversion was seen in the Covovax group
on day 36 (14 days after the second dose). The immunogenicity data
indicates that Covovax is highly immunogenic in the children of
12–17 years of age18 (Table 3).
Seroconversion was 95.5% (92.7, 97.4) 28 (21+7) days after dose
1 and 98.8% (96.9, 99.7) 21 (14+7) days after dose 2. No significant
seroconversion was seen in the placebo group.21
In December 2021, the Drugs Controller General of India (DCGI)
granted EUA for Covovax in those >18 years and in March 2022 for
the 12–17 years age group.
TABLE 3: Immunogenicity of Covovax: anti-S IgG.

Timepoint Statistic Covovax N = 333 Placebo N = 108
Baseline N 333 108
GMEU 1664.2 1366.6
95% CI 413.7, 1959.1 1033.1, 1807.8
28 (21+7) days N 332 108
after dose 1
GMEU 72660.4 1614.6
95% CI (63586.3, 83029.4) (1174.7, 2219.3)
21 (14+7) days N 330 107
after dose 1
GMEU 170193.6 1480.4
95% CI (157429.7, 183992.4) (1110.1, 1974.3)
(CI: confidence interval; N: number of subjects; GMEU: geometric mean ELISA
units)
ZyCoV-D
This is a DNA-based vaccine for prevention of COVID-19. It comprises
a DNA plasmid vector carrying full-length spike (S) gene region
expressing SARS-CoV-2 spike (S) protein along with gene coding for
signal peptide. The spike gene region was selected from submitted
Wuhan Hu-1 isolate sequence. The S protein of the virus includes
the RBD, responsible for binding to the human angiotensin-
converting enzyme-2 (ACE-2) receptor, which mediates the entry of
virus inside the cell. The DNA plasmid construct was transformed
into Escherichia coli cells for large-scale production.
Each 0.1 mL contains:

■ DNA plasmid construct with spike protein gene region from SARS-
CoV-2 virus produced in E. coli: 1.0 mg
■ Phosphate-buffered saline: qs
■ Mode of administration: This vaccine has to be injected
intradermally using the needle-free injector (Pharmajet Tropis
device) only. It should preferably be administered in the deltoid

region of both the arms
■ Schedule: 0.1 mL ID, two doses on days 0–28–56
■ Contraindications: In individuals known to have hypersensitivity
to the active substance or to any of the excipients.
Administration should be postponed in individuals suffering
from an acute severe febrile illness.22
Interchangeability
There is no data on the use of ZyCoV-D in persons who have
previously received partial/complete vaccine series with another
COVID-19 vaccine.
The phase 3 study was done on 27,703 participants aged
>12 years, of whom 3.23% were 12–17 years, 89.26% in the 18–60 years
age group, and 7.5% in >60 years age group. The VE of ZyCoV-D was
found to be 66.6% (95% CI: 47.6–80.7) against the first occurrence
of symptomatic RT-PCR-positive COVID-19, 28 days after the third
dose. The efficacy against mild cases was 64.9% (95% CI: 44.9–79.8).
The efficacy against moderate and severe cases was 100%, after
2 doses.23
The occurrence of solicited AEs was similar between the
treatment groups [623 (4.49%) in the ZyCoV-D group vs. 620 (4.47%)
in the placebo group].
The seroconversion rates, the IgG, geometric mean concentra
tions (GMCs), and geometric mean fold rise (GMFR) at day 84 were
higher in the ZyCoV-D group compared with the placebo group
(Table 4). The immunogenicity response at day 84 in the group
aged 12–17 years was higher than the overall participant population
(Table 5).
The proportion of participants who achieved seroconversion of
Nabs at day 84, the Nabs GMTs, and GMFR was significantly higher
in the ZyCoV-D group than the placebo group (Table 6).23
Robust cellular response (IFN-γ) to ZyCoV-D was seen.23
In August 2021, ZyCoV-D was granted EUA, in a three-dose
schedule for subjects >12 years of age.
TABLE 4: ZyCoV D: Immunogenicity antibody titers.

ZyCoV D Placebo
Day 0 GMT (95% CI) 7 (7.00–7.00) 7 (7.00–7.00)
Day 56 GMT (95% CI) 407.58 (266.73–622.83) 57.97 (36.10–93.07)
GMFR (95% CI) 58.23 (38.10–88.98) 8.28 (5.16–13.30)
Day 84 GMT (95% CI) 952.67 (707.94–1282.00) 154.82 (91.25–262.70)
GMFR (95% CI) 136.10 (101.13–183.14) 22.12 (13.04–37.53)
(GMT: geometric mean titer; GMFR: geometric mean fold rise)
TABLE 5: Immunogenicity response in 12–17 years vs overall cohort.

Adolescents 12–17 years Overall
SCR % 100 93.3
GMT 2083 952.67
GMFR 297.65 136.1
TABLE 6: Neutralizing antibody response on day 84.

ZyCoV D Placebo
SCR% 88 42.55
GMT (95% CI) 133.39 PRNT50, 30.40 PRNT50,
(86.88–204.81) (16.35–56.53)
GMFR (95% CI) 26.68, (17.38–40.96) 5.74, (3.14–10.48)
In April 2022, ZyCoV-D received EUA from the DCGI as a two-

dose vaccine, be administered on day 0 and day 28.22,24
BNT162b2 (Pfizer) Vaccine

In a phase 3 trial involving 2,260 adolescents 12–15 years of age,
BNT162b2 was found to have a favorable safety and side effect profile.
The GMT geometric ratios of Nabs after dose 2, in 12–15-year-old
participants relative to 16–25-year-old participants were 1.76 (95%
CI: 1.47–2.10), which satisfied the noninferiority criterion, indicating
a greater response in the 12–15-year-old cohort. The observed VE

was 100% (95% CI: 75.3–100).25
The EUA was granted by the US Food and Drug Administration
(FDA), on May 10, 2020, for use in children 12–15 years of age and is
now being used in this age group in many countries.
In the 5–11 years cohort, with a dose of 10 µg, the Nab GMT
was 1,197.6 (95% CI: 1,106.1–1,296.6), as compared to [1,146.5
(95% CI: 1,045.5–1,257.2)] the 16–25 years cohort.26 This proved
noninferiority. On October 29, 2021, EUA was granted by the US FDA
for use in children 5–11 years.
mRNA-1273 (Moderna) Vaccine

Following two doses of 100 μg/dose of Moderna vaccines, at
0–28 days, in adolescents aged 12–17 years, the GMTs of Nabs were
1,401.7 (1,276.3–1,539.4) compared to levels of 1,301.3 (1,177.0–
1,438.8) in young adults, thus proving noninferiority. The VE against
COVID-19, 14 days after second dose, was 100% (28.9 to NE—not
estimated). On September 4, 2021, this vaccine was granted EUA
by the US FDA for adolescent 12–17 years and subsequently from
>6 months of age.27,28
Bivalent Vaccines
The US FDA has granted EUA for the bivalent mRNA COVID-19
vaccines. The BNT162b2 (Pfizer) vaccine contains 30 µg of mRNA
(15 µg original strain, 15 µg Omicron BA.4/BA.5).
The Moderna mRNA bivalent vaccine contains 50 µg of mRNA
(25 µg original strain and 25 µg Omicron BA.4/BA.5).
Both formulations are recommended only for the booster dose
and not for the primary series (Table 7).29
POSTIMMUNIZATION MYOCARDITIS
In April 2021, increased cases of myocarditis and pericarditis were
reported in the United States after mRNA COVID-19 vaccination
(Pfizer-BioNTech and Moderna). Myocarditis and/or pericarditis
occurs most frequently in adolescent and young adult males, ages
16 years and older, within 7 days after receiving the second dose
TABLE 7: mRNA vaccines recommendations in the United States.

Vaccine
Age indication composition Dose: Primary Dose: Booster
Pfizer:
6 m–4 y Monovalent 3 mcg NA
5–11 y Monovalent 10 mcg 10 mcg
>12 y Monovalent 30 mcg NA
>12 y Bivalent NA 30 mcg
Moderna:
6 m–5 y Monovalent 25 mcg NA
6–11 y Monovalent 50 mcg NA
12–17 y Monovalent 100 mcg NA
>18 y Monovalent 100 mcg NA
>18 y Bivalent NA 50 mcg
of an mRNA COVID-19 vaccine. Postimmunization myocarditis

is relatively straightforward to diagnose and treat, and the clinical
course tends to be mild in most patients. In USA, the reporting rates
of myocarditis were 40.6/100,000 cases after second doses of mRNA
COVID-19 vaccines in males aged 12−29 years and 2.4/100,000
second doses administered to males aged ≥30 years. In females, the
reporting rates were much lower, at 4.2 and 1.0 per million second
doses, respectively, in the same age groups. The highest reporting
rates were among males aged 12–17 years (62.5/100,000) and
those aged 18–24 years (50.5/100,000) after second doses of mRNA
COVID-19 vaccine administered, respectively.30
REFERENCES
1. Unicef. (2022). COVID-19 confirmed cases and deaths. [online]
Available from https://data.unicef.org/resources/covid-19-confirmed-
cases-and-deaths-dashboard/. [Last accessed November, 2022].
2. Ministry of Health and Family, Government of India. (2020). Graphical
illustration of data from COVID-19 cases in India. National Centre for
Disease. [online] Available from https://ncdc.gov.in/dashboard.php.
3. Wu Z, McGoogan JM. Characteristics of and important lessons from

the coronavirus disease 2019 (COVID-19) outbreak in China: summary
of a report of 72/314 cases from the Chinese center for disease control
and prevention. JAMA. 2020;323:1239-42.
4. Swann OV, Holden KA, Turtle L, Pollock L, Fairfield CJ, Drake TM,
et al. Clinical characteristics of children and young people admitted to
hospital with COVID-19 in United Kingdom: prospective multicentre
observational cohort study. BMJ. 2020;370:m3249.
5. Bhopal SS, Bagaria J, Olabi B, Bhopal R. Children and young people
remain at low risk of COVID-19 mortality. Lancet Child Adolesc Health.
2021;5(5):e12-3.
6. Kitano T, Kitano M, Krueger C, Jamal H, Al Rawahi H, Lee-Kruege R,
et al. The differential impact of pediatric COVID-19 between high-
income countries and low- and middle-income countries: A systematic
review of fatality and ICU admission in children worldwide. PLoS One.
2021;16(1):e0246326.
7. Ahmeda M, Advanib S, Moreiraa A, Zoreticd S, Martinezd J, Chorathe K,
et al. Multisystem inflammatory syndrome in children: A systematic
review. EClinical Medicine. 2020;26:100527.
8. Pellegrino R, Chiappini E, Licari A, Galli L, Marseglia GL. Prevalence
and clinical presentation of long COVID in children: a systematic
review. Eur J Pediatr. 2022;181:3995-4009.
9. Howard-Jones AR, Bowen AC, Danchin M, Koirala A, Sharma K,
Yeoh DK, et al. COVID-19 in children: I. Epidemiology, prevention and
indirect impacts. J Paediatr Child Health. 2022;58:39-45.
10. Chanchlani N, Buchanan F, Gill PJ. Addressing the indirect effects
of COVID-19 on the health of children and young people. CMAJ.
2020;192:E921-7.
11. Bharat Biotech. Summary of product characteristics (SmPC). [online]
Available from https://www.bharatbiotech.com/images/covaxin/
covaxin-smpc.pdf. [Last accessed November, 2022].
12. Ella R, Reddy S, Blackwelder W, Potdar V, Yadav P, Sarangi V, et al.
Efficacy, safety, and lot-to-lot immunogenicity of an inactivated SARS-
CoV-2 vaccine (BBV152): interim results of a randomised, double-
blind, controlled, phase 3 trial. Lancet. 2021;398:2173-84.
13. Vadrevu KM, Reddy S, Jogdand H, Ganneru B, Mirza N, Tripathy VN,
et al. Immunogenicity and reactogenicity of an inactivated SARS-
CoV-2 vaccine (BBV152) in children aged 2–18 years: interim data from
an open-label, non-randomised, age de-escalation phase 2/3 study.
Lancet Infect Dis. 2022;22:1303-12.
14. Biological E. Limited. Summary of Product Characteristics (SmPC):
SARS-CoV-2 (COVID-19) Vaccine [CORBEVAX]. [online] Available
from https://www.biologicale.com/pdf/SmPC_CORBEVAX.pdf. [Last

15. Thuluva S, Paradkar V, Gunneri SR, Yerroju V, Mogulla R, Turaga K,
et al. Evaluation of safety and immunogenicity of receptor-binding
domain-based COVID-19 vaccine (Corbevax) to select the optimum
formulation in open-label, multicentre, and randomised phase-1/2
and phase-2 clinical trials. eBioMedicine. 2022;83:104217.
16. Thuluva S, Paradkar V, Turaga K, Gunneri SR, Yerroju V, Mogulla R,
et al. Immunogenic superiority and safety of Biological E’s CORBEVAXTM
vaccine compared to COVISHIELDTM (ChAdOx1 nCoV-19) vaccine
studied in a phase III, single blind, multicenter, randomized clinical
trial. medRxiv. 2022.03.20.22271891.
17. Thuluva S, Paradkar V, Gunneri SR, Yerroju V, Mogulla R, Suneetha PV,
et al. Safety, tolerability and immunogenicity of Biological E’s
CORBEVAXTM vaccine in children and adolescents: A Prospective,
Randomised, Double-blind, Placebo controlled, Phase2/3 Study.
Vaccine. 2022;40(49):7130-40.
18. Serum Institute of India Pvt. Ltd. SUMMARY OF PRODUCT
CHARACTERISTICS/ PACKAGE INSERT: SARS-CoV-2 rS Protein
(COVID-19) recombinant spike protein Nanoparticle Vaccine. [online]
Available from https://www.seruminstitute.com/pdf/COVOVAX_
SmPC.pdf. [Last accessed November, 2022].
19. Heath PT, Galiza EP, Baxter DN, Boffito M, Browne D, Burns F, et al.
Safety and Efficacy of NVX-CoV2373 COVID-19 Vaccine (UK). N Engl J
Med. 2021;385:1172-83.
20. Dunkle LM, Kotloff KL, Gay CL, Áñez G, Adelglass JM, Hernández
AQB, et al. Efficacy and Safety of NVX-CoV2373 in Adults in the United
States and Mexico. N Engl J Med. 2022;386:531-43.
21. Novavax. Novavax Announces Positive Results of COVID-19 Vaccine
in Pediatric Population of PREVENT-19 Phase 3 Clinical Trial. [online]
Available from https://ir.novavax.com/2022-02-10-Novavax-Announces-
Positive-Results-of-COVID-19-Vaccine-in-Pediatric-Population-of-
PREVENT-19-Phase-3-Clinical-Trial. [Last accessed November, 2022].
22. Central Drugs Standard Control Organisation. ZyCov-D, SmPC.
Approved for restricted use in emergency situation of COVID-19.
[online] Available from https://cdsco.gov.in/opencms/opencms/
system/modules/CDSCO.WEB/elements/download_file_division.
jsp?num_id=ODgyMw==. [Last accessed November, 2022].
23. Khobragade A, Bhate S, Ramaiah V, Deshpande S, Giri K, Phophle H,
et al. Efficacy, safety, and immunogenicity of the DNA SARS-
CoV-2 vaccine (ZyCoV-D): the interim efficacy results of a phase 3,
randomised, double-blind, placebo-controlled study in India. Lancet.

2022;399:1313-21.
24. The Times of India. (2022). ZyCov-D gets EUA from DCGI as two-
dose vax. [online] Available from https://timesofindia.indiatimes.
com/city/ahmedabad/zycov-d-gets-eua-from-dcgi-as-two-dose-vax/
articleshow/91111138.cms. [Last accessed November, 2022].
25. Frenck RW, Klein NP, Kitchin N, Gurtman A, Absalon J, Lockhart S,
et al. Safety, Immunogenicity, and Efficacy of the BNT162b2 COVID-19
Vaccine in Adolescents. N Engl J Med. 2021;385:239-50.
26. Walter EB, Talaat KR, Sabharwal C, Gurtman A, Lockhart S,
Paulsen GC, et al. Evaluation of the BNT162b2 COVID-19 Vaccine in
Children 5 to 11 Years of Age. N Engl J Med. 2022;386:35-46.
27. Creech CB, Anderson E, Berthaud V, Yildirim I, Atz AM, Baez IM, et al.
Evaluation of mRNA-1273 COVID-19 Vaccine in Children 6 to 11 Years
of Age. N Engl J Med. 2022;386:2011-23.
28. Centers for Disease Control and Prevention. Summary Document for
Interim Clinical Considerations. [online] Available from https://www.
cdc.gov/vaccines/covid-19/downloads/summary-interim-clinical-
considerations.pdf. [Last accessed November, 2022].
29. Center for Disease Control and Prevention. Interim Clinical
Considerations for COVID-19 Vaccines: Bivalent Boosters. [online]
https://www.cdc.gov/vaccines/covid-19/clinical-considerations/
covid-19-vaccines-us.html. [Last accessed November, 2022].
30. Center for Disease Control and Prevention. (2021). Use of mRNA
COVID-19 Vaccine After Reports of Myocarditis Among Vaccine
Recipients: Update from the Advisory Committee on Immunization
Practices — United States, June 2021. [online] Available from https://
www.cdc.gov/mmwr/volumes/70/wr/mm7027e2.htm. [Last accessed
November, 2022].
4 Vaccination of
Special Groups
Chapter
4.1 ADOLESCENT VACCINATION

INTRODUCTION
Immune protection induced by vaccines given during infancy
wanes over the years. 1,2 This leads to higher-than-expected
incidence of vaccine-preventable diseases (VPDs) in adolescents
and young adults. Adolescents need vaccinations for the following
reasons:
■ To protect against diseases that have higher morbidity in
adolescence (hepatitis A, varicella)
■ To boost the waning immune responses of certain vaccines
administered during infancy/early childhood (measles,
pertussis, tetanus, diphtheria, etc.)
■ Adolescents also need vaccines to prevent diseases that appear
later in adult life (cervical cancer)
■ As a part of control or elimination projects of some VPDs such
as measles elimination, and rubella and congenital rubella
syndrome (CRS) control program
■ For travel and study abroad
■ As a catch-up who missed the previous opportunities.
The adolescent-specific vaccines are Tdap/Td and human
papillomavirus (HPV) vaccines.
Indian Academy of Pediatrics (IAP)-recommended vaccines for
adolescents are given in Table 1.
422 Vaccination of Special Groups
TABLE 1: Indian Academy of Pediatrics, Advisory Committee on Vaccines

and Immunization Practices-recommended vaccines in adolescents
(11–18 years).
Vaccine Schedule
Tdap/Td* 10 years
†
HPV 9 years
Covid vaccines 12 years onwards
*Tdap preferred to Td, followed by repeat Td every 10 years.
†
Two doses at 0 and 6 months (ages 9–14 years) or 0, 2, and 6 months (15 years
or above).
[HPV: human papillomavirus; Td: tetanus and diphtheria (low dose); Tdap:
tetanus diphtheria (low dose) toxoid and acellular pertussis]
PERTUSSIS VACCINATION
Pertussis vaccination in adolescents is of particular interest, as
it is known that the humoral and cellular immunities evoked by
vaccines tend to wane after some years, and this has been confirmed
by immunological and clinical studies in recent years.3,4 Many
factors determine the speed at which the immunity wanes such as
vaccination schedule and the type of vaccine. Acellular pertussis
vaccines have shown to provide shorter-lasting protection than
whole-cell pertussis (wP) vaccines.5 Waning of protection has led to
increase in incidence of pertussis in older children and adolescents
worldwide. In fact, adolescents have become the main cause of
the spread of pertussis in the community and the persistently high
incidence of disease in infants, who are at the greatest risk of severe
disease because they are not fully vaccinated.6 Pertussis vaccination
in adolescents has many advantages including significant lowering
of new cases among vaccinated subjects. A retrospective analysis
of pertussis cases reported in the United States between 1990 and
2009 showed that the introduction of diphtheria toxoid and acellular
pertussis (Tdap) for adolescents in 2005 was associated with a
considerable decrease in the number of cases involving subjects
aged 11–18 years.7 It is also expected that unvaccinated or partially
vaccinated infants may benefit from herd effect due to reduction
of circulation of pertussis organism. In Australia, where Tdap was
administered to all high school students during the 2008–2009
Vaccination of Special Groups 423
epidemic, there was a decrease in pertussis case reports involving

adolescents and infants aged <6 months.8 Adolescents’ vaccination
is also highly cost-effective: Vaccination of all in 10–19 years age
group in the United States in 2005 may prevent 0.4–1.8 million
cases of pertussis and lead to 10-year savings of US $0.3–1.6 billion.9
A detailed account on pertussis immunization through all ages is
available in a recent publication.10 In India, the incidence of pertussis
in adolescents is unknown. In a recently published article titled
“prospective multinational serosurveillance study of B. pertussis
infection among 10-18 years subjects from 8 Asian countries”, with
200 subjects from India, high titers of anti-PT immunoglobulin
G (IgG) >62.5 IU/mL (indicative of B. pertussis infection within
12 months prior) was found in 18% of subjects.11
In a study done in Vellore on 281 subjects, of whom all had
received three primary vaccines and one booster, 42.7% had received
the second booster and 5.3% had received the adolescent booster
of pertussis containing vaccines, around 7% of adolescents had evi
dence of recent infection and 54% of the adolescents tested had no
detectable antibodies, suggesting waning immunity and suscepti
bility to pertussis, which can lead to periodic epidemics.12
Safety and Immunogenicity in Adolescents and Adults

Studies comparing the adverse effect profile of subjects who received
Tdap followed by another dose of Tdap or Td, after varying intervals,
revealed that the adverse effects profile was similar in both groups.
The seroprotective levels of antibodies to tetanus and diphtheria
were similar in both groups.13-17
Anti-pertussis antibodies decline rapidly after the first year
following a Tdap vaccination and protection begins to wane within
2–4 years after receipt of a single Tdap dose. Moreover, Tdap vaccines
have an uncertain role in prevention of transmission and in herd
protection. Thus, a second dose of Tdap is unlikely to have significant
public health impact.18
There are no published data comparing rates of adverse
events among pregnant women who received multiple doses of
Tdap during a single pregnancy with those who received a single
Tdap dose and additional Td doses for catch-up vaccination.
A cohort study examining reactogenicity of Tdap in pregnant women

included only eight study participants who received more than one
Tdap dose within a 12-month period; none experienced severe
reactions or fever.19 A study on safety of Tdap in 633,542 singleton
pregnancies identified 187 women who had received more than one
Tdap dose during a single pregnancy found similar rates of adverse
birth outcomes (i.e., small for gestational age, preterm delivery, and
low birthweight) in those women receiving multiple Tdap compared
with women who had received a single Tdap dose in pregnancy.20
Conclusion
Advisory Committee on Immunization Practices (ACIP) in 2018
concluded that due to higher cost of Tdap relative to Td and
uncertainty about the impact of multiple Tdap doses on pertussis
control and transmission, evidence appeared to be insufficient
to preferentially recommend Tdap to replace Td.21 There is no
advantage in replacing Td with Tdap for the decennial Td booster,
tetanus prophylaxis for wound management, and for additional
required doses in the catch-up immunization schedule if a person
has received at least one Tdap dose.18
Routine Immunization Recommendations

■ Adolescents: 11–18 years: Single dose of Tdap at age 11–12 years
followed by booster dose of either Td or Tdap every 10 years
throughout life.
■ Adults above 19 years: Adults above 19 years who have never
received Tdap should get one dose of Tdap regardless of the
interval since their last tetanus or diphtheria toxoid containing
vaccine followed by booster doses of either Td or Tdap every
10 years throughout life.
■ Pregnant women: Pregnant women should receive one dose
of Tdap during each pregnancy, irrespective of their history of
receiving the vaccine, at 27–36 weeks’ gestation, preferably during
the earlier part of this period, although it may be administered at
any time during pregnancy.21,22
■ Wound management: A tetanus toxoid containing vaccine is indi-
cated if >5 years have passed since the last tetanus toxoid con-
taining vaccine, in case of contaminated wounds and 10 years in
case of clean wounds. In adolescent of age >11 years who have

not previously received Tdap or whose Tdap history is unknown,
Tdap is preferred. For a pregnant woman if a tetanus toxoid con-
taining vaccine is indicated, Tdap should be used. Nonpregnant
persons with documented previous Tdap if a tetanus toxoid
containing vaccine is indicated, either Td or Tdap may be used.21
Catch-up Immunization Recommendations

■ Children and adolescents: 7–18 years: Children and adolescents
aged 7 years and older, and adults who have never received
tetanus containing vaccines, or whose vaccination history is
unknown, should receive the three-dose series. In this situation,
Tdap for dose one, followed 4 weeks later by Td or Tdap for dose
two, followed at least 6 months later by Td or Tdap for dose three.
Following the primary series, booster doses of Td or Tdap should
be given every 10 years thereafter. The vaccination series does
not need to be restarted for those with incomplete DTaP/DTwP
history, regardless of the time that has elapsed between doses.
■ Children aged 7–9 years: Children aged 7–9 years who receive a
dose of Tdap as part of the catch-up series, an adolescent Tdap
dose should be administered at age 11–12 years. If a Tdap dose
is administered in children 10 years or older, it may count as the
adolescent Tdap dose.
■ DTaP/DTwP is not indicated for children aged older than 7 years.
If DTaP/DTwP is administered inadvertently to an incompletely
vaccinated child aged 7–9 years, this dose should count as the
Tdap dose of the catch-up series, and the child should receive
an adolescent Tdap dose at age 11–12 years. If DTaP/DTwP is
administered inadvertently to a person aged 10 years or older,
this dose should count as the adolescent Tdap dose routinely
administered at age 11–12 years.
■ Pregnant women: To prevent neonatal tetanus, pregnant women
who have completed the childhood schedule should receive a
dose of Tdap. Incompletely vaccinated or unvaccinated woman
should receive at least two doses, of which one should be Tdap.
If more than one dose is needed, either Td or Tdap may be
used. The three-dose primary series should be completed at the
recommended intervals of 0–1–6 months in unvaccinated.21
HUMAN PAPILLOMAVIRUS VACCINE

Human papillomavirus vaccination (HPV) in adolescents also
deserves special attention as HPV infection is the most common
sexually transmitted infection in humans; HPV is closely associated
with the development of various anogenital and oropharyngeal
cancers, of which cervical cancer is the most frequent; most infections
are acquired early during adolescence, at the time of initial sexual
activities,23 HPV-related diseases are mainly caused by a few types
of oncogenic HPV strains, against which three vaccines have been
developed, the bivalent HPV vaccine (types 16 and 18), the quadrivalent
HPV vaccine (HPV types 6, 11, 16, and 18), and the nonavalent vaccine
(types 6, 11, 16, 18, 31, 33, 45, 52, and 58). Extensive trials have shown
that all the vaccines are safe and efficacious against precancerous
lesions due to types 16 and 18 of HPV in 90–100% of cases.24
Regarding the time of administration, HPV vaccines should
be administered to adolescents before they start to engage in
sexual activity.25 This is due to the fact that HPV vaccines are
inactive against the types of HPV previously acquired by a vaccine
recipient and because antibody responses are the highest between
the ages of 9 and 15 years.
Recommendations
■ 4vHPV: Indicated in females aged 9–45 years
■ 9–14 years: Two doses in a 0–6 months schedule
■ 15 years and above: Three dose 0–2–6 months
■ 9vHPV:
y 9–14 years females and males: Two doses 0–6 months
y 15–26 years females: Three doses 0–2–6 months.
For more details, please refer to chapter on HPV vaccines.
CURRENT STATUS OF ADOLESCENT’S

IMMUNIZATION
In India, routine immunization given to young children is dismally
low. National Family Health Survey 4 (2015–2016) shows that only
62.0% children aged 12–23 months are fully immunized. There is also
tremendous heterogeneity in state- and district-level immunization
coverage in India with immunization coverage ranging from 91.3%

in Puducherry to 35.7% in Nagaland.26 It is thus likely that many
children reach adolescent period with no or partial immunization. A
large number of adolescents thus are at greater risk of VPDs as they
are more exposed to infection due to greater mobility.
Considering that teenage pregnancy rate is very high in the
country, catch-up vaccination program of adolescents, especially
girls, not only will protect them but will also have a direct role
in protecting young infants from diseases such as pertussis. IAP
recommendations for catch-up immunization in adolescents are
given in Table 2. There are also special circumstances for adolescents
and vaccination schedule for these situations which are given in
Table 3. For adolescents going abroad, information on travelers’
vaccination can be obtained in Chapter 4.3 and from the Center for
Disease Control and Prevention website at the following link: http://
wwwnc.cdc.gov/travel/.

and Immunization Practices-recommended vaccines in adolescents for
catch-up.
Vaccine Schedule
MMR* Two doses at 4–8 weeks’ interval
†
Hepatitis B Three doses 0, 1, and 6 months
Hepatitis A Two doses at 0 and 6 months (prior check for anti-HAV IgG
may be cost-effective in children of age >10 years)
Typhoid TCV‡ Single dose
Varicella Two doses at 4–8 weeks of interval
HPV • 9–14 years (boys and girls): Two dose 6 months apart
• 15 years or older (girls and women): 4vHPV: 0–2–6 months
• 9vHPV (females): 15–26 years 0–2–6 months
*One dose if previously vaccinated with one dose.
†
Combination of hepatitis B and hepatitis A may be used in 0, 1, and 6 months
of schedule.
‡
Up to 45 years.
[HAV: hepatitis A vaccine; HPV: human papillomavirus; IgG: immunoglobulin G;
MMR: measles, mumps, and rubella; TCV: typhoid conjugate vaccine; Td: tetanus
and diphtheria (low dose); Tdap: tetanus diphtheria (low dose) toxoid and
acellular pertussis]

and Immunization Practices-recommended vaccines in adolescents in
special circumstances.
Vaccine Schedule
Influenza One dose every year
Japanese encephalitis vaccine Catch-up. Up to 15 years*
PPSV23 (pneumococcal) Maximum two doses 5 years apart†
Rabies vaccine 0, 3, 7, 14, and 28 days
*Only in endemic area as catch-up.
†
Maximum number of doses—two.
(PPSV: pneumococcal polysaccharide vaccine)
WHAT IS NEEDED?
Universally, the uptake of vaccines in adolescents is inadequate.
Reasons for low vaccine uptake among adolescents include:
■ Lack of knowledge about the vaccines necessary for adolescents,
among providers, parents, and adolescents
■ Lack of specific adolescent immunization programs
■ Behavioral attitude of adolescents toward vaccinations
■ Lack of routine “well-adolescent clinics” and thus fewer
encounters with the healthcare system
■ Missed opportunities for vaccination as visits for minor illnesses
are not utilized for promoting vaccinations.
Successful strategies for improving adolescent vaccination rates
involve communication of benefits of vaccination to the general
public, presentation of information in an evidence-based and youth-
friendly way, sensitizing the providers with information regarding
adolescent vaccinations, creating adolescent-specific immunization
programs, having adolescent-friendly immunization clinics, and
utilizing all missed opportunities.
Currently, the United States is the only country to issue
recommendations for adolescent immunization, which is regularly
prepared and annually updated since 2005. These recommendations
(Table 4) highlight the importance of catch-up strategies for
adolescents who did not regularly complete their childhood
immunizations as well as the need of vaccination in adolescents of
high-risk groups because of underlying chronic disease.27

and Immunization Practices-recommended vaccines in adolescents with
range.
Age
Vaccine 7–10 years 11–12 years 13–18 years
Tdap One dose (if One dose One dose (if
indicated) indicated)
HPV-1 Two doses Two doses Two doses 0–6
(see Footnote 1) 0–6 months 0–6 months months till 14
completed years.
Above 15 years,
three-dose
series—0–2–6
months
MMR Complete two-dose series, at least 4 weeks apart
Hepatitis B Complete three-dose series, 0–1–6 months
Hepatitis A Complete two doses 6–12 months apart, series of
inactivated or single dose live
Varicella Two doses at 4–8 weeks’ interval
Typhoid conjugate Single dose
vaccine
Influenza Single annual dose
Japanese encephalitis Two doses at 4 weeks’ interval
Pneumococcal See Footnote 2
polysaccharide PPSV23
Meningococcal See Footnote 3
• MenACWY-D
• MenACWY-CRM
Range of recommended ages for all children.
Range of recommended ages for catch-up immunization.
Range of recommended ages for certain high-risk groups.
(HPV: human papillomavirus; MMR: measles, mumps, and rubella; PPSV: pneu
mococcal polysaccharide vaccine)
FOOTNOTES
HPV Vaccines
■ Minimum age: 9 years
■ HPV4 and HPV9 are recommended in a two-dose series (0 and
6 months) for females and males aged 9–14 years of age.
■ HPV4 is recommended in a three-dose series (0, 2, and 6 months)

for females aged 15–45 years.
■ HPV9 is recommended in females aged 15–26 years in a three-
dose schedule 0–2–6 months.
■ The vaccine series can be started beginning at age 9 years.
■ Administer the vaccine series to females (HPV 4) at age 13 years
through 45 years if not previously vaccinated.
■ Administer the second dose 2 months after the first dose and the
third dose 6 months after the first dose (at least 24 weeks after the
first dose).
Pneumococcal Vaccines
■ Pneumococcal conjugate vaccine (PCV) and pneumococcal
polysaccharide vaccine (PPSV) both are used in certain high-risk
group of children.
■ A single dose of PCV may be administered to children aged
6 years through 18 years who have anatomic/functional asplenia,
human immunodeficiency syndrome infection, or other
immunocompromising condition, cochlear implant, or cerebral
spinal fluid leak.
■ Administer PPSV at least 8 weeks after the last dose of PCV to
children aged 2 years or older with certain underlying medical
conditions, including a cochlear implant.
■ A single revaccination (with PPSV) should be administered after
5 years to children with anatomic/functional asplenia or an
immunocompromising condition.
Meningococcal Vaccine
■ Recommended only for certain high-risk group of children,
during outbreaks, children residing in endemic zones, and
international travelers, including students going for study abroad
and travelers to Hajj and sub-Saharan Africa.
■ Meningococcal conjugate vaccines (quadrivalent MenACWY-D,
Menactra® Sanofi Pasteur, Menveo and monovalent group A, PsA-
TT, MenAfriVac® by Serum Institute of India) and polysaccharide
vaccines (bi- and quadrivalent) are licensed in India.
■ These vaccines are not recommended for routine use.
Special situations: Anatomic or functional asplenia (including sickle

cell disease), human immunodeficiency virus (HIV) infection,
persistent complement component deficiency, complement
inhibitor (e.g., eculizumab, ravulizumab), use:
■ After primary immunization, one booster every 5 years in cases
of persistent risk such as asplenia.
■ Children for whom boosters are recommended because of an
ongoing increased risk of meningococcal disease (e.g., those with
complement deficiency, HIV, or asplenia): Follow the booster
schedule for persons at increased risk.
■ Children for whom boosters are not recommended (e.g., a healthy
child who received a single dose for travel to a country where
meningococcal disease is endemic): Administer MenACWY
according to the recommended adolescent schedule with dose
one at age 11–12 years and dose two at age 16 years.
REFERENCES
1. Hinman AR, Orenstein WA, Schuchat A. Vaccine-preventable
diseases, immunizations, and the Epidemic Intelligence Service. Am J
Epidemiol. 2011;174(Suppl 11):S16-22.
2. Pichichero ME. Booster vaccinations: can immunologic memory
outpace disease pathogenesis? Pediatrics. 2009;124(6):1633-41.
3. Tartof SY, Lewis M, Kenyon C, White K, Osborn A, Liko J, et al.
Waning immunity to pertussis following 5 doses of DTaP. Pediatrics.
2013;131(4):e1047-52.
4. Esposito S, Agliardi T, Giammanco A, Faldella G, Cascio A, Bosis S,
et al. Long-term pertussis-specific immunity after primary vaccination
with a combined diphtheria, tetanus, tricomponent acellular pertussis,
and hepatitis B vaccine in comparison with that after natural infection.
Infect Immun. 2001;69(7):4516-20.
5. Clark TA, Messonnier NE, Hadler SC. Pertussis control: time for
something new? Trends Microbiol. 2012;20(5):211-3.
6. Cherry JD. Epidemic pertussis in 2012—the resurgence of a
vaccinepreventable disease. N Engl J Med. 2012;367(9):785-7.
7. Skoff TH, Cohn AC, Clark TA, Messonnier NE, Martin SW. Early Impact
of the US Tdap vaccination program on pertussis trends. Arch Pediatr
Adolesc Med. 2012;166(4):344-9.
8. Quinn HE, McIntyre PB. The impact of adolescent pertussis
immunization, 2004–2009: lessons from Australia. Bull World Health
Organ. 2011;89(9):666-74.
9. Hay JW, Ward JI. Economic considerations for pertussis booster

vaccination in adolescents. Pediatr Infect Dis J. 2005;24(Suppl 6):
S127-33.
10. Vashishtha VM, Bansal CP, Gupta SG. Pertussis vaccines: position paper
of Indian Academy of Pediatrics (IAP). Indian Pediatr. 2013;50(11):
1001-9.
11. Son S, Thamlikitkul V, Chokephaibulkit K, Perera J, Jayatilleke K,
Hsueh PR, et al. Prospective multinational serosurveillance study of
Bordetella pertussis infection among 10- to 18-year-old Asian children
and adolescents Clinical Microbiology and Infection. 2019;25(2):250.
e1-250.e7.
12. Jennifer L, Basker MM, Verghese VP, Anandan S, Sethuvel DPM,
Abirami SB, et al. A seroepidemiological survey for pertussis among
adolescents. Indian J Pediatr. 2021;88(5):509.
13. Halperin SA, Donovan C, Marshall GS, Pool V, Decker MD, Johnson DR,
et al. Randomized controlled trial of the safety and immunogenicity
of revaccination with tetanus-diphtheria-acellular pertussis vaccine
(Tdap) in adults 10 years after a previous dose. J Pediatric Infect Dis
Soc. 2019;8:105-14.
14. Kovac M, Kostanyan L, Mesaros N, Kuriyakose S, Varman M.
Immunogenicity and safety of a second booster dose of an acellular
pertussis vaccine combined with reduced antigen content diphtheria-
tetanus toxoids 10 years after a first booster in adolescence: an
open, phase III, non-randomized, multi-center study. Hum Vaccin
Immunother. 2018;14(8):1977-86.
15. Brandon D, Kimmel M, Kuriyakose SO, Kostanyan L, Mesaros N.
Antibody persistence and safety and immunogenicity of a second
booster dose nine years after a first booster vaccination with a reduced
antigen diphtheria-tetanus-acellular pertussis vaccine (Tdap) in
adults. Vaccine. 2018;36(42):6325-33.
16. Jackson ML, Yu O, Nelson JC, Nordin JD, Tartof SY, Klein NP,
et al. Safety of repeated doses of tetanus toxoid, reduced diphtheria
toxoid, and acellular pertussis vaccine in adults and adolescents.
Pharmacoepidemiol Drug Saf. 2018;27:921-5.
17. Theeten H, Rümke H, Hoppener FJ, Vilatimó R, Del Moral I, Brotons C,
et al. Primary vaccination of adults with reduced antigen-content
diphtheria-tetanus-acellular pertussis or dTpa-inactivated poliovirus
vaccines compared to diphtheria-tetanus-toxoid vaccines. Curr Med
Res Opin. 2007;23:2729-39.
18. Havers FP, Moro PL, Hunter P, Hariri S, Bernstein H. Use of tetanus
toxoid, reduced diphtheria toxoid, and acellular pertussis vaccines:
Updated recommendations of the Advisory Committee on
Immunization Practices—United States, 2019. MMWR Morb Mortal

Wkly Rep. 2019;69(3):77-83.
19. Fortner KB, Swamy GK, Broder KR, Jimenez-Truque N, Zhu Y, Moro PL,
et al. Reactogenicity and immunogenicity of tetanus toxoid, reduced
diphtheria toxoid, and acellular pertussis vaccine (Tdap) in pregnant
and nonpregnant women. Vaccine. 2018;36(42):6354-60.
20. Sukumaran L, McCarthy NL, Kharbanda EO, McNeil MM, Naleway AL,
Klein NP, et al. Association of Tdap vaccination with acute events and
adverse birth outcomes among pregnant women with prior tetanus-
containing immunizations. JAMA 2015;314(15):1581-7.
21. Liang JL, Tiwari T, Moro P, Messonnier NE, Reingold A, Sawyer M, et
al. Prevention of pertussis, tetanus, and diphtheria with vaccines in
the United States: recommendations of the Advisory Committee on
Immunization Practices (ACIP). MMWR Recomm Rep. 2018;67(2):1-44.
22. Centers for Disease Control and Prevention (CDC). Updated
recommendations for use of tetanus toxoid, reduced diphtheria toxoid,
and acellular pertussis vaccine (Tdap) in pregnant women—Advisory
Committee on Immunization Practices (ACIP), 2012. MMWR Morb
Mortal Wkly Rep. 2013;62(7):131-5.
23. Forman D, de Martel C, Lacey CJ, Soerjomataram I, Lortet-Tieulent
J, Bruni L, et al. Global burden of human papillomavirus and related
diseases. Vaccine. 2012;30(Suppl 5):F12-23.
24. Lehtinen M, Dillner J. Clinical trials of human papillomavirus vaccines
and beyond. Nat Rev Clin Oncol. 2013;10(7):400-10.
25. American Academy of Pediatrics. Policy Statement. HPV vaccine
recommendations. Pediatrics. 2012;129(3):602-6.
26. Ministry of Health and Family Welfare. National Health Profile
(NHP) of India–2018, Government of India, Central Bureau of Health
Intelligence, DGHS. [online] Available from http://cbhidghs.nic.in/
WriteReadData/1892s/Chapter%203.pdf. [Last accessed December,
2022].
27. Capua T, Katz JA, Bocchini Jr JA. Update on adolescent immunizations:
selected review of US recommendations and literature. Curr Opin
Pediatr. 2013;25(3):397-406.
4.2 IMMUNIZATION IN SPECIAL SITUATIONS

Srinivas G Kasi, Sanjay Srirampur
IMMUNIZATION IN THE IMMUNOCOMPROMISED

The immunocompromised are in greater need for vaccines as
they are more susceptible to infections. But at the same time,
the immunogenicity or efficacy is lower and risk of adverse
effects with live vaccines is higher. However, vaccination in an
immunocompromised child is safer than often perceived. General
principles for vaccination of the immunocompromised are:1-3
■ All inactivated vaccines can be given but immunogenicity and
efficacy may be lower.
■ In severe immunodeficiency, all live vaccines are contraindi-
cated. In mild or moderate immunodeficiency, live vaccines may
be given, if benefits outweigh the risks. Patients administered live
vaccines inadvertently prior to diagnosis of immunodeficiency,
should be watched for vaccine-related adverse effects.
■ Ideally, antibody titers should be checked postimmunization
on regular basis, and regular boosters may be administered if
needed.
■ Higher doses and/or greater number of doses should be given if
indicated (hepatitis B).
■ For major or contaminated wounds, tetanus immunoglobulin
(Ig) is required in addition to tetanus toxoid (TT), even if three or
more doses of TT have been received in the past.
■ Household contacts of immunocompromised should not
receive transmissible vaccines such as oral polio vaccine (OPV)
but can safely receive other nontransmissible live vaccines
such as measles, mumps, rubella (MMR) and varicella. All
household contacts should be fully immunized, including
varicella and influenza, to reduce risk of transmission to the
immunocompromised. After administration of oral rotavirus
vaccines, strict hand hygiene should be observed by all caregivers
for a week after administration.
■ Some vaccines including pneumococcal, varicella

(depending on degree of immunocompromise), hepatitis A,
and inactivated influenza vaccines (IIVs) should be given.
Although, there are no guidelines regarding rotavirus vaccines
in the immunocompromised (except in severe combined
immunodeficiency), there have been no safety concerns when
administered to HIV infected subjects.
An international panel of experts prepared an evidence-based
guideline for vaccination of immunocompromised adults and
children. These guidelines are intended for use by primary care and
subspecialty providers who care for immunocompromised patients.4
HUMAN IMMUNODEFICIENCY VIRUS INFECTION

Children infected by human immunodeficiency virus (HIV) are
vulnerable to severe, recurrent, or unusual infections by vaccine-
preventable pathogens. The efficacy and safety of vaccines depend on
the degree of immunodeficiency. Generally, cluster of differentiation
4+ (CD4+) counts <200 cells/mm3 or < 15% is known to elicit minimal
or no host response. Even if there is a better antibody response, such
antibody response may wane at a faster rate in HIV-infected persons.
Antiretroviral therapy can improve immune responses to vaccine
but not to the levels of an uninfected subject. Live viral and bacterial
vaccines pose an enhanced risk for uncontrolled replication of the
vaccine strains.
Vaccination is usually safe and effective early in infancy before
HIV infection causes severe immune suppression. The duration of
protection may be compromised as there is impairment of memory
response with immune attrition. In older HIV-1 infected children and
adults, the immune response to primary immunization may be less
but protective immunity to vaccines received prior to the infection
is usually maintained. However, immunity to measles, tetanus, and
hepatitis B wanes faster than other antigens.5
Indian Academy of Pediatrics (IAP), World Health Organization
(WHO), American Academy of Pediatrics (AAP), Advisory Committee
on Immunization Practices (ACIP), and Centers for Disease
Control and Prevention (CDC) recommend all the live vaccines
in asymptomatic HIV-1 infected children except OPV. However, in

a symptomatic child, all live vaccines are forbidden, but at times
measles/MMR/varicella vaccines may be considered on individual
merit. Yellow fever vaccine is contraindicated in symptomatic but
can be given in asymptomatic and those at risk of exposure. For
killed vaccines in an HIV-infected child, ideally postvaccination
monitoring of seroconversion is desirable. In an HIV-infected child,
there is a multifold enhanced risk of diseases such as tuberculosis,
hepatitis (A and B), measles, influenza, varicella, pneumococcal, and
meningococcal disease. Hence, in such situations, a judicious and
intelligent decision of the physician is warranted. Table 1 summarizes
IAP recommendations for vaccination of HIV-infected children.
TABLE 1: Indian Academy of Pediatrics recommendations for immunization

of human immunodeficiency virus (HIV)-infected children.
Vaccine Asymptomatic Symptomatic
BCG Yes (at birth) No
DTwP/DTaP/TT/Td/ Yes, as per routine schedule at 6, 10, 14 weeks,
Tdap 18 months, and 5 years
Polio vaccines • IPV at 6, 10, 14 weeks, 12–18 months, and 5 years
• If indicated IPV to household contacts
• If IPV is not affordable, OPV should be given in
asymptomatic subjects
MMR Yes, at 9 months, Yes, if CD4+ count >15%
15 months and 5 years
Hepatitis B Yes, at 0, 1, and Yes, four doses, double
6 months* dose, check for
seroconversion and give
regular boosters
Hib Yes, as per routine schedule at 6, 10, and 14 weeks
and 12–18 months
Pneumococcal • PCV: Yes, as per routine schedule at 6, 10, and
vaccines (PCV and 14 weeks and 12–15 months
PPSV23) • PPSV23: One dose 8 weeks after PCV, second dose
5 years after first dose (not more than two doses)
Inactivated Yes, as per routine schedule beginning at 6 months,
influenza vaccine revaccination every year
Contd…
Contd…
Vaccine Asymptomatic Symptomatic
Rotavirus vaccine Insufficient data to recommend, to be given as per
ACIP/WHO recommendations in asymptomatic
Hepatitis A vaccine Yes Yes, check for
(inactivated only) seroconversion, boosters
if needed
Varicella vaccine Yes, two doses at 4– • Yes, if CD4 count ≥15%
12 weeks interval. Use <5 years for ≥6 months,
single antigen vaccine, CD4 count >200/mm3
MMRV in HIV infected for ≥6 months
children have not been • Two doses at 4–12 weeks
studied** apart
Vi-typhoid/ Yes, as per routine schedule
Vi-conjugate vaccine
HPV vaccine Yes, as per routine schedule of three doses at 0–2 and
6 months starting at 9 years of age. For details see
chapter on HPV vaccines
*Hepatitis B virus surface antigen (HBsAg) positive mothers, infant to be given
hepatitis immunoglobulin (HBIg) within 12 hours of birth as per birth weight,
if status unknown <2,000 g infant to be given both HBV vaccine and HBIg. If
>2,000 g to check the status and give HBIg accordingly (not later than 1 week).
**As per Advisory Committee on Immunization Practices/Centers for Disease
Control and Prevention and World Health Organization. If varicella vaccine
was given before initiation of combination antiretroviral therapy (c-ART),
repeat the doses of varicella vaccine after start of c-ART.
(BCG: bacillus Calmette-Guérin; CD: cluster of differentiation; DTP:
diphtheria, tetanus, and pertussis; Hib: Haemophilus influenzae type b;
HIV: human immunodeficiency virus; HPV: human papillomavirus; IPV:
inactivated poliovirus vaccine; MMR: measles, mumps, and rubella; OPV: oral
polio vaccine; PCV: pneumococcal conjugate vaccine; PPSV: pneumococcal
polysaccharide vaccine; TT: tetanus toxoid)
CORTICOSTEROIDS/OTHER IMMUNOSUPPRESSIVE
THERAPY
Corticosteroids
Children receiving oral corticosteroids in high doses (prednisolone
2 mg/kg/day for those weighing <10 kg or for those weighing >10 kg,
20 mg/day or its equivalent) for >2 weeks should not receive live
virus vaccines until the steroids have been discontinued for at least
1 month. Killed vaccines are safe but may be less efficacious.
Children receiving oral corticosteroids in high doses
(prednisolone 2 mg/kg/day for those weighing <10 kg or for those
weighing >10 kg, 20 mg/day or its equivalent) for <2 weeks can
receive live-virus vaccines after discontinuation of treatment.
Children receiving oral corticosteroids in lower doses (predniso-
lone <2 mg/kg/day for those weighing <10 kg or for those weighing
>10 kg, <20 mg/day or its equivalent) can receive live vaccines,
while on therapy. These doses are not immunosuppressive.
Children who are receiving only maintenance physiologic doses
of corticosteroids can receive live-virus vaccines.
Children on alternate day therapy, inhaled or topical therapy
may be safely and effectively given their age-appropriate vaccines.
Low or moderate doses of systemic corticosteroids or locally
administered corticosteroids in children who have a disease
(e.g., systemic lupus erythematosus) that in itself is considered to
suppress the immune response should not receive live-virus vaccines
during therapy, except in special circumstances during which the
potential benefit of protection and the risk of adverse reaction are
weighed.6
Other Immunosuppressive Medications

Children receiving methotrexate at a dosage of ≤0.4 mg/kg/week,
azathioprine at a dosage of ≤3 mg/kg/day, or 6-mercaptopurine at
a dosage of ≤1.5 mg/kg/day are not immunosuppressed and can
receive all vaccines.6
Biologic Response-modifying Drugs

The biologic response-modifying drugs (BRMs) target different
components of the immune system causing various degrees of
immunosuppression that can last for weeks to several months
after discontinuation. Inactivated vaccines should be preferably
administered at least 2 weeks before the initiation of biologics. Live-
attenuated vaccines are generally contraindicated during and for
weeks to months following discontinuation of the BRMs. They should
be administered at least 4 weeks before the initiation of therapy.
Biologic response-modifying drugs are considered highly immu-

nosuppressive and live-virus vaccines are contraindicated during
therapy; inactivated vaccines, including IIV, should be administered as
per the immunization schedule and should not be withheld.
The interval between cessation of BRM therapy and safe
administration of live vaccines has not been established and
is likely to vary by agent. Generally, live vaccines may be
administered 3 months after cessation of BRM therapy. However,
the recommendations following rituximab therapy is different. Any
vaccine history prior to rituximab therapy should be disregarded
and complete re-immunization should be done. Once B-cell and
Ig levels have recovered, immunization should be recommenced,
which is generally 6 months after cessation of rituximab therapy.7
In-utero exposure to BRMs: Concerns exist regarding immunosup
pression in infants exposed in utero to maternally administered
BRMs as detectable drug concentrations may be present for many
months following delivery. For such infants, live vaccines should be
avoided for 12 months after the last maternal dose during pregnancy.
BCG, OPV, and MMR/MR should be avoided in the first year of life.
The safety of rotavirus vaccines in such infants is debatable and
hence may be avoided.
All inactivated vaccines should be administered according to
routine schedule, immune response during the first few months
may be suboptimal, depending on the monoclonal used and the
gestational period during which it was administered.8
CANCER CASES ON CHEMOTHERAPY/

RADIOTHERAPY
Influence of cancer per se on immune function is minimal and does not
contribute to a major extent in inducing immunocompromised state.
Total Ig concentrations, specific antibody concentrations to already
given vaccines are normal at the time of diagnosis indicating that the
effect of cancer on the adaptive immune system is likely to be small.9
However, chemotherapy for cancer causes major secondary immuno-
deficiency. The effects of radiotherapy on immune function are likely
to be small in comparison to chemotherapy. Vaccination requirements
for cancer cases need special consideration as described below.6,10
Specific recommendations for children with cancer and their

family members:
■ Live vaccines are contraindicated during and for 6 months after
the end of chemotherapy. Nonlive vaccines are also best given
after 6 months from the end of treatment for durable immunity.
■ Annual IIV is the only vaccine recommended for all children
during chemotherapy, whereas hepatitis B vaccine is
recommended only for previously unimmunized children with
risk of transfusion-associated transmission.
■ Post-treatment reimmunization or catch-up schedule largely
depends on the prechemotherapy immunization status.
■ In general, a booster dose of all age-appropriate vaccines should
be administered.
■ Sibling immunization should continue uninterrupted except for
OPV which needs to be substituted by the injectable vaccine.
IIV is recommended and varicella vaccine is encouraged for all
contacts including siblings or parents. OPV is contraindicated
including pulse polio doses. Sibling should receive inactivated
poliovirus vaccine (IPV) and if OPV is either given by mistake or
given because there is no other option, then the sibling should
remain away from index child for at least 2 weeks.
The vaccine recommendations in a child who has received
chemotherapy are shown in Table 2.
Special Situations in Cancer Patients

■ Postexposure prophylaxis for rabies:11 Children with cancer
undergoing treatment, may mount a significantly lower
neutralizing antibody response to rabies. In such patients in whom
the presence of immunological memory is no longer assured as a
result of other causes, proper and thorough wound management
and antisepsis accompanied by local infiltration of rabies Ig or
monoclonal antibody followed by antirabies vaccination are of
utmost importance. Even immunocompromised patients with
category II exposures should receive passive prophylaxis for
rabies in addition to a full postexposure vaccination including
the 6th dose on day 90 which is also mandatory.
TABLE 2: Vaccine recommendations in child who has received chemotherapy.
After end of chemotherapy*
Children with completed
Vaccine During chemotherapy* Previously unimmunized children immunization
BCG Not recommended, contact Single dose BCG at 6 months after Not recommended in previously
vaccination not discouraged completion of chemotherapy immunized children with visible
BCG scar
OPV Not recommended, IPV preferred, when unavailable three IPV preferred, when unavailable
contact vaccination not doses of bOPV 1 month apart (maximum two doses of bOPV 1 month apart
recommended age 5 years) (maximum age 5 years)
MMR Not recommended, contact Two doses of MMR (1–3 months apart) One dose of MMR should be
vaccination not discouraged should be given to all children after given to all children after at
at least 6 months of completion of least 6 months of completion of
chemotherapy chemotherapy
Varicella Not recommended, contact Two doses of vaccine 1–3 months One dose of vaccine (after
vaccination encouraged apart (after 6 months of completing 6 months of completing
chemotherapy) chemotherapy)
Live- Not recommended Single dose after 6 months of Single dose after 6 months of
attenuated completing chemotherapy completing chemotherapy
hepatitis A
Rotavirus Not recommended, contact Generally, child outgrows the maximum Generally, child outgrows the
vaccination not discouraged permissible age, therefore not indicated maximum permissible age,
therefore not indicated
Vaccination of Special Groups
Contd…
441
Contd…
DPT Not recommended during • Three doses at 0, 1, and 6 months (6 • Single booster dose (6 months
ongoing chemotherapy months after stopping chemotherapy) after stopping chemotherapy)
• If <7 years: DTaP/DTwP • If <7 years: DtaP/DTwP
• If >7 years: Tdap-Td-Td • If >7 years: Tdap
Hib Not recommended during 6–12 months: Two doses 8 weeks apart, Single booster dose (6 months
ongoing chemotherapy followed by booster at 12 months; 12–15 after stopping chemotherapy)
months single dose followed by booster

at 18 months; 15–60 months single dose
(6 months after stopping chemotherapy)
IPV Not recommended during Two doses of IPV 2 months apart and Single booster dose (6 months
ongoing chemotherapy third dose after 6 months (6 months after stopping chemotherapy).
after stopping chemotherapy) Two doses for children who
received OPV as primary
immunization
HBV** Four doses of vaccine (0, 1, Three doses at 0, 1, and 6 months (6 Single booster dose (6 months
2, and 12 months) at double months after stopping chemotherapy) after stopping chemotherapy)
dosage is recommended for
previously unimmunized
children, no further doses
for children who completed
primary schedule prior to
diagnosis
Contd…
Contd…
HAV Not recommended during Two doses 6 months apart (6 months Single booster dose (6 months
(inactivated) ongoing chemotherapy after stopping chemotherapy) after stopping chemotherapy)
IIV*** Recommended single Not recommended routinely beyond 1 Not recommended routinely
dose annually during year from the end of chemotherapy**** beyond 1 year from the end of
chemotherapy chemotherapy****
Pneumococcal Not recommended during Age <1 year: Two doses of PCV-13 Single booster dose (6 months
ongoing chemotherapy at 4–8 weeks interval followed by a after stopping chemotherapy)
booster dose at 12–15 months age
Age 1–2 years: Two doses of PCV-13,
4–8 weeks apart; age >2 years: 1
dose of PCV-13. PPV-23 booster is not
recommended for this group of children
(6 months after stopping chemotherapy)
TCV Not recommended during Single-dose typhoid conjugate vaccine Single dose typhoid conjugate
ongoing chemotherapy 6 months after stopping chemotherapy vaccine 6 months after stopping
chemotherapy
Contd…
443
Contd…
HPV Not recommended during 3-dose series of 0–2–6 months for all No recommendation for booster.
ongoing chemotherapy above 9 years of age Single dose may be considered in
females
Notes:
BCG: IAP recommended upper age limit for vaccination is 5 years. It is contraindicated during ongoing chemotherapy and can only be
given after 6 months of completion of chemotherapy as a single dose in previously unimmunized children. In children with previously
completed immunization with visible scar no further doses are recommended.

*Catch-up vaccination for children with cancer should be given 6 months after stoppage of chemotherapy. Exception is HBV and
influenza vaccine. No vaccine is recommended while ongoing chemotherapy.
**For HBV vaccine in those previously unimmunized and started on chemotherapy—unimmunized and who is hepatitis B surface
antigen negative, then it is recommended to administer four doses of vaccine at 0, 1, 2 and 12 months at double dosage as well as age
appropriate dose of hepatitis B immunoglobulin every 3 months till there is no risk of exposure to blood products.
***No IAP recommended upper age limit for vaccination. Recommended during ongoing chemotherapy and up to 1 year after
completion of treatment: Age 6 months to 9 years—two doses 1 month apart and then single dose every year till indicated. Age >9
years—single dose every year till indicated.4,5 Recommended time to vaccinate—as soon as the new vaccine is released and available
in market. Just before the onset of the rainy season (before June for most of India and before October for some of the southern states).
****Recommendation 1 year after stoppage of chemotherapy—not recommended routinely unless the child continues to have
high-risk conditions necessitating influenza vaccination, e.g., chronic cardiac, pulmonary, liver and renal disease, diabetes, human
immunodeficiency virus (HIV), etc.
(BCG: bacille Calmette-Guérin; DPT: diphtheria, pertussis, and tetanus; HAV: hepatitis A virus; HBV: hepatitis B virus; HPV: human
papillomavirus; IAP: Indian Academy of Pediatrics; IPV: inactivated poliovirus vaccine; MMR: measles, mumps, and rubella; OPV: oral
polio vaccine; PCV: pneumococcal conjugate vaccine; PPSV: pneumococcal polysaccharide vaccine)
■ Tetanus prophylaxis in wound management: 11 All patients

presenting with skin wounds or infections should be evaluated
for tetanus prophylaxis. Cleaning of the wound, removal of
devitalized tissue, irrigation, and drainage is important to prevent
anaerobic environment which is conducive to tetanus toxin
production. In a child with cancer who is on treatment and who
then gets a wound, it can be assumed that the antibody levels are
inadequate. So tetanus wound management is as follows:
y In a clean, minor wound: TT booster regardless of immuni-
zation status.
y All other wounds: TT + tetanus Ig.
■ Varicella post-exposure prophylaxis: Children exposed to
varicella infection during ongoing chemotherapy should be
given prophylaxis with varicella zoster immunoglobulin (VZIg)/
intravenous immunoglobulin (IVIg) and/or oral acyclovir. Under
ideal circumstances, VZV IgG levels should be assessed at the
time of exposure and for children with less than protective levels,
VZIg should be offered (dose: 125 u/10 kg, 62.5 U if <2 kg, to a
maximum of 625 U) by the intramuscular (IM) route. If VZIg is
unavailable, IVIg at 400 mg/kg can be administered intravenously.
In case both the above are unaffordable/unavailable, acyclovir
(20 mg/kg per dose, administered orally four times per day, with
a maximum daily dose of 3,200 mg) or valacyclovir (20 mg/kg per
dose, administered orally three times per day, with a maximum
daily dose of 3,000 mg) beginning 7 days after exposure and
continuing for 7 days can be used.12
■ Other vaccines: Other nonlive vaccines such as meningococcal
vaccine, Japanese encephalitis vaccine, cholera vaccine, and
yellow fever vaccine are not recommended by IAP for routine use
in healthy children. They also have no specific role in children
with cancer during or after treatment. It is recommended to
consider special conditions for these vaccines as mentioned in
respective vaccination recommendation.
TRANSPLANT RECIPIENTS
Hematopoietic Stem Cell Transplants
Patients for whom hematopoietic stem cell transplant (HSCT) is
planned should receive all routinely recommended inactivated
vaccines (including IIV) at least 2 weeks before the start of the

conditioning period, when possible. Routinely recommended live-
virus vaccines should be administered if the patient is not already
immunosuppressed and the interval to the start of the conditioning
period is at least 4 weeks. By vaccinating the nonimmune patient
before HSCT, some protection likely will persist in the months after
transplant.
However, recipients of HSCT are like the unimmunized, as
they have lost all memory responses during marrow ablation.
Vaccination requirements for recipients of HSCT cases need special
consideration as described below.4
■ Three doses of tetanus or diphtheria-containing vaccine should
be administered 6 months after HSCT. For patients aged ≥7 years,
a dose of Tdap vaccine may be administered followed by two
doses of Td vaccine.
■ Three doses of IPV, Haemophilus influenzae type b (Hib),
hepatitis B vaccine should be administered 6–12 months after
HSCT. If a postvaccination hepatitis B surface antibody (antiHBs)
concentration of ≥10 mIU/mL is not attained, hepatitis B vaccine
course can be repeated.
■ Three doses of pneumococcal conjugate vaccine (PCV) should
be administered to adults and children starting at age 3–6 months
after HSCT. At 12 months after HSCT, one dose of pneumococcal
polysaccharide vaccine 23 (PPSV23) should be given provided
the patient does not have chronic graft-versus-host disease
(GVHD). For patients with chronic GVHD, a fourth dose of PCV
can be given at 12 months after HSCT.
■ One dose of influenza (IIV) should be administered annually
to persons aged ≥6 months starting 6 months after HSCT
and starting 4 months after if there is a community outbreak
of influenza. For children aged 6 months to 8 years, who are
receiving influenza vaccine for the first time, two doses should
be administered. Influenza vaccine is recommended annually
lifelong in post-transplant recipient (Tables 3 to 5).
■ Two doses of meningococcal conjugate vaccine (MCV4)
should be administered 6–12 months after HSCT, if the risk of
meningococcal disease is high.
TABLE 3: Schedule for post-HSCT vaccinations.14
Vaccine Months post-HSCT Schedule Comments
BCG Contraindicated
DPT/Tdap 6–12 months Three doses at 0–1–6 months <7 years: DTaP/DTwP
interval >7 years: Tdap-Td-Td
Hib 6–12 months Three doses at 4 weeks
interval
IPV 6–12 months Three doses at 4 weeks
interval
HBV 6–12 months Three doses at 4 weeks Postvaccination, check anti-HBs.
interval If <10 u/mL, repeat schedule with
standard or double dose
PCV13 3–6 months Three doses at 4 weeks Give regardless of age
interval
PPSV23 12–18 months, if no GVHD One dose Consider reimmunization after 1 year
(6–12 months after the last dose
of PCV13). If GVHD, give fourth
dose of Pneu-C-13 and delay
polysaccharide until GVHD
resolved
Rotavirus Contraindicated
Contd…
447
Contd…
IIV 4–6 months Two doses, 4 weeks apart, Repeat annually
the first year post-transplant,
if <9 years old
MMR 24 months Two doses, 4 weeks apart Serology recommended after second
dose
TCV 6–12 months One dose
Hep A Inactivated 6–12 months Two doses at 6–12 months Serology recommended after second
interval dose
Varicella 24 months Two doses, 4 weeks apart Serology recommended after second
dose
HPV 6–12 months Three doses Recommended if indicated by age
Meningococcal 6–12 months (Menactra) <24 months: For people with ongoing increased
conjugate vaccine If the risk of meningococcal 2 doses, 3 months apart risk of invasive meningococcal
disease is high (Menactra and Menveo) disease who completed the primary
>24 months: One dose series at: ≤6 years of age—3 years
after completing the primary
schedule, then every 5 years after
that ≥7 years of age—every 5 years
after completing the primary
schedule
JE vaccines 6–12 months Two doses, 4 weeks apart Use if indicated
Contd…
Contd…
Rabies 6 months (PrEP) Use if indicated ID not recommended
five-dose PEP recommended
post-immunization serology
recommended RIG/Mabs for cat two
bites
MMRV Contraindicated
Yellow fever 24 months May be given if indicated
(BCG: bacille Calmette-Guérin; DPT: diphtheria, pertussis, and tetanus; DTaP: diphtheria, tetanus, and pertussis; DTwP: diphtheria
toxoid, tetanus toxoid, whole cell pertussis; GVHD: graft-versus-host disease; HB: hepatitis B; HBV: hepatitis B virus; Hib: Haemophilus
influenzae type b; HPV: human papillomavirus; IIV: inactivated influenza vaccine; IPV: inactivated poliovirus vaccine; JE: Japanese
encephalitis; MMR: measles, mumps, rubella; MMRV: measles, mumps, rubella, varicella; PCV: pneumococcal conjugate vaccine; PEP:
postexposure prophylaxis; PPSV: pneumococcal polysaccharide vaccine; PrEP: pre-exposure prophylaxis; RIG: rabies immunoglobulin;
TCV: typhoid conjugate vaccine; Td: tetanus and diphtheria; Tdap: tetanus, diphtheria, and pertussis)
449
TABLE 4: Immunization of children with primary immunodeficiency.
Vaccines that are
Clinical syndrome contraindicated Comments
X-linked All live vaccines Annual IIV is the only vaccine administered
agammaglobulinemia routinely to patients receiving IVIG replacement
therapy
B-lymphocyte Common variable All live vaccines
defects immunodeficiency
Selective IgA deficiency OPV All inactivated and live-virus vaccines on the
IgG subclass deficiency None standard annual schedule are safe, likely are
effective (although responses may be attenuated),
and should be administered. PPSV23 should be
administered beginning at 2 years of age
T-lymphocytes Severe combined All live viral and bacterial All inactivated vaccines are ineffective. Annual
defects immunodeficiency (SCID) vaccines IIV is the only vaccine administered routinely to
Complete Di George patients receiving IG replacement therapy, if there
syndrome is some residual antibody-producing capacity
• Partial Di George All live viral and bacterial • All inactivated vaccines are safe and may be
syndrome vaccines effective depending on the degree of the
• Wiskott–Aldrich immune defect. Age-appropriate vaccines
syndrome should be administered.
• Hyper IgM syndrome, • MMR and varicella vaccine (not MMRV) can
ataxia telangiectasia be considered for those with ≥500 CD3+ T
lymphocytes/mm3, ≥200 CD8+ T lymphocytes/
mm3, and normal mitogen response
Contd…
Contd…
Vaccines that are
Clinical syndrome contraindicated Comments
Interferon-alpha; All live-bacteria vaccines • All age-appropriate inactivated vaccines are safe
interferon-gamma; and YF vaccine; other live- and should be administered
interleukin 12 axis virus vaccines if severely • MMR and Varicella vaccines may be safe
deficiencies; STAT1 lymphopenic
deficiencies
Complement Deficiency of None • All age-appropriate inactivated and live-virus
deficiencies components C1-C9, vaccines are safe and should be administered
properdin, factor B • Hib, meningococcal, pneumococcal, typhoid
Chronic granulomatous All live bacterial vaccines All inactivated and live-virus vaccines are safe,
disease effective, and should be administered
• Ill-defined phagocytic All live viral and bacterial • All age-appropriate inactivated vaccines are
Phagocytic defects+/− defects in vaccines safe, effective, and should be given
defects T-lymphocyte and NK • PPSV23 should be administered >2 years
cell dysfunction • Consider MenACWY-CRM series beginning in
• Leukocyte adhesion infancy
defects, Chediak-
Higashi syndrome,
MPO deficiency
(IgA: immunoglobulin A; IgG: immunoglobulin G; IgM: immunoglobulin M; IVIG: intravenous immunoglobulin; MMR: measles,
mumps, rubella; MMRV: measles, mumps, rubella, varicella; MPO: myeloperoxidase; NK: natural killer; OPV: oral polio vaccine; PPSV:
pneumococcal polysaccharide vaccine; YF: yellow fever)
451
TABLE 5: Vaccination prior to and after solid organ transplant.

Pre- Post- Evaluation of serologic
Vaccine Type transplant transplant response
BCG LAV Yes No No
Diphtheria I Yes Yes No
Pertussis I Yes Yes No
Tetanus I Yes Yes Yes
Hepatitis B I Yes Yes Yes
Hib I Yes Yes No
IPV I Yes Yes No
Rotavirus LA Yes No No
PCV I Yes Yes No
PPSV23 I Yes Yes No
MMR LA Yes No Yes
Varicella LA Yes No Yes
TCV I Yes Yes No
Hepatitis A I Yes Yes Yes
Influenza I Yes Yes No
HPV I Yes Yes No
Rabies I Yes Yes Yes
JE I Yes Yes No
MCV4 I Yes Yes No
(HPV: human papilloma virus; IPV: injectable polio vaccine; LAV: live attenuated
vaccines; MCV4: meningococcal conjugate vaccine; MMR: measles, mumps
and rubella; PCV: pneumococcal conjugate vaccine; PPSV23: pneumococcal
polysaccharide vaccine; TCV: typhoid conjugate vaccine)
• Pre-transplant: Inactivated (I) vaccines: complete schedule at least 2 weeks
prior to date of transplant, LAV: Complete schedule at least 4 weeks prior to
date of transplant
• Post-transplant: 6 months post-transplant, when immunosuppression is at
baseline levels. Inactivated influenza vaccine can be administered as early as
1–2 months post-transplant.
• Serological response should be assesses at least 4 weeks after the final dose.
■ Three doses of human papillomavirus (HPV) vaccine 6–12

months after HSCT for female patients aged 11–26 years may be
considered.
■ Live vaccines should not be administered to HSCT patients
with active GVHD or ongoing immunosuppression. MMR
and varicella vaccines should be administered 24 months
after transplantation if the HCT recipient is presumed to be
immunocompetent.11,13
Solid Organ Transplants

The need for immunization in solid organ transplant (SOT) recipients
can arise from three factors, each causing suppression of the
immune system: The immunosuppressive activity of the underlying
disease (e.g., chronic renal failure), rejection of the organ graft,
and the immunosuppressive therapy given after transplantation.
Immunizations can be given to candidates awaiting transplantation
because the immune response then is less likely to be significantly
suppressed and the patient is more likely to respond, to the
vaccine.15 Many of the conditions for which patients undergo organ
transplantation are at least to some extent immunosuppressive, and
vaccinations should be considered early during the disease. Solid
organ recipients generally receive lifelong immunosuppression. The
degree of immune suppression is greatest in the first 3–6 months
post-transplant.
Pre-solid Organ Transplantation

Generally, standard vaccine series should be given to children
awaiting SOT. Recipients of SOTs should complete all age-
appropriate immunizations prior to transplant, in accelerated
schedules if needed. HPV vaccine should be given using a three-
dose schedule regardless of age. Transplant candidates should
receive PCV regardless of age, PPSV if 2 years of age or older,
and one dose of Hib vaccine after age 5 years regardless of prior
Hib vaccination history. Quadrivalent conjugate meningococcal
vaccine is recommended if there are risk factors for meningococcal
infection (e.g., hyposplenia, complement deficiency, or increased
risk of exposure from travel or occupation). Vaccination schedules

with inactivated vaccines should be completed at least 2 weeks
before the scheduled transplant. Vaccination with live vaccines
should be completed at least 4 weeks prior to transplant. 15
MMR and varicella vaccine may be given to infants 6–11 months
of age if transplantation is expected to occur before age 12 months.
If transplantation is delayed, repeat doses should be given
starting at 1 year of age. It is desirable that seroconversion be
documented.15
Post-solid Organ Transplantation

The optimal time to begin vaccine administration after
transplantation is not defined. Immunosuppressive therapy is often
most intense during the first couple of months and might influence
the effect of vaccination. Inactivated vaccines are safe in the post-
transplant period, however, they are best administered at least
6 months post-transplant, to elicit an optimal immune response.
In patients where immunization has not been completed prior to
transplant, vaccination with inactivated vaccines can recommence
6 months post-transplant when immunosuppression has been
lowered. Boosters for inactivated vaccines should be given as
per schedule or when antibody levels wane (hepatitis A and B),
starting 6 months post-transplant. Annual influenza vaccination
is recommended. All household and healthcare workers (HCWs)
contacts should be immunized against influenza, measles, rotavirus,
and varicella. Generally, all live vaccines are contraindicated in
the post-transplant period. However, recent studies show that live
vaccines may be administered at least 1 year after transplant and
when the degree of immunosuppression is very low.15
ASPLENIA OR HYPOSPLENIA
Asplenia or hyposplenia may result from sickle cell disease or
radiation therapy involving spleen. Children with asplenia or
hyposplenia are at high risk of serious infections with encapsulated
organisms. Vaccination with pneumococcal (both conjugate and
polysaccharide), Hib conjugate vaccine, meningococcal conjugate
vaccine, and typhoid conjugate vaccines is indicated in addition
to all routine vaccines. In patients with planned splenectomy,

vaccination schedules should be completed at least 2 weeks prior
to splenectomy for achieving a superior immunologic response. In
those who have undergone emergency splenectomy, studies indicate
that vaccination done 2 weeks after splenectomy is associated with
a superior functional antibody response as compared to vaccination
immediately following surgery. However, vaccination can be initiated
at the time of discharge. All live vaccines may be safely given.16,17
CONGENITAL IMMUNODEFICIENCY (PRIMARY

IMMUNODEFICIENCY DISORDERS) (see TABLE 4)
Primary immunodeficiency diseases (PIDs) are a heterogenous
group of inherited disorders that may involve one or multiple
components of the immune system. PIDs are classified according to
the compartment of the immune system that is primarily involved.
Vaccine recommendation vary according to the type and severity of
the immune deficiency.18
CHRONIC DISEASES
Children with chronic neurologic, endocrinologic (diabetes),
liver, renal, hematologic, cardiac, pulmonary, and gastrointestinal
disease are at increased risk of infections and serious infections.
Live vaccines may be given safely in these children. These children
should be offered pneumococcal, hepatitis A, varicella, influenza,
and rotavirus vaccines. The immunogenicity, efficacy, and duration
of protection of vaccines are lower than healthy children and hence
if indicated higher antigen content or more doses (hepatitis B).
Assessment for antibody response and frequent boosters (hepatitis
A and B) are recommended. It is important to stress the role of
hepatitis A vaccine in patients with liver disease and pertussis
booster in those with stable neurologic disease. Children with cystic
fibrosis or celiac disease may mount a suboptimal immune response
and hence assessment of antibody response is recommended.
Children with severe cardiac and pulmonary diseases should receive
pneumococcal and annual influenza vaccines.19
IMMUNIZATION IN CHILDREN WITH

HISTORY OF ALLERGY
It is essential that parents should be asked whether their children
experienced any allergic symptoms following previous vaccinations.
First time immunization with any vaccine is contraindicated in
children with history of serious hypersensitivity or anaphylaxis
to any of vaccine components. The package label should always
be checked for vaccine constituents which in addition to antigen
include stabilizers or buffers, preservatives, antibiotics, and residue
from the manufacturing process. All vaccinating units need to have
adrenaline, antihistamine, parenteral steroids, and oxygen available
at the site of vaccination. Children with history of serious egg allergy
should not receive yellow fever vaccines but can safely receive
other vaccines including measles and MMR vaccines. Children
with a history of egg allergy who have experienced only hives after
exposure to egg should receive any influenza vaccine (inactivated,
recombinant, or live-attenuated) without specific precautions
(except a 15-minute observation period). Children with previous
anaphylaxis to egg can receive the IIV, in a center wherein staff
experienced in recognizing and treating anaphylactic reactions are
available and the child should be under observation for a minimum
of 1 hour. Children who have had a serious hypersensitivity
reaction or anaphylaxis to a particular vaccine must never receive
it again. A mild reaction is not a contraindication to vaccination.
In any case all children should be watched for at least 15 minutes
after vaccination for allergy and resuscitation equipment should be
kept standby.19 Children sensitized to a vaccine or its components
with previous anaphylaxis to this vaccine should be revaccinated
only if absolutely necessary (rabies vaccine). In this situation, rapid
desensitization with increasing vaccine doses are administered
every 15–30 minutes provided that there are no signs of allergic
reaction (0.05 mL of 1:10 dilution, then 0.05 mL, 0.1 mL, 0.15 mL,
0.2 mL, of a 0.5 mL full-strength vaccine). This results in transient
desensitization and such children must still be considered allergic
to the vaccine. This protocol should be done in a setting where
prompt treatment of anaphylaxis by experienced staff is available.20
IMMUNIZATIONS FOR HEALTHCARE PERSONNEL

Healthcare personnel (HCPs) need to be immunized for two reasons.
First, susceptible HCPs are at increased risk for occupational
acquisition of VPDs. Elderly HCPs and HCPs who have underlying
diseases (e.g., immunosuppression, chronic diseases) or specific
conditions (pregnancy, elderly) should be protected.
Second, HCPs may transmit VPDs to their patients, many of
whom are at high risk for a serious disease course, complications,
or even death because of their age (e.g., neonates, young infants,
elderly) and/or underlying conditions (e.g., pregnant women,
immunocompromised patients, patients with underlying
diseases).
In many outbreaks of VPDs including influenza, pertussis,
measles, rubella, varicella, hepatitis A, and hepatitis B, HCPs have
been traced as the primary source of infection.21
Moreover, HCPs may have significant immunity gaps against
some of the common VPDs.21
Vaccine Recommendations for Healthcare Personnel

■ Hepatitis B: HCPs without documented evidence of a complete
HepB vaccine series or no serologic evidence of immunity should
receive three doses of HepB vaccine in a 0–1–6 months schedule.
Anti-HBs serologic test should be done 1–2 months after the final
dose. A vaccinee whose anti-HBs remains <10 mIU/mL after two
complete series is considered a “non-responder.”
■ Influenza: HCPs should receive annual influenza vaccination.
Live-attenuated influenza vaccine (LAIV) may only be given
to nonpregnant healthy HCP age 49 years and younger
and such HCPs should avoid close contact with severely
immunosuppressed patients who require protective isolation for
at least 7 days after vaccine administration.
■ MMR: HCPs without documented evidence of MMR vaccine
series or no serologic evidence of immunity to MMR should
receive two doses of MMR at an interval of at least 28 days. During
outbreaks of measles or mumps, HCPs without documentation
of vaccination or serologic evidence of immunity to measles or
mumps should receive two doses of MMR vaccine. One dose of

MMR vaccine should be considered for HCP with no laboratory
evidence of disease or immunity to rubella.
■ Varicella: HCPs without documented evidence of varicella
vaccine series or no serologic evidence of immunity to varicella
should receive two doses of Varicella vaccine, at an interval of at
least 28 days.
■ Tdap: HCPs without documentation of receipt of Tdap should
receive a dose of Tdap, followed by decennial Td doses. Pregnant
HCPs should be revaccinated during each pregnancy.22
IMMUNIZATION IN RELATION TO ANTIBODY-

CONTAINING PRODUCTS (WHOLE BLOOD,
PACKED RED CELLS, PLASMA, IMMUNOGLOBULIN)
Live Vaccines
Blood (e.g., whole blood, packed red blood cells, and plasma)
and other antibody-containing blood products (e.g. Ig,
hyperimmunoglobulin, and IVIg) can inhibit the immune response
to live vaccines such as measles and rubella vaccines for 3 months
or longer. The effect of blood and Ig preparations on the response to
mumps and varicella vaccines is unknown; however, commercial Ig
preparations contain antibodies to these viruses. Other live vaccines
such as Ty21a typhoid, rotavirus, yellow fever, LAIV, and zoster
vaccines may be administered at any time before, concurrent with,
or after administration of any Ig, hyperimmunoglobulin, or IVIg.19
The length of time that interference with injectable live-virus vaccine
can persist after the antibody-containing product depends upon
the amount of antigen-specific antibody contained in the product.
Therefore, after an antibody-containing product is received, live
vaccines (other than oral Ty21a typhoid, LAIV, rotavirus zoster,
and yellow fever) should be delayed until the passive antibody has
degraded (Table 6).
If a dose of injectable live virus vaccine (other than yellow fever
and zoster) is administered after an antibody-containing product
but at an interval shorter than recommended (see Table 6), the
vaccine dose should be repeated unless serologic testing is feasible
TABLE 6: Guidelines for administering antibody-containing products* and

vaccines.23
Type of Products Recommended minimum interval
administration administered between doses
Simultaneous Antibody- Can be administered simultaneously at
(during the containing different anatomic sites or at any time
same office products and interval between doses
visit) inactivated
antigen
Antibody- Should not be administered
containing simultaneously.† If simultaneous
products and administration of measles-containing
live antigen vaccine or varicella vaccine is
unavoidable, administer at different
sites and revaccinate or test for
seroconversion after the recommended
interval (Table 7)
Non Administered Administered
simultaneous first second
Antibody- Inactivated antigen No interval
containing necessary
products
Inactivated Antibody- No interval
antigen containing products necessary
Antibody- Live antigen Dose-related†,§
containing
products
Live antigen Antibody- 2 weeks†
containing products
Notes:
*Blood products containing substantial amounts of immunoglobulin include
intramuscular and intravenous immunoglobulin, specific hyperimmunoglobulin
(e.g., hepatitis B immunoglobulin, tetanus immunoglobulin, varicella zoster
immunoglobulin, and rabies immunoglobulin), whole blood, packed red blood
cells, plasma, and platelet products.
†
Yellow fever vaccine; rotavirus vaccine; oral Ty21a typhoid vaccine; live-
attenuated influenza vaccine; and zoster vaccine are exceptions to
these recommendations. These live, attenuated vaccines can be administered
at any time before or after or simultaneously with an antibody-containing
product.
§
The duration of interference of antibody-containing products with the immune
response to the measles component of measles-containing vaccine, and
possibly varicella vaccine is dose-related (Table 7).
TABLE 7: Recommended intervals between administration of antibody-

containing products and measles or varicella-containing vaccine, by
product and indication for vaccination.28
Recommended
interval before
measles containing
vaccine† or
varicella vaccine
administration
Product/indication Dose (mg IgG/kg) Route* (months)
Tetanus Ig 250 units (10 mg IM 3
IgG/kg)
Hepatitis A Ig 0.02–0.06 mL/kg IM 3
(3.3–10 mg IgG/
kg)
Hepatitis B Ig 0.06 mL/kg (10 mg IM 3
IgG/kg)
Rabies Ig 20 IU/kg (22 mg IM 4
IgG/kg)
Varicella Ig 125 units/10 kg IM 5
(60–200 mg IgG/kg)
maximum 625
units
Measles prophylaxis Ig:
Standard 0.25 mL/kg (40 mg 5
IgG/kg)
IM
Immunocompromised 0.50 mL/kg (80 mg 6
IgG/kg)
Blood transfusion:
RBCs, washed 10 mL/kg, None
negligible IgG/kg
RBCs, adenine-saline 10 mL/kg (10 mg 3
added IgG/kg)
Packed RBCs 10 mL/kg (60 mg 6
(hematocrit 65%)§ IgG/kg)
IV
Whole blood 10 mL/kg (80–100 6
(hematocrit 35–50%)§ mg IgG/kg)
Plasma/platelet 10 mL/kg (160 mg 7
products IgG/kg)
Contd…
Contd…
Recommended
interval before
measles containing
vaccine† or
varicella vaccine
administration
Product/indication Dose (mg IgG/kg) Route* (months)
IVIG:
Replacement 300–400 mg/kg 8
therapy for immune
deficiencies¶
Immune 400 mg/kg 8
thrombocytopenic
purpura treatment
IV
Postexposure varicella 400 mg/kg 8
prophylaxis**
Immune 1,000 mg/kg 10
thrombocytopenic
purpura treatment
Kawasaki disease 2 g/kg 11
Monoclonal antibody 15 mg/kg IM None
to respiratory syncytial
virus (MedImmune)††
Cytomegalovirus IGIV 150 mg/kg IV 6
maximum
Notes:
*This table is not intended for determining the correct indications and dosages
for using antibody-containing products. Unvaccinated persons might not be
protected fully against measles during the entire recommended interval, and
additional doses of Ig or measles vaccine might be indicated after measles
exposure. Concentrations of measles antibody in an Ig preparation can vary by
manufacturer’s lot. Rates of antibody clearance after receipt of an Ig preparation
also might vary. Recommended intervals are extrapolated from an estimated
half-life of 30 days for passively acquired antibody and an observed interference
with the immune response to measles vaccine for 5 months after a dose of
80 mg IgG/kg.
†
Does not include zoster vaccine. Zoster vaccine may be given with antibody-
containing blood products.
§
Assumes a serum IgG concentration of 16 mg/mL.
Contd…
Contd…
¶
Measles and varicella vaccinations are recommended for children with
asymptomatic or mildly symptomatic HIV infection but are contraindicated
for persons with severe immunosuppression from HIV or any other
immunosuppressive disorder.
**The investigational VariZIG, similar to licensed varicella-zoster Ig (VZIG), is
a purified human Ig preparation made from plasma containing high levels of
antivaricella antibodies (IgG). The interval between VariZIG and varicella vaccine
is 5 months.
††
Contains antibody only to respiratory syncytial virus.
(HIV: human immunodeficiency virus; Ig: immunoglobulin; IM: intramuscular; IV:
intravenous; IVIG: intravenous immunoglobulin; RBC: red blood cells)
and indicates a response to the vaccine. The repeat dose or serologic

testing should be performed after the interval indicated for the
antibody containing product (Table 7). Although passively acquired
antibodies can interfere with the response to rubella vaccine,
the low dose of antiRho(D) globulin administered to postpartum
women has not been demonstrated to reduce the response to the
rubella vaccine.11 Because of the importance of rubella and varicella
immunity among women of child-bearing age, the postpartum
vaccination of women without evidence of immunity to rubella or
varicella with MMR or varicella vaccines should not be delayed
because of receipt of antiRho(D) globulin or any other blood
product during the last trimester of pregnancy or at delivery. These
women should be vaccinated immediately after giving birth and, if
possible, tested ≥3 months later to ensure immunity to rubella and
measles.19
Interference might occur if administration of an antibody-
containing product becomes necessary after administration of
MMR or varicella vaccines. Usually, vaccine virus replication and
stimulation of immunity occurs 1–2 weeks after vaccination. If
the interval between administration of any of these vaccines and
subsequent administration of an antibody-containing product is
<14 days, vaccination should be repeated after the recommended
interval (see Tables 6 and 7) unless serologic testing indicates a
protective antibody response.19
Inactivated Vaccines
Antibody-containing products interact less with inactivated vaccines,
toxoids, recombinant subunit, and polysaccharide vaccines than
with live vaccines. Therefore, administering inactivated vaccines and
toxoids either simultaneously with or at any interval before or after
receipt of an antibody-containing product should not substantially
impair development of a protective antibody response [exception is
administration of rabies immunoglobulin (RIG) 7 days after rabies
vaccine]. The vaccine or toxoid and antibody preparation should
be administered at different sites using the standard recommended
dose. Increasing the vaccine dose volume or number of vaccinations
is not indicated or recommended.19
IMMUNIZATION DURING ILLNESS

Immunization during acute illness may lead to lower immuno
genicity or vaccine failure. Hence, vaccination should be postponed
in a moderate or severe acute illness and parents instructed to
return for vaccination when the illness resolves. Vaccination is
also postponed to avoid superimposing vaccine reaction on the
underlying illness and to mistakenly attribute a manifestation of
underlying illness to vaccination. However, vaccination opportunity
should not be missed during minor illnesses such as upper
respiratory tract infections, mild diarrhea, and otitis media.19
IMMUNIZATION OF CHILDREN WITH

BLEEDING DISORDERS OR THOSE RECEIVING
ANTICOAGULANTS
Persons with bleeding disorders such as hemophilia and persons
receiving anticoagulant therapy are at increased risk for bleeding
after IM injection. When vaccines recommended to be given only by
the IM route are to be given, vaccination can be scheduled shortly
after administration of clotting factor replacement.
A 23 gauge or smaller needle should be used for the vaccination
and firm pressure without rubbing should be applied to the site for
at least 5–10 minutes. Alternately, vaccines recommended for IM
injection could be administered subcutaneously to persons with a
bleeding disorder if the immune response and clinical reaction to

these vaccines are expected to be comparable by either route of
injection, such as Hib conjugate vaccine, IPV, and PPSV.19
IMMUNIZATION IN PREGNANCY
Live vaccines are generally contraindicated in pregnant women.
The yellow fever vaccine should be avoided in pregnant women
as far as possible. However, if travel is unavoidable, the vaccine
should be given as the risks of infection outweigh the risks of
vaccination (preferably in the first trimester).24 Measles, MMR, and
varicella vaccines are contraindicated in pregnancy and pregnancy
should be avoided for 4 weeks after vaccination. However, routine
testing for pregnancy prior to immunizing with these vaccines is
not recommended. If the vaccine is inadvertently given during
pregnancy or pregnancy occurs within 4 weeks of vaccination,
termination of pregnancy is not warranted. Small cohort studies
show no increased rates of congenital abnormalities in infants
born to mothers inadvertently vaccinated in pregnancy. Measles,
MMR, and varicella vaccines can be safely given to contacts of
pregnant women as these vaccines do not spread from vaccine to
contacts.
Smallpox vaccine is the only vaccine known to be harmful to the
fetus.
All inactivated vaccines may be safely given during pregnancy
and readers are referred to the chapters on individual vaccines for
recommendations. Important are Td/TT/Tdap vaccines. The IAP
ACVIP and CDC ACIP have recommended immunization with
Tdap in every pregnancy preferably in the third trimester to reduce
the burden of pertussis in young infants.13,25 IIV and hepatitis B are
other vaccines of importance in pregnant women. Pregnant women
should not be given LAIV.6 Rabies vaccine should be administered to
pregnant women if indicated and is safe.
Passive immunization with Ig-containing preparations is safe in
pregnancy. All pregnant women should be evaluated for immunity to
rubella, varicella, and hepatitis B and those found susceptible should
be vaccinated immediately after delivery. All pregnant women
should be tested for hepatitis B virus surface antigen (HbsAg) and
if found HBsAg positive should be followed carefully to ensure that

the infant receives HBIg and begins the hepatitis B vaccine series
no later than 12 hours after birth and completes the recommended
hepatitis B vaccine series on schedule.
IMMUNIZATION IN LACTATION
All inactivated vaccines, whether conjugated, toxoid, or subunit
vaccines, are safe in breastfeeding women and pose no harm to
the babies. Although live vaccines multiply in the body of the
mother, most pose no harm to the babies as they are generally
not excreted in breast milk. Rubella vaccine may be excreted
in milk but does not infect the baby or if it all causes mild
asymptomatic infection. The only exception to live vaccine
use is yellow fever vaccine. Transmission of the yellow fever
vaccine virus through breast milk and resulting in infantile
meningoencephalitis has been described. Hence, yellow
fever vaccine should be avoided in breastfeeding mothers. If
mandatory, then breastfeeding should be interrupted for the
10-day postvaccination viremic period.24
IMMUNIZATION IN PRETERM/LOW BIRTH

WEIGHT INFANTS
In principle, all vaccines may be administered as per schedule
according to the chronological age irrespective of birth weight
or period of gestation. BCG and birth dose of OPV can be safely
and effectively given to low birth weight and preterm babies after
stabilization and preferably at the time of discharge.26,27 Studies
have shown that the take of BCG as assessed by induration following
Mantoux test and lymphocyte migration inhibition test (LMIT)
is similar in preterm or low birth weight babies whether given at
discharge or later.28 The birth dose of hepatitis B vaccine can be
administered at any time after birth in babies weighing 2 kg. However,
in babies <2 kg that immunogenicity of the birth dose of the vaccine
has been shown to be suboptimal in some studies.26 Hence, the
birth dose of hepatitis B vaccine in these babies should be delayed
till the age of 1 month. Alternatively, these babies may also be given
the first dose of the vaccine at the time of discharge if consistent

weight gain is achieved. In babies <2 kg born to a hepatitis B
positive mother, hepatitis B vaccine should be given along with HBIg
within 12 hours of birth and three more doses at 1, 2, and 6 months
are recommended. Since most developing countries employ the UPI
schedule of 6–10–14 weeks, with a pentavalent or hexavalent vaccine,
containing the Hepatitis B antigen, in 2017, the WHO recommended
that a birth dose of hepatitis B vaccine can be given to low birth weight
and premature infants. For these infants, the birth dose should not
count as part of the primary three-dose series; the three doses of the
standard primary series should be given according to the national
vaccination schedule.23
All other childhood vaccines may be given as per chronologic
age if medically stable infant while in hospital except rotavirus
vaccine, which should be deferred until discharge from hospital
to prevent the potential health care-associated spread of this live
vaccine virus and have acceptable safety, immunogenicity, and
efficacy. Full dose of the vaccines should be used. Since preterm
and low birth weight babies may have low muscle mass, the
use of needles with lengths of 5/8 inch or less is appropriate to
ensure effective, safe, and deep anterolateral thigh intramuscular
administration. As preterm, low birth weight babies have increased
susceptibility to infections, vaccines such as PCV, rotavirus, and
influenza should be offered if resources permit. Preterm babies
are at increased risk of chronic complication from influenza,
immunization of babies age appropriate (6 months) as well as
immunization of HCPs handling babies and all household contacts
should be considered.6
LAPSED IMMUNIZATION/PREPONED
IMMUNIZATION/UNKNOWN IMMUNIZATION
STATUS
There is no need to restart a vaccine series regardless of the
time that has elapsed between individual doses due to immune
memory. Immunizations should be given at the next visit as if
the usual interval had elapsed and the immunization scheduled
should be completed at the next available opportunity. Doses

should not be given 4 or less days from the minimum interval. If
inadvertently given 5 or more days from the minimum interval, the
dose should not be counted. In case of unknown immunization
status, the child should be considered unimmunized and
vaccinated accordingly. Self-reported doses should not be
accepted in the absence of documentation with the exception of
influenza and PPSV vaccines. Serologic testing is also an option
in patients with uncertain status but is usually not cost-effective,
may reduce compliance, and may result in missed opportunities
for vaccination.19
CATCH-UP IMMUNIZATION
Vaccination catch-up regimens should preferably be individualized.
The basic principles are discussed. Any number of vaccines live
or inactivated may be given on the same day either singly or
as combination vaccines maintaining a gap of 2.5 cm between
different vaccination sites. Inactivated vaccines can be given
at any time in relation to any other live or inactivated vaccines.
If not given on the same day, a gap of 4 weeks should be maintained
between two live injectable vaccines, especially MMR and varicella
and also yellow fever and LAIV. However, OPV, rotavirus, and oral
typhoid vaccines may be given at any time in relation to any live
or inactivated vaccine. For catchup immunization, doses should
preferably be given at the minimum possible interval to entail early
protection.19
REFERENCES
1. Casswall TH, Fischler B. Vaccination of the immunocompromised
child. Expert Rev Vaccines. 2005;4(5):725-38.
2. McFarland E. Immunizations for the immunocompromised child.
Pediatr Ann. 1999;28(8):487-96.
3. Canadian Immunization Guide. (2021). General recommendations
and principles. [online] Available from: https://www.canada.ca/en/
public-health/services/canadian-immunization-guide.html [Last
4. Rubin GL, Levin MJ, Ljungman P, Davies EG, Avery R, Tomblyn M,

et al. 2013 IDSA clinical practice guidelines for vaccination of the
immunocompromised host. Clin Infect Dis. 2014;58(3):e44-100.
5. Moss W, Halsey N. Vaccination of human immunodeficiency virus
infected persons. In: Plotkin S, Orenstein W, Offit P (Eds). Vaccines,
7th edition. US: Saunders Elsevier Publishers & Distributors; 2018.
pp. 1370-82.
6. American Academy of Pediatrics. Immunization in special clinical
circumstances. In: Pickering LK, Baker CJ, Kimberlin DW, Long SS
(Eds). Red Book: 2018 Report of the Committee on Infectious Diseases,
28th edition. Elk Grove Village, IL: American Academy of Pediatrics;
2009.
7. Martire B, Ottaviano G, Sangerardi M, Sgrulletti M, Chini L, Dellepiane
RM, et al. Vaccinations in Children and adolescents treated with
immune-modifying biologics: Update and current developments.
J Allergy Clin Immunol Pract. 2022;10(6):1485-96.
8. Zerbo O, Modaressi S, Goddard K, Lewis E, Getahun D, Palmsten KK,
et al. Safety of live-attenuated vaccines in children exposed to biologic
response modifiers in utero. Pediatrics. 2022;150(1):e2021056021.
9. Martín Ibáñez I, Arce Casas A, Cruz Martínez O, Estella Aguado J,
Martín Mateos MA. Humoral immunity in pediatric patients with
acute lymphoblastic leukaemia. Allergol Immunopathol (Madr).
2003;31(6):303-10.
10. Moulik NR, Mandal P, Chandra J, Bansal S, Jog P, Sanjay S,
et al. Immunization of children with cancer in India treated with
chemotherapy - Consensus Guideline from the Pediatric Hematology-
Oncology Chapter and the Advisory Committee on Vaccination and
Immunization Practices of the Indian Academy of Pediatrics. Indian
Pediatr. 2019;56(12):1041-8.
11. Indian Academy of Pediatrics Committee on Immunization (IAPCOI).
Consensus recommendations on immunization and IAP immunization
timetable 2012. Indian Pediatr. 2012;49(7):549-64.
12. American Academy of Pediatrics. Varicella-Zoster virus infections. In:
Kimberlin DW, Barnett MD (Eds). Red Book: 2021–2024 Report of the
Committee on Infectious Diseases, 32nd edition. Itasca: American
Academy of Pediatrics; 2021.
13. Indian Academy of Pediatrics, Advisory Committee on Vaccines and
Immunization Practices (ACVIP), Vashishtha VM, Kalra A, Bose A,
Choudhury P, Yewale VN, et al. Indian Academy of Pediatrics (IAP)
Recommended Immunization Schedule for Children Aged 0 through
18 years—India, 2013 and Updates on Immunization. Indian Pediatr.
2013;50(12):1095-108.
14. Australian Immunization Handbook. Recommendations for

re-vaccinations after HSCT. [online] Available from: https://
immunisationhandbook.health.gov.au/contents/vaccination-
f o r-s p e c i a l - r i s k- g rou p s / va c c i nat i o n - f o r-p e o p l e - w h o - a re -
immunocompromised. [Last accessed December, 2022].
15. Danziger‐Isakov L, Kumar D; AST ID Community of Practice.
Vaccination of solid organ transplant candidates and recipients:
Guidelines from the American society of transplantation infectious
diseases community of practice. Clinical Transplantation.
2019;33(9):e13563.
16. Shatz DV, Schinsky MF, Pais LB, Romero-Steiner S, Kirton OC,
Carlone GM. Immune responses of splenectomized trauma
patients to the 23-valent pneumococcal polysaccharide vaccine at
1 versus 7 versus 14 days after splenectomy. J Trauma. 1998;44(5):
760-5.
17. Price VE, Blanchette VS, Ford-Jones EL. The prevention and
management of infections in children with asplenia or hyposplenia.
Infect Dis Clin North Am. 2007;21:697-710.
18. Papadopoulou-Alataki E, Hassan A, Davie EG. Prevention of infection
in children and adolescents with primary immunodeficiency disor-
ders. Asian Pac J Allergy Immunol. 2012;30:249-58.
19. Centers for Disease Control and Prevention (CDC). General
Recommendations on Immunization. Recommendations of the
Advisory Committee on Immunization Practices (ACIP). MMWR.
2019;60:1-61.
20. Nilsson L, Brockow K, Alm J, Cardona V, Caubet JC, Gomes E, et al.
Vaccination and allergy: EAACI position paper, practical aspects.
Pediatr Allergy Immunol. 2017;28:628-40.
21. Maltezou HC, Poland GA. Immunization of health-care providers:
Necessity and public health policies. Healthcare. 2016;4:47.
22. Centers for Disease Control and Prevention. Recommended vaccines
for healthcare workers. [online] Available from :https://www.cdc.gov/
vaccines/adults/rec-vac/hcw.html. [Last accessed December, 2022].
23. World Health Organization. Hepatitis B vaccines: WHO position paper
– July 2017. [online] Available from: http://www.who.int/wer. [Last
24. Imbert P, Moulin F, Mornand P, Méchaï F, Rapp C. Should yellow fever
vaccination be recommended during pregnancy or breastfeeding?
Med Trop (Mars). 2010;70(4):321-4.
25. Centers for Disease Control and Prevention (CDC). Updated
recommendations for use of tetanus toxoid, reduced diphtheria toxoid,
and acellular pertussis vaccine (Tdap) in pregnant women—Advisory
Committee on Immunization Practices (ACIP), 2012. MMWR Morb

Mortal Wkly Rep. 2013;62:131-5.
26. Saari TN, American Academy of Pediatrics Committee on Infectious
Diseases. Immunization of preterm and low birth weight infants.
Pediatrics. 2003;112:193-8.
27. Thayyil-Sudhan S, Singh M, Broor S, Xess I, Paul VK, Deorari AK. Is
zero dose oral polio vaccine effective in preterm babies? Ann Trop
Paediatr. 1998;18(4):321-4.
28. Thayyil-Sudhan S, Kumar A, Singh M, Paul VK, Deorari AK. Safety and
effectiveness of BCG vaccination in preterm babies. Arch Dis Child
Fetal Neonatal Ed. 1999;81(1):F64-6.
4.3 VACCINATION STRATEGIES FOR TRAVELERS
Srinivas G Kasi, Harish Kumar Pemde
INTRODUCTION
The importance of protecting the health of individual travelers, as
well as safeguarding the health of the communities to which they
return, cannot be overstated. In the past 10 years, e.g., travelers
have faced newly emerging threats, including Ebola, chikungunya,
Zika, multidrug-resistant typhoid, and tuberculosis (TB). For
travelers, vaccination offers the possibility of avoiding a number
of diseases that may be encountered during international travel.
While evaluating the need for vaccination in travelers, it is important
to consider not only the incidence rate but also the impact of the
respective infection.1 Immunized travelers will also be less likely to
contaminate other travelers or the local population with a number of
potentially serious diseases.
Travelers in most countries rarely seek health advice before
travel. From a cross-sectional survey in Europe, it is noticed that only
52.1% of responders had sought travel health advice.2
The travelers need to know about prevalence of diseases in
destination country, magnitude and risk of acquiring the diseases,
and means to prevent illness. The risk to a traveler of acquiring a
disease also depends on age, immunization status and current
health state of traveler, travel itinerary, duration, and style of travel.
Based on these factors, healthcare professional has to decide about
need for immunizations and/or preventive medication (prophylaxis)
and provide advice. Regardless of administration of vaccine/
medications, traveler should always follow all possible precautions
against infection for avoiding disease.
VACCINATION SCHEDULE
There cannot be a single schedule for the administration of
immunizing agents, which may be applicable to all travelers. With
considering individual traveler’s immunization history, the countries
to be visited, the type and duration of travel, and the availability of

time for vaccination before departure, a tailored-made schedule
should be suggested to travelers.
TIMING OF VACCINATION
Traveler should consult healthcare provider sufficiently in advance
before departure about the need of immunization. The time period
may vary depending on the type of vaccine and number of doses
required for immunity to develop. At times, usual vaccination schedule
may have to vary marginally to meet the requirement of the travelers.
If full vaccination is not possible, partial vaccination may be done
with advice to complete the schedule after reaching the destination
country. If multiple live vaccines are to be given, they should be given
simultaneously at multiple sites, as otherwise inoculation of two live
virus vaccines should be separated by at least 4 weeks. All schedules
should be completed at least 2 weeks before the day of travel.
Combination vaccines offer important advantages of compliance
because of reduced number of injection and visits.
CHOICE OF VACCINES
Vaccines for travelers include: (1) Basic vaccines used in routine
immunization programs in all age groups and (2) vaccines that may
be advised before travel to countries or areas at risk of these diseases.
As per International Health Regulations, vaccination to prevent
yellow fever and meningococcal diseases is required for visiting
certain countries.3
The vaccines that may be recommended or considered for
travelers are summarized in Table 1.
ROUTINE VACCINATION
Travelers need to be up-to-date in age-recommended vaccinations
or have a change in the routine immunization schedule as it applies
to travelers.3,4
Bacillus Calmette–Guérin Vaccine

Bacillus Calmette–Guérin (BCG) immunization may be considered
for travelers planning extended stays in areas of high tuberculosis
TABLE 1: Vaccines for travelers.

Routine vaccination • Diphtheria
• Hepatitis B
• Haemophilus influenzae type b
• Seasonal influenza
• Measles
• Mumps
• Pertussis
• Rubella
• Pneumococcal disease
• Poliomyelitis (Polio)
• Rotavirus
• Tuberculosis
• Tetanus
• Varicella
Selective use for • Hepatitis A
travelers • Typhoid fever
• Rabies
• Cholera
• Japanese encephalitis
• Tick-borne encephalitis
Country-specific • Yellow fever
mandatory vaccines for • Meningococcal conjugate
travelers • Oral poliovirus vaccines
prevalence and where tuberculin skin testing and appropriate

chemoprophylaxis may not be feasible or where primary isoniazid
resistance of Mycobacterium tuberculosis is high. This may not be
relevant to Indian travelers, who have all received BCG during the
neonatal period.
Diphtheria, Tetanus, and Whole-cell

Pertussis/Diphtheria, Tetanus, and Acellular
Pertussis/Diphtheria Toxoid, and Acellular Pertussis
and its Combination Vaccine
For infants embarking on travel, the primary vaccination series
with diphtheria, tetanus, whole cell/acellular pertussis, polio, and
Haemophilus influenzae type b can be accelerated and can be
started at 6 weeks of age. For adults who have not previously received
a dose of pertussis vaccine, it is recommended that they are offered
diphtheria toxoid and acellular pertussis (Tdap) vaccine rather than
the tetanus and diphtheria booster dose (Td).
Measles and Measles, Mumps, and Rubella Vaccine

Pan-American Health Organization (PAHO)/World Health
Organization (WHO) recommends vaccination against measles and
rubella for all travelers visiting countries in the Americas. PAHO
also recommends that any resident of the Americas planning to
travel to other regions of the world should be protected against
measles and rubella prior to departing on their trip. Two doses of
a measles containing vaccine (MR/MMR) is recommended for all
unimmunized adult travelers who were born in or after 1957 and
who are en route to a measles-endemic area, unless there is serologic
proof of immunity or physician documentation of prior measles.
Infants aged 6–11 months should have at least one MCV dose.
Infants vaccinated before age 12 months must be revaccinated on or
after the first birthday with two doses of MCV separated by ≥28 days.
Preschool children aged ≥12 months and school-age children should
have two MCV doses separated by ≥28 days.3,5
Hepatitis B Vaccine
Travelers including children who will be visiting areas with high
levels of endemic hepatitis B infection and are likely to have contact
with blood or blood products are recommended pretravel hepatitis
B vaccination.
SELECTIVE USE FOR TRAVELERS

Meningococcal Disease
Invasive meningococcal disease, in both endemic and epidemic
forms, is the cause of significant morbidity and mortality worldwide.
Among the different serogroups of Neisseria meningitidis, serogroups
A, B, and C account for up to 90% of the disease.6 In the last few years,
there has been a shift in the epidemic pattern of meningococcal
disease during the Hajj (pilgrimage) season, with predominance of

N. meningitidis serogroup W135.
The recommendation for meningococcal vaccine for travelers
mainly relates to: (1) Travelers to areas with current outbreaks;
(2) travelers particularly <30 years of age who are traveling to the
sub-Saharan meningitis belt during the dry season (December–
June); (3) all pilgrims arriving to Saudi Arabia for purposes of Umrah
and Hajj;7 (4) refugee settings with overcrowding, and persons who
travel to work in these settings; (5) individuals with underlying health
problems recognized to increase the risk of acquiring meningococcal
disease, e.g., functional or anatomic asplenia, terminal complement
deficiency, or any other immune-suppressing conditions.
The quadrivalent meningococcal vaccine is already mandatory
for Hajj pilgrims. For travelers or pilgrims who have received prior
bivalent meningococcal vaccine, crossover vaccination with the
quadrivalent meningococcal vaccine may be justified in view of
the seriousness of the W135 problem. Travelers who have already
received the conjugate C vaccine need to additionally receive the
quadrivalent meningococcal vaccine, if traveling to countries where
serogroups other than serogroup C are prevalent.
Yellow Fever
Yellow fever occurs in sub-Saharan Africa and tropical South
America, where it is endemic and intermittently epidemic. In rural
West Africa, yellow fever virus transmission is seasonal (usually July–
October) while that in South America is highest during the rainy
season (January–May).8
Yellow fever is currently the only disease for which proof of
vaccination may be required for travelers as a condition of entry to
a State Party under Annex 7 of the International Health Regulations
(2005). The 17D live-attenuated yellow fever vaccine is the only
commercially available vaccine and has been widely acknowledged
as one of the most effective vaccine in use.9 Yellow fever vaccine is
contraindicated for infants aged <9 months, those with history of
hypersensitivity and for people with acquired immunodeficiency
syndrome. A single subcutaneous (or intramuscular) injection of
live, attenuated vaccine should be administered 10 days before the
travel date. The period of validity of the International Vaccination

Certificate for yellow fever is life time beginning 10 days after
vaccination.10
Hepatitis A
Protection against hepatitis A is highly recommended for all
nonimmune travelers to areas or with inadequate sanitary facilities
in countries where the disease is endemic. As the hepatitis A
virus has long incubation period even if the inactivated vaccine is
administered on the day of departure will be protective. One dose
of monovalent hepatitis A vaccine administered at any time before
departure can provide adequate protection for most healthy people
aged ≤40 years. For adults aged >40 years, immunocompromised
people, and people with chronic liver disease or other chronic
medical conditions planning to depart to an area in <2 weeks should
receive the initial dose of vaccine along with immunoglobulin in
dose of 0.02 mL/kg.11 For infants <1 year of age protection may be
provided by immune globulin. Since immune globulin provides
protection for only 3–5 months, it should be given immediately
before departure and would provide protection for only 3–5 months.
Rabies
Countries are categorized as 1 (no risk) to 4 (high risk). In countries
or areas belonging to categories 2–4, preexposure immunization
against rabies is recommended for travelers. Modern rabies vaccines
cell-culture or embryonated egg origin are safer and more effective.
Pre-exposure immunization should be considered for: (1) travelers
intending to live or work in areas where rabies is enzootic and rabies
control programs for domestic animals are inadequate; (2) travel
to area where adequate and safe postexposure management is not
available; (3) travelers with extensive outdoor exposure in rural
areas—such as might occur while running, bicycling, hiking, and
camping, irrespective of the travel duration; (4) individuals traveling
to countries or areas where modern rabies vaccines are in short
supply.
A course of one-site intramuscular (or two sites intradermal)
injection of modern vaccines should be administered on day 0 and
7 (total of two doses). The national guidelines on rabies prophylaxis

(National Center for Disease Control, India; 2019) recommends
one full dose of the rabies vaccine intramuscularly or 0.1 mL
intradermally on one site on days 0, 7, and booster on either day 21
or 28 (total three doses).
Japanese Encephalitis
Japanese encephalitis (JE) occurs in many Asian countries. The
risk varies according to season, destination, duration of travel, and
activities. The recommendations for JE vaccine for travelers are
for: (1) Travelers who plan to spend ≥1 month in endemic areas
during the Japanese encephalitis virus (JEV) transmission season;
(2) expatriates who will be based in urban areas but are likely to
visit endemic rural or agricultural areas during a high-risk period
of JEV transmission; (3) short-term (<1 month) travelers to endemic
areas during the JEV transmission season for travelers with extensive
outdoor exposure (camping, hiking, working, etc.); (4) travelers to an
area with an ongoing JE outbreak.12
The live-attenuated SA 14-14-2 vaccine is widely used in China
and in an increasing number of countries within the Asian region,
including India, the Republic of Korea, Sri Lanka, and Thailand. Two
doses of the inactivated JE vaccines should be administered at an
interval of 4 weeks and the schedule should be completed at least
1 week before potential exposure to JEV.
Typhoid Fever
Vaccine should be recommended to those traveling to destinations
where the risk of typhoid fever is high, especially individuals staying
in endemic areas for >1 month and/or in locations where antibiotic
resistant strains of Salmonella typhi are prevalent. The vaccination
should be given 1 week before departure. Travelers should be
informed that typhoid immunization is not 100% effective and other
hygienic measure should be undertaken. For the unimmunized, a
single dose of the typhoid-conjugated vaccine can be administered
at any age beyond 6 months. The polysaccharide typhoid vaccine
can be used above 2 years of age.
Cholera
Cholera vaccination is not required as a condition of entry to any
country. The vaccine should be considered for travelers visiting
endemic areas and who are at high risk, e.g., emergency or relief
workers. In India, killed bivalent oral O1 and O139 (ShancolTM) is
available. Two doses are given 14 days apart for individuals aged
≥1 year. One booster dose is recommended after 3 years. Whenever
to be used, the first dose should be administered at least 2 weeks
before the departure and for the effective protection, ideally the full
course of two doses should be completed before departure.
Polio
As per the Government of India regulation, people traveling from
India to polio-endemic countries (Afghanistan and Pakistan)
and those traveling to countries where poliovirus is in circulation
following importation will require to take a dose of oral polio at
least 4 weeks before the travel date irrespective of the age. The oral
poliovirus vaccines (OPVs) vaccination certificate will be issued
after additional dose and it will remain valid for 1 year. Any person
of any age residing in any of aforementioned countries traveling
to India will need to take a single dose of OPV 4 weeks before the
travel date.
Recently, it has been recommended to give one dose of OPV
and one fractional dose of inactivated polio vaccine (IPV) to all the
immigrants/returnees from Afghanistan and stool samples of the
immigrants up to 15 years of age, to be collected, to detect polio virus.
VACCINATION FOR IMMUNOCOMPROMISED

TRAVELERS
Immunocompromised hosts traveling overseas are at risk for
exposure to endemic pathogens. In general, the vaccine response
rate in these patients is diminished and they may be more likely
to have adverse effects from vaccines containing live-attenuated
virus. In addition, vaccines are immunomodulatory and may
impact immunologic conditions. Immunocompromised hosts
planning to travel overseas should be evaluated by a travel medicine
specialist familiar with the patient’s immunocompromised state and

medications.13,14
The traveler’s immune status is particularly relevant to immu
nizations. Overall considerations for vaccine recommendations,
such as destination and the likely risk of exposure to disease, are the
same for immunocompromised travelers as for other travelers. The
risk of a severe outcome from a vaccine-preventable disease must
be weighed against potential adverse events from administering a
live vaccine to an immunocompromised patient. In some complex
cases when travelers cannot tolerate recommended immunizations
or prophylaxis, the traveler should consider changing the itinerary,
altering the activities planned during travel, or deferring the trip.15
The travelers who have been on corticosteroid therapy for >2 weeks at
a dose equivalent to >20 mg/day of prednisone should be considered
analogous to patients with human immunodeficiency virus (HIV)
infection with a CD4 cell count <200 cells/mm3 and decision of
administration of live vaccines should be taken accordingly. Patients
receiving other immunosuppressive drugs should be advised on a
case-by-case basis depending on the degree of immune suppression
as judged by the prescribing physician.
Asplenic patients and persons with terminal complement
deficiencies are susceptible to overwhelming sepsis with
encapsulated bacterial pathogens. These groups of people should
be immunized with the meningococcal A/C/Y/W-135 conjugate
vaccine. Patients with limited immune deficits or asymptomatic
HIV going to yellow fever endemic areas may be offered yellow
fever vaccine and monitored closely for possible adverse effects. As
vaccine response may be suboptimal, such vaccinees are candidates
for serologic testing 1 month after vaccination. Travelers with
severe immune compromise should not be vaccinated with yellow
fever vaccine and should be strongly discouraged from travel to
destinations that put them at risk for yellow fever.
COVID VACCINATION FOR TRAVELER

Most countries insist on a fully vaccinated certificate for entry into
the country. According to the Centers for Disease Control and
Prevention (CDC), “Fully vaccinated” implies:
■ 2 weeks (14 days) after a dose of an accepted single-dose vaccine

■ 2 weeks (14 days) after the second dose of an accepted two-dose
series
■ 2 weeks (14 days) after receipt of the full series of an accepted
COVID-19 vaccine (not placebo) in a clinical trial
■ 2 weeks (14 days) after receipt of two doses of any “mix-and-
match” combination of accepted COVID-19 vaccines
administered at least 17 days apart.
Generally, all WHO listed COVID-19 vaccines are accepted
in most countries. Some countries require traveler to get tested
for COVID virus 3–5 days after arrival and some have mandatory
quarantine period (7–14 days).
VACCINATION FOR PREGNANT TRAVELERS

No evidence exists of risk from vaccinating pregnant women with
inactivated virus, bacterial vaccines, or toxoids. The benefits of
vaccinating pregnant women usually outweigh potential risks when
the likelihood of disease exposure is high, infection would pose a
risk to the mother or the fetus, and the vaccine is unlikely to cause
harm. Pregnant travelers may visit areas of the world where diseases
eliminated by routine vaccination in their native country are still
endemic, and therefore may require immunizations before travel. If
the pregnant traveler is at risk for influenza on this trip (high season),
she should be advised to be vaccinated with inactivated whole virus
or subunit influenza vaccine.
VACCINATION DOCUMENT
Travelers should be provided with a written record of all vaccines
administered preferably using the international vaccination
certificate. This certificate must be signed by the clinician or
authorized health worker. The certificate must also bear the official
stamp of the administering center. The certificate should be either in
English or in French. However, in addition to these two languages,
the certificate may also be completed in another language on the
same document. The traveler should be advised to carry copy of
the certificate. Yellow fever vaccines should be administered only
in authorized vaccination centers. Receipt of vaccine with date of
administration should be mentioned in the International Certificate

of Vaccination and signed by the administering authority. As a
proof of yellow fever vaccination, traveler must carry the original
International Certificate of Vaccination.
REFERENCES
1. Steffen R, Connor BA. Vaccines in travel health: from risk assessment
to priorities. J Travel Med. 2005;12(1):26-35.
2. Van Herck K, Van Damme P, Castelli F, Zuckerman J, Nothdurft
H, Dahlgren AL, et al. Knowledge, attitudes and practices in travel-
related infectious diseases: the European airport survey. J Travel Med.
2004;11(1):3-8.
3. World Health Organization. Vaccine preventable diseases and
vaccines. International travel and health, Annex 1—As of 1 July
2019. [online] Available from: https://www.who.int/publications/i/
item/9789241580472. [Last accessed December, 2022].
4. CDC. Traveller’s Health. [online] Available from: http://wwwnc.cdc.
gov/travel/destinations/list. [Last accessed December, 2022].
5. Epidemiological Alert: PAHO recommendations to travellers to
preserve America without measles or rubella (28/04/2011). [online]
Available from: http://www.who.int/immunization/GIN_June_2011.
pdf. [Last accessed December, 2022].
6. World Health Organization (WHO). Control of Epidemic Meningococcal
Disease: WHO Practical Guidelines, 2nd edition. Geneva: WHO; 1998.
p. 1, WHO/EMC/BAC/98.3.
7. Ministry of Hajj. Kingdom of Saudi Arabia. Important notices. Visas.
2010. [online] Available from: http://www.hajinformation.com/main/
t1510.htm. [Last accessed December, 2022].
8. Monath TP, Cetron MS. Prevention of yellow fever in persons traveling
to the tropics. Clin Infect Dis. 2002;34(10):1369-78.
9. Monath TP, Nichols R, Archambault WT, Moore L, Marchesani
R, Tian J, et al. Comparative safety and immunogenicity of two
yellow fever 17D vaccines (ARILVAX and YFVAX) in a phase III
multicenter, double-blind clinical trial. Am J Trop Med Hyg. 2002;66(5):
533-41.
10. World Health Organization. Yellow fever vaccine. WHO Position Paper.
Wkly Epidemiol Rec. 2003;78(40):349-59.
11. CDC. Update: Prevention of hepatitis A after exposure to hepatitis A
virus and in international travellers. Updated recommendations of the
Advisory Committee on Immunization Practices (ACIP). MMWR Morb
Mortal Wkly Rep. 2007;56(41):1080-4.
12. Fischer M, Lindsey N, Staples JE, Hills S; Centers for Disease Control and
Prevention (CDC). Japanese encephalitis vaccines: recommendations
of the Advisory Committee on Immunization Practices (ACIP). MMWR
Recomm Rep. 2010;59(RR-1):1-27.
13. Boggild AK, Sano M, Humar A. Travel patterns and risk behavior in
solid organ transplant recipients. J Travel Med. 2004;11:37-43.
14. Roukens AH, van Dissel JT, de Fijter JW, Visser LG. Health preparations
and travel-related morbidity of kidney transplant recipients traveling
to developing countries. Clin Transplant. 2007;21(4):567-70.
15. CDC. Immunocompromised Travellers. [online] Available from:
http://wwwnc.cdc.gov/travel/yellowbook/2014/chapter-8-advising-
travelerswith-specific-needs/immunocompromised-travellers. [Last
5 Future Vaccines and
Vaccine Hesitancy
Chapter
5.1 FUTURE VACCINES

Srinivas G Kasi, S Balasubramanium
INTRODUCTION
Since the introduction of the first vaccine by Edward Jenner in
1798, vaccination has helped control 14 major diseases—smallpox,
diphtheria, tetanus, yellow fever, pertussis, Haemophilus influenzae
type b disease, poliomyelitis, measles, mumps, rubella, typhoid,
rabies, rotavirus, and hepatitis B. In the case of smallpox, complete
worldwide eradication was achieved in 1980. Cases of poliomyelitis
have been reduced by 99% and it is targeted for eradication in the near
future. While rubella and congenital rubella syndrome have been
declared as eliminated from the Americas in 2015,1 they still persist
in other parts of the world. Eradication of more infectious diseases
is imminent as newer vaccines are expected to be introduced in the
near future.
NEWER TECHNOLOGIES
In the early stages of modern vaccinology, vaccines were produced
by the “empirical approach,” which consisted of isolate, inactivate,
and inject the microorganism which causes the disease. Many of
the highly successful vaccines, such as the diphtheria and tetanus
toxoids, pertussis, rabies, influenza, smallpox, polio, and the bacillus
Calmette-Guérin (BCG) vaccines, were produced utilizing this
technology. This was followed by the period of recombinant DNA
vaccines and the glycol-conjugated vaccines. Reverse vaccinology,
484 Future Vaccines and Vaccine Hesitancy
which was the first successful platform in the genomic area, resulted
in successful vaccines against the Group B meningococcus.2
Next-generation technologies are playing a very important role
in the development of vaccines against some of the diseases for
which vaccines are presently unavailable. These new technologies
have been made possible by the integration of developments in
biology, computer science, engineering, bioinformatics, physics,
and many other physical sciences. Structural vaccinology, wherein
protective B-cell epitopes are optimized in terms of stability epitope,
presentation, ease of production, and safety, has enabled design of
rationally engineered vaccines. The systems biology approach to
vaccines development enables prediction of immune response on
the basis of molecular signatures, which are identified within a few
days of vaccine administration.3,4
Several new platforms are in development and some are in
use. These include DNA vaccines, mRNA vaccines, viral-vectored
vaccines, and chimeric vaccines. The rapid development and
deployment of COVID-19 vaccines has resulted in some of these
platforms entering clinical usage.
With vaccines utilizing hidden epitopes, which are generally
less immunogenic, there is a need for potent adjuvants which are
also capable of skewing the immune response to a Th1 type. Some
of the novel adjuvants include MF59, liposomes, saponins, toll-like
receptor (TLR) agonists, and oligodendronucleotides.5
Needle-free vaccine delivery devices are being actively
investigated. These devices increase the ease and speed of delivery
vaccines, offer improved safety and compliance, decrease costs,
and reduce the pain associated with vaccinations, thereby making
vaccinations more acceptable. Transcutaneous immunization
using patches with microneedles coated with vaccine and antigen is
proving to be successful and is found to initiate robust humoral and
cell mediated immune responses.6
Vaccines in development are targeting pathogens with multiple
stages of development (malaria), unstable genomes [human
immunodeficiency virus (HIV)], or chronic infections [hepatitis B
virus (HBV) and human papillomavirus (HPV)]. Therapeutic cancer
vaccines, vaccines against autoimmune diseases, diabetes mellitus,
Future Vaccines and Vaccine Hesitancy 485
hypertension, allergies, addictions, obesity, and pregnancy are being

actively investigated.
NEWER VIRAL VACCINES

Dengue Virus Vaccine
DengvaxiaTM (also referred to as CYD-TDV) is a live recombinant
tetravalent dengue vaccine developed by Sanofi Pasteur and
administered in a three-dose schedule (0/6/12 months). Dengvaxia
was first licensed in December 2015. Due to the occurrence of
vaccine-induced antibody-dependent enhancement, in 2018, the
World Health Organization (WHO) issued fresh recommendations
for its use. The WHO recommended that only persons with evidence
of a past dengue infection should be vaccinated (based on an
antibody test, or on a documented laboratory confirmed dengue
infection in the past). Where pre-vaccination screening is not feasible,
the vaccine should be administered only in those areas vaccination
wherein recent serosurveys have documented seroprevalence rates
of at least 80% by age 9 years.7
Vaccines in phase III trials:
■ The Takeda vaccine (TAK-003) is a tetravalent vaccine in which
wild DEN2 is attenuated and the Env and PrM genes of DEN 1,
3, and 4 are inserted into the genome of the attenuated DENV2
backbone. The primary efficacy data from part 1 of an ongoing
phase 3 randomized trial was recently published.8 Vaccine
efficacy was 80.2% [95% confidence interval (CI), 73.3–85.3]
against virologically confirmed dengue and 95.4% (95% CI, 88.4–
98.2) against dengue leading to hospitalization. In those who
were seronegative at baseline (27.7%), the vaccine efficacy was
74.9% (95% CI, 57.0–85). VE against DEN 1 was 73.7% (74.5–87.6),
DEN 2: 97.7% (92.7–99.3), DEN 3: 62.6% (43.3–75.4), and DEN 4:
63.2% (−64.6 to 91.8).
The incidence of serious adverse events was similar in the vaccine
group and placebo group (3.1% and 3.8%, respectively).
In August 2022, Takeda’s QDENGA [Dengue Tetravalent Vaccine
(live, attenuated)] received approval in Indonesia, for use regardless
of prior dengue exposure.
■ TetraVax-DV (NIH) is a combination of four monovalent

attenuated DENVs, which have been attenuated by a targeted
30-nucleotide (nt) deletion (D30) in the 30 non-translated region
(NTR).9,10 Approximately 17,000 subjects including children,
adolescents, and adults have been included in a multicenter
trial in Brazil.9 Additional phase II trials of TetraVax-DV are also
ongoing in Thailand, Taiwan, and Bangladesh.10,11 This vaccine
has been licensed for further development to Instituto Butantan
in Brazil; VaBiotech in Vietnam; Panacea Biotec, Serum Institute
of India and Indian Immunologicals in India, and Medigen
Biotech in Taiwan.12
Vaccines in phase II trials:
■ TDENV-PIV: This is a purified inactivated vaccine (TDENV-PIV),
which consists of all four dengue serotypes. The encouraging
results in phase 1 trials in USA and Puerto Rico have resulted in
progress to phase 2 trials.13,14
Vaccines in phase I trials:
■ Merck’s V180, a recombinant subunit dengue vaccine, adjuvanted
with ISCOMATRIX, is in phase 1 studies.12
A DNA vaccine by the US Naval Medical Research Center (NMRC)
is being evaluated in a phase 1 trial.12
The Serum Institute of India is currently recruiting in
Australia for its phase I trial of its Dengusiil TM dengue vaccine
candidate.15
Human Immunodeficiency Virus Vaccine

The extraordinary genetic diversity and high mutability rate of
the virus and its capacity to “evade and escape” inside lymphoid
and macrophage cells, and the tropism of the virus for T helper
cells facilitating infection, spread, and persistence are some of the
obstacles researchers face in the development of vaccines against
HIV infections. Nevertheless, the possibility of T cell-based or
broadly neutralizing antibody-based vaccines hold promise and are
the cornerstone of future research.16
A heterologous prime-boost regimen consisting of priming with
a canary-pox HIV vector ALVAC-HIV and a booster with a full-length
recombinant gp120 envelope protein AIDSVAX B/E was tested in

the RV144 trial in 16,000 Thai subjects. A vaccine efficacy of 31.2%
(74 seroconversions versus 51) was seen in this trial. There was,
however, no effect on viral load at the set point. This was the first time
that a HIV vaccine trial showed a positive efficacy. Immunogenicity
analysis suggested that IgG specific for the V1V2 region of gp120 was
associated with reduced risk of HIV-1 infection and that plasma Env
IgA was directly correlated with infection risk.17
Two HIV vaccines are in phase 3 trials. The Imbokodo trial (HVTN
705/HPX2008) is evaluating a prime-boost regimen consisting
of priming immunizations with adenovirus serotype 26 (Ad26)
vectors encoding four different HIV “mosaic” antigens that combine
elements from multiple virus clades, followed by a boost containing
the HIV gp140 envelope protein in alum adjuvant. The gp140 boost
is derived from a clade C virus.18
The Mosaico trial is also evaluating a prime-boost strategy with
priming similar to the Imbokodo trial, while the boosting is done
with a bivalent clade C and mosaic gp140 protein construct.18
HVTN 704/HPTN 085 and HVTN 703/HPTN 081 trials
investigated the efficacy of intravenous infusions of the broadly
neutralizing antibody (bNAb) VRC01, administered every 8 weeks.
Unfortunately, both trials did not demonstrate any significant
efficacy.19
ALVAC-HIV (vCP2438) Bivalent clade C gp120/MF59, which is a
Canarypox vector encoding HIV-1 clade C gp120, clade B gp41, Gag,
and protease + protein boost comprising two clade C Env proteins
(TV1.C gp120 and 1086.C gp120), is in phase IIb/III trials (HVTN
702).20
HIV DNA-rTV: DNA prime and replication-competent Tiantan
vaccinia virus vector boost encoding Gag, Pol, and Env proteins from
HIV-1 CN54 is in phase IIb trials.20
ALVAC-HIV vCP1521 AIDSVAX B/E: Canarypox vector encoding
HIV-1 CRF01_AE Env, clade B Gag, the protease-encoding portion of
the Pol protein, and a synthetic polypeptide encompassing several
known CD8+ T-cell epitopes from the Nef and Pol proteins. AIDSVAX
B/E recombinant protein vaccine containing gp120 from HIV-1
clades B and CRF01_AE is in phase II trials.20
Respiratory Syncytial Virus Vaccine

Currently, there are at least 17 investigational RSV vaccines in
clinical development, including live-attenuated, vector-based,
particle-based, nucleic acid, and subunit vaccines. Target groups
include pediatrics, elderly, and maternal immunization to protect
the infant.21
An effective antiviral response following an RSV vaccine must
include a prolonged neutralizing antibody response, Th-1 polarized
immunity that promotes both CD8+ and CD4+ T cells, type I inter-
feron (IFN) secretion and an efficient mucosa immune response.
Figure 1 lists the recent efforts to develop safe and effective RSV
vaccines for populations at risk, with a primary focus on vaccine
candidates currently being evaluated in clinical trials.22
The only vaccine to complete phase 3 trials, ResVax, an
aluminum adjuvanted, fusion (F) protein recombinant nanoparticle
vaccine, showed a vaccine efficacy of 39% against medically
significant RSV LRTI (97.5% CI, −1 to 64%) 44% against RSV LRTI
hospitalizations (95% CI, 20–62%), and 48% against RSV LRTI with
severe hypoxemia (95% CI, −8 to 75%). This study did not meet the
prespecified success criterion for the primary clinical endpoint of
this trial.23
It is estimated that it will be at least 5–10 years until a safe and
effective vaccine is approved for clinical use.
HEPATITIS C VIRUS VACCINE

Hepatitis C virus (HCV) is a positive-strand ribonucleic acid (RNA)
virus, infecting approximately 185 million people worldwide.
HCV infection can potentially progress into liver cirrhosis and
hepatocellular carcinoma. Till date no effective vaccine is licensed.
Recent approvals of direct-acting antiviral agents (DAAs) that can
cure HCV infection are quite promising but concerns loom over
therapy accessibility and potential drug resistance. Evolution of viral
infections has proven that is it has been difficult to eliminate them by
therapeutics alone. Therefore, it is essential to develop an effective
prophylactic HCV vaccine.
Though a number of potential HCV vaccines have been
developed, none of them have proceeded to the late clinical
Fig. 1: RSV vaccines in development.

phases. A major hurdle of HCV vaccine development is induction

of protective immunity against this virus, which has a high genomic
diversity. It has been reported that recombinant soluble E2 (sE2) of
a GT1b strain produced from insect cells could induce neutralizing
antibodies in mice and macaques and also protect humanized
mice from HCV infection. The E2 antigen production is simple and
has a high yield (up to 100 mg/L culture supernatants), making it
technically possible to explore a multivalent vaccine that consists of
E2 of multiple genotypes to increase the antigenic coverage.24
A recombinant E1E2 protein (rE1E2) derived from a Gt1a isolate,
adjuvanted with MF59, has completed phase 1 trials. It was found to
be safe. The vaccine elicited polyfunctional CD4+ T cell responses
and humoral responses. Some participants also elicited cross
reactive nAbs.24
A new trivalent vaccine, which contains sE2 from genotype 1a,
1, and 3a, elicited stronger pan-genotypic neutralizing antibodies
than the monovalent vaccine in mice. Each sE2 component of this
trivalent vaccine elicited unique spectrum of neutralizing antibodies,
which acted synergistically to inhibit HCV infection.4 The trivalent
vaccine triggered stronger and more uniform multi-genotypic
neutralizing antibody responses than the monovalent vaccine in
rhesus macaques.24
Ebola Virus Vaccine

No approved vaccines are available to prevent the spread of Ebola
virus; however,5,6 during the epidemic in West Africa, accelerated
paths were developed for vaccine testing and introduction into
field use.25 ERVEB is a replication-competent, live, attenuated
recombinant vesicular stomatitis virus (rVSV) vaccine manufactured
by Merck. It is approved by the US Food and Drug Administration
(FDA) for the prevention of disease caused by Zaire ebolavirus in
individuals 18 years of age and older as a single-dose administration.26
A 6-month safety study found that the VSV-Ebola vaccine was
generally well-tolerated, supporting its use for persons at risk of
Ebola virus disease. The recombinant VSV-Ebola vaccine may also
have a role in preventing disease and death when administered
promptly after an exposure.
Malaria Vaccine
Vaccine development efforts have focused on preventing illness
from Plasmodium falciparum and to a lesser extent, on Plasmodium
vivax. Significant roles for both humoral and cell-mediated effectors
have been demonstrated in animal models, and both humoral
and cell-mediated immune responses are induced in humans
after natural malaria infection and following inoculation of many
candidate malaria vaccines including the vaccine described below.9
Malarial Vaccines
The RTS,S/AS01 vaccine is the only malaria vaccine to be
recommended for use by the WHO. The WHO has recommended
this vaccine for the prevention of P. falciparum malaria in children
living in regions with moderate-to-high malaria transmission, as
defined by WHO.27
Schedule: Three primary doses at a minimum interval of 4 weeks
between doses, beginning at 5 months of age, with a fourth dose
provided approximately 12–18 months after the third dose.
In the pivotal phase 3 studies done in 11 countries, over 12 months
of follow-up after the third dose, the vaccine efficacy against clinical
malaria (uncomplicated and severe) was 51% (95% CI 47–55) and
against severe malaria was 45% (95% CI 22–60). Over 46 months’
follow-up after the third dose, children who received a fourth dose
18 months after the third dose showed vaccine efficacy against
clinical malaria was 39% (95% CI 34–43) and against severe malaria
29% (95% CI 6–46).27
In addition, a reduction of 61% (95% CI 27–81) was seen in
malarial anemia, 29% (95% CI 4–47) reduction in blood transfusions
and 37% (95% CI 24–49) in malarial hospitalization, over a follow-up
of 4 years.27
PfSPZ, an attenuated whole sporozoite vaccine, which is
given intravenously, has shown a vaccine efficacy of 100% against
Controlled Human Malarial Infection model up to 79 days of
follow-up. It is now being studied in a cohort of 2,100 subjects.28
The R21/Matrix-M vaccine has shown an efficacy of 71–76%
against at least one malaria episode over 12 months (depending on
adjuvant dosage).28
RH5.1, which is a vaccine targeting blood stages, has completed

phase 2 trials and Pfs230D1M, which is a transmission blocking
agent, has completed phase 2 trials. 28
In addition, over 30 candidate vaccines are in various stages of
clinical trials.28
BACTERIAL VACCINES
Tuberculosis Vaccine
As on date, there are 14 tuberculosis (TB) vaccine candidates in
clinical trials (Fig. 2). These include vaccines based on subunits,
whole-cell mycobacteria, mycobacterial fusion protein(s) in new
adjuvant formulations (ID93: GLA-SE, H56.IC31, M72:ASO1E,
GamTBVac), and recombinant live-attenuated or replication-
deficient virus-vectored expressing one or more Mtb proteins
(Ad5Ag85, ChadOx1.85/MVA85A, TB/FLU-04L).29,30
Three vaccines are in phase 3 trials. These include the
recombinant BCG (VPM1002), which is being assessed in
newborns as a BCG replacement, in adolescents and adults
as a BCG booster and as a therapeutic vaccine. Mycobacterium
indicus pranii (MIP) vaccine by Cadilla and Indian Council
of Medical Research (ICMR) is a heat-killed MIP vaccine,
approved by the Drug Controller General of INDIA and FDA
as an immune-therapeutic and immunoprophylactic adjunct
therapy in multibacillary leprosy patients and for preventing the
development of leprosy among close contacts of leprosy patients.
The phase 3 trial, in India, is investigating the efficacy and safety
for the prevention of pulmonary TB among healthy household
contacts of sputum smear-positive TB patients. M. vaccae TM
vaccine, which is inactivated Mycobacterium vaccae, is licensed
in China as a therapeutic vaccine to shorten TB treatment for
patients with drug-susceptible TB.29,30
Shigella Vaccine
Shigellosis is an important cause of morbidity and mortality,
particularly in children <5 years old in developing countries. Several
vaccines are in various phases of clinical development.31
Fig. 2: Tuberculosis vaccines in clinical trials.
Future Vaccines and Vaccine Hesitancy
493
The chemically prepared glycoconjugate (O polysaccharide

covalently linked to carrier protein) of National Institutes of Health
(NIH) is in phase 3 trials.
The virG-based live-attenuated (WRSS1, WRSs3, WRSf3) of
WRAIR, Silver Spring, Maryland, USA, and the Recombinant
glycoconjugate O polysaccharide specific biconjugate vaccine of
LimmaTech Biologics AG Schlieren, Switzerland, are in phase 2
trials.
Inactivated trivalent Shigella whole cell formalin inactivated
vaccine of PATH and WRAIR, guaBA-based live-attenuated (CVD
1208, CVD 1208S) University of Maryland School of Medicine,
Baltimore, and the GMMA vaccine of Sclavo Behring Vaccines
Institute for Global Health are in phase 1 trials.
Nine vaccines are in the preclinical phase of development.31
Escherichia coli Vaccine

The majority of enterotoxigenic Escherichia coli (ETEC) vaccine
candidates currently under development use various platforms
to induce anti-labile toxin (LT) and anti-colonization factor/coli
surface (CF/CS) antibodies. This will result in thereby blockage of
adherence to the intestinal lining and pathogenicity. Two cellular
candidate vaccines have completed phase ½ studies. ACE527 is a
vaccine consisting of three ETEC strains expressing major colonizing
factor (CF) and coli surface (CS) antigens, combined with the B
subunit of labile toxin, was demonstrated a significant efficacy, when
combined with a mucosal adjuvant, nontoxic double mutant of LT,
dmLT. This candidate is not currently under active development.31
ETVAX, consists of four E. coli preparations engineered to express
large quantities of colonization factors (CFA/I) and coli surface
proteins designated CS3, CS5, or CS6, formulated with B subunit
of the cholera toxin and coadministered with dmLT as a mucosal
adjuvant. This vaccine has successfully completed a phase 1/2
trial in Bangladeshi children in three age groups between 6 and 23
months.32 It was found to be safe and elicited mucosal IgA antibody
responses in most participants in the two older age groups, whereas
such responses to four of the five antigens were less frequent and of
lower magnitude in infants aged 6–11 months than in older children.
This vaccine was successful in a protection trial in Finnish travelers

to Benin.33
Group B Streptococcus Vaccine

Maternal immunization against group B Streptococcus (GBS) during
pregnancy might protect infants across the period of susceptibility
to invasive disease, but no licensed vaccine exists. A phase 1b/2,
randomized, observer-blind single-center study of an investigational
trivalent GBS vaccine in healthy nonpregnant women (cohort 1) and
a dose-ranging study in healthy pregnant women (cohort 2) assessed
the safety and immunogenicity of a CRM197-conjugated trivalent
GBS vaccine in nonpregnant and pregnant women, and antibody
transfer to their infants. The vaccine was well-tolerated and induced
capsular-specific antibody responses, in nonpregnant and pregnant
women. Maternal vaccination led to higher GBS serotype-specific
antibody concentrations in infants than did placebo, with both
interventions resulting in similar safety profiles.34
Other vaccines in development include vaccines targeting
hepatitis E,35 Staphylococcus aureus,36 cytomegalovirus,37 Epstein–
Barr virus,38 Group A streptococci,39 and vaccines targeting the
neglected tropical diseases.40
While vaccines have long been considered to be prophylactic
interventions, therapeutic vaccines against cancers,41 autoimmune
diseases,42 and chronic infections, e.g., hepatitis B, HPV, and HCV
are being investigated. In addition, vaccines targeting hypertension,
obesity, allergies, and addictions are also being investigated.
Cancer Vaccines
The only currently approved vaccine-based therapy for advanced
cancer is Sipuleucel-T, which is an autologous dendritic-cell
preparation engineered to target prostatic acid phosphatase (PAP).
It demonstrated an overall survival benefit in men with castrate-
resistant prostate adenocarcinoma.43
Single-peptide vaccines continue to be tested extensively,
especially in “immunogenic” cancers such as melanoma. 41
A patient-specific anti-idiotypic vaccine in B cell lymphoma, which
offers a modest prolongation of remission, is an exception, which has
not failed phase III. Therefore, there is currently some interest in

different approaches to cancer vaccines, namely seeking to inhibit
regulatory pathways which down-modulate the body’s own immune
response to tumor-associated antigens. In the long run, a better
target for cancer vaccines may be minimal residual disease rather
than eliminating extensive metastatic deposits.
REFERENCES
1. Orenstein W, Offit P, Edwards KM, Plotkin S. Plotkin’s Vaccines, 7th
edition, Philadelphia: Elsevier; 2018.
2. Cianci R, Franza L. Recent Advances in Vaccine Technology and
Design. Vaccines. 2022;10:624.
3. Finco O, Rappuoli R. Designing vaccines for the twenty-first century
society. Front Immunol. 2014;5:12.
4. Mao HH, Chao S. Advances in vaccines. Adv Biochem Eng Biotechnol.
2020;171:155-88.
5. Pulendran B, Arunachalam PS, O’Hagan DT. Emerging concepts in the
science of vaccine adjuvants. Nat Rev Drug Discov. 2021;20(6):454-75.
6. Garg N, Aggarwal A. Advances towards painless vaccination and newer
modes of vaccine delivery. Indian J Pediatr. 2018;85(2):132-8.
7. World Health Organization. Dengue Vaccine: WHO Position Paper,
September 2018. [online] Available from: who.int/publications-detail-
redirect/who-wer9335-457-476. [Last accessed December, 2022].
8. Rivera L, Biswal S, Sáez-Llorens X, Reynales H, López-Medina E, Borja-
Tabora C, et al. Three-year Efficacy and Safety of Takeda’s Dengue
Vaccine Candidate (TAK-003). Clin Infect Dis. 2022;75(1):107-17.
9. National Institutes of Health. Phase II trial to evaluate safety and
immunogenicity of a dengue 1,2,3,4 (attenuated) vaccine. [online]
Available from: https://clinicaltrials.gov/ct2/show/NCT01696422.
10. National Institutes of Health. A clinical study to evaluate TV003 in
healthy adults in Taiwan. [online] Available from: https://clinicaltrials.
gov/ct2/show/NCT03485144. [Last accessed December, 2022].
11. National Institutes of Health. Safety and immunogenicity of the
dengue virus vaccine TV005 (TetraVax-DV TV005) in healthy adults,
adolescents, and children in Dhaka, Bangladesh. [online] Available
from: https://clinicaltrials.gov/ct2/show/NCT02678455. [Last
12. Swaminathan S, Khanna N. Dengue vaccine development: Global and
Indian scenarios. Int J Infect Dis. 2019;84:S80-6.
13. Schmidt AC, Lin L, Martinez LJ, Ruck RC, Eckels KH, Collard A, et al.
Phase 1 randomized study of a tetravalent dengue purified inactivated
vaccine in healthy adults in the United States. Am J Trop Med Hyg.
2017;96(6):1325-37.
14. Diaz C, Lin L, Martinez LJ, Eckels KH, Campos M, Jarman RG, et al.
Phase I Randomized study of a tetravalent dengue purified inactivated
vaccine in healthy adults from Puerto Rico. Am J Trop Med Hyg.
2018;98(5):1435-43.
15. National Institutes of Health. A phase 1 safety study of dengusiil in
healthy adults. [online] Available from: https://clinicaltrials.gov/ct2/
show/NCT04035278. [Last accessed December, 2022].
16. Haynes BF. New approaches to HIV vaccine development. Curr Opin
Immunol. 2015;35:39-47.
17. Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, Kaewkungwal J, Chiu J,
Paris R, et al. Vaccination with ALVAC and AIDSVAX to Prevent HIV-1
Infection in Thailand. N Engl J Med. 2009;361:2209-20.
18. Stieh D. HVTN 705-706 Imbokodo & Mosaico updates, plans for
correlates and sieve analyses. Paper presented at: HVTN Full Group
Meeting; 2021.
19. HIV Prevention Trials Network. Most advanced clinical trials testing
broadly neutralizing antibody against HIV demonstrate efficacy against
sensitive strains. [online] Available from: https://www.hptn.org/news-
and-events/press-releases/most-advanced-clinical-trials-testing-
broadly-neutralizing-antibody. [Last accessed December, 2022].
20. Pipeline Report » 2021. HIV Vaccines & Passive Immunization [online]
Available from: https://www.treatmentactiongroup.org/wp-content/
uploads/2021/07/pipeline_2021_HIV_vaccine_final.pdf. [Last
21. Domachowske JB, Anderson EJ, Goldstein M. The future of respiratory
syncytial virus disease prevention and treatment. Infect Dis Ther.
2021;10:S47-60.
22. PATH. RSV Vaccine and mAb Snapshot. [online] Available from:
https://www.path.org/resources/rsv-vaccine-and-mab-snapshot/.
23. CTA. Novavax RSV vaccine ResVax fails in Phase III trial. [online]
Available from: https://www.clinicaltrialsarena.com/news/novavax-
resvax-fails-phase-iii/. [Last accessed December, 2022].
24. Duncan JD, Urbanowicz RA, Tarr AW, Ball JK. Hepatitis C virus vaccine:
Challenges and prospects. Vaccines. 2020;8(1):90.
25. Wang Y, Li J, Hu Y, Liang Q, Wei M, Zhu F. Ebola vaccines in clinical
trial: The promising candidates. Hum Vaccin Immunother. 2017;13(1):
153-68.
26. Henao-Restrepo A, Camacho A, Longini I, Watson CH, Edmunds

WJ, Egger M, et al. Efficacy and effectiveness of an rVSV-vectored
vaccine in preventing Ebola virus disease: final results from the
Guinea ring vaccination, open-label, cluster randomized trial. Lancet.
2017;389(10068):505-18.
27. World Health Organization. Malaria vaccine: WHO position paper –
March 2022. 2022;97(9):61-80.
28. Wilson KL, Flanagan KL, Prakash MD, Plebanski M. Malaria vaccines
in the eradication era: current status and future perspectives. Expert
Rev Vaccines. 2019;18(2):133-51.
29. Martin C, Aguilo N, Marinova D, Gonzalo-Asensio J. Update on TB
vaccine pipeline. Appl Sci. 2020;10:2632.
30. Pipeline Report » 2021. Tuberculosis vaccines. [online] Available
from : https ://www.treatmentactiongroup.org/wp-content/
uploads/2021/10/2021_pipeline_TB_vaccines_final.pdf. [Last
31. Walker R, Kaminski RW, Porter C, Choy RKM, White JA, Fleckenstein
JM, et al. Vaccines for protecting infants from bacterial causes of
diarrheal disease. Microorganisms. 2021;9(7):1382.
32. Qadri F, Akhtar M, Bhuiyan TR, Chowdhury MI, Ahmed T, Rafique TA,
et al. Safety and immunogenicity of the oral, inactivated, entero
toxigenic Escherichia coli vaccine ETVAX in Bangladeshi children and
infants: a double-blind, randomised, placebo-controlled phase 1/2
trial. Lancet Infect Dis. 2020;20(2):208-19.
33. Behrens R, Cramer J, Jelinek T, Shaw H, von Sonnenburg F, Wilbraham
D, et al. Efficacy and safety of a patch vaccine containing heat-
labile toxin from Escherichia coli against travellers’ diarrhea: a
phase 3, randomized, double-blind, placebo-controlled field trial in
travellers from Europe to Mexico and Guatemala. Lancet Infect Dis.
2014;14(3):197-204.
34. Grammeniatis A, Burriel AR, Pappa K, Ioannidis A. A review of current
knowledge on the development of a group B streptococcus vaccine
for pregnant women and the protection of neonates. J Clin Obstet
Gynecol. 2022;32(2):56-66.
35. Melgaço JG, Gardinali NR, da Motta de Mello V, Leal M, Lewis-Ximenez
LL, Pinto MA. Hepatitis E: Update on prevention and control. Hindawi.
BioMed Res Int. 2018;2018:5769201.
36. Clegg J, Soldaini E, McLoughlin RM, Rittenhouse S, Bagnoli F, Phogat S.
Staphylococcus aureus vaccine research and development: The past,
present and future, including novel therapeutic strategies. Front
Immunol. 2021;12:705360.
37. Anderholm KM, Bierle CJ, Schleiss MR. Cytomegalovirus vaccines:

Current status and future prospects. Drugs. 2016;76(17):1625-45.
38. van Zyl DG, Mautner J, Delecluse H-J. Progress in EBV vaccines. Front
Oncol. 2019;9:104.
39. Castro SA, Dorfmueller HC. A brief review on Group A Streptococcus
pathogenesis and vaccine development. R Soc Open Sci. 2021;8(3):
201991.
40. Bottazzi ME, Hotez PJ. “Running the Gauntlet”: Formidable challenges
in advancing neglected tropical diseases vaccines from development
through licensure, and a “Call to Action”, Hum Vaccin Immunother.
2019;15(10):2235-42.
41. Saxena M, van der Burg SH, Melief CJM, Bhardwaj N. Therapeutic
cancer vaccines. Nat Rev Cancer. 2021;21:360-78.
42. Rosenthal KS, Carambula R, Zimmerman DH. Why don’t we have a
vaccine against autoimmune diseases? – A review. J Clin Cell Immunol.
2019;10(1):574.
43. Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF,
et al. Sipuleucel-T immunotherapy for castration-resistant prostate
cancer. N Engl J Med. 2010;363(5):411-22.
5.2 VACCINE HESITANCY

M Indra Shekhar Rao, Srinivas Kalyani
INTRODUCTION
Vaccine hesitancy, the reluctance, or refusal to vaccinate despite
the availability of vaccines threatens to reverse the progress
made in tackling vaccine-preventable diseases (VPDs). Vaccine
hesitancy has been recognized as an important emerging risk
factor for nonvaccination and was listed as one of the World Health
Organization (WHO)’s Ten Threats to Global Health in 2019.1
Worldwide, despite the success of the vaccination programs
and the safety of vaccines, there exist a number of vaccine-hesitant
parents and vaccine refusers. These should not be confused with anti-
vaccinationists or the anti-vaccine lobby with its global existence.
Vaccine hesitancy is a behavior influenced by a number of
factors. The WHO’s Strategic Advisory Group of Experts (SAGE) on
immunization defines vaccine hesitancy as an individual’s behavior
that is influenced by the 3Cs, i.e., issues of Confidence (no trust in
the vaccine or provider), Complacency (does not perceive a need for
the vaccine, does not value the vaccine), and Convenience (ease or
difficulty of access) (Fig. 1).2
A 2018 Wellcome Trust study3 on vaccine hesitancy found that
over 95% of Indian parents surveyed believed vaccines to be safe,
effective, and important. In a study done in Chandigarh in 2021, it
was found that those with a high school education had 0.10 times the
odds of vaccine hesitancy compared to those with less education.
Those having more antenatal care visits were less vaccine hesitant.4
In a cross-sectional study conducted in the pediatric outpatient
department of a tertiary care hospital in Chennai, among mothers
of children between 1 and 5 years of age attending the pediatrics
outpatient department of the tertiary care hospital, it was noted that
>99% of mothers felt that childhood vaccines are important and
effective, ~61% felt that the newer vaccines carried a greater risk of
adverse effects, >90% had concerns about serious adverse effects,
and surprisingly ~85% felt that there was no need for vaccines
against diseases that were uncommon.
Fig. 1: Vaccine hesitancy determinants. (VPD: vaccine-preventable disease)

Source: SAGE Working Group on Vaccine Hesitancy Final Report www.who.int/
immunization/sage/meetings/2014/october/SAGE_working_group_revised_
report_vaccine_hesitancy.pdf?ug=1.
The reasons for missing vaccination sessions, during the Mission

Indradhanush program, obtained by routine monitoring interviews
with caregivers of undervaccinated children between October 2017
and February 2018 are shown in Figure 2. It is to be noted that
awareness gap was responsible for 48% of missed vaccine sessions,
fear of adverse event following immunization (AEFI) was noted in
24%, and vaccine resistance in 11%.
During the Covid pandemic, inadequate primary healthcare
services, disruption of immunization services, fear of getting infected
with Covid, social distancing norms, and other infection prevention
control practices have adversely affected health-seeking behavior
and routine visits to healthcare facilities.
Vaccine-hesitant individuals hold varying degrees of indecision
regarding certain vaccines or vaccination in general. In trying to
understand vaccine hesitancy, it is important to conduct a local
communication analysis of knowledge, attitudes, and practices
(KAP). This analysis should include social norms, cultural beliefs,
and traditions associated with health and immunization among
Fig. 2: Reasons for missing vaccination sessions.
primary stakeholder groups (parents, guardians, and healthcare

providers). The analysis should also look into channel availability
and audience preferences, including existing community
engagement mechanisms that can guide communication
interventions.
As vaccine uptake peaks, the disease incidence declines, and
the total number of adverse events after vaccination increases, but
these adverse events may lead to loss of confidence in the vaccine
as the public perceives the risk of vaccination to outweigh the risk
of disease (“loss of confidence” phase). This, in turn, may increase
vaccine refusal and ultimately lead to disease resurgence. After
disease resurgence or an outbreak, as the public again appreciates
the increasing burden of disease, vaccine acceptance is restored
and vaccination rates increase (“resumption of confidence” phase).
In the rare incidents in which disease is eradicated by vaccine,
as occurred with smallpox, vaccination can stop (“eradication”
phase). This conceptual framework is more applicable to diseases
for which the time between exposure and infection is short,
such as measles, pertussis, or polio, and less relevant to vaccines
against human papillomavirus (HPV), for which the benefits of
immunization in preventing cancer may take years or decades to

become apparent.
PRE-EMPTING VACCINE HESITANCY

Discussions and dissemination of information about vaccines
should be initiated with the prospective parents before the delivery
and during the first few postnatal appointments. At these visits,
parents can be provided with the “IAP Q & A on vaccines” leaflets,
information about credible web sources for information about
vaccines, and opportunities should be provided to ask questions.
It is necessary to have a presumptive approach to discussions
about vaccinations and restating the recommendation after
addressing parents’ concerns. Tell the parents that “Today we are
going to give your child the recommended vaccines to keep your
child healthy and your child needs three vaccines today” instead of
saying “What do you want to do about the shots?”
The vaccine provider should initiate a conversation about the
role of vaccines in saving lives, hospitalization, and improving child
survival. Emphasis should be placed on the safety aspects, which
are investigated at every stage of vaccine development and are
continued even after licensure and usage in the population. It is to
be emphasized that minor adverse effects are common but serious
adverse effects are very uncommon and the benefit–risk ratio is
heavily tilted toward benefit.
VACCINE FEARS AND MISUNDERSTANDINGS

The three main factors affecting the acceptance of vaccines are
concerns about vaccine safety, doubts about the necessity of
vaccines, and a lack of trust in the authorities recommending the
vaccines (Fig. 3).
APPROACH TO MANAGEMENT OF
VACCINE HESITANCY
Vaccine hesitancy is a continuum, from a parent who accepts
all vaccines to a parent who refuses all vaccines (Fig. 4). The aim of
any vaccine hesitancy intervention is to move the caregiver from a
state of hesitancy to acceptance of vaccinations.
Fig. 3: Factors affecting the acceptance of vaccines.
Fig. 4: The vaccine hesitancy continuum.
The first step is to establish a positive dialog. Listen to the

caregiver’s concerns and ask for the sources of information on
the basis of which hesitancy has occurred and summarizes the
concerns.
At this stage, the vaccine provider should initiate a conversation
about the role of vaccines in saving lives, hospitalization, and
improving child survival. Emphasis should be placed on the safety
aspects that are investigated at every stage of vaccine development
and even after licensure and usage in the population.
As the conversation evolves, explore the concerns further.
Provide information, obtained from authentic sources, and explain
using simple language. Verify what they have understood and what
they will do with this information. Discuss specific concerns. Some
of these concerns include pain during vaccination, adjuvants,
preservatives, formaldehyde, mercury, and overload of immune
system.
Motivational Interviewing8
Motivational interviewing (MI) is an effective counseling method
that enhances motivation through the resolution of ambivalence.
MI emphasizes a collaborative therapeutic relationship in
which the autonomy of the patient is respected and the patient’s
intrinsic resources for change are elicited by the therapist.
Adoption of a nonconfrontational approach to guide the patient
toward change is the essence of MI. The process of MI includes the
following:
■ Ask open-ended questions: Do you think MMR vaccines cause
autism? is a close-ended question. The response could be yes or
no. If the answer is yes, the conversation ends. On the other hand
“What is your opinion about the link between MMR vaccine
and autism?” is an open-ended question. There is scope for
discussion.
■ Reflective listening is a special type of listening that involves paying
respectful attention to the content and feeling expressed in
another persons’ communication. Reflective listening is hearing
and understanding, and then letting the other know that he or
she is being heard and understood.
■ Eliciting pros and cons of change: Risk of disease versus the risk of
vaccination. Discuss the indirect benefits of vaccination.
■ Inquiring about the importance and confidence of making a
change.
If the end result is reversal of hesitancy, vaccinate and offer praise
to affirm the positive decision.
IF FOR FOLLOW-UP (if possible): Schedule a new discussion:

“Let’s revisit this once you have had a chance to think more about
vaccination. When could you come back?”
IF REFUSAL: Do not debate. Leave the door open:

“I understand. Please know that if you change your mind and
want to talk about vaccinating, we are always available.”
COMMUNICATION STRATEGIES5,9
At the public health level, the goal is to maintain public trust in
vaccines and immunization safety and achieve a high level of
immunization coverage. This entails the ability of healthcare
workers to understand and be able to communicate the importance
and the benefits of vaccination, as well as restore confidence in
the National Immunization Programme (NIP), should an AEFI
occur. The involvement of community leaders/stakeholders in
organizing community dialogs with parents and other target groups
for immunization in strengthening the capacity of their healthcare
workers to provide inclusive services should be tapped.
Concerns that drive vaccine hesitancy have also been found to
be highly context specific. This is demonstrated globally, differing
within high-, middle-, or low-income countries as well as within
countries based on factors such as socioeconomic and educational
status.7
Within local regions, there may be reasons related to religious
beliefs about the contents of vaccines, belief in naturopathy and
alternative medicine, conspiracy theories related to “big pharma,” etc.
These have to be determined and answered by the healthcare worker,
sometimes with the help of religious leaders, influential individuals,
leaders from among the alternative medicine practitioners, etc., who
will be able to send a clear message to certain communities to get
their buy-in.
Maintain relationship with parents:6 Providers to make continuous
and strident efforts toward educating parents who are vaccine
hesitant, with every visit, child comes to the center for any ailment.
ROLE OF MEDIA
The modern communication environment allows any individual
with a negative opinion about vaccine safety issues to voice
their views online without professional input. In that context, the
challenge for NIPs in the region is to proactively apply innovative

and participatory communication approaches with evidence-based
messages.
Mobile applications have surpassed traditional internet, and
will work with social media presence to provide a potential direct
channel to communicate with individuals about vaccination.
Applications that are helpful in reminding parents of their children’s
next vaccination appointments while providing information on child
development, growth, nutrition, and vaccines would prove to be
popular.
In the short and long term, building partnerships with the media
and social media influencers is key to keeping the public regularly
informed about and engaged with the benefits of immunization and
to timely information sharing on vaccine safety issues. The media can
reinforce messages shared through interpersonal communication to
motivate families and communities to maintain trust in, and sustain
their demand for, immunization services.
CONCLUSION
Vaccine hesitancy is a complex issue. In addition to the need for more
educational materials for healthcare workers, vaccination strategies
need to be contextualized. The social sciences have an important
role in future vaccination strategies. One-on-one discussion with a
trusted pediatrician is the most likely avenue for changing a parent’s
stance on vaccines. An observational study found that 47% of parents
eventually consented to vaccines after initial refusal when their
physicians continued to engage with them on the issue.
REFERENCES
1. Lane S, MacDonald NE, Marti M, Dumolard L. Vaccine hesitancy
around the globe: Analysis of three years of WHO/UNICEF joint
reporting form data 2015–2017. Vaccine. 2018;36(26):3861-7.
2. World Health Organization. Ten Threats to Global Health in 2019.
[online] Available from: https://www.who.int/emergencies/ten-
threats-to-globalhealth-in-2019. [Last accessed December, 2022].
3. Wellcome Trust. Wellcome Global Monitor: How Does the
World Feel About Science and Health? (2019). [online]
Available from: https://wellcome.ac. uk/sites/default/files/
wellcome-global-monitor-questionnaire-developmentreport_0.pdf.
4. Wagner AL, Shotwell AR, Boulton ML, Carlson BF, Mathew JL. Vaccine
hesitancy in Chandigarh, India. 2021;7:585579.
5. World Health Organization (WHO). Vaccine Safety Communication:
Guide for Immunization Programme Managers and National
Regulatory Authorities (1. Immunization Programs—Organization and
Administration, 2. Safety Management, and 3. Vaccines—Standards. I).
Manila: WHO Regional Office for the Western Pacific; 2016. p. 76.
6. Omer SB, Salmon DA, Orenstein WA, deHart MP, Halsey N. Vaccine
refusal, mandatory immunization, and the risks of vaccine-preventable
diseases. N Engl J Med. 2009;360(19):1981-8.
7. Salmon DA, Moulton LH, Omer SB, DeHart MP, Stokley S, Halsey NA.
Factors associated with refusal of childhood vaccines among parents
of school-aged children: a case-control study. Arch Pediatr Adolesc
Med. 2005;159(5):470-6.
8. Motivational interviewing techniques. Facilitating behaviour change
in the general practice setting. [online] Available from: https://
www.racgp.org.au/afp/2012/september/motivational-interviewing-
techniques. [Last accessed December, 2022].
9. Shen SC, Dubey V. Addressing vaccine hesitancy: Clinical guidance
for primary care physicians working with parents. Can Fam Physician.
2019;65(3):175-81.
Annexures
Annexure I: Immunization Schedule 2022
Annexure II: Internet Resources on Immunization Information
Annexure III: Ready Reckoner for Vaccines Currently Available in India
Annexure IV: AEFI Reporting Form
I Immunization
Schedule 2022
Annexure
TABLE 1: National Immunization Schedule (NIS) for pregnant women, infants, and
children (Vaccine-wise).
For pregnant women:
Tetanus Early in pregnancy 0.5 mL Intramuscular Upper arm
and adult
diphtheria (Td)
Td-2 4 weeks after Td-1 0.5 mL Intramuscular Upper arm
Td-booster If received 2 TT/Td 0.5 mL Intramuscular Upper arm
doses in a
pregnancy within
the last 3 years*
For infants:
Bacillus- At birth or as early 0.1 mL Intradermal Left upper
Calmette as possible till 1 year (0.05 mL until arm
Guérin (BCG) of age 1 month age)
Hepatitis At birth or as early 0.5 mL Intramuscular Antero-lateral
Β-birth dose as possible within side of mid-
24 hours thigh
Oral polio At birth or as early 2 drops Oral Oral
vaccine as possible within
(OPV)-0 the first 15 days
OPV-1, 2, At 6 weeks, 2 drops Oral Oral
and 3 10 weeks and
14 weeks (OPV can
be given till
5 years of age)
Contd...
512 Immunization Schedule 2022
Contd...
Pentavalent 1, At 6 weeks, 10 0.5 mL Intramuscular Antero-lateral
2, and 3 weeks, and 14 side of mid-
weeks (can be thigh
given till 1 year
of age)
Pneumococcal Two primary 0.5 mL Intramuscular Antero-lateral
conjugate doses at 6 and 14 side of mid-
vaccine (PCV) weeks followed by thigh
booster dose at
9–12 months
Rotavirus At 6 weeks, 10 5 drops Oral Oral
vaccine (RV) weeks, and 14 (liquid
weeks (can be vaccine)
given till 1 year 2.5 mL
of age) (lyophilized
vaccine)
Inactivated Three fractional 0.1 mL Intradermal two Intradermal:
polio vaccine doses at 6–14 fractional dose Right upper
(IPV) weeks and arm (UA) at
9 months 6–14 weeks
Left UA at
9 months
Measles- 9 completed 0.5 mL Subcutaneous Right UA
rubella (MR) months–12
1-dose months. (Measles
can be given till
5 years of age)
Japanese 9 completed 0.5 mL • Subcutaneous • Left upper
encephalitis months– (Live- arm (Live-
(JE)-1 12 months attenuated attenuated
vaccine) vaccine)
• Intramuscular • Anterolateral
(Killed vaccine) aspect of
mid-thigh
(Killed
vaccine)
Vitamin A (1- At 9 completed 1 mL (1 lakh Oral Oral
dose) months with IU)
measles-rubella
Contd...
Immunization Schedule 2022 513
Contd...

For children:
Diphtheria, 16–24 months 0.5 mL Intramuscular Antero-lateral
pertussis, and side of mid-
tetanus (DPT) thigh
booster-1
MR-2-dose 16–24 months 0.5 mL Subcutaneous Right upper
arm
OPV booster 16–24 months 2 drops Oral Oral
JE-2 16–24 months 0.5 mL • Subcutaneous • Left upper
(Live- arm (Live-
attenuated attenuated
vaccine) vaccine)
• Intramuscular • Anterolateral
(Killed aspect of
vaccine) mid-thigh
(Killed
vaccine)
Vitamin A (2nd 16–18 months. Then 2 mL Oral Oral
to 9th dose) one dose every (2 lakh IU)
6 months up to the
age of 5 years
DPT booster-2 5–6 years 0.5 mL Intramuscular Upper arm
Td 10 years and 0.5 mL Intramuscular Upper arm
16 years
*One dose if previously vaccinated within 3 years.
Note:
• Japanese encephalitis vaccine is introduced in select endemic districts after the
campaign.
• The 2nd to 9th doses of vitamin A can be administered to children 1–5 years old
during biannual rounds, in collaboration with ICDS.
TABLE 2: Indian Academy of Pediatrics (IAP) immunization timetable: IAP

recommended vaccines for routine use.
Age Vaccine Comments
Birth BCG BCG: Before discharge
OPV OPV: As soon as possible after birth
Hepatitis B-l (BD) Hep Β should be administered
6 weeks DTwP, DTaP-1 • DTwP or DTaP may be
IPV-1 administered in primary
immunization
Hib-1 • IPV: 6–10–14 weeks is the
Hep B-2 recommended schedule. If
Rotavirus-1 IPV, as part of a hexavalent
combination vaccine is
PCV-1 unaffordable, the infant should
be sent to a government facility
for primary immunization as per
UIP schedule
10 weeks DTwP, DTaP-2 RV1: 2-dose schedule: All other
rotavirus brands: 3-dose schedule
IPV-2
Hib-2
Hep B-3
Rotavirus-2
PCV-2
14 weeks DTwP, DTaP-3 An additional 4th dose of Hep Β
vaccine is safe and is permitted
as a component of a combination
vaccine
IPV-3
Hib-3
Hep B-4
Rotavirus-3
PCV-3
6 months Influenza (IIV)-1 Uniform dose of 0.5 mL for DCGI
approved brands
Contd...
Contd...
Age Vaccine Comments

7 months Influenza (IIV)-2 To be repeated every year in
premonsoon period till 5 years of
age
6–9 months Typhoid conjugate As of available data, there is no
vaccine recommendation for a booster
dose
9 months MMR-1
12 months Hepatitis A Single dose for live-attenuated
vaccine
15 months MMR-2, varicella-1,
PCV booster
16–18 DTwP/DTaP-B1, Hib-B1,
months IPV-B1
18–19 Hep A-2, varicella-2 Only for inactivated Hep A vaccine
months
4–6 years DTwP/DTaP-B2, IPV-B2,
MMR-3
10–12 years Tdap, HPV Tdap is to be administered even if
it has been administered earlier
(as DTP-B2)
• HPV: 9–14-year-old girls: 9vHPV
and 4vHPV are recommended in a
2-dose series (0–6 m)
• 9–14 years boys: HPV9 is
recommended in a 2-dose
schedule of 0-6 months
• 15–45 years: 4vHPV (0–2–6 m) is
recommended in a 3-dose series
• 15–26 years: 9vHPV is
recommended in a 3-dose
schedule of 0–2–6 months
(BCG: bacille Calmette-Guérin; DCGI: Drugs Controller General of India; DPT:
diphtheria, pertussis and tetanus; DTaP: diphtheria, tetanus, and pertussis;
DTwP: diphtheria, tetanus, and whole cell pertussis; HPV: human papilloma
virus; IPV: injectable polio vaccine; MMR: measles, mumps, and rubella; OPV:
oral poliovirus vaccines; PCV: pneumococcal conjugate vaccine; Tdap: tetanus,
diphtheria toxoids, and acellular pertussis; UIP: Universal Immunization
Programme)
TABLE 3: Age in completed weeks/month/years.
Vaccine Birth 6 w 10 w 14 w 6m 7m 9m 12 m 13 m 15 m 16–18 m 18–24 m 2–3 y 4–6 y 9–14 y 15–18 y
BCG
Hepatitis Β HB 1a HB 2 HB 3 HB 4b
Polio OPV IPV 1c IPV 2c IPV 3c IPVc B1 ΙΡVc Β2
DTwP/DTaP DPT 1 DPT 2 DPT 3 DPT B1 DPT B2
Hib Hib 1 Hib 2 Hib 3 Hib B1
PCV PCV 1 PCV 2 PCV 3 PCV Β

Rotavirus RV 1 RV 2 RV 3d
Influenza Dose 1e Dose 2 Annual vaccination
MMR Dose 1 Dose 2 Dose 3
TCV
Hepatitis A Dose 1 Dose 2f
Varicella Dose 1 Dose 2g
Tdaph/Td
HPV 1 and 2i 1, 2, and 3j
Meningo-
Dose 1 Dose 2
coccalk
JE Dose 1 Dose 2
Cholera Dose 1 Dose 2
Contd...
Contd...
Vaccine Birth 6 w 10 w 14 w 6m 7m 9m 12 m 13 m 15 m 16–18 m 18–24 m 2–3 y 4–6 y 9–14 y 15–18 y
PPSV-23
Rabies
Yellow fever
Recommended age Catch up age range Vaccines in special situations
(BCG: bacille Calmette-Guérin; DTaP: diphtheria, tetanus, and pertussis; DTwP: diphtheria, tetanus, and whole cell pertussis; DPT: diphtheria, pertussis and tetanus;
HPV: human papilloma virus; IPV: injectable polio vaccine; JE: Japanese encephalitis; MMR: measles, mumps, and rubella; OPV: oral poliovirus vaccines; PCV:
pneumococcal conjugate vaccine; PPSV: pneumococcal polysaccharide vaccine; Tdap: tetanus, diphtheria toxoids, and acellular pertussis; TCV: typhoid conjugate
vaccine)
Notes:
a
To be given within 24 hours after birth. When this is missed, it can be administered at first contact with health facility; bAn extra dose of Hepatitis B vaccine is
permitted as part of a combination vaccine when use of this combination vaccine is necessary; cIPV can be given as part of a combination vaccine; d3rd dose of
Rota vaccine is not necessary for RV1; eInfluenza vaccine should be started after 6 months of age, 2 doses 4 weeks apart, usually in the pre-monsoon period. At
other times of the year, the most recent available strain should be used. Annual influenza vaccination should be continued, for all, till 5 years of age; after the age of
5 years, this vaccine is recommended in the high-risk group only; fSingle dose is to be given for the live attenuated Hepatitis A vaccine. The inactivated vaccine needs
two doses; g2nd dose of varicella vaccine should be given 3–6 months of age after dose 1. However, it can be administered anytime 3 months after dose 1 or at 4–
6 years; hTdap should not be administered as the second booster of DPT at 4–6 years. For delayed 2nd booster, Tdap can be given after 7 years of age. A dose of Tdap
is necessary at 10–12 years, irrespective of previous Tdap administration. If Tdap is unavailable/unaffordable, it can be substituted with Td; iBefore 14 completed years,
HPV vaccines are recommended as a 2-dose schedule, 6 months apart; jFrom 15th year onwards and the immunocompromised subjects at all ages, HPV vaccines are
recommended as a 3-dose schedule, 0-1-6 (HPV2) or 0-2-6 (HPV4); kMenactra is approved in a 2-dose schedule between 9 and 23 months. Minimum interval between
two doses should be 3 months. Menveo is recommended as a single dose schedule after 2 years of age.
Immunization Schedule 2022
517
Japanese encephalitis (JE) vaccine:

■ Only for individuals living in endemic areas
■ For travelers to JE endemic areas provided their expected stay is
for a minimum period of 4 weeks
■ Any of the licensed JE vaccine can be administered
■ Live-attenuated SA-14-14-2 is not available in private market.
Meningococcal vaccines:
■ Any of the licensed vaccine can be administered.
■ 9 months through 23 months: Two doses at least 3 months apart
(Only Menactra)
■ 2 years through 55 years: Single dose. (Menactra and Menveo)
Cholera vaccine:
■ Minimum age: 1 year (killed whole cell Vibrio cholera)
■ Not recommended for routine use in healthy individuals;
recommended only for the vaccination of persons residing in high
endemic areas and traveling to areas where risk of transmission
is very high.
■ Two doses 2 weeks apart for >1 year old.
Yellow-fever vaccine.
Refer to topic on Travelers’ Vaccination.
High-risk category of children:
■ Congenital or acquired immunodeficiency (including HIV
infection)
■ Chronic cardiac, pulmonary (including asthma if treated with
prolonged high-dose oral corticosteroids), hematologic, renal
(including nephrotic syndrome), liver disease, and diabetes
mellitus
■ Children on long-term steroids, salicylates, immunosuppressive
or radiation therapy
■ Diabetes mellitus, cerebrospinal fluid leak, cochlear implant,
and malignancies
■ Children with functional/anatomic asplenia/hyposplenia
■ During disease outbreaks
■ Laboratory personnel and healthcare workers
■ Travelers
■ Children having pets in home (for rabies PrEP)
■ Children perceived with higher threat of being bitten by dogs
such as hostellers, risk of stray dog menace while going outdoor
(for rabies PrEP).
■ Influenza vaccination annually is recommended yearly for high-
risk children from 5 years of age onward.
II Internet Resources on
Immunization Information
Annexure
Organization/
Sponsor Web address Salient contents
National Center www.pubmed.com Abstracts and full
for Biotechnology texts of vaccine-
Information related articles
published in
indexed journals
Indian Academy of www.acvip.org Electronic copy of
Pediatrics Advisory guidebook, Q&A
Committee on facility
Vaccines and
Immunization
Practices
World Health https://www.who.int/ WHO position
Organization (WHO) immunization/en/ papers, WHO policy
https://www.who.int/teams/ recommendations,
immunization-vaccines-and- national programs
biologicals/policies/position- and systems,
papers monitoring and
https://www.who.int/ surveillance, pre-
health-topics/vaccines-and- qualification status
immunization of vaccines
Contd...
Internet Resources on Immunization Information 521
Contd...
Organization/
Centers for Disease www.cdc.gov/vaccines/ Advisory Committee
Control and on Immunization
Prevention (CDC) Practices vaccine
recommendations,
travel immunization,
general best practice
guidelines for
immunization, Pink
Book [epidemiology
and prevention of
vaccine preventable
diseases (VPDs)],
vaccine storages
Immunization Action https://www.immunize.org/ Answers to >1000
Coalition askexperts/ questions about
vaccines and
administration
National Network http://www.nnii.org/ Information on
for Immunization VPD, background
Information on vaccine
development and
vaccine safety,
resource kit to
help healthcare
providers discuss
immunization with
their patients
Children’s Hospital www.vaccine.chop.edu/ Information for
Philadelphia parents, vaccine
safety, vaccine
ingredients
Global Alliance www.gavialliance.org Information on
for Vaccines and GAVI programmatic
Immunization policies and funding
PATH www.path.org/ Vaccine resource
vaccineresources/index.php library
Contd...
522 Internet Resources on Immunization Information
Contd...
Organization/
Vaccine https://www.abbott.in/ Prescribing
manufacturers (in products/therapy-areas. information for
alphabetical order) vaccine.html various vaccines
(Not all-inclusive) www.bharatbiotech.com
www.biologicale.com
www.gskvaccines.com
www.indimmune.com
www.msdindia.in
www.novomedi.com
www.panacea-biotec.com
www.pfizer.com
www.sanofipasteur.com
www.seruminstitute.com
https://zyduslife.com/
research
https://www.indimmune.
com/business-unit/human-
health/vaccines/
www. drreddys.com
Miscellaneous Indian Pediatrics: www. Information,
indianpediatrics.net/ presentations, and
Vaccines: www.sciencedirect. journal articles
com/journal/vaccine on vaccines and
Expert Review of Vaccines: immunization
www.tandfonline.com/loi/ practices
ierv20
https://www.medscape.
com/resource/vaccines
https://www.health.gov.au/
committees-and-groups/
Australian-technical-advisory-
group-on-immunisation-atagi
https://www.canada.ca/
en/public-health/services/
canadianimmunization-guide.
html
https://vaccine.icmr.org.in
(GAVI: Global Alliance for Vaccines and Immunization)
ANNEXURE III
Ready Reckoner for Vaccines Currently Available in India
This List is not Exhaustive. Details as per Product Inserts
Vaccine/type/ Nature and Dose, route, Protective Major adverse
brand name/s Content/Dose diluent Storage and site Schedule efficacy effects Contraindications
BCG-LAV Each 1 mL contains 2 × 106 Normal Freezer/ 0.05 mL/ Single dose at 0–80% Axillary lym Defects of cell
Tubervac to 8 × 106 CFU of viable saline 2–8°C, 0.1 mL birth or first phadenitis mediated-
mycobacteria protect 0.1 mL ID, contact below immunity
from light left deltoid 5 years
bOPV-LAV Sabin strain: Liquid vaccine Freezer/ Two drops Birth, 6–10–14 • HIG coun- VAPP, VDPV Immunodefi-
BioPolio • Type 1: 106 CCID50 2–8°C orally weeks, 15–18 tries: 100% cient patients
• Type 3: 106 CCID50 months, NIDs, after three and household
and SNIDs doses contacts of such
• LIG countries: patients
73/90/70%
to type 1, 2, 3
IPV (inact) Salk strain: Liquid vaccine 2–8°C 0.5 mL IM or Birth, 6–10– 95–100% None Serious hypersen-
Poliovac • Type 1: 40 µ Not to SC, thigh/ 14 weeks, sitivity
• Type 2: 8 µ freeze deltoid boosters at
• Type 3: 32 µ 15–18 months
and 4–6 years
DTwP-Inact Diphtheria toxoid 20–30 Lf, Liquid vaccine 2–8°C 0.5 mL • Birth, 6–10– 95–100% for Excessive Serious hyper
Triple antigen SII tetanus toxoid 5–25 Lf, Not to IM thigh/ 14 weeks, diphtheria/ crying, sensitivity,
wP 4 IU freeze deltoid boosters at tetanus and seizures, HHE encephalopathy
15–18 months 70–90% for following previ-
and 4–6 years pertussis ous dose
• Not to be
used above
7 years
Contd...
Contd...

DTaP-Inact • Diphtheria toxoid: Liquid vaccine 2–8°C 0.5 mL IM or Birth, 6–10– 95–100% for As for DTwP Serious
Tripacel ≥30 IU (15 Lf) Not to SC, thigh/ 14 weeks, diphtheria/ but much hypersensitivity,
• Tetanus toxoid: ≥40 IU (5 Lf) freeze deltoid boosters at tetanus and less in encephalopathy
• Pertussis toxoid: 10 µg 15–18 months 70–90% for intensity and following
• FHA: 5 µg and 4–6 years pertussis frequency previous dose
• Fimbriae: 5 µg Not to be used
• Pertactin: 3 µg above 7 years
• AlPO4: 1.5 mg
Tetanus toxoid: Tetanus toxoid 5 Lf Liquid vaccine 2–8°C 0.5 mL IM or As routine at 10 years and every 10 years thereafter, pregnancy and
Inact BE-TT Not to SC, thigh/ wound management (Td/TdaP preferred to TT)
freeze deltoid
Td: Inact. Tetanus toxoid 5 Lf, Liquid vaccine 2–8°C 0.5 mL IM or As replacement for DTwP/DTaP/DT for catch-up vaccination in those
Tdvac, BE: Td diphtheria 2 Lf Not to SC, thigh/ aged above 7 years (along with Tdap), and as replacement for TT at
freeze deltoid all ages
Tdap: Inact • DT: Not <2.5 Lf, TT: Not <5 Lf Liquid vaccine 2–8°C 0.5 mL IM or Single dose at 90% As for DTwP Serious hyper
Boostrix • PT: 8 µg Not to SC, thigh/ 10–12 years but much sensitivity,
• FHA: 8 µg, Pertactin: 2.5 µg freeze deltoid and beyond less in encephalopathy
• Al(OH)3: 0.3 mg intensity and following
• AlPO4: 0.2 mg of frequency previous dose
Tdap: Inact TT: 5 Lf, DT: 2 Lf, PT: 2.5 µg, Liquid vaccine 2–8°C 0.5 mL IM or Single dose at 90% As for DTwP Serious hyper
524 Ready Reckoner for Vaccines Currently Available in India
Adacel FHA: 5 µg, PRN: 3 µg, Not to SC, thigh/ 11–54 years but much sensitivity,
FIM 2 and 3: 5 µg, AlPO4: freeze deltoid less in encephalopathy
(adjuvant) 1.5 mg, intensity and following
2-phenoxyethanol 0.6% v/v frequency previous dose
Contd...
Contd...

Rubella-LAV 5,000 CCID50 of RA 27/3 Lyophilized, Freezer/ 0.5 mL SC Given com- 95% Mild rubella- Severely immuno
R-Vac strain of rubella virus diluent sterile 2–8°C thigh/ bined with like illness in compromised,
water deltoid measles and <5%, rarely pregnancy. Avoid
mumps arthritis, ITP pregnancy for
9 months to 1 month
15 months to
5 years
MMR-LAV • Tresivac: Edmonston- Lyophilized, Freezer/ 0.5 mL SC 9 months to 86–95% • Measles: Severely immuno
Tresivac Priorix Zagreb, Measles virus diluent sterile 2–8°C thigh/ 15 months to Mild compromised,
ZyVac-MMR not <1,000, CCID50, water deltoid 5 years measles- pregnancy
L-Zagreb, Mumps like illness
virus 5,000, CCID50 and in <5%,
Wistar RA 27/3 Rubella rarely ITP
virus 1,000, CCID50 • Mumps:
• ZyVac MMR: (Edmonston- Rarely,
Zagreb Strain) NLT 1,000 fever,
CCID, live-attenuated
transient
mumps virus (Hoshino
parotitis,
Strain) NLT 5,000 CCIDs
aseptic
and live-attenuated
rubella virus (RA27/13 meningitis,
strain) NLT 1,000 CCIDs ITP
• Priorix: Measles Schwarz • Rubella:
strain not <103 CCID50, Mild
mumps virus RIT 4385 rubella-like
strain, derived from Jeryl illness in
Lynn strain, not <103.7 <5%, rarely
CCID50 and rubella virus arthritis,
Wistar RA 27/3 strain not ITP
<103 CCID50
Contd...
525
Contd...

• Hepatitis Ped: Liquid vaccine 2–8°C Ped. dose: Primary: >90% Nil Known serious
B-Inact • HBsAg: 10 µg Not to 10 µg/0.5 mL Birth: 6–10–14 hypersensitivity to
• Bevac 0.5 mL • Al(OH)3: 0.25 mg freeze Adult dose: weeks vaccine compo-
• Bevac 1 mL • Thiomersal: 0.025 mg 20 µg in nents or following
• Revac B MCF 1 mL Catchup: 0–1– a previous dose
Thiomersal free Adult: <18 years 6 months
• Genevac 0.5 mL • HBsAg: 20 µg 0.5 mL, >18
• Genevac B • Al(OH)3: 0.5 mg years 1 m
1.0 mL • Thiomersal: 0.05 mg IM deltoid/
• Genevac B thigh
10 mL
multidose
DTwP/Hib As for DTwP and Hib Liquid vaccine 2–8°C 0.5 mL 6–10–14 weeks As for DTwP and Hib
Quadrovax Not to IM thigh/ booster at 15–
freeze deltoid 18 months
DTwP/Hib/HBV As for DTwP, HBV, and Hib Liquid vaccine 2–8°C 0.5 mL IM 6–10–14 weeks As for DTwP, Hib, and Hib
Pentavac Not to thigh/ booster at 15–
Easyfive-TT freeze deltoid 18 months
Combivac5
DTaP/HepB/Hib As per DTaP HBV and Hib DTaP/IPV 2–8o C 0.5 mL IM 16–18 months As for DTaP, Hib, and HBV
Pentaxim component is Not to Thigh/ booster
a turbid white freeze deltoid

suspension. Hib
component is a
white powder
DTwP/Hib/HBV/ As for DTwP, Hib, 10 mg of Liquid vaccine 2–8°C 0.5 mL IM 6–10–14 weeks As for DTwP, Hib, Hib, and IPV
IPV Hep B; IPV Salk strain: Not to thigh/ Can be given
EasySix • Type 1: 40 units freeze deltoid up to 2 years
• Type 2: 8 units
• Type 3: 32 units
Contd...
Contd...

DTaP/Hib/HBV/ • DT: Not <30 IU, TT: Not DTaP/HBV/IPV 2–8°C 0.5 mL 6–10–14 weeks As for DTaP, Hib, Hib, and IPV
IPV <40 IU component is Not to IM thigh/ Can be given
Infanrix Hexa • Acellular PT: 25 µg, FHA: a turbid white freeze deltoid up to 2 years
25 µg, Pertactin: 8 µg suspension. Hib
• HbsAg: 10 µg component is a
• IPV: Type 1: 40 D-Ag U, white powder
type 2: 8 D-Ag U, type 3:
32 D-Ag U
• Hib-PRP: 10 µg, conjuga
ted to tetanus toxoid:
25 µg
DTaP/Hib/HBV/ • DT: 30 Lf, TT: 10 Lf, HepB: Liquid vaccine 2–8°C 0.5 mL IM 6–10–14 weeks As for DTaP, Hib, HBV, and IPV
IPV 10 µg, Hib: 12 µg Not to thigh/ Can be given
Hexaxim (TT: 22–36 µg) freeze deltoid up to 2 years
• Acellular PT and FHA:
25 µg each
• IPV: Type 1: 40 D-Ag U,
type 2: 8 D-Ag U, type
3: 32 D-Ag U hydroxide:
0.6 mg
DTaP/Hib/ (DT ≥30 IU), (TT ≥40 IU), Liquid vaccine 2–8°C 0.5 mL 4–6 years As for DTaP and IPV
IPV acellular PT 25 µg, FHA: Not to IM thigh/ booster
Tetraxim 25 µg, IPV: type 1: 40 DU, freeze deltoid
type 2: 8 DU, type 3; 32
DU. Adsorbed on hydrox-
ide, hydrated 0.3 mg Al3+
Contd...
527
Contd...

• Vi Typhoid 25–30 mg of Liquid vaccine 2–8°C 0.5 mL Above 2 years, 60% None Known serious
polysaccha- Vi-polysaccharide Not to IM thigh/ single dose, hypersensitivity to
ride-Inact freeze deltoid revaccination vaccine compo-
• Typbar, every 3 years nents or following
VacTyph a previous dose
• Vi-CPS 25 μg of Vi-CPS Liquid vaccine 2–8°C 0.5 mL Single >90% serocon- None, only Known serious
conjugate conjugated to tetanus Not to IM thigh/ dose at version in minor hypersensitivity to
vaccine-Inact. toxoid per 0.5 mL freeze deltoid ≥6 months >6 months to systemic and vaccine compo-
• Typbar TCV, Enteroshield: Conjugated 45 years local side nents or following
Enteroshield, to CRM197 Efficacy: 80– effects a previous dose
Zyvac TCV, 87% over
TyphiBev, 2 years
Biovac TCV
HPV-Inact. Each 0.5-mL dose contains Liquid vaccine 2–8°C 0.5 mL In females: 9– >90% against None Known serious
Gardasil 20 µg of HPV 6 L1 protein, Not to IM thigh/ 14 years, 0 and serotype- hypersensitivity
40 µg of HPV 11 L1 protein, freeze deltoid 6 months; specific cervi- to vaccine
40 µg of HPV 16 L1 protein, 15–45 years, 0, cal cancer components
20 µg of HPV 18 L1 protein 1, and 6 months or following a
and 225 µg of aluminum previous dose
Gardasil 9 HPV: Type 6: 30 µg, type Liquid vaccine 2–8°C 0.5 mL IM 9–14 years: Girls >90% against None Known serious
11: 40 µg, type 16: 60 µg Not to thigh/ and boys: Two- serotype- hypersensitivity
and type 18: 40 µg type freeze deltoid dose series specific to vaccine
31: 20 µg, type 33: 20 µg, (0–6 months) cervical cancer components
type 45: 20 µg, type 52: 15–26 years: or following a
20 µg, type 58: 20 µg and 9vHPV (0–2– previous dose

500 µg of aluminum 6 months) is
recommended
in a three-dose
series. All immu-
nocompromised
should receive
a three-dose
schedule
Contd...
Contd...

PCV10-Inact Capsular polysaccharide Liquid vaccine 2–8°C 0.5 mL IM 6–10–14 weeks, 95% against None Known serious
Synflorix of serotypes 1, 4, 5, 6B, Not to thigh/ booster 15– serotype- hypersensitivity to
7F, 9V, 14, and 23F linked freeze deltoid 18 months specific vaccine compo-
to protein D (NTHi), 18C invasive nents or following
linked to TT and 19F to disease a previous dose
diphtheria toxoid
PCV 13 Inact. Capsular polysaccharide Liquid vaccine 2–8°C 0.5 mL IM 6–10–14 weeks, 95% against None Known serious
Prevenar 13 of serotypes 4, 6B, 9V, 14, Not to thigh/ booster 15– serotype- hypersensitivity to
18C, 19F, 23, 1, 5, 6A, 7F, freeze deltoid 18 months specific invasive vaccine compo-
and 3 linked to CRM 197 disease, except nents or following
ST3 a previous dose
PCV10 Inact. Contains capsular poly- Liquid vaccine 2–8°C 0.5 mL IM 6–10–14 weeks, Licensed None Known serious
Pneumosil saccharides of 1, 5, 6A, 6B, Not to thigh/ booster 15– on basis of hypersensitivity to
7F, 9V, 14, 19A, 19F, 23F, 2 freeze deltoid 18 months immunological vaccine compo-
µg of each and 4 µg of 6B, noninferiority nents or following
conjugated to CRM197, to PCV13 and a previous dose
with AlPO4: 0.125 mg PCV10-GSK
PPSV23-Inact. CPS of serotypes 1, 2, 3, Liquid vaccine 2–8°C 0.5 mL IM Single dose 70% against None Known serious
Pneumovax-23 4, 5, 6B, 7F, 8, 9N, 9V, 10A, Not to thigh/ after 2 years invasive hypersensitivity to
11A, 12F, 14, 15B, 17F, 18C, freeze deltoid Revaccination disease in high- vaccine compo-
19F, 19A, 20, 22F, 23F, and only once after risk children nents or following
33F unconjugated 3–5 years a previous dose
Hep A Inact. • Havrix 720: Each 0.5 Liquid vaccine 2–8°C 0.5 mL IM Two doses >95% None Known serious
Avaxim 80, mL contains 720 E.U. Not to thigh/ 6 months hypersensitivity to
Havrix 720, of viral antigen (strain freeze deltoid apart, after vaccine compo-
HavShield, HM175), adsorbed onto 1 year of age nents or following
HapiBEV 0.25 mg of aluminum. a previous dose
• Avaxim 80: GBM strain 80
U, Al. hydroxide: 150 mg,
2-PE: as preservative.
HavShield and HapiBEV:
250 U of TZ84 strain and

hydroxide
529
Contd...
Contd...

Hep A-LAV 6.5 log particles of H2 Lyophilized, 2–8°C 0.5 mL SC One dose after >95% None Pregnancy,
BioVac A strain sterile water 1 year of age severely immuno
compromised
Varicella-LAV At least 1,000 PFU of Oka Lyophilized, 2–8°C 0.5 mL SC Two doses, first 70–90% with Varicella-like Pregnancy,
Varilrix, Variped, strain (varies according to sterile water Protect dose after one dose rash in 5% severely immuno
Nexipox product) from light 15 months and >95% with two compromised
second dose doses
after 3 months
of first dose
Rotavirus human Human rotavirus stain Lyophilized, 2–8°C 1 mL, orally Two doses: 85–98% None SCID, history of
monovalent 89-12 (G1P8) sterile water- Protect • First dose: against severe intussusception.
(LAV) based specific from light 6–14 weeks rotavirus Known serious
Rotarix liquid diluent • Second dose: diarrhea, in hypersensitivity
Before HIC and MIC. to vaccine
24 weeks Asia: 48.3% components
4-week or following a
interval previous dose
between
doses
Rotavirus human Five rotavirus reassortant Liquid vaccine 2–8°C 2 mL, orally Three doses: 85–98% None SCID, history of
bovine pen- strains G1, G2, G3, G4, and Protect • First dose: against severe intussusception.
tavalent vaccine P1A (8) from light 6–14 weeks rotavirus Known serious
(LAV) • Third dose: diarrhea, in hypersensitivity to
RotaTeq Before HIC and MIC. vaccine compo-
32 weeks Africa: 39.3% nents or following
4-week a previous dose
interval
between
doses
Contd...
Contd...

Rotavirus human Naturally occurring Liquid vaccine 2–8°C for 0.5 mL Three doses: 54.4% against None SCID, history of
bovine mon- reassortant 116E strain 6 months orally • First dose: SRVGE intussusception.
ovalent vaccine Protect 6–14 weeks Known serious
(LAV) from light • Third dose: hypersensitivity to
Rotavac Before vaccine compo-
RotaSure 32 weeks nents or following
Rotavac 5D 2–8°C 5 drops 4-week a previous dose
throughout interval
the shelf between
life of 24 doses
months
Rotavirus human Five rotavirus reassortant Liquid Liquid for- Liquid: 2 mL Three doses: Niger: 66.8% None SCID, history of
bovine pentava- strains G1, G2, G3, G4, mulation: • First dose: India: 60.5%- intussusception.
lent vaccine-LAV and G9 2–8°C 6–14 weeks against Known serious
Rotasiil • Third dose: VS-RVGE hypersensitivity to
Before 1 year vaccine compo-
4-week nents or following
interval a previous dose
between
doses
Inactivated, Kolar Inactivated, Kolar strain, Liquid vaccine 2–8°C 0.5 mL Two doses at >90% serocon- None, only fe- Known serious
strain, JE vaccine, 821564XY, JE vaccine IM thigh/ 4 weeks interval version and ver and local hypersensitivity
JEN-VAC 5.0 μg per 0.5 mL deltoid from 1 year of seroprotection side effects to vaccine
age and onward after one dose components
(up to 50 years) or following a
No recom- previous dose
mendation for
boosters
Contd...
531
Contd...

Inactivated 3 μg and 6 μg per 0.5 mL Liquid vaccine 2–8°C 1–3 years: Two doses at >90% serocon- None, only fe- Known serious
SA-14-14-2 of inactivated vero cell 3 μg 4 weeks interval version ver and local hypersensitivity
strain, JE vaccine culture-derived SA 14-14-2 3–18 years: No recom- side effects to vaccine
JEEV JE vaccine 6 μg IM; mendation for components
deltoid/ booster or following a
thigh previous dose
Live JE vaccine, 5.4 log PFU of SA 14-14-2 Liquid vaccine 2–8°C 0.5 mL SC Two doses at >90% in Nepal None Immunodefi-
SA-14-14-2 strain of JE virus 9 months and and China with cient patients
15–18 months one dose and household
India: ~70% contacts of such
with one dose patients
• Conjugated 4 μg of Meningococcal Liquid vaccine 2–8°C 0.5 mL IM 9–23 months: Effectiveness: None, no Known serious
• Quadrivalent group A, C, Y, and W Two doses 80–85% extra risk of hypersensitivity
• Meningococcal 135 polysaccharides 3 months apart GBS among to vaccine
vaccine conjugated to 48 μg of 24 months to vaccinees components
• Menactra diphtheria toxoid 55 years: Single or following a
dose previous dose
Menveo Menveo: Men Gp A: 10 μg, The freeze- 2–8°C 0.5 mL IM Single dose Effectiveness: None, no Known serious
Men Gp C: 5 μg, Men Gp dried MenA >2 years 80–85% extra risk of hypersensitivity
W-135: 5 μg, Men Gp powder is to be GBS among to vaccine
Y: 5 μg, each bound to reconstituted vaccinees components
CRM197 in MenCWY or following a

solution previous dose
Contd...
Contd...
Flu vaccine 15 μg of HA of two Type Liquid vaccine 2–8°C 0.5 mL IM Vaccine naïve: 50–75% None Known serious
Quadrivalent A and two Type B (differs Two doses, at 63.2% efficacy hypersensitivity
(IIV4) according to Northern/ 4 weeks against mode to vaccine
Influvac Tetra, Southern hemisphere and interval, below rate to severe components
Fluarix Tetra, usually yearly) inactivated 8 years, single influenza and or following a
FluQuadri, Vaxi- influenza virus dose yearly. 49.8% effi- previous dose
Flu4 0.5 mL >6 cacy against
months of age influenza of
any severity in
children
6–35 months
Flu vaccine 107 EID50 of two Type A Liquid 2–8°C 0.25 mL in Single dose Vary widely, None Severe hyper-
live-attenuated and 106.5 EID50 of one formulation each nostril >2 years ranging from sensitivity to any
influenza (LAIV) Type B (differs according 0 to 50% constituent, <2
Nasovac S4 to Northern/Southern years, h/o asthma,
hemisphere and usually GBS, on antiflu
yearly) inactivated medications or as-
influenza virus pirin, pregnancy
Yellow fever 17D strain of yellow fever Lyophilized, 2–8°C 0.5 mL SC Single dose >90% Rarely Below 6 months,
vaccine-LAV virus sterile water >9 months neurologic/ serious egg allergy
Stamaril, CRI diluent viscerotropic severe immuno-
Kasauli vaccine disease deficiency, thymus
disease
Oral cholera 1.5 mL contains killed Liquid vaccine 2–8°C 1.5 mL • >1 year, two 60% None Known serious
Inact. bivalent (O1 and O139) orally doses 2 weeks hypersensitivity
Shanchol strains of V. Cholerae apart to vaccine
• Booster may components
be considered or following a
after 3 years previous dose
Contd...
533
Contd...

Rabies vaccines All contain not <2.5 IU Lyophilized pow- 2–8°C 1 mL IM 100% None None
Inact. per dose der with diluent seroprotective
Chirorab (PCEC) to a volume of titers of
Rabivax-S 1 mL. >0.5 IU, by
(VeroCell) Sterile water: day 14
Vaxirab Chirorab,
(VeroCell) Rabivax-S, Vaxirab.
AbhayRab and 0.9% saline for
IndiRab Abhayrab and
(VeroCell) IndiRab
ThRabies Recombinant nanoparticle- Liquid vaccine 2–8°C 1 mL IM 0–3–7 days 100% seropro- None None
based rabies G protein Licensed for tective titers
vaccine is prepared using >18 years only of >0.5 IU, by
VLP technology. day 14
50 µg per dose
Covid vaccines- Covaxin: SARS Ag: 6 µg Liquid vaccine 2–8°C 0.5 mL IM Covaxin: >6 Licensed None Known serious
Inact Covaxin, TLR 7/8 agonist: 15 mg years on basis of hypersensitivity
Corbevax, 2-PE: 2.5 mg Corbevax: >5 noninferiority to vaccine
Covovax Aluminium hydroxide: 0.25 mg years to components
Corbevax: Each dose of Covovax: >12 immunological or following a
0.5 mL contains RBD antigen years responses in previous dose
of SARS-CoV-2: 25 µg
Two doses 4 adults
hydroxide: 750 µg
weeks apart
CpG 1018: 750 µg

Covovax: Each dose (0.5 mL)
contains SARS-CoV-2
spike protein 5 µg and is
adjuvanted with Matrix-
M-Fraction-A (42.5 µg and
Fraction-C (7.5 µg of Quillaja
saponaria Molina extract)
Contd...
Contd...

Specific immunoglobulins/Mabs:
Rabies:
HRIg: 150 IU/mL Liquid 2–8°C 20 IU/kg to a maximum of 1,500 IU. Maximum volume to be infiltrated into depth of
Kamrab 2 mL vials wound. No need for IM administration of remaining volume
Berirab
ERIg: 300 IU/mL Liquid 2–8°C 40 IU/kg to a maximum of 3,000 IU. Maximum volume to be infiltrated into depth of
Equirab 5 mL vials wound. No need for IM administration of remaining volume
Rabishield 50 IU/1.25 mL Liquid 2–8°C 3.33 IU/kg. Maximum volume to be infiltrated into depth of wound. No need for IM
100 IU/2.5 mL administration of remaining volume
Twinrab 600 IU/mL Liquid 2–8°C 40 IU/kg. Maximum volume to be infiltrated into depth of wound. No need for IM
1,500 IU/mL/2.5 mL administration of remaining volume
Hepatitis B:
Hepabsv 100 IU/1 mL Liquid 2–8°C 100 IU for IM
newborn
0.06 mL/kg
for others IM
Hepabig 200 IU/mL/2 mL Liquid 2–8°C 100 µ for IM
newborn
0.06 mL/kg
for others IM
Tetanus:
TetGlob 250 IU Liquid 2–8°C 250–500 µ IM
500 IU IM
Contd...
535
Contd...
Diphtheria:
Diphtheria 10,000 µ in 10 mL Liquid 2–8°C • Pharyngeal or laryngeal disease of 2 days’ duration: 20,000–40,000
antitoxin: Equine • Nasopharyngeal disease: 40,000–60,000
• Extensive disease of 3 or more days duration, or any patient with diffuse swelling
of neck: 80,000–100,000
• Skin lesions only (rare case where treatment is indicated)
• 20,000–40,000
• Administered IM. Larger volumes may be administered IV
• Sensitivity testing essential prior to administration
(BCG: bacillus Calmette–Guérin; bOPV: bivalent oral polio vaccine; CFU: colony-forming unit; CPS: capsule polysaccharide; DT: diphtheria and tetanus; DTaP: diphtheria,
tetanus, and pertussis; DTwP: diphtheria tetanus whole-cell pertussis; ERIg: equine rabies immunoglobulin; FHA: filamentous hemagglutinin; GBM: glioblastoma
multiforme; GBS: Group B Streptococcus; HBsAg: hepatitis B surface antigen; HBIg: hepatitis B immune globulin; HBV: hepatitis B virus; HHE: hemiconvulsion-hemiplegia
epilepsy; Hib: Haemophilus influenzae type b; HIC: high-income countries; ID: intradermal; IIV: inactivated influenza vaccine; IM: intramuscular; IPV: inactivated
polio vaccine; ITP: immune thrombocytopenic purpura; IV: intravenous; JE: Japanese encephalitis; LAV: live attenuated vaccines; MIC: middle-income countries;
MMR: measles, mumps and rubella; NID: national immunization day; NTHi: nontypeable Haemophilus influenzae; PFU: plaque-forming unit; PPSV: pneumococcal
polysaccharide vaccine; PT: pertussis toxoid; RBD: receptor-binding domain; SARS-COV-2: severe acute respiratory syndrome coronavirus 2; SC: subcutaneous; SNID:
subnational immunization day; Td: tetanus and diphtheria; TdaP: tetanus, diphtheria, and pertussis; TLR: toll-like receptor; TT: tetanus toxoid; VAPP: vaccine-associated
paralytic polio; VDPV: vaccine-derived poliovirus; VLP: virus-like particles)
IV
AEFI Reporting Form
Annexure

Purple Book IAP Guidebook On Immunization 2022-2023

Uploaded by

Document Information

Original Description:

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Purple Book IAP Guidebook On Immunization 2022-2023

Uploaded by

Copyright:

Available Formats

Inhalt

1. Immunization in India: Past, Present,

2. General Aspects of Vaccination 9

3. Licensed Vaccines 102

3.5 Haemophilus Influenzae Type B Conjugate Vaccines 185

4. Vaccination of Special Groups 421

4.2 Immunization in Special Situations 434

5. Future Vaccines and Vaccine Hesitancy 483

M Indra Shekhar Rao, Shivananda S

BACKGROUND NOTES AND PRESENT STATUS

TABLE 1: Vaccine milestones in India.

Immunization Coverage in India

THE ROAD AHEAD AND THE FUTURE

TABLE 2: The immunization coverage in India.

Proper Monitoring of the Program

Develop Effective Surveillance Systems

ADVERSE EFFECTS, DETECTION, REPORTING,

REGULATORY AND ETHICAL ISSUES

SUPPORT TO INDIGENOUS VACCINE INDUSTRY,

development is bound to pay rich dividends. A large number of

INTEGRATED DELIVERY OF HEALTH

will do well to dedicate itself to continue to expand its coverage,

2.1 BASIC IMMUNOLOGY

INNATE AND ADAPTIVE IMMUNE RESPONSES

TABLE 1: Differentiating features between innate and adaptive immunity.

Humoral immunity is conferred by B lymphocytes, which is the

Fig. 1: Innate and adaptive immunity. (APC: antigen-presenting cell; NK cells:

Th17, and iTreg, as defined by their pattern of cytokine production

HOW DO VACCINES WORK?

T cell-independent antigens can be converted to T cell-dependent

FIRST STEP AFTER IMMUNIZATION

live vaccines. Finally, due to focal lymph node activation, multiple

IMMUNE RESPONSES TO VACCINES

Immune Response to Protein Antigens or

Germinal Center Reaction (Fig. 2)

Immune Response to Live Vaccines

Fig. 2: The germinal center reaction. (DC: dendritic cell)

PRIMARY VERSUS SECONDARY

DETERMINANTS OF INTENSITY AND DURATION

and persistence (depot or slow-release formulations) or

Fig. 3: Schematic presentation of various components of 0–1–6 months

between primary doses avoids competition between successive

Secondary Immune Responses

IMMUNE MEMORY AND NEED FOR BOOSTERS

IMMUNE RESPONSES DURING EARLY

amount of unmasked vaccine antigens may be sufficient for priming

Impact of Young Age Limitations on

is required for durable immunity. As the age of commencement

CORRELATES OF VACCINE-MEDIATED IMMUNITY

5. MacLennan IC, Toellner KM, Cunningham AF, Serre K, Sze DM,

2.2 ELEMENTARY EPIDEMIOLOGY

Impact of Vaccinology on Disease Epidemiology

INCIDENCE AND PREVALENCE OF DISEASES

tuberculosis (TB) cases]. Prevalence relates to total number of cases

FORCE OF TRANSMISSION AND BASIC

behavioral factors. The magnitude of Ro can be ascertained by

ENDEMIC, EPIDEMIC, AND PANDEMIC

VACCINE CHARACTERISTICS AND DEVELOPMENT

PHASES IN VACCINE DEVELOPMENT

HERD IMMUNITY, HERD EFFECT, HERD

meaning of the word.7 It should not be confused with “herd effect”

term often used to describe a group of unimmunized individuals