H I S TO R I C A L P E R S P E C T I V E

Vaccines: past, present and future

© 2005 Nature Publishing Group http://www.nature.com/naturemedicine

Stanley A Plotkin

The vaccines developed over the first two hundred years since Jenner’s lifetime have accomplished striking reductions of infection
and disease wherever applied. Pasteur’s early approaches to vaccine development, attenuation and inactivation, are even now
the two poles of vaccine technology. Today, purification of microbial elements, genetic engineering and improved knowledge
of immune protection allow direct creation of attenuated mutants, expression of vaccine proteins in live vectors, purification
and even synthesis of microbial antigens, and induction of a variety of immune responses through manipulation of DNA, RNA,
proteins and polysaccharides. Both noninfectious and infectious diseases are now within the realm of vaccinology. The profusion
of new vaccines enables new populations to be targeted for vaccination, and requires the development of routes of administration
additional to injection. With all this come new problems in the production, regulation and distribution of vaccines.

“The Circassians [a Middle Eastern people] perceived that of a thou- mild illness in humans, could prevent smallpox. This discovery not
sand persons hardly one was attacked twice by full blown smallpox; only led to the eradication of smallpox in the twentieth century, but
that in truth one sees three or four mild cases but never two that are also gave cachet to the idea of deliberate protection against exposure
serious and dangerous; that in a word one never truly has that illness to infectious diseases.
twice in life.” The history of vaccination as a deliberate endeavor began in the
Voltaire, “On Variolation,” Philosophical Letters, 1734 laboratory of Louis Pasteur. His aphorism that ‘chance favors the pre-
pared mind’ was never more aptly illustrated than by his own discovery
Early successes of attenuation. Pasteur was on vacation in the summer of 1881, and
The beginnings of vaccination, defined as an overt attempt to use part returned in the autumn to studies of chicken cholera, caused by what
or all of a microbial pathogen to protect against that microbe, are lost we call today Pasteurella multocida. A culture left on the bench during
in the proverbial mists of time. Vaccination probably originated in the summer was inoculated into chickens but did not cause disease.
homeopathic beliefs about small doses of disease protecting against Pasteur then made a fresh culture and inoculated the same chickens,
severe disease, verified empirically by ingestion of small doses of poi- whether through parsimony or purpose we do not know. In any case,
son to prevent fatal intentional poisoning of rulers by rivals. By the the chickens were resistant to the fresh challenge, and Pasteur realized
eleventh century there were hints in Chinese literature of the use of that the aged culture had rendered them immune4.
variola scabs insufflated into the nose to immunize against smallpox, From these observations Pasteur constructed the hypothesis that
perhaps based on observations that prior smallpox protected against pathogens could be attenuated by exposure to environmental insults
subsequent exposure1,2. such as high temperature, oxygen and chemicals. His ensuing work
Whereas the Chinese are generally given credit for the invention of on anthrax and rabies confirmed the hypothesis5. Table 1 outlines the
variolation, support for that view comes only in writings of the seven- strategies used subsequently for the development of live vaccines. In
teenth century. The other candidate region for the origin of variolation the next century, Calmette and Guérin used passage in artificial media
is India, where a scarification procedure was invented either separately to attenuate Mycobacterium bovis6, and Theiler used passage in mice
or imported from China. From there cutaneous variolation passed to and chick embryos to attenuate yellow fever virus7.
the Middle East and Africa, and as is well known, from Turkey to Great Meanwhile, the concept of antibodies and cellular immune
Britain, the rest of Europe and elsewhere, as the epigraph above from responses had developed from the original work of Paul Ehrlich and
Voltaire suggests. Ilya Metchnikoff, respectively, and measurement thereof by relatively
Although variolation was a success (for example, as confirmed during primitive methods established the dual nature of the adaptive immune
the American Revolution by the immunity of British troops to small- system. Vaccinologists consequently focused on stimulating these
pox outbreaks and Washington’s later decision to inoculate his army3), responses.
significant and even fatal reactions acted as a brake on its use. No doubt
this was the impetus for Jenner’s epochal observation that cowpox, a The cell-culture revolution
In the middle of the twentieth century, cell culture was adapted to
growth of viruses8, and it was not long before it was realized that pas-
Sanofi Pasteur and the University of Pennsylvania, 4650 Wismer Road, sage in cell culture was also a means of attenuation, presumably by
Doylestown, Pennsylvania 18901, USA. Correspondence should be addressed to
fortuitous selection of mutants better adapted to replication in vitro
S.A.P. ([email protected]).
than in the living host. Cell culture also permitted conscious selection of
Published online 5 April 2005; doi:10.1038/nm1209 mutants by isolation of single clones and by incubation at temperatures

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 H I S TO R I C A L P E R S P E C T I V E

concomitant T-cell stimulation15. The use of peptides as vaccines has

Table 1 Live vaccines and their approximate times of availability
been slowed by the need for strong adjuvants, but peptides do have a
Development strategy Date Vaccine or target
role in experimental cancer vaccines16.
Use of related animal virus 1798 Smallpox
Chemical attenuation 1885 Rabies Genetic engineering
1881 Anthrax The advent of molecular biology and genetic engineering, as in every
Passage in vitro 1927 BCG other domain of biology, has had a dramatic effect on vaccine develop-
1935 Yellow fever ment, providing greater opportunities for construction of inactivated
Cell culture passage 1962 OPV antigens and for rational attenuation of organisms through directed
1963 Measles mutation. Table 3 lists some of the newer strategies that depend on
© 2005 Nature Publishing Group http://www.nature.com/naturemedicine

1971 Adenoviruses molecular biology.

1995 Varicella The first success of genetic engineering was a hepatitis B vaccine
2005 Rotavirus 89-12
manufactured in a yeast recombinant carrying the gene for the S pro-
tein17, which replaced a vaccine based on purification of S particles
Cell culture passage with cold adaptation 1969 Rubella
from plasma of infected individuals18. Subsequently, insertion of genes
2003 Live influenza
into yeast, Escherichia coli or Chinese hamster ovary cells enabled pro-
Auxotrophy 1989 Ty21a typhoid
duction of a variety of recombinant proteins, such as Lyme OspA19,
Use of reassortants 1970s Inactivated influenza
cytomegalovirus gB20 and pertussis toxin21.
seed
Recombinants of viruses and bacteria also may be used as live vac-
2003 Live influenza
cines, on condition that they are apathogenic. For example, bovine or
2005 Rotavirus bovine-human
attenuated human parainfluenza 3 viruses can serve as the backbone
OPV, oral polio vaccine.
for insertion of genes from other parainfluenza viruses or from respira-
tory syncytial virus22, and attenuated yellow fever virus can serve as the
below the normal temperature of the host. Thus, the period between carrier for genes from dengue or West Nile viruses23. Protein expression
1950 and 1980 saw the development of numerous attenuated virus vac- by the inserted genes is immunizing.
cines, including those for polio (Sabin oral), measles, rubella, mumps The term ‘vectored vaccine’ is often used for live recombinants, as the
and varicella. key issue is to have a vector, or carrier, that will incorporate and express
An important technology applicable to viruses with segmented the gene for a pathogen without itself causing illness. Many viral and
genomes has been reassortment in cell culture. The development of bacterial vectors have been proposed, but those most favored have been
influenza and rotavirus vaccines is greatly aided by the ability to mix
RNA segments from attenuated strains with RNA encoding protective
antigens from circulating wild strains. Both live and killed influenza Table 2 Nonliving vaccines and their approximate times of availability
vaccines are dependent on reassortment: live vaccine contains replicat- Vaccine strategy Date Vaccine or target
ing reassortants, whereas inactivated vaccines are produced from live Inactivated whole organisms 1896 Typhoid
reassortant seeds9. Two of the three rotavirus vaccines developed so
1896 Cholera
far have depended on reassortants containing the vp7 genes of human
1897 Plague
strains with the genes from animal rotaviruses nonpathogenic for
1926 Whole-cell pertussis
humans10,11.
1938 Influenza

Inactivated vaccines 1955 IPV

The idea of complete inactivation as a means of vaccine development 1995 Hepatitis A
also started in the nineteenth century, not long after Pasteur’s original Use of extracts and subunits 1944 Japanese encephalitis
insight. Here priority probably goes to Daniel Salmon and Theobald 1970s Influenza
Smith in the United States, although Pasteur’s team, led by Emile Roux, 1960 Anthrax
made an independent discovery of the same principle2,12. 1976 Cell-culture rabies
Table 2 outlines the subsequent strategies for the development of Use of toxoids 1923 Diphtheria
inactivated vaccines, the first ones being directed against the typhoid 1927 Tetanus
and cholera bacilli. More recently, the inactivated polio vaccine (Salk 2008 (?) New anthrax
type), which together with oral vaccine has almost eradicated polio
Use of capsular polysaccharides 1977 Pneumococcal
from the world, and the hepatitis A vaccine contain whole inactivated
1974 Meningococcal
viruses.
1995 Typhoid
The recognition of extracellular bacterial toxins by Roux, Yersin,
Use of protein-conjugated capsular 1987 H. influenzae type b
Behring and Kitasato permitted the development of toxoids (inacti-
vated toxins) by Ramon for diphtheria and tetanus13,14. As technology polysaccharides 2002 Pneumococcal

advanced, it became possible to separate and use subunits of organisms 2002 Meningococcal
in the form of extracts of infected tissues (e.g., rabies), capsular polysac- Future Staphylococcal
charides (e.g., typhoid Vi and pneumococci) and proteins (e.g., acel- Use of purified or recombinant proteins 1986 Hepatitis Ba
lular pertussis). Late in the twentieth century, conjugation of proteins 1996 Acellular pertussisb
by polysaccharides became a powerful weapon against encapsulated 1998 Lyme disease
bacteria (e.g., Haemophilus influenzae type b), when it was realized aPlasma-derived vaccine in 1981. bEarlier in Japan. IPV, inactivated polio
that infants would not respond to stimulation of B cells without a vaccine.

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Table 3 Newer strategies for vaccine development starting from microbial DNA, cDNA or RNA
Strategy Examples of pathogens targeted
Recombinant protein production Hepatitis B S Ag , pertussis toxin, Lyme outer surface protein A, CMV gB protein
Live recombinants carrying genes from related agents Dengue genes in yellow fever 17D, parainfluenza 1
+ 2 genes in parainfluenza 3, M. tuberculosis genes in BCG
Recombinant vectors recombining genes from pathogens HIV, CMV
Alpha virus replicons HIV, Hemorrhagic Fevers
Replication-defective particles HPV, SARS
© 2005 Nature Publishing Group http://www.nature.com/naturemedicine

‘Naked’ DNA plasmids HIV and many others

Prime boost using DNA and/or vectors HIV, malaria, tuberculosis
Reverse vaccinology Meningococcus B
Microarrays for expression of virulence genes Mainly bacteria
Synthetic peptides Cancer, CTL vaccines
Synthetic capsular polysaccharides Hib
Reverse genetics Influenza, parainfluenza, RSV
Hib, H. influenza type b; IPV, inactivated polio vaccine; T, tetanus; d, adult diphtheria dose; CMV, cytomegalovirus; HPV, human papillomavirus; HSV, herpes simplex virus; RSV,
respiratory syncytial virus; HIV, human immunodeficiency virus; CTL, cytotoxic T lymphocyte.

poxviruses, adenoviruses and Bacille Calmette-Guérin (BCG)24. All of further development. This process has been called ‘reverse
these, as well as others, have been employed in an effort to develop vaccinology’38. Similarly, microarray analysis can be used to identify
HIV and malaria vaccines, often in a prime-boost configuration, so the microbial genes that are turned on during invasive infection, and
called because the immune system is primed with proteins expressed thus the proteins that may be virulence factors to be countered by prior
by injected DNA plasmid or vector, and then boosted with the same immunization39,40.
proteins in soluble form or expressed by another vector25–27. Alphavirus
replicons are a special case of vectors, in which the replicon particle Immunology finally helps vaccinology
carries no viral genome but expresses foreign genes in a single cycle It must be admitted that until recently immunology has not contributed
of replication28. much to the development of vaccines. As emphasized in an accompa-
The production of some viral proteins in vitro results in self-assem- nying article41, most successes in immunization have been mediated
bly of structures resembling the whole virus, so-called virus-like par- through the induction of protective antibodies42, whereas the major
ticles (Fig. 1). The particles are more immunogenic than the soluble challenges now facing us (e.g., HIV, malaria, tuberculosis) will require
proteins, and have led to highly effective papillomavirus vaccines29,30 the induction of T cell immunity as well. Fortunately, several of the new
and other vaccines still to be tested in humans, such as one against strategies, including vectors, plasmid DNA and lipidated peptides43,
SARS virus31. A widely used technology in modern vaccinology, both are capable of inducing both CD4+ and CD8+ cellular responses.
for antigen discovery and for vaccine development is the fruit of a In addition, the paucity of adjuvants for vaccines, until recently
discovery as fully serendipitous as that of Pasteur: that bacterial DNA
plasmids containing genes from viral pathogens would express the cor-
responding proteins after intramuscular or intradermal injection in
vivo32. The antigens thus produced are carried to the bone marrow,
where antibody and cellular immunity are elicited33. Unfortunately,
this technology has not proven reliable in humans, although induc-
tion of cellular immunity is more frequent than that of antibodies.
Nevertheless, DNA plasmids have interesting properties, such as the
ability to induce responses despite the presence of passive maternal
antibodies34, and are still much studied.
One particular application of DNA plasmids has been reverse genet-
ics35,36, which has allowed the construction of novel negative-strand
segmented RNA viruses by mutation of their cDNA and then introduc-
tion of multiple cDNA plasmids containing the entire viral genome
into cell culture, together with other plasmids expressing enzymes for
reconstitution of the virus. This technique is currently being incor-
porated into the manufacture of influenza vaccines, and will allow,
for example, the more rapid production of seed virus for an H5 avian
influenza vaccine if, as feared, the virus adapts to humans37.
The ability to sequence microbial genomes has permitted the identi-
fication of new protective factors. The predicted genes from a nucleo-
tide sequence are expressed in E. coli, and the resulting proteins used
to immunize mice. If antibodies are produced against the organism Figure 1 Pseudo-particles of human papillomavirus type 16 formed by
of interest, especially bactericidal or neutralizing antibodies that pro- self-assembly of the L1 viral protein. Courtesy of Drs. John Schiller and
tect against a wide range of strains, the protein becomes of interest for Susana Pang.

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from plants made transgenic for vaccine antigens57,58. Demonstration

Table 4 Nonparenteral routes of administration
of adequate immune responses in human is awaited. Immunization by
Route Example of use
rectal or vaginal application of antigens is also under investigation59.
Intranasal Live influenza
Closest to actual use is vaccination by transdermal application60–64.
Aerosol Measles
Many devices have been developed to deliver antigens across the skin.
Rubella These include patches containing adjuvant applied to lightly abraded
Oral Plants transgenic for Hepatitis BsAg skin and microneedles to pierce the stratum corneum. Figure 2 shows
Transcutaneous (patches, Hepatitis B, anthrax one such microneedle device. Once past the superficial layer, the antigen
microneedles, powder)
comes in contact with dendritic antigen-presenting cells, which travel to
lymph nodes and initiate immune responses61. If transdermal immuni-
© 2005 Nature Publishing Group http://www.nature.com/naturemedicine

essentially limited to aluminum salts that stimulate a T helper type zation works well, vaccination practice could be revolutionized.
2 (TH2) response, is at last being corrected by the creation of new
oil-in-water emulsions, liposomes, Toll-like receptor agonists, cytokines Extension to noninfectious diseases
and other substances that push the immune system in a T helper type Active immunization has heretofore been largely confined to infec-
1 (TH1) direction44. tious diseases, with some use of desensitization to treat allergies. Now
Moreover, immunologists have recently provided us with tests for cellu- consideration is being given to immunization against a wide variety of
lar immunity that can be done on a large scale, such as ELISPOT assays for noninfectious diseases. Most effort is being directed against cancers,
cytokine induction and tetramer staining for CD8+ cell peptide specific- in which novel cellular antigens are often present65,66. Vaccine incor-
ity45. The recent rediscovery of T regulatory cells may also have an impact porating proteins or peptides from cancer antigens are in advanced
on vaccines for pathogens that try to evade the immune system46. trials, with promising results measured by prolongation of life. It is also
intriguing that individuals with inherited mutations that predispose to
New means and new ends cancer might be immunized prophylactically before cancer develops.
In the early days of the twenty-first century, one can descry several Tolerization to autoantigens is being attempted in many autoimmune
notable tendencies in vaccine development. Combinations of vaccines diseases, such as multiple sclerosis67 and diabetes mellitus68. Better anti-
have become ever more necessary as new components become part gens for inducing IgG rather than IgE antibodies against allergens are
of routine vaccination. Already hexavalent combinations containing in development69. Contraception can be maintained by immunization
diphtheria, tetanus, pertussis, H. influenzae type b (Hib), hepatitis B and against hormones70. Atherosclerosis and Alzheimer disease can perhaps
inactivated polio vaccines are used in Europe, and pentavalent combi- be controlled by immunization against cholesterol fractions or amyloid,
nations in many other parts of the world47. Varicella vaccine has been respectively71,72. Lastly, drug addictions, including nicotine, metham-
incorporated into measles-mumps-rubella vaccines, and various com- phetamine and cocaine, may be controllable by inducing antibodies
binations of H. influenzae type b, pneumococcal and meningococcal that rapidly remove the drugs from the body73.
conjugated bacterial polysaccharide vaccines will become available.
Another easily discerned tendency is toward the stimulation of innate New targets
as well as adaptive immune responses. This can be accomplished by the New populations are being targeted for vaccination, as summarized in
choice of proper adjuvants such as CpG oligonucleotides48, which stimu- Table 5. Until now, most vaccination has been directed at infants and
late both types of responses. Proteomics will probably advance to the point children; but it has become increasingly clear that adolescents and adults
of allowing construction in vitro of proteins with more natural conforma- also need universal immunizations. Aside from new recommendations
tions, and polysaccharide synthesis is just beginning to be practical.
Whereas vaccination is usually considered as prophylaxis, serious
attempts are being made to develop therapeutic vaccines for chronic
infections49. The basic idea is to induce cellular immune responses
that suppress infection, even when the host has been unable to mount
those responses naturally. Examples include immunization against the
E6 and E7 oncogenes of papillomaviruses for the treatment of cervical
cancer, and against the gag and tat genes of HIV for the suppression of
viral replication in AIDS50–53.
A very important part of the future is the enlargement of routes of
immunization (Table 4). Most vaccines today are given by parenteral
injection, which induces systemic immune responses expressed by B
and T cells in the blood. But the need for mucosal immune responses
has become increasingly obvious. The new live, attenuated influenza
vaccine is given intranasally, induces both systemic and local responses
and gives a broader protection against antigenically drifted strains54.
Aerosol administration of measles and rubella vaccines implants the
attenuated viruses at the natural sites of replication and elicits immu-
nity equivalent to that after injection55. The aerosol route could lend
itself to mass immunization using inhalation devices. Oral immuniza-
tion has been used for some time to immunize with living organisms Figure 2 Scanning electron photomicrograph of a microprojection array used
that replicate in the intestine, such as oral polio and typhoid Ty21a to deliver antigen to the skin. A 25-gauge needle is shown (at right) for size
vaccines. Now attempts are being made to induce mucosal responses comparison. Figure reprinted from ref. 87 courtesy of J. Matriano (ALZA
with nonliving antigens56. One approach is to develop oral vaccines Corporation) with kind permission of Springer Science and Business Media.

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for booster immunization with diphtheria-tetanus-acellular pertussis

Table 5 New target groups for vaccination
vaccine74, the possible incorporation of vaccines against meningococci,
papillomaviruses, Herpes simplex75 and cytomegalovirus76 into routine Groups Vaccine targets
vaccination will require an adolescent immunization date to prevent, Infants Diphtheria, tetanus, acellular pertussis,
(combination vaccines) Hameophilus influenzae type b, hepatitis B,
respectively, sepsis, cervical cancer, genital herpes and congenital infec- inactivated polio vaccine
tion. Adults currently receive influenza and pneumococcal vaccines, but
Adolescents Tetanus, adult diphtheria dose, acellular
vaccination may also come into play against varicella virus to prevent pertussis, CMV, HPV, HSV-2
reactivation in the form of zoster77. Also, during the course of their lives, Adults Zoster, HSV-2
adults may need vaccination during pregnancy, hospitalization and travel. Hospital patients Staphylococcal, Candida
An experimental Group B streptococcal vaccine is available to prevent
© 2005 Nature Publishing Group http://www.nature.com/naturemedicine

Pregnant women Group B Streptococcus, RSV

transmission of the bacteria from mothers to neonates78 and pregnant
Civil defense workers New vaccinia, anthrax, plague, Ebola, etc.
women could be immunized against a number of other pathogens (e.g.,
Individuals with Cancer, Alzheimer disease, dental caries,
pneumococci, respiratory syncytial virus) in order to transmit protec- noninfectious diseases autoimmune disorders, drug addiction
tive antibodies that will protect their newborns for some months79. Individuals with chronic infec- HIV, HPV
Antibiotic-resistant nosocomial bacteria are an increasing problem and tions (therapeutic vaccines)
a staphylococcal capsular polysaccharide vaccine is in a later stage of CMV, cytomegalovirus; HPV, human papillomavirus; HSV, herpes simplex virus; RSV,
development for patients susceptible to secondary infections80. respiratory syncytial virus; HIV, human immunodeficiency virus.
Although bioterrorism is unpleasant to think about, augmented
financial support has stimulated development of new vaccines against
anthrax, plague and smallpox, to name but a few. In the case of anthrax Jenner’s vaccinia will be replaced by further attenuated vaccinia82 and
and plague, purified antigens will afford better protection and safety, Bacille Calmette-Guérin by engineered vaccines for tuberculosis85.
whereas poxvirus research has generated attenuated strains of vaccinia Indeed, one of the advantages of the newer molecular technologies is
to protect against smallpox81,82. improved safety. As risk-benefit ratios become more controversial when
disease presence declines, it will be important to reduce vaccine-associ-
New problems ated reactions to a minimum. On the other hand, zero risk is impossible
The prospects for control of diseases by vaccination are thus quite to attain, and there will always be tension between the needs of public
bright, but it must be admitted that several problems loom large and health and the regulatory impulse to guard against even remote and
darken the picture. First, vaccine supply is insufficient. Even in industri- theoretical risks. The latter tendency acts as a brake on the rapid appli-
alized countries, shortages of vaccines occur because there are too few cation of new public health measures. Thus, there is disagreement as to
manufacturers, and regulatory pressures render production ever more whether to err on the side of safety or of disease prevention.
difficult. In the event of an emergency, such as an influenza pandemic, As vaccines are key tools for maintenance of public health, govern-
it is difficult to see how demand could be satisfied or access provided to ments have a major role in their dissemination through recommen-
developing countries. The growth of new manufacturers in developing dations and purchase. Although governmental agencies (particularly
countries like India, China, Indonesia and Brazil may fill this gap, but the US National Institutes of Health) importantly support the basic
the solution to supply shortage is not yet clear. research that provides candidate vaccines, their direct involvement in
Cost of vaccines is also now a problem, because new vaccines require industrial development and production has decreased. It is doubtless
$300 to $800 million to develop and those companies that do research more efficient for industry to take vaccines from concept to license,
and development must recoup the costs. If vaccines are to be applied but governments should advise about the choice of targets for vaccine
broadly throughout the world, several circumstances must be main- development and guarantee markets for products developed at their
tained: higher price in developed countries, recognition by governments request. Moreover, it has become obvious that governments must be
that the financial savings because of vaccination justify expenditures proactive in preventing vaccine shortages by inducements for multiple
to buy vaccines, and support by donor agencies of vaccine purchases suppliers.
for poor countries. When the vaccine target is one that concerns only There are many diseases as yet uncontrolled by vaccination, and new
developing countries, the problem becomes even more difficult. The diseases are sure to emerge through evolution by mutation and gene
support of the Bill and Melinda Gates Foundation for the development exchange, interspecies transfer or human exposure to new environ-
of vaccines against those targets has been crucial, but at a certain point ments86. Fortunately, we have many new tools with which to produce
industrial manufacture will be necessary. This will require vaccine pro- protective antigens. Two hundred years of research have enabled us to
duction facilities outside of developed countries or subsidized facilities turn the immune system to our advantage, and increased understand-
at major manufacturers. ing of microbial pathogenesis and host responses should allow us to
There is a growing demand for vaccine safety, fueled in part by extend control of disease by vaccination.
antivaccination groups. As disease recedes, the need for vaccination
COMPETING INTERESTS STATEMENT
becomes less evident to the public, and more people opt out of the
The author declares competing financial interests (see the Nature Medicine website
social contract to be vaccinated, depending instead on the herd immu- for details).
nity of surrounding vaccinated persons. Of course, herd immunity will
fail if too many refuse to be vaccinated. But there are real safety prob- Published online at http://www.nature.com/naturemedicine/
lems associated with vaccines, such as paralysis after oral polio vaccine83
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