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Vaccines History
Vaccines History
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
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.
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
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.
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.
Wang, New York, 2001). 42. Plotkin, S.A. Immunologic correlates of protection induced by vaccination. Pediatr.
4. Pasteur, L. De l’attenuation du virus du cholera des poules. C. R. Acad. Sci. Paris 91, Infect. Dis. J. 20, 63–75 (2001).
673–680 (1880). 43. BenMohamed, L., Wechsler, S.L. & Nesburn, A.B. Lipopeptide vaccines—yesterday,
5. Pasteur, L., Chamberland, C.-E.: Sur la vaccination charbonneuse. C. R. Acad. Sci. today, and tomorrow. Lancet Infect. Dis. 2, 425–431 (2002).
Paris 92, 1378–1383 (1881). 44. Moingeon, P., Haensler, J. & Lindberg, A. Towards the rational design of Th1 adjuvants.
6. Calmette, A., Guerin, C., Breton, M. Contribution a l’etude de la tuberculose experi- Vaccine 19, 4363–4372 (2001).
mental du cobaye (infection et essais de vaccination par la voie digestive). Ann. Inst. 45. Autran, B., Molet, L. & Lederman, M.M. Host defenses against viral infection. in
Pasteur Paris 21, 401–416 (1907). Practical Guidelines in Antiviral Therapy (eds. Boucher, C.A. & Galasso, G.A) 65–94
7. Theiler, M., Smith, H.H. The use of yellow fever virus by in vitro cultivation for human (Elsevier, Philadelphia, 2002).
immunization. J. Exp. Med. 65, 787–800 (1937). 46. O’Garra, A. & Vieira, P. Regulatory T cells and mechanisms of immune system control.
8. Weller, T.H. Cultivation of poliomyelitis virus in cultures of human foreskin and embry- Nat. Med. 10, 801–805 (2004).
onic tissues. Proc. Soc. Exp. Biol. Med. 72,153–155 (1949). 47. Decker, M.D., Edwards, K.M. & Bogaerts, H.H. Combination vaccines. in Vaccine 4th
9. Kilbourne, E.D. & Murphy, J.S. Genetic studies of influenza viruses. I. Viral morphology edn. (eds. Plotkin, S.A. & Orenstein, W.A.) 825-861 (Elsevier, Philadelphia, 2004)
© 2005 Nature Publishing Group http://www.nature.com/naturemedicine
and growth capacity as exchangeable genetic traits. Rapid in ovo adaptation of early 48. Klinman, D.M. Immunotherapeutic uses of CpG oligodeoxynucleotides. Nat. Rev.
passage Asian strain isolates by combination with PR8. J. Exp. Med. 111, 387–406 Immunol. 4, 249–258 (2004).
(1960). 49. Sela, M. & Hilleman, M.R. Therapeutic vaccines: realities of today and hopes for
10. Clark, H.F., Offit, P., Glass, R.I., Ward, R.L. Rotavirus vaccines. in Vaccines 4th edn. tomorrow. Proc. Natl. Acad. Sci. USA 101 Suppl 2, 14559 (2004).
(eds. Plotkin, S.A. & Orenstein, W.A.) 1327–1345 (Elsevier, Philadelphia, 2004). 50. Vandepapeliere, P. Therapeutic vaccination against chronic viral infections. Lancet
11. Bernstein, D.I. et al. Safety and immunogenicity of live, attenuated human rotavirus Infect. Dis. 2, 353–367 (2002).
vaccine 89-12. Vaccine 16, 381–387 (1998). 51. Hallez, S. et al. Phase I/II trial of immunogenicity of a human papillomavirus (HPV)
12. Salmon, D.E. & Smith, T. On a new method of producing immunity from infectious type 16 E7 protein-based vaccine in women with oncogenic HPV-positive cervical
diseases. Am. Vet. Rev. 10, 63–69 (1886). intraepithelial neoplasia. Cancer Immunol. Immunother. 53, 642–650 (2004).
13. Ramon, G. Sur le pouvoir floculant et sur les proprietes immunisantes d’une toxine 52. Markowitz, M. et al. Discontinuation of antiretroviral therapy commenced early during
diphterique rendu anatoxique (anatosine). C. R. Acad. Sci. Paris 177, 1338–1340 the course of human immunodeficiency virus type 1 infection, with or without adjunc-
(1923). tive vaccination. J. Infect. Dis. 186, 634–643 (2002).
14. Ramon, G. & Zeller, C. De la valeur antigenique de l’anatoxine tetanique chez l’homme. 53. Buckner, C. et al. Priming B cell-mediated anti-HIV envelope responses by vaccination
C. R. Acad. Sci. Paris 182, 245–247 (1926). allows for the long-term control of infection in macaques exposed to a R5-tropic SHIV.
15. Schneerson, R., Barrera, O., Sutton, A. & Robbins, J.B. Preparation, characteriza- Virology 320, 167–180 (2004).
tion, and immunogenicity of Haemophilus influenzae type b polysaccharide-protein 54. Belshe, R.B. et al. Efficacy of vaccination with live attenuated, cold-adapted, trivalent,
conjugates. J. Exp. Med. 152, 361–376 (1980). intranasal influenza virus vaccine against a variant (A/Sydney) not contained in the
16. Moingeon, P. Cancer vaccines. Vaccine 9, 1305–1326 (2001). vaccine. J. Pediatr. 136, 168–175 (2000).
17. McAleer, W.J., Buynak, E.B., Maigetter, R.Z., Wampler, D.E., Miller, W.J. & Hilleman 55. Sepulveda-Amor, J. et al. A randomized trial demonstrating successful boosting
M.R. Human hepatitis B vaccine from recombinant yeast. Nature 307, 178–180 responses following simultaneous aerosols of measles and rubella (MR) vaccines in
(1984). school age children. Vaccine 20, 2790–2795 (2002).
18. Szmuness, W., Stevens, C.E., Zang, E.A., Harley, E.J. & Kellner, A. A controlled clinical 56. Jones, T. et al. A nasal Proteosome influenza vaccine containing baculovirus-derived
trial of the efficacy of the hepatitis B vaccine (Heptavax B): a final report. Hepatology hemagglutinin induces protective mucosal and systemic immunity. Vaccine 21,
1, 377–385 (1981). 3706–3712 (2003).
19. Fikrig, E., Barthold, S.W., Kantor, F.S. & Flavell, R.A. Protection of mice against the 57. Tacket, C.O. Garden-variety vaccines: antigens derived from transgenic plants. Expert
Lyme disease agent by immunizing with recombinant OspA. Science 250, 553–556 Rev. Vaccines 3, 529–531 (2004).
(1990). 58. Webster, D.E. et al. Successful boosting of a DNA measles immunization with an oral
20. Spaete, R.R. A recombinant subunit vaccine approach to HCMV vaccine development. plant-derived measles virus vaccine. J. Virol. 76, 7910–7912 (2002).
Transplant. Proc. 23, 90–96 (1991). 59. Stevceva, L. & Strober, W. Mucosal HIV vaccines: where are we now? Curr. HIV Res.
21. Pizza, M. et al. Mutants of pertussis toxin suitable for vaccine development. Science 2, 1–10 (2004).
246, 497–500 (1989). 60. Hammond, S.A., Walwender, D., Alving, C.R. & Glenn, G.M. Transcutaneous immuni-
22. Durbin, A.P. & Karron, R.A. Progress in the development of respiratory syncytial virus zation: T cell responses and boosting of existing immunity. Vaccine 19, 2701–2707
and parainfluenza virus vaccines. Clin. Infect. Dis. 37, 1668–1677 (2003). (2001).
23. Guirakhoo, F. et al. Safety and efficacy of chimeric yellow Fever-dengue virus tetrava- 61. Glenn, G.M., Kenney, R.T., Ellingsworth, L.R., Frech, S.A., Hammond, S.A. &
lent vaccine formulations in nonhuman primates. J. Virol. 78, 4761–4775 (2004). Zoeteweij, J.P. Transcutaneous immunization and immunostimulant strategies: capi-
24. Plotkin, S.A. Six revolutions in vaccinology. Pediatr. Infect. Dis. J. 24, 1–9 (2005) talizing on the immunocompetence of the skin. Expert Rev. Vaccines 2, 253–267
25. Excler, J.L. & Plotkin, S. The prime-boost concept applied to HIV preventive vaccines. (2003).
AIDS 11 Suppl A, S127–S137 (1997). 62. Matyas, G.R., Friedlander, A.M., Glenn, G.M., Little, S., Yu, J. & Alving, C.R. Needle-
26. Amara, R.R. et al. Control of a mucosal challenge and prevention of AIDS by a mul- free skin patch vaccination method for anthrax. Infect. Immun. 72, 1181–1183
tiprotein DNA/MVA vaccine. Vaccine 20, 1949–1955 (2002). (2004).
27. Moore, A.C. & Hill, A.V. Progress in DNA-based heterologous prime-boost immunization 63. Chen, D. et al. Epidermal powder immunization of mice and monkeys with an influenza
strategies for malaria. Immunol. Rev. 199, 126–143 (2004). vaccine. Vaccine 21, 2830–2836 (2003).
28. Rayner, J.O., Dryga, S.A. & Kamrud, K.I. Alphavirus vectors and vaccination. Rev. 64. Mikszta, J.A., Alarcon, J.B., Brittingham, J.M., Sutter, D.E., Pettis, R.J. & Harvey,
Med. Virol. 12, 279–296 (2002). N.G. Improved genetic immunization via micromechanical disruption of skin-barrier
29. Schiller, J.T. & Davies, P. Delivering on the promise: HPV vaccines and cervical cancer. function and targeted epidermal delivery. Nat. Med. 8, 415–419 (2002).
Nat. Rev. Microbiol. 2, 343–347 (2004). 65. Finn, O.J. Cancer vaccines: between the idea and the reality. Nat. Rev. Immunol. 3,
30. Koutsky, L.A. et al. A controlled trial of a human papillomavirus type 16 vaccine. N. 630–641 (2003).
Engl. J. Med. 347, 1645–1651 (2002). 66. Lewis, J.J. Therapeutic cancer vaccines: using unique antigens. Proc. Natl. Acad. Sci.
31. Huang, Y., Yang, Z.-Y., Kong, W.P. & Nabel, G.J. Generation of synthetic severe acute USA 101 Suppl 2, 14653–14656 (2004).
respiratory syndrome coronavirus pseudoparticles: implications for assembly and vac- 67. Hohlfeld, R. & Wekerle, H. Autoimmune concepts of multiple sclerosis as a basis for
cine production. J. Virol. 78, 12557–12565 (2004). selective immunotherapy: from pipe dreams to (therapeutic) pipelines. Proc. Natl.
32. Ulmer, J.B. et al. Heterologous protection against influenza by injection of DNA Acad. Sci. USA 101 Suppl 2, 14599–14606 (2004).
encoding a viral protein. Science 259, 1745–1749 (1993). 68. Petrovsky, N., Silva, D. & Schatz, D.A. Vaccine therapies for the prevention of type 1
33. Robinson, H.L. Nucleic acid vaccines: an overview. Vaccine 15, 785–787 (1997). diabetes mellitus. Paediatr. Drugs 5, 575–582 (2003).
34. Reddy, S.T. & Ertl, H.C. The potential use of DNA vaccines for neonatal immunization. 69. Niederberger, V. et al. Vaccination with genetically engineered allergens prevents pro-
Curr. Opin. Mol. Ther. 1, 22–29 (1999). gression of allergic disease. Proc. Natl. Acad. Sci. USA 101 Suppl 2, 14677–14682
35. Neumann, G. et al. Generation of influenza A viruses entirely from cloned cDNAs. (2004).
Proc. Natl. Acad. Sci. USA 96, 9345–9350 (1999). 70. Singh, M., Das, S.K., Suri, S., Singh, O. & Talwar, G.P. Regain of fertility and normality
36. Palese, P. & Garcia, S.A. Influenza vaccines: present and future. J. Clin. Invest. 110, of progeny born during below protective threshold antibody titers in women immunized
9–13 (2002). with the HSD-hCG vaccine. Am. J. Reprod. Immunol. 39, 395–398 (1998).
37. Wood, J.M. & Robertson, J.S. From lethal virus to life-saving vaccine: developing inac- 71. Mettens, P. & Monteyne, P. Life-style vaccines. Br. Med. Bull. 62, 175–186
tivated vaccines for pandemic influenza. Nat. Rev. Microbiol. 2, 842–847 (2004). (2002).
38. Mora, M., Veggi, D., Santini, L., Pizza, M. & Rappuoli, R. Reverse vaccinology. Drug 72. Gelinas, D.S., DaSilva, K., Fenili, D., George-Hyslop, P. & McLaurin, J. Immunotherapy
Discov. Today 8, 459–464 (2003). for Alzheimer’s disease. Proc. Natl. Acad. Sci. USA 101 Suppl 2, 14657–14662
39. Dhiman, N., Bonilla, R., O’Kane, D.J. & Poland, G.A. Gene expression microarrays: a (2004).
21st century tool for directed vaccine design. Vaccine 20, 22–30 (2001). 73. Kantak, K.M., Collins, S.L., Lipman, E.G., Bond, J., Giovanoni, K. & Fox, B.S.
40. Serruto, D., Adu-Bobie, J., Capecchi, B., Rappuoli, R., Pizza, M. & Masignani, Evaluation of anti-cocaine antibodies and a cocaine vaccine in a rat self-administra-
V. Biotechnology and vaccines: application of functional genomics to tion model. Psychopharmacology (Berl.) 148, 251–262 (2000).
Neisseria meningitidis and other bacterial pathogens. J. Biotechnol. 113, 15–32 74. Forsyth, K.D., et al. New pertussis vaccination strategies beyond infancy: recom-
(2004). mendations by the Global Pertussis Initiative. Clin. Infect. Dis. 39, 1802–1809
41. Lambert, P-H. Companion paper. Nat. Med. 11 Suppl 1, S54–S62 (2005). (2004).
75. Stanberry, L.R. Clinical trials of prophylactic and therapeutic herpes simplex virus 81. Hassani, M., Patel, M.C. & Pirofski, L.A. Vaccines for the prevention of diseases caused
vaccines. Herpes 11 Suppl 3, 161A–169A (2004). by potential bioweapons. Clin. Immunol. 111, 1–15 (2004).
76. Arvin, A.M., Fast, P., Myers, M., Plotkin, S. & Rabinovich, R. Vaccine development to 82. McCurdy, L.H., Larkin, B.D., Martin, J.E. & Graham, B.S. Modified vaccinia Ankara:
prevent cytomegalovirus disease: report from the National Vaccine Advisory Committee. potential as an alternative smallpox vaccine. Clin. Infect. Dis. 38, 1749–1753
Clin. Infect. Dis. 39, 233–239 (2004). (2004).
77. Levin, M.J. et al. Decline in varicella-zoster virus (VZV)-specific cell-mediated immu- 83. WHO collaborative study group: The relationship between persisting spinal paralysis
nity with increasing age and boosting with a high-hose VZV vaccine. J. Infect. Dis. and poliomyelitis vaccine—results of a ten-year enquiry. Bull WHO 60, 231–242
188, 1336–1344 (2003). (1982).
78. Baker, C.J., Paoletti, L.C., Rench, M.A., Guttormsen, H.K., Edwards, M.S. & Kasper, 84. Hoft, D.F. et al. Clinical reactogenicity of intradermal bacille Calmette-Guerin vac-
D.L. Immune response of healthy women to 2 different group B streptococcal type V cination. Clin. Infect. Dis. 28, 785–790 (1999).
capsular polysaccharide-protein conjugate vaccines. J. Infect. Dis. 189, 1103–1112 85. Horwitz, M.A. & Harth, G. A new vaccine against tuberculosis affords greater survival
(2004). after challenge than the current vaccine in the guinea pig model of pulmonary tuber-
79. Munoz, F.M., Piedra, P.A. & Glezen, W.P. Safety and immunogenicity of respiratory culosis. Infect. Immun. 71, 1672–1679 (2003).
© 2005 Nature Publishing Group http://www.nature.com/naturemedicine
syncytial virus purified fusion protein-2 vaccine in pregnant women. Vaccine 21, 86. Morse, S.S. The viruses of the future? Emerging viruses and evolution. in The
3465–3467 (2003). Evolutionary Biology of Viruses (ed Morse, S.S.) 325–335 (Raven Press, New York,
80. Fattom, A.I., Horwith, G., Fuller, S., Propst, M. & Naso, R. Development of StaphVAX, 1994).
a polysaccharide conjugate vaccine against S. aureus infection: from the lab bench 87. Matriano, J.A. et al. Macroflux microprojection array patch technology: a new and effi-
to phase III clinical trials. Vaccine 22, 880–887 (2004). cient approach for intracutaneous immunization. Pharm. Res. 19, 63–70 (2002).