Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Timeline
  • Published:

From empiricism to rational design: a personal perspective of the evolution of vaccine development

Nature Reviews Immunology volume 14, pages 505–514 (2014)Cite this article

Subjects

Abstract

Vaccination, which is the most effective medical intervention that has ever been introduced, originated from the observation that individuals who survived a plague or smallpox would not get the disease twice. To mimic the protective effects of natural infection, Jenner — and later Pasteur — inoculated individuals with attenuated or killed disease-causing agents. This empirical approach inspired a century of vaccine development and the effective prophylaxis of many infectious diseases. From the 1980s, several waves of new technologies have enabled the development of novel vaccines that would not have been possible using the empirical approach. The technological revolution in the field of vaccination is now continuing, and it is delivering novel and safer vaccines. In this Timeline article, we provide our views on the transition from empiricism to rational vaccine design.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: A timeline of the history of vaccines showing the technologies that have enabled their development.
Figure 2: Glycoconjugate vaccines.
Figure 3: Reverse vaccinology applied to meningococcus serogroup B.
Figure 4: Structural vaccinology for respiratory syncitial virus.
Figure 5: Synthetic biology for influenza vaccines.

References

  1. van Panhuis, W. G. et al. Contagious diseases in the United States from 1888 to the present. N. Engl. J. Med. 369, 2152–2158 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. World Health Organization. Global Vaccine Action Plan 2011-2020. (WHO, 2013).

  3. Thucydides. The History of the Peloponnesian War (University of Chicago Press, 1989).

  4. Needham, J. China and the origins of immunology. East Horiz. 19, 6–12 (1980).

    CAS  PubMed  Google Scholar 

  5. Leung, A. K. in Vaccinia, Vaccination, Vaccinoiogy: Jenner, Pasteur and Their Successors (eds Plotkin, S. A. & Fantini, B.) 65–71 (Elsevier, 1996).

    Google Scholar 

  6. Blower, S. & Bernoulli, D. An attempt at a new analysis of the mortality caused by smallpox and of the advantages of inoculation to prevent it. Rev. Med. Virol. 14, 275–288 (2004).

    Article  PubMed  Google Scholar 

  7. De Gregorio, E. et al. in Fundamental Immunology (ed. Paul W. E.) 1032–1068 (Lippicott Williams & Wilkins, 2013).

    Google Scholar 

  8. Jenner, E. An Inquiry into the Causes and Effects ofthe Variolae Vaccinae (Sampson Low, 1798).

    Google Scholar 

  9. Tognotti, E. The eradication of smallpox, a success story for modern medicine and public health: what lessons for the future? J. Infect. Dev. Ctries 4, 264–266 (2010).

    Article  PubMed  Google Scholar 

  10. Pasteur, L. De l'attenuation du virus du cholera des poules. C. R. Acad. Sci. Paris 91, 673–680 (in French) (1880).

    Google Scholar 

  11. Pasteur, L. Méthode pour prévenir la rage après morsure. C. R. Acad. Sci. Paris 101, 765–772 (in French) (1885).

    Google Scholar 

  12. von Behring, E. et al. Uber das zustandekommen der diphtherie-immunitat und der tetanus-immunitat bie tieren. Dtsch Med. Wochenschr. 16, 1113–1114 (in German) (1890).

    Article  Google Scholar 

  13. Von Behring, E. Untersuchungen iiber das zustandekommen der diphterie-immunitat bei tieren. Dtsch Med. Wochenschr. 16, 1145–1148 (in German) (1890).

    Article  Google Scholar 

  14. Calmette, A. & Guérin, C. Contribution à l'étude de l'immunité antituberculose chez les bovidés. Ann. Inst. Pasteur 28, 329–337 (in French) (1914).

    Google Scholar 

  15. Glenny, A. T. & Hopkins, B. E. Diphtheria toxoid as an immunising agent. Br. J. Exp. Pathol. 4, 283–288 (1923).

    CAS  PubMed Central  Google Scholar 

  16. Ramon, G. Sur le pouvoir floculant et sur les propriétés immunisationes d'une toxine diphtérique rendue anatoxique (anatoxine). C R. Acad. Sci. Paris 177, 1338–1340 (in French) (1923).

    Google Scholar 

  17. Salk, J. E. et al. Formaldehyde treatment and safety testing of experimental poliomyelitis vaccines. Am. J. Publ. Health Nat. Health 44, 563–570 (1954).

    Article  CAS  Google Scholar 

  18. Sabin, A. B., Hennessen, W. A. & Winsser, J. Studies on variants of poliomyelitis virus. I. Experimental segregation and properties of avirulent variants of three immunologic types. J. Exp. Med. 99, 551–576 (1954).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Katz, S. L. et al. Studies on an attenuated measles-virus vaccine. VIII. General summary and evaluation of the results of vaccine. N. Engl. J. Med. 263, 180–184 (1960).

    Article  CAS  PubMed  Google Scholar 

  20. Hilleman, M. R. et al. Development and evaluation of the Moraten measles virus vaccine. JAMA 206, 587–590 (1968).

    Article  CAS  PubMed  Google Scholar 

  21. Hilleman, M. R., Buynak, E. B., Weibel, R. E. & Stokes, J. Jr. Live, attenuated mumps-virus vaccine. N. Engl. J. Med. 278, 227–232 (1968).

    Article  CAS  PubMed  Google Scholar 

  22. Plotkin, S. A., Farquhar, J. D., Katz, M. & Buser, F. Attenuation of RA 27–23 rubella virus in WI-38 human diploid cells. Am. J. Dis. Child 118, 178–185 (1969).

    CAS  PubMed  Google Scholar 

  23. Weibel, R. E. et al. Live attenuated varicella virus vaccine. Efficacy trial in healthy children. N. Engl. J. Med. 310, 1409–1415 (1984).

    Article  CAS  PubMed  Google Scholar 

  24. Plotkin, S. A. New rotavirus vaccines. Pediatr. Infect. Dis. J. 25, 575–576 (2006).

    Article  PubMed  Google Scholar 

  25. Hall, C. B., Douglas, G. Jr & Fralonardo, S. A. Live attenuated influenza virus vaccine trial in children. Pediatrics 56, 991–998 (1975).

    CAS  PubMed  Google Scholar 

  26. Goldschneider, I., Gotschlich, E. C. & Artenstein, M. S. Human immunity to the meningococcus. I. The role of humoral antibodies. J. Exp. Med. 129, 1307–1326 (1969).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Gotschlich, E. C., Liu, T. Y. & Artenstein, M. S. Human immunity to the meningococcus. 3. Preparation and immunochemical properties of the group A, group B, and group C meningococcal polysaccharides. J. Exp. Med. 129, 1349–1365 (1969).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Austrian, R. in Vaccinia, Vaccination, Vaccinology: Jenner, Pasteur, and Their Successors. (eds Plotkin, S. A. & Fantini, B.) 127–133 (Elsevier, 1996).

    Google Scholar 

  29. Austrian, R. et al. Prevention of pneumococcal pneumonia by vaccination. Trans. Assoc. Am. Physicians 89, 184–194 (1976).

    CAS  PubMed  Google Scholar 

  30. Anderson, P. et al. Immunization of humans with polyribophosphate, the capsular antigen of Hemophilus influenzae, type b. J. Clin. Invest. 51, 39–44 (1972).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Avery, O. T. & Goebel, W. F. Chemo-immunological studies on conjugated carbohydrate-proteins: II. immunological specificity of synthetic sugar-protein antigens. J. Exp. Med. 50, 533–550 (1929).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Schneerson, R. et al. Haemophilus influenzae type B polysaccharide-protein conjugates: model for a new generation of capsular polysaccharide vaccines. Prog. Clin. Biol. Res. 47, 77–94 (1980).

    CAS  PubMed  Google Scholar 

  33. Costantino, P. et al. Development and phase 1 clinical testing of a conjugate vaccine against meningococcus A and C. Vaccine 10, 691–698 (1992).

    Article  CAS  PubMed  Google Scholar 

  34. Lakshman, R. et al. Safety of a new conjugate meningococcal C vaccine in infants. Arch. Dis. Child 85, 391–397 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Black, S. et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Pediatr. Infect. Dis. J. 19, 187–195 (2000).

    Article  CAS  PubMed  Google Scholar 

  36. Pichichero, M. E. Meningococcal conjugate vaccines. Expert Opin. Biol. Ther. 5, 1475–1489 (2005).

    Article  CAS  PubMed  Google Scholar 

  37. Abdelnour, A. et al. Safety of a quadrivalent meningococcal serogroups A, C, W and Y conjugate vaccine (MenACWY-CRM) administered with routine infant vaccinations: results of an open-label, randomized, phase 3b controlled study in healthy infants. Vaccine 32, 965–972 (2014).

    Article  CAS  PubMed  Google Scholar 

  38. Plosker, G. L. 13-valent pneumococcal conjugate vaccine: a review of its use in infants, children, and adolescents. Paediatr. Drugs 15, 403–423 (2013).

    Article  PubMed  Google Scholar 

  39. Madhi, S. A. et al. Considerations for a phase-III trial to evaluate a group B Streptococcus polysaccharide-protein conjugate vaccine in pregnant women for the prevention of early- and late-onset invasive disease in young-infants. Vaccine 31 (Suppl. 4), D52–D57 (2013).

    Article  CAS  PubMed  Google Scholar 

  40. Lin, F. Y. et al. The efficacy of a Salmonella typhi Vi conjugate vaccine in two-to-five-year-old children. N. Engl. J. Med. 344, 1263–1269 (2001).

    Article  CAS  PubMed  Google Scholar 

  41. Bhutta, Z. A. et al. Immunogenicity and safety of the Vi-CRM197 conjugate vaccine against typhoid fever in adults, children, and infants in south and southeast Asia: results from two randomised, observer-blind, age de-escalation, phase 2 trials. Lancet Infect. Dis. 14, 119–129 (2013).

    Article  CAS  PubMed  Google Scholar 

  42. Rappuoli, R. & De Gregorio, E. A sweet T cell response. Nature Med. 17, 1551–1552 (2011).

    Article  CAS  PubMed  Google Scholar 

  43. Buynak, E. B. et al. Development and chimpanzee testing of a vaccine against human hepatitis B. Proc. Soc. Exp. Biol. Med. 151, 694–700 (1976).

    Article  CAS  PubMed  Google Scholar 

  44. Valenzuela, P., Medina, A., Rutter, W. J., Ammerer, G. & Hall, B. D. Synthesis and assembly of hepatitis B virus surface antigen particles in yeast. Nature 298, 347–350 (1982).

    Article  CAS  PubMed  Google Scholar 

  45. Dahl-Hansen, E., Siebke, J. C., Froland, S. S. & Degré, M. Immunogenicity of yeast-derived hepatitis B vaccine from two different producers. Epidemiol. Infect. 104, 143–149 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Zhou, J., Sun, X. Y., Stenzel, D. J. & Frazer, I. H. Expression of vaccinia recombinant HPV 16 L1 and L2 ORF proteins in epithelial cells is sufficient for assembly of HPV virion-like particles. Virology 185, 251–257 (1991).

    Article  CAS  PubMed  Google Scholar 

  47. Lua, L. H. et al. Bioengineering virus-like particles as vaccines. Biotechnol. Bioeng. 111, 425–440 (2014).

    Article  CAS  PubMed  Google Scholar 

  48. Arai, H. & Sato, Y. Separation and characterization of two distinct hemagglutinins contained in purified leukocytosis-promoting factor from Bordetella pertussis. Biochim. Biophys. Acta 444, 765–782 (1976).

    Article  CAS  PubMed  Google Scholar 

  49. Sato, Y., Kimura, M. & Fukumi, H. Development of a pertussis component vaccine in Japan. Lancet 1, 122–126 (1984).

    Article  CAS  PubMed  Google Scholar 

  50. Hewlett, E. L. Pertussis: current concepts of pathogenesis and prevention. Pediatr. Infect. Dis. J. 16 (Suppl. 4), 78–84 (1997).

    Article  Google Scholar 

  51. Pizza, M. et al. Mutants of pertussis toxin suitable for vaccine development. Science 246, 497–500 (1989).

    Article  CAS  PubMed  Google Scholar 

  52. Rappuoli, R. Rational design of vaccines. Nature Med. 3, 374–376 (1997).

    Article  CAS  PubMed  Google Scholar 

  53. Greco, D. et al. A controlled trial of two acellular vaccines and one whole-cell vaccine against pertussis. Progetto Pertosse Working Group. N. Engl. J. Med. 334, 341–348 (1996).

    Article  CAS  PubMed  Google Scholar 

  54. Ashton, F. E., Ryan, J. A., Michon, F. & Jennings, H. J. Protective efficacy of mouse serum to the N-propionyl derivative of meningococcal group B polysaccharide. Microb. Pathog. 6, 455–458 (1989).

    Article  CAS  PubMed  Google Scholar 

  55. Ala'Aldeen, D. A. Transferrin receptors of Neisseria meningitidis promising candidates for a broadly cross-protective vaccine. J. Med. Microbiol. 44, 237–243 (1996).

    Article  CAS  PubMed  Google Scholar 

  56. Martin, D. et al. Candidate Neisseria meningitidis NspA vaccine. J. Biotechnol. 83, 27–31 (2000).

    Article  CAS  PubMed  Google Scholar 

  57. Holst, J. et al. Vaccines against meningococcal serogroup B disease containing outer membrane vesicles (OMV): lessons from past programs and implications for the future. Hum. Vaccin. Immunother. 9, 1241–1253 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Tondella, M. L. et al. Distribution of Neisseria meningitidis serogroup B serosubtypes and serotypes circulating in the United States. The Active Bacterial Core Surveillance Team. J. Clin. Microbiol. 38, 3323–3328 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Fleischmann, R. D. et al. Whole-genome random sequencing and assembly of Haemophilus influenzae Rd. Science 269, 496–512 (1995).

    Article  CAS  PubMed  Google Scholar 

  60. Tettelin, H. et al. Complete genome sequence of Neisseria meningitidis serogroup B strain MC58. Science 287, 1809–1815 (2000).

    Article  CAS  PubMed  Google Scholar 

  61. Pizza, M. et al. Identification of vaccine candidates against serogroup B meningococcus by whole-genome sequencing. Science 287, 1816–1820 (2000).

    Article  CAS  PubMed  Google Scholar 

  62. Princeton University. Emergency guidelines for the campus community: meningitis information. [online], (2014).

  63. Rivera, C. UC Santa Barbara to offer meningitis vaccine to students. Los Angeles Times [online], (2014).

    Google Scholar 

  64. Etz, H. et al. Identification of in vivo expressed vaccine candidate antigens from Staphylococcus aureus. Proc. Natl Acad. Sci. USA 99, 6573–6578 (2002).

    Article  CAS  PubMed  Google Scholar 

  65. Maione, D. et al. Identification of a universal group B streptococcus vaccine by multiple genome screen. Science 309, 148–150 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Moriel, D. et al. Identification of protective and broadly conserved vaccine antigens from the genome of extraintestinal pathogenic Escherichia coli. Proc. Natl Acad. Sci. USA 107, 9072–9077 (2010).

    Article  PubMed  Google Scholar 

  67. Capo, S. et al. Chlamydia pneumoniae genome sequence analysis and identification of HLA-A2-restricted CD8+ T cell epitopes recognized by infection-primed T cells. Vaccine 23, 5028–5037 (2007).

    Article  CAS  Google Scholar 

  68. Bertholet, S. et al. Identification of human T cell antigens for the development of vaccines against Mycobacterium tuberculosis. J. Immunol. 181, 7948–7957 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Ross, B. C. et al. Identification of vaccine candidate antigens from a genomic analysis of Porphyromonas gingivalis. Vaccine 19, 4135–4142 (2001).

    Article  CAS  PubMed  Google Scholar 

  70. Giefing, C. et al. Discovery of a novel class of highly conserved vaccine antigens using genomic scale antigenic fingerprinting of pneumococcus with human antibodies. J. Exp. Med. 205, 117–131 (2007).

    Article  CAS  PubMed  Google Scholar 

  71. Bensi, G. et al. Multi high-throughput approach for highly selective identification of vaccine candidates: the group A streptococcus case. Mol. Cell. Proteomics 11, M111.015693 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Rappuoli, R. Reverse vaccinology. Curr. Opin. Microbiol. 3, 445–450 (2000).

    Article  CAS  PubMed  Google Scholar 

  73. Sette, A. & Rappuoli, R. Reverse vaccinology: developing vaccines in the era of genomics. Immunity 33, 530–541 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Dormitzer, P. R., Ulmer, J. B. & Rappuoli, R. Structure-based antigen design: a strategy for next generation vaccines. Trends Biotechnol. 26, 659–667 (2008).

    Article  CAS  PubMed  Google Scholar 

  75. Scarselli, M. et al. Rational design of a meningococcal antigen inducing broad protective immunity. Sci. Transl. Med. 3, 91ra62 (2011).

    Article  CAS  PubMed  Google Scholar 

  76. McLellan, J. S. Structure-based design of a fusion glycoprotein vaccine for respiratory syncytial virus. Science 342, 592–598 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. In vaccine design, looks do matter [News]. Science 342, 1442–1443 (2013).

  78. Gibson, D. G. et al. Creation of a bacterial cell controlled by a chemically synthesized genome. Science 329, 52–56 (2010).

    Article  CAS  PubMed  Google Scholar 

  79. Dormitzer, P. R. et al. Synthetic generation of influenza vaccine viruses for rapid responses to pandemics. Sci. Transl. Med. 5, 185ra68 (2013).

    Article  CAS  PubMed  Google Scholar 

  80. Bart, S. A. A cell culture-derived MF59-adjuvanted pandemic A/H7N9 vaccine is immunogenic in adults. Sci. Transl. Med. 6, 234ra55 (2014).

    Article  CAS  PubMed  Google Scholar 

  81. Geall, A. J. et al. Nonviral delivery of self-amplifying RNA vaccines. Proc. Natl Acad. Sci. USA 109, 14604–14609 (2012).

    Article  PubMed  Google Scholar 

  82. Hekele, A. Rapidly produced SAM® vaccine against H7N9 influenza is immunogenic in mice. Emerg. Microbes Infect. 2, e52 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  83. Mbow, M. L., De Gregorio, E., Valiante, N. M. & Rappuoli, R. New adjuvants for human vaccines. Curr. Opin. Immunol. 22, 411–416 (2010).

    Article  CAS  PubMed  Google Scholar 

  84. Vesikari, T. et al. Oil-in-water emulsion adjuvant with influenza vaccine in young children. N. Engl. J. Med. 365, 1406–1416 (2011).

    Article  CAS  PubMed  Google Scholar 

  85. Garçon, N., Vaughan, D. W. & Didierlaurent, A. M. Development and evaluation of AS03, an adjuvant system containing α-tocopherol and squalene in an oil-in-water emulsion. Expert Rev. Vaccines 11, 349–366 (2012).

    Article  CAS  PubMed  Google Scholar 

  86. Clegg, C. H. et al. Adjuvant solution for pandemic influenza vaccine. Proc. Natl Acad. Sci. USA 109, 17585–17590 (2012).

    Article  PubMed  Google Scholar 

  87. Garçon, N. et al. Development AS04-adjuvanted HPV vaccine with the adjuvant system approach. BioDrugs 25, 217–226 (2011).

    Article  PubMed  Google Scholar 

  88. RTS,S Clinical Trials Partnership. A phase 3 trial of RTS,S/AS01 malaria vaccine in African infants. N. Engl. J. Med. 367, 2284–2295 (2012).

  89. Janssen, R. S. et al. Immunogenicity and safety of an investigational hepatitis B vaccine with a toll-like receptor 9 agonist adjuvant (HBsAg-1018) compared with a licensed hepatitis B vaccine in patients with chronic kidney disease. Vaccine 31, 5306–5313 (2013).

    Article  CAS  PubMed  Google Scholar 

  90. Michael, A., Relph, K., Annels, N. & Pandha, H. Prostate cancer vaccines. Expert Rev. Vaccines 12, 253–262 (2013).

    Article  CAS  PubMed  Google Scholar 

  91. Ladjemi, M. Z. Anti-idiotypic antibodies as cancer vaccines: achievements and future improvements. Front. Oncol. 2, 158 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Ulmer, J. B. et al. Heterologous protection against influenza by injection of DNA encoding a viral protein. Science 259, 1745–1749 (1993).

    Article  CAS  PubMed  Google Scholar 

  93. Fitzgerald, D. W. et al. An Ad5-vectored HIV-1 vaccine elicits cell-mediated immunity but does not affect disease progression in HIV-1-infected male subjects: results from a randomized placebo-controlled trial (the Step Study). J. Infect. Dis. 203, 765–772 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. UNAIDS. Factsheet. [online], (2013).

  95. The rgp120 HIV Vaccine Study Group. Placebo-controlled phase 3 trial of a recombinant glycoprotein 120 vaccine to prevent HIV-1 infection. J. Infect. Dis. 191, 654–665 (2005).

  96. Pitisuttithum, P. et al. Randomized, double-blind, placebo-controlled efficacy trial of a bivalent recombinant glycoprotein 120 HIV-1 vaccine among injection drug users in Bangkok, Thailand. J. Infect. Dis. 194, 1661–1671 (2006).

    Article  CAS  PubMed  Google Scholar 

  97. Buchbinder, S. P. et al. Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial. Lancet 372, 1881–1893 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Rerks-Ngarm, S. et al. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N. Engl. J. Med. 361, 2209–2220 (2009).

    Article  CAS  PubMed  Google Scholar 

  99. Barouch, D. H. et al. Therapeutic efficacy of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys. Nature 503, 224–228 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. World Health Organization. Global tuberculosis report 2013. (WHO, 2013).

  101. AERAS. Crucell Ad35/MVA85A. [online], (2014).

  102. World Health Organization. World Malaria Day, 25 April 2014. Invest in the future. Defeat malaria. [online], (2014).

  103. Seder, R. A. et al. Protection against malaria by intravenous immunization with a nonreplicating sporozoite vaccine. Science 341, 1359–1365 (2013).

    Article  CAS  PubMed  Google Scholar 

  104. Rappuoli, R. & Aderem, A. A 2020 vision for vaccines against HIV, tuberculosis and malaria. Nature 473, 463–469 (2011).

    Article  CAS  PubMed  Google Scholar 

  105. Mosca, F. et al. Molecular and cellular signatures of human vaccine adjuvants. Proc. Natl Acad. Sci. USA 105, 10501–10506 (2008).

    Article  PubMed  Google Scholar 

  106. Querec, T. D. Systems biology approach predicts immunogenicity of the yellow fever vaccine in humans. Nature Immunol. 10, 116–125 (2009).

    Article  CAS  Google Scholar 

  107. Gaucher, D. et al. Yellow fever vaccine induces integrated multilineage and polyfunctional immune responses. J. Exp. Med. 205, 3119–3131 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Ravindran, R. et al. Vaccine activation of the nutrient sensor GCN2 in dendritic cells enhances antigen presentation. Science 343, 313–317 (2014).

    Article  CAS  PubMed  Google Scholar 

  109. Li, S. et al. Molecular signatures of antibody responses derived froma systems biology study of five human vaccines. Nature Immunol. 15, 195–204 (2014).

    Article  CAS  Google Scholar 

  110. Tsang, J. S. et al. Global analyses of human immune variation reveal baseline predictors of postvaccination. Cell 157, 499–513 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Rappuoli, R. & Dormitzer, P. R. Influenza: options to improve pandemic preparation. Science 336, 1531–1533 (2012).

    Article  CAS  PubMed  Google Scholar 

  112. Centers for Disease Control and Prevention. Updated CDC Estimates of 2009 H1N1 Influenza Cases, Hospitalizations and Deaths in the United States, April 2009 – April 10, 2010. [online], (2010).

  113. Centers for Disease Control and Prevention. FluView. A weekly influenza surveillance report prepared by the Influenza Division. [online]

Download references

Acknowledgements

The authors' work is supported by the Advanced Immunization Technologies (ADITEC) grant from the European Commission of the Seventh Framework Program (grant number 280873). The work cited in the main text as “E.D.G. and colleagues, unpublished observations” has been submitted for publication by the following authors: T. Y.-H. Wu, M. Singh, A. T. Miller, E.D.G., F. Doro, U. D'Oro, D. Skibinskib, M. Lamine Mbow, S. Bufali, A. Hermanc, A. Cortezc, Y. Lic, B. P. Nayak, E. Trittob, C. M. Filippi, G. R. Otten, L. A. Britoa, E. Monacib, C. Lic, S. Aprea, S. Valentinib, S. Calabró, D. Laera, B. Brunelli, E. Caproni, D. T. O'Hagan, M. P. Cooke and N. M. Valiante.

Author information

Authors and Affiliations

  1. Novartis Vaccines, Via Fiorentina 1, Siena, 53100, Italy

    Ennio De Gregorio & Rino Rappuoli

Authors
  1. Ennio De Gregorio
    View author publications

    Search author on:PubMed Google Scholar

  2. Rino Rappuoli
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to Rino Rappuoli.

Ethics declarations

Competing interests

Ennio De Gregorio and Rino Rappuoli are full-time employees and shareholders of Novartis Vaccines. The following products are commercialized by Novartis or are in the pipeline of Novartis Vaccines: MF59 adjuvant; TLR7-based adjuvants; vaccines against Haemophilus influenzae, meningococcus serogroups B, C and ACYW, influenza virus, pertussis, respiratory syncytial virus, and group A and group B streptococcus; and RNA vaccines based on self-amplifying mRNA (SAM).

Related links

FURTHER INFORMATION

PATH Malaria Vaccine Initiative

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

De Gregorio, E., Rappuoli, R. From empiricism to rational design: a personal perspective of the evolution of vaccine development. Nat Rev Immunol 14, 505–514 (2014). https://doi.org/10.1038/nri3694

Download citation

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/nri3694

This article is cited by

Search

Advanced search

Quick links

Nature Briefing Microbiology

Sign up for the Nature Briefing: Microbiology newsletter — what matters in microbiology research, free to your inbox weekly.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing: Microbiology