Yellow Fever Vaccines: The Success of Empiricism, Pitfalls of Application, and Transition to Molecular Vaccinology

  • Thomas P. Monath


In 1951, Max Theiler was awarded the Nobel Prize in Medicine and Physiology for the development of yellow fever vaccine. The discovery phase of Theiler’s research preceded the prize by only about 20 years, during which time his vaccine against yellow fever had been put into wide-scale use in Africa and South America, and tens of thousands of yellow fever deaths had been averted. After smallpox vaccine, which had been discovered some 135 years before, yellow fever was the first human vaccine to be used at a population level for control of a major epidemic disease. Yellow fever vaccines were developed during an early stage in the history of virology, using empirical methods. Approximately 50 years later, research was initiated on the molecular basis of attenuation; progress is briefly reviewed here. The history of yellow fever vaccines provided a number of important paradigms for vaccine development in general (Table 1).


Rabies Virus Yellow Fever Yellow Fever Virus Smallpox Vaccine Avian Leukosis Virus 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Dr A. Barrett kindly shared unpublished data on yellow fever vaccine and parental strain molecular comparisons and insights as to their relevance. Dr V. Deubel assisted in finding, photographs of Drs Mathis and Laigret in the Pasteur Institute archives. Dr F. Rey, Harvard Medical School, kindly provided the figure showing the location of yellow fever 17D virus mutations in the crystal structure of the flavivirus E protein dimer. The author is indebted to the Rockefeller Archive Center, North Tarrytown, NY and the Francis A. Countway Library of Medicine, Boston, MA for photographs of yellow fever researchers.


  1. 1.
    Finlay C. El mosquito hipoteticamente considerado como agente de transmission de la fiebre amarilla. Anal Real Acad Ciencias Med Fisicas Naturales 1881;18:147–69Google Scholar
  2. 2.
    Finlay C. Yellow fever: its transmission by means of the Culex mosquito. Am J Med Sci 1886;92:395–409CrossRefGoogle Scholar
  3. 3.
    Finlay C. Inoculations for yellow fever by means of contaminated mosquitoes. Am J Med Sci 1891;102:264–8CrossRefGoogle Scholar
  4. 4.
    Yellow fever. A compilation of various publications. Results of the work of Maj Walter Reed, Medical Corps, United States Army, and the Yellow Fever Commission. 61st Congress Doc No 822, Washington DC; Govt Printing Office, 1911Google Scholar
  5. 5.
    Guiteras J. Experimental yellow fever at the inoculation station of the sanitary department of Havana, with a view to producing immunization. Amer Med 1901;28:809–17Google Scholar
  6. 6.
    Löwy I. Yellow fever in Rio de Janeiro and the Pasteur Institute mission (1901–1905): the transfer of science to the periphery. Med Hist 1990;34:144–63PubMedGoogle Scholar
  7. 7.
    Warren AJ. Landmarks in the conquest of yellow fever. In: Strode G, ed. Yellow Fever. New York: McGraw Hill, 1951;5–37Google Scholar
  8. 8.
    Stokes A, Bauer JH, Hudson NP. Transmission of yellow fever virus to Macacus rhesus, preliminary note. JAMA 1928;90:604–6Google Scholar
  9. 9.
    Sawyer WA, Lloyd WDM, Kitchen SF. Preservation of yellow fever virus. J Exp Med 1929;50:1–13PubMedCrossRefGoogle Scholar
  10. 10.
    Mathis C, Sellards AW, Laigret J. Sensibilité du Macacus rhesus au virus de la fièvre juane. C R Acad Sci 1928;186:604–6Google Scholar
  11. 11.
    Hindle E. A yellow fever vaccine. Br Med J 1928;1:976–7PubMedCrossRefGoogle Scholar
  12. 12.
    Petit MA. Rapport sur la valeur immunisante des vaccins employés contre le fièvre juane et la valeur thérapeutique du sérum antiamaril. Bull Acad Natl Méd 1931;105:522–6Google Scholar
  13. 13.
    Davis NC. Attempts to determine the amount of yellow fever virus injected by the bite of a single infected Stegomyia mosquito. Am J Trop Med 1934;14:343–54Google Scholar
  14. 14.
    Okell CC. Experiments with yellow fever vaccine in monkeys. Trans Roy Soc Trop Med Hyg 1930;24:251–4CrossRefGoogle Scholar
  15. 15.
    Theiler M, Sellards AW. The immunological relationship of yellow fever as it occurs in West Africa and in South America. Ann Trop Med Parasitol 1928;22:449–60Google Scholar
  16. 16.
    Duval CW. Observations upon the nature of the virus of hog cholera. Proc Soc Exp Biol Med 1929;27:87–9Google Scholar
  17. 17.
    Bendiner E. Max Theiler: Yellow Jack and the jackpot. Hosp Pract 1988;23:211–44Google Scholar
  18. 18.
    Andervont HB. Activity of herpetic virus in mice. J Infect Dis 1929;44:383–93CrossRefGoogle Scholar
  19. 19.
    Theiler M. Susceptibility of white mice to yellow fever virus. Science 1930;71:367PubMedCrossRefGoogle Scholar
  20. 20.
    Theiler M. Studies on action of yellow fever in mice. Ann Top Med Parasitol 1930;24:249–72Google Scholar
  21. 21.
    Lloyd W, Penna HA, Mahaffy AF. Yellow fever in rodents. Am J Hyg 1933;18:323–44Google Scholar
  22. 22.
    Sawyer WA, Kitchen SF, Lloyd W. Vaccination against yellow fever with immune serum and virus fixed for mice. J Exp Med 1932;55:945–69PubMedCrossRefGoogle Scholar
  23. 23.
    Sawyer WA, Kitchen SF, Lloyd W. Vaccination of humans against yellow fever with immune serum and virus for mice. Proc Soc Biol Med 1931;29:62–4Google Scholar
  24. 24.
    Berry GP, Kitchen SF. Yellow fever accidentally contracted in the laboratory: study of seven cases. Am J Trop Med 1931;11:365–434Google Scholar
  25. 25.
    Sellards AW. Behavior of virus of yellow fever in monkeys and mice. Proc Natl Acad Sci USA 1931;17:339–43PubMedCrossRefGoogle Scholar
  26. 26.
    Theiler M. Neutralization tests with immune yellow fever sera and a strain of yellow fever virus adapted to mice. Ann Trop Med Parasitol 1931;25:69–77Google Scholar
  27. 27.
    Sawyer WA. Enquête sur l’immunité vis-à-vis la fièvre juane au moyen de l’épreuve de protection de la souris. Bull Off Intl Hyg Pub 1934;26:1057–9Google Scholar
  28. 28.
    Findlay GM. Immunization against yellow fever with attenuated neurotropic virus. Lancet 1934;2:983–5CrossRefGoogle Scholar
  29. 29.
    Petit A, Stefanopoulo GJ. Utilisation du sérum antiamaril d’origine animale pour la vaccination de l’homme. Bull Acad Natl MédI 1933;110:67–76Google Scholar
  30. 30.
    Smith HH. Life’s a Pleasant Institution: the Peregrination of a Rockefeller Doctor, Tucson AZ: Hugh Smith, 1978Google Scholar
  31. 31.
    Theiler M, Smith HH. Use of Hyperimmune monkey serum in human vaccination against yellow fever. Bull Off Intl Hyg Pub 1936;28:2354–7Google Scholar
  32. 32.
    Sellards AW, Laigret J. Vaccination de l’homme contre la fièvre juane. C R Acad Sci 1932;194:1609–11Google Scholar
  33. 33.
    Laigret J. Recherches expérimentales sur la fièvre jaune. Arch Inst Pasteur Tunis 1933;21:412–30Google Scholar
  34. 34.
    Mathic C, Laigret J, Durieux C. Troi mille vaccinations contra la fièvre juane en Afrique Occidentale Française au moyen du virus vivant de souris, atténué par vieillissement. C R Acad Sci (Paris) 1934;199:742–4Google Scholar
  35. 35.
    Nicolle C, Laigret J. La vaccination contre la fièvre jaune par le virus amaril desséché et enrobé. Compt Rend Acad Sci (Paris) 1935;201:312–4Google Scholar
  36. 36.
    Durieux C. Preparation of yellow fever vaccine at the Institute Pasteur, Dakar. In: Smithburn K et al., eds. Yellow Fever Vaccination. Geneva: World Health Organization, 1956;31–43Google Scholar
  37. 37.
    Sorel F. La vaccination anti-amarile en Afrique occidentale française, mise en application du procédé de vaccination Sellards-Laigret. Bull Off Intl Hyg Pub 1936;28:1325–56Google Scholar
  38. 38.
    Laigret J. De l’interprétation des troubles consécutifs aux vaccinations par les virus vivants en particulier à la vaccination de la fièvre jaune. Bull Soc Path Exot 1936;29:230–4Google Scholar
  39. 39.
    Peltier M, Durieux C, Jonchère H, Arquié E. Pénétration du virus amaril neurotrope par voie cuntanée: vaccination contra la fièvre jaune et la variole, note préliminaire. Bull Acad Méd (Paris) 1939;121:657–60Google Scholar
  40. 40.
    Peltier M. Yellow fever vaccination, simple or associated with vaccination against smallpox, of the population of French West Africa by the method of the Pasteur Institute of Dakar. Am J Pub Health 1947;37:1026–32PubMedCrossRefGoogle Scholar
  41. 41.
    Peltier M. Vaccination antiamarile simple et associée à la vaccination antivariolique par scarification. Méd Trop 1941;1–49Google Scholar
  42. 42.
    Findlay GM, Clarke LP. Reconversion of neurotropic into viscerotropic strain of yellow fever virus in rhesus monkeys. Trans Roy Soc Trop Med Hyg 1935;28:579–600CrossRefGoogle Scholar
  43. 43.
    Carrell A, Rivers TM. La fabrication du vaccin in vitro. C R Soc Biol 1927;96:848–50Google Scholar
  44. 44.
    Rivers TM. Cultivation of vaccine virus for Jennerian prophylaxis in man. J Exp Med 1931;54:453–61PubMedCrossRefGoogle Scholar
  45. 45.
    Haagen E, Theiler M. Untersuchungen über das Verhalten des Gelbfiebervirus in der Gewebekultur. Zentralbl Bakt 1932;125:145–58Google Scholar
  46. 46.
    Findlay GM, Stern RO. Essential neurotropism of yellow fever virus. J Pathol Bact 1935;41:431–8CrossRefGoogle Scholar
  47. 47.
    Lloyd W, Theiler M, Ricci N. Modification of the virulence of yellow fever virus by cultivation of tissues in vitro. Trans Roy Soc Trop Med Hyg 1937;24:481–529Google Scholar
  48. 48.
    Lloyd W. Use of cultivated virus together with immune serum in vaccination against yellow fever. Bull Off Intl d’Hyg Pub 1935;27:2365–8Google Scholar
  49. 49.
    Sawyer WA. A history of the activities of the Rockefeller Foundation in the investigation and control of yellow fever. Am J Top Med 1937;17:35–50Google Scholar
  50. 50.
    Theiler M, Smith HH. The effect of prolonged cultivation in vitro upon the pathogenicity of yellow fever virus. J Exp Med 1934;65;767–86CrossRefGoogle Scholar
  51. 51.
    Theiler M, Smith HH. The use of yellow fever virus modified by in vitro cultivation for human immunization. J Exp Med 1937;65:787–800PubMedCrossRefGoogle Scholar
  52. 52.
    Theiler M. The virus. In: Strode G, ed. Yellow Fever. New York: McGraw Hill, 1951;43–136Google Scholar
  53. 53.
    Smith HH, Penna HA, Paoliello A. Yellow fever vaccination with cultured virus (17D) without immune serum. Am J Trop Med 1938;18:437–68Google Scholar
  54. 54.
    Fox JP, Lennette EH, Manso C, Aguiar JRS. Encephalitis in man following vaccination with 17D yellow fever virus. Am J Hyg 1942;36:117–42Google Scholar
  55. 55.
    Fox JP, Penna HA. Behavior of 17D yellow fever virus in rhesus monkeys. Relation to substrain, dose and neural or extraneural inoculation. Am J Hyg 1943;38:152–72Google Scholar
  56. 56.
    Fox JP, Kossobudzki SL, Fonseca da Cunha J. Field studies on immune response to 17D yellow fever virus: relation to virus substrain, dose, and route of inoculation. Am J Hyg 1943;38:113–38Google Scholar
  57. 57.
    Soper FL, Smith HH. Vaccination with virus 17D in the control of jungle yellow fever in Brazil. Trans 3rd Intl Congr Trop Med & Malaria 1938;1:295–313Google Scholar
  58. 58.
    Panthier R. A propos de quelques cas de reactions nerveuses tardives observées chez de nourissons après vaccination antiamarile (17D). Bull Soc Pathol Exot 1956;49:477–94Google Scholar
  59. 59.
    Standards for the manufacture and control of yellow fever vaccine. Epidem Inform Bull 1945;1:365–8 (original standards for the vaccine developed by the United Nations Relief and Rehabilitation Administration (UNRRA), according to Article XI of the International Sanitary Convention for Aerial Navigation)Google Scholar
  60. 60.
    Requirements for Biological Substances No 3. WHO Tech Rep Ser No 1957;136:Annex 1Google Scholar
  61. 61.
    Peltier M. Yellow fever vaccination, simple or associated with vaccination against smallpox, of the population of French West Africa by the method of the Pasteur Institute of Dakar. Am J Pub Health 1947;37:1026–32PubMedCrossRefGoogle Scholar
  62. 62.
    Durieux C. Mass yellow fever vaccination in French West Africa south of the Sahara. In: Smithburn K et al., eds. Yellow Fever Vaccination, Geneva: WHO, 1956:115–21Google Scholar
  63. 63.
    Peltier M. Vaccin antiamarile et vaccinvations antiamariles et antivariolo-amarile par la méthode dakaroise en Afrique occidentale française. Proc 4th Intl Cong Trop Med & Malaria 1948;1:489–97Google Scholar
  64. 64.
    Jadin J, Arnaldi E. Considérations au sujet de l’épidémie intérigène de Zongo et vaccination anti-amarile. Ann Soc belge Méd Trop 1939;19:377–91Google Scholar
  65. 65.
    MacNamara FN. Reactions following neurotropic yellow fever vaccine given by scarification in Nigeria. Trans Roy Soc Trop Med Hyg 1953;47:199–208PubMedCrossRefGoogle Scholar
  66. 66.
    Elton NW. Public health aspects of the campaign against yellow fever in Central America. Am J Public Health 1952;42:170–4CrossRefGoogle Scholar
  67. 67.
    Chambon L, Wone I. Une épidémie de fièvre jaune au Sénégal en 1965. Bull WHO 1957;11:325–50Google Scholar
  68. 68.
    Brés P, Lacan A, Diop I, Michel R, Peretti P, Vidal C. Des campagnes de vaccination antiamarile en République du Sénégal. Bull Soc Pathol Exot 1963;64:1038–43Google Scholar
  69. 69.
    Sankalé M, Bourgeade A, Wade F. Bèye B. Contribution à l’étude de reactions vaccinales observée en dehors de Dakar. Bull Soc Méd Afr Noire Lgue Fr 1966;11:617–24Google Scholar
  70. 70.
    Rey M, Satge P, Collomb H et al. Aspects épidémiologiques et cliniques des encephalites consécutives à la vaccination antiamarile. Bull Soc Méd Afr Noire Lgue Fr 1966;11:560–74Google Scholar
  71. 71.
    Ricossé JH, Albert JP. La vaccination antiamarile dans les états de l’OCCGE. Conférence sur l’épidémiologie et le contrôle de la fièvre jaune en Afrique de l’Ouest, Bobo Dioulasso, March 20–23, 1971 (unpublished document No 266, OCCGE, Centre Muraz, Bobo Dioulasso, Haute Volta)Google Scholar
  72. 72.
    Findlay GM, MacCallum FO. Note on acute hepatitis and yellow fever immunization. Trans Roy Soc Trop Med Hyg 1937;31:297–309CrossRefGoogle Scholar
  73. 73.
    Soper FL, Smith HH. Yellow fever vaccination with cultivated virus and immune and hyperimmune serum. Am J Trop Med 1938;18:111–34Google Scholar
  74. 74.
    Lurman A. Eine Ictrusepidemie. Berl Klin Wochenschr 1885;22:20–3Google Scholar
  75. 75.
    Anon. Acute infectious jaundice and the administration of measles serum. In: McNalby A, ed. On the state of public health. Annual Report of the Chief medical officer, Ministry of Health, for the year 1937. London: HMSO 1937;4:235Google Scholar
  76. 76.
    Fox JP, Manso C, Penna HA, Para M. Observations on the occurrence of icterus in Brazil following vaccination against yellow fever. Am J Hyg 1942;36:68–116Google Scholar
  77. 77.
    Smithburn KC. Immunology of yellow fever. In: Smithburn et al., eds. Yellow Fever Vaccination. Geneva: WHO, 1956;11–30Google Scholar
  78. 78.
    Sawyer WA, Meyer KF, Eaton MD, Bauer JH, Putnam P, Schuentker FF. Jaundice in Armey personnel in the western region United States and its relation to vaccination against yellow fever. Am J Hyg 1944;39:337–430Google Scholar
  79. 79.
    Hargett MV, Burrus HW, Donovan A. Aqueous-base yellow fever vaccine. Public Health Rep 1943;58:505–12Google Scholar
  80. 80.
    Seeff LB, Beebe GW, Hootnagle JH. A serologic follow-up of the 1942 epidemic of post-vaccination hepatitis in the US Army. N Engl J Med 1987;316:965–70PubMedCrossRefGoogle Scholar
  81. 81.
    Harris RJC, Dougherty RM, Biggs PM et al. Containment viruses in two live virus vaccines. J Hyg (Cambr) 1966;64:1–7CrossRefGoogle Scholar
  82. 82.
    Rubin H, Fanshier L, Cornelius A, Hilaghes WF. Tolerance and immunity in chicken after congenital and contact infection with a avian leukosis virus. Virology 1962;17:143–56PubMedCrossRefGoogle Scholar
  83. 83.
    Piraino F, Krumbiegel ER, Wisniewski HJ. Serologic survey of man for avian leukosis virus infection. J Immunol 1967;98:702–6PubMedGoogle Scholar
  84. 84.
    Richman AV, Alusio CG, Jahnes WG, Tauraso NM. Avian Leukosis antibody response in individuals given chicken embryo derived vaccines, Proc Soc Exp Biol Med 1972;139:235–7PubMedGoogle Scholar
  85. 85.
    Melnick JL. Latent virus infections in donor tissues and in recipients of vaccines. Natl Cancer Inst Mongr 1968;29:337–49Google Scholar
  86. 86.
    Draper CC. A yellow fever vaccine free from avian leukosis viruses. J Hyg (Cambr) 1967;65:505–13CrossRefGoogle Scholar
  87. 87.
    Tauraso NM, Spector SL, Jahnes WG, Shelokov A. Yellow fever vaccine: I. Development of a vaccine seed free from contaminating avian leukosis viruses. Proc Soc Exp Biol Med 1968;127:1116–20PubMedGoogle Scholar
  88. 88.
    Burrus HW, Hargett MV. Yellow fever vaccine inactivation studies. Public Health Rep 1947;62;940–56Google Scholar
  89. 89.
    Robin Y, Saenz AC, Outschoorn AS et al. Etude de la thermostabilité du vaccin anti-amaril sur des échantillons de huit lots provenant de divers pays. Bull WHO 1971;44:729–37PubMedGoogle Scholar
  90. 90.
    Burfoot C, Yound PA, Finter NB. Thermal stability of stabilized 17D yellow fever virus ­vaccine. J Biol Stand 1977;5:173–9PubMedCrossRefGoogle Scholar
  91. 91.
    Barme M, Bronnert C. Thermostabilisation du vaccin antiamaril 17D lyophilize. I. Essai des substances protectrices. J Biol Stand 1984;12:435–42PubMedCrossRefGoogle Scholar
  92. 92.
    World Health Organization. Yellow fever vaccines: thermostability of freeze-dried vaccines. WHO Wkly Epidemiol Rep 1988;62:181–83Google Scholar
  93. 93.
    World Health Organization. Requirements for yellow fever vaccine, Addendum 1987. WHO Tech Rep Ser No. 71, Annex 9, 1988;208–9Google Scholar
  94. 94.
    Ruben FL, Smith EA, Foster SO et al. Simultaneous administration of smallpox, measles, yellow fever, and diphtheria-pertussis-tetanus antigens to Nigerian Children. Bull WHO 1973;48:175–81PubMedGoogle Scholar
  95. 95.
    Gateff C, Le Gonidec G, Boche R et al. Influence de la vaccination anti-cholérique sur la vaccination anti-amarile associée. Bull Soc Path Exot 1973;66:266–75Google Scholar
  96. 96.
    Felsenfeld O, Wolf RH, Gyr K et al. Simultaneous vaccination against cholera and yellow fever. Lancet 1973;i:457–8Google Scholar
  97. 97.
    Yvonnet B, Coursaget P, Deubel V, Diop Mar I, Digoutte JP, Chiron JP. Simultaneous administration of hepatitis B and yellow fever vaccines. J Med Virol 1986;19:307–11PubMedCrossRefGoogle Scholar
  98. 98.
    Ambrosch F, Fritzell B, Gregor J et al. Combined vaccination against yellow fever and typhoid fever, a comparative trial. Vaccine 1994;12:625–8PubMedCrossRefGoogle Scholar
  99. 99.
    Monath TP, Kinney RM, Schlesinger JJ, Brandriss MW, Bres P. Ontogeny of yellow fever 17D vaccine: RNA oligonucleotide fingerprint and monoclonal antibody analyses of vaccines produced world-wide. J Gen Virol 1983;64:627–37PubMedCrossRefGoogle Scholar
  100. 100.
    Rice CM, Lenches EM, Eddy SR. Nucleotide sequence of yellow fever: implications for flavoring gene expression and evolution. Science 1985;229:726–33PubMedCrossRefGoogle Scholar
  101. 101.
    Hahn CS, Dalrymple JM, Strauss JH, Rice CM. Comparison of the virulent Asibi strain of ­yellow fever virus with the 17D strain derived from it. Proc Natl Acad Sci USA 1987;84:2019–23PubMedCrossRefGoogle Scholar
  102. 102.
    Duarte dos Santos CN, Post CR, Carvalho R, Ferreira H, Rice CM, Galler R. Complete nucleotide sequence of yellow fever virus vaccine strains 17DD and 17D-213. Virus Res 1995;35:35–41Google Scholar
  103. 103.
    Jennings AD, Whitby JE, Minor PD, Barrett ADT. Comparison of the nucleotide and deduced amino acid sequences of the structural protein genes of the yellow fever 17D vaccine strain from Senegal with those of other yellow fever vaccine viruses. Vaccine 1993;11:679–81PubMedCrossRefGoogle Scholar
  104. 104.
    Dupuy A, Despres P, Cahour A et al. Nucleotide sequence comparison of the genome of two 17D-204 yellow fever vaccines. Nucl Acid Res 1989;17:39–89CrossRefGoogle Scholar
  105. 105.
    Burke DS, Monath TP, Flaviviruses. In Knipe OM, Howley PM (Eds) Fourth Eds Lippincott, Williams and Williams, Philadelphia, vol 1, 2001;1043–1126Google Scholar
  106. 106.
    Barrett ADT. Yellow fever vaccines. Biologicals 1997;25:17–25Google Scholar
  107. 107.
    Jennings AD, Gibson CA, Miller BR et al. Analysis of a yellow fever virus isolated from a fatal case of vaccine-associated human encephalitis. J Infect Dis 1994;169:512–8PubMedCrossRefGoogle Scholar
  108. 108.
    Rey FA, Heinz FX, Mandl C, Kunz C, Harrison SC. The envelope glycoprotein from the tick-borne encephalitis virus at 2 Å resolution. Nature 1995;375:291–8PubMedCrossRefGoogle Scholar
  109. 109.
    Rice CM, Grakoui A, Galler R, Chambers TJ. Transcription of infectious yellow fever RNA from full-length templates produced by in vitro ligation. New Biol 1989;1:285–96Google Scholar
  110. 110.
    Marchevsky RS, Mariano J, Ferreira VS et al. Phenotypic analysis of yellow fever virus derived from complementary DNA. Am J Trop Med Hyg 1995;52:70–80Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Kleiner Perkins Caufield & ByersCambridgeUSA

Personalised recommendations