Three Decades of Hepatitis Vaccinology in Historic Perspective. A Paradigm of Successful Pursuits

  • Maurice R. Hilleman


Hepatitis is an apt subject for discussions of the history of vaccination, since it is clearly an example of recognizable diseases of ancient recorded history, as well as of clinical diseases of diverse and multiple etiologies. Hepatitis, with its distinguishing yellow jaundice, must have been a recognizable feature for an illness of human beings ever since the species discarded its hairy overcoat in favor of the buff.


Acquire Immune Deficiency Syndrome Yellow Fever Vaccine Carrier Plasma Human Immune Globulin Live Attenuate Virus Vaccine 
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.


  1. 1.
    Zuckerman, A J The history of viral hepatitis from antiquity to the present. In: Deinhardt F, Deinhardt J (eds) Viral Hepatitis: Laboratory and Clinical Science 1983: 2–32. New York: Marcel DekkerGoogle Scholar
  2. 2.
    Hilleman M R Hepatitis and hepatitis A vaccine: a glimpse of history. J Hepatol 1993;18 (suppl 2): S5–S10PubMedCrossRefGoogle Scholar
  3. 3.
    Blumberg BS, Alter HJ, Visnich S A “new” antigen in leukemia sera. JAMA 1965;91:541–46Google Scholar
  4. 4.
    Blumberg BS Australia antigen, hepatitis and leukemia. Tokyo J Med Sci 1968;76:1Google Scholar
  5. 5.
    Prince AM An antigen detected in the blood during the incubation period of serum hepatitis. Proc Natl Acad Sci USA 1968;60:814–21PubMedCrossRefGoogle Scholar
  6. 6.
    Deinhardt F, Holmes AW, Capps RB et al Studies on the transmission of human viral hepatitis to marmoset monkeys. I. Transmission of disease, serial passages and description of liver lesions. J Exp Med 1967;125:673–88PubMedCrossRefGoogle Scholar
  7. 7.
    Mascoli CC, Ittensohn OL, Villarejos VM et al Recovery of hepatitis agents in the marmoset from human cases occurring in Costa Rica. Proc Soc Exp Biol Med 1973;142:276–82PubMedGoogle Scholar
  8. 8.
    Houghton M, Weiner A, Han J et al Molecular biology of the hepatitis C viruses: implications for diagnosis, development and control of viral disease Hepatology 1991;14:381–88PubMedCrossRefGoogle Scholar
  9. 9.
    Lazinski DW, Taylor JM. Recent developments in hepatitis delta virus research. In: Maramorosch K, Murphy FA, Shatkin AJ, eds. Advances in Virus Research. Elsevier, New York 1994;43:187–231Google Scholar
  10. 10.
    Bradley DW. Hepatitis E virus: a brief review of the biology, molecular virology, and immunology of a novel virus. J Hepatol 1995;22 (suppl 1):140–5PubMedGoogle Scholar
  11. 11.
    Deka N, Sharma MD, Mukerjee R. Isolation of the novel agent from human stool samples that is associated with sporadic non-A, non-B hepatitis. J Virol 1994;68:7810–5PubMedGoogle Scholar
  12. 12.
    Simons JN, Pilot-Matias TJ, Leary TP et al. Identification of two flavivirus-like genomes in the GB hepatitis agent. Proc Natl Acad Sci USA 1995;92:3401–5PubMedCrossRefGoogle Scholar
  13. 13.
    Zuckerman AJ. The new GB hepatitis viruses. Lancet 1995;345:1453–4PubMedCrossRefGoogle Scholar
  14. 14.
    Denis F, Nicot T. Découverte de nouveaux virus des hépatites, les “GBV”: quelle est leur place et quel est leur pouvoir pathogène? Médicine/Science 1995;92:3401–5Google Scholar
  15. 15.
    Craske J. Hepatitis C and non-A and non-B hepatitis revisited: Hepatitis E, F, and G. J Infection 1992;25:243–50CrossRefGoogle Scholar
  16. 16.
    Fields HA, Favorov MO, Margolis HS. The hepatitis E virus: a review. J Clin Immunoassay 1993;16:215–23Google Scholar
  17. 17.
    Tsarev SA, Tsarev TS, Emerson SU, Govindarajan S, Shapiro M, Gerin JL, Purcell RH. Successful passive and active immunization of cynomolgus monkey against hepatitis E. Proc Natl Acad Sci USA 1994;91:10198–202PubMedCrossRefGoogle Scholar
  18. 18.
    Zuckerman AJ, Zuckerman JN. Prospects for hepatitis C vaccine. J Hepatol 1995;22 (suppl 1):97–100PubMedGoogle Scholar
  19. 19.
    André FE, D’Hondt E, Delem AD, Safary A. Clinical assessment of the safety and efficacy of an inactivated hepatitis-A vaccine – rationale and summary of findings. Vaccine 1992;10:S106–68CrossRefGoogle Scholar
  20. 20.
    Provost PJ, Ittensohn OL, Villarejos VM, Arguedas JA, Hilleman MR. Etiologic relationship of marmoset-propagated CR326 hepatitis A virus to man. Proc Soc Exp Biol Med 1973;142:1257–67PubMedGoogle Scholar
  21. 21.
    Hilleman MR, Provost PJ, Miller WJ, Villarejos VM, Ittensohn OL, McAleer WJ. Immune adherence and complement fixation tests for human hepatitis A. Diagnostic and epidemiologic investigations. International Symposium on Viral Hepatitis, Milan, Italy, 4 December, 1974. Dev Biol Stand 1975;30:383–9 (S Karger, Basel)Google Scholar
  22. 22.
    Hilleman MR, Provost PJ, Wolanski BS, Miller WJ, Ittensohn O, McAleer WJ. Characterization of CR326 human hepatitis A virus, a probable enterovirus, International Symposium on Viral Hepatitis, Milan, Italy, 4 December, 1974. Dev Biol Stand 1975;30:418–24 (S Karger, Basel)Google Scholar
  23. 23.
    Provost PJ, Ittensohn OL, Villarejos VM, Hillerman MR. A specific complement-fixation test for human hepatitis A employing CR326 virus antigen. Diagnosis and epidemiology. Proc Soc Exp Biol Med 1975;148:962–9PubMedGoogle Scholar
  24. 24.
    Miller WJ, Provost PJ, McAleer WJ, Ittensohn OL, Villarejos, Hilleman MR. Specific immune adherence assay for human hepatitis A antibody. Application to diagnostic and epidemiologic investigations. Proc Soc Exp Biol Med 1975;49:254–61Google Scholar
  25. 25.
    Provost PJ, Wolanski BS, Miller WJ, Ittensohn OL, McAleer WJ, Hilleman MR. Physical, chemical and morphologic dimensions of human hepatitis A virus strain CR326. Proc Soc Exp Biol Med 1975;148:532–9PubMedGoogle Scholar
  26. 26.
    Feinstone SM, Kapikian AZ, Purcell RH. Hepatitis A: Detection by immune electron microscopy of a virus-like antigen associated with acute illness. Science 1973;182:1026–8PubMedCrossRefGoogle Scholar
  27. 27.
    Francki RB, Fauquet CM, Knudson DL, Brown F, eds. Classification and nomenclature of viruses. Fifth Report of the International Committee on Taxonomy of Viruses, Vienna, Austria. Arch Virol 1991; (suppl 2)Google Scholar
  28. 28.
    Provost PJ, Hilleman MR. An inactivated hepatitis A virus vaccine prepared from infect marmoset liver. Proc Soc Exp Biol Med 1978;159:201–3PubMedGoogle Scholar
  29. 29.
    Provost PJ, Hilleman MR. Propagation of human hepatitis A virus in cell culture in vitro. Proc Soc Exp Biol Med 1979;160:213–1PubMedGoogle Scholar
  30. 30.
    Provost PJ, McAleer WJ, Hilleman MR. In vitro cultivation of hepatitis A virus. In: Szumness W, Alter H, Maynard J, eds. Viral Hepatitis. International Symposium 1981. Philadelphia: The Franklin Institute Press, 1982;21–30Google Scholar
  31. 31.
    Provost PJ, Banker FS, Geisa PA, McAleer WJ, Buynak EB, Hilleman MR. Progress toward a live, attenuated human hepatitis A vaccine. Proc Soc Exp Biol Med 1982;170:8–14PubMedGoogle Scholar
  32. 32.
    Provost PJ, Conti PA, Geisa PA, Banker FS, Buynak EB, Hilleman MR. Studies in chimpanzees of live, attenuated hepatitis A vaccine candidates. Proc Soc Exp Biol Med 1983;172:357–63PubMedGoogle Scholar
  33. 33.
    Provost PJ, Bishop RP, Gerety RJ, Hilleman MR, McAleer WJ, Scolnick EM, Stevens CE. New findings in live, attenuated hepatitis A vaccine development. J Med Virol 1986;20:165–75PubMedCrossRefGoogle Scholar
  34. 34.
    Provost PJ, Emini EA, Lewis JA, Gerety RJ. Progress toward the development of a hepatitis A vaccine. In: Zuckerman AJ, ed. Viral Hepatitis and Liver Disease. New York: Alan R Liss, 1988;83–6Google Scholar
  35. 35.
    Midthun K, Ellerbeck E, Gershman K et al. Safety and immunogenicity of a live attenuated hepatitis A virus vaccie in seronegative volunteers. J Infect Dis 1991;163:735–9PubMedCrossRefGoogle Scholar
  36. 36.
    Provost PJ, Banker PS, Wadsworth CW, Krah DL. Further evaluation of a live hepatitis A vaccine in marmosets. J Med Virol 1991;34:227–31PubMedCrossRefGoogle Scholar
  37. 37.
    Provost PJ, Hughes JV, Miller WJ, Giesa PA, Banker PS, Emini EA. An inactivated hepatitis A viral vaccine of cell culture origin. J Med Virol 1986; 19:23–31PubMedCrossRefGoogle Scholar
  38. 38.
    Lewis JA, Armstrong ME, Larson VM et al. Use of a live, attenuated hepatitis A vaccine to prepare a highly purified, formalin-inactivated hepatitis A vaccine. In: Hollinger FB, Lemon SM, Margolis H, eds. Viral Hepatitis and Liver Disease. Baltimore: Williams & Wilkins, 1991;91–3Google Scholar
  39. 39.
    Ellerbeck E, Lewis J, Midthun K, Gershman K, Nalin D, McCaughtry M, Provost P, Calandra G. Safety and immunogenicity of an inactivated hepatitis A vaccine. In: Hollinger FB, Lemon SM, Margolis H, eds. Viral Hepatitis and Liver Disease. Baltimore: Williams & Wilkins, 1991;91–3Google Scholar
  40. 40.
    Werzberger A, Mensch B, Kuter B et al. A controlled trial of formalin-inactivated hepatitis A vaccine in healthy children. New Engl J Med 1992;327:453–7PubMedCrossRefGoogle Scholar
  41. 41.
    Nalin DR, Kuter BJ, Brown L et al. Worldwide experience with the CR326F-derived inactivated hepatitis A virus vaccine in pediatric and adult populations: an overview. J Hepatol 1993;18:S51–5PubMedCrossRefGoogle Scholar
  42. 42.
    Peetermans J. Production, quality control and characterization of an inactivated hepatitis-A vaccine. Vaccine 1992;10:S99–S101PubMedCrossRefGoogle Scholar
  43. 43.
    Flehmig B, Heinricy U, Pfisterer M. Immunogenicity of a killed hepatitis A vaccine in seronegative volunteers. Lancet 1989;1:1039–41PubMedCrossRefGoogle Scholar
  44. 44.
    Loutan L, Bovier P, Althaus B, Glück R. Inactivated virosome hepatitis A vaccine. Lancet 1994;343;322–4PubMedCrossRefGoogle Scholar
  45. 45.
    Hilleman MR, Bertland AU, Buynak EB et al. Clinical and laboratory studies of HBsAg vaccine. In: Vyas GN, Cohen SN, Schmid R, eds. Viral Hepatitis. Philadelphia: Franklin Institute Press, 1978;525–37Google Scholar
  46. 46.
    Hilleman MR. Plasma derived hepatitis B vaccine: a breakthrough in preventive medicine. In: Ellis R, ed. Hepatitis B Vaccines in Clinical Practice. New York: Marcel Dekker, 1993;17–39Google Scholar
  47. 47.
    Maupas Ph, Goudeau A, Coursaget P, Drucker J, Brian F, André M. Immunization against hepatitis B in man: a pilot study of two years duration. In Vyas GN, Cohen SN, Schmid R, eds. Viral Hepatitis. Philadelphia: Franklin Institute Press, 1978;539–56Google Scholar
  48. 48.
    Krugman S, Giles JP, Hammond J. Viral hepatitis, type B (MS-2 strain): studies on active immunization. JAMA 1971;217:41PubMedCrossRefGoogle Scholar
  49. 49.
    Szumuness W, Stevens CE, Zang EA, Harley EJ, Kellner A. A controlled clinical trial of the efficacy of the hepatitis B vaccine (Heptavax B): a final report. Hepatology 1981;1:377–85CrossRefGoogle Scholar
  50. 50.
    Francis DP, Hadler SC, Thompson SE et al. The prevention of hepatitis B with vaccine: report of the Centers for Disease Control multi-center efficacy trial among homosexual men. Ann Intern Med 1982;97:362–6PubMedGoogle Scholar
  51. 51.
    Valenzuela P, Medina A, Rutter WJ, Ammerer G, Hall BD. Synthesis and assembly of hepatitis B virus surface antigen particles in yeast. Nature 298:1982;347–50PubMedCrossRefGoogle Scholar
  52. 52.
    McAleer WJ, Buynak EB, Maigetter RZ, Wampler DE, Milier WJ, Hilleman MR. Human hepatitis B vaccine from recombinant yeast. Nature 1984; 307:178–80PubMedCrossRefGoogle Scholar
  53. 53.
    Adamowicz Ph, Tron F, Vinas R et al. Hepatitis B vaccine containing the S and the PreS-2 antigens produced in Chinese hamster ovary cells. In: Zuckerman AJ, ed. Viral Hepatitis and Liver Disease. New York: Alan R Liss, 1988;1087–90Google Scholar
  54. 54.
    Hilleman MR. Yeast recombinant hepatitis B vaccine. Infection 1987;15:2–6CrossRefGoogle Scholar
  55. 55.
    Stevens CE, Taylor PE, Tong MJ, Toy PT, Vyas GN, Zang EA, Krugman S. Prevention of perinatal hepatitis B virus infection with hepatitis B immune globulin and hepatitis B vaccine. In: Zuckerman AJ, ed. Viral Hepatitis and Liver Disease. New York: Alan R Liss, 1988;982–8Google Scholar
  56. 56.
    Hilleman MR, Calandra GB, Hesley TM, Nalin DR, Ryan JL, West DJ. Vaccines against hepatitis A and B. J Gastroenterol Hepatol 1993;8:S21–6CrossRefGoogle Scholar
  57. 57.
    Hilleman MR. Comparative biology and pathogenesis of AIDS and hepatitis B viruses: related but different. AIDES Res Hum Retroviruses 1994;10:1409–19CrossRefGoogle Scholar
  58. 58.
    Schirmbeck R, Melber K, Kuhröber A, Janowicz ZA, Reimann J. Immunization with soluble hepatitis B virus surface protein elicits murine H-2 Class I-restricted CD8+ cytotoxic T lymphocyte responses in vivo. J Immunol 1994;152:1110–9PubMedGoogle Scholar
  59. 59.
    Schirmbeck R, Melber K, Mertens T, Reimann J. Selective stimulation of murine cytotoxic T cell and antibody responses by particulate or monomeric hepatitis B virus surface (S) antigen. Eur J Immunol 1994;24:1088–96PubMedCrossRefGoogle Scholar
  60. 60.
    Carman W, Thomas H, Domingo E. Viral genetic variation: hepatitis B virus as a clinical example. Lancet 1993; 341:349–53PubMedCrossRefGoogle Scholar
  61. 61.
    Howard CR, Stirk HJ, Brown SE, Steward MW. Towards the development of synthetic hepatitis B vaccines. In: Zuckerman AJ, ed. Viral Hepatitis and Liver Disease. New York: Alan R Liss, 1988;1094–1101Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Maurice R. Hilleman
    • 1
  1. 1.West PointUSA

Personalised recommendations