Anthrax pp 33-60 | Cite as

Anthrax Vaccines

  • A. M. Friedlander
  • S. L. Welkos
  • B. E. Ivins
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 271)


The only impetus for the development of new anthrax vaccines is to protect humans against the intentional use of Bacillus anthracis as a bioterrorist or warfare agent. Live attenuated vaccines against anthrax in domesticated animals were among the very first vaccines developed. This was followed by the development of nonliving component vaccines leading to the eventual licensure of protein-based vaccines for human use in the 1970s. This chapter will review the recent advances in developing protein, live attenuated, and genetic vaccines against anthrax.


Protective Antigen Live Vaccine Bacillus Anthracis Lethal Toxin Anthrax Toxin 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Auerbach S, Wright GG (1955) Studies on immunity in anthrax. VI. Immunizing activity of protective antigen against various strains of Bacillus anthracis. J Immunol 75: 129–133PubMedGoogle Scholar
  2. Bail O (1904) Untersuchungen uber naturliche und kuntliche Milzbrandimmunitat. Centralbl f Bakt 37: 270–280Google Scholar
  3. Barnard JP, Friedlander AM (1999) Vaccination against anthrax with attenuated recombinant strains of Bacillus anthracis that produce protective antigen. Infect Immun 67: 562–567PubMedGoogle Scholar
  4. Belton FC, Strange RE (1954) Studies on a protective antigen produced in vitro from Bacillus anthracis: medium and methods of production. Br J Exp Pathol 35: 144–152PubMedGoogle Scholar
  5. Benson EL, Huynh PD, Finkelstein A, Collier RJ (1998) Identification of residues lining the anthrax protective antigen channel. Biochemistry 37: 3941–3948PubMedCrossRefGoogle Scholar
  6. Berendt R, Jemski J, Johnson-Winegar A, Ivins B (1985) The use of toxin components for the immunoprophylaxis of inhalation anthrax. Abstr Ann Meeting Am Soc Microbiol E61: 85Google Scholar
  7. Brachman P, Friedlander AM (1999) Anthrax. In: Plotkin SA, Orenstein WA (eds) Vaccines. W. B. Saunders Philadelphia p. 629–637Google Scholar
  8. Brachman PS, Gold H, Plotkin SA, Fekety FR, Werrin M, Ingraham NR (1962) Field evaluation of a human anthrax vaccine.Am J Public Health 52: 632–645Google Scholar
  9. Brossier F, Mock M, Sirard J-C (1999) Antigen delivery by attenuated Bacillus anthracis: new prospects in veterinary vaccines. J Appl Microbiol 87: 298–302PubMedCrossRefGoogle Scholar
  10. Brossier F, Weber-Levy M, Mock M, Sirard J-C (2000) Role of toxin functional domains in anthrax pathogenesis. Infect Immun 68: 1781–1786PubMedCrossRefGoogle Scholar
  11. Brossier F, Sirard JC, Guidi-Rontani C, Duflot E, Mock M (1999) Functional analysis of the carboxy-terminal domain of Bacillus anthracis protective antigen. Infect Immun 67: 964–967PubMedGoogle Scholar
  12. Broster MG, Hibbs SE (1990) Protective efficacy of anthrax vaccines against aerosol challenge. Proceedings of the International Workshop on Anthrax, 11–13 April 1989, Winchester, UK Salisbury Med Bull Special suppl No. 68, pp 91–92Google Scholar
  13. Cataldi A, Labruyere E, Mock M (1990) Construction and characterization of a pro- tective antigen-deficient Bacillus anthracis strain. Mol Microbiol 4: 1111–1117PubMedCrossRefGoogle Scholar
  14. Chatfield S, Roberts M, Li J, Starns A, Dougan G (1994) The use of live attenuated Salmonella for oral vaccination. Dev Biol Stand 82: 35–42PubMedGoogle Scholar
  15. Cohen S, Mendelson I, Altboum Z, Kobiler D, Elhanany E, Bino T, Leitner M, Inbar I, Rosenberg H, Gozes Y, Barak R, Fisher M, Kronman C, Velan B, Shafferman A (2000) Attenuated nontoxigenic and nonencapsulated Bacillus anthracis spore vaccines protect against anthrax. Infect Immun 68:4549– 4558Google Scholar
  16. Coulson NM, Fulop M, Titball RM (1994) Bacillus anthracis protective antigen, expressed in Salmonella typhimurium SL3261, affords protection against anthrax spore challenge. Vaccine 12: 1395–1401Google Scholar
  17. Cromartie WJ, Watson DW, Bloom WL, Heckly RJ (1947) Studies on infection with Bacillus anthracis. II. The immunological and tissue damaging properties of extracts prepared from lesions of B. anthracis infection. J Infect Dis 80: 14–27PubMedCrossRefGoogle Scholar
  18. Ezzell JW Jr,Abshire TG (1988) Immunological analysis of cell-associated antigens of Bacillus anthracis. Infect Immun 56: 349–356PubMedGoogle Scholar
  19. Ezzell JW Jr, Abshire TG (1992) Serum protease cleavage of Bacillus anthracis protective antigen. J Gen Microbiol 138: 543–549PubMedCrossRefGoogle Scholar
  20. Farchaus JW, Ribot WJ, Jendrek S, Little SF (1998) Fermentation, purification, and characterization of protective antigen from a recombinant, avirulent strain of Bacillus anthracis. Appl Environ Microbiol 64: 982–991PubMedGoogle Scholar
  21. Fellows PF, Linscott MK, Iv ins BE, Pitt MLM, Rossi CA, Gibbs PH, Friedlander AM (200 1) Efficacy of a human anthrax vaccine in guinea pigs, rabbits, and rhesus macaques against challenge by Bacillus anthracis isolates of diverse geographical origin. Vaccine (in press)Google Scholar
  22. Fellows PF, Linscott MK, Little SF, Gibbs P, Iv ins BE (2000) Anthrax vaccine efficacy in the syrian golden hamster. Abstr Ann Meeting Am Soc Microbiol, Los Angeles CA P. 299 E-28Google Scholar
  23. Friedlander AM, Pittman PR, Parker GW (1999) Anthrax vaccine: evidence for safety and efficacy against inhalational anthrax. JAMA 282: 2104–2106PubMedCrossRefGoogle Scholar
  24. Fubra ES (1966) Nonproteolytic, avirulent Bacillus anthracis as a live vaccine. J Bacteriol 91: 930–933PubMedGoogle Scholar
  25. Gefen NE, Shustikov VM, Rudneva, OA, Fedyaev SF, Tsimlyansky GT, Golubitsky EA, Lazareva ES (1970) A study of reactogenicity, harmlessness and immunological efficacy of aerosol method of immunization against anthrax in trial on man. Zh Mikrobiol Epidemiol Immunobiol 47: 81–85 (In Russian)Google Scholar
  26. Gladstone GP (1946) Immunity to anthrax: protective antigen present in cell-free culture filtrates. Br J Exp Pathol 27: 394–418PubMedGoogle Scholar
  27. Gordon RE, Haynes WD, Hor-Nay Pang C (1973) The genus Bacillus. U. S. Dep Agric Agric Handb No. 427Google Scholar
  28. Gu M-L, Leppla SH, Klinman DM (1999) Protection against anthrax toxin by vaccination with a DNA plasmid encoding anthrax protective antigen. Vaccine 17:340– 344Google Scholar
  29. Gupta P, Waheed SM, Bhatnagar R (1999) Expression and purification of the recombinant protective antigen of Bacillus anthracis. Protein Expr Purif 16:369– 376Google Scholar
  30. Gupta RK, Siber GR (1995) Adjuvants for human vaccines-current status, problems and future prospects. Vaccine 13: 1263–1276PubMedCrossRefGoogle Scholar
  31. Hambleton P, Carman JA, Turnbull PCB (1984) Anthrax: the disease in relation to vaccines. Vaccine 2: 125–132PubMedCrossRefGoogle Scholar
  32. Hambleton P, Turnbull PCB (1990) Anthrax vaccine development: a continuing story. In: Mizrahi, A (ed) Bacterial Vaccines. Liss, New York, pp 105–122Google Scholar
  33. Hodgson AE (1941) Cutaneous anthrax. Lancet 1: 811–813CrossRefGoogle Scholar
  34. Iacono-Connors LC, Welkos SL, Ivins BE, Dalrymple JM (1991) Protection against anthrax with recombinant virus-expressed protective antigen in experimental animals. Infect Immun 59: 1961–1965PubMedGoogle Scholar
  35. Ivins BE, Ezzell Jr, JW, Jemski J, Hedlund, KW, Ristroph JD, Leppla SH (1986) Immunization studies with attenuated strains of Bacillus anthracis. Infect Immun 52: 454–458PubMedGoogle Scholar
  36. Ivins BE, Fellows PF, Nelson GO (1994) Efficacy of a standard human anthrax vaccine against Bacillus anthracis spore challenge in guinea pigs. Vaccine 12:872– 874Google Scholar
  37. Ivins BE, Fellows P, Pitt L, Estep J, Farchaus J, Friedlander A, Gibbs P (1995) Experimental anthrax vaccines: efficacy of adjuvants combined with protective antigen against an aerosol Bacillus anthracis spore challenge in guinea pigs. Vaccine 13: 1779–1784PubMedCrossRefGoogle Scholar
  38. Ivins BE, Fellows PF, Pitt MLM, Estep JE, Welkos SL, Worsham PL, Friedlander AM (1996) Efficacy of a standard human anthrax vaccine against Bacillus anthracis aerosol spore challenge in rhesus monkeys. Salisbury Med Bull 87: 125–126Google Scholar
  39. Ivins BE, Pitt MLM, Fellows PF, Farchaus JW, Benner GE, Waag DM, Little SF, Anderson JR, Gibbs PH, Friedlander AM (1998) Comparative efficacy of experimental anthrax vaccine candidates against inhalation anthrax in rhesus macaques. Vaccine 16: 1141–1148PubMedCrossRefGoogle Scholar
  40. Ivins BE, Welkos SL (1986) Cloning and expression of the Bacillus anthracis protective antigen gene in Bacillus subtilis. J Bacteriol 54: 537–542Google Scholar
  41. Ivins BE, Welkos SL (1988) Recent advances in the development of an improved, human anthrax vaccine. Eur J Epidemiol 4: 12–19PubMedCrossRefGoogle Scholar
  42. Ivins BE, Welkos SL, Knudson GB, Little SF (1990) Immunization against anthrax with aromatic compound-dependent (Aro–) mutants of Bacillus anthracis and with recombinant strains of Bacillus subtilis that produce anthrax protective antigen. Infect Immun 58: 303–308PubMedGoogle Scholar
  43. Ivins BE, Welkos SL, Little SF, Crumrine MH, Nelson GO (1992) Immunization against anthrax with Bacillus anthracis protective antigen combined with adjuvants. Infect Immun 60: 662–668PubMedGoogle Scholar
  44. Ivins BE, Welkos SL, Little SF, Knudson GB (1990) Cloned protective activity and progress in development of improved anthrax vaccines. Proceedings of the International Workshop on Anthrax, 11–13 April 1989, Winchester, UK Salisbury Med Bull Special suppl No. 68, pp 86–88Google Scholar
  45. Jackson FC, Wright GG,Armstrong J (1957) Immunization of cattle against experimental anthrax with alum-precipitated protective antigen or spore vaccine. Am J Vet Res 18: 771–777PubMedGoogle Scholar
  46. Klein F, DeArmon Jr, IA, Lincoln RE, Mahlandt BG, Fernelius AL (1962) Immunological studies of anthrax. II. Levels of immunity against Bacillus anthracis obtained with protective antigen and live vaccine. J Immunol 88: 15–19PubMedGoogle Scholar
  47. Leppla SH (1996) Anthrax Toxins in: Moss J, Iglewksi B, Vaughan M, Tu AT (eds) Bacterial toxins and virulence factors in disease. Marcel Dekker Inc P. 543–572Google Scholar
  48. Lincoln RE, Fish DC (1970) Anthrax toxin. In: Montie, TC, Kadis S, Ajl SJ (eds) Microbial Toxins. Academic Press, New York, pp 361–414Google Scholar
  49. Little SF, Ivins BE (1999) Molecular pathogenesis of Bacillus anthracis infection. Microbes and Infection 2: 131–139CrossRefGoogle Scholar
  50. Little SF, Ivins BE, Fellows PF, Friedlander AM (1997) Passive protection studies against Bacillus anthracis infection in guinea pigs using monoclonal and polyclonal antibodies. Infect Immun 65: 5171–5175PubMedGoogle Scholar
  51. Little SF, Knudson GB (1986) Comparative efficacy of Bacillus anthracis live spore vaccine and protective antigen vaccine against anthrax in the guinea pig. Infect Immun 52: 509–512PubMedGoogle Scholar
  52. Little SF, Leppla SH, Friedlander AM(1990) Production and characterization of monoclonal antibodies against the lethal factor component of Bacillus anthracis lethal toxin. Infect Immun 58: 1606–1613PubMedGoogle Scholar
  53. Little SP, Novak JM, Lowe JR, Leppla SH, Singh Y, Klimpel KR, Lidgerding BC, Friedlander AM (1996) Characterization of lethal factor binding and cell receptor binding domains of protective antigen of Bacillus anthracis using monoclonal antibodies. Microbiology 142: 707–715PubMedCrossRefGoogle Scholar
  54. Mahlandt BG, Klein F, Lincoln RE, Haines BW, Jones WI, Friedman RH (1966) Immunologic studies of anthrax. IV. Evaluation of the immunogenicity of three components of anthrax toxin. J Immunol 96: 727–733Google Scholar
  55. McBride BW, Mogg A, Telfer JL, Lever MS, Miller J, Turnbull PCB, Baillie L (1998) Protective efficacy of a recombinant protective antigen against Bacillus anthracis challenge and assessment of immunological markers. Vaccine 16: 810–817PubMedCrossRefGoogle Scholar
  56. Mikesell P, Ivins BE, Ristroph JD, Dreier TM (1983) Evidence for plasmid-mediated toxin production in Bacillus anthracis. Infect Immun 38: 371–376Google Scholar
  57. Miller J, McBride BW, Manchee RJ, Moore P, Baillie LWJ (1998) Production and purification of recombinant protective antigen and protective efficacy against Bacillus anthracis. Lett Appl Microbiol 26: 56–60PubMedCrossRefGoogle Scholar
  58. Novak JM, Stein M-P, Little SF, Leppla SH, Friedlander AM (1992) Functional characterization of protease-treated Bacillus anthracis protective antigen. J Biol Chem 267: 17186–17193PubMedGoogle Scholar
  59. Oh H-B, Park Y-M, Seong W-K (1998) Expression of Bacillus anthracis protective antigen in Bacillus brevis. Abstracts of the 3rd International Conference on Anthrax, Plymouth, England, September 7–10, 1998. P. 64.Google Scholar
  60. Pasteur L (1881) De l’attenuation des virus et de leur retour a la virulence. CR Acad Sci Agric Bulg 92: 429–435Google Scholar
  61. Petosa C, Collier RJ, Klimpel KR, Leppla SH, Liddington RC (1997) Crystal structure of the anthrax toxin protective antigen. Nature 385: 833–838PubMedCrossRefGoogle Scholar
  62. Pezard C, Berche P, Mock M (199 1) Contribution of individual toxin components to virulence of Bacillus anthracis. Infect Immun 59: 3472–3477Google Scholar
  63. Pezard C, Duflot E, Mock M (1993) Construction of B. anthracis mutant strains producing a single toxin component. J Gen Microbiol 139: 2459–2463PubMedCrossRefGoogle Scholar
  64. Pezard C, Weber-Levy M, Sirard J-C, Berche P, Mock M (1995) Protective immunity induced by Bacillus anthracis toxin-deficient strains. Infect Immun 63: 1369–1372PubMedGoogle Scholar
  65. Pitt MLM, Ivins B, Estep J, Farchaus J, Friedlander AM (1996 a) Comparative efficacy of a recombinant protective antigen vaccine against inhalation anthrax in guinea pigs, rabbits, and rhesus monkeys. Abstr Ann Meeting Am Soc Microbiol, Atlanta GA P. 278 E-70Google Scholar
  66. Pitt MLM, Ivins BE, Estep JE, Farchaus J, Friedlander AM (1996b) Comparison of the efficacy of purified protective antigen and MDPH to protect non-human primates from inhalation anthrax. Salisbury Med Bull 87: 130Google Scholar
  67. Pitt MLM, Little SF, Ivins BE, Fellows PF, Boles J, Barth J, Hewetson JH, Friedlander, AM (1999) In vitro correlate of immunity in an animal model of inhalational anthrax. J Appl Microbiol 87: 304PubMedCrossRefGoogle Scholar
  68. Plotkin SL, Plotkin SA (1999) A short history of vaccination. In: Plotkin SA, Orenstein WA (eds) Vaccines.WB Saunders, Philadelphia pp 1–12Google Scholar
  69. Preisz H (1911) Quoted in Anthrax. (1955) In: Wilson GS, Miles AA (eds) Topley and Wilson’s Principles of Bacteriology and Immunity. Williams Wilkins, Baltimore p 1950Google Scholar
  70. Pushko P, Parker M, Ludwig GV, Davis NL, Johnston RE, Smith JF (1997) Replicon-helper systems from attenuated Venezuelan Equine Encephalitis Virus: Expression of heterologous genes in vitro and immunization against heterologous pathogens in vivo. Virology 239: 389–401Google Scholar
  71. Puziss M, Manning LC, Lynch LW, Barclay E,Abelow I, Wright GG (1963) Large-scale production of protective antigen of Bacillus anthracis anaerobic cultures. Appl Microbiol 11: 330–334Google Scholar
  72. Puziss M, Wright GG (1962) Studies on immunity in anthrax. X. Gel-adsorbed protective antigen for immunization of man. J Bacteriol 85: 230–236Google Scholar
  73. Salsbery CE (1926) Anthrax aggressin. J Am Vet Med Assn 68: 755–772Google Scholar
  74. Sellmann BR, Nassi S, Collier RJ (2001) Point mutations in anthrax protective antigen that block translocation. J Biol Chem 276: 8371–8376CrossRefGoogle Scholar
  75. Schodel F, Curtiss 3rd R (1995) Salmonella as oral vaccine carriers. Dev Biol Stand 84: 245–253PubMedGoogle Scholar
  76. Shlyakhov E, Rubinstein E (1994) Human live anthrax vaccine in the former USSR. Vaccine 12: 727–730PubMedCrossRefGoogle Scholar
  77. Shuylak VP (1970) Epidemiological efficacy of anthrax STI vaccine in Tadjik SSR. Zh Microbiol Epidemiol Immunobiol 47: 117–120 (In Russian)Google Scholar
  78. Singh Y, Klimpel KR, Quinn CP, Chaudhary VK, Leppla SH(1991) The carboxyl-terminal end of protective antigen is required for receptor binding and anthrax toxin activity. J Biol Chem 266: 15493–15497PubMedGoogle Scholar
  79. Singh Y, Ivins BE, Leppla SH (1998) Study of immunization against anthrax with the purified recombinant protective antigen of Bacillus anthracis. Infect Immun 66: 3447–3448PubMedGoogle Scholar
  80. Singh Y, Klimpel KR, Goel S, Swain PK, Leppla SH (1999) Oligomerization of anthrax toxin protective antigen and binding of lethal factor during endocytic uptake into mammalian cells. Infect Immun 67: 1853–1859PubMedGoogle Scholar
  81. Smith H, Stoner H (1967) Anthrax toxic complex. Fed Proc 26: 1554–1557PubMedGoogle Scholar
  82. Stanley JL, Smith H (1963) The three factors of anthrax toxin: their immunogenicity and lack of demonstrable enzymatic activity. J Gen Microbiol 31: 329–337PubMedCrossRefGoogle Scholar
  83. Sterne M (1937) Variation in Bacillus anthracis. Onderstepoort J Vet Sci Anim Ind 8: 271Google Scholar
  84. Sterne M, Nichol J, Lambrechts NS (1942) The effect of large-scale active immunization against anthrax. J S African Vet Med Assoc 13: 53–63Google Scholar
  85. Tigertt WD (1980) Anthrax. William Smith Greenfield, MD FRCP. Concerning the priority due to him for the production of the first vaccine against anthrax. J Hyg 85: 415–420CrossRefGoogle Scholar
  86. Turnbull PCB (1991) Anthrax vaccines: past, present and future. Vaccine 9: 533–539PubMedCrossRefGoogle Scholar
  87. Turnbull PCB (2000) Current status of immunization against anthrax: old vaccines may be here to stay for a while. Current Opinion in Infectious Diseases 13: 113–120PubMedCrossRefGoogle Scholar
  88. Turnbull PC, Broster, MG, Carman JA, Manchee RJ, Melling J (1986) Development of antibodies to protective antigen and lethal factor components of anthrax toxin in humans and guinea pigs and their relevance to protective immunity. Infect Immun 52: 356–359PubMedGoogle Scholar
  89. Turnbull PCB, Leppla SH, Broster MG, Melling J (1988) Antibodies to anthrax toxin in humans and guinea pigs and their relevance to protective immunity. Med Microbiol Immunol 177: 293–303PubMedCrossRefGoogle Scholar
  90. Turnbull PCB, Quinn CP, Hewson R, Stockbridge MC, Melling J (1990) Protection conferred by microbially-supplemented UK and purified PA vaccines. Proceedings of the International Workshop on Anthrax, 11–13 April 1989, Winchester, UK Salisbury Med Bull Special suppl No. 68, pp 89–91Google Scholar
  91. Varughese M, Teixeira AV, Liu S, Leppla SH (1999) Identification of a receptor-binding region within domain 4 of the protective antigen component of anthrax toxin. Infect Immun 67: 1860–1865PubMedGoogle Scholar
  92. Vodkin M, Leppla SH (1983) Cloning of the protective antigen gene of Bacillus anthracis. Cell 34: 693–696PubMedCrossRefGoogle Scholar
  93. Watson DW, Cromartie WJ, Bloom WL, Kegeles G, Heckly RJ (1947) Studies on infection with Bacillus anthracis. III. Chemical and immunological properties of the protective antigen in crude extracts of skin lesions of B. anthracis. J Infect Dis 80: 28–52PubMedCrossRefGoogle Scholar
  94. Welkos S, Becker D, Friedlander A, Trotter R (1990) Pathogenesis and host resistance to Bacillus anthracis: a mouse model. Proceedings of the International Workshop on Anthrax, 11– 13 April 1989, Winchester, UK Salisbury Med Bull Special suppl No. 68 pp 49–52Google Scholar
  95. Welkos SL, Friedlander AM (1988) Comparative safety and efficacy against Bacillus anthracis of protective antigen and live vaccines in mice. Microbiol Pathog 5: 127–139CrossRefGoogle Scholar
  96. Welkos SL, Vietri NJ, Gibbs PH (1993) Non-toxigenic derivatives of the Ames strain of Bacillus anthracis are fully virulent for mice: role of plasmid pX02 and chromosome in strain-dependent virulence. Microbial Pathogenesis 14: 381–388PubMedCrossRefGoogle Scholar
  97. Williamson ED, Beedham RJ, Bennett AM, Perkins SD, Miller J, Baillie LW J (1999) Presentation of protective antigen to the mouse immune system: immune sequelae. J Appl Microbiol 87: 315–317PubMedCrossRefGoogle Scholar
  98. Wilson GS, Miles AA (1955) Anthrax. In: Topley and Wilson’s Principles of Bacteriology and Immunity. Williams Wilkins, Baltimore, pp 1938–1954Google Scholar
  99. Worsham PL, Sowers MR (1999) Isolation of an asporogenic (spoOA) protective antigen-producing strain of Bacillus anthracis. Can J Microbiol 45: 1–8PubMedGoogle Scholar
  100. Wright GG, Green T, Kanode Jr R (1954) Studies on immunity in anthrax. V. Immunizing activity of alum-precipitated protective antigen. J Immunol 73:387– 391Google Scholar
  101. Zegers ND, Kluter E, van der Stap H, van Dura E, van Dalen P, Shaw M, Baillie L (1998) Expression of the protective antigen of Bacillus anthracis by Lactobacillus casei: Towards the development of an oral vaccine against anthrax. J Appl Microbiol 87: 309–314Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2002

Authors and Affiliations

  • A. M. Friedlander
    • 1
  • S. L. Welkos
    • 1
  • B. E. Ivins
    • 1
  1. 1.U. S. Army Medical Research Institute of Infectious DiseasesFrederickUSA

Personalised recommendations