The development of vaccines for microorganisms and bacterial toxins with the potential to be used as biowarfare and bioterrorism agents is an important component of the US biodefense program. DVC is developing two vaccines, one against inhalational exposure to botulinum neurotoxins A1 and B1 and a second for Yersinia pestis, with the ultimate goal of licensure by the FDA under the Animal Rule. Progress has been made in all technical areas, including manufacturing, nonclinical, and clinical development and testing of the vaccines, and in assay development. The current status of development of these vaccines, and remaining challenges are described in this chapter. 1. Introduction Certain highly pathogenic microorganisms and their products have the potential to be used as weapons against either military or civilian populations. The Centers for Disease Control and Prevention (CDC) classifies these agents into one of three categories (A, B, or C) according to seriousness of consequences following exposure (http://emergency.cdc.gov/agent/agentlist-category.asp; accessed April 7, 2011). The US Department of Defense (DoD) has a long history of developing therapeutics and prophylactics (vaccines) to protect the warfighter against offensive use of these agents. Until relatively recently, these countermeasures could be used under an investigational new drug application (IND) mechanism. Now, the DoD mandates that any such products administered to the US warfighters be licensed by the US Food and Drug Administration (FDA). Currently, DVC is developing two vaccines for DoD’s Joint Vaccine Acquisition Program (JVAP); these include a recombinant vaccine to protect against fatal botulism following inhalational exposure to the A1 and B1 serotypes of botulinum neurotoxin (rBV A/B), as well as a recombinant vaccine to protect against pneumonic plague following inhalational exposure to Yersinia pestis (Y. pestis) (rF1V). The specific performance and regulatory requirements, progress, challenges, and successes in each program are reviewed below. 2. Disease Characteristics 2.1. Botulism Botulism is caused by neurotoxins produced by the bacterium Clostridium botulinum (C. botulinum), and disease presents in different forms including infant, wound, adult colonization, and foodborne botulism [1]. The clinical picture is due to cholinergic inhibition, and characteristic signs include a descending muscle weakness, dry mouth, difficulty swallowing, slurred speech, double or blurred vision, and drooping eyelids. The botulinum neurotoxin (BoNT) eventually causes paralysis of the
References
[1]
Centers for Disease Control, “Botulism in the United States, 1899–1996: handbook for epidemiologists, clinicians, and laboratory workers,” Public Health Service, U.S. Department of Health and Human Services, Atlanta, Ga, 1998, http://www.cdc.gov/nczved/dfbmd/ disease listing/files/botulism.pdf.
[2]
S. S. Arnon, R. Schechter, T. V. Inglesby et al., “Botulinum toxin as a biological weapon: medical and public health management,” Journal of the American Medical Association, vol. 285, no. 8, pp. 1059–1070, 2001.
[3]
J. L. Middlebrook and D. R. Franz, “Botulinum toxins,” in Medical Aspects of Biological Warfare, M. K. Lenhart, D. E. Lounsbury, J. W. Martin, and Z. F. Dembek, Eds., pp. 643–654, US Department of the Army, Office of the Surgeon General and the Borden Institute, Washington, DC, USA, 2007.
[4]
B. J. Hinnebusch and D. L. Erickson, “Yersinia pestis biofilm in the flea vector and its role in the transmission of plague,” Current Topics in Microbiology and Immunology, vol. 322, pp. 229–248, 2008.
[5]
V. Vadyvaloo, C. Jarrett, D. Sturdevant, F. Sebbane, and B. J. Hinnebusch, “Analysis of Yersinia pestis gene expression in the flea vector,” Advances in Experimental Medicine and Biology, vol. 603, pp. 192–200, 2007.
[6]
M. Daya and Y. Nakamura, “Pulmonary disease from biological agents: anthrax, plague, Q fever, and tularemia,” Critical Care Clinics, vol. 21, no. 4, pp. 747–763, 2005.
[7]
T. V. Inglesby, D. T. Dennis, D. A. Henderson et al., “Plague as a biological weapon: medical and public health management,” Journal of the American Medical Association, vol. 283, no. 17, pp. 2281–2290, 2000.
[8]
J. Koirala, “Plague: disease, management, and recognition of act of terrorism,” Infectious Disease Clinics of North America, vol. 20, no. 2, pp. 273–287, 2006.
[9]
M. B. Prentice and L. Rahalison, “Plague,” Lancet, vol. 369, no. 9568, pp. 1196–1207, 2007.
[10]
T. W. McGovern and A. M. Friedlander, “Plague,” in Medical Aspects of Chemical and Biological Warfare, F. R. Sidell, E. T. Takafugi, and D. R. Franz, Eds., pp. 479–502, US Department of the Army, Office of the Surgeon General, and Borden Institute, Washington, DC, USA, 1997, Textbook of Military Medicine.
[11]
R. D. Perry and J. D. Fetherston, “Yersinia pestis-Etiologic agent of plague,” Clinical Microbiology Reviews, vol. 10, no. 1, pp. 35–66, 1997.
[12]
M. P. Byrne and L. A. Smith, “Development of vaccines for prevention of botulism,” Biochimie, vol. 82, no. 9-10, pp. 955–966, 2000.
[13]
D. G. Heath, G. W. Anderson, J. M. Mauro et al., “Protection against experimental bubonic and pneumonic plague by a recombinant capsular F1-V antigen fusion protein vaccine,” Vaccine, vol. 16, no. 11-12, pp. 1131–1137, 1998.
[14]
D. C. Sanford, R. E. Barnewall, M. L. Vassar et al., “Inhalational botulism in rhesus macaques exposed to botulinum neurotoxin complex serotypes A1 and B1,” Clinical and Vaccine Immunology, vol. 17, no. 9, pp. 1293–1304, 2010.
[15]
R. Warren, H. Lockman, R. Barnewall et al., “Cynomolgus macaque model for pneumonic plague,” Microbial Pathogenesis, vol. 50, no. 1, pp. 12–22, 2011.
[16]
J. J. Adamovicz and P. L. Worsham, “Plague,” in Biodefense Research Methodology and Animal Models, J. R. Swearengen, Ed., pp. 107–135, CSC Press, Boca Raton, Fla, USA, 2006.
[17]
J. D. Shearer, M. L. Vassar, W. Swiderski, K. Metcalfe, N. Niemuth, and I. Henderson, “Botulinum neurotoxin neutralizing activity of immune globulin (IG) purified from clinical volunteers vaccinated with recombinant botulinum vaccine (rBV A/B),” Vaccine, vol. 28, no. 45, pp. 7313–7318, 2010.
[18]
P. Fellows, J. Adamovicz, J. Hartings et al., “Protection in mice passively immunized with serum from cynomolgus macaques and humans vaccinated with recombinant plague vaccine (rF1V),” Vaccine, vol. 28, no. 49, pp. 7748–7756, 2010.
[19]
Z. F. Dembek, L. A. Smith, and J. M. Rusnak, “Botulinum toxin,” in Medical Aspects of Biological Warfare, M. K. Lenhart, D. E. Lounsbury, J. W. Martin, and Z. F. Dembek, Eds., pp. 337–353, US Department of the Army, Office of the Surgeon General and the Borden Institute, Washington, DC, USA, 2007.
[20]
S. S. Arnon, R. Schechter, S. E. Maslanka, N. P. Jewell, and C. L. Hatheway, “Human botulism immune globulin for the treatment of infant botulism,” New England Journal of Medicine, vol. 354, no. 5, pp. 462–471, 2006.
[21]
D. R. Franz, L. M. Pitt, M. A. Clayton, M. A. Hanes, and K. J. Rose, “Efficacy of prophylactic and therapeutic administration of antitoxin for inhalation botulism,” in Botulinum and Tetanus Neurotoxins: Neurotransmission and Biomedical Aspects, B. R. Das Gupta, Ed., pp. 473–477, Plenum, New York, NY, USA, 1993.
[22]
L. W. Cheng, L. H. Stanker, T. D. Henderson, J. Lou, and J. D. Marks, “Antibody protection against botulinum neurotoxin intoxication in mice,” Infection and Immunity, vol. 77, no. 10, pp. 4305–4313, 2009.
[23]
T. R. Gelzleichter, M. A. Myers, R. G. Menton, N. A. Niemuth, M. C. Matthews, and M. J. Langford, “Protection against botulinum toxins provided by passive immunization with botulinum human immune globulin: evaluation using an inhalation model,” Journal of Applied Toxicology, vol. 19, 1, pp. S35–S38, 1999.
[24]
A. M. Iakovlev, “Significance of antitoxic immunity in protection of the organism in respiratory penetration of bacterial toxins. I. Role of passive immunity in protection of the organism from respiratory lesions by B. botulinum toxins,” Zhurnal Mikrobiologii Epidemiologii i Immunobiologii, vol. 29, no. 6, pp. 63–68, 1958.
[25]
M. A. Cardella, “Botulinum toxoids,” in Proceedings of the Symposium on Botulism, K. H. Lewis and K. Cassel, Eds., pp. 113–130, U.S. Department of Health, Education and Welfare, Cincinnati, Ohio, USA, 1964.
[26]
A. P. Anisimov and K. K. Amoako, “Treatment of plague: promising alternatives to antibiotics,” Journal of Medical Microbiology, vol. 55, no. 11, pp. 1461–1475, 2006.
[27]
G. I. Viboud and J. B. Bliska, “Yersinia outer proteins: role in modulation of host cell signaling responses and pathogenesis,” Annual Review of Microbiology, vol. 59, pp. 69–89, 2005.
[28]
G. P. Andrews, D. G. Heath, G. W. Anderson Jr., S. L. Welkos, and A. M. Friedlander, “Fraction 1 capsular antigen (F1) purification from Yersinia pestis CO92 and from an Escherichia coli recombinant strain and efficacy against lethal plague challenge,” Infection and Immunity, vol. 64, no. 6, pp. 2180–2187, 1996.
[29]
J. Heesemann, A. Sing, and K. Trülzsch, “Yersinia's stratagem: targeting innate and adaptive immune defense,” Current Opinion in Microbiology, vol. 9, no. 1, pp. 55–61, 2006.
[30]
S. T. Smiley, “Current challenges in the development of vaccines for pneumonic plague,” Expert Review of Vaccines, vol. 7, no. 2, pp. 209–221, 2008.
[31]
E. D. Williamson, S. M. Eley, K. F. Griffin et al., “A new improved sub-unit vaccine for plague: the basis of protection,” FEMS Immunology and Medical Microbiology, vol. 12, no. 3-4, pp. 223–230, 1995.
[32]
G. W. Anderson, D. G. Heath, C. R. Bolt, S. L. Welkos, and A. M. Friedlander, “Short- and long-term efficacy of single-dose sub unit vaccines against Yersinia pestis in mice,” American Journal of Tropical Medicine and Hygiene, vol. 58, no. 6, pp. 793–799, 1998.
[33]
E. D. Williamson, S. M. Eley, A. J. Stagg, M. Green, P. Russell, and R. W. Titball, “A single dose sub-unit vaccine protects against pneumonic plague,” Vaccine, vol. 19, no. 4-5, pp. 566–571, 2000.
[34]
S. R. Morris, “Development of a recombinant vaccine against aerosolized plague,” Vaccine, vol. 25, no. 16, pp. 3115–3117, 2007.
[35]
V. L. Motin, R. Nakajima, G. B. Smirnov, and R. R. Brubaker, “Passive immunity to yersiniae mediated by anti-recombinant V antigen and protein A-V antigen fusion peptide,” Infection and Immunity, vol. 62, no. 10, pp. 4192–4201, 1994.
[36]
E. D. Williamson, H. C. Flick-Smith, E. Waters et al., “Immunogenicity of the rF1+rV vaccine for plague with identification of potential immune correlates,” Microbial Pathogenesis, vol. 42, no. 1, pp. 11–21, 2007.
[37]
M. A. Parent, L. B. Wilhelm, L. W. Kummer, F. M. Szaba, I. K. Mullarky, and S. T. Smiley, “Gamma interferon, tumor necrosis factor alpha, and nitric oxide synthase 2, key elements of cellular immunity, perform critical protective functions during humoral defense against lethal pulmonary Yersinia pestis infection,” Infection and Immunity, vol. 74, no. 6, pp. 3381–3386, 2006.
[38]
L. W. Kummer, F. M. Szaba, M. A. Parent et al., “Antibodies and cytokines independently protect against pneumonic plague,” Vaccine, vol. 26, no. 52, pp. 6901–6907, 2008.
[39]
G. W. Anderson, S. E. C. Leary, E. D. Williamson et al., “Recombinant V antigen protects mice against pneumonic and bubonic plague caused by F1-capsule-positive and -negative strains of Yersinia pestis,” Infection and Immunity, vol. 64, no. 11, pp. 4580–4585, 1996.
[40]
A. Roggenkamp, A. M. Geiger, L. Leitritz, A. Kessler, and J. Heesemann, “Passive immunity to infection with Yersinia spp. mediated by anti-recombinant V antigen is dependent on polymorphism of V antigen,” Infection and Immunity, vol. 65, no. 2, pp. 446–451, 1997.
[41]
G. W. Anderson Jr., P. L. Worsham, C. R. Bolt et al., “Protection of mice from fatal bubonic and pneumonic plague by passive immunization with monoclonal antibodies against the F1 protein of Yersinia pestis,” American Journal of Tropical Medicine and Hygiene, vol. 56, no. 4, pp. 471–473, 1997.
[42]
J. Hill, C. Copse, S. Leary, A. J. Stagg, E. D. Williamson, and R. W. Titball, “Synergistic protection of mice against plague with monoclonal antibodies specific for the F1 and V antigens of Yersinia pestis,” Infection and Immunity, vol. 71, no. 4, pp. 2234–2238, 2003.
[43]
J. S. Lin, S. Park, J. J. Adamovicz et al., “TNFα and IFNγ contribute to F1/LcrV-targeted immune defense in mouse models of fully virulent pneumonic plague,” Vaccine, vol. 29, no. 2, pp. 357–362, 2010.
[44]
S. Lin, L. W. Kummer, F. M. Szaba, and S. T. Smiley, “IL-17 contributes to cell-mediated defense against pulmonary Yersinia pestis infection,” Journal of Immunology, vol. 186, no. 3, pp. 1675–1684, 2011.
[45]
K. F. Meyer and L. E. Foster, “Measurement of protective serum antibodies in human volunteers inoculated with plague prophylactics,” Stanford Medical Bulletin, vol. 6, no. 1, pp. 75–79, 1948.
[46]
K. F. Meyer, “Effectiveness of live or killed plague vaccines in man,” Bulletin of the World Health Organization, vol. 42, no. 5, pp. 653–666, 1970.
[47]
J. Bashaw, S. Norris, S. Weeks, S. Trevino, J. J. Adamovicz, and S. Welkos, “Development of in vitro correlate assays of immunity to infection with Yersinia pestis,” Clinical and Vaccine Immunology, vol. 14, no. 5, pp. 605–616, 2007.
[48]
S. Welkos, S. Norris, and J. Adamovicz, “Modified caspase-3 assay indicates correlation of caspase-3 activity with immunity of nonhuman primates to Yersinia pestis infection,” Clinical and Vaccine Immunology, vol. 15, no. 7, pp. 1134–1137, 2008.
[49]
S. Weeks, J. Hill, A. Friedlander, and S. Welkos, “Anti-V antigen antibody protects macrophages from Yersinia pestis-induced cell death and promotes phagocytosis,” Microbial Pathogenesis, vol. 32, no. 5, pp. 227–237, 2002.
[50]
E. D. Williamson, H. C. Flick-Smith, E. Waters et al., “Immunogenicity of the rF1+rV vaccine for plague with identification of potential immune correlates,” Microbial Pathogenesis, vol. 42, no. 1, pp. 11–21, 2007.
[51]
A. Zauberman, S. Cohen, Y. Levy et al., “Neutralization of Yersinia pestis-mediated macrophage cytotoxicity by anti-LcrV antibodies and its correlation with protective immunity in a mouse model of bubonic plague,” Vaccine, vol. 26, no. 13, pp. 1616–1625, 2008.
