The goal of this application is to develop a multicomponent anthrax vaccine that can be easily administered, induces Iong-lasting high antibody titers, and provides protection against Bacillus anthracis infection. Three novel platform technologies, needle-free skin patch transcutaneous immunization (TCI), phage T4 multicomponent display, and liposome and emulsion adjuvant formulations, will be brought to bear on developing an efficacious anthrax vaccine. The research wilt be carried out by two complementary laboratories, one highly skilled in the genetics and manufacture of T4 bacteriophage particles and expression of proteins on the surface of T4, and the other with broad experience with TCI, immunogenic liposomes, emulsions, vaccine formulations, and vaccine clinical trials, in close collaboration with a third laboratory that is a leader in anthrax toxin biology and production. Mutant forms of all three anthrax toxin components, protective antigen (PA), lethal factor (LF) and edema factor (EF), will be expressed either as individual proteins or as N-terminal fusions of the highly antigenic outer capsid protein (Hoc) of bacteriophage T4. The toxin-Hoc fusion proteins with an N-terminal hexa-histidine tag will be purified in large quantities and loaded onto the phage T4 icosahedral surface using an in vitro assembly system. The TCI and intramuscular (IM) routes of delivery for combinations of soluble proteins or T4 displayed antigens with liposome and emulsion adjuvant formulations will be evaluated in parallel tracks, using the mouse model, for generation of protective antibody titers. The immunized mice will be challenged with (i) anthrax toxin, (ii) Sterne strain, and (iii) Ames strain, to determine the efficacy of the vaccines. The best combinations that induce protection in mice against challenge with virulent Bacillus anthracis will be tested in a guinea pig model. Immune responses will be characterized, and challenge experiments with the virulent anthrax strain will be performed to select the best vaccine product(s) that induce long-lasting immunity. The most promising anthrax vaccine candidates will be tested in a nonhuman primate model, in addition to characterization of immune responses, the immunized macaques will be challenged with the aerosolized spores of Bacillus anthracis. The duration of protection as well as pathological changes will be assessed.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZAI1-GPJ-M (M1))
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Baker, Phillip J
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Catholic University of America
Schools of Arts and Sciences
United States
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Peachman, Kristina K; Li, Qin; Matyas, Gary R et al. (2012) Anthrax vaccine antigen-adjuvant formulations completely protect New Zealand white rabbits against challenge with Bacillus anthracis Ames strain spores. Clin Vaccine Immunol 19:11-6
Rao, Mangala; Peachman, Kristina K; Li, Qin et al. (2011) Highly effective generic adjuvant systems for orphan or poverty-related vaccines. Vaccine 29:873-7
Sathaliyawala, Taheri; Islam, Mohammad Z; Li, Qin et al. (2010) Functional analysis of the highly antigenic outer capsid protein, Hoc, a virus decoration protein from T4-like bacteriophages. Mol Microbiol 77:444-55
Qin, Li; Fokine, Andrei; O'Donnell, Erin et al. (2010) Structure of the small outer capsid protein, Soc: a clamp for stabilizing capsids of T4-like phages. J Mol Biol 395:728-41
Rao, Venigalla B (2009) A virus DNA gate: zipping and unzipping the packed viral genome. Proc Natl Acad Sci U S A 106:8403-4
Li, Qin; Peachman, Kristina K; Sower, Laurie et al. (2009) Anthrax LFn-PA Hybrid Antigens: Biochemistry, Immunogenicity, and Protection Against Lethal Ames Spore Challenge in Rabbits. Open Vaccine J 2:92-99
Shivachandra, Sathish B; Li, Qin; Peachman, Kristina K et al. (2007) Multicomponent anthrax toxin display and delivery using bacteriophage T4. Vaccine 25:1225-35
Fokine, Andrei; Bowman, Valorie D; Battisti, Anthony J et al. (2007) Cryo-electron microscopy study of bacteriophage T4 displaying anthrax toxin proteins. Virology 367:422-7
Li, Qin; Shivachandra, Sathish B; Zhang, Zhihong et al. (2007) Assembly of the small outer capsid protein, Soc, on bacteriophage T4: a novel system for high density display of multiple large anthrax toxins and foreign proteins on phage capsid. J Mol Biol 370:1006-19
Li, Qin; Shivachandra, Sathish B; Leppla, Stephen H et al. (2006) Bacteriophage T4 capsid: a unique platform for efficient surface assembly of macromolecular complexes. J Mol Biol 363:577-88

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