Inhalation anthrax has emerged as a significant and continuing biowarfare and bioterrorism threat. Though vaccine strategies have substantially controlled this disease in animal populations, the current vaccine licensed for human use has several shortcomings, including significant adverse reactions and low immunogenicity resulting in the need for multiple immunizations. The biology of anthrax infection and specifically the actions of its toxins have been elegantly elucidated at the molecular and cellular level. This presents a unique opportunity to rationally design and develop an improved vaccine that can counter current anthrax, as well as modified forms that may be encountered in the future. In this project, we will use the substantial body of knowledge and insight available relating to anthrax toxin to develop molecularly targeted vaccines to prevent the catastrophic effects of toxin following infection. Based on careful analysis of the crystal structure, sequence, and functional studies of all components of the anthrax toxins, we will develop soluble protein vaccines that direct antibody responses towards the critical protein segments involved in toxin activation, assembly, and adherence to cells. We will test these vaccine constructs for their ability to elicit strong antibody responses with the ability to neutralize toxin activity in in vitro assays. Based on analysis of responses to the soluble protein constructs, selected constructs will be moved into the adeno-associated virus vaccine platform for development of an expression vaccine. Traditionally such vaccines have exhibited higher immunogenicity, and AAV in particular has yielded very durable responses. The AAV-based vaccines will be tested for immunogenicity and their ability to elicit toxin-neutralizing antibodies, as well as for use in concert with soluble protein immunogens. Finally, the most promising constructs of both soluble protein and expressed forms will be tested in anthrax spore inhalation challenge studies in rabbits. Such experiments have been extensively validated against primate experiments previously and also appear to correlate most closely with human anthrax disease and protection. Through this approach, we will develop promising candidate anthrax vaccines that can protect against currently existing strains of anthrax, as well as new and enhanced threats based on engineered forms of anthrax.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01AI056580-01
Application #
6690634
Study Section
Special Emphasis Panel (ZAI1-ALR-M (M4))
Program Officer
Zou, Lanling
Project Start
2003-08-15
Project End
2008-01-31
Budget Start
2003-08-15
Budget End
2004-01-31
Support Year
1
Fiscal Year
2003
Total Cost
$339,821
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Oscherwitz, Jon; Quinn, Conrad P; Cease, Kemp B (2015) Anthrax vaccine recipients lack antibody against the loop neutralizing determinant: A protective neutralizing epitope from Bacillus anthracis protective antigen. Vaccine 33:2342-6
Oscherwitz, Jon; Feldman, Daniel; Yu, Fen et al. (2015) Epitope-focused peptide immunogens in human use adjuvants protect rabbits from experimental inhalation anthrax. Vaccine 33:430-6
Oscherwitz, Jon; Yu, Fen; Jacobs, Jana L et al. (2013) Recombinant vaccine displaying the loop-neutralizing determinant from protective antigen completely protects rabbits from experimental inhalation anthrax. Clin Vaccine Immunol 20:341-9
Oscherwitz, Jon; Yu, Fen; Cease, Kemp B (2010) A synthetic peptide vaccine directed against the 2ß2-2ß3 loop of domain 2 of protective antigen protects rabbits from inhalation anthrax. J Immunol 185:3661-8
Oscherwitz, Jon; Yu, Fen; Cease, Kemp B (2009) A heterologous helper T-cell epitope enhances the immunogenicity of a multiple-antigenic-peptide vaccine targeting the cryptic loop-neutralizing determinant of Bacillus anthracis protective antigen. Infect Immun 77:5509-18
Oscherwitz, Jon; Yu, Fen; Jacobs, Jana L et al. (2009) Synthetic peptide vaccine targeting a cryptic neutralizing epitope in domain 2 of Bacillus anthracis protective antigen. Infect Immun 77:3380-8
Oscherwitz, Jon; Hankenson, F C; Yu, Fen et al. (2006) Low-dose intraperitoneal Freund's adjuvant: toxicity and immunogenicity in mice using an immunogen targeting amyloid-beta peptide. Vaccine 24:3018-25