Does the vaccine protect? Soldiers are vaccinated against anthrax due to the high probability of malicious infection with the spores of B. anthracis. But will the vaccine actually protect them from disease morbidity and mortality? There is no means to test the FDA-approved AVA vaccine or any other vaccine candidate directly in humans. Antibody titers, epitope specificity, and toxin neutralizing activity in vaccinated individuals show a disturbing degree of variability. In concert with our U19 immunologists, this proposal will address these issues using nonhuman primate models of anthrax that mimic human responses. In the previous funding period, we developed, characterized and validated a baboon anthrax bacteremia model that mimics late stage disease in humans after spore germination, demonstrating the critical role of sepsis toward lethality. The current proposal builds on this foundation and is based on the hypothesis that if antibodies of known specificity and neutralizing activity can prevent infection or reduce disease severity due to B.anthracis in validated baboon models, then vaccinated individuals with similar antibodies will likewise be protected. Since not everyone responds in the same way to the vaccine, this information may contribute to risk stratification of vaccinated individuals.
We aim to 1) identify polyclonal and monoclonal antibodies of known epitope specificity and functionality;2) develop and characterize pulmonary spore models in baboons;and use these to 3) test whether the characterized antibodies are protective in the nonhuman primate disease models. The approach is strong because both baboon and human humoral responses to AVA will be characterized, many antigen-specific antibodies will be screened, and the most promising will be comprehensively tested in the baboon disease models. Minimally, we will be able to identify several candidate antibodies that may be useful immediately as passive immunity adjunctive therapeutics. We have a unique opportunity to answer critical questions by combining a genetically diverse nonhuman primate model which has a proven history of mimicking human responses to anthrax challenge with novel technologies provided by the immunologists on this U19 grant.
The risk of anthrax infection is a serious problem for the military and high risk civilians because of the high probability of malicious attacks with the spores that cause infection. There is a vaccine available but individuals have responded very differently to the vaccine, making different antibodies that may or may not protect them. We have a way to separate these different antibodies, find out how they work and test them individually in an animal model that responds like humans. The antibodies that protect against anthrax can be developed immediately as a drug to treat people exposed to anthrax spores.
|Morris, D L; Fernando, M M A; Taylor, K E et al. (2014) MHC associations with clinical and autoantibody manifestations in European SLE. Genes Immun 15:210-7|
|Garman, Lori; Smith, Kenneth; Farris, A Darise et al. (2014) Protective antigen-specific memory B cells persist years after anthrax vaccination and correlate with humoral immunity. Toxins (Basel) 6:2424-31|
|Garman, Lori; Vineyard, Amanda J; Crowe, Sherry R et al. (2014) Humoral responses to independent vaccinations are correlated in healthy boosted adults. Vaccine 32:5624-31|
|Lupu, Florea; Keshari, Ravi S; Lambris, John D et al. (2014) Crosstalk between the coagulation and complement systems in sepsis. Thromb Res 133 Suppl 1:S28-31|
|Joshi, Sunil K; Lang, Mark L (2013) Fine tuning a well-oiled machine: Influence of NK1.1 and NKG2D on NKT cell development and function. Int Immunopharmacol 17:260-6|
|Lee, Benjamin C; Mayer, Chad L; Leibowitz, Caitlin S et al. (2013) Quiescent complement in nonhuman primates during E coli Shiga toxin-induced hemolytic uremic syndrome and thrombotic microangiopathy. Blood 122:803-6|
|Dumas, Eric K; Nguyen, Melissa L; Cox, Philip M et al. (2013) Stochastic humoral immunity to Bacillus anthracis protective antigen: identification of anti-peptide IgG correlating with seroconversion to Lethal Toxin neutralization. Vaccine 31:1856-63|
|Sun, Dawei; Popescu, Narcis I; Raisley, Brent et al. (2013) Bacillus anthracis peptidoglycan activates human platelets through FcýýRII and complement. Blood 122:571-9|
|Chiu, Christopher; Wrammert, Jens; Li, Gui-Mei et al. (2013) Cross-reactive humoral responses to influenza and their implications for a universal vaccine. Ann N Y Acad Sci 1283:13-21|
|Smith, Kenneth; Muther, Jennifer J; Duke, Angie L et al. (2013) Fully human monoclonal antibodies from antibody secreting cells after vaccination with Pneumovaxýý23 are serotype specific and facilitate opsonophagocytosis. Immunobiology 218:745-54|
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