Vaccines remain the most cost-effective medical intervention known to prevent morbidity and mortalitycaused by infectious agents. Vaccines may also become a major component in the armamentarium to protectourselves against the deliberate release of bioterrorism agents. The goal of this thematic area is to develop,characterize and optimize live viral and bacterial vectors to deliver antigens of bioterrorism agents,ultimately resulting in the protection of humans against a variety of threatening diseases. We will concentrateon the development of vectors, because traditional vaccine approaches cannot easily be applied to many ofthe category A, B and C agents. The first subproject (Crystal) aims at the use of recombinant adenovirusvectors expressing the Bacillus antkracis PA antigen and/or a single chain antibody against this antigen.Such a dual approach may provide instant protection via expression of the antibody, as well as long termimmunity against the toxin elaborated by anthrax. The second (Rose) and third (Palese) subprojects takeadvantage of recombinant vesicular stomatitis virus and recombinant Newcastle disease virus,respectively. Humans have no immunity against either of these viruses and their pathogenicity in humans islow or absent, making them promising vectors to use in developing effective vaccines against such categoryA pathogens as B. anthracis, Yersinia pestis, and Ebola virus. It is also hoped that these viral vectors can beused as generic vehicles for inducing protective immune responses against a broad range of pathogens. Wewill also study bacterial vectors, including Salmonella typhimurium (subproject 4. Galan) which offersseveral advantages over other antigen delivery systems, including a strong mucosal immune response.Avirulent strains of S. typhimurium will be constructed which deliver, through their type III secretion system,protective antigens against B. anthracis, Y. pestis, and Burkholderia mallei. Appropriate animal systems willbe used to evaluate the ability of such vectors to protect against anthrax, pneumonic plague and glanders.Subproject 5 (Jacobs) will make use of other bacterial vectors (recombinant BCG strain of M. tuberculosisand attenuated strains of M. tuberculosis) to express different antigens, including the West Nile virus E andNS-1 proteins. By trying different vector approaches against the same pathogen, we hope to set up synergisticrelationships that should allow us to quickl2 compare and develop more effective vaccines against thesepotential agents ofbioterrorism.
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