Development of Novel Vaccines for High Priority Pathogens

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The large number of pathogens with potential for use in an act of bioterrorism and the inability to predict the particular pathogen threat dictates the need for a therapeutic platform that can be adapted in response to particular biothreats. In this context, the ideal biodefense therapeutic platform should have the following properties: (1) rapid adaptation, allowing simple alterations as the pathogen threat changes; (2) ease of manufacture in large quantities at reasonable cost; (3) no pre-existing immunity in the population; and (4) induction of rapid and sustained protection with a single administration. To meet these criteria, we have developed a versatile strategy to elicit protective immunity based on adenovirus (Ad) and adeno-associated virus (AAV) gene transfer vectors expressing either pathogen-specific antigens or pathogen-neutralizing antibodies. For antigen delivery, Ad and AAV gene transfer vectors have demonstrated efficacy as vaccines against a variety of pathogens. For antibody delivery, the different kinetic expression profiles of Ad (rapid, but short, 1 to 21 days) and AAV (slower, but persistent; from 1 wk to years) gene transfer vectors can be exploited for short-term protection, long-term protection or a combination when the vectors are coadministered. To circumvent issues of pre-existing immunity against common Ad and AAV serotypes, we will focus on the use of non-human primate-derived Ad (AdC7) and AAV (AAVrh.10) serotypes that do not circulate in the human population, and for which humans do not have pre-existing immunity. This proposal addresses the efficacy of this technology for Chikungunya virus (CHIKV) and Nipah virus (NiV), two emerging pathogens for which no therapeutics exist. The proposed specific aims include (1) the development of AdC7- and AAVrh.10-based vaccine vectors for induction of acquired immune responses with an analysis of the relevant cellular immunity profiles elicited by each vector; (2) the production of AdC7- and AAVrh.10-based vectors expressing CHIKV or NiV-neutralizing monoclonal antibodies with a comparison of IgG site-directed mutants to evaluate the mechanism of antibody-mediated protection; and (3) an assessment of combinations of the vaccine vectors for rapid and sustained protective efficacy against virulent CHIKV or NiV challenge following a single co-administration.