Viral agents known to cause hemorrhagic fever disease with high morbidity and mortality in humans, such as theBunyaviruses - Crimean-Congo hemorrhagic fever virus, Rift Valley fever virus, and Hantaan virus or the Filoviruses -Ebola and Marburg virus, are priority pathogens of biodefense concern. In addition, there have been several outbreaksof newly discovered and/or emerging viruses which have also resulted in significant numbers of human fatalities, andthese include the Flavivirus West Nile virus and the Henipaviruses Nipah and Hendra virus. These emerging viruseshave also been classified as agents of biodefense concern because they possess characteristics making them suitablefor weaponization. For all of these viruses there are neither approved vaccines nor therapeutics for the prevention ofinfection or disease. As a potential gap-filling approach for the rapid development of safe and efficacious antiviraltherapies for these agents, we propose to identify, isolate and characterize neutralizing human monoclonal antibodies(nhMAbs) reactive to the native forms of the envelope glycoproteins (Envs) of these viruses. The development of thesenhMAbs would provide a valuable battery of post-exposure or post-infection therapeutics to combat disease caused bythese agents. The antibodies will be obtained by screening human phage display libraries against the viral Envs. OurResearch Project will be comprised of four Sub-Projects. The unifying strategy of these projects will be the developmentof recombinant-based assays for measuring virus entry along with the production of native viral Envs as antigens forphage panning procedures. Sub-Project 1 will develop the assays and Env antigens for the Henipaviruses andBunyaviruses; Sub-Project 2 will focus on the Flaviviruses; Sub-Project 3 will employ the Ebola and Marburg virussystems; while Sub-Project 4 will develop a second-generation alphavirus-based replicon system as a vaccine platformutilizing one or more of the viral Envs derived from the other Sub-Projects. The overall objectives of the ResearchProject will be to develop a battery of potent nhMAbs capable of being used as passive immunotherapy against severalimportant viral pathogens, and develop a vaccine platform capable of eliciting a humoral response which includes theantibody reactivities observed by those nhMAbs developed by the other Sub-Projects. The overall Research Project'sSpecific Aims will be 1) Develop high-throughput recombinant assays for virus entry and develop recombinant viralEnvs; 2) identify and isolate Fabs and scFvs capable of blocking virus entry by using recombinant viral Envs and/orfunctional pseudotyped or virus-like particles as antigens for phage panning; and 3) develop and test a novelalphavirus-based vaccine platform. In summary, the short-term goals of this research Program will be the developmentof nhMAbs that could be used for passive immunotherapy, while the long-term objective is the creation of a vaccineplatform capable of eliciting similar antibody responses in an animal host. Both of these research goals are priorities asimmediate and long-term objectives for biodefense research on viral hemorrha0ic fevers and emerging viruses.
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