Responding to the threat of bioterrorism we have continued to identify and characterize neutralizing mAbs to the following biodefense-related microbes which are on the NIAID list of category A or C pathogens: Yersinia pestis (which causes plague, category A), Nipah and Hendra viruses (Henipaviruses) (causing acute infections with high, up to 70%, mortality, category C), Ebola and Marburg viruses (causing hemorrhagic fever with high, up to 90%, mortality, category A), Crimean-Congo virus (CCHFV) (causing hemorrhagic fever with relatively high, up to 50%, mortality, category C), dengue virus (which causes dengue hemorrhagic fever with relatively low mortality, category A), and SARS CoV (causing acute infections with relatively low mortality, category C). Previously, we reported the isolation of henipavirus-neutralizing recombinant hmAbs including one, m102.4, which exhibited exceptionally potent and cross-reactive inhibitory activity against both HeV and NiV. HeV is categorized as a biosafety level 4 agent, which has made development of animal models and testing of potential therapeutics and vaccines challenging. Recently, lethal infection of African Green monkeys (AGM) was demonstrated and disease essentially mirrored the severe illness seen in HeV-infected humans, including multisystemic vasculitis with virus replicating in vascular tissues including lung, spleen and brain. We and our collaborators demonstrated that m102.4 can completely protect AGMs from a lethal HeV challenge. The success of m102.4 represents the first HeV therapeutic with post-exposure in vivo efficacy and highlights the importance of developing human monoclonal antibodies to combat infectious disease. It has been also administered to humans exposed to HeV with no adverse reactions. These results further confirm our proposition that m102.4 has potential as a therapeutic for treatment of diseases caused by henipaviruses, and could save human lives now. It could be also used for prophylaxis, diagnosis and as a research reagent. Animal studies with this antibody continue and more are planned with GMP produced m102.4. We have previously identified several novel potent hmAbs against Yersinia pestis these are the first human antibodies against this category A agent. These antibodies continue to be characterized. We have also performed experiments to identify neutralizing hmAbs against dengue virus and Ebola virus. One Fab against dengue virus was identified and is being tested. Experiments are ongoing to develop better antigens and identify novel antibodies against these and other microbes of biodefense importance.
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