The major accomplishments for this year are summarized below. 1) Nipah virus (NiV) is an emerging zoonotic paramyxovirus related to HeV that causes severe and often fatal disease in pigs and humans. There are currently no vaccines or treatments approved for human use. Studies in small-animal models of NiV infection suggest that antibody therapy may be a promising treatment. However, most studies have assessed treatment at times shortly after virus exposure before animals show signs of disease. The efficacy of the m102.4 was evaluated at several time points after virus exposure including at the onset of clinical illness in a uniformly lethal nonhuman primate model of NiV disease. Sixteen African green monkeys (AGMs) were challenged intratracheally with a lethal dose of NiV, and 12 animals were infused twice with m102.4 (15 mg/kg) beginning at either 1, 3, or 5 days after virus challenge and again about 2 days later. The presence of viral RNA, infectious virus, and/or NiV-specific immune responses demonstrated that all subjects were infected after challenge. All 12 AGMs that received m102.4 survived infection, whereas the untreated control subjects succumbed to disease between days 8 and 10 after infection. AGMs in the day 5 treatment group exhibited clinical signs of disease, but all animals recovered by day 16. These results represent the successful therapeutic in vivo efficacy by an investigational drug against NiV in a nonhuman primate. Overall these results and previous results from animal studies and 12 humans administered with this mAb 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. 2) The recently discovered Middle East Respiratory Syndrome Coronavirus (MERS-CoV) continues to infect humans with high mortality. Specific, highly effective therapeutics and vaccines against the MERS-CoV are urgently needed to safe human lives and address the pandemic concerns. We identified three human monoclonal antibodies (mAbs), m336, m337 and m338, targeting the receptor (CD26/DPP4) binding domain (RBD) of the MERS-CoV spike glycoprotein from a very large (size 1011) naive human antibody library. They bound with high affinity - equilibrium dissociation constants equal to 4.2, 9.3 and 15 nM, respectively, as measured by Biacore for Fabs binding to RBD. The avidity for IgG1 m336, m337 and m338 as measured by Biacore was even higher - 99, 820 and 560 pM, respectively. The antibodies bound to overlapping epitopes which overlap with the receptor binding site on the RBD as suggested by competition experiments, and further supported by site directed mutagenesis of the RBD and a docking model of the m336-RBD complex. The highest affinity mAb, m336, neutralized both pseudotyped and live MERS-CoV with exceptional potency: 50% neutralization at 0.005 and 0.07 ug/ml, respectively, likely by competing with DPP4 for binding to the S glycoprotein. The exceptionally high neutralizing activity of these antibodies and especially m336 suggest that they have great potential for prophylaxis and therapy of MERS-CoV infection in humans and a tool for development of vaccine immunogens. The rapid (several weeks) identification of three potent mAbs suggests a possibility to use the new large antibody library and related methodology for quick response to public threat resulting from emerging coronaviruses.
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