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. A clinical trial phase I was completed with 40 healthy volunteers who were administered the antibody 2) The recently discovered Middle East Respiratory Syndrome Coronavirus (MERS-CoV) continues to infect humans with high (36%) 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 previously 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 10to11) naive human antibody library. The most potent antibody, m336, was tested this year in a rabbit model of MERS-CoV infections. m336 was administered to rabbits intravenously or intranasally before infection with MERS-CoV. Prophylaxis with m336 resulted in a reduction of pulmonary viral RNA titers by 40-9000-fold, compared with an irrelevant control antibody with little to no inflammation or viral antigen detected. This protection in rabbits supports further clinical development of m336. 3) We also showed that m336 is almost germline with only one somatic mutation in the heavy chain. The structure of Fab m336 in complex with the MERS-CoV receptor-binding domain reveals that its IGHV1-69-derived heavy chain provides more than 85% binding surface and that its epitope almost completely overlaps with the receptor-binding site. Analysis of antibodies from 69 healthy humans suggests an important role of the V(D)J recombination-generated junctional and allele-specific residues for achieving high affinity of binding at such low levels of somatic hypermutation. Our results also have important implications for development of vaccine immunogens based on the newly identified m336 epitope as well as for elucidation of mechanisms of neutralization by m336-like antibodies and their elicitation in vivo.
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