Importance of Neutralizing Monoclonal Antibodies Targeting Multiple Antigenic Sites on the Middle East Respiratory Syndrome Coronavirus Spike Glycoprotein To Avoid Neutralization Escape

• DOI: 10.1128/jvi.02002-17
• Publication Date: 2018-03-06T10:08:39Z
• Authors: Lingshu Wang; Wei Shi; James D. Chappell; M. Gordon Joyce; Yi Zhang; Masaru Kanekiyo; Michelle M. Becker; Neeltje van Dorem...; Robert Fischer; Nianshuang Wang; Kizzmekia S. Corbett; Misook Choe; Rosemarie D. Mason; Joseph G. Van Galen; Tongqing Zhou; Kevin O. Saunders; Kathleen M. Tatti; Lia M. Haynes; Peter D. Kwong; Kayvon Modjarrad; Wing-Pui Kong; Jason S. McLellan; Mark R. Denison; Vincent J. Munster; John R. Mascola; Barney S. Graham
• Keywords: Coronavirus

ABSTRACT Middle East respiratory syndrome coronavirus (MERS-CoV) causes a highly lethal pulmonary infection with ∼35% mortality. The potential for future pandemic originating from animal reservoirs or health care-associated events is major public concern. There are no vaccines therapeutic agents currently available MERS-CoV. Using probe-based single B cell cloning strategy, we have identified and characterized multiple neutralizing monoclonal antibodies (MAbs) specifically binding to the receptor-binding domain (RBD) S1 (non-RBD) regions convalescent MERS-CoV-infected patient immunized rhesus macaques. RBD-specific MAbs tended greater potency than non-RBD S1-specific MAbs. Six five could be sorted into four RBD three distinct patterns, based on competition assays, mapping neutralization escape variants, structural analysis. We determined cocrystal structures two targeting different angles show they can bind only in “out” position. then showed that selected RBD-specific, S1-specific, S2-specific given prophylactically prevented MERS-CoV replication lungs protected mice challenge. Importantly, combining RBD- delayed emergence of mutations cell-based virus assay. These studies identify antigenic sites S will useful defining mechanisms developing more effective interventions prevent treat infections. IMPORTANCE which antiviral options available. Based continuing exposure established dromedary camels bats, transmission humans outbreaks expected. structurally defined probes spike glycoprotein (S), target antibodies, cells were human nonhuman primates (NHPs). produced paired immunoglobulin gene sequences mapped epitopes within outside against MERS murine model following passive immunization. viral RBD-directed data suggest antibody responses domains CoV protein may improve immunity guide vaccine development efforts.