Neutralizing and protective human monoclonal antibodies recognizing the N-terminal domain of the SARS-CoV-2 spike protein
Naveenchandra Suryadevara, Swathi Shrihari, Pavlo Gilchuk, Laura A. VanBlargan, Elad Binshtein, Seth J. Zost, Rachel S. Nargi, Rachel E. Sutton, Emma S. Winkler, Elaine C. Chen, Mallorie E. Fouch, Edgar Davidson, Benjamin J. Doranz, Robert H. Carnahan, Larissa B. Thackray, Michael Diamond, James E. Crowe
Abstract
Abstract Most human monoclonal antibodies (mAbs) that neutralize SARS-CoV-2 isolated to date recognize the spike (S) protein receptor-binding domain (RBD) and block virus interaction with the cellular receptor angiotensin converting enzyme 2 (ACE2). We isolated a panel of human mAbs binding to diverse epitopes on the spike protein N-terminal domain (NTD) from SARS-CoV2 convalescent donors and found that a minority of these possessed neutralizing activity. Two mAbs (designated COV2-2489 and COV2-2676) inhibited infection of both authentic SARS-CoV-2 and recombinant chimeric VSV/SARS-CoV-2 reporter viruses. We mapped their binding epitopes by alanine scanning mutagenesis and selection of functional SARS-CoV-2 S protein variants with mutations in the NTD that conferred resistance to recombinant chimeric VSV/SARS-CoV-2 reporter virus. Mechanistic studies showed that the antibodies neutralize in part by inhibiting at a post-attachment step in the infection cycle. COV2-2676 and COV2-2489 prevented infection and disease in mice when administered either as prophylaxis or therapy, and Fc effector functions were required for optimal protection. Thus, a subset of human NTD-specific mAbs protects against infection using multiple functional attributes including neutralizing activity and Fc-mediated activities.