American Association of Immunologists, The Journal of Immunology, 1_Supplement(206), p. 30.13-30.13, 2021
DOI: 10.4049/jimmunol.206.supp.30.13
Elsevier, Cell, 9(184), p. 2316-2331.e15, 2021
DOI: 10.1016/j.cell.2021.03.029
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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.