Neutralizing and protective human monoclonal antibodies recognizing the N-terminal domain of the SARS-CoV-2 spike protein

Suryadevara, Naveenchandra; Shrihari, Swathi; Gilchuk, Pavlo; VanBlargan, Laura A.; Binshtein, Elad; Zost, Seth J.; Nargi, Rachel S.; Sutton, Rachel E.; Winkler, Emma S.; Chen, Elaine C.; Fouch, Mallorie E.; Davidson, Edgar; Doranz, Benjamin J.; Chen, Rita E.; Shi, Pei-Yong; Carnahan, Robert H.; Thackray, Larissa B.; Diamond, Michael S.; Crowe, James E.

Most human monoclonal antibodies (mAbs) neutralizing SARS-CoV-2 recognize the spike (S) protein receptor-binding domain and block virus interactions with the cellular receptor angiotensin-converting enzyme 2. We describe a panel of human mAbs binding to diverse epitopes on the N-terminal domain (NTD) of S protein from SARS-CoV-2 convalescent donors and found a minority of these possessed neutralizing activity. Two mAbs (COV2-2676 and COV2-2489) inhibited infection of authentic SARS-CoV-2 and recombinant VSV/SARS-CoV-2 viruses. We mapped their binding epitopes by alanine-scanning mutagenesis and selection of functional SARS-CoV-2 S neutralization escape variants. Mechanistic studies showed that these antibodies neutralize in part by inhibiting a post-attachment step in the infection cycle. COV2-2676 and COV2-2489 offered protection either as prophylaxis or therapy, and Fc effector functions were required for optimal protection. Thus, natural infection induces a subset of potent NTD-specific mAbs that leverage neutralizing and Fc-mediated activities to protect against SARS-CoV-2 infection using multiple functional attributes.