• 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, Rita E Chen, Pei-Yong Shi, Robert H Carnahan, Larissa B Thackray, Michael S Diamond, and James E Crowe.
• Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
• Cell. 2021 Apr 29; 184 (9): 2316-2331.e15.

AbstractMost 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.Copyright © 2021 Elsevier Inc. All rights reserved.

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