Journal
CELL
Volume 184, Issue 9, Pages 2316-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2021.03.029
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Funding
- NIAID/NIH [T32 AI095202, T32 AI007163, R01 AI157155]
- HHSN [75N93019C00074, 75N93019C00073]
- DARPA [HR0011-18-2-0001]
- Dolly Parton COVID-19 Research Fund at Vanderbilt University Medical Center
- Mercatus Center, George Mason University
- Merck KGaA
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The study found that a subset of human monoclonal antibodies derived from convalescent SARS-CoV-2 patients possess neutralizing activity, with two antibodies capable of inhibiting infection. Mechanistic studies revealed these antibodies neutralize in part by inhibiting post-attachment steps in the infection cycle.
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.
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