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, Rita E. Chen, Pei Yong Shi, Robert H. Carnahan, Larissa B. Thackray, Michael S. Diamond, James E. Crowe

Research output: Contribution to journalArticlepeer-review

234 Scopus citations


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.

Original languageEnglish
Pages (from-to)2316-2331.e15
Issue number9
StatePublished - Apr 29 2021


  • N-terminal domain
  • SARS-CoV-2
  • coronavirus
  • monoclonal antibodies
  • neutralizing antibodies
  • viral antibodies


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