N-terminal domain antigenic mapping reveals a site of vulnerability for SARS-CoV-2
- PMID: 33761326
- PMCID: PMC7962585
- DOI: 10.1016/j.cell.2021.03.028
N-terminal domain antigenic mapping reveals a site of vulnerability for SARS-CoV-2
Abstract
The SARS-CoV-2 spike (S) glycoprotein contains an immunodominant receptor-binding domain (RBD) targeted by most neutralizing antibodies (Abs) in COVID-19 patient plasma. Little is known about neutralizing Abs binding to epitopes outside the RBD and their contribution to protection. Here, we describe 41 human monoclonal Abs (mAbs) derived from memory B cells, which recognize the SARS-CoV-2 S N-terminal domain (NTD) and show that a subset of them neutralize SARS-CoV-2 ultrapotently. We define an antigenic map of the SARS-CoV-2 NTD and identify a supersite (designated site i) recognized by all known NTD-specific neutralizing mAbs. These mAbs inhibit cell-to-cell fusion, activate effector functions, and protect Syrian hamsters from SARS-CoV-2 challenge, albeit selecting escape mutants in some animals. Indeed, several SARS-CoV-2 variants, including the B.1.1.7, B.1.351, and P.1 lineages, harbor frequent mutations within the NTD supersite, suggesting ongoing selective pressure and the importance of NTD-specific neutralizing mAbs for protective immunity and vaccine design.
Keywords: COVID-19; N-terminal domain; NTD; SARS-CoV-2; memory B cells; neutralizing antibody; spike glycoprotein.
Copyright © 2021 Elsevier Inc. All rights reserved.
Conflict of interest statement
Declaration of interests A.D.M., F.A.L., D.P., M.B., F.Z., J.d.I., M.M.-R., J.Z., L.E.R., S.B., B.G., C.S.F., F.B., E.C., G.S., A.T., H.W.V., D.C., and M.S.P. are employees of Vir Biotechnology Inc. and may hold shares in Vir Biotechnology Inc. D.C. is currently listed as an inventor on multiple patent applications, which disclose the subject matter described in this manuscript. The Neyts laboratories have received sponsored research agreements from Vir Biotechnology Inc. H.W.V. is a founder of PierianDx and Casma Therapeutics. Neither company provided funding for this work or is performing related work. D.V. is a consultant for Vir Biotechnology Inc. The Veesler laboratory has received a sponsored research agreement from Vir Biotechnology Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Update of
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N-terminal domain antigenic mapping reveals a site of vulnerability for SARS-CoV-2.bioRxiv [Preprint]. 2021 Jan 14:2021.01.14.426475. doi: 10.1101/2021.01.14.426475. bioRxiv. 2021. Update in: Cell. 2021 Apr 29;184(9):2332-2347.e16. doi: 10.1016/j.cell.2021.03.028. PMID: 33469588 Free PMC article. Updated. Preprint.
Comment in
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An NTD supersite of attack.Cell Host Microbe. 2021 May 12;29(5):744-746. doi: 10.1016/j.chom.2021.04.010. Cell Host Microbe. 2021. PMID: 33984277 Free PMC article.
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