An antibody targeting the N-terminal domain of SARS-CoV-2 disrupts the spike trimer

Naveenchandra Suryadevara, Andrea R. Shiakolas, Laura A. VanBlargan, Elad Binshtein, Rita E. Chen, James Brett Case, Kevin J. Kramer, Erica C. Armstrong, Luke Myers, Andrew Trivette, Christopher Gainza, Rachel S. Nargi, Christopher N. Selverian, Edgar Davidson, Benjamin J. Doranz, Summer M. Diaz, Laura S. Handal, Robert H. Carnahan, Michael S. Diamond, Ivelin S. GeorgievJames E. Crowe

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

The protective human antibody response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) focuses on the spike (S) protein, which decorates the virion surface and mediates cell binding and entry. Most SARS-CoV-2 protective antibodies target the receptor-binding domain or a single dominant epitope (“supersite”) on the N-terminal domain (NTD). Using the single B cell technology called linking B cell receptor to antigen specificity through sequencing (LIBRA-Seq), we isolated a large panel of NTD-reactive and SARS-CoV-2–neutralizing antibodies from an individual who had recovered from COVID-19. We found that neutralizing antibodies against the NTD supersite were commonly encoded by the IGHV1-24 gene, forming a genetic cluster representing a public B cell clonotype. However, we also discovered a rare human antibody, COV2-3434, that recognizes a site of vulnerability on the SARS-CoV-2 S protein in the trimer interface (TI) and possesses a distinct class of functional activity. COV2-3434 disrupted the integrity of S protein trimers, inhibited the cell-to-cell spread of the virus in culture, and conferred protection in human angiotensin-converting enzyme 2–transgenic (ACE2-transgenic) mice against the SARS-CoV-2 challenge. This study provides insight into antibody targeting of the S protein TI region, suggesting this region may be a site of virus vulnerability.

Original languageEnglish
Article numbere159062
JournalJournal of Clinical Investigation
Volume132
Issue number11
DOIs
StatePublished - Jun 1 2022

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