N-terminal domain antigenic mapping reveals a site of vulnerability for SARS-CoV-2

Cell. 2021 Apr 29;184(9):2332-2347.e16. doi: 10.1016/j.cell.2021.03.028. Epub 2021 Mar 16.


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.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / chemistry
  • Antibodies, Monoclonal / immunology
  • Antibodies, Neutralizing / immunology
  • Antigens, Viral / immunology*
  • COVID-19 / immunology
  • COVID-19 / virology
  • Cricetinae
  • Epitope Mapping
  • Genetic Variation
  • Models, Molecular
  • Mutation / genetics
  • Neutralization Tests
  • Protein Domains
  • RNA, Viral / genetics
  • SARS-CoV-2 / immunology*
  • SARS-CoV-2 / isolation & purification
  • SARS-CoV-2 / ultrastructure


  • Antibodies, Monoclonal
  • Antibodies, Neutralizing
  • Antigens, Viral
  • RNA, Viral