Cross-Neutralization of a SARS-CoV-2 Antibody to a Functionally Conserved Site Is Mediated by Avidity

Immunity. 2020 Dec 15;53(6):1272-1280.e5. doi: 10.1016/j.immuni.2020.10.023. Epub 2020 Nov 25.


Most antibodies isolated from individuals with coronavirus disease 2019 (COVID-19) are specific to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, COVA1-16 is a relatively rare antibody that also cross-neutralizes SARS-CoV. Here, we determined a crystal structure of the COVA1-16 antibody fragment (Fab) with the SARS-CoV-2 receptor-binding domain (RBD) and negative-stain electron microscopy reconstructions with the spike glycoprotein trimer to elucidate the structural basis of its cross-reactivity. COVA1-16 binds a highly conserved epitope on the SARS-CoV-2 RBD, mainly through a long complementarity-determining region (CDR) H3, and competes with the angiotensin-converting enzyme 2 (ACE2) receptor because of steric hindrance rather than epitope overlap. COVA1-16 binds to a flexible up conformation of the RBD on the spike and relies on antibody avidity for neutralization. These findings, along with the structural and functional rationale for epitope conservation, provide insights for development of more universal SARS-like coronavirus vaccines and therapies.

MeSH terms

  • Angiotensin-Converting Enzyme 2 / metabolism*
  • Antibodies, Viral / genetics
  • Antibodies, Viral / metabolism*
  • Broadly Neutralizing Antibodies / genetics
  • Broadly Neutralizing Antibodies / metabolism
  • COVID-19 / immunology*
  • COVID-19 Vaccines / immunology*
  • Conserved Sequence / genetics
  • Cross Reactions
  • Crystallization
  • Epitope Mapping
  • Epitopes, B-Lymphocyte / genetics
  • Epitopes, B-Lymphocyte / metabolism
  • Humans
  • Immunoglobulin Fab Fragments / genetics
  • Immunoglobulin Fab Fragments / metabolism
  • Protein Binding
  • Protein Conformation
  • Protein Interaction Domains and Motifs / genetics
  • SARS Virus / immunology*
  • SARS-CoV-2 / immunology*


  • Antibodies, Viral
  • Broadly Neutralizing Antibodies
  • COVID-19 Vaccines
  • Epitopes, B-Lymphocyte
  • Immunoglobulin Fab Fragments
  • Angiotensin-Converting Enzyme 2