Immunizations with diverse sarbecovirus receptor-binding domains elicit SARS-CoV-2 neutralizing antibodies against a conserved site of vulnerability

Immunity. 2021 Dec 14;54(12):2908-2921.e6. doi: 10.1016/j.immuni.2021.10.019. Epub 2021 Oct 29.


Viral mutations are an emerging concern in reducing SARS-CoV-2 vaccination efficacy. Second-generation vaccines will need to elicit neutralizing antibodies against sites that are evolutionarily conserved across the sarbecovirus subgenus. Here, we immunized mice containing a human antibody repertoire with diverse sarbecovirus receptor-binding domains (RBDs) to identify antibodies targeting conserved sites of vulnerability. Antibodies with broad reactivity against diverse clade B RBDs targeting the conserved class 4 epitope, with recurring IGHV/IGKV pairs, were readily elicited but were non-neutralizing. However, rare class 4 antibodies binding this conserved RBD supersite showed potent neutralization of SARS-CoV-2 and all variants of concern. Structural analysis revealed that the neutralizing ability of cross-reactive antibodies was reserved only for those with an elongated CDRH3 that extends the antiparallel beta-sheet RBD core and orients the antibody light chain to obstruct ACE2-RBD interactions. These results identify a structurally defined pathway for vaccine strategies eliciting escape-resistant SARS-CoV-2 neutralizing antibodies.

Keywords: SARS-CoV-2; antigenic variation; class 4 epitope site; cross-reactivity; epitope conservation; escape mutations; human antibodies; mouse model; neutralization; next generation vaccines; variants of concern.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Neutralizing / metabolism
  • Antibodies, Viral / metabolism
  • Betacoronavirus / physiology*
  • COVID-19 Vaccines / immunology*
  • Conserved Sequence / genetics
  • Coronavirus Infections / immunology*
  • Evolution, Molecular
  • Humans
  • Immunization
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Protein Binding
  • Protein Domains / genetics
  • Severe acute respiratory syndrome-related coronavirus / physiology*
  • Spike Glycoprotein, Coronavirus / genetics
  • Spike Glycoprotein, Coronavirus / immunology
  • Spike Glycoprotein, Coronavirus / metabolism*
  • Vaccine Development


  • Antibodies, Neutralizing
  • Antibodies, Viral
  • COVID-19 Vaccines
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2