Cryptic-site-specific antibodies to the SARS-CoV-2 receptor binding domain can retain functional binding affinity to spike variants

J Virol. 2023 Dec 21;97(12):e0107023. doi: 10.1128/jvi.01070-23. Epub 2023 Nov 29.


Multiple SARS-CoV-2 variants of concern have emerged and caused a significant number of infections and deaths worldwide. These variants of concern contain mutations that might significantly affect antigen-targeting by antibodies. It is therefore important to further understand how antibody binding and neutralization are affected by the mutations in SARS-CoV-2 variants. We highlighted how antibody epitope specificity can influence antibody binding to SARS-CoV-2 spike protein variants and neutralization of SARS-CoV-2 variants. We showed that weakened spike binding and neutralization of Beta (B.1.351) and Omicron (BA.1) variants compared to wildtype are not universal among the panel of antibodies and identified antibodies of a specific binding footprint exhibiting consistent enhancement of spike binding and retained neutralization to Beta variant. These data and analysis can inform how antigen-targeting by antibodies might evolve during a pandemic and prepare for potential future sarbecovirus outbreaks.

Keywords: ACE-2 blocking; COVID-19; RBD; SARS-CoV-2; binding kinetics; biolayer interferometry; epitope binning; monoclonal antibodies; neutralizing antibodies; surface plasmon resonance.

MeSH terms

  • Antibodies, Neutralizing* / chemistry
  • Antibodies, Neutralizing* / immunology
  • Antibodies, Neutralizing* / metabolism
  • Antibodies, Viral* / chemistry
  • Antibodies, Viral* / immunology
  • Antibodies, Viral* / metabolism
  • COVID-19
  • Humans
  • SARS-CoV-2* / genetics
  • Severe acute respiratory syndrome-related coronavirus
  • Spike Glycoprotein, Coronavirus* / chemistry
  • Spike Glycoprotein, Coronavirus* / metabolism


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

Supplementary concepts

  • SARS-CoV-2 variants