Antibody escape and cryptic cross-domain stabilization in the SARS-CoV-2 Omicron spike protein

Cell Host Microbe. 2022 Sep 14;30(9):1242-1254.e6. doi: 10.1016/j.chom.2022.07.016. Epub 2022 Aug 4.


The worldwide spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to the repeated emergence of variants of concern. For the Omicron variant, sub-lineages BA.1 and BA.2, respectively, contain 33 and 29 nonsynonymous and indel spike protein mutations. These amino acid substitutions and indels are implicated in increased transmissibility and enhanced immune evasion. By reverting individual spike mutations of BA.1 or BA.2, we characterize the molecular effects of the Omicron spike mutations on expression, ACE2 receptor affinity, and neutralizing antibody recognition. We identified key mutations enabling escape from neutralizing antibodies at a variety of epitopes. Stabilizing mutations in the N-terminal and S2 domains of the spike protein can compensate for destabilizing mutations in the receptor binding domain, enabling the record number of mutations in Omicron. Our results provide a comprehensive account of the mutational effects in the Omicron spike protein and illustrate previously uncharacterized mechanisms of host evasion.

Keywords: COVID-19; VOCs; cell display; flow cytometry; high throughput; viral glycoprotein.

MeSH terms

  • Angiotensin-Converting Enzyme 2 / genetics
  • Antibodies, Neutralizing / genetics
  • Antibodies, Viral
  • COVID-19*
  • Epitopes
  • Humans
  • Membrane Glycoproteins
  • Mutation
  • SARS-CoV-2 / genetics
  • Spike Glycoprotein, Coronavirus* / genetics
  • Viral Envelope Proteins


  • Antibodies, Neutralizing
  • Antibodies, Viral
  • Epitopes
  • Membrane Glycoproteins
  • Spike Glycoprotein, Coronavirus
  • Viral Envelope Proteins
  • spike protein, SARS-CoV-2
  • Angiotensin-Converting Enzyme 2

Supplementary concepts

  • SARS-CoV-2 variants