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

Kamyab Javanmardi, Thomas H. Segall-Shapiro, Chia Wei Chou, Daniel R. Boutz, Randall J. Olsen, Xuping Xie, Hongjie Xia, Pei Yong Shi, Charlie D. Johnson, Ankur Annapareddy, Scott Weaver, James M. Musser, Andrew D. Ellington, Ilya J. Finkelstein, Jimmy D. Gollihar

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1242-1254.e6
JournalCell Host and Microbe
Issue number9
StatePublished - Sep 14 2022


  • COVID-19
  • VOCs
  • cell display
  • flow cytometry
  • high throughput
  • viral glycoprotein
  • SARS-CoV-2/genetics
  • Antibodies, Neutralizing/genetics
  • Humans
  • Viral Envelope Proteins
  • Epitopes
  • Antibodies, Viral
  • Angiotensin-Converting Enzyme 2/genetics
  • Spike Glycoprotein, Coronavirus/genetics
  • Membrane Glycoproteins
  • Mutation

ASJC Scopus subject areas

  • Virology
  • Parasitology
  • Microbiology


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