The spike gene is a major determinant for the SARS-CoV-2 Omicron-BA.1 phenotype

Nat Commun. 2022 Oct 7;13(1):5929. doi: 10.1038/s41467-022-33632-y.


Variant of concern (VOC) Omicron-BA.1 has achieved global predominance in early 2022. Therefore, surveillance and comprehensive characterization of Omicron-BA.1 in advanced primary cell culture systems and animal models are urgently needed. Here, we characterize Omicron-BA.1 and recombinant Omicron-BA.1 spike gene mutants in comparison with VOC Delta in well-differentiated primary human nasal and bronchial epithelial cells in vitro, followed by in vivo fitness characterization in hamsters, ferrets and hACE2-expressing mice, and immunized hACE2-mice. We demonstrate a spike-mediated enhancement of early replication of Omicron-BA.1 in nasal epithelial cultures, but limited replication in bronchial epithelial cultures. In hamsters, Delta shows dominance over Omicron-BA.1, and in ferrets Omicron-BA.1 infection is abortive. In hACE2-knock-in mice, Delta and a Delta spike clone also show dominance over Omicron-BA.1 and an Omicron-BA.1 spike clone, respectively. Interestingly, in naïve K18-hACE2 mice, we observe Delta spike-mediated increased replication and pathogenicity and Omicron-BA.1 spike-mediated reduced replication and pathogenicity, suggesting that the spike gene is a major determinant of replication and pathogenicity. Finally, the Omicron-BA.1 spike clone is less well-controlled by mRNA-vaccination in K18-hACE2-mice and becomes more competitive compared to the progenitor and Delta spike clones, suggesting that spike gene-mediated immune evasion is another important factor that led to Omicron-BA.1 dominance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COVID-19*
  • Cricetinae
  • Ferrets
  • Humans
  • Melphalan
  • Mice
  • Phenotype
  • RNA, Messenger
  • SARS-CoV-2* / genetics
  • Spike Glycoprotein, Coronavirus / genetics
  • gamma-Globulins


  • K-18 conjugate
  • RNA, Messenger
  • Spike Glycoprotein, Coronavirus
  • gamma-Globulins
  • spike protein, SARS-CoV-2
  • Melphalan