The spike gene is a major determinant for the SARS-CoV-2 Omicron-BA.1 phenotype
Abstract
Variant of concern (VOC) Omicron-BA1 has achieved global predominance in early 2022. Therefore, surveillance and comprehensive characterization of Omicron-BA.1 in advanced primary cell culture systems and multiple animal models is urgently needed. Here, we characterized 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 naïve hamsters, ferrets and hACE2-expressing mice, and in 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 Syrian hamsters, Delta showed dominance over Omicron-BA.1 and in ferrets, Omicron-BA.1 infection was abortive. In mice expressing the authentic hACE2-receptor, Delta and a Delta spike clone also showed dominance over Omicron-BA.1 and an Omicron-BA.1 spike clone, respectively. Interestingly, in naïve K18-hACE2 mice, we observed 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 both Delta and Omicron-BA.1 replication and pathogenicity. Finally, the Omicron-BA.1 spike clone was less well controlled by mRNA-vaccination in K18-hACE2-mice and became 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.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
↵† These authors contributed equally to this work.
‡ These authors jointly lead this work.
Subject Area
- Biochemistry (11755)
- Bioengineering (8757)
- Bioinformatics (29209)
- Biophysics (14980)
- Cancer Biology (12103)
- Cell Biology (17416)
- Clinical Trials (138)
- Developmental Biology (9425)
- Ecology (14187)
- Epidemiology (2067)
- Evolutionary Biology (18314)
- Genetics (12246)
- Genomics (16807)
- Immunology (11870)
- Microbiology (28101)
- Molecular Biology (11599)
- Neuroscience (60995)
- Paleontology (452)
- Pathology (1872)
- Pharmacology and Toxicology (3238)
- Physiology (4961)
- Plant Biology (10429)
- Synthetic Biology (2887)
- Systems Biology (7341)
- Zoology (1651)