Role of spike in the pathogenic and antigenic behavior of SARS-CoV-2 BA.1Omicron
Chen, D.-Y.; Kenney, D.; Chin, C.-V.; Tavares, A. H.; Khan, N.; Conway, H. L.; Liu, G.; Choudhary, M. C.; Gertje, H. P.; O'Connell, A. K.; Kotton, D. N.; Herrmann, A.; Ensser, A.; Connor, J. H.; Bosmann, M.; Li, J. Z.; Gack, M. U.; Baker, S. C.; Kirchdoerfer, R. N.; Kataria, Y.; Crossland, N. A.; Douam, F.; Saeed, M.
Show abstract
The recently identified, globally predominant SARS-CoV-2 Omicron variant (BA.1) is highly transmissible, even in fully vaccinated individuals, and causes attenuated disease compared with other major viral variants recognized to date1-7. The Omicron spike (S) protein, with an unusually large number of mutations, is considered the major driver of these phenotypes3,8. We generated chimeric recombinant SARS-CoV-2 encoding the S gene of Omicron in the backbone of an ancestral SARS-CoV-2 isolate and compared this virus with the naturally circulating Omicron variant. The Omicron S-bearing virus robustly escapes vaccine-induced humoral immunity, mainly due to mutations in the receptor-binding motif (RBM), yet unlike naturally occurring Omicron, efficiently replicates in cell lines and primary-like distal lung cells. In K18-hACE2 mice, while Omicron causes mild, non-fatal infection, the Omicron S-carrying virus inflicts severe disease with a mortality rate of 80%. This indicates that while the vaccine escape of Omicron is defined by mutations in S, major determinants of viral pathogenicity reside outside of S.
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