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.; OConnell, 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.

doi:10.1101/2022.10.13.512134

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bioRxiv · 10.1101/2022.10.13.512134

Role of spike in the pathogenic and antigenic behavior of SARS-CoV-2 BA.1Omicron

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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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Chen, D.-Y., Kenney, D., Chin, C.-V., Tavares, A. H., Khan, N., Conway, H. L., Liu, G., Choudhary, M. C., Gertje, H. P., OConnell, 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.. 2022-10-14. Role of spike in the pathogenic and antigenic behavior of SARS-CoV-2 BA.1Omicron. https://doi.org/10.1101/2022.10.13.512134

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