Structural and functional ramifications of antigenic drift in recent SARS-CoV-2 variants

Yuan, M.; Huang, D.; Lee, C.-C. D.; Wu, N. C.; Jackson, A. M.; Zhu, X.; Liu, H.; Peng, L.; van Gils, M. J.; Sanders, R. W.; Burton, D. R.; Reincke, S. M.; Prüss, H.; Kreye, J.; Nemazee, D.; Ward, A. B.; Wilson, I. A.

doi:10.1101/2021.02.16.430500

bioRxiv · 10.1101/2021.02.16.430500

Structural and functional ramifications of antigenic drift in recent SARS-CoV-2 variants

Yuan, M.·Huang, D.·Lee, C.-C. D.·Wu, N. C.·Jackson, A. M.·Zhu, X.·Liu, H.·Peng, L.·van Gils, M. J.·Sanders, R. W.·Burton, D. R.·Reincke, S. M.·Prüss, H.·Kreye, J.·Nemazee, D.·Ward, A. B.·Wilson, I. A.

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Abstract

The protective efficacy of neutralizing antibodies (nAbs) elicited during natural infection with SARS-CoV-2 and by vaccination based on its spike protein has been compromised with emergence of the recent SARS-CoV-2 variants. Residues E484 and K417 in the receptor-binding site (RBS) are both mutated in lineages first described in South Africa (B.1.351) and Brazil (B.1.1.28.1). The nAbs isolated from SARS-CoV-2 patients are preferentially encoded by certain heavy-chain germline genes and the two most frequently elicited antibody families (IGHV3-53/3-66 and IGHV1-2) can each bind the RBS in two different binding modes. However, their binding and neutralization are abrogated by either the E484K or K417N mutation, whereas nAbs to the cross-reactive CR3022 and S309 sites are largely unaffected. This structural and functional analysis illustrates why mutations at E484 and K417 adversely affect major classes of nAbs to SARS-CoV-2 with consequences for next-generation COVID-19 vaccines.

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Yuan, M., Huang, D., Lee, C.-C. D., Wu, N. C., Jackson, A. M., Zhu, X., Liu, H., Peng, L., van Gils, M. J., Sanders, R. W., Burton, D. R., Reincke, S. M., Prüss, H., Kreye, J., Nemazee, D., Ward, A. B., Wilson, I. A.. 2021-02-17. Structural and functional ramifications of antigenic drift in recent SARS-CoV-2 variants. https://doi.org/10.1101/2021.02.16.430500

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