A natural mutation between SARS-CoV-2 and SARS-CoV determines neutralization by a cross-reactive antibody

Wu, N. C.; Yuan, M.; Bangaru, S.; Huang, D.; Zhu, X.; Lee, C.-C. D.; Turner, H. L.; Peng, L.; Yang, L.; Nemazee, D.; Ward, A. B.; Wilson, I. A.

doi:10.1101/2020.09.21.305441

bioRxiv · 10.1101/2020.09.21.305441

A natural mutation between SARS-CoV-2 and SARS-CoV determines neutralization by a cross-reactive antibody

Wu, N. C.·Yuan, M.·Bangaru, S.·Huang, D.·Zhu, X.·Lee, C.-C. D.·Turner, H. L.·Peng, L.·Yang, L.·Nemazee, D.·Ward, A. B.·Wilson, I. A.

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Abstract

Epitopes that are conserved among SARS-like coronaviruses are attractive targets for design of cross-reactive vaccines and therapeutics. CR3022 is a SARS-CoV neutralizing antibody to a highly conserved epitope on the receptor binding domain (RBD) on the spike protein that can cross-react with SARS-CoV-2, but with lower affinity. Using x-ray crystallography, mutagenesis, and binding experiments, we illustrate that of four amino acid differences in the CR3022 epitope between SARS-CoV-2 and SARS-CoV, a single mutation P384A fully determines the affinity difference. CR3022 does not neutralize SARS-CoV-2, but the increased affinity to SARS-CoV-2 P384A mutant now enables neutralization with a similar potency to SARS-CoV. We further investigated CR3022 interaction with the SARS-CoV spike protein by negative-stain EM and cryo-EM. Three CR3022 Fabs bind per trimer with the RBD observed in different up-conformations due to considerable flexibility of the RBD. In one of these conformations, quaternary interactions are made by CR3022 to the N-terminal domain (NTD) of an adjacent subunit. Overall, this study provides insights into antigenic variation and potential for cross-neutralizing epitopes on SARS-like viruses.

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Wu, N. C., Yuan, M., Bangaru, S., Huang, D., Zhu, X., Lee, C.-C. D., Turner, H. L., Peng, L., Yang, L., Nemazee, D., Ward, A. B., Wilson, I. A.. 2020-09-21. A natural mutation between SARS-CoV-2 and SARS-CoV determines neutralization by a cross-reactive antibody. https://doi.org/10.1101/2020.09.21.305441

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