Vaccine-elicited murine antibody WS6 neutralizes diverse beta-coronaviruses by recognizing a helical stem supersite of vulnerability

Shi, W.; Wang, L.; Zhou, T.; Sastry, M.; Yang, E. S.; Zhang, Y.; Chen, M.; Chen, X.; Choe, M.; Creanga, A.; Leung, K.; Olia, A. S.; Pegu, A.; Rawi, R.; Shen, C.-H.; Stancofski, E.-S. D.; Talana, C. A.; Teng, I.-T.; Wang, S.; Corbett, K. S.; Tsybovsky, Y.; Mascola, J. R.; Kwong, P. D.

doi:10.1101/2022.01.25.477770

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bioRxiv · 10.1101/2022.01.25.477770

Vaccine-elicited murine antibody WS6 neutralizes diverse beta-coronaviruses by recognizing a helical stem supersite of vulnerability

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Abstract

Immunization with SARS-CoV-2 spike elicits diverse antibodies, but can any of these neutralize broadly? Here, we report the isolation and characterization of antibody WS6, from a mouse immunized with mRNA encoding the SARS-CoV-2 spike. WS6 bound diverse beta-coronavirus spikes and neutralized SARS-CoV-2 variants, SARS-CoV, and related sarbecoviruses. Epitope mapping revealed WS6 to target a region in the S2 subunit, which was conserved among SARS-CoV-2, MERS-CoV, and hCoV-OC43. The crystal structure at 2-[A] resolution of WS6 with its S2 epitope revealed recognition to center on a conserved helix, which was occluded in both prefusion and post-fusion spike conformations. Structural and neutralization analyses indicated WS6 to neutralize by inhibiting fusion, post-viral attachment. Comparison of WS6 to other antibodies recently identified from convalescent donors or mice immunized with diverse spikes indicated a stem-helical supersite - centered on hydrophobic residues Phe1148, Leu1152, Tyr1155, and Phe1156 - to be a promising target for vaccine design. HighlightsO_LISARS-CoV-2 spike mRNA-immunized mouse elicited an antibody, WS6, that cross reacts with spikes of diverse human and bat beta-coronaviruses C_LIO_LIWS6 neutralizes SARS-CoV-2 variants, SARS-CoV, and related viruses C_LIO_LICrystal structure at 2-[A] resolution of WS6 in complex with a conserved S2 peptide reveals recognition of a helical epitope C_LIO_LIWS6 neutralizes by inhibition of fusion, post-viral attachment C_LIO_LIWS6 recognizes a supersite of vulnerability also recognized by other recently identified antibodies C_LIO_LIHelical supersite of vulnerability comprises a hydrophobic cluster spanning three helical turns, with acid residues framing the center turn C_LIO_LIGenetic and structural analysis indicate supersite recognition to be compatible with diverse antibody ontogenies C_LI

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Shi, W., Wang, L., Zhou, T., Sastry, M., Yang, E. S., Zhang, Y., Chen, M., Chen, X., Choe, M., Creanga, A., Leung, K., Olia, A. S., Pegu, A., Rawi, R., Shen, C.-H., Stancofski, E.-S. D., Talana, C. A., Teng, I.-T., Wang, S., Corbett, K. S., Tsybovsky, Y., Mascola, J. R., Kwong, P. D.. 2022-01-26. Vaccine-elicited murine antibody WS6 neutralizes diverse beta-coronaviruses by recognizing a helical stem supersite of vulnerability. https://doi.org/10.1101/2022.01.25.477770

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