Site of vulnerability on SARS-CoV-2 spike induces broadly protective antibody to antigenically distinct omicron SARS-CoV-2 subvariants

Changrob, S.; Halfmann, P. J.; Liu, H.; Torres, J. L.; McGrath, J. J. C.; Ozorowski, G.; Li, L.; Kuroda, M.; Maemura, T.; Huang, M.; Wilbanks, D. G.; Zheng, N.-Y.; Turner, H. L.; Erickson, S. A.; Fu, Y.; Singh, G.; Krammer, F.; Sather, D. N.; Ward, A. B.; Wilson, I. A.; Kawaoka, Y.; Wilson, P. C.

doi:10.1101/2022.10.31.514592

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bioRxiv · 10.1101/2022.10.31.514592

Site of vulnerability on SARS-CoV-2 spike induces broadly protective antibody to antigenically distinct omicron SARS-CoV-2 subvariants

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Abstract

The rapid evolution of SARS-CoV-2 Omicron variants has emphasized the need to identify antibodies with broad neutralizing capabilities to inform future monoclonal therapies and vaccination strategies. Herein, we identify S728-1157, a broadly neutralizing antibody (bnAb) targeting the receptor-binding site (RBS) and derived from an individual previously infected with SARS-CoV-2 prior to the spread of variants of concern (VOCs). S728-1157 demonstrates broad cross-neutralization of all dominant variants including D614G, Beta, Delta, Kappa, Mu, and Omicron (BA.1/BA.2/BA.2.75/BA.4/BA.5/BL.1). Furthermore, it protected hamsters against in vivo challenges with wildtype, Delta, and BA.1 viruses. Structural analysis reveals that this antibody targets a class 1 epitope via multiple hydrophobic and polar interactions with its CDR-H3, in addition to common class 1 motifs in CDR-H1/CDR-H2. Importantly, this epitope is more readily accessible in the open and prefusion state, or in the hexaproline (6P)-stabilized spike constructs, as compared to diproline (2P) constructs. Overall, S728-1157 demonstrates broad therapeutic potential, and may inform target-driven vaccine design against future SARS-CoV-2 variants.

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Changrob, S., Halfmann, P. J., Liu, H., Torres, J. L., McGrath, J. J. C., Ozorowski, G., Li, L., Kuroda, M., Maemura, T., Huang, M., Wilbanks, D. G., Zheng, N.-Y., Turner, H. L., Erickson, S. A., Fu, Y., Singh, G., Krammer, F., Sather, D. N., Ward, A. B., Wilson, I. A., Kawaoka, Y., Wilson, P. C.. 2022-11-01. Site of vulnerability on SARS-CoV-2 spike induces broadly protective antibody to antigenically distinct omicron SARS-CoV-2 subvariants. https://doi.org/10.1101/2022.10.31.514592

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