Antibodies that neutralize all current SARS-CoV-2 variants of concern by conformational locking

Liu, L.; Casner, R. G.; Guo, Y.; Wang, Q.; Iketani, S.; Chan, J. F.-W.; Yu, J.; Dadonaite, B.; Nair, M. S.; Mohri, H.; Reddem, E. R.; Yuan, S.; Poon, V. K.-M.; Chan, C. C.-S.; Yuen, K.-Y.; Sheng, Z.; Huang, Y.; Bloom, J. D.; Shapiro, L.; Ho, D. D.

doi:10.1101/2023.04.08.536123

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bioRxiv · 10.1101/2023.04.08.536123

Antibodies that neutralize all current SARS-CoV-2 variants of concern by conformational locking

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Abstract

SARS-CoV-2 continues to evolve and evade most existing neutralizing antibodies, including all clinically authorized antibodies. We have isolated and characterized two human monoclonal antibodies, 12-16 and 12-19, which exhibited neutralizing activities against all SARS-CoV-2 variants tested, including BQ.1.1 and XBB.1.5. They also blocked infection in hamsters challenged with Omicron BA.1 intranasally. Structural analyses revealed both antibodies targeted a conserved quaternary epitope located at the interface between the N-terminal domain and subdomain 1, revealing a previously unrecognized site of vulnerability on SARS-CoV-2 spike. These antibodies prevent viral receptor engagement by locking the receptor-binding domain of spike in the down conformation, revealing a novel mechanism of virus neutralization for non-RBD antibodies. Deep mutational scanning showed that SARS-CoV-2 could mutate to escape 12-19, but the responsible mutations are rarely found in circulating viruses. Antibodies 12-16 and 12-19 hold promise as prophylactic agents for immunocompromised persons who do not respond robustly to COVID-19 vaccines.

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Liu, L., Casner, R. G., Guo, Y., Wang, Q., Iketani, S., Chan, J. F.-W., Yu, J., Dadonaite, B., Nair, M. S., Mohri, H., Reddem, E. R., Yuan, S., Poon, V. K.-M., Chan, C. C.-S., Yuen, K.-Y., Sheng, Z., Huang, Y., Bloom, J. D., Shapiro, L., Ho, D. D.. 2023-04-10. Antibodies that neutralize all current SARS-CoV-2 variants of concern by conformational locking. https://doi.org/10.1101/2023.04.08.536123

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