Rational identification of potent and broad sarbecovirus-neutralizing antibody cocktails from SARS convalescents

Cao, Y. R.; Jian, F.; Zhang, Z.; Yisimayi, A.; Hao, X.; Bao, L.; Yuan, F.; Yu, Y.; Du, S.; Wang, J.; Xiao, T.; Song, W.; Zhang, Y.; Liu, P.; An, R.; Wang, P.; Wang, Y.; Yang, S.; Niu, X.; Gu, Q.; Shao, F.; Hu, Y.; Yin, W.; Zheng, A.; Qin, C.; Jin, R.; Xiao, J.; Xie, X. S.

doi:10.1101/2022.08.03.499114

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bioRxiv · 10.1101/2022.08.03.499114

Rational identification of potent and broad sarbecovirus-neutralizing antibody cocktails from SARS convalescents

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Abstract

SARS-CoV-2 Omicron sublineages have escaped most RBD-targeting therapeutic neutralizing antibodies (NAbs), which proves the previous NAb drug screening strategies deficient against the fast-evolving SARS-CoV-2. Better broad NAb drug candidate selection methods are needed. Here, we describe a rational approach for identifying RBD-targeting broad SARS-CoV-2 NAb cocktails. Based on high-throughput epitope determination, we propose that broad NAb drugs should target non-immunodominant RBD epitopes to avoid herd immunity-directed escape mutations. Also, their interacting antigen residues should focus on sarbecovirus conserved sites and associate with critical viral functions, making the antibody-escaping mutations less likely to appear. Following the criteria, a featured non-competing antibody cocktail, SA55+SA58, is identified from a large collection of broad sarbecovirus NAbs isolated from SARS convalescents. SA55+SA58 potently neutralizes ACE2-utilizing sarbecoviruses, including circulating Omicron variants, and could serve as broad SARS-CoV-2 prophylactics to offer long-term protection. Our screening strategy can also be applied to identify broad-spectrum NAb drugs against other fast-evolving viruses, such as influenza viruses.

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Cao, Y. R., Jian, F., Zhang, Z., Yisimayi, A., Hao, X., Bao, L., Yuan, F., Yu, Y., Du, S., Wang, J., Xiao, T., Song, W., Zhang, Y., Liu, P., An, R., Wang, P., Wang, Y., Yang, S., Niu, X., Gu, Q., Shao, F., Hu, Y., Yin, W., Zheng, A., Qin, C., Jin, R., Xiao, J., Xie, X. S.. 2022-08-04. Rational identification of potent and broad sarbecovirus-neutralizing antibody cocktails from SARS convalescents. https://doi.org/10.1101/2022.08.03.499114

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