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

• Published in: Cell reports (Cambridge) Vol. 41; no. 12; p. 111845
• Main Authors: Cao, Yunlong, Jian, Fanchong, Zhang, Zhiying, Yisimayi, Ayijiang, Hao, Xiaohua, Bao, Linlin, Yuan, Fei, Yu, Yuanling, Du, Shuo, Wang, Jing, Xiao, Tianhe, Song, Weiliang, Zhang, Ying, Liu, Pulan, An, Ran, Wang, Peng, Wang, Yao, Yang, Sijie, Niu, Xiao, Zhang, Yuhang, Gu, Qingqing, Shao, Fei, Hu, Yaling, Yin, Weidong, Zheng, Aihua, Wang, Youchun, Qin, Chuan, Jin, Ronghua, Xiao, Junyu, Xie, Xiaoliang Sunney
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.12.2022; Cell Press
• Subjects: Antibodies, Neutralizing; Antibodies, Viral; antibody; broad-spectrum; Broadly Neutralizing Antibodies; cocktail; Combined Antibody Therapeutics; COVID-19; Epitopes; Humans; omicron; prophylactics; sarbecovirus; SARS-CoV-2; Severe acute respiratory syndrome-related coronavirus; CP: Immunology; SARS-CoV-2; omicron; antibody; cocktail; broad-spectrum; CP: Microbiology; prophylactics; sarbecovirus
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.111845

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron sublineages have escaped most receptor-binding domain (RBD)-targeting therapeutic neutralizing antibodies (NAbs), which proves that previous NAb drug screening strategies are 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 these criteria, a featured non-competing antibody cocktail, SA55+SA58, is identified from a large collection of broad sarbecovirus NAbs isolated from SARS-CoV-2-vaccinated 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, especially for individuals who are immunocompromised or with high-risk comorbidities. [Display omitted] •A rational strategy helps identify broad SARS-CoV-2 NAbs that are hard to evade•Broad NAbs from SARS-CoV-2-vaccinated SARS convalescents form non-competing cocktail•SA55+SA58 broadly and potently neutralizes SARS-CoV-2 variants and sarbecoviruses•SA55+SA58 tolerates escape mutations and protects mice from BA.1 and BA.5 infection Cao et al. describe a strategy to identify a broad sarbecovirus-neutralizing antibody cocktail that would be hard to escape for future SARS-CoV-2 variants using high-throughput epitope mapping. The resulting antibody cocktail, named SA55+SA58, exhibits high neutralizing potency and breadth against ACE2-utilizing sarbecoviruses and efficiently protects mice from BA.1 and BA.5 infection.