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

• DOI: 10.1016/j.celrep.2022.111845
• Publication Date: 2022-12-01T12:35:49Z
• Authors: Yunlong Cao; Fanchong Jian; Zhiying Zhang; Ayijiang Yisimayi; Xiaohua Hao; Linlin Bao; Fei Yuan; Yuanling Yu; Shuo Du; Jing Wang; Tianhe Xiao; Weiliang Song; Ying Zhang; Pulan Liu; Ran An; Peng Wang; Yao Wang; Sijie Yang; Xiao Niu; Yuhang Zhang; Qingqing Gu; Fei Shao; Yaling Hu; Weidong Yin; Aihua Zheng; Youchun Wang; Chuan Qin; Ronghua Jin; Junyu Xiao; Xiaoliang Sunney Xie
• Keywords: 0301 basic medicine; 0303 health sciences; SARS-CoV-2; COVID-19; Combined Antibody Therapeutics; Antibodies, Viral; Antibodies, Neutralizing; Article; 3. Good health; Epitopes; 03 medical and health sciences; Severe acute respiratory syndrome-related coronavirus; Humans; Broadly Neutralizing Antibodies

AbstractSARS-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.