Identification of a broad sarbecovirus neutralizing antibody targeting a conserved epitope on the receptor-binding domain
Yanqun Wang, Zhaoyong Zhang, Minnan Yang, Xinyi Xiong, Qihong Yan, Lei Cao, Peilan Wei, Yuting Zhang, Lu Zhang, Kexin Lv, Jiantao Chen, Xuesong Liu, Xuesong Liu, Xiaochu Zhao, Juxue Xiao, Shengnan Zhang, Airu Zhu, Mian Gan, Jingjun Zhang, Ruoxi Cai, Jianfen Zhuo, Yanjun Zhang, Haiyue Rao, Bin Qu, Yuanyuan Zhang, Lei Chen, Jun Dai, Linling Cheng, Qing‐Tao Hu, Yao-Qing Chen, Huibin Lv, Ray T. Y. So, Malik Peiris, Jingxian Zhao, Jingxian Zhao, Xiaoqing Liu, Xiaoqing Liu, Chris Ka Pun Mok, Xiangxi Wang, Jincun Zhao, Jincun Zhao
Abstract
Omicron, as the emerging variant with enhanced vaccine tolerance, has sharply disrupted most therapeutic antibodies. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) belongs to the subgenus Sarbecovirus, members of which share high sequence similarity. Herein, we report one sarbecovirus antibody, 5817, which has broad-spectrum neutralization capacity against SARS-CoV-2 variants of concern (VOCs) and SARS-CoV, as well as related bat and pangolin viruses. 5817 can hardly compete with six classes of receptor-binding-domain-targeted antibodies grouped by structural classifications. No obvious impairment in the potency is detected against SARS-CoV-2 Omicron and subvariants. The cryoelectron microscopy (cryo-EM) structure of neutralizing antibody 5817 in complex with Omicron spike reveals a highly conserved epitope, only existing at the receptor-binding domain (RBD) open state. Prophylactic and therapeutic administration of 5817 potently protects mice from SARS-CoV-2 Beta, Delta, Omicron, and SARS-CoV infection. This study reveals a highly conserved cryptic epitope targeted by a broad sarbecovirus neutralizing antibody, which would be beneficial to meet the potential threat of pre-emergent SARS-CoV-2 VOCs.