Broadly neutralizing and protective nanobodies against SARS-CoV-2 Omicron subvariants BA.1, BA.2, and BA.4/5 and diverse sarbecoviruses
Mingxi Li, Yifei Ren, Zhen Qin Aw, Bo Chen, Ziqing Yang, Yuqing Lei, Lin Cheng, Qingtai Liang, Junxian Hong, Yiling Yang, Jing Chen, Yi Hao Wong, Jing Wei, Sisi Shan, Senyan Zhang, Jiwan Ge, Ruoke Wang, Jay Zengjun Dong, Yuxing Chen, Xuanling Shi, Qi Zhang, Zheng Zhang, Justin Jang Hann Chu, Xinquan Wang, Linqi Zhang
Abstract
As SARS-CoV-2 Omicron and other variants of concern (VOCs) continue spreading worldwide, development of antibodies and vaccines to confer broad and protective activity is a global priority. Here, we report on the identification of a special group of nanobodies from immunized alpaca with potency against diverse VOCs including Omicron subvariants BA.1, BA.2 and BA.4/5, SARS-CoV-1, and major sarbecoviruses. Crystal structure analysis of one representative nanobody, 3-2A2-4, discovers a highly conserved epitope located between the cryptic and the outer face of the receptor binding domain (RBD), distinctive from the receptor ACE2 binding site. Cryo-EM and biochemical evaluation reveal that 3-2A2-4 interferes structural alteration of RBD required for ACE2 binding. Passive delivery of 3-2A2-4 protects K18-hACE2 mice from infection of authentic SARS-CoV-2 Delta and Omicron. Identification of these unique nanobodies will inform the development of next generation antibody therapies and design of pan-sarbecovirus vaccines.