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 () and Linqi Zhang ()
Additional contact information
Mingxi Li: Tsinghua University
Yifei Ren: Tsinghua University
Zhen Qin Aw: National University of Singapore
Bo Chen: NB BIOLAB Co., Ltd
Ziqing Yang: Tsinghua University
Yuqing Lei: Tsinghua University
Lin Cheng: Shenzhen Third People’s Hospital
Qingtai Liang: Tsinghua University
Junxian Hong: Tsinghua University
Yiling Yang: Tsinghua University
Jing Chen: Tsinghua University
Yi Hao Wong: National University of Singapore
Jing Wei: Tsinghua University
Sisi Shan: Tsinghua University
Senyan Zhang: Tsinghua University
Jiwan Ge: Tsinghua University
Ruoke Wang: Tsinghua University
Jay Zengjun Dong: HplanetBio Co., Ltd
Yuxing Chen: Hua Bio Co., Ltd
Xuanling Shi: Tsinghua University
Qi Zhang: Tsinghua University
Zheng Zhang: Shenzhen Third People’s Hospital
Justin Jang Hann Chu: National University of Singapore
Xinquan Wang: Tsinghua University
Linqi Zhang: Tsinghua University

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-35642-2

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