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; 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; Qingtao Hu; Yaoqing Chen; Huibin Lv; Ray T Y So; Malik Peiris; Jingxian Zhao; Xiaoqing Liu; Chris Ka Pun Mok; Xiangxi Wang; Jincun Zhao

doi:10.1016/j.celrep.2023.113653

Identification of a broad sarbecovirus neutralizing antibody targeting a conserved epitope on the receptor-binding domain

Cell Rep. 2024 Jan 23;43(1):113653. doi: 10.1016/j.celrep.2023.113653. Epub 2024 Jan 3.

Authors

Yanqun Wang¹, Zhaoyong Zhang², Minnan Yang³, Xinyi Xiong⁴, Qihong Yan², Lei Cao³, Peilan Wei⁵, Yuting Zhang², Lu Zhang⁶, Kexin Lv⁷, Jiantao Chen², Xuesong Liu⁸, Xiaochu Zhao⁹, Juxue Xiao², Shengnan Zhang², Airu Zhu², Mian Gan², Jingjun Zhang², Ruoxi Cai², Jianfen Zhuo², Yanjun Zhang², Haiyue Rao², Bin Qu⁴, Yuanyuan Zhang², Lei Chen², Jun Dai⁶, Linling Cheng², Qingtao Hu², Yaoqing Chen⁷, Huibin Lv¹⁰, Ray T Y So¹¹, Malik Peiris¹², Jingxian Zhao⁵, Xiaoqing Liu¹³, Chris Ka Pun Mok¹⁴, Xiangxi Wang¹⁵, Jincun Zhao¹⁶

Affiliations

¹ State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China; GMU-GIBH Joint School of Life Sciences, Guangzhou Medical University, Guangzhou, Guangdong, China; Clinical Laboratory Medicine Department, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
² State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
³ CAS Key Laboratory of Infection and Immunity, National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
⁴ Shanghai Institute for Advanced Immunochemical Studies, School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
⁵ State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China; Guangzhou National Laboratory, Bio-Island, Guangzhou, China.
⁶ Health and Quarantine Laboratory, Guangzhou Customs District Technology Centre, Guangzhou, China.
⁷ School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, China.
⁸ Department of Critical Care Medicine, State Key Lab of Respiratory Diseases, Guangzhou Institute of Respiratory Health, National Clinical Research Center for Respiratory Disease, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
⁹ School of Basic Medical Sciences, Capital Medical University, Beijing, China.
¹⁰ HKU-Pasteur Research Pole, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
¹¹ School of Public Health, The University of Hong Kong, Hong Kong, China.
¹² HKU-Pasteur Research Pole, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China; School of Public Health, The University of Hong Kong, Hong Kong, China.
¹³ Department of Critical Care Medicine, State Key Lab of Respiratory Diseases, Guangzhou Institute of Respiratory Health, National Clinical Research Center for Respiratory Disease, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China. Electronic address: lxq1118@126.com.
¹⁴ The Jockey Club School of Public Health and Primary Care, The Chinese University of Hong Kong, Hong Kong, China; Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China; S.H. Ho Research Centre for Infectious Diseases, Chinese University of Hong Kong, Hong Kong, China. Electronic address: kapunmok@cuhk.edu.hk.
¹⁵ CAS Key Laboratory of Infection and Immunity, National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. Electronic address: xiangxi@ibp.ac.cn.
¹⁶ State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China; Shanghai Institute for Advanced Immunochemical Studies, School of Life Science and Technology, ShanghaiTech University, Shanghai, China; Guangzhou National Laboratory, Bio-Island, Guangzhou, China; Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital, the Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology, Shenzhen, China. Electronic address: zhaojincun@gird.cn.

PMID: 38175758
DOI: 10.1016/j.celrep.2023.113653

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.

Keywords: CP: Immunology; conserved epitope; in vivo; mouse model; neutralizing antibody; receptor binding domain; sarbecovirus.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibodies, Neutralizing
Antibodies, Viral
Broadly Neutralizing Antibodies
Cryoelectron Microscopy
Epitopes
Mice
Severe acute respiratory syndrome-related coronavirus*

Substances

Broadly Neutralizing Antibodies
Antibodies, Neutralizing
Epitopes
Antibodies, Viral