Fortuitous somatic mutations during antibody evolution endow broad neutralization against SARS-CoV-2 Omicron variants

Jianbo Wu; Zhenguo Chen; Yidan Gao; Zegen Wang; Jiarong Wang; Bing-Yu Chiang; Yunjiao Zhou; Yuru Han; Wuqiang Zhan; Minxiang Xie; Weiyu Jiang; Xiang Zhang; Aihua Hao; Anqi Xia; Jiaying He; Song Xue; Christian T Mayer; Fan Wu; Bin Wang; Lunan Zhang; Lei Sun; Qiao Wang

doi:10.1016/j.celrep.2023.112503

Fortuitous somatic mutations during antibody evolution endow broad neutralization against SARS-CoV-2 Omicron variants

Cell Rep. 2023 May 30;42(5):112503. doi: 10.1016/j.celrep.2023.112503. Epub 2023 May 3.

Authors

Jianbo Wu¹, Zhenguo Chen¹, Yidan Gao¹, Zegen Wang², Jiarong Wang², Bing-Yu Chiang², Yunjiao Zhou³, Yuru Han¹, Wuqiang Zhan¹, Minxiang Xie¹, Weiyu Jiang¹, Xiang Zhang¹, Aihua Hao¹, Anqi Xia¹, Jiaying He¹, Song Xue¹, Christian T Mayer⁴, Fan Wu¹, Bin Wang⁵, Lunan Zhang⁶, Lei Sun⁷, Qiao Wang⁸

Affiliations

¹ Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, Shanghai Fifth People's Hospital, Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, School of Public Health, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
² Advaccine Biopharmaceuticals Suzhou Co., Ltd., Suzhou, China.
³ Fundamental Research Center, Shanghai Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), School of Medicine, Tongji University, Shanghai 201619, China.
⁴ Experimental Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
⁵ Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, Shanghai Fifth People's Hospital, Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, School of Public Health, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; Advaccine Biopharmaceuticals Suzhou Co., Ltd., Suzhou, China.
⁶ Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, Shanghai Fifth People's Hospital, Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, School of Public Health, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; Advaccine Biopharmaceuticals Suzhou Co., Ltd., Suzhou, China. Electronic address: lunan@advaccine.com.
⁷ Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, Shanghai Fifth People's Hospital, Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, School of Public Health, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China. Electronic address: llsun@fudan.edu.cn.
⁸ Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, Shanghai Fifth People's Hospital, Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, School of Public Health, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China. Electronic address: wangqiao@fudan.edu.cn.

Abstract

Striking antibody evasion by emerging circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants drives the identification of broadly neutralizing antibodies (bNAbs). However, how a bNAb acquires increased neutralization breadth during antibody evolution is still elusive. Here, we identify a clonally related antibody family from a convalescent individual. One of the members, XG005, exhibits potent and broad neutralizing activities against SARS-CoV-2 variants, while the other members show significant reductions in neutralization breadth and potency, especially against the Omicron sublineages. Structural analysis visualizing the XG005-Omicron spike binding interface reveals how crucial somatic mutations endow XG005 with greater neutralization potency and breadth. A single administration of XG005 with extended half-life, reduced antibody-dependent enhancement (ADE) effect, and increased antibody product quality exhibits a high therapeutic efficacy in BA.2- and BA.5-challenged mice. Our results provide a natural example to show the importance of somatic hypermutation during antibody evolution for SARS-CoV-2 neutralization breadth and potency.

Keywords: CP: Immunology; CP: Microbiology; SARS-CoV-2; bNAb; broadly neutralizing antibody; clonally related antibody family; somatic hypermutation; variant of concern.

Publication types

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

MeSH terms

Animals
Antibodies
Antibodies, Neutralizing
Antibodies, Viral
Broadly Neutralizing Antibodies
COVID-19*
Mice
Mutation / genetics
SARS-CoV-2*

Substances

Antibodies
Broadly Neutralizing Antibodies
Antibodies, Viral
Antibodies, Neutralizing

Supplementary concepts

SARS-CoV-2 variants