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:10.1101/2022.12.12.520172

Fortuitous Somatic Mutations during Antibody Evolution Endow Broad Neutralization against SARS-CoV-2 Omicron Variants

bioRxiv [Preprint]. 2022 Dec 13:2022.12.12.520172. doi: 10.1101/2022.12.12.520172.

Authors

Jianbo Wu^{1

2}, Zhenguo Chen^{1

2}, Yidan Gao^{1

2}, Zegen Wang^{3

2}, Jiarong Wang^{3

2}, Bing-Yu Chiang^{3

2}, Yunjiao Zhou^{4

2}, Yuru Han^{1

2}, Wuqiang Zhan^{1

2}, Minxiang Xie^{1

2}, Weiyu Jiang¹, Xiang Zhang¹, Aihua Hao¹, Anqi Xia¹, Jiaying He¹, Song Xue¹, Christian T Mayer⁵, Fan Wu^{1

6}, Bin Wang^{1

4

6}, Lunan Zhang^{1

3}, Lei Sun¹, Qiao Wang¹

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 These authors contributed equally.
³ Advaccine Biopharmaceuticals Suzhou Co., Ltd, Suzhou, China.
⁴ Fundamental Research Center, Shanghai Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), School of Medicine, Tongji University, Shanghai 201619, China.
⁵ Experimental Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
⁶ Co-senior author.

Abstract

Striking antibody evasion by emerging circulating 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 identified a clonally-related antibody family from a convalescent individual. One of the members, XG005, exhibited potent and broad neutralizing activities against SARS-CoV-2 variants, while the other members showed significant reductions in neutralization breadth and potency, especially against the Omicron sublineages. Structural analysis visualizing the XG005-Omicron spike binding interface revealed how crucial somatic mutations endowed 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, exhibited a high therapeutic efficacy in BA.2- and BA.5-challenged mice. Our results provided a natural example to show the importance of somatic hypermutation during antibody evolution for SARS-CoV-2 neutralization breadth and potency.

Publication types

Preprint