Orphan broadly RBD-binding antibodies annotate three remaining conserved RBD epitopes along SARS-CoV-2 evolution

Minxiang Xie, Yinong Qiu, Xiaoyu Zhao, Jialu Shi, Yuanchen Liu, Qingsong Zhang, Jiaying He, Jiayan Li, Luotian Liu, Siyuan Sun, Yuzhen Zhu, Qiyu Mao, Yiming Long, Thiago Y. Oliveira, Zijun Wang, Yunjiao Zhou, Yan Yan, Anqi Xia, Wenjing Zai, Christian T. Mayer, Youhua Xie, Shibo Jiang, Lu Lu, Rong Xia (), Fan Wu (), Lei Sun (), Pengfei Wang (), Hin Chu () and Qiao Wang ()
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Minxiang Xie: Fudan University, Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, Shanghai Fifth People’s Hospital, Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, School of Basic Medical Sciences
Yinong Qiu: Fudan University, Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, Shanghai Fifth People’s Hospital, Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, School of Basic Medical Sciences
Xiaoyu Zhao: Fudan University, Shanghai Sci-Tech Inno Center for Infection & Immunity, National Medical Center for Infectious Diseases, Huashan Hospital, Institute of Infection and Health
Jialu Shi: Hong Kong Special Administrative Region, State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam
Yuanchen Liu: Hong Kong Special Administrative Region, State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam
Qingsong Zhang: Fudan University, Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, Shanghai Fifth People’s Hospital, Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, School of Basic Medical Sciences
Jiaying He: Baoshan District Center for Disease Control and Prevention, Microbiological Testing Department
Jiayan Li: Fudan University, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai Institute of Infectious Disease and Biosecurity, State Key Laboratory of Genetic Engineering, MOE Engineering Research Center of Gene Technology, School of Life Sciences
Luotian Liu: Fudan University, Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, Shanghai Fifth People’s Hospital, Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, School of Basic Medical Sciences
Siyuan Sun: Fudan University, Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, Shanghai Fifth People’s Hospital, Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, School of Basic Medical Sciences
Yuzhen Zhu: Fudan University, Department of gastroenterology, Jingan District Central Hospitals
Qiyu Mao: Fudan University, Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, Shanghai Fifth People’s Hospital, Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, School of Basic Medical Sciences
Yiming Long: Fudan University, Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, Shanghai Fifth People’s Hospital, Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, School of Basic Medical Sciences
Thiago Y. Oliveira: The Rockefeller University, Laboratory of Molecular Immunology
Zijun Wang: The Rockefeller University, Laboratory of Molecular Immunology
Yunjiao Zhou: Tongji University, Fundamental Research Center, Shanghai Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), School of Medicine
Yan Yan: Fudan University, Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, Shanghai Fifth People’s Hospital, Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, School of Basic Medical Sciences
Anqi Xia: Fudan University, Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, Shanghai Fifth People’s Hospital, Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, School of Basic Medical Sciences
Wenjing Zai: Fudan University, Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, Shanghai Fifth People’s Hospital, Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, School of Basic Medical Sciences
Christian T. Mayer: National Institutes of Health, Experimental Immunology Branch, Center for Cancer Research, National Cancer Institute
Youhua Xie: Fudan University, Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, Shanghai Fifth People’s Hospital, Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, School of Basic Medical Sciences
Shibo Jiang: Fudan University, Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, Shanghai Fifth People’s Hospital, Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, School of Basic Medical Sciences
Lu Lu: Fudan University, Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, Shanghai Fifth People’s Hospital, Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, School of Basic Medical Sciences
Rong Xia: Fudan University, Department of Transfusion Medicine, Shanghai Huashan Hospital
Fan Wu: Fudan University, Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, Shanghai Fifth People’s Hospital, Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, School of Basic Medical Sciences
Lei Sun: Fudan University, Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, Shanghai Fifth People’s Hospital, Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, School of Basic Medical Sciences
Pengfei Wang: Fudan University, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai Institute of Infectious Disease and Biosecurity, State Key Laboratory of Genetic Engineering, MOE Engineering Research Center of Gene Technology, School of Life Sciences
Hin Chu: Hong Kong Special Administrative Region, State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam
Qiao Wang: Fudan University, Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, Shanghai Fifth People’s Hospital, Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, School of Basic Medical Sciences

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract The receptor-binding domain (RBD) of the SARS-CoV-2 spike (S) protein continues to evolve, facilitating antibody evasion. It remains unclear whether any conserved RBD epitopes persist across SARS-CoV-2 variants and whether vaccination and/or breakthrough infection (BTI) can elicit antibodies capable of targeting these conserved regions to counter future variants. Here, using a heterogeneous double-bait single B-cell sorting strategy, we identify a subset of antibodies with broad-spectrum RBD binding, including recognition of SARS-CoV-1 and emerging variants such as EG.5.1, BA.2.86, JN.1, and KP.2/3. These broadly binding antibodies (bbAbs) exhibit elevated levels of somatic hypermutation but are infrequently derived from clonally expanded B lymphocytes. Passive transfer of representative bbAbs reduces viral infection in a male hamster model. Structural analyses reveals that these bbAbs primarily target three distinct, highly conserved RBD epitopes, suggesting potential regions of future mutational pressure and highlighting the presence of conserved and immunogenic RBD conformations that may serve as a foundation for the development of broadly protective vaccines.

Date: 2025
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DOI: 10.1038/s41467-025-65596-0

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