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Mapping cross-variant neutralizing sites on the SARS-CoV-2 spike protein.
Emerg Microbes Infect. 2022 Dec; 11(1):351-367.EM

Abstract

The emergence of multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern threatens the efficacy of currently approved vaccines and authorized therapeutic monoclonal antibodies (MAbs). It is hence important to continue searching for SARS-CoV-2 broadly neutralizing MAbs and defining their epitopes. Here, we isolate 9 neutralizing mouse MAbs raised against the spike protein of a SARS-CoV-2 prototype strain and evaluate their neutralizing potency towards a panel of variants, including B.1.1.7, B.1.351, B.1.617.1, and B.1.617.2. By using a combination of biochemical, virological, and cryo-EM structural analyses, we identify three types of cross-variant neutralizing MAbs, represented by S5D2, S5G2, and S3H3, respectively, and further define their epitopes. S5D2 binds the top lateral edge of the receptor-binding motif within the receptor-binding domain (RBD) with a binding footprint centred around the loop477-489, and efficiently neutralizes all variant pseudoviruses, but the potency against B.1.617.2 was observed to decrease significantly. S5G2 targets the highly conserved RBD core region and exhibits comparable neutralization towards the variant panel. S3H3 binds a previously unreported epitope located within the evolutionarily stable SD1 region and is able to near equally neutralize all of the variants tested. Our work thus defines three distinct cross-variant neutralizing sites on the SARS-CoV-2 spike protein, providing guidance for design and development of broadly effective vaccines and MAb-based therapies.

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Authors+Show Affiliations

Xu S
CAS Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, People's Republic of China.
Wang Y
State Key Laboratory of Molecular Biology, National Center for Protein Science Shanghai, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, People's Republic of China.
Wang Y
State Key Laboratory of Molecular Biology, National Center for Protein Science Shanghai, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, People's Republic of China.
Zhang C
CAS Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, People's Republic of China.
Hong Q
State Key Laboratory of Molecular Biology, National Center for Protein Science Shanghai, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, People's Republic of China.
Gu C
Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
Xu R
CAS Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, People's Republic of China.
Wang T
CAS Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, People's Republic of China.
Yang Y
CAS Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, People's Republic of China.
Zang J
CAS Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, People's Republic of China.
Zhou Y
CAS Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, People's Republic of China.
Li Z
State Key Laboratory of Molecular Biology, National Center for Protein Science Shanghai, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, People's Republic of China.
Liu Q
CAS Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, People's Republic of China.
Zhou B
CAS Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, People's Republic of China.
Bai L
CAS Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, People's Republic of China.
Zhu Y
Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China. BSL-3 Laboratory of Fudan University, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
Deng Q
Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
Wang H
CAS Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, People's Republic of China.
Lavillette D
CAS Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, People's Republic of China.
Wong G
CAS Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, People's Republic of China.
Xie Y
Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China. BSL-3 Laboratory of Fudan University, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
Cong Y
State Key Laboratory of Molecular Biology, National Center for Protein Science Shanghai, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, People's Republic of China.
Huang Z
CAS Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, People's Republic of China.

MeSH

AnimalsAntibodies, NeutralizingAntibodies, ViralCOVID-19Epitope MappingFemaleHumansMiceMice, Inbred BALB CNeutralization TestsSARS-CoV-2Spike Glycoprotein, Coronavirus

Pub Type(s)

Journal Article

Language

eng

PubMed ID

34964428

Citation

Xu, Shiqi, et al. "Mapping Cross-variant Neutralizing Sites On the SARS-CoV-2 Spike Protein." Emerging Microbes & Infections, vol. 11, no. 1, 2022, pp. 351-367.
Xu S, Wang Y, Wang Y, et al. Mapping cross-variant neutralizing sites on the SARS-CoV-2 spike protein. Emerg Microbes Infect. 2022;11(1):351-367.
Xu, S., Wang, Y., Wang, Y., Zhang, C., Hong, Q., Gu, C., Xu, R., Wang, T., Yang, Y., Zang, J., Zhou, Y., Li, Z., Liu, Q., Zhou, B., Bai, L., Zhu, Y., Deng, Q., Wang, H., Lavillette, D., ... Huang, Z. (2022). Mapping cross-variant neutralizing sites on the SARS-CoV-2 spike protein. Emerging Microbes & Infections, 11(1), 351-367. https://doi.org/10.1080/22221751.2021.2024455
Xu S, et al. Mapping Cross-variant Neutralizing Sites On the SARS-CoV-2 Spike Protein. Emerg Microbes Infect. 2022;11(1):351-367. PubMed PMID: 34964428.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mapping cross-variant neutralizing sites on the SARS-CoV-2 spike protein. AU - Xu,Shiqi, AU - Wang,Yifan, AU - Wang,Yanxing, AU - Zhang,Chao, AU - Hong,Qin, AU - Gu,Chenjian, AU - Xu,Rong, AU - Wang,Tingfeng, AU - Yang,Yong, AU - Zang,Jinkai, AU - Zhou,Yu, AU - Li,Zuyang, AU - Liu,Qixing, AU - Zhou,Bingjie, AU - Bai,Lulu, AU - Zhu,Yuanfei, AU - Deng,Qiang, AU - Wang,Haikun, AU - Lavillette,Dimitri, AU - Wong,Gary, AU - Xie,Youhua, AU - Cong,Yao, AU - Huang,Zhong, PY - 2021/12/30/pubmed PY - 2022/1/28/medline PY - 2021/12/29/entrez KW - Cryo-EM KW - SARS-CoV-2 KW - SD1 KW - antibody KW - epitope SP - 351 EP - 367 JF - Emerging microbes & infections JO - Emerg Microbes Infect VL - 11 IS - 1 N2 - The emergence of multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern threatens the efficacy of currently approved vaccines and authorized therapeutic monoclonal antibodies (MAbs). It is hence important to continue searching for SARS-CoV-2 broadly neutralizing MAbs and defining their epitopes. Here, we isolate 9 neutralizing mouse MAbs raised against the spike protein of a SARS-CoV-2 prototype strain and evaluate their neutralizing potency towards a panel of variants, including B.1.1.7, B.1.351, B.1.617.1, and B.1.617.2. By using a combination of biochemical, virological, and cryo-EM structural analyses, we identify three types of cross-variant neutralizing MAbs, represented by S5D2, S5G2, and S3H3, respectively, and further define their epitopes. S5D2 binds the top lateral edge of the receptor-binding motif within the receptor-binding domain (RBD) with a binding footprint centred around the loop477-489, and efficiently neutralizes all variant pseudoviruses, but the potency against B.1.617.2 was observed to decrease significantly. S5G2 targets the highly conserved RBD core region and exhibits comparable neutralization towards the variant panel. S3H3 binds a previously unreported epitope located within the evolutionarily stable SD1 region and is able to near equally neutralize all of the variants tested. Our work thus defines three distinct cross-variant neutralizing sites on the SARS-CoV-2 spike protein, providing guidance for design and development of broadly effective vaccines and MAb-based therapies. SN - 2222-1751 UR - https://www.unboundmedicine.com/medline/citation/34964428/Mapping_cross_variant_neutralizing_sites_on_the_SARS_CoV_2_spike_protein_ DB - PRIME DP - Unbound Medicine ER -