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Comprehensive structural analysis reveals broad-spectrum neutralizing antibodies against SARS-CoV-2 Omicron variants.

ABSTRACT: The pandemic of COVID-19 caused by SARS-CoV-2 continues to spread around the world. Mutant strains of SARS-CoV-2 are constantly emerging. At present, Omicron variants have become mainstream. In this work, we carried out a systematic and comprehensive analysis of the reported spike protein antibodies, counting the epitopes and genotypes of these antibodies. We further comprehensively analyzed the impact of Omicron mutations on antibody epitopes and classified these antibodies according to their binding patterns. We found that the epitopes of the H-RBD class antibodies were significantly less affected by Omicron mutations than other classes. Binding and virus neutralization experiments showed that such antibodies could effectively inhibit the immune escape of Omicron. Cryo-EM results showed that this class of antibodies utilized a conserved mechanism to neutralize SARS-CoV-2. Our results greatly help us deeply understand the impact of Omicron mutations. Meanwhile, it also provides guidance and insights for developing Omicron antibodies and vaccines.

SUBMITTER: Chi X

PROVIDER: S-EPMC10071473 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Comprehensive structural analysis reveals broad-spectrum neutralizing antibodies against SARS-CoV-2 Omicron variants.

Chi Xiangyang X Xia Lingyun L Zhang Guanying G Chi Ximin X Huang Bangdong B Zhang Yuanyuan Y Chen Zhengshan Z Han Jin J Wu Liushu L Li Zeya Z Sun Hancong H Huang Ping P Yu Changming C Chen Wei W Zhou Qiang Q

Cell discovery 20230404 1

The pandemic of COVID-19 caused by SARS-CoV-2 continues to spread around the world. Mutant strains of SARS-CoV-2 are constantly emerging. At present, Omicron variants have become mainstream. In this work, we carried out a systematic and comprehensive analysis of the reported spike protein antibodies, counting the epitopes and genotypes of these antibodies. We further comprehensively analyzed the impact of Omicron mutations on antibody epitopes and classified these antibodies according to their b ...[more]

PMID: 37015915

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Project description:The emergence of novel variants of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) continues to pose an ongoing challenge for global public health services, highlighting the urgent need for effective therapeutic interventions. Neutralizing monoclonal antibodies (mAbs) are a major therapeutic strategy for the treatment of COVID-19 and other viral diseases. In this study, we employed hybridoma technology to generate mAbs that target the BA.5 receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. Through a comprehensive screening process, we identified four mAbs capable of effectively neutralizing BA.5, XBB.1.16, and related variant infections in vitro, among which ORB10 was found to neutralize BA.5 variants with a plaque reduction neutralization test (PRNT50) of 8.7 ng/mL. Additionally, competitive binding assays, sequencing of heavy and light chain variable regions, and binding kinetics characterization provided insights into the epitopes and binding affinities of the identified mAbs. Moreover, in vivo experiments in the K18-hACE2 mouse model demonstrated the protective efficacy of ORB10 against both BA.5 and XBB.1.16 variants. Finally, cryo-electron microscopy structural analysis of the ORB10-RBD complex identified key residues involved in the antibody-antigen interactions, providing insights into the molecular mechanisms of neutralization and immune escape of SARS-CoV-2 Omicron variants from mAbs.ImportanceThe ongoing evolution of SARS-CoV-2 has led to the emergence of variants capable of evading immune responses elicited by natural infection and vaccination, especially the highly transmissible and immune-evasive Omicron variants. This study generated and characterized a panel of monoclonal antibodies (mAbs) specifically targeting the RBD of the Omicron BA.5 variant, of which the ORB10 showed efficacy against Omicron BA.5 and XBB.1.16 variants both in vitro and in vivo. Cryo-EM structural analysis further elucidated the binding epitope interactions and neutralization mechanism between ORB10 and the BA.5 RBD protein. This study enhances our understanding of antibody-mediated neutralization of SARS-CoV-2 and provides valuable insights into the development of effective therapeutic strategies to combat ongoing SARS-CoV-2 variant infections.

Dataset Information

Comprehensive structural analysis reveals broad-spectrum neutralizing antibodies against SARS-CoV-2 Omicron variants.

Publications

Comprehensive structural analysis reveals broad-spectrum neutralizing antibodies against SARS-CoV-2 Omicron variants.

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