Dataset Information

Structural insights for neutralization of Omicron variants BA.1, BA.2, BA.4, and BA.5 by a broadly neutralizing SARS-CoV-2 antibody.

ABSTRACT: In this study, by characterizing several human monoclonal antibodies (mAbs) isolated from single B cells of the COVID-19-recovered individuals in India who experienced ancestral Wuhan strain (WA.1) of SARS-CoV-2 during early stages of the pandemic, we found a receptor binding domain (RBD)-specific mAb 002-S21F2 that has rare gene usage and potently neutralized live viral isolates of SARS-CoV-2 variants including Alpha, Beta, Gamma, Delta, and Omicron sublineages (BA.1, BA.2, BA.2.12.1, BA.4, and BA.5) with IC₅₀ ranging from 0.02 to 0.13 μg/ml. Structural studies of 002-S21F2 in complex with spike trimers of Omicron and WA.1 showed that it targets a conformationally conserved epitope on the outer face of RBD (class 3 surface) outside the ACE2-binding motif, thereby providing a mechanistic insights for its broad neutralization activity. The discovery of 002-S21F2 and the broadly neutralizing epitope it targets have timely implications for developing a broad range of therapeutic and vaccine interventions against SARS-CoV-2 variants including Omicron sublineages.

SUBMITTER: Kumar S

PROVIDER: S-EPMC9534492 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Structural insights for neutralization of Omicron variants BA.1, BA.2, BA.4, and BA.5 by a broadly neutralizing SARS-CoV-2 antibody.

Kumar Sanjeev S Patel Anamika A Lai Lilin L Chakravarthy Chennareddy C Valanparambil Rajesh R Reddy Elluri Seetharami ES Gottimukkala Kamalvishnu K Davis-Gardner Meredith E ME Edara Venkata Viswanadh VV Linderman Susanne S Nayak Kaustuv K Dixit Kritika K Sharma Pragati P Bajpai Prashant P Singh Vanshika V Frank Filipp F Cheedarla Narayanaiah N Verkerke Hans P HP Neish Andrew S AS Roback John D JD Mantus Grace G Goel Pawan Kumar PK Rahi Manju M Davis Carl W CW Wrammert Jens J Godbole Sucheta S Henry Amy R AR Douek Daniel C DC Suthar Mehul S MS Ahmed Rafi R Ortlund Eric E Sharma Amit A Murali-Krishna Kaja K Chandele Anmol A

Science advances 20221005 40

In this study, by characterizing several human monoclonal antibodies (mAbs) isolated from single B cells of the COVID-19-recovered individuals in India who experienced ancestral Wuhan strain (WA.1) of SARS-CoV-2 during early stages of the pandemic, we found a receptor binding domain (RBD)-specific mAb 002-S21F2 that has rare gene usage and potently neutralized live viral isolates of SARS-CoV-2 variants including Alpha, Beta, Gamma, Delta, and Omicron sublineages (BA.1, BA.2, BA.2.12.1, BA.4, and ...[more]

PMID: 36197988

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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

Structural insights for neutralization of Omicron variants BA.1, BA.2, BA.4, and BA.5 by a broadly neutralizing SARS-CoV-2 antibody.

Publications

Structural insights for neutralization of Omicron variants BA.1, BA.2, BA.4, and BA.5 by a broadly neutralizing SARS-CoV-2 antibody.

Similar Datasets

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