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Molecular basis of SARS-CoV-2 Omicron variant evasion from shared neutralizing antibody response.

ABSTRACT: Understanding the molecular features of neutralizing epitopes is important for developing vaccines/therapeutics against emerging SARS-CoV-2 variants. We describe three monoclonal antibodies (mAbs) generated from COVID-19 recovered individuals during the first wave of the pandemic in India. These mAbs had publicly shared near germline gene usage and potently neutralized Alpha and Delta, poorly neutralized Beta, and failed to neutralize Omicron BA.1 SARS-CoV-2 variants. Structural analysis of these mAbs in complex with trimeric spike protein showed that all three mAbs bivalently bind spike with two mAbs targeting class 1 and one targeting a class 4 receptor binding domain epitope. The immunogenetic makeup, structure, and function of these mAbs revealed specific molecular interactions associated with the potent multi-variant binding/neutralization efficacy. This knowledge shows how mutational combinations can affect the binding or neutralization of an antibody, which in turn relates to the efficacy of immune responses to emerging SARS-CoV-2 escape variants.

SUBMITTER: Patel A

PROVIDER: S-EPMC10171968 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Molecular basis of SARS-CoV-2 Omicron variant evasion from shared neutralizing antibody response.

Patel Anamika A Kumar Sanjeev S Lai Lilin L Chakravarthy Chennareddy C Valanparambil Rajesh R Reddy Elluri Seetharami ES Gottimukkala Kamalvishnu K Bajpai Prashant P Raju Dinesh Ravindra DR Edara Venkata Viswanadh VV Davis-Gardner Meredith E ME Linderman Susanne S Dixit Kritika K Sharma Pragati P Mantus Grace G Cheedarla Narayanaiah N Verkerke Hans P HP Frank Filipp F Neish Andrew S AS Roback John D JD Davis Carl W CW Wrammert Jens J Ahmed Rafi R Suthar Mehul S MS Sharma Amit A Murali-Krishna Kaja K Chandele Anmol A Ortlund Eric A EA

Structure (London, England : 1993) 20230511 7

Understanding the molecular features of neutralizing epitopes is important for developing vaccines/therapeutics against emerging SARS-CoV-2 variants. We describe three monoclonal antibodies (mAbs) generated from COVID-19 recovered individuals during the first wave of the pandemic in India. These mAbs had publicly shared near germline gene usage and potently neutralized Alpha and Delta, poorly neutralized Beta, and failed to neutralize Omicron BA.1 SARS-CoV-2 variants. Structural analysis of thes ...[more]

PMID: 37167972

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Project description:BackgroundThe recently emerged SARS-CoV-2 Omicron variant exhibits several mutations on the spike protein, enabling it to escape the immunity elicited by natural infection or vaccines. Avidity is the strength of binding between an antibody and its specific epitope. The SARS-CoV-2 spike protein binds to its cellular receptor with high affinity and is the primary target of neutralizing antibodies. Therefore, protective antibodies should show high avidity. This study aimed at investigating the avidity of receptor-binding domain (RBD) binding antibodies and their neutralizing activity against the Omicron variant in SARS-CoV-2 infected patients and vaccinees.MethodsSamples were collected from 42 SARS-CoV-2 infected patients during the first pandemic wave, 50 subjects who received 2 doses of mRNA vaccine before the Omicron wave, 44 subjects who received 3 doses of mRNA vaccine, and 35 subjects who received heterologous vaccination (2 doses of adenovirus-based vaccine plus mRNA vaccine) during the Omicron wave. Samples were tested for the avidity of RBD-binding IgG and neutralizing antibodies against the wild-type SARS-CoV-2 virus and the Omicron variant.ResultsIn patients, RBD-binding IgG titers against the wild-type virus increased with time, but remained low. High neutralizing titers against the wild-type virus were not matched by high avidity or neutralizing activity against the Omicron variant. Vaccinees showed higher avidity than patients. Two vaccine doses elicited the production of neutralizing antibodies, but low avidity for the wild-type virus; antibody levels against the Omicron variant were even lower. Conversely, 3 doses of vaccine elicited high avidity and high neutralizing antibodies against both the wild-type virus and the Omicron variant.ConclusionsRepeated vaccination increases antibody avidity against the spike protein of the Omicron variant, suggesting that antibodies with high avidity and high neutralizing potential increase cross-protection against variants that carry several mutations on the RBD.

Dataset Information

Molecular basis of SARS-CoV-2 Omicron variant evasion from shared neutralizing antibody response.

Publications

Molecular basis of SARS-CoV-2 Omicron variant evasion from shared neutralizing antibody response.

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