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

• Authors: Anamika Patel, Emory University; Sanjeev Kumar, Emory University; Lilin Lai, Emory University; Chennareddy Chakravarthy, Emory University; Rajesh Valanparambil, Emory University; Elluri Seetharami Reddy, International Centre for Genetic Engineering and Biotechnology, New Delhi; Kamalvishnu Gottimukkala, International Centre for Genetic Engineering and Biotechnology, New Delhi; Prashant Bajpai, International Centre for Genetic Engineering and Biotechnology, New Delhi; Dinesh Ravindra Raju, Emory University; Venkata V Edara, Emory University; Meredith E Davis-Gardner, Emory University; Susanne Linderman, Emory University; Kritika Dixit, International Centre for Genetic Engineering and Biotechnology, New Delhi; Pragati Sharma, International Centre for Genetic Engineering and Biotechnology, New Delhi; Grace Mantus, Emory University; Narayanaiah Cheedarla, Emory University; Hans P Verkerke, Emory University; Filipp Frank, Emory University; Andrew Sharma, International Centre for Genetic Engineering and Biotechnology, New Delhi; John Roback, Emory University; Carl Davis, Emory University; Jens Wrammert, Emory University; Rafi Ahmed, Emory University; Mehul Suthar, Emory University; Amit Sharma, International Center for Genetic Engineering and Biotechnology, New Delhi; Kaja Murali-Krishna, International Centre for Genetic Engineering and Biotechnology, New Delhi; Anmol Chandele, Emory University; Eric Ortlund, Emory University
• Journal Title: Structure
• Volume: Volume 31, Number 7
• Publisher: bioRxiv | 2023-07-06, Pages 801-811.e5
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1016/j.str.2023.04.010
• Subjects: Chemistry, Biochemistry; Health Sciences, Pathology; Biology, Microbiology; Health Sciences, Immunology
• Keywords: COVID-19; SARS-CoV-2 variants; cryo-EM structure; human monoclonal antibodies; neutralizing antibodies; shared antibody response; Humans; Antibodies, Neutralizing; SARS-CoV-2; COVID-19; Antibodies, Monoclonal; Epitopes; Neutralization Tests

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.