Molecular Basis of SARS-CoV-2 Omicron Variant Evasion from Shared Neutralizing Antibody Response

A detailed understanding of the molecular features of the neutralizing epitopes developed by viral escape mutants is important for predicting and developing vaccines or therapeutic antibodies against continuously emerging SARS-CoV-2 variants. Here, we report three human monoclonal antibodies (mAbs) generated from COVID-19 recovered individuals during first wave of pandemic in India. These mAbs had publicly shared near germline gene usage and potently neutralized Alpha and Delta, but poorly neutralized Beta and completely failed to neutralize Omicron BA.1 SARS-CoV-2 variants. Structural analysis of these three mAbs in complex with trimeric spike protein showed that all three mAbs are involved in bivalent spike binding with two mAbs targeting class-1 and one targeting class-4 Receptor Binding Domain (RBD) epitope. Comparison of immunogenetic makeup, structure, and function of these three mAbs with our recently reported class-3 RBD binding mAb that potently neutralized all SARS-CoV-2 variants revealed precise antibody footprint, specific molecular interactions associated with the most potent multi-variant binding / neutralization efficacy. This knowledge has timely significance for understanding how a combination of certain mutations affect the binding or neutralization of an antibody and thus have implications for predicting structural features of emerging SARS-CoV-2 escape variants and to develop vaccines or therapeutic antibodies against these.

Funding Information: This research was supported by the Indian Council of Medical Research VIR/COVID-19/02/2020/ECD-1 (A.C.). S.K. is supported through DBT/Wellcome Trust India Alliance Early Career Fellowship grant IA/E/18/1/504307. Both E.A.O and A.P are supported by the National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health (under award numbers 75N92019P00328, U54EB015408, and U54EB027690) as part of the Rapid Acceleration of Diagnostics (RADx) initiative. A.P. is 17 also supported through CCHI grant 5U19 AI14237-04 (subaward 000520244-SP008-SC014). Both K.N. and E.S.R. are supported through Dengue Translational Research Consortia National Biopharma Mission BT/NBM099/02/18 (A.C.). K.G. was supported through DBT grant BT/PR30260/MED/15/194/2018 (A.C, K.M). C.W.D. is supported through the National Institute of Allergy and Infectious Diseases (NIAID) U19 AI142790, Consortium for Immunotherapeutics against Emerging Viral Threats. Work done in M.S.S. lab was funded in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under HHSN272201400004C (NIAID Centers of Excellence for Influenza Research and Surveillance, CEIRS). This work was supported in part by grants (NIH P51OD011132 and NIH/NIAID CEIRR under contract 75N93021C00017 to Emory University) from the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) and by intramural funding from the NIAID. This work was also supported in part by the Emory Executive Vice President for Health Affairs Synergy Fund award, COVID-Catalyst-I3 Funds from the Woodruff Health Sciences Center and Emory School of Medicine, the Pediatric Research Alliance Center for Childhood Infections and Vaccines and Children’s Healthcare of Atlanta, and Woodruff Health Sciences Center 2020 COVID-19 CURE Award.

Declaration of Interests: The International Centre for Genetic Engineering and Biotechnology, New Delhi, India, Emory Vaccine Center, Emory University, Atlanta, USA, Indian Council of Medical Research, India and Department of Biotechnology, India have filed a provisional patent application on human monoclonal antibodies mentioned in this study on which A.C., S.K., M.K.K., and A.S. are inventors (Indian patent 202111052088). N.C., H.V., A.S.N., and J.D.R. are co-inventors on a pending patent related to SARS-CoV-2 WT, Delta and Omicron spike protein structures and ACE2 Interactions from BoAb assay technology filed by Emory University (US Patent Application No. 63/265,361, Filed on 14 December 2021). M.S.S. has previously served as a consultant for Moderna and Ocugen. J.D.R. is a Co-founder and Consultant for Cambium Medical Technologies. J.D.R. is a Consultant for Secure Transfusion Services. All other authors declare no competing interests.

Keywords: COVID-19, SARS-CoV-2 variants, human monoclonal antibodies, Cryo-EM structure, neutralizing antibodies

Suggested Citation: Suggested Citation

Patel, Anamika and Kumar, Sanjeev and Lai, Lilin and Chennareddy, Chakravarthy and Valanparambil, Rajesh M. and Reddy, Elluri Seetharami and Gottimukkala, Kamalvishnu and Bajpai, Prashant and Raju, Dinesh Ravindra and Edara, Venkata and Davis Gardner, Meredith Elizabeth and Linderman, Susanne L. and Dixit, Kritika and Sharma, Pragati and Mantus, Grace and Cheedarla, Narayanaiah and Verkerke, Hans P. and Frank, Filipp and Neish, Andrew S. and Roback, John and Davis, Carl W. and Wrammert, Jens and Ahmed, Rafi and Suthar, Mehul and Sharma, Amit and Murali-Krishna, Kaja and Chandele, Anmol and Ortlund, Eric, Molecular Basis of SARS-CoV-2 Omicron Variant Evasion from Shared Neutralizing Antibody Response. Available at SSRN: https://ssrn.com/abstract=4281071 or http://dx.doi.org/10.2139/ssrn.4281071

This version of the paper has not been formally peer reviewed.