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

• Published in: Structure (London) Vol. 31; no. 7; pp. 801 - 811.e5
• Main Authors: Patel, Anamika, Kumar, Sanjeev, Lai, Lilin, Chakravarthy, Chennareddy, Valanparambil, Rajesh, Reddy, Elluri Seetharami, Gottimukkala, Kamalvishnu, Bajpai, Prashant, Raju, Dinesh Ravindra, Edara, Venkata Viswanadh, Davis-Gardner, Meredith E., Linderman, Susanne, Dixit, Kritika, Sharma, Pragati, Mantus, Grace, Cheedarla, Narayanaiah, Verkerke, Hans P., Frank, Filipp, Neish, Andrew S., Roback, John D., Davis, Carl W., Wrammert, Jens, Ahmed, Rafi, Suthar, Mehul S., Sharma, Amit, Murali-Krishna, Kaja, Chandele, Anmol, Ortlund, Eric A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 06.07.2023
• Subjects: Antibodies, Monoclonal; Antibodies, Neutralizing; COVID-19; cryo-EM structure; Epitopes; human monoclonal antibodies; Humans; Neutralization Tests; neutralizing antibodies; SARS-CoV-2 - genetics; SARS-CoV-2 variants; shared antibody response; COVID-19; SARS-CoV-2 variants; neutralizing antibodies; human monoclonal antibodies; cryo-EM structure; shared antibody response
• ISSN: 0969-2126; 1878-4186; 1878-4186
• DOI: 10.1016/j.str.2023.04.010

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. [Display omitted] •Identified publicly shared mAbs capable of neutralizing SARS-CoV-2 variants•Defined a new public clonotype containing a CDRH3 CxGGxC motif•Class 1 and 4 RBD antibodies inhibit ACE2 binding through distinct mechanisms•Illustrating RBD mutations accommodation and escape from Omicron Patel et al. describe 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.