Cross-Neutralization of a SARS-CoV-2 Antibody to a Functionally Conserved Site Is Mediated by Avidity

• Published in: Immunity (Cambridge, Mass.) Vol. 53; no. 6; pp. 1272 - 1280.e5
• Main Authors: Liu, Hejun, Wu, Nicholas C., Yuan, Meng, Bangaru, Sandhya, Torres, Jonathan L., Caniels, Tom G., van Schooten, Jelle, Zhu, Xueyong, Lee, Chang-Chun D., Brouwer, Philip J.M., van Gils, Marit J., Sanders, Rogier W., Ward, Andrew B., Wilson, Ian A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.12.2020; Elsevier Limited; Cell Press
• Subjects: ACE2; Amino acids; Angiotensin; Angiotensin-converting enzyme 2; Angiotensin-Converting Enzyme 2 - metabolism; Antibodies; Antibodies, Viral - genetics; Antibodies, Viral - metabolism; Avidity; BASIC BIOLOGICAL SCIENCES; Binding sites; Broadly Neutralizing Antibodies - genetics; Broadly Neutralizing Antibodies - metabolism; Competition; Complementarity-determining region; Conformation; Conserved Sequence - genetics; Coronaviridae; Coronaviruses; COVID-19; COVID-19 - immunology; COVID-19 Vaccines - immunology; Cross Reactions; Cross-reactivity; Crystal structure; Crystallization; Electron microscopy; Epitope Mapping; Epitopes; Epitopes, B-Lymphocyte - genetics; Epitopes, B-Lymphocyte - metabolism; Glycoproteins; Humans; Immunoglobulin Fab Fragments - genetics; Immunoglobulin Fab Fragments - metabolism; Immunoglobulins; Neutralization; Peptidyl-dipeptidase A; Protein Binding; Protein Conformation; Protein Interaction Domains and Motifs - genetics; Proteins; Receptors; SARS-CoV-2 - immunology; Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Severe acute respiratory syndrome-related coronavirus - immunology; Spike glycoprotein; Steric hindrance; Structure-function relationships; Trimers; Vaccines; Viral diseases
• ISSN: 1074-7613; 1097-4180; 1097-4180
• DOI: 10.1016/j.immuni.2020.10.023

Most antibodies isolated from individuals with coronavirus disease 2019 (COVID-19) are specific to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, COVA1-16 is a relatively rare antibody that also cross-neutralizes SARS-CoV. Here, we determined a crystal structure of the COVA1-16 antibody fragment (Fab) with the SARS-CoV-2 receptor-binding domain (RBD) and negative-stain electron microscopy reconstructions with the spike glycoprotein trimer to elucidate the structural basis of its cross-reactivity. COVA1-16 binds a highly conserved epitope on the SARS-CoV-2 RBD, mainly through a long complementarity-determining region (CDR) H3, and competes with the angiotensin-converting enzyme 2 (ACE2) receptor because of steric hindrance rather than epitope overlap. COVA1-16 binds to a flexible up conformation of the RBD on the spike and relies on antibody avidity for neutralization. These findings, along with the structural and functional rationale for epitope conservation, provide insights for development of more universal SARS-like coronavirus vaccines and therapies. [Display omitted] •X-ray and EM structures of cross-neutralizing antibody COVA1-16 with SARS-CoV-2 RBD•COVA1-16 binding to SARS-CoV-2 RBD is dominated by CDR H3•COVA1-16 binds to a highly conserved non-RBS epitope but still competes with ACE2•IgG avidity is the key for the cross-neutralization activity of COVA1-16 COVA1-16 is a SARS-CoV-2 antibody from an individual with COVID-19 that cross-neutralizes SARS-CoV. Liu et al. reveal that COVA1-16 binds to a highly conserved epitope using a long CDR H3, where its approach angle sterically blocks ACE2 from engaging the RBS. Virus neutralization by COVA1-16 is driven by IgG avidity.