Molecular basis of immune evasion by the Delta and Kappa SARS-CoV-2 variants

• Published in: Science (American Association for the Advancement of Science) Vol. 374; no. 6575; pp. 1621 - 1626
• Main Authors: McCallum, Matthew, Walls, Alexandra C., Sprouse, Kaitlin R., Bowen, John E., Rosen, Laura E., Dang, Ha V., De Marco, Anna, Franko, Nicholas, Tilles, Sasha W., Logue, Jennifer, Miranda, Marcos C., Ahlrichs, Margaret, Carter, Lauren, Snell, Gyorgy, Pizzuto, Matteo Samuele, Chu, Helen Y., Van Voorhis, Wesley C., Corti, Davide, Veesler, David
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 24.12.2021
• Subjects: 2019-nCoV Vaccine mRNA-1273 - immunology; ACE2; Ad26COVS1 - immunology; Affinity; Angiotensin; Angiotensin-converting enzyme 2; Angiotensin-Converting Enzyme 2 - metabolism; Antibodies, Neutralizing - blood; Antibodies, Neutralizing - immunology; Antibodies, Neutralizing - metabolism; Antibodies, Viral - blood; Antibodies, Viral - immunology; Antibodies, Viral - metabolism; Antigens; Antigens, Viral - chemistry; Antigens, Viral - immunology; Binding; BNT162 Vaccine - immunology; Coronaviruses; COVID-19; COVID-19 Vaccines - immunology; Cryoelectron Microscopy; Disease transmission; Glycoproteins; Humans; Immune Evasion; Immunotherapy; Models, Molecular; Monoclonal antibodies; Mutation; Neutralizing; Peptidyl-dipeptidase A; Protein Binding; Protein Conformation; Protein Domains; Protein Folding; Receptors; Receptors, Coronavirus - metabolism; Recognition; Respiratory diseases; SARS-CoV-2 - chemistry; SARS-CoV-2 - genetics; SARS-CoV-2 - immunology; SARS-CoV-2 - pathogenicity; Severe acute respiratory syndrome coronavirus 2; Spike Glycoprotein, Coronavirus - chemistry; Spike Glycoprotein, Coronavirus - genetics; Spike Glycoprotein, Coronavirus - immunology; Spike Glycoprotein, Coronavirus - metabolism; Vaccines; Viral diseases
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.abl8506

In the course of the COVID-19 epidemic, variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue to emerge, some of which evade immunity or increase transmission. In late 2020, the Delta and Kappa variants were detected, and the Delta variant became globally dominant by June 2021. McCallum et al . show that vaccine-elicited serum-neutralizing activity is reduced against these variants. Based on biochemistry and structural studies, the authors show that mutations in the domain that binds the ACE2 receptor abrogate binding to some monoclonal antibodies but do not improve ACE2 binding, suggesting that they emerged to escape immune recognition. Remodeling of the N-terminal domain allows the variants to escape recognition by most neutralizing antibodies that target it. The work could guide the development of next-generation vaccines and antibody therapies. —VV Changes to the SARS-CoV-2 viral spike protein allow it to evade neutralizing antibodies but do not increase binding to the host receptor. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission leads to the emergence of variants, including the B.1.617.2 (Delta) variant of concern that is causing a new wave of infections and has become globally dominant. We show that these variants dampen the in vitro potency of vaccine-elicited serum neutralizing antibodies and provide a structural framework for describing their immune evasion. Mutations in the B.1.617.1 (Kappa) and Delta spike glycoproteins abrogate recognition by several monoclonal antibodies via alteration of key antigenic sites, including remodeling of the Delta amino-terminal domain. The angiotensin-converting enzyme 2 binding affinities of the Kappa and Delta receptor binding domains are comparable to the Wuhan-Hu-1 isolate, whereas B.1.617.2+ (Delta+) exhibits markedly reduced affinity.