Defining variant-resistant epitopes targeted by SARS-CoV-2 antibodies

SCIENCE VOLUME 374 | ISSUE 6566 | 23 SEPT 2021

Kathryn M. Hastie, Haoyang Li, Daniel Bedinger, Sharon L. Schendel, S. Moses Dennison, Kan Li, Vamseedhar Rayaprolu, Xiaoying Yu, Colin Mann, Michelle Zandonatti, Ruben Diaz Avalos, Dawid Zyla, Tierra Buck, Sean Hui, Kelly Shaffer, Chitra Hariharan, Jieyun Yin, Eduardo Olmedillas, Adrian Enriquez, Diptiben Parekh, Milite Abraha, Elizabeth Feeney, Gillian Q. Horn, CoVIC–DB team, Yoann Aldon, Hanif Ali, Sanja Aracic, Ronald R. Cobb, Ross S. Federman, Joseph M. Fernandez, Jacob Glanville, Robin Green, Gevorg Grigoryan, Ana G. Lujan Hernandez, David D. Ho, Kuan–Ying A. Huang, John Ingraham, Weidong Jiang, Paul Kellam, Cheolmin Kim, Minsoo Kim, Hyeong Mi Kim, Chao Kong, Shelly J. Krebs, Fei Lan, Guojun Lang, Sooyoung Lee, Cheuk Lun Leung, Junli Liu, Yanan Lu, Anna MacCamy, Andrew T. McGuire, Anne L. Palser, Terence H. Rabbitts, Zahra Rikhtegaran Tehrani, Mohammad M. Sajadi, Rogier W. Sanders, Aaron K. Sato, Liang Schweizer, Jimin Seo, Bingqing Shen, Jonne J. Snitselaar, Leonidas Stamatatos, Yongcong Tan, Milan T. Tomic, Marit J. van Gils, Sawsan Youssef, Jian Yu, Tom Z. Yuan, Qian Zhang, Bjoern Peters, Georgia D. Tomaras, Timothy Germann, Erica Ollmann Saphire

Abstract

Antibody-based therapeutics and vaccines are essential to combat COVID-19 morbidity and mortality following severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Multiple mutations in SARS-CoV-2 that could impair antibody defenses propagated in human-to-human transmission and spillover/spillback events between humans and animals. To develop prevention and therapeutic strategies, we formed an international consortium to map the epitope landscape on the SARS-CoV-2 Spike, defining and structurally illustrating seven receptor-binding domain (RBD)-directed antibody communities with distinct footprints and competition profiles. Pseudovirion-based neutralization assays reveal Spike mutations, individually and clustered together in variants, that impact antibody function among the communities. Key classes of RBD-targeted antibodies maintain neutralization activity against these emerging SARS-CoV-2 variants. These results provide a framework for selecting antibody treatment cocktails and understanding how viral variants might affect antibody therapeutic efficacy.

Report

Cell entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is mediated by its surface glycoprotein, Spike. The S1 subunit of Spike contains the N-terminal domain (NTD) and the receptor-binding domain (RBD), which mediates recognition of the host cell receptor angiotensin-converting enzyme 2 (ACE2). The S2 subunit drives fusion between virus and host cell membranes. Spike, particularly the S1 subunit, is the primary target of neutralizing antibodies against SARS-CoV-2.

Since SARS-CoV-2 first emerged, recurrent mutations in Spike arose during both human-to-human transmission and spillover/spillback events between humans and animals. Distinct Variants of Concern (VOCs) or Variants of Interest (VOIs), including those first identified in the UK (alpha, B.1.1.7), South Africa (beta, B.1.351), Brazil (gamma, P.1), India (delta, B.1.617.2) and California (epsilon, B.1.429) carry several mutations associated with enhancement of human-to-human transmission. In particular, the receptor-binding motif (RBM) mutations K417, L452, E484 and N501 affect ACE2-Spike interactions. Variations at positions N439 and S477 are frequently detected in patient samples, whereas others such as V367F, Y453F and F486L are associated with cross-species transmission. The NTD is also highly mutable and is especially prone to deletions: ∆HV69-70 and ∆Y144 are both seen in B.1.1.7 and ∆HV69-70 is in the mink-associated Cluster V. ∆LAL242-244 appears in B.1.351, and ∆FR157-158 is found in B.1.617.2. The NTD point mutations S13I and W152C alter disulfide bonding and conformation of the B.1.429 NTD.