@article{20209962e7de421680f7842c796254df,
title = "SARS-COV-2 Omicron variants conformationally escape a rare quaternary antibody binding mode",
abstract = "The ongoing evolution of SARS-CoV-2 into more easily transmissible and infectious variants has provided unprecedented insight into mutations enabling immune escape. Understanding how these mutations affect the dynamics of antibody-antigen interactions is crucial to the development of broadly protective antibodies and vaccines. Here we report the characterization of a potent neutralizing antibody (N3-1) identified from a COVID-19 patient during the first disease wave. Cryogenic electron microscopy revealed a quaternary binding mode that enables direct interactions with all three receptor-binding domains of the spike protein trimer, resulting in extraordinary avidity and potent neutralization of all major variants of concern until the emergence of Omicron. Structure-based rational design of N3-1 mutants improved binding to all Omicron variants but only partially restored neutralization of the conformationally distinct Omicron BA.1. This study provides new insights into immune evasion through changes in spike protein dynamics and highlights considerations for future conformationally biased multivalent vaccine designs.",
keywords = "Antibodies, Neutralizing, COVID-19, SARS-CoV-2/genetics, Humans, Spike Glycoprotein, Coronavirus/genetics",
author = "Jule Goike and Hsieh, {Ching Lin} and Horton, {Andrew P.} and Gardner, {Elizabeth C.} and Ling Zhou and Foteini Bartzoka and Nianshuang Wang and Kamyab Javanmardi and Andrew Hebert and Abbasi, {Shawn A.} and Xuping Xie and Hongjie Xia and Shi, {Pei Yong} and Rebecca Renberg and Thomas Segall-Shapiro and Terrace, {Cynthia I.} and Wesley Wu and Raghav Shroff and Michelle Byrom and Ellington, {Andrew D.} and Marcotte, {Edward M.} and Musser, {James M.} and Kuchipudi, {Suresh V.} and Vivek Kapur and George Georgiou and Scott Weaver and Dye, {John M.} and Boutz, {Daniel R.} and McLellan, {Jason S.} and Gollihar, {Jimmy D.}",
note = "Funding Information: We thank Greg Ippolito, Jason Lavinder, and Will Voss for technical assistance. We would like to thank Dr. Sasha Dickinson from the Sauer Structural Biology Laboratory at the University of Texas at Austin for his assistance with microscope data collection. The Sauer Structural Biology Laboratory is supported by the University of Texas College of Natural Sciences and by award RR160023 from the Cancer Prevention and Research Institute of Texas (CPRIT). Funding for USAMRIID was provided through the CARES Act with programmatic oversight from the Military Infectious Diseases Research Program–project 14066041. Opinions, conclusions, interpretations, and recommendations are those of the authors and are not necessarily endorsed by the U.S. Army. The mention of trade names or commercial products does not constitute endorsement or recommendation for use by the Department of the Army or the Department of Defense. Molecular graphics and analyses were performed with UCSF Chimera, developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, with support from NIH P41-GM103311. SEC-MALS analysis and interpretation was performed by the Biomolecular Characterization Unit, Protein and Monoclonal Antibody Production Core at Baylor College of Medicine under the direction of Josephine C. Ferreon and funding from NIH S10-OD030276. This research was funded in part by: the Army Research Laboratory{\textquoteright}s TRANSFORME Essential Research Program (JDG, DRB, RR, THSS); a Cooperative Agreement (W911NF-17-2-0091) between ARL and UT Austin to ADE, EMM, and GG; a grant from DTRA (HDTRA12010011) awarded to JDG and ADE; a National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases (NIAID) grant awarded to JSM (R01 AI127521); financial assistance award 70NANB20H037 to JDG from the US Department of Commerce, National Institutes of Standards and Technology (NIST) via the National Institute for Innovation in Manufacturing Biopharmaceuticals (NIIMBL); a Welch grant (F-1016) awarded to IJF; a Welch grant (F-1515) awarded to EMM; funding support from the Huck Institutes of Life Sciences and the Pennsylvania Agricultural Experiment Station (to VK and SK); an NIH grant (R01 AI158177-01) to SK; and an NIH grant (R35 GM122480) to EMM. Funding Information: We thank Greg Ippolito, Jason Lavinder, and Will Voss for technical assistance. We would like to thank Dr. Sasha Dickinson from the Sauer Structural Biology Laboratory at the University of Texas at Austin for his assistance with microscope data collection. The Sauer Structural Biology Laboratory is supported by the University of Texas College of Natural Sciences and by award RR160023 from the Cancer Prevention and Research Institute of Texas (CPRIT). Funding for USAMRIID was provided through the CARES Act with programmatic oversight from the Military Infectious Diseases Research Program–project 14066041. Opinions, conclusions, interpretations, and recommendations are those of the authors and are not necessarily endorsed by the U.S. Army. The mention of trade names or commercial products does not constitute endorsement or recommendation for use by the Department of the Army or the Department of Defense. Molecular graphics and analyses were performed with UCSF Chimera, developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, with support from NIH P41-GM103311. SEC-MALS analysis and interpretation was performed by the Biomolecular Characterization Unit, Protein and Monoclonal Antibody Production Core at Baylor College of Medicine under the direction of Josephine C. Ferreon and funding from NIH S10-OD030276. This research was funded in part by: the Army Research Laboratory{\textquoteright}s TRANSFORME Essential Research Program (JDG, DRB, RR, THSS); a Cooperative Agreement (W911NF-17-2-0091) between ARL and UT Austin to ADE, EMM, and GG; a grant from DTRA (HDTRA12010011) awarded to JDG and ADE; a National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases (NIAID) grant awarded to JSM (R01 AI127521); financial assistance award 70NANB20H037 to JDG from the US Department of Commerce, National Institutes of Standards and Technology (NIST) via the National Institute for Innovation in Manufacturing Biopharmaceuticals (NIIMBL); a Welch grant (F-1016) awarded to IJF; a Welch grant (F-1515) awarded to EMM; funding support from the Huck Institutes of Life Sciences and the Pennsylvania Agricultural Experiment Station (to VK and SK); an NIH grant (R01 AI158177-01) to SK; and an NIH grant (R35 GM122480) to EMM. Publisher Copyright: {\textcopyright} 2023, The Author(s).",
year = "2023",
month = dec,
day = "11",
doi = "10.1038/s42003-023-05649-6",
language = "English (US)",
volume = "6",
pages = "1250",
journal = "Communications Biology",
issn = "2399-3642",
publisher = "Springer Nature",
}