SARS-COV-2 Omicron variants conformationally escape a rare quaternary antibody binding mode

Jule Goike, Ching Lin Hsieh, Andrew P. Horton, Elizabeth C. Gardner, Ling Zhou, Foteini Bartzoka, Nianshuang Wang, Kamyab Javanmardi, Andrew Herbert, Shawn Abbassi, Xuping Xie, Hongjie Xia, Pei-Yong Shi, Rebecca Renberg, Thomas H. Segall-Shapiro, Cynthia I. Terrace, Wesley Wu, Raghav Shroff, Michelle Byrom, Andrew D. EllingtonEdward M. Marcotte, James M. Musser, Suresh V. Kuchipudi, Vivek Kapur, George Georgiou, Scott C. Weaver, John M. Dye, Daniel R. Boutz, Jason S. McLellan, Jimmy D. Gollihar

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Article number1250
JournalCommunications Biology
Volume6
Issue number1
DOIs
StatePublished - Dec 2023

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • General Biochemistry, Genetics and Molecular Biology
  • General Agricultural and Biological Sciences

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