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 Ellington; Edward 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

doi:10.1038/s42003-023-05649-6

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

Commun Biol. 2023 Dec 11;6(1):1250. doi: 10.1038/s42003-023-05649-6.

Authors

Jule Goike^#^{1

2}, Ching-Lin Hsieh^#², Andrew P Horton^#^{1

2

3}, Elizabeth C Gardner^#^{1

2}, Ling Zhou², Foteini Bartzoka^{1

2}, Nianshuang Wang², Kamyab Javanmardi^{1

2}, Andrew Herbert⁴, Shawn Abbassi⁴, Xuping Xie⁵, Hongjie Xia⁵, Pei-Yong Shi⁵, Rebecca Renberg⁶, Thomas H Segall-Shapiro^{3

7}, Cynthia I Terrace⁷, Wesley Wu³, Raghav Shroff^{1

2

3

7}, Michelle Byrom¹, Andrew D Ellington^{1

2

8}, Edward M Marcotte^{1

2}, James M Musser³, Suresh V Kuchipudi⁹, Vivek Kapur¹⁰, George Georgiou^{1

2

8

11

12}, Scott C Weaver¹³, John M Dye⁴, Daniel R Boutz^{14

15

16

17}, Jason S McLellan¹⁸, Jimmy D Gollihar^{19

20

21

22}

Affiliations

¹ Center for Systems and Synthetic Biology, Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, USA.
² Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, USA.
³ Antibody Discovery and Accelerated Protein Therapeutics, Department of Pathology and Genomic Medicine, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, USA.
⁴ U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD, USA.
⁵ Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA.
⁶ DEVCOM Army Research Laboratory, Biotechnology Branch, Adelphi, MD, USA.
⁷ DEVCOM Army Research Laboratory-South, Austin, TX, USA.
⁸ Department of Chemistry, The University of Texas at Austin, Austin, TX, USA.
⁹ Department of Veterinary and Biomedical Science and Animal Diagnostic Laboratory, The Pennsylvania State University, University Park, PA, USA.
¹⁰ Department of Animal Science and the Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, PA, USA.
¹¹ Department of Chemical Engineering, The University of Texas at Austin, Austin, TX, USA.
¹² Department of Oncology, Dell Medical School, The University of Texas at Austin, Austin, TX, USA.
¹³ University of Texas Medical Branch, World Reference Center for Emerging Viruses and Arboviruses, Galveston, TX, USA.
¹⁴ Center for Systems and Synthetic Biology, Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, USA. drboutz@houstonmethodist.org.
¹⁵ Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, USA. drboutz@houstonmethodist.org.
¹⁶ Antibody Discovery and Accelerated Protein Therapeutics, Department of Pathology and Genomic Medicine, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, USA. drboutz@houstonmethodist.org.
¹⁷ DEVCOM Army Research Laboratory-South, Austin, TX, USA. drboutz@houstonmethodist.org.
¹⁸ Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, USA. jmclellan@austin.utexas.edu.
¹⁹ Center for Systems and Synthetic Biology, Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, USA. jgollihar2@houstonmethodist.org.
²⁰ Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, USA. jgollihar2@houstonmethodist.org.
²¹ Antibody Discovery and Accelerated Protein Therapeutics, Department of Pathology and Genomic Medicine, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, USA. jgollihar2@houstonmethodist.org.
²² DEVCOM Army Research Laboratory-South, Austin, TX, USA. jgollihar2@houstonmethodist.org.

^# Contributed equally.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Antibodies, Neutralizing
COVID-19*
Humans
SARS-CoV-2* / genetics
Spike Glycoprotein, Coronavirus / genetics

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

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