Bivalent intra-spike binding provides durability against emergent Omicron lineages: Results from a global consortium

Heather M Callaway; Kathryn M Hastie; Sharon L Schendel; Haoyang Li; Xiaoying Yu; Jeremy Shek; Tierra Buck; Sean Hui; Dan Bedinger; Camille Troup; S Moses Dennison; Kan Li; Michael D Alpert; Charles C Bailey; Sharon Benzeno; Jody L Bonnevier; Jin-Qiu Chen; Charm Chen; Hyeseon Cho; Peter D Crompton; Vincent Dussupt; Kevin C Entzminger; Yassine Ezzyat; Jonathan K Fleming; Nick Geukens; Amy E Gilbert; Yongjun Guan; Xiaojian Han; Christopher J Harvey; Julia M Hatler; Bryan Howie; Chao Hu; Ailong Huang; Maya Imbrechts; Aishun Jin; Nik Kamachi; Gladys Keitany; Mark Klinger; Jay K Kolls; Shelly J Krebs; Tingting Li; Feiyan Luo; Toshiaki Maruyama; Michael A Meehl; Letzibeth Mendez-Rivera; Andrea Musa; C J Okumura; Benjamin E R Rubin; Aaron K Sato; Meiying Shen; Anirudh Singh; Shuyi Song; Joshua Tan; Jeffrey M Trimarchi; Dhruvkumar P Upadhyay; Yingming Wang; Lei Yu; Tom Z Yuan; Erik Yusko; Bjoern Peters; Georgia Tomaras; Erica Ollmann Saphire

doi:10.1016/j.celrep.2023.112014

Bivalent intra-spike binding provides durability against emergent Omicron lineages: Results from a global consortium

Cell Rep. 2023 Jan 31;42(1):112014. doi: 10.1016/j.celrep.2023.112014. Epub 2023 Jan 12.

Authors

Heather M Callaway¹, Kathryn M Hastie¹, Sharon L Schendel¹, Haoyang Li¹, Xiaoying Yu¹, Jeremy Shek¹, Tierra Buck¹, Sean Hui¹, Dan Bedinger², Camille Troup², S Moses Dennison³, Kan Li³, Michael D Alpert⁴, Charles C Bailey⁴, Sharon Benzeno⁵, Jody L Bonnevier⁶, Jin-Qiu Chen⁷, Charm Chen⁷, Hyeseon Cho⁸, Peter D Crompton⁸, Vincent Dussupt⁹, Kevin C Entzminger¹⁰, Yassine Ezzyat¹¹, Jonathan K Fleming¹⁰, Nick Geukens¹², Amy E Gilbert⁵, Yongjun Guan¹³, Xiaojian Han¹⁴, Christopher J Harvey¹⁵, Julia M Hatler⁶, Bryan Howie⁵, Chao Hu¹⁴, Ailong Huang¹⁶, Maya Imbrechts¹², Aishun Jin¹⁴, Nik Kamachi⁷, Gladys Keitany⁵, Mark Klinger⁵, Jay K Kolls¹⁷, Shelly J Krebs⁹, Tingting Li¹⁴, Feiyan Luo¹⁴, Toshiaki Maruyama¹⁰, Michael A Meehl¹¹, Letzibeth Mendez-Rivera⁹, Andrea Musa⁵, C J Okumura¹⁰, Benjamin E R Rubin⁵, Aaron K Sato¹⁸, Meiying Shen¹⁹, Anirudh Singh¹¹, Shuyi Song¹⁴, Joshua Tan²⁰, Jeffrey M Trimarchi²¹, Dhruvkumar P Upadhyay²², Yingming Wang¹⁴, Lei Yu²³, Tom Z Yuan¹⁸, Erik Yusko⁵, Bjoern Peters²⁴, Georgia Tomaras³, Erica Ollmann Saphire²⁵

Affiliations

¹ Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA 92037, USA.
² Carterra, 825 N. 300 W. Ste. C309, Salt Lake City, UT 84103, USA.
³ Center for Human Systems Immunology, Departments of Surgery, Immunology, and Molecular Genetics and Microbiology and Duke Human Vaccine Institute, Duke University, Durham, NC 27701, USA.
⁴ Emmune, Inc., 14155 US Highway 1, Juno Beach, FL 33408, USA.
⁵ Adaptive Biotechnologies, 1551 Eastlake Ave East, Seattle, WA 98102, USA.
⁶ Bio-techne, 614 McKinley Place NE, Minneapolis, MN 55413, USA.
⁷ ACRO Biosystems, 1 Innovation Way, Newark, DE 19711, USA.
⁸ Antibody Biology Unit, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA; Malaria Infection Biology and Immunity Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA.
⁹ Emerging Infectious Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA.
¹⁰ Abwiz Bio, Inc., 9823 Pacific Heights Blvd. Suite J, San Diego, CA 92121, USA.
¹¹ Jounce Therapeutics, Inc., 780 Memorial Drive, Cambridge, MA 02139, USA.
¹² PharmAbs, The KU Leuven Antibody Center, KU Leuven, 3000 Leuven, Belgium.
¹³ Antibody BioPharm, Inc., 401 Professional Dr Ste 241, Gaithersburg, MD 20879, USA; Shanghai Life Technology Co., Ltd., 781 Cai Lun Rd, Ste 801, Pudong, Shanghai 201203, China.
¹⁴ Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing 400010, China.
¹⁵ Jounce Therapeutics, Inc., 780 Memorial Drive, Cambridge, MA 02139, USA; Phenomic AI, 661 University Avenue, Suite 1300 MaRS Centre, West Tower, Toronto, ON M5G 0B7, Canada.
¹⁶ Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, China.
¹⁷ Tulane School of Medicine, Center for Translational Research in Infection and Inflammation, New Orleans, LA 70112, USA.
¹⁸ Twist Bioscience, 681 Gateway Blvd., South San Francisco, CA 94080, USA.
¹⁹ Department of Endocrine Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China.
²⁰ Antibody Biology Unit, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA.
²¹ Emmune, Inc., 14155 US Highway 1, Juno Beach, FL 33408, USA; Department of Biological Sciences, Lehigh University, 111 Research Drive, Bethlehem, PA 18015, USA.
²² Jounce Therapeutics, Inc., 780 Memorial Drive, Cambridge, MA 02139, USA; Amgen, Inc., 360 Binney St., Cambridge, MA 02141, USA.
²³ Guangzhou Eighth People's Hospital & Guangzhou Medical University, Guangzhou 510060, China.
²⁴ Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA 92037, USA; Department of Medicine, University of California San Diego, La Jolla, CA 92039, USA.
²⁵ Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA 92037, USA; Department of Medicine, University of California San Diego, La Jolla, CA 92039, USA. Electronic address: erica@lji.org.

Abstract

The SARS-CoV-2 Omicron variant of concern (VoC) and its sublineages contain 31-36 mutations in spike and escape neutralization by most therapeutic antibodies. In a pseudovirus neutralization assay, 66 of the nearly 400 candidate therapeutics in the Coronavirus Immunotherapeutic Consortium (CoVIC) panel neutralize Omicron and multiple Omicron sublineages. Among natural immunoglobulin Gs (IgGs), especially those in the receptor-binding domain (RBD)-2 epitope community, nearly all Omicron neutralizers recognize spike bivalently, with both antigen-binding fragments (Fabs) simultaneously engaging adjacent RBDs on the same spike. Most IgGs that do not neutralize Omicron bind either entirely monovalently or have some (22%-50%) monovalent occupancy. Cleavage of bivalent-binding IgGs to Fabs abolishes neutralization and binding affinity, with disproportionate loss of activity against Omicron pseudovirus and spike. These results suggest that VoC-resistant antibodies overcome mutagenic substitution via avidity. Hence, vaccine strategies targeting future SARS-CoV-2 variants should consider epitope display with spacing and organization identical to trimeric spike.

Keywords: COVID-19; CP: Immunology; SARS-CoV-2; bivalent antibody binding; coronavirus; neutralization; therapeutic antibodies.

Publication types

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

MeSH terms

Antibodies, Neutralizing
Antibodies, Viral
COVID-19*
Epitopes
Ethnicity
Humans
Neutralization Tests
SARS-CoV-2

Bivalent intra-spike binding provides durability against emergent Omicron lineages: Results from a global consortium

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