Cell Reports (Jan 2023)
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
Affiliations
- Heather M. Callaway
- Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA 92037, USA
- Kathryn M. Hastie
- Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA 92037, USA
- Sharon L. Schendel
- Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA 92037, USA
- Haoyang Li
- Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA 92037, USA
- Xiaoying Yu
- Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA 92037, USA
- Jeremy Shek
- Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA 92037, USA
- Tierra Buck
- Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA 92037, USA
- Sean Hui
- Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA 92037, USA
- Dan Bedinger
- Carterra, 825 N. 300 W. Ste. C309, Salt Lake City, UT 84103, USA
- Camille Troup
- Carterra, 825 N. 300 W. Ste. C309, Salt Lake City, UT 84103, USA
- S. Moses Dennison
- 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
- Kan Li
- 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
- Michael D. Alpert
- Emmune, Inc., 14155 US Highway 1, Juno Beach, FL 33408, USA
- Charles C. Bailey
- Emmune, Inc., 14155 US Highway 1, Juno Beach, FL 33408, USA
- Sharon Benzeno
- Adaptive Biotechnologies, 1551 Eastlake Ave East, Seattle, WA 98102, USA
- Jody L. Bonnevier
- Bio-techne, 614 McKinley Place NE, Minneapolis, MN 55413, USA
- Jin-Qiu Chen
- ACRO Biosystems, 1 Innovation Way, Newark, DE 19711, USA
- Charm Chen
- ACRO Biosystems, 1 Innovation Way, Newark, DE 19711, USA
- Hyeseon Cho
- 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
- Peter D. Crompton
- 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
- Vincent Dussupt
- 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
- Kevin C. Entzminger
- Abwiz Bio, Inc., 9823 Pacific Heights Blvd. Suite J, San Diego, CA 92121, USA
- Yassine Ezzyat
- Jounce Therapeutics, Inc., 780 Memorial Drive, Cambridge, MA 02139, USA
- Jonathan K. Fleming
- Abwiz Bio, Inc., 9823 Pacific Heights Blvd. Suite J, San Diego, CA 92121, USA
- Nick Geukens
- PharmAbs, The KU Leuven Antibody Center, KU Leuven, 3000 Leuven, Belgium
- Amy E. Gilbert
- Adaptive Biotechnologies, 1551 Eastlake Ave East, Seattle, WA 98102, USA
- Yongjun Guan
- 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
- Xiaojian Han
- Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing 400010, China
- Christopher J. Harvey
- 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
- Julia M. Hatler
- Bio-techne, 614 McKinley Place NE, Minneapolis, MN 55413, USA
- Bryan Howie
- Adaptive Biotechnologies, 1551 Eastlake Ave East, Seattle, WA 98102, USA
- Chao Hu
- Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing 400010, China
- Ailong Huang
- 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
- Maya Imbrechts
- PharmAbs, The KU Leuven Antibody Center, KU Leuven, 3000 Leuven, Belgium
- Aishun Jin
- Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing 400010, China
- Nik Kamachi
- ACRO Biosystems, 1 Innovation Way, Newark, DE 19711, USA
- Gladys Keitany
- Adaptive Biotechnologies, 1551 Eastlake Ave East, Seattle, WA 98102, USA
- Mark Klinger
- Adaptive Biotechnologies, 1551 Eastlake Ave East, Seattle, WA 98102, USA
- Jay K. Kolls
- Tulane School of Medicine, Center for Translational Research in Infection and Inflammation, New Orleans, LA 70112, USA
- Shelly J. Krebs
- 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
- Tingting Li
- Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing 400010, China
- Feiyan Luo
- Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing 400010, China
- Toshiaki Maruyama
- Abwiz Bio, Inc., 9823 Pacific Heights Blvd. Suite J, San Diego, CA 92121, USA
- Michael A. Meehl
- Jounce Therapeutics, Inc., 780 Memorial Drive, Cambridge, MA 02139, USA
- Letzibeth Mendez-Rivera
- 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
- Andrea Musa
- Adaptive Biotechnologies, 1551 Eastlake Ave East, Seattle, WA 98102, USA
- C.J. Okumura
- Abwiz Bio, Inc., 9823 Pacific Heights Blvd. Suite J, San Diego, CA 92121, USA
- Benjamin E.R. Rubin
- Adaptive Biotechnologies, 1551 Eastlake Ave East, Seattle, WA 98102, USA
- Aaron K. Sato
- Twist Bioscience, 681 Gateway Blvd., South San Francisco, CA 94080, USA
- Meiying Shen
- Department of Endocrine Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
- Anirudh Singh
- Jounce Therapeutics, Inc., 780 Memorial Drive, Cambridge, MA 02139, USA
- Shuyi Song
- Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing 400010, China
- Joshua Tan
- Antibody Biology Unit, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA
- Jeffrey M. Trimarchi
- Emmune, Inc., 14155 US Highway 1, Juno Beach, FL 33408, USA; Department of Biological Sciences, Lehigh University, 111 Research Drive, Bethlehem, PA 18015, USA
- Dhruvkumar P. Upadhyay
- Jounce Therapeutics, Inc., 780 Memorial Drive, Cambridge, MA 02139, USA; Amgen, Inc., 360 Binney St., Cambridge, MA 02141, USA
- Yingming Wang
- Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing 400010, China
- Lei Yu
- Guangzhou Eighth People’s Hospital & Guangzhou Medical University, Guangzhou 510060, China
- Tom Z. Yuan
- Twist Bioscience, 681 Gateway Blvd., South San Francisco, CA 94080, USA
- Erik Yusko
- Adaptive Biotechnologies, 1551 Eastlake Ave East, Seattle, WA 98102, USA
- Bjoern Peters
- 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
- Georgia Tomaras
- 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
- Erica Ollmann Saphire
- 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; Corresponding author
- Journal volume & issue
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Vol. 42,
no. 1
p. 112014
Abstract
Summary: 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.
