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

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

作者地址："[Callaway, Heather M.; Hastie, Kathryn M.; Schendel, Sharon L.; Li, Haoyang; Yu, Xiaoying; Shek, Jeremy; Buck, Tierra; Hui, Sean; Peters, Bjoern; Saphire, Erica Ollmann] La Jolla Inst Immunol, Ctr Infect Dis & Vaccine Res, La Jolla, CA 92037 USA; [Bedinger, Dan; Troup, Camille] Carterra, 825 N W Ste C309, Salt Lake City, UT 84103 USA; [Dennison, S. Moses; Li, Kan; Tomaras, Georgia] Duke Univ, Ctr Human Syst Immunol, Dept Surg, Durham, NC 27701 USA; [Dennison, S. Moses; Li, Kan; Tomaras, Georgia] Duke Univ, Ctr Human Syst Immunol, Dept Immunol, Durham, NC 27701 USA; [Dennison, S. Moses; Li, Kan; Tomaras, Georgia] Duke Univ, Ctr Human Syst Immunol, Dept Mol Genet & Microbiol, Durham, NC 27701 USA; [Dennison, S. Moses; Li, Kan; Tomaras, Georgia] Duke Univ, Duke Human Vaccine Inst, Durham, NC 27701 USA; [Alpert, Michael D.; Bailey, Charles C.; Trimarchi, Jeffrey M.] Emmune Inc, 14155 US Highway 1, Juno Beach, FL 33408 USA; [Benzeno, Sharon; Gilbert, Amy E.; Howie, Bryan; Keitany, Gladys; Klinger, Mark; Musa, Andrea; Rubin, Benjamin E. R.; Yusko, Erik] Adapt Biotechnol, 1551 Eastlake Ave East, Seattle, WA 98102 USA; [Bonnevier, Jody L.; Hatler, Julia M.] Biotechne, 614 McKinley Pl NE, Minneapolis, MN 55413 USA; [Chen, Jin-Qiu; Chen, Charm; Geukens, Nick] ACRO Biosyst, 1 Innovat Way, Newark, DE 19711 USA; [Cho, Hyeseon; Crompton, Peter D.; Tan, Joshua] NIAID, Antibody Biol Unit, Lab Immunogenet, NIH, Rockville, MD 20852 USA; [Cho, Hyeseon; Crompton, Peter D.] NIAID, Malaria Infect Biol & Immun Sect, Lab Immunogenet, NIH, 401 Profess Dr Ste 241, Rockville, MD 20852 USA; [Dussupt, Vincent; Krebs, Shelly J.; Mendez-Rivera, Letzibeth] Walter Reed Army Inst Res, Emerging Infect Dis Branch, Silver Spring, MD USA; [Dussupt, Vincent; Krebs, Shelly J.; Mendez-Rivera, Letzibeth] Henry M Jackson Fdn Adv Mil Med, Bethesda, MD USA; [Entzminger, Kevin C.; Fleming, Jonathan K.; Maruyama, Toshiaki; Okumura, C. J.] Abwiz Bio Inc, 9823 Pacific Hts Blvd Suite J, San Diego, CA 92121 USA; [Ezzyat, Yassine; Harvey, Christopher J.; Meehl, Michael A.; Singh, Anirudh; Upadhyay, Dhruvkumar P.] Jounce Therapeut Inc, 780 Mem Dr, Cambridge, MA 02139 USA; [Geukens, Nick; Imbrechts, Maya] Katholieke Univ Leuven, KU Leuven Antibody Ctr, PharmAbs, B-3000 Leuven, Belgium; [Guan, Yongjun] Antibody BioPharm Inc, 401 Professional Dr Ste 241, Gaithersburg, MD 20879 USA; [Guan, Yongjun] Shanghai Life Technol Co Ltd, 781 Cai Lun Rd,Ste 801, Shanghai 201203, Peoples R China; [Han, Xiaojian; Hu, Chao; Song, Shuyi; Wang, Yingming] Chongqing Med Univ, Coll Basic Med, Dept Immunol, Chongqing 400010, Peoples R China; [Harvey, Christopher J.] Phenom AI, 661 Univ Ave,Suite 1300 MaRS Ctr,West Tower, Toronto, ON M5G 0B7, Canada; [Huang, Ailong] Chongqing Med Univ, Affiliated Hosp 2, Inst Viral Hepatitis,Minist Educ, Dept Infect Dis,Key Lab Mol Biol Infect Dis, Chongqing 400010, Peoples R China; [Kolls, Jay K.] Tulane Sch Med, Ctr Translat Res Infect & Inflammat, New Orleans, LA 70112 USA; [Sato, Aaron K.; Yuan, Tom Z.] Twist Biosci, 681 Gateway Blvd, San Francisco, CA 94080 USA; [Shen, Meiying] Chongqing Med Univ, Affiliated Hosp 1, Dept Endocrine Breast Surg, Chongqing 400010, Peoples R China; [Trimarchi, Jeffrey M.] Lehigh Univ, Dept Biol Sci, 111 Res Dr, Bethlehem, PA 18015 USA; [Upadhyay, Dhruvkumar P.] Amgen Inc, 360 Binney St, Cambridge, MA 02141 USA; [Yu, Lei] Guangzhou Eighth Peoples Hosp, Guangzhou 510060, Peoples R China; [Yu, Lei] Guangzhou Med Univ, Guangzhou 510060, Peoples R China; [Peters, Bjoern; Saphire, Erica Ollmann] Univ Calif San Diego, Dept Med, La Jolla, CA 92039 USA"

通信作者："Saphire, EO (通讯作者)，La Jolla Inst Immunol, Ctr Infect Dis & Vaccine Res, La Jolla, CA 92037 USA.; Saphire, EO (通讯作者)，Univ Calif San Diego, Dept Med, La Jolla, CA 92039 USA."

来源：CELL REPORTS

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:000946045500001

JCR分区：Q1

影响因子：7.5

年份：2023

卷号：42

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：　

摘要："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 organiza-tion identical to trimeric spike."

基金机构："Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID); National Institutes of Health (NIH); Bill and Melinda Gates Foundation; NIH; GHR Foundation [INV-0006133, INV-008612]; NIH/NIAID [U19 AI142790-03S1]; Guangzhou Municipal Science and Technology Bureau; US Department of Defense, Defense Health Agency [R44AI145491, R44AI134269]; Medical Research and Development Command of the Army Futures Command in the US Department of the Army [202201020528]; Henry M. Jackson Foundation; KU Leuven [W81XWH-18-2-0040]; Chongqing Medical University [W81XWH-18-2-0040]; Chongqing Science and Technology Commission of China [KOOR ZKD8270, SARS-CoV-2 mAb OF2, C3/20/105]; [cstc2021jscx-fyzxX0001]"

基金资助正文："We thank Dr. Ruben Dias Avalos and the LJI Cryoelectron Microscopy Facility for data collection at LJI and Milite Abraha and Gillian Q. Horn for data collection at Duke. The development and analysis of one set of antibodies was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID) , National Institutes of Health (NIH) . We thank the Overton family for launching the study of variants for the CoVIC. The authors are indebted to the many contributors of samples to the CoVIC study. Without their generosity and contributions, a study on this scale would not have been possible. We are thankful for INV-0006133 (E.O.S. and B.P.) and INV-008612 (G.T.) of the Bill and Melinda Gates Foundation, NIH U19 AI142790-03S1, and the GHR Foundation (E.O.S.) for support of this study. We also acknowledge funding from NIH/NIAID grants R44AI145491 and R44AI134269 (M.D.A., C.C.B., and J.M.T.) . L.Y. was supported by project # 202201020528 of Guangzhou Municipal Science and Technology Bureau. S.K. acknowledges funding from the US Department of Defense, Defense Health Agency, through the CARES Act. Additional funding was executed through a cooperative agreement (W81XWH-18-2-0040) between the Medical Research and Development Command of the Army Futures Command in the US Department of the Army and the Henry M. Jackson Foundation. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting true views of the Department of the Army or the Department of Defense. M.G. and N.I. acknowledge support from KU Leuven KOOR ZKD8270, KU Leuven SARS-CoV-2 mAb OF2, and KU Leuven C3/20/105. Isolation of one set of antibodies was supported by the Emergency Project for COVID-19 from Chongqing Medical University and Chongqing Science and Technology Commission (cstc2021jscx-fyzxX0001) of China."