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Title: Importance of Neutralizing Monoclonal Antibodies Targeting Multiple Antigenic Sites on the Middle East Respiratory Syndrome Coronavirus Spike Glycoprotein To Avoid Neutralization Escape

Abstract

Middle East respiratory syndrome coronavirus (MERS-CoV) causes a highly lethal pulmonary infection with ~35% mortality. The potential for a future pandemic originating from animal reservoirs or health care-associated events is a major public health concern. There are no vaccines or therapeutic agents currently available for MERS-CoV. Using a probe-based single B cell cloning strategy, we have identified and characterized multiple neutralizing monoclonal antibodies (MAbs) specifically binding to the receptor-binding domain (RBD) or S1 (non-RBD) regions from a convalescent MERS-CoV-infected patient and from immunized rhesus macaques. RBD-specific MAbs tended to have greater neutralizing potency than non-RBD S1-specific MAbs. We report six RBD-specific and five S1-specific MAbs could be sorted into four RBD and three non-RBD distinct binding patterns, based on competition assays, mapping neutralization escape variants, and structural analysis. We determined cocrystal structures for two MAbs targeting the RBD from different angles and show they can bind the RBD only in the “out” position. We then showed that selected RBD-specific, non-RBD S1-specific, and S2-specific MAbs given prophylactically prevented MERS-CoV replication in lungs and protected mice from lethal challenge. Importantly, combining RBD- and non-RBD MAbs delayed the emergence of escape mutations in a cell-based virus escape assay. These studies identify MAbs targetingmore » different antigenic sites on S that will be useful for defining mechanisms of MERS-CoV neutralization and for developing more effective interventions to prevent or treat MERS-CoV infections.« less

Authors:
 [1];  [1];  [2];  [1];  [1];  [1];  [2];  [3];  [3];  [4];  [1];  [1];  [1];  [1]; ORCiD logo [1];  [1];  [5];  [5];  [1];  [1] more »;  [1];  [4];  [2];  [3];  [1]; ORCiD logo [1] « less
  1. National Inst. of Health, Bethesda, MD (United States). National Inst. of Allergy and Infectious Diseases, Vaccine Research Center
  2. Vanderbilt Univ. Medical Center, Nashville, TN (United States)
  3. National Inst. of Health, Hamilton, MT (United States). National Inst. of Allergy and Infectious Diseases, Rocky Mountain Lab., Virus Ecology Unit
  4. Geisel School of Medicine at Dartmouth, Hanover, NH (United States)
  5. Centers for Disease Control and Prevention (CDC), Atlanta, GA (United States). National Center for Immunization and Respiratory Diseases, Division of Viral Disease
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases. Vaccine Research Center; USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)
OSTI Identifier:
1435835
Grant/Contract Number:  
HHSN261200800001E; AC02-06CH11357; W-31-109-Eng-38
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Journal of Virology
Additional Journal Information:
Journal Volume: 92; Journal Issue: 10; Journal ID: ISSN 0022-538X
Publisher:
American Society for Microbiology
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; MERS-CoV; protection; RBD; S1; escape mutation; monoclonal antibody

Citation Formats

Wang, Lingshu, Shi, Wei, Chappell, James D., Joyce, M. Gordon, Zhang, Yi, Kanekiyo, Masaru, Becker, Michelle M., van Doremalen, Neeltje, Fischer, Robert, Wang, Nianshuang, Corbett, Kizzmekia S., Choe, Misook, Mason, Rosemarie D., Van Galen, Joseph G., Zhou, Tongqing, Saunders, Kevin O., Tatti, Kathleen M., Haynes, Lia M., Kwong, Peter D., Modjarrad, Kayvon, Kong, Wing-Pui, McLellan, Jason S., Denison, Mark R., Munster, Vincent J., Mascola, John R., and Graham, Barney S. Importance of Neutralizing Monoclonal Antibodies Targeting Multiple Antigenic Sites on the Middle East Respiratory Syndrome Coronavirus Spike Glycoprotein To Avoid Neutralization Escape. United States: N. p., 2018. Web. doi:10.1128/JVI.02002-17.
Wang, Lingshu, Shi, Wei, Chappell, James D., Joyce, M. Gordon, Zhang, Yi, Kanekiyo, Masaru, Becker, Michelle M., van Doremalen, Neeltje, Fischer, Robert, Wang, Nianshuang, Corbett, Kizzmekia S., Choe, Misook, Mason, Rosemarie D., Van Galen, Joseph G., Zhou, Tongqing, Saunders, Kevin O., Tatti, Kathleen M., Haynes, Lia M., Kwong, Peter D., Modjarrad, Kayvon, Kong, Wing-Pui, McLellan, Jason S., Denison, Mark R., Munster, Vincent J., Mascola, John R., & Graham, Barney S. Importance of Neutralizing Monoclonal Antibodies Targeting Multiple Antigenic Sites on the Middle East Respiratory Syndrome Coronavirus Spike Glycoprotein To Avoid Neutralization Escape. United States. doi:10.1128/JVI.02002-17.
Wang, Lingshu, Shi, Wei, Chappell, James D., Joyce, M. Gordon, Zhang, Yi, Kanekiyo, Masaru, Becker, Michelle M., van Doremalen, Neeltje, Fischer, Robert, Wang, Nianshuang, Corbett, Kizzmekia S., Choe, Misook, Mason, Rosemarie D., Van Galen, Joseph G., Zhou, Tongqing, Saunders, Kevin O., Tatti, Kathleen M., Haynes, Lia M., Kwong, Peter D., Modjarrad, Kayvon, Kong, Wing-Pui, McLellan, Jason S., Denison, Mark R., Munster, Vincent J., Mascola, John R., and Graham, Barney S. Wed . "Importance of Neutralizing Monoclonal Antibodies Targeting Multiple Antigenic Sites on the Middle East Respiratory Syndrome Coronavirus Spike Glycoprotein To Avoid Neutralization Escape". United States. doi:10.1128/JVI.02002-17. https://www.osti.gov/servlets/purl/1435835.
@article{osti_1435835,
title = {Importance of Neutralizing Monoclonal Antibodies Targeting Multiple Antigenic Sites on the Middle East Respiratory Syndrome Coronavirus Spike Glycoprotein To Avoid Neutralization Escape},
author = {Wang, Lingshu and Shi, Wei and Chappell, James D. and Joyce, M. Gordon and Zhang, Yi and Kanekiyo, Masaru and Becker, Michelle M. and van Doremalen, Neeltje and Fischer, Robert and Wang, Nianshuang and Corbett, Kizzmekia S. and Choe, Misook and Mason, Rosemarie D. and Van Galen, Joseph G. and Zhou, Tongqing and Saunders, Kevin O. and Tatti, Kathleen M. and Haynes, Lia M. and Kwong, Peter D. and Modjarrad, Kayvon and Kong, Wing-Pui and McLellan, Jason S. and Denison, Mark R. and Munster, Vincent J. and Mascola, John R. and Graham, Barney S.},
abstractNote = {Middle East respiratory syndrome coronavirus (MERS-CoV) causes a highly lethal pulmonary infection with ~35% mortality. The potential for a future pandemic originating from animal reservoirs or health care-associated events is a major public health concern. There are no vaccines or therapeutic agents currently available for MERS-CoV. Using a probe-based single B cell cloning strategy, we have identified and characterized multiple neutralizing monoclonal antibodies (MAbs) specifically binding to the receptor-binding domain (RBD) or S1 (non-RBD) regions from a convalescent MERS-CoV-infected patient and from immunized rhesus macaques. RBD-specific MAbs tended to have greater neutralizing potency than non-RBD S1-specific MAbs. We report six RBD-specific and five S1-specific MAbs could be sorted into four RBD and three non-RBD distinct binding patterns, based on competition assays, mapping neutralization escape variants, and structural analysis. We determined cocrystal structures for two MAbs targeting the RBD from different angles and show they can bind the RBD only in the “out” position. We then showed that selected RBD-specific, non-RBD S1-specific, and S2-specific MAbs given prophylactically prevented MERS-CoV replication in lungs and protected mice from lethal challenge. Importantly, combining RBD- and non-RBD MAbs delayed the emergence of escape mutations in a cell-based virus escape assay. These studies identify MAbs targeting different antigenic sites on S that will be useful for defining mechanisms of MERS-CoV neutralization and for developing more effective interventions to prevent or treat MERS-CoV infections.},
doi = {10.1128/JVI.02002-17},
journal = {Journal of Virology},
issn = {0022-538X},
number = 10,
volume = 92,
place = {United States},
year = {2018},
month = {3}
}

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    Works referencing / citing this record:

    Structural definition of a neutralization epitope on the N-terminal domain of MERS-CoV spike glycoprotein
    journal, July 2019