Importance of Neutralizing Monoclonal Antibodies Targeting Multiple Antigenic Sites on the Middle East Respiratory Syndrome Coronavirus Spike Glycoprotein To Avoid Neutralization Escape.
Identifieur interne : 000977 ( PubMed/Corpus ); précédent : 000976; suivant : 000978Importance of Neutralizing Monoclonal Antibodies Targeting Multiple Antigenic Sites on the Middle East Respiratory Syndrome Coronavirus Spike Glycoprotein To Avoid Neutralization Escape.
Auteurs : Lingshu Wang ; Wei Shi ; James D. Chappell ; M Gordon Joyce ; Yi Zhang ; Masaru Kanekiyo ; Michelle M. Becker ; Neeltje Van Doremalen ; Robert Fischer ; Nianshuang Wang ; Kizzmekia S. Corbett ; Misook Choe ; Rosemarie D. Mason ; Joseph G. Van Galen ; Tongqing Zhou ; Kevin O. Saunders ; Kathleen M. Tatti ; Lia M. Haynes ; Peter D. Kwong ; Kayvon Modjarrad ; Wing-Pui Kong ; Jason S. Mclellan ; Mark R. Denison ; Vincent J. Munster ; John R. Mascola ; Barney S. GrahamSource :
- Journal of virology [ 1098-5514 ] ; 2018.
English descriptors
- KwdEn :
- Animals, Antibodies, Monoclonal (chemistry), Antibodies, Monoclonal (metabolism), Antibodies, Neutralizing (chemistry), Antibodies, Neutralizing (metabolism), Antibodies, Viral (chemistry), Antibodies, Viral (metabolism), Coronavirus Infections (immunology), Crystallography, X-Ray, Humans, Macaca mulatta, Mice, Middle East Respiratory Syndrome Coronavirus (immunology), Middle East Respiratory Syndrome Coronavirus (metabolism), Spike Glycoprotein, Coronavirus (chemistry), Spike Glycoprotein, Coronavirus (immunology), Vaccination.
- MESH :
- chemical , chemistry : Antibodies, Monoclonal, Antibodies, Neutralizing, Antibodies, Viral, Spike Glycoprotein, Coronavirus.
- chemical , immunology : Spike Glycoprotein, Coronavirus.
- chemical , metabolism : Antibodies, Monoclonal, Antibodies, Neutralizing, Antibodies, Viral.
- immunology : Coronavirus Infections, Middle East Respiratory Syndrome Coronavirus.
- metabolism : Middle East Respiratory Syndrome Coronavirus.
- Animals, Crystallography, X-Ray, Humans, Macaca mulatta, Mice, Vaccination.
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. 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.IMPORTANCE MERS-CoV causes a highly lethal respiratory infection for which no vaccines or antiviral therapeutic options are currently available. Based on continuing exposure from established reservoirs in dromedary camels and bats, transmission of MERS-CoV into humans and future outbreaks are expected. Using structurally defined probes for the MERS-CoV spike glycoprotein (S), the target for neutralizing antibodies, single B cells were sorted from a convalescent human and immunized nonhuman primates (NHPs). MAbs produced from paired immunoglobulin gene sequences were mapped to multiple epitopes within and outside the receptor-binding domain (RBD) and protected against lethal MERS infection in a murine model following passive immunization. Importantly, combining MAbs targeting distinct epitopes prevented viral neutralization escape from RBD-directed MAbs. These data suggest that antibody responses to multiple domains on CoV spike protein may improve immunity and will guide future vaccine and therapeutic development efforts.
DOI: 10.1128/JVI.02002-17
PubMed: 29514901
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pubmed:29514901Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Importance of Neutralizing Monoclonal Antibodies Targeting Multiple Antigenic Sites on the Middle East Respiratory Syndrome Coronavirus Spike Glycoprotein To Avoid Neutralization Escape.</title><author><name sortKey="Wang, Lingshu" sort="Wang, Lingshu" uniqKey="Wang L" first="Lingshu" last="Wang">Lingshu Wang</name><affiliation><nlm:affiliation>Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Shi, Wei" sort="Shi, Wei" uniqKey="Shi W" first="Wei" last="Shi">Wei Shi</name><affiliation><nlm:affiliation>Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Chappell, James D" sort="Chappell, James D" uniqKey="Chappell J" first="James D" last="Chappell">James D. Chappell</name><affiliation><nlm:affiliation>Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Joyce, M Gordon" sort="Joyce, M Gordon" uniqKey="Joyce M" first="M Gordon" last="Joyce">M Gordon Joyce</name><affiliation><nlm:affiliation>Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Zhang, Yi" sort="Zhang, Yi" uniqKey="Zhang Y" first="Yi" last="Zhang">Yi Zhang</name><affiliation><nlm:affiliation>Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Kanekiyo, Masaru" sort="Kanekiyo, Masaru" uniqKey="Kanekiyo M" first="Masaru" last="Kanekiyo">Masaru Kanekiyo</name><affiliation><nlm:affiliation>Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Becker, Michelle M" sort="Becker, Michelle M" uniqKey="Becker M" first="Michelle M" last="Becker">Michelle M. Becker</name><affiliation><nlm:affiliation>Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Van Doremalen, Neeltje" sort="Van Doremalen, Neeltje" uniqKey="Van Doremalen N" first="Neeltje" last="Van Doremalen">Neeltje Van Doremalen</name><affiliation><nlm:affiliation>Virus Ecology Unit, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Fischer, Robert" sort="Fischer, Robert" uniqKey="Fischer R" first="Robert" last="Fischer">Robert Fischer</name><affiliation><nlm:affiliation>Virus Ecology Unit, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Wang, Nianshuang" sort="Wang, Nianshuang" uniqKey="Wang N" first="Nianshuang" last="Wang">Nianshuang Wang</name><affiliation><nlm:affiliation>Department of Biochemistry and Cellular Biology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Corbett, Kizzmekia S" sort="Corbett, Kizzmekia S" uniqKey="Corbett K" first="Kizzmekia S" last="Corbett">Kizzmekia S. Corbett</name><affiliation><nlm:affiliation>Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Choe, Misook" sort="Choe, Misook" uniqKey="Choe M" first="Misook" last="Choe">Misook Choe</name><affiliation><nlm:affiliation>Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Mason, Rosemarie D" sort="Mason, Rosemarie D" uniqKey="Mason R" first="Rosemarie D" last="Mason">Rosemarie D. Mason</name><affiliation><nlm:affiliation>Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Van Galen, Joseph G" sort="Van Galen, Joseph G" uniqKey="Van Galen J" first="Joseph G" last="Van Galen">Joseph G. Van Galen</name><affiliation><nlm:affiliation>Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Zhou, Tongqing" sort="Zhou, Tongqing" uniqKey="Zhou T" first="Tongqing" last="Zhou">Tongqing Zhou</name><affiliation><nlm:affiliation>Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Saunders, Kevin O" sort="Saunders, Kevin O" uniqKey="Saunders K" first="Kevin O" last="Saunders">Kevin O. Saunders</name><affiliation><nlm:affiliation>Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Tatti, Kathleen M" sort="Tatti, Kathleen M" uniqKey="Tatti K" first="Kathleen M" last="Tatti">Kathleen M. Tatti</name><affiliation><nlm:affiliation>Division of Viral Disease, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Haynes, Lia M" sort="Haynes, Lia M" uniqKey="Haynes L" first="Lia M" last="Haynes">Lia M. Haynes</name><affiliation><nlm:affiliation>Division of Viral Disease, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Kwong, Peter D" sort="Kwong, Peter D" uniqKey="Kwong P" first="Peter D" last="Kwong">Peter D. Kwong</name><affiliation><nlm:affiliation>Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Modjarrad, Kayvon" sort="Modjarrad, Kayvon" uniqKey="Modjarrad K" first="Kayvon" last="Modjarrad">Kayvon Modjarrad</name><affiliation><nlm:affiliation>Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Kong, Wing Pui" sort="Kong, Wing Pui" uniqKey="Kong W" first="Wing-Pui" last="Kong">Wing-Pui Kong</name><affiliation><nlm:affiliation>Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Mclellan, Jason S" sort="Mclellan, Jason S" uniqKey="Mclellan J" first="Jason S" last="Mclellan">Jason S. Mclellan</name><affiliation><nlm:affiliation>Department of Biochemistry and Cellular Biology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Denison, Mark R" sort="Denison, Mark R" uniqKey="Denison M" first="Mark R" last="Denison">Mark R. Denison</name><affiliation><nlm:affiliation>Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Munster, Vincent J" sort="Munster, Vincent J" uniqKey="Munster V" first="Vincent J" last="Munster">Vincent J. Munster</name><affiliation><nlm:affiliation>Virus Ecology Unit, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Mascola, John R" sort="Mascola, John R" uniqKey="Mascola J" first="John R" last="Mascola">John R. Mascola</name><affiliation><nlm:affiliation>Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Graham, Barney S" sort="Graham, Barney S" uniqKey="Graham B" first="Barney S" last="Graham">Barney S. Graham</name><affiliation><nlm:affiliation>Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA bgraham@nih.gov.</nlm:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2018">2018</date><idno type="RBID">pubmed:29514901</idno><idno type="pmid">29514901</idno><idno type="doi">10.1128/JVI.02002-17</idno><idno type="wicri:Area/PubMed/Corpus">000977</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000977</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Importance of Neutralizing Monoclonal Antibodies Targeting Multiple Antigenic Sites on the Middle East Respiratory Syndrome Coronavirus Spike Glycoprotein To Avoid Neutralization Escape.</title><author><name sortKey="Wang, Lingshu" sort="Wang, Lingshu" uniqKey="Wang L" first="Lingshu" last="Wang">Lingshu Wang</name><affiliation><nlm:affiliation>Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Shi, Wei" sort="Shi, Wei" uniqKey="Shi W" first="Wei" last="Shi">Wei Shi</name><affiliation><nlm:affiliation>Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Chappell, James D" sort="Chappell, James D" uniqKey="Chappell J" first="James D" last="Chappell">James D. Chappell</name><affiliation><nlm:affiliation>Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Joyce, M Gordon" sort="Joyce, M Gordon" uniqKey="Joyce M" first="M Gordon" last="Joyce">M Gordon Joyce</name><affiliation><nlm:affiliation>Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Zhang, Yi" sort="Zhang, Yi" uniqKey="Zhang Y" first="Yi" last="Zhang">Yi Zhang</name><affiliation><nlm:affiliation>Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Kanekiyo, Masaru" sort="Kanekiyo, Masaru" uniqKey="Kanekiyo M" first="Masaru" last="Kanekiyo">Masaru Kanekiyo</name><affiliation><nlm:affiliation>Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Becker, Michelle M" sort="Becker, Michelle M" uniqKey="Becker M" first="Michelle M" last="Becker">Michelle M. Becker</name><affiliation><nlm:affiliation>Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Van Doremalen, Neeltje" sort="Van Doremalen, Neeltje" uniqKey="Van Doremalen N" first="Neeltje" last="Van Doremalen">Neeltje Van Doremalen</name><affiliation><nlm:affiliation>Virus Ecology Unit, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Fischer, Robert" sort="Fischer, Robert" uniqKey="Fischer R" first="Robert" last="Fischer">Robert Fischer</name><affiliation><nlm:affiliation>Virus Ecology Unit, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Wang, Nianshuang" sort="Wang, Nianshuang" uniqKey="Wang N" first="Nianshuang" last="Wang">Nianshuang Wang</name><affiliation><nlm:affiliation>Department of Biochemistry and Cellular Biology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Corbett, Kizzmekia S" sort="Corbett, Kizzmekia S" uniqKey="Corbett K" first="Kizzmekia S" last="Corbett">Kizzmekia S. Corbett</name><affiliation><nlm:affiliation>Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Choe, Misook" sort="Choe, Misook" uniqKey="Choe M" first="Misook" last="Choe">Misook Choe</name><affiliation><nlm:affiliation>Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Mason, Rosemarie D" sort="Mason, Rosemarie D" uniqKey="Mason R" first="Rosemarie D" last="Mason">Rosemarie D. Mason</name><affiliation><nlm:affiliation>Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Van Galen, Joseph G" sort="Van Galen, Joseph G" uniqKey="Van Galen J" first="Joseph G" last="Van Galen">Joseph G. Van Galen</name><affiliation><nlm:affiliation>Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Zhou, Tongqing" sort="Zhou, Tongqing" uniqKey="Zhou T" first="Tongqing" last="Zhou">Tongqing Zhou</name><affiliation><nlm:affiliation>Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Saunders, Kevin O" sort="Saunders, Kevin O" uniqKey="Saunders K" first="Kevin O" last="Saunders">Kevin O. Saunders</name><affiliation><nlm:affiliation>Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Tatti, Kathleen M" sort="Tatti, Kathleen M" uniqKey="Tatti K" first="Kathleen M" last="Tatti">Kathleen M. Tatti</name><affiliation><nlm:affiliation>Division of Viral Disease, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Haynes, Lia M" sort="Haynes, Lia M" uniqKey="Haynes L" first="Lia M" last="Haynes">Lia M. Haynes</name><affiliation><nlm:affiliation>Division of Viral Disease, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Kwong, Peter D" sort="Kwong, Peter D" uniqKey="Kwong P" first="Peter D" last="Kwong">Peter D. Kwong</name><affiliation><nlm:affiliation>Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Modjarrad, Kayvon" sort="Modjarrad, Kayvon" uniqKey="Modjarrad K" first="Kayvon" last="Modjarrad">Kayvon Modjarrad</name><affiliation><nlm:affiliation>Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Kong, Wing Pui" sort="Kong, Wing Pui" uniqKey="Kong W" first="Wing-Pui" last="Kong">Wing-Pui Kong</name><affiliation><nlm:affiliation>Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Mclellan, Jason S" sort="Mclellan, Jason S" uniqKey="Mclellan J" first="Jason S" last="Mclellan">Jason S. Mclellan</name><affiliation><nlm:affiliation>Department of Biochemistry and Cellular Biology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Denison, Mark R" sort="Denison, Mark R" uniqKey="Denison M" first="Mark R" last="Denison">Mark R. Denison</name><affiliation><nlm:affiliation>Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Munster, Vincent J" sort="Munster, Vincent J" uniqKey="Munster V" first="Vincent J" last="Munster">Vincent J. Munster</name><affiliation><nlm:affiliation>Virus Ecology Unit, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Mascola, John R" sort="Mascola, John R" uniqKey="Mascola J" first="John R" last="Mascola">John R. Mascola</name><affiliation><nlm:affiliation>Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Graham, Barney S" sort="Graham, Barney S" uniqKey="Graham B" first="Barney S" last="Graham">Barney S. Graham</name><affiliation><nlm:affiliation>Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA bgraham@nih.gov.</nlm:affiliation></affiliation></author></analytic><series><title level="j">Journal of virology</title><idno type="eISSN">1098-5514</idno><imprint><date when="2018" type="published">2018</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Antibodies, Monoclonal (chemistry)</term><term>Antibodies, Monoclonal (metabolism)</term><term>Antibodies, Neutralizing (chemistry)</term><term>Antibodies, Neutralizing (metabolism)</term><term>Antibodies, Viral (chemistry)</term><term>Antibodies, Viral (metabolism)</term><term>Coronavirus Infections (immunology)</term><term>Crystallography, X-Ray</term><term>Humans</term><term>Macaca mulatta</term><term>Mice</term><term>Middle East Respiratory Syndrome Coronavirus (immunology)</term><term>Middle East Respiratory Syndrome Coronavirus (metabolism)</term><term>Spike Glycoprotein, Coronavirus (chemistry)</term><term>Spike Glycoprotein, Coronavirus (immunology)</term><term>Vaccination</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Antibodies, Monoclonal</term><term>Antibodies, Neutralizing</term><term>Antibodies, Viral</term><term>Spike Glycoprotein, Coronavirus</term></keywords><keywords scheme="MESH" type="chemical" qualifier="immunology" xml:lang="en"><term>Spike Glycoprotein, Coronavirus</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Antibodies, Monoclonal</term><term>Antibodies, Neutralizing</term><term>Antibodies, Viral</term></keywords><keywords scheme="MESH" qualifier="immunology" xml:lang="en"><term>Coronavirus Infections</term><term>Middle East Respiratory Syndrome Coronavirus</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Middle East Respiratory Syndrome Coronavirus</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Crystallography, X-Ray</term><term>Humans</term><term>Macaca mulatta</term><term>Mice</term><term>Vaccination</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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. 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.<b>IMPORTANCE</b> MERS-CoV causes a highly lethal respiratory infection for which no vaccines or antiviral therapeutic options are currently available. Based on continuing exposure from established reservoirs in dromedary camels and bats, transmission of MERS-CoV into humans and future outbreaks are expected. Using structurally defined probes for the MERS-CoV spike glycoprotein (S), the target for neutralizing antibodies, single B cells were sorted from a convalescent human and immunized nonhuman primates (NHPs). MAbs produced from paired immunoglobulin gene sequences were mapped to multiple epitopes within and outside the receptor-binding domain (RBD) and protected against lethal MERS infection in a murine model following passive immunization. Importantly, combining MAbs targeting distinct epitopes prevented viral neutralization escape from RBD-directed MAbs. These data suggest that antibody responses to multiple domains on CoV spike protein may improve immunity and will guide future vaccine and therapeutic development efforts.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">29514901</PMID><DateCompleted><Year>2019</Year><Month>08</Month><Day>30</Day></DateCompleted><DateRevised><Year>2019</Year><Month>10</Month><Day>08</Day></DateRevised><Article PubModel="Electronic-Print"><Journal><ISSN IssnType="Electronic">1098-5514</ISSN><JournalIssue CitedMedium="Internet"><Volume>92</Volume><Issue>10</Issue><PubDate><Year>2018</Year><Month>05</Month><Day>15</Day></PubDate></JournalIssue><Title>Journal of virology</Title><ISOAbbreviation>J. Virol.</ISOAbbreviation></Journal><ArticleTitle>Importance of Neutralizing Monoclonal Antibodies Targeting Multiple Antigenic Sites on the Middle East Respiratory Syndrome Coronavirus Spike Glycoprotein To Avoid Neutralization Escape.</ArticleTitle><ELocationID EIdType="pii" ValidYN="Y">e02002-17</ELocationID><ELocationID EIdType="doi" ValidYN="Y">10.1128/JVI.02002-17</ELocationID><Abstract><AbstractText>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. 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.<b>IMPORTANCE</b> MERS-CoV causes a highly lethal respiratory infection for which no vaccines or antiviral therapeutic options are currently available. Based on continuing exposure from established reservoirs in dromedary camels and bats, transmission of MERS-CoV into humans and future outbreaks are expected. Using structurally defined probes for the MERS-CoV spike glycoprotein (S), the target for neutralizing antibodies, single B cells were sorted from a convalescent human and immunized nonhuman primates (NHPs). MAbs produced from paired immunoglobulin gene sequences were mapped to multiple epitopes within and outside the receptor-binding domain (RBD) and protected against lethal MERS infection in a murine model following passive immunization. Importantly, combining MAbs targeting distinct epitopes prevented viral neutralization escape from RBD-directed MAbs. These data suggest that antibody responses to multiple domains on CoV spike protein may improve immunity and will guide future vaccine and therapeutic development efforts.</AbstractText><CopyrightInformation>Copyright © 2018 American Society for Microbiology.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y" EqualContrib="Y"><LastName>Wang</LastName><ForeName>Lingshu</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y" EqualContrib="Y"><LastName>Shi</LastName><ForeName>Wei</ForeName><Initials>W</Initials><AffiliationInfo><Affiliation>Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y" EqualContrib="Y"><LastName>Chappell</LastName><ForeName>James D</ForeName><Initials>JD</Initials><AffiliationInfo><Affiliation>Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Joyce</LastName><ForeName>M Gordon</ForeName><Initials>MG</Initials><AffiliationInfo><Affiliation>Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Zhang</LastName><ForeName>Yi</ForeName><Initials>Y</Initials><AffiliationInfo><Affiliation>Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kanekiyo</LastName><ForeName>Masaru</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Becker</LastName><ForeName>Michelle M</ForeName><Initials>MM</Initials><AffiliationInfo><Affiliation>Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>van Doremalen</LastName><ForeName>Neeltje</ForeName><Initials>N</Initials><AffiliationInfo><Affiliation>Virus Ecology Unit, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Fischer</LastName><ForeName>Robert</ForeName><Initials>R</Initials><AffiliationInfo><Affiliation>Virus Ecology Unit, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Wang</LastName><ForeName>Nianshuang</ForeName><Initials>N</Initials><AffiliationInfo><Affiliation>Department of Biochemistry and Cellular Biology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Corbett</LastName><ForeName>Kizzmekia S</ForeName><Initials>KS</Initials><AffiliationInfo><Affiliation>Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Choe</LastName><ForeName>Misook</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Mason</LastName><ForeName>Rosemarie D</ForeName><Initials>RD</Initials><AffiliationInfo><Affiliation>Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Van Galen</LastName><ForeName>Joseph G</ForeName><Initials>JG</Initials><AffiliationInfo><Affiliation>Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Zhou</LastName><ForeName>Tongqing</ForeName><Initials>T</Initials><Identifier Source="ORCID">0000-0002-3935-4637</Identifier><AffiliationInfo><Affiliation>Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Saunders</LastName><ForeName>Kevin O</ForeName><Initials>KO</Initials><AffiliationInfo><Affiliation>Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Tatti</LastName><ForeName>Kathleen M</ForeName><Initials>KM</Initials><AffiliationInfo><Affiliation>Division of Viral Disease, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Haynes</LastName><ForeName>Lia M</ForeName><Initials>LM</Initials><AffiliationInfo><Affiliation>Division of Viral Disease, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kwong</LastName><ForeName>Peter D</ForeName><Initials>PD</Initials><AffiliationInfo><Affiliation>Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Modjarrad</LastName><ForeName>Kayvon</ForeName><Initials>K</Initials><AffiliationInfo><Affiliation>Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kong</LastName><ForeName>Wing-Pui</ForeName><Initials>WP</Initials><AffiliationInfo><Affiliation>Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>McLellan</LastName><ForeName>Jason S</ForeName><Initials>JS</Initials><AffiliationInfo><Affiliation>Department of Biochemistry and Cellular Biology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Denison</LastName><ForeName>Mark R</ForeName><Initials>MR</Initials><AffiliationInfo><Affiliation>Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Munster</LastName><ForeName>Vincent J</ForeName><Initials>VJ</Initials><AffiliationInfo><Affiliation>Virus Ecology Unit, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Mascola</LastName><ForeName>John R</ForeName><Initials>JR</Initials><AffiliationInfo><Affiliation>Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Graham</LastName><ForeName>Barney S</ForeName><Initials>BS</Initials><Identifier Source="ORCID">0000-0001-8112-0853</Identifier><AffiliationInfo><Affiliation>Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA bgraham@nih.gov.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>HHSN261200800001C</GrantID><Acronym>RC</Acronym><Agency>CCR NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>HHSN261200800001E</GrantID><Acronym>CA</Acronym><Agency>NCI NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>R01 AI127521</GrantID><Acronym>AI</Acronym><Agency>NIAID NIH HHS</Agency><Country>United States</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D052060">Research Support, N.I.H., Intramural</PublicationType><PublicationType UI="D013486">Research Support, U.S. Gov't, Non-P.H.S.</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2018</Year><Month>04</Month><Day>27</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>J Virol</MedlineTA><NlmUniqueID>0113724</NlmUniqueID><ISSNLinking>0022-538X</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000911">Antibodies, Monoclonal</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D057134">Antibodies, Neutralizing</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000914">Antibodies, Viral</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D064370">Spike Glycoprotein, Coronavirus</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000911" MajorTopicYN="N">Antibodies, Monoclonal</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D057134" MajorTopicYN="N">Antibodies, Neutralizing</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000914" MajorTopicYN="N">Antibodies, Viral</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D018352" MajorTopicYN="N">Coronavirus Infections</DescriptorName><QualifierName UI="Q000276" MajorTopicYN="Y">immunology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D018360" MajorTopicYN="N">Crystallography, X-Ray</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008253" MajorTopicYN="N">Macaca mulatta</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D051379" MajorTopicYN="N">Mice</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D065207" MajorTopicYN="N">Middle East Respiratory Syndrome Coronavirus</DescriptorName><QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D064370" MajorTopicYN="N">Spike Glycoprotein, Coronavirus</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000276" MajorTopicYN="Y">immunology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D014611" MajorTopicYN="N">Vaccination</DescriptorName></MeshHeading></MeshHeadingList><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="Y">MERS-CoV</Keyword><Keyword MajorTopicYN="Y">RBD</Keyword><Keyword MajorTopicYN="Y">S1</Keyword><Keyword MajorTopicYN="Y">escape mutation</Keyword><Keyword MajorTopicYN="Y">monoclonal antibody</Keyword><Keyword MajorTopicYN="Y">protection</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2017</Year><Month>11</Month><Day>21</Day></PubMedPubDate><PubMedPubDate 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