title: Evaluation of candidate vaccine approaches for MERS-CoV.
abstract: The emergence of Middle East respiratory syndrome coronavirus (MERS-CoV) as a cause of severe respiratory disease highlights the need for effective approaches to CoV vaccine development. Efforts focused solely on the receptor-binding domain (RBD) of the viral Spike (S) glycoprotein may not optimize neutralizing antibody (NAb) responses. Here we show that immunogens based on full-length S DNA and S1 subunit protein elicit robust serum-neutralizing activity against several MERS-CoV strains in mice and non-human primates. Serological analysis and isolation of murine monoclonal antibodies revealed that immunization elicits NAbs to RBD and, non-RBD portions of S1 and S2 subunit. Multiple neutralization mechanisms were demonstrated by solving the atomic structure of a NAb-RBD complex, through sequencing of neutralization escape viruses and by constructing MERS-CoV S variants for serological assays. Immunization of rhesus macaques confers protection against MERS-CoV-induced radiographic pneumonia, as assessed using computerized tomography, supporting this strategy as a promising approach for MERS-CoV vaccine development.
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Lingshu
authors.initials: L
authors.lastname: Wang
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: M Gordon
authors.initials: MG
authors.lastname: Joyce
authors.affiliation: 1] Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA [2] U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, USA [3] Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland 20817, USA.
authors.forename: Kayvon
authors.initials: K
authors.lastname: Modjarrad
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Kwanyee
authors.initials: K
authors.lastname: Leung
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Lees
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Tongqing
authors.initials: T
authors.lastname: Zhou
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Hadi M
authors.initials: HM
authors.lastname: Yassine
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Masaru
authors.initials: M
authors.lastname: Kanekiyo
authors.affiliation: 1] Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA [2] Sanofi-Aventis, 270 Albany Street, Cambridge, Massachusetts 02139, USA.
authors.forename: Zhi-yong
authors.initials: ZY
authors.lastname: Yang
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Becker
authors.affiliation: Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
authors.forename: Megan
authors.initials: M
authors.lastname: Freeman
authors.affiliation: Emerging Respiratory Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Leatrice
authors.initials: L
authors.lastname: Vogel
authors.affiliation: Integrated Research Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, Maryland,21702, USA.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Johnson
authors.affiliation: Integrated Research Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, Maryland,21702, USA.
authors.forename: Gene
authors.initials: G
authors.lastname: Olinger
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Todd
authors.affiliation: 1] Center for Infectious Disease Imaging, Department of Radiology and Imaging Sciences, National Institutes of Health, Bethesda, Maryland 20892, USA [2] Center for Research in Computer Vision (CRCV), University of Central Florida, Orlando, Florida 32816, USA.
authors.forename: Ulas
authors.initials: U
authors.lastname: Bagci
authors.affiliation: Center for Infectious Disease Imaging, Department of Radiology and Imaging Sciences, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Solomon
authors.affiliation: Center for Infectious Disease Imaging, Department of Radiology and Imaging Sciences, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Mollura
authors.affiliation: Integrated Research Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, Maryland,21702, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Hensley
authors.affiliation: Integrated Research Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, Maryland,21702, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Jahrling
authors.affiliation: 1] Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA [2] Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Denison
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Srinivas S
authors.initials: SS
authors.lastname: Rao
authors.affiliation: Emerging Respiratory Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Kanta
authors.initials: K
authors.lastname: Subbarao
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Kwong
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Mascola
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Wing-Pui
authors.initials: WP
authors.lastname: Kong
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Barney S
authors.initials: BS
authors.lastname: Graham
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D057134:Antibodies, Neutralizing / Q000276:immunology*; D000914:Antibodies, Viral / Q000276:immunology*; D018352:Coronavirus Infections / Q000517:prevention & control*; D004279:DNA, Viral / Q000276:immunology*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D065207:Middle East Respiratory Syndrome Coronavirus / Q000276:immunology*; D064370:Spike Glycoprotein, Coronavirus / Q000276:immunology*; D019444:Vaccines, DNA / Q000276:immunology*; D014765:Viral Vaccines / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D004279:DNA, Viral; D007074:Immunoglobulin G; D064370:Spike Glycoprotein, Coronavirus; D019444:Vaccines, DNA; D014765:Viral Vaccines