title: Structure-based design of a fusion glycoprotein vaccine for respiratory syncytial virus.
abstract: Respiratory syncytial virus (RSV) is the leading cause of hospitalization for children under 5 years of age. We sought to engineer a viral antigen that provides greater protection than currently available vaccines and focused on antigenic site Ø, a metastable site specific to the prefusion state of the RSV fusion (F) glycoprotein, as this site is targeted by extremely potent RSV-neutralizing antibodies. Structure-based design yielded stabilized versions of RSV F that maintained antigenic site Ø when exposed to extremes of pH, osmolality, and temperature. Six RSV F crystal structures provided atomic-level data on how introduced cysteine residues and filled hydrophobic cavities improved stability. Immunization with site Ø-stabilized variants of RSV F in mice and macaques elicited levels of RSV-specific neutralizing activity many times the protective threshold.
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Jason S
authors.initials: JS
authors.lastname: McLellan
authors.forename: Man
authors.initials: M
authors.lastname: Chen
authors.forename: M Gordon
authors.initials: MG
authors.lastname: Joyce
authors.forename: Mallika
authors.initials: M
authors.lastname: Sastry
authors.forename: Guillaume B E
authors.initials: GB
authors.lastname: Stewart-Jones
authors.forename: Yongping
authors.initials: Y
authors.lastname: Yang
authors.forename: Baoshan
authors.initials: B
authors.lastname: Zhang
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.forename: Sanjay
authors.initials: S
authors.lastname: Srivatsan
authors.forename: Anqi
authors.initials: A
authors.lastname: Zheng
authors.forename: Tongqing
authors.initials: T
authors.lastname: Zhou
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Graepel
authors.forename: Azad
authors.initials: A
authors.lastname: Kumar
authors.forename: Syed
authors.initials: S
authors.lastname: Moin
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Boyington
authors.forename: Gwo-Yu
authors.initials: GY
authors.lastname: Chuang
authors.forename: Cinque
authors.initials: C
authors.lastname: Soto
authors.forename: Ulrich
authors.initials: U
authors.lastname: Baxa
authors.forename: Arjen Q
authors.initials: AQ
authors.lastname: Bakker
authors.forename: Hergen
authors.initials: H
authors.lastname: Spits
authors.forename: Tim
authors.initials: T
authors.lastname: Beaumont
authors.forename: Zizheng
authors.initials: Z
authors.lastname: Zheng
authors.forename: Ningshao
authors.initials: N
authors.lastname: Xia
authors.forename: Sung-Youl
authors.initials: SY
authors.lastname: Ko
authors.forename: John-Paul
authors.initials: JP
authors.lastname: Todd
authors.forename: Srinivas
authors.initials: S
authors.lastname: Rao
authors.forename: Barney S
authors.initials: BS
authors.lastname: Graham
authors.forename: Peter D
authors.initials: PD
authors.lastname: Kwong
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D000956:Antigens, Viral / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D018360:Crystallography, X-Ray; D003545:Cysteine / Q000737:chemistry / Q000235:genetics; D006023:Glycoproteins / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D006801:Humans; D008251:Macaca; D051379:Mice; D015202:Protein Engineering; D055503:Protein Multimerization; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D018357:Respiratory Syncytial Virus Infections / Q000517:prevention & control*; D022261:Respiratory Syncytial Virus Vaccines / Q000737:chemistry*; D014611:Vaccination; D014760:Viral Fusion Proteins / Q000737:chemistry* / Q000235:genetics / Q000276:immunology
chemical_list: D057134:Antibodies, Neutralizing; D000956:Antigens, Viral; D006023:Glycoproteins; D022261:Respiratory Syncytial Virus Vaccines; D014760:Viral Fusion Proteins; D003545:Cysteine