title: Structural basis for immunization with postfusion respiratory syncytial virus fusion F glycoprotein (RSV F) to elicit high neutralizing antibody titers.
abstract: Respiratory syncytial virus (RSV), the main cause of infant bronchiolitis, remains a major unmet vaccine need despite more than 40 years of vaccine research. Vaccine candidates based on a chief RSV neutralization antigen, the fusion (F) glycoprotein, have foundered due to problems with stability, purity, reproducibility, and potency. Crystal structures of related parainfluenza F glycoproteins have revealed a large conformational change between the prefusion and postfusion states, suggesting that postfusion F antigens might not efficiently elicit neutralizing antibodies. We have generated a homogeneous, stable, and reproducible postfusion RSV F immunogen that elicits high titers of neutralizing antibodies in immunized animals. The 3.2-Å X-ray crystal structure of this substantially complete RSV F reveals important differences from homology-based structural models. Specifically, the RSV F crystal structure demonstrates the exposure of key neutralizing antibody binding sites on the surface of the postfusion RSV F trimer. This unanticipated structural feature explains the engineered RSV F antigen's efficiency as an immunogen. This work illustrates how structural-based antigen design can guide the rational optimization of candidate vaccine antigens.
authors.affiliation: Novartis Vaccines and Diagnostics, Cambridge, MA 02139, USA.
authors.forename: Kurt A
authors.initials: KA
authors.lastname: Swanson
authors.forename: Ethan C
authors.initials: EC
authors.lastname: Settembre
authors.forename: Christine A
authors.initials: CA
authors.lastname: Shaw
authors.forename: Antu K
authors.initials: AK
authors.lastname: Dey
authors.forename: Rino
authors.initials: R
authors.lastname: Rappuoli
authors.forename: Christian W
authors.initials: CW
authors.lastname: Mandl
authors.forename: Philip R
authors.initials: PR
authors.lastname: Dormitzer
authors.forename: Andrea
authors.initials: A
authors.lastname: Carfi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000378:metabolism; D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing / Q000276:immunology / Q000378:metabolism; D000914:Antibodies, Viral / Q000276:immunology* / Q000378:metabolism; D001666:Binding Sites, Antibody; D002942:Circular Dichroism; D018360:Crystallography, X-Ray; D006801:Humans; D007114:Immunization; D007223:Infant; D051379:Mice; D008807:Mice, Inbred BALB C; D008854:Microscopy, Electron; D008958:Models, Molecular; D008969:Molecular Sequence Data; D000069455:Palivizumab; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology* / Q000821:virology; D012136:Respiratory Syncytial Viruses / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D016205:Sigmodontinae; D014760:Viral Fusion Proteins / Q000737:chemistry / Q000276:immunology* / Q000648:ultrastructure
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; C526850:F protein, human respiratory syncytial virus; D014760:Viral Fusion Proteins; C506968:motavizumab; D000069455:Palivizumab