Structural basis for immunization with postfusion respiratory syncytial virus fusion F glycoprotein (RSV F) to elicit high neutralizing antibody titers

Proc Natl Acad Sci U S A. 2011 Jun 7;108(23):9619-24. doi: 10.1073/pnas.1106536108. Epub 2011 May 17.

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.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / metabolism
  • Antibodies, Monoclonal, Humanized
  • Antibodies, Neutralizing / immunology
  • Antibodies, Neutralizing / metabolism
  • Antibodies, Viral / immunology*
  • Antibodies, Viral / metabolism
  • Binding Sites, Antibody
  • Circular Dichroism
  • Crystallography, X-Ray
  • Humans
  • Immunization
  • Infant
  • Mice
  • Mice, Inbred BALB C
  • Microscopy, Electron
  • Models, Molecular
  • Molecular Sequence Data
  • Palivizumab
  • Protein Multimerization
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Respiratory Syncytial Virus Infections / immunology*
  • Respiratory Syncytial Virus Infections / virology
  • Respiratory Syncytial Viruses / genetics
  • Respiratory Syncytial Viruses / immunology*
  • Respiratory Syncytial Viruses / metabolism
  • Sequence Homology, Amino Acid
  • Sigmodontinae
  • Viral Fusion Proteins / chemistry
  • Viral Fusion Proteins / immunology*
  • Viral Fusion Proteins / ultrastructure

Substances

  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Antibodies, Neutralizing
  • Antibodies, Viral
  • F protein, human respiratory syncytial virus
  • Viral Fusion Proteins
  • motavizumab
  • Palivizumab

Associated data

  • PDB/3RKI