A highly stable prefusion RSV F vaccine derived from structural analysis of the fusion mechanism

Nat Commun. 2015 Sep 3;6:8143. doi: 10.1038/ncomms9143.

Abstract

Respiratory syncytial virus (RSV) causes acute lower respiratory tract infections and is the leading cause of infant hospitalizations. Recently, a promising vaccine antigen based on the RSV fusion protein (RSV F) stabilized in the native prefusion conformation has been described. Here we report alternative strategies to arrest RSV F in the prefusion conformation based on the prevention of hinge movements in the first refolding region and the elimination of proteolytic exposure of the fusion peptide. A limited number of unique mutations are identified that stabilize the prefusion conformation of RSV F and dramatically increase expression levels. This highly stable prefusion RSV F elicits neutralizing antibodies in cotton rats and induces complete protection against viral challenge. Moreover, the structural and biochemical analysis of the prefusion variants suggests a function for p27, the excised segment that precedes the fusion peptide in the polypeptide chain.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antibodies, Neutralizing / immunology*
  • Antigens, Viral / genetics
  • Antigens, Viral / immunology*
  • Blotting, Western
  • Crystallization
  • Crystallography, X-Ray
  • Electrophoresis, Polyacrylamide Gel
  • Enzyme-Linked Immunosorbent Assay
  • Mice
  • Microscopy, Electron
  • Mutation
  • Protein Conformation
  • Respiratory Syncytial Virus Infections / immunology
  • Respiratory Syncytial Virus Infections / prevention & control*
  • Respiratory Syncytial Virus Vaccines / immunology*
  • Respiratory Syncytial Viruses / genetics
  • Respiratory Syncytial Viruses / immunology*
  • Sigmodontinae
  • Viral Fusion Proteins / genetics
  • Viral Fusion Proteins / immunology*

Substances

  • Antibodies, Neutralizing
  • Antigens, Viral
  • Respiratory Syncytial Virus Vaccines
  • Viral Fusion Proteins

Associated data

  • PDB/5C69
  • PDB/5C6B