Proof of Principle for Epitope-Focused Vaccine Design

Nature. 2014 Mar 13;507(7491):201-6. doi: 10.1038/nature12966. Epub 2014 Feb 5.

Abstract

Vaccines prevent infectious disease largely by inducing protective neutralizing antibodies against vulnerable epitopes. Several major pathogens have resisted traditional vaccine development, although vulnerable epitopes targeted by neutralizing antibodies have been identified for several such cases. Hence, new vaccine design methods to induce epitope-specific neutralizing antibodies are needed. Here we show, with a neutralization epitope from respiratory syncytial virus, that computational protein design can generate small, thermally and conformationally stable protein scaffolds that accurately mimic the viral epitope structure and induce potent neutralizing antibodies. These scaffolds represent promising leads for the research and development of a human respiratory syncytial virus vaccine needed to protect infants, young children and the elderly. More generally, the results provide proof of principle for epitope-focused and scaffold-based vaccine design, and encourage the evaluation and further development of these strategies for a variety of other vaccine targets, including antigenically highly variable pathogens such as human immunodeficiency virus and influenza.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Antibodies, Monoclonal / analysis
  • Antibodies, Monoclonal / immunology
  • Antibodies, Neutralizing / analysis
  • Antibodies, Neutralizing / immunology
  • Antibodies, Viral / analysis
  • Antibodies, Viral / immunology
  • Antigens, Viral / chemistry
  • Antigens, Viral / immunology
  • Crystallography, X-Ray
  • Drug Design*
  • Enzyme-Linked Immunosorbent Assay
  • Epitopes / chemistry*
  • Epitopes / immunology*
  • Macaca mulatta / immunology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Models, Molecular
  • Neutralization Tests
  • Protein Conformation
  • Protein Stability*
  • Respiratory Syncytial Virus Vaccines / chemistry*
  • Respiratory Syncytial Virus Vaccines / immunology*
  • Respiratory Syncytial Viruses / chemistry
  • Respiratory Syncytial Viruses / immunology

Substances

  • Antibodies, Monoclonal
  • Antibodies, Neutralizing
  • Antibodies, Viral
  • Antigens, Viral
  • Epitopes
  • Respiratory Syncytial Virus Vaccines

Associated data

  • PDB/4JLR
  • PDB/4L8I
  • PDB/4N9G