Iterative structure-based improvement of a fusion-glycoprotein vaccine against RSV

Nat Struct Mol Biol. 2016 Sep;23(9):811-820. doi: 10.1038/nsmb.3267. Epub 2016 Aug 1.


Structure-based design of vaccines, particularly the iterative optimization used so successfully in the structure-based design of drugs, has been a long-sought goal. We previously developed a first-generation vaccine antigen called DS-Cav1, comprising a prefusion-stabilized form of the fusion (F) glycoprotein, which elicits high-titer protective responses against respiratory syncytial virus (RSV) in mice and macaques. Here we report the improvement of DS-Cav1 through iterative cycles of structure-based design that significantly increased the titer of RSV-protective responses. The resultant second-generation 'DS2'-stabilized immunogens have their F subunits genetically linked, their fusion peptides deleted and their interprotomer movements stabilized by an additional disulfide bond. These DS2 immunogens are promising vaccine candidates with superior attributes, such as their lack of a requirement for furin cleavage and their increased antigenic stability against heat inactivation. The iterative structure-based improvement described here may have utility in the optimization of other vaccine antigens.

Publication types

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

MeSH terms

  • Animals
  • Crystallography, X-Ray
  • Female
  • Glycoproteins / chemistry*
  • Glycoproteins / immunology
  • HEK293 Cells
  • Humans
  • Male
  • Mice, Inbred C57BL
  • Models, Molecular
  • Protein Engineering
  • Protein Stability
  • Respiratory Syncytial Virus Infections / prevention & control*
  • Respiratory Syncytial Virus Infections / virology
  • Respiratory Syncytial Viruses / immunology*
  • Vaccination
  • Viral Fusion Proteins / chemistry*
  • Viral Fusion Proteins / immunology
  • Viral Vaccines / chemistry*
  • Viral Vaccines / immunology


  • Glycoproteins
  • Viral Fusion Proteins
  • Viral Vaccines