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TitleRational design of a highly immunogenic prefusion-stabilized F glycoprotein antigen for a respiratory syncytial virus vaccine.
Journal, issue, pagesSci Transl Med, Vol. 15, Issue 693, Page eade6422, Year 2023
Publish dateApr 26, 2023
AuthorsYe Che / Alexey V Gribenko / Xi Song / Luke D Handke / Kari S Efferen / Kristin Tompkins / Srinivas Kodali / Lorna Nunez / A Krishna Prasad / Lynn M Phelan / Mark Ammirati / Xiaodi Yu / Joshua A Lees / Wei Chen / Lyndsey Martinez / Vidia Roopchand / Seungil Han / Xiayang Qiu / John P DeVincenzo / Kathrin U Jansen / Philip R Dormitzer / Kena A Swanson /
PubMed AbstractRespiratory syncytial virus (RSV) is the leading, global cause of serious respiratory disease in infants and is an important cause of respiratory illness in older adults. No RSV vaccine is currently ...Respiratory syncytial virus (RSV) is the leading, global cause of serious respiratory disease in infants and is an important cause of respiratory illness in older adults. No RSV vaccine is currently available. The RSV fusion (F) glycoprotein is a key antigen for vaccine development, and its prefusion conformation is the target of the most potent neutralizing antibodies. Here, we describe a computational and experimental strategy for designing immunogens that enhance the conformational stability and immunogenicity of RSV prefusion F. We obtained an optimized vaccine antigen after screening nearly 400 engineered F constructs. Through in vitro and in vivo characterization studies, we identified F constructs that are more stable in the prefusion conformation and elicit ~10-fold higher serum-neutralizing titers in cotton rats than DS-Cav1. The stabilizing mutations of the lead construct (847) were introduced onto F glycoprotein backbones of strains representing the dominant circulating genotypes of the two major RSV subgroups, A and B. Immunization of cotton rats with a bivalent vaccine formulation of these antigens conferred complete protection against RSV challenge, with no evidence of disease enhancement. The resulting bivalent RSV prefusion F investigational vaccine has recently been shown to be efficacious against RSV disease in two pivotal phase 3 efficacy trials, one for passive protection of infants by immunization of pregnant women and the second for active protection of older adults by direct immunization.
External linksSci Transl Med / PubMed:37023209
MethodsEM (single particle) / X-ray diffraction
Resolution3.5 - 3.7 Å
Structure data

26562

7uja

EMDB-26562, PDB-7uja:
Cryo-EM structure of Human respiratory syncytial virus F variant (construct pXCS847A)
Method: EM (single particle) / Resolution: 3.7 Å

PDB-7uj3:
Crystal structure of Human respiratory syncytial virus F variant (construct pXCS847A)
Method: X-RAY DIFFRACTION / Resolution: 3.5 Å

Chemicals

ChemComp-SO4:
SULFATE ION / Sulfate

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

Source
  • respiratory syncytial virus
  • mus musculus (house mouse)
KeywordsVIRUS / RSV / RSVF / pre-fusion / VIRAL PROTEIN

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