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TitleA foldon-free prefusion F trimer vaccine for respiratory syncytial virus to reduce off-target immune responses.
Journal, issue, pagesNat Microbiol, Vol. 9, Issue 12, Page 3254-3267, Year 2024
Publish dateNov 20, 2024
AuthorsMark J G Bakkers / Freek Cox / Annemart Koornneef / Xiaodi Yu / Daan van Overveld / Lam Le / Ward van den Hoogen / Joost Vaneman / Anne Thoma / Richard Voorzaat / Lisanne Tettero / Jarek Juraszek / Leslie van der Fits / Roland Zahn / Johannes P M Langedijk /
PubMed AbstractRespiratory syncytial virus (RSV) is a major cause of severe respiratory disease in infants and older people. Current RSV subunit vaccines are based on a fusion protein that is stabilized in the ...Respiratory syncytial virus (RSV) is a major cause of severe respiratory disease in infants and older people. Current RSV subunit vaccines are based on a fusion protein that is stabilized in the prefusion conformation and linked to a heterologous foldon trimerization domain to obtain a prefusion F (preF) trimer. Here we show that current RSV vaccines induce undesirable anti-foldon antibodies in non-human primates, mice and humans. To overcome this, we designed a foldon-free RSV preF trimer by elucidating the structural basis of trimerization-induced preF destabilization through molecular dynamics simulations and by introducing amino acid substitutions that negate hotspots of charge repulsion. The highly stable prefusion conformation was validated using antigenic and cryo-electron microscopy analysis. The preF is immunogenic and protective in naive mouse models and boosts neutralizing antibody titres in RSV-pre-exposed mice and non-human primates, while achieving similar titres to approved RSV vaccines in mice. This stable preF design is a promising option as a foldon-independent candidate for a next-generation RSV vaccine immunogen.
External linksNat Microbiol / PubMed:39567664 / PubMed Central
MethodsEM (single particle)
Resolution3.28 Å
Structure data

44117

9b2x

EMDB-44117, PDB-9b2x:
Cryo-EM structure of Prefusion RSV F (RSV220975)
Method: EM (single particle) / Resolution: 3.28 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

Source
  • Human metapneumovirus
  • human orthopneumovirus
KeywordsVIRAL PROTEIN / Prefusion / RSV / Cryo-EM / VIRUS

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