A foldon-free prefusion F trimer vaccine for respiratory syncytial virus to reduce off-target immune responses.

ABSTRACT: 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 microscop

SUBMITTER: Bakkers MJG 

PROVIDER: S-EPMC11602707 | biostudies-literature | 2024 Dec

REPOSITORIES: biostudies-literature