9B2X

Cryo-EM structure of Prefusion RSV F (RSV220975)

Summary for 9B2X

• Entry DOI: 10.2210/pdb9b2x/pdb
• EMDB information: 44117
• Descriptor: Fusion glycoprotein F0, 2-acetamido-2-deoxy-beta-D-glucopyranose (2 entities in total)
• Functional Keywords: prefusion, rsv, cryo-em, virus, viral protein
• Biological source: Human orthopneumovirus
• Total number of polymer chains: 3
• Total formula weight: 176226.88

Authors

Yu, X.,Langedijk, J.P.M. (deposition date: 2024-03-17, release date: 2024-10-16, Last modification date: 2024-12-11)

Primary citation

Bakkers, M.J.G.,Cox, F.,Koornneef, A.,Yu, X.,van Overveld, D.,Le, L.,van den Hoogen, W.,Vaneman, J.,Thoma, A.,Voorzaat, R.,Tettero, L.,Juraszek, J.,van der Fits, L.,Zahn, R.,Langedijk, J.P.M.
A foldon-free prefusion F trimer vaccine for respiratory syncytial virus to reduce off-target immune responses.
Nat Microbiol, 9:3254-3267, 2024

PubMed 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 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.

PubMed: 39567664
DOI: 10.1038/s41564-024-01860-1

Experimental method

ELECTRON MICROSCOPY (3.28 Å)