Universal paramyxovirus vaccine design by stabilizing regions involved in structural transformation of the fusion protein

Johannes P. M. Langedijk, Freek Cox, Nicole V. Johnson, Daan Overveld, Lam Le, Ward Hoogen, Richard Voorzaat, Roland Zahn, Leslie Fits, Jarek Juraszek, Jason S. McLellan and Mark J. G. Bakkers ()
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Johannes P. M. Langedijk: Janssen Vaccines & Prevention BV
Freek Cox: Janssen Vaccines & Prevention BV
Nicole V. Johnson: The University of Texas at Austin
Daan Overveld: Janssen Vaccines & Prevention BV
Lam Le: Janssen Vaccines & Prevention BV
Ward Hoogen: Janssen Vaccines & Prevention BV
Richard Voorzaat: Janssen Vaccines & Prevention BV
Roland Zahn: Janssen Vaccines & Prevention BV
Leslie Fits: Janssen Vaccines & Prevention BV
Jarek Juraszek: Janssen Vaccines & Prevention BV
Jason S. McLellan: The University of Texas at Austin
Mark J. G. Bakkers: Janssen Vaccines & Prevention BV

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract The Paramyxoviridae family encompasses medically significant RNA viruses, including human respiroviruses 1 and 3 (RV1, RV3), and zoonotic pathogens like Nipah virus (NiV). RV3, previously known as parainfluenza type 3, for which no vaccines or antivirals have been approved, causes respiratory tract infections in vulnerable populations. The RV3 fusion (F) protein is inherently metastable and will likely require prefusion (preF) stabilization for vaccine effectiveness. Here we used structure-based design to stabilize regions involved in structural transformation to generate a preF protein vaccine antigen with high expression and stability, and which, by stabilizing the coiled-coil stem region, does not require a heterologous trimerization domain. The preF candidate induces strong neutralizing antibody responses in both female naïve and pre-exposed mice and provides protection in a cotton rat challenge model (female). Despite the evolutionary distance of paramyxovirus F proteins, their structural transformation and local regions of instability are conserved, which allows successful transfer of stabilizing substitutions to the distant preF proteins of RV1 and NiV. This work presents a successful vaccine antigen design for RV3 and provides a toolbox for future paramyxovirus vaccine design and pandemic preparedness.

Date: 2024
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DOI: 10.1038/s41467-024-48059-w

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