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-Structure paper
Title | Universal paramyxovirus vaccine design by stabilizing regions involved in structural transformation of the fusion protein. |
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Journal, issue, pages | Nat Commun, Vol. 15, Issue 1, Page 4629, Year 2024 |
Publish date | May 31, 2024 |
Authors | Johannes P M Langedijk / Freek Cox / Nicole V Johnson / Daan van Overveld / Lam Le / Ward van den Hoogen / Richard Voorzaat / Roland Zahn / Leslie van der Fits / Jarek Juraszek / Jason S McLellan / Mark J G Bakkers / |
PubMed 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 ...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. |
External links | Nat Commun / PubMed:38821950 / PubMed Central |
Methods | EM (single particle) |
Resolution | 3.0 Å |
Structure data | EMDB-42981, PDB-8v5a: |
Source |
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Keywords | VIRAL PROTEIN/IMMUNE SYSTEM / fusion protein / viral glycoprotein / membrane fusion / VIRAL PROTEIN / VIRAL PROTEIN-IMMUNE SYSTEM complex |