Stabilization of norovirus GII.3 virus-like particles by rational disulfide engineering

Stabilization of norovirus GII.3 virus-like particles by rational disulfide engineering

Abstract Noroviruses are non-enveloped, single-stranded positive-sense RNA viruses and the leading cause of gastroenteritis worldwide. The major capsid protein, VP1, can self-assemble into non-infectious virus-like particles (VLPs), representing an attractive vaccine platform. It was demonstrated th...

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Main Authors: Christopher Warren, Jennifer D. Galli, Karin Bystol, Gregory O’Donnell, Andrew R. Swartz, Emily A. Dewar, Corey May Fulton, Pamela Shen, Estibaliz Gonzalez-Fernandez, Lizzy Aurora DeWitt, Uijin Jeong, Oscar Chi-Chien Pan, Sean Miller, Arthur Fridman, Courtney David, Zhifeng Chen, Jiajie Wei
Format: Article
Language:English
Published: Nature Portfolio 2025-08-01
Series:npj Vaccines
Online Access:https://doi.org/10.1038/s41541-025-01254-2
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Summary:Abstract Noroviruses are non-enveloped, single-stranded positive-sense RNA viruses and the leading cause of gastroenteritis worldwide. The major capsid protein, VP1, can self-assemble into non-infectious virus-like particles (VLPs), representing an attractive vaccine platform. It was demonstrated that engineered disulfide bonds within VP1 could significantly stabilize VLPs of the archetypal GI.1 strain. Here, we apply a similar strategy to VLPs of multiple circulating GII genotypes. We find that engineered disulfide mutations can significantly stabilize VLPs of the GII.3 strain, but not the closely related GII.6 strain. Disulfide-stabilized GII.3 VLPs (GII.3-DS1) exhibit increased yields, greater homogeneity, and higher thermal stability compared to wild-type GII.3 VLPs. GII.3-DS1 VLPs are a superior reagent in immunological assays compared to the wild-type counterpart. Importantly, mRNA encoding GII.3-DS1 elicits superior humoral immune responses compared to wild-type GII.3 mRNA in mice. These results demonstrate the utility of rational VLP stabilization for advancing vaccine development efforts.
ISSN:2059-0105

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