Parenteral CHIKV mRNA Vaccination Reshapes the Gut Microbial, Metabolic, and Immune Landscapes.

Abstract

The gut microbiota is increasingly recognized as a critical modulator of vaccine efficacy. However, how parenteral vaccines-particularly those against non-enteric viruses-reshape the intestinal microenvironment remains poorly defined. Here, we investigated the impact of two validated CHIKV mRNA vaccines on gut microbial composition, metabolic activity, and immune features in rhesus macaques. Using a longitudinal multi-omics approach, including metagenomics, metabolomics, and proteomics, and comparing with CHIKV-infected animals, we assessed whether systemic vaccination alone, in the absence of intestinal viral replication, was associated with changes in the gut microenvironment. We demonstrate that vaccination induces reproducible shifts in gut microbiota composition, notably enriching Segatella copri, similar to infection-associated changes. These alterations are accompanied by remodeling of purine and bile acid metabolism, with persistent increases in xanthine and uric acid. Upon viral challenge, vaccinated animals exhibit reduced intestinal viral burden, attenuated pathology, and elevated expression of proteins related to antigen presentation, immunoglobulins, and epithelial barrier function. These findings provide direct evidence that systemic CHIKV mRNA vaccination is associated with changes in the gut microbial, metabolic, and immune landscapes, highlighting the gastrointestinal tract as an active and responsive target of parenteral vaccinations.

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