Fever is a common adverse reaction to vaccination, contributing to vaccine hesitancy and reduced uptake. Variation in fever responses after vaccination is unexplained. To explore the basis of fever variability, we longitudinally profiled fecal microbiota, oral temperature, and serological markers in 171 healthy adults receiving SARS-CoV-2 vaccines. Vegans and vegetarians showed least fever responses despite robust antibody production. Fever risk correlated with pre-vaccination intestinal inflammation and dietary markers of processed foods. While microbiota composition was stable post-vaccination, high-fever individuals were enriched for the flagellated genus Waltera and for flagellin gene expression, which we observed upregulated in response to the processed diet additive carboxymethylcellulose. Microbiomes from high-fever donors triggered stronger inflammatory responses in human intestinal organoids and drove flagellin-dependent vaccine reactions in gnotobiotic mouse models, without impairing antibody titers. These findings identify the gut microbiome as a driver of vaccine-induced fever and implicate processed diets as a modifiable risk factor, suggesting that microbiome-based strategies could improve vaccine tolerability in humans.
Fever is a common adverse reaction to vaccination, contributing to vaccine hesitancy and reduced uptake. Variation in fever responses after vaccination is unexplained. To explore the basis of fever variability, we longitudinally profiled fecal microbiota, oral temperature, and serological markers in 171 healthy adults receiving SARS-CoV-2 vaccines. Vegans and vegetarians showed least fever responses despite robust antibody production. Fever risk correlated with pre-vaccination intestinal inflammation and dietary markers of processed foods. While microbiota composition was stable post-vaccination, high-fever individuals were enriched for the flagellated genus Waltera and for flagellin gene expression, which we observed upregulated in response to the processed diet additive carboxymethylcellulose. Microbiomes from high-fever donors triggered stronger inflammatory responses in human intestinal organoids and drove flagellin-dependent vaccine reactions in gnotobiotic mouse models, without impairing antibody titers. These findings identify the gut microbiome as a driver of vaccine-induced fever and implicate processed diets as a modifiable risk factor, suggesting that microbiome-based strategies could improve vaccine tolerability in humans.
Georgia State University