The human gut microbiome primes fever after vaccination

Fever is a common adverse reaction to vaccination, contributing to vaccine hesitancy and reduced uptake. To understand variation in fever risk, we longitudinally profiled fecal microbiota, oral temperature, and serological markers in 171 healthy adults receiving SARS-CoV-2 vaccines. Fever risk correlated with low-grade intestinal inflammation, increased abundance of flagellated Lachnospiraceae members, and increased flagellin expression pre-vaccine. Associations between Lachnospiraceae and vaccine fever risk were validated in over 1000 participants from the independent Canadian CHILD cohort. In addition, microbiomes from fever-high donors triggered stronger inflammation in human intestinal organoids and drove flagellin-dependent vaccine reactions in gnotobiotic mice, indicating causality. Moreover, microbiome flagellin phenotypes and murine vaccine reactions were modifiable by diet: both were exacerbated by industrialized dietary additives. Consistent with this, human fever risk was associated with self-reported diet and metabolic markers. These findings identify the gut microbiome as a driver of vaccine-induced fever, suggesting microbiome-targeted strategies could modulate immune tone and improve vaccine side effects. In the future, the newly established Huus Lab aims to better understand how diet-microbiome-immune interactions impact human vaccine reactions and will test dietary strategies to reduce side effect risk in vaccine recipients.