Why You Get a Fever After a Shot: It Was in the Gut Bacteria. A Study of 171 Adults

After a vaccination, some people feel fine and others get a fever. There has been no clear answer as to why this difference arises, and fever as a side effect is one reason people avoid vaccines. A team led by Professor Ruth Ley at the Max Planck Institute for Biology in Tübingen, Germany, published in Science a study showing that a large part of the answer lies in the gut microbiome.

Human follow-up, then organoids, then germ-free mice

The researchers repeatedly measured stool microbes, oral body temperature and serum markers in 171 healthy adults before and after they received a SARS-CoV-2 mRNA vaccine. People who already had low-grade gut inflammation before vaccination, had more flagellated bacteria of the family Lachnospiraceae and had higher expression of the flagellar protein flagellin had a higher risk of fever.

To go beyond correlation, the researchers added microbes from people who had high fevers to human gut organoids and checked whether stronger inflammatory responses appeared, and when they transplanted them into germ-free (gnotobiotic) mice and then vaccinated the mice, a flagellin-dependent vaccination response was reproduced. The microbes' flagellin phenotype and the mice's vaccination response were altered by diet, and in people as well, fever risk was associated with self-reported diet and metabolic markers.

Significance and limits

This study showed, in a human cohort and in animal experiments together, that gut bacteria regulate the immune system's "baseline tension" and thereby create individual differences in vaccine side effects. It could become the basis for future strategies that target the microbiome to reduce vaccine side effects. However, the human data are an observational study of 171 people and are limited to one type of mRNA vaccine. Whether adjusting diet can actually reduce fever in people needs a separate intervention trial, and mouse results cannot be applied directly to people.