Research published in the journal Science has identified an unanticipated variable that may help explain the divergence in how individuals respond to mRNA COVID-19 vaccination — with some developing fever and others registering no noticeable reaction at all.
A team based at Germany's Max Planck Institute for Biology Tübingen observed that adults who developed elevated body temperatures following mRNA COVID-19 vaccination tended to harbour gut bacteria with higher output of flagellin, a structural protein that microorganisms assemble into the whip-like appendages enabling their locomotion.
Of the 171 healthy young adults enrolled in the study, the majority were partway through a third round of mRNA vaccination. Three times each day, for roughly a fortnight bracketing their vaccination date, study participants recorded their own oral temperature readings. For each participant, the recorded measurements were set against that individual's own established baseline temperature, matched to the corresponding hour of the day.
Among those who mounted a stronger fever response after vaccination, gut bacteria had shown notably higher activity in flagellin-related genes beforehand. A bacterial group known as Lachnospiraceae was identified as the source of a substantial portion of those findings, the study's summary noted. Elevated inflammatory markers — detectable in both blood draws and stool specimens — were present at baseline among those participants who responded most strongly.
Post-vaccination responses such as elevated temperature and flu-like discomfort turn up frequently after mRNA doses, though a portion of recipients experience no reaction at all, and those who do tend to encounter similar effects when subsequent doses are administered. Researchers turned to the gut microbiome as a plausible candidate, given that recurring patterns in the data pointed toward an individual-level driver and that this microbial community plays a well-documented role in regulating immune responses across the body.
Researchers now have a potential biological mechanism to account for a side effect that tends to be transient and is widely reported among patients. Flagellin functions as a molecular marker that the immune system associates with bacterial presence, a detection that can set off inflammatory responses within the body. Prolonged contact between intestinal tissue and flagellin, according to the team's working hypothesis, may hold immune defences at a low-level baseline of alertness — one that, in certain individuals, then amplifies the fever response once a vaccine is administered.
Ruth Ley, who directs the institute's Department of Microbiome Science, noted in a Max Planck Society release that microbial flagellin functions as one contributing factor to the body's baseline immune state. The research team, seeking to determine whether gut microbes themselves were involved, introduced intestinal bacteria drawn from study participants into mice raised in a germ-free environment. When transplanted microbes from high-responding animals took hold in recipient mice, those animals displayed greater temperature shifts alongside heightened inflammatory signalling after vaccination — a pattern that broke down once the capacity to detect flagellin was removed.
Laboratory experiments involving food additives found elevated flagellin output from gut bacteria in petri dish conditions, while mouse trials pointed to a high-fat, Western-pattern diet amplifying inflammatory responses to vaccines. Chassaing, based at Inserm and Institut Pasteur, noted that the data point toward certain components of an industrialised diet as potential drivers of flagellated bacterial growth in the gut, while Huus — who conducted the research at Max Planck — observed that although a direct link between diet and vaccine responses in humans remained beyond what the study could establish, the evidence nonetheless positions dietary patterns as one factor capable of shaping a microbiome with inflammatory characteristics.
Human trials would be needed to determine whether dietary adjustments can shift flagellin output and, in turn, influence how the body runs a temperature in response to vaccination. Writing in a companion Science Perspective piece, immunologist Bali Pulendran noted that both diet and microbial ecology remain open to change — a point that opens the door to the idea of people one day intentionally adjusting their bodies before receiving a vaccine, according to media reports.
None of those three variables — flagellin levels, gut inflammation, or dietary patterns — turned out to have any bearing on how strongly participants' bodies mounted antibody responses following vaccination, the research team found. None of the intestinal markers associated with fever showed any connection to how much or how little antibody the body produced.
The study's authors pointed out that concern about adverse reactions has the potential to put people off attending appointments for subsequent doses. Those findings, drawn from human data, point to associations rather than established causes, and the dietary information on which they rest came from participants' own accounts.
The study drew exclusively from healthy young adults, leaving open the question of whether its findings would hold for older populations, children, or people living with long-term health conditions. Those findings relating to diet and flagellin rest entirely on cell cultures and animal models, and because the research examined mRNA COVID-19 vaccines specifically, whether the same relationship holds for influenza or other immunisations remains an open question.
No evidence exists that adjusting one's diet holds any power to ward off fever. Mild reactions like a slight fever typically clear up within a few days as the body's immune defences process their response to the vaccination. Adequate hydration, physical rest, and non-prescription medications that bring down fever — provided a clinician has confirmed their suitability — together form a standard approach to easing post-vaccination discomfort.
The study's findings do not provide a basis for adjusting diet, starting probiotics, or forgoing a recommended vaccine. Clinical trials examining whether modifying gut microbiota ahead of vaccination can ease post-injection reactions have yet to be conducted. Anyone who develops a persistent high fever, breathing difficulties, facial or throat swelling, chest pain, or a racing heartbeat following vaccination is advised to seek medical attention without delay.
