Why do some people get worse vaccine side-effects than others?
New research highlights the role of the innate immune system in triggering temporary side-effects such as fever, fatigue, headache and injection site pain following vaccination.
- 25 September 2026
- 3 min read
- by Linda Geddes
At a glance
- To better understand why some people may be more prone to vaccine side-effects, researchers tracked symptoms and immune responses in people receiving mRNA-based COVID-19 vaccines.
- People with a more active interferon-relate innate immune response – part of the body’s rapid, non-specific first line of defence against infection – tended to experience more pronounced responses to vaccination.
- Such findings could eventually aid the design of vaccines that are effective, yet better tolerated.
The reason some people feel wiped out after vaccination while others barely notice it could partly come down to differences in their immune systems before they even receive a vaccine, new research suggests.
Short-lived side-effects such as pain and redness at the injection site, fever, fatigue or headaches are common, but their frequency and severity vary considerably from person to person.
Collectively known as reactogenicity, these symptoms result from the immune response triggered by vaccination. They are usually mild and temporary but can range from no noticeable reaction to pronounced flu-like symptoms.
“Whilst we know that older people tend to experience fewer reactions to vaccination because of age-related declines in immune function, and that the vaccine dose can influence the severity of side-effects, the biological mechanisms underlying these individual differences in symptoms have remained poorly understood,” said Prof Arnaud Didierlaurent, Associate Professor at the University of Geneva in Switzerland, who led the study.
What causes temporary vaccine side-effects?
To investigate, Didierlaurent and his colleagues monitored immune responses in 51 healthy people before and after they received two doses of an mRNA vaccine against COVID-19.
Doing so revealed that people who tended to experience more pronounced temporary side-effects showed differences in their innate immune responses: the body’s rapid, non-specific first line of defence against infection.
When cells detect viral infection, they release signalling molecules called interferons that warn neighbouring cells and prime them to defend themselves. But people appear to differ in how active this system is before they even encounter a virus or receive a vaccine.
“For reasons we do not yet fully understand – but which may be linked to genetic factors, a particular microbiome or a previous inflammatory episode – some individuals have a stronger interferon-related immune signature before receiving the vaccine, which appears to influence how strongly they react to vaccination,” Didierlaurent said.
The study, published in Science Translational Medicine, also identified a possible explanation for why reactions can be stronger after a second vaccine dose.
Have you read?
Animal experiments suggested that antibodies and T-cells generated by the first vaccination can amplify inflammation when a second dose is given, triggering the recruitment and activation of innate immune cells, particularly cells called monocytes, at the injection site.
The researchers suggested that inflammatory molecules may then spill over into the bloodstream, potentially contributing to more generalised symptoms such as fever, fatigue and headache.
The higher the levels of vaccine-specific antibodies before the second dose, the greater the reactogenicity tended to be.
However, Didierlaurent stressed that experiencing mild reactions or no symptoms after vaccination didn't suggest vaccination was ineffective. “The severity of side-effects is not, in itself, an indicator of how well a vaccine is working,” he said.
How could these discoveries aid vaccine design?
Identifying the immune pathways responsible for vaccine reactogenicity could eventually aid the development of vaccines that are better tolerated while remaining just as effective, the researchers said.
Crucially, experiments in mice suggested that it may be possible to dampen some of the inflammatory processes associated with reactogenicity without weakening the desired immune response.
The team is now investigating whether these same mechanisms underpin responses to other types of vaccines.
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