Innate immune system variations determine vaccine side effects

Redness and pain at the injection site, fever, fatigue or headaches: vaccines can cause side effects, but their frequency and severity vary considerably from person to person. Why? A team from the Center for Vaccinology at the University of Geneva (UNIGE) and Geneva University Hospital (HUG) has found that, even before vaccination, some people's innate immune systems are more reactive than others, showing a heightened response to interferons, key molecules involved in antiviral defence naturally produced by the body. The stronger this response, the more likely individuals are to experience these transient symptoms. These findings have been published in Science Translational Medicine.

The reactions experienced by some people after vaccination are, in most cases, mild and temporary. They result from activation of the immune system by the vaccine, enabling the body to learn to recognise antigens – characteristic molecules of the virus present in the vaccine – and thereby prepare to better fight off any future infection. This activation can cause local inflammation at the injection site (redness and swelling) or more peripheral symptoms such as fatigue or fever. However, the response varies considerably from person to person, ranging from no reaction at all 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."

Arnaud Didierlaurent, Associate Professor, Center for Vaccinology (UNIGE/HUG) and Department of Pathology and Immunology, Faculty of Medicine, UNIGE

The role of our immune ''capital''

To investigate these differences, the researcher and his team monitored the immune systems of 51 healthy individuals recruited at HUG who received two doses of an mRNA vaccine against COVID-19. As side effects generally occur one to two days after vaccination, particularly after the second dose, participants were monitored for seven days following each injection.

"This study allowed us to identify an important role for an interferon-related antiviral defence system in explaining differences in side effects between individuals. This innate immune defence system helps us, in particular, to fight viral infections. The more active a person's natural interferon response is, even before vaccination, the more pronounced their reactions to vaccination are likely to be," explains Natacha Madelon, Senior Research and Teaching Assistant at the Center for Vaccinology and first author of the study.

Interferon is produced by cells when they are infected with a virus, alerting neighbouring cells and preparing them to defend themselves. But not everyone starts from the same 'baseline'. "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," explains Arnaud Didierlaurent.

Differences emerge after the second dose

The research team identified a second potential mechanism in an animal model. Following the first vaccination, the body develops antibodies and T cells capable of recognising the vaccine antigen. When a subsequent dose is administered, this acquired immunity can rapidly amplify the activation of certain innate immune cells, notably monocytes, a type of white blood cell. These cells then react more strongly, attracting more inflammatory cells to the injection site.

These findings open up new avenues for vaccine research. In particular, they suggest that it may eventually be possible to better distinguish between the mechanisms needed to generate a robust immune response and those that primarily contribute to the symptoms experienced following vaccination. Prof. Didierlaurent's team is now seeking to determine whether these same mechanisms occur with other types of vaccines.

In the long term, this research could contribute to the development of vaccines that are better tolerated while remaining just as effective. "In any case, a mild reaction, or even the absence of symptoms following vaccination, does not in any way mean that the vaccine is ineffective. The severity of side effects is therefore not, in itself, an indicator of how well a vaccine is working" concludes Arnaud Didierlaurent.

This research was supported by the HUG Private Foundation, the Giorgio Cavaglieri Foundation and Moderna.