The reactions experienced by some people after vaccination are, in most cases, mild and temporary.
Photo Credit: Tubagus Andri Maulana
Scientific Frontline: Extended "At a Glance" Summary: Immune Baseline and mRNA Vaccine Side Effects
The Core Concept: The frequency and severity of transient side effects following mRNA vaccination are significantly influenced by an individual's pre-existing innate immune reactivity, specifically their baseline response to interferons.
Key Distinction/Mechanism: Rather than the vaccine alone dictating the reaction, individuals with a naturally more active interferon-related antiviral defense system prior to vaccination experience more pronounced symptoms. Additionally, acquired immunity from a first dose can amplify the innate response (particularly involving monocytes) upon a second dose, increasing inflammation at the injection site.
Major Frameworks/Components:
- Innate immune system reactivity baseline.
- Interferon-related antiviral defense pathways.
- Monocyte activation amplified by acquired immunity (antibodies and T cells) following initial exposure.
Branch of Science: Immunology, Vaccinology.
Future Application: The findings could guide the development of new vaccines designed to minimize post-vaccination symptoms without compromising the strength of the resulting immune response, leading to better-tolerated inoculations.
Why It Matters: Understanding the biological mechanisms behind varying vaccine side effects helps demystify these reactions, potentially reducing vaccine hesitancy and paving the way for optimized, personalized vaccine formulations.
A team from UNIGE and HUG reveals why some people develop more pronounced transient symptoms following mRNA vaccination against COVID-19.
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 naturally produced by the body that are involved in antiviral defense. 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 the activation of the immune system by the vaccine, enabling the body to learn to recognize 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.
“While 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,” explains Arnaud Didierlaurent, associate professor at the Center for Vaccinology (UNIGE/HUG) and in the Department of Pathology and Immunology at the Faculty of Medicine, UNIGE.
The more active a person’s natural interferon response, even before vaccination, the more pronounced their reactions to vaccination are likely to be.
The Role of Our Immune "Capital"
To investigate these differences, the researcher and his team monitored the immune systems of fifty-one 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 defense system in explaining differences in side effects between individuals. This innate immune defense 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 neighboring 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 recognizing 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. Professor 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.
Funding: This research was supported by the HUG Private Foundation, the Giorgio Cavaglieri Foundation, and Moderna.
Published in journal: Science Translational Medicine
Authors: Natacha Madelon, Gustavo A. Ruiz Buendía, Paula Torres Rodriguez, Yves R. Donati, Paola Fontannaz, Matias Ciancaglini, Wafae Adouan, Emma Arsac, Nicolas Fonta, Rachel Goldstein, Nelli Heikkila, Nicolas Page, Jamie Sugrue, Darragh Duffy, Doron Merkler, Daniel D. Pinschewer, Christiane S. Eberhardt, Raphael Gottardo, Cathal Harmon, Anthony Dipiazza, and Arnaud M. Didierlaurent
Source/Credit: Université de Genève
Edited by: Scientific Frontline
Reference Number: imgy091726_01
