Redness or pain at the injection site, fever, fatigue and headaches are common side effects of vaccination, but not everyone experiences them in the same way. Some people notice almost nothing, while others develop more noticeable flu-like symptoms. Researchers at the University of Geneva (UNIGE) and Geneva University Hospital (HUG) may have discovered an important reason for these differences.

Their study found that some people have more reactive innate immune systems even before they are vaccinated. In particular, they show a stronger response involving interferons, molecules naturally produced by the body that play an important role in antiviral defence. The stronger this pre-existing response, the more likely a person may be to experience temporary symptoms following vaccination. The findings were published in Science Translational Medicine.

Most vaccine reactions are mild and short-lived. They occur as the immune system responds to the vaccine and learns to recognise antigens associated with a virus, helping prepare the body to respond to future infection. This immune activation can produce inflammation around the injection site, causing redness, swelling or pain, as well as symptoms such as fatigue, headache or fever.

Scientists have long known that factors such as age and vaccine dose can affect side effects. Older adults, for example, often experience fewer reactions because immune function tends to decline with age. However, the biological reasons why people of similar ages can react very differently have remained less clear.

To investigate, researchers monitored 51 healthy people who received two doses of an mRNA COVID-19 vaccine. Participants were followed for seven days after each injection. The researchers found that people whose immune systems already showed greater interferon-related activity before vaccination tended to report stronger reactions afterwards.

Interferons are produced when cells become infected with a virus. They alert nearby cells and help prepare them to defend against infection. However, people appear to have different baseline levels of this antiviral activity. Researchers say these differences could be related to factors such as genetics, the microbiome or previous episodes of inflammation, although the precise reasons are not yet fully understood.

The researchers also identified another possible mechanism that may help explain why side effects can become more noticeable after a second vaccine dose. After the first dose, the body develops antibodies and T cells that recognise the vaccine antigen. When another dose is given, this acquired immunity can rapidly activate innate immune cells, including monocytes, which can then attract additional inflammatory cells to the injection site.

The findings could eventually help scientists design vaccines that cause fewer uncomfortable reactions while maintaining strong protection. Researchers are now investigating whether similar mechanisms occur with other vaccines. Importantly, they emphasise that experiencing few or no side effects does not mean a vaccine has failed to work. The severity of symptoms following vaccination is not, by itself, a measure of how effective the vaccine will be.

More information: Natacha Madelon et al, Baseline interferon signaling in monocytes and antibody-mediated innate activation are associated with reactogenicity to mRNA vaccines, Science Translational Medicine. DOI: 10.1126/scitranslmed.aee4776

Journal information: Science Translational Medicine Provided by Université de Genève