A research team from the Center for Vaccinology at the University of Geneva (UNIGE) and Geneva University Hospital (HUG) investigated why some people experience stronger short-term reactions after seasonal vaccination. The investigators used COVID-19 mRNA vaccines as a case study and combined human participant monitoring with mouse-model experiments. Their results were published in Science Translational Medicine. Some funding for the work came from Moderna.
The human component enrolled 51 healthy adults with a median age of 43.5 years. Each participant received two doses of an mRNA COVID-19 vaccine, and researchers monitored side effects for one week after each dose to record symptom frequency and severity. The study aimed to identify biological mechanisms behind individual differences in post-vaccination symptoms rather than to reassess vaccine safety broadly.
The investigators focused on innate antiviral pathways and found that activity in an interferon-related signaling system likely explains differences in side effects between individuals. Interferons are signaling proteins that cells release when they detect viral components; their role is to alert surrounding cells and prime antiviral defenses.
Study authors reported that persons who have a more active natural interferon response even before vaccination tended to experience more pronounced reactions after immunization. That heightened baseline activity appears to shape how the immune system responds when it encounters the vaccine antigen and the accompanying immune activation that produces the cold- or flu-like symptoms some people notice.
The senior author noted that known factors such as older age—associated with declines in immune function—and vaccine dose can influence post-vaccination symptoms, but that the molecular mechanisms underlying individual variability were previously unclear. This study points to subtle differences in innate signaling as an explanatory factor.
The research team complemented human observations with experiments in mouse models. After the first vaccine dose, mice developed antibodies and trained T cells that recognized the vaccine antigen. On receipt of a second dose, this acquired immunity rapidly boosted the activity of other innate immune cells, particularly monocytes, which can amplify inflammatory responses.
This chain of immune activation offers a mechanistic explanation for why some people report stronger side effects after a second dose: prior exposure through the first dose primes adaptive immunity, which in turn can escalate innate-cell responses when re-exposed to the antigen. The mouse data supported the human findings that stronger innate antiviral signaling correlates with more pronounced short-term reactions.
A general practitioner who was not involved in the study described the findings as indicating that some people are naturally more prone to short-term vaccine reactions because their innate immune systems exhibit a more active interferon response. She noted possible contributors to those baseline differences could include genetics, the microbiome, and prior inflammation, but emphasized that more research is needed to establish those links.
Clinicians and the article’s commentators stressed that the reactions observed in the study were generally mild and temporary rather than serious complications. They also highlighted an important clinical point: experiencing stronger side effects does not necessarily mean the vaccine is working better, and having little or no reaction does not imply reduced effectiveness.
According to the clinical commentator, there is currently no validated way to predict or prevent the immune responses that underlie stronger short-term vaccine reactions. For symptomatic management, standard measures remain appropriate: rest, adequate hydration, and simple interventions such as paracetamol (acetaminophen) where suitable and advised.
The advice is aimed at easing common, transient symptoms that typically resolve within a few days. The study reinforces that symptomatic management is the practical approach in the absence of predictive tests or preventive strategies based on the interferon-response findings.
The study did not identify any population that should avoid seasonal or COVID-19 vaccination because of the mechanisms it describes. The clinical commentator recommended that, for now, the only people who should seek medical counsel before receiving a seasonal vaccine are those concerned about a potential serious allergic reaction to a vaccine ingredient.
The researchers are continuing to investigate whether the same interferon-related mechanisms apply to other vaccines, including seasonal influenza vaccines. Until further evidence emerges, current vaccine guidance remains unchanged: most people should proceed with vaccination while following routine precautions for known allergies and discussing any specific concerns with a healthcare professional.