Researchers at the University of Geneva and Geneva University Hospitals have made a significant discovery about why some individuals experience more severe side effects after receiving an mRNA vaccine. The study, published in Science Translational Medicine, found that an individual’s innate immune activity before vaccination can help predict how strongly they will react to the vaccine.
The team, led by Arnaud Didierlaurent, associate professor at the Center for Vaccinology, monitored 51 healthy individuals who received two doses of an mRNA vaccine against COVID-19. They tracked symptoms for seven days following each injection and found that individuals with a preexisting interferon-stimulated gene signature in their monocytes were more likely to develop systemic symptoms after vaccination.
Study Findings
The team found that individuals with a preexisting interferon-stimulated gene signature in their monocytes—detectable at both the transcriptomic and epigenetic levels—were significantly more likely to develop systemic symptoms after vaccination. The investigators noted that this baseline variability may stem from genetics, the microbiome, or a prior inflammatory episode, though the precise drivers remain unclear.
The researchers identified two converging pathways that intensify symptoms after the second dose. First, antigen-specific T cells generated after the initial dose produce interferon that primes an accelerated response to subsequent exposure. Second, antibodies generated after the first dose trigger Fc-gamma receptor–dependent chemokine induction, which recruits and activates monocytes at the injection site.
Clinical Implications
The study’s findings have significant implications for pharmacists administering immunizations. For instance, patients who experience a sore arm, low-grade fever, or fatigue after their shot can be reassured that this reflects a normal, individualized immune response. Conversely, patients who experience minimal or no symptoms can be reassured that their vaccine is still expected to be effective.
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As pharmacists prepare for a season of co-administered flu and COVID-19 vaccinations, understanding the biology behind individual differences in reactogenicity may prove to be a valuable addition to counseling conversations at the pharmacy counter. This is particularly important, as fear of side effects remains one of the most commonly cited reasons eligible adults skip COVID-19 boosters.
Didierlaurent’s team is now investigating whether the same interferon-driven mechanisms apply to other vaccine platforms, with the goal of designing formulations that are equally effective but better tolerated. In the meantime, major medical associations, including the American Medical Association, have released their own vaccination recommendations for the upcoming respiratory virus season, continuing to endorse flu vaccination for individuals six months and older and COVID-19 vaccination for high-risk populations.
Addressing Vaccine Hesitancy
With flu, COVID-19, and respiratory syncytial virus all expected to circulate simultaneously this season, it is essential to address vaccine hesitancy. Pharmacists can play a key role in reassuring patients that side effects are a normal part of the immune response and that the vaccine is still effective, even if they do not experience any symptoms. By understanding the biology behind reactogenicity, pharmacists can provide more informed counseling and help increase vaccine uptake.
In practice, this means that pharmacists can use the study’s findings to inform their conversations with patients, helping to alleviate concerns about side effects and emphasizing the importance of vaccination. As the CDC and other medical associations continue to update their guidance, pharmacists will be well-equipped to provide accurate and reassuring information to their patients.
