Baseline Interferon Activity in Monocytes Predicts mRNA Vaccine Adverse Effects, Study Finds

New research from the University of Geneva (UNIGE) and Geneva University Hospitals (HUG) has identified why reactogenicity—the redness, fatigue, fever, and headaches some individuals experience after vaccination—varies so widely from person to person.

Published in Science Translational Medicine, the findings show that an individual’s innate immune activity before they are ever vaccinated can help predict how strongly they will react to an mRNA vaccine.^1,2

Study Design and Key Findings

Investigators led by Arnaud Didierlaurent, associate professor at the Center for Vaccinology (UNIGE/HUG), longitudinally monitored 51 healthy individuals who received 2 doses of an mRNA vaccine against COVID-19, tracking symptoms for 7 days following each injection, the window in which reactogenicity typically peaks. 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.^1,2

"The more active a [individual’s] natural interferon response is, even before vaccination, the more pronounced their reactions to vaccination are likely to be," said Natacha Madelon, senior research and teaching assistant at the Center for Vaccinology and first author of the study. The investigators noted this baseline variability may stem from genetics, the microbiome, or a prior inflammatory episode, though the precise drivers remain unclear.²

Two Mechanisms Behind Amplified Reactions

Using a mouse model, the researchers identified 2 converging pathways that intensify symptoms after the second dose specifically. 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. Both mechanisms compound the effect of a person's baseline interferon signature, helping explain why side effects are so often more pronounced after the second mRNA dose than the first.^1,3

Complementary research examining pre-vaccination immune profiles has similarly linked baseline dendritic cell and monocyte states to both reactogenicity and antibody magnitude following BNT162b2 vaccination, reinforcing that innate immune "resting states" carry predictive value across cohorts.³

Notably, the study authors emphasized that reactogenicity is not a proxy for efficacy. "A mild reaction, or even the absence of symptoms following vaccination, does not in any way mean that the vaccine is ineffective," Didierlaurent said. The severity of adverse effects and the strength of the resulting antigen-specific immune response, while correlated, are not interchangeable measures of protection.²

Clinical Implications for Pharmacists

For pharmacists administering immunizations, this research offers a mechanistic, evidence-based explanation to share with patients who are anxious about—or discouraged by—vaccine adverse effects. That conversation carries added weight this fall: fear of side effects remains one of the most commonly cited reasons eligible adults skip COVID-19 boosters, alongside the belief that prior infection already provides adequate protection.⁴

With flu, COVID-19, and respiratory syncytial virus (RSV) all expected to circulate simultaneously this respiratory virus season, and with the CDC yet to issue updated 2026-2027 guidance, several major medical associations—including the American Medical Association—have independently released their own vaccination recommendations to fill the gap, continuing to endorse flu vaccination for individuals 6 months and older and COVID-19 vaccination for high-risk populations.⁵

Addressing Hesitancy Ahead of Respiratory Virus Season

As pharmacists prepare for a season of co-administered flu and COVID-19 vaccinations, findings like these can be a practical counseling tool: 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—not a sign that something went wrong, and not a signal of how well the vaccine is working. Conversely, patients who experience minimal or no symptoms can be reassured their vaccine is still expected to be effective.

Didierlaurent's team is now investigating whether the same interferon-driven mechanisms apply to other vaccine platforms, with the eventual goal of designing formulations that are equally effective but better tolerated.²

As pharmacists field more questions about reactogenicity during this year's back-to-school and flu-season vaccination push, understanding the biology behind these individual differences may prove to be a valuable addition to counseling conversations at the pharmacy counter.

REFERENCES

1. Madelon N, Ruiz Buendia G, Didierlaurent A, 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

2. Vaccination: why don't we all experience the same side effects? News release. EurekAlert! September 17, 2026. Accessed September 17, 2026. https://www.eurekalert.org/news-releases/1144256

3. Zelkoski AE, Goguet E, Samuels Darcey E, et al. Pre-Vaccination Immune Profiles and Responsiveness to Innate Stimuli Predict Reactogenicity and Antibody Magnitude Following mRNA Vaccination. Vaccines (Basel). 2025;13(7):718. doi:10.3390/vaccines13070718

4. Soucheray S. COVID booster uptake hindered by prior infections, fear of side effects. News release. CIDRAP. https://www.cidrap.umn.edu/covid-19/covid-booster-uptake-hindered-prior-infections-fear-side-effects

5. Medical groups release 2026-2027 flu, COVID and RSV vaccine recommendations for fall season. News release. Scripps News. Updated September 2, 2026. Accessed September 17, 2026. https://www.scrippsnews.com/health/medical-groups-release-2026-2027-flu-covid-and-rsv-vaccine-recommendations-for-fall-season