COVID-19 mRNA vaccination and immune-related adverse events in patients with cancer receiving immune checkpoint inhibitors: a target trial emulation study

BACKGROUND: COVID-19 messenger RNA (mRNA) vaccines enhance immune checkpoint inhibitor (ICI) efficacy through type I interferon responses, but may theoretically increase the burden of immune-related adverse events (irAEs). This study aimed to determine whether vaccination increases irAE risk in patients with ICI-treated cancer and to quantify the balance between toxicity and survival benefits. METHODS: We conducted a retrospective cohort study using target trial emulation methodology within the TriNetX Research Global Network (January 2021 to December 2025). We identified 7,218 adult patients with metastatic cancer initiating ICI therapy. Patients who received COVID-19 mRNA vaccination within 100 days before ICI initiation (n=3,609) were matched 1:1 to unvaccinated controls (n=3,609) using propensity scores. The primary outcome was the composite incidence of irAEs at 36 months. Secondary outcomes included severe irAEs, organ-specific irAEs, all-cause mortality, and intensive care unit (ICU) admission. Probabilistic quantitative bias analysis (VanderWeele-Ding formulation) and a composite ocular negative-control outcome (incident age-related cataract and glaucoma) were used to assess robustness to unmeasured confounding and differential ophthalmological surveillance. RESULTS: Vaccinated patients had a significantly increased risk of overall irAEs compared with unvaccinated controls (HR 1.22, 95% CI 1.17 to 1.28; E-value 1.74). This increase included clinically significant severe irAEs (HR 1.11, 95% CI 1.04 to 1.18). Organ-specific analyses revealed that the overall increase was primarily driven by ocular irAEs (HR 1.48, 95% CI 1.17 to 1.87), with non-significant trends for dermatologic and rheumatologic irAEs. However, vaccination was associated with substantial survival benefits, including 14% lower all-cause mortality (HR 0.86, 95% CI 0.80 to 0.93) and 57% fewer ICU admissions (HR 0.43, 95% CI 0.25 to 0.73). Point estimates were numerically higher in females and patients aged ≥50 years, although tests for interaction were not statistically significant. CONCLUSIONS: COVID-19 mRNA vaccination is associated with a modest but clinically meaningful 22% increase in irAEs, driven largely by ocular manifestations. However, the substantial survival benefits clearly outweigh these toxicity risks. Vaccination should continue in all eligible patients, with enhanced monitoring recommended for irAEs, particularly ophthalmological surveillance for high-risk groups.