Real‐world evidence from over one million COVID‐19 vaccinations is consistent with reactivation of the varicella‐zoster virus

BACKGROUND: Reactivation of the varicella‐zoster virus (VZV), which causes herpes zoster (HZ, synonym: shingles) in humans, can be a rare adverse reaction to vaccines. Recently, reports of cases after COVID‐19 vaccination have arisen. OBJECTIVES: The aim of this study was to assess whether the frequency of HZ is found to increase after COVID‐19 vaccination in a large cohort, based on real‐world data. As a hypothesis, the incidence of HZ was assumed to be significantly higher in subjects who received a COVID‐19 vaccine (Cohort I) vs. unvaccinated individuals (Cohort II). METHODS: The initial cohorts of 1 095 086 vaccinated and 16 966 018 unvaccinated patients were retrieved from the TriNetX database and were matched on age and gender in order to mitigate confounder bias. RESULTS: After matching, each cohort accounted for 1 095 086 patients. For the vaccinated group (Cohort I), 2204 subjects developed HZ within 60 days of COVID‐19 vaccination, while among Cohort II, 1223 patients were diagnosed with HZ within 60 days after having visited the clinic for any other reason (i.e. not vaccination). The risk of developing shingles was calculated as 0.20% and 0.11% for cohort I and cohort II, respectively. The difference was statistically highly significant (P < 0.0001; log‐rank test). The risk ratio and odds ratio were 1.802 (95% confidence interval [CI] = 1.680; 1.932) and 1.804 (95% CI = 1.682; 1.934). CONCLUSIONS: Consistent with the hypothesis, a higher incidence of HZ was statistically detectable post‐COVID‐19 vaccine. Accordingly, the eruption of HZ may be a rare adverse drug reaction to COVID‐19 vaccines. Even though the molecular basis of VZV reactivation remains murky, temporary compromising of VZV‐specific T‐cell‐mediated immunity may play a mechanistic role in post‐vaccination pathogenesis of HZ. Note that VZV reactivation is a well‐established phenomenon both with infections and with other vaccines (i.e. this adverse event is not COVID‐19‐specific).