Association between live herpes-zoster vaccine and stroke risk: A population-based nested case–control study

Background: Evidence on the role of herpes-zoster (shingles) vaccination in reducing stroke risk is inconsistent and limited, particularly concerning intracerebral hemorrhage (ICH). We aimed to examine the association between zoster live vaccine (ZVL) and overall stroke, as well as its main subtypes. Methods: We conducted a population-based nested case–control study using the database of Israel’s largest healthcare provider. The underlying cohort consisted of individuals aged 50 years or older, regardless of prior stroke status, from 2015 to 2022, with follow-up through June 2023. Stroke cases diagnosed during follow-up were matched with controls based on age, sex, population sector, and index date. ZVL exposure was defined as the prior filling of a prescription of the vaccine. Results: Among 37,027 matched case–control pairs, ZVL was associated with significantly reduced odds of stroke, with an adjusted odds ratio (OR) of 0.65 (95% confidence interval (CI), 0.58–0.72) for overall stroke, 0.65 (95% CI, 0.58–0.73) for ischemic stroke, and 0.64 (95% CI, 0.47–0.89) for ICH. The protective association with overall stroke decreased as time since vaccination increased; adjusted OR of 0.56 (0.48–0.65) within the first 2.5 years, 0.71 (95% CI, 0.58–0.87) after 2.5 to 5 years, and 0.81 (95% CI, 0.65–1.01) after 5 years. The association between ZVL and stroke was modified by age and sex, with a stronger association in individuals younger than 65 years ( p for interaction = 0.004) and males ( p for interaction = 0.031). Conclusions: ZVL is associated with a reduced risk of both ischemic stroke and ICH. The protective association appears to decrease over time and to be stronger in males and younger individuals.