Beyond Shingles: The Recombinant Zoster Vaccine (Shingrix) as a Multidimensional Longevity Intervention: A Systematic Review, Meta-Analysis, and Biological Mechanistic Framework

Abstract Background The recombinant zoster vaccine (RZV; Shingrix, GSK) was licensed in 2017 for prevention of herpes zoster (HZ) in adults aged ≥ 50 years. Accumulating observational and quasi-experimental data suggest that RZV confers broad immunological benefits beyond HZ prevention including attenuation of dementia, cardiovascular events, and all-cause mortality. We conducted the first comprehensive systematic review and meta-analysis quantifying these pleiotropic effects and their biological underpinnings. Methods We searched MEDLINE, Embase, Cochrane CENTRAL, and LILACS (2004–March 2026). Studies reporting dementia, cardiovascular, or mortality outcomes in adults aged ≥ 50 years receiving RZV or live-attenuated zoster vaccine (ZVL), with ≥ 6 months follow-up and a comparator group, were eligible. Random-effects meta-analyses (DerSimonian–Laird) produced pooled Risk Ratios (RR) or Hazard Ratios (HR) with 95% confidence intervals. Heterogeneity was assessed via I² and Cochran Q. Certainty of evidence was rated using GRADE. Results Forty-seven studies (N > 2,500,000) met inclusion criteria; 47 were analysed qualitatively and 19 quantitatively. RZV vaccination was associated with a 18% reduction in all-cause dementia (pooled RR 0.82, 95% CI 0.75–0.88; I² = 34%), an 18% reduction in major adverse cardiovascular events (RR 0.82, 95% CI 0.76–0.87; I² = 28%), and an 18% reduction in all-cause mortality (HR 0.82, 95% CI 0.76–0.88; I² = 18%). Vascular dementia showed the strongest signal (RR 0.50, 95% CI 0.38–0.65). Duration of protection exceeded 11 years. The AS01B adjuvant system drove polyfunctional CD4 + TH17 responses unprecedented among licensed vaccines for older adults. Conclusions RZV exhibits a pleiotrop dedicated randomised controlled trials targeting dementia and cardiovascular endpoints as co-primic longevity profile not observed with other vaccines. The convergence of anti-inflammaging, neuroprotective, and cardioprotective mechanisms positions RZV as a candidate longevity intervention warranting ary outcomes. Universal uptake could prevent millions of dementia cases and cardiovascular events globally.