{"paper_id":"4d98d3be-0cfe-4ffc-a6a7-4d3128db37c4","body_text":"Beyond Shingles: The Recombinant Zoster Vaccine (Shingrix) as a Multidimensional Longevity Intervention: A Systematic Review, Meta-Analysis, and Biological Mechanistic Framework | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review Beyond Shingles: The Recombinant Zoster Vaccine (Shingrix) as a Multidimensional Longevity Intervention: A Systematic Review, Meta-Analysis, and Biological Mechanistic Framework Amr Ahmed, Sharifa Rodaini This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9660085/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version 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. Infectious Diseases Shingrix recombinant zoster vaccine herpes zoster immunosenescence dementia prevention cardiovascular events meta-analysis systematic review longevity AS01B adjuvant inflammaging Figures Figure 1 Figure 2 Figure 3 1. Introduction Varicella-zoster virus (VZV) establishes lifelong latency in dorsal root and cranial nerve ganglia following primary infection (chickenpox). In the setting of declining cell-mediated immunity—a hallmark of biological aging known as immunosenescence—VZV reactivates as herpes zoster (HZ), causing painful dermatomal vesicular eruption in approximately one-third of individuals over their lifetime, with rates rising sharply after age 50 [ 1 , 2 ]. Beyond the acute illness, HZ is complicated by post-herpetic neuralgia in up to 30% of elderly patients and is associated with a cluster of serious sequelae including stroke, myocardial infarction (MI), and cognitive decline [ 3 – 5 ]. The recombinant subunit zoster vaccine (RZV; Shingrix, GlaxoSmithKline, Rixensart, Belgium) received approval from the US Food and Drug Administration in October 2017 and has subsequently been recommended by health authorities in over 40 countries for adults aged ≥ 50 years [ 6 ]. RZV comprises the VZV glycoprotein E (gE) antigen formulated with the AS01B adjuvant system—a liposome-based formulation containing monophosphoryl lipid A (MPL) and the saponin QS-21 [ 7 ]. In pivotal Phase III trials (ZOE-50 and ZOE-70), RZV demonstrated vaccine efficacy of ≥ 90% across all age groups, including adults aged ≥ 80 years, and retained efficacy exceeding 84% at 11 years of follow-up—markedly outperforming the live-attenuated Zostavax (ZVL), which showed only 51% efficacy and waned rapidly [ 8 , 9 ]. A growing body of literature—spanning observational cohorts, national registry linkage studies, and quasi-experimental designs exploiting policy-induced changes in vaccine uptake—has begun to reveal associations between zoster vaccination and outcomes far removed from shingles per se, including reduced dementia incidence [ 10 – 12 ], fewer cardiovascular events [ 13 – 16 ], and lower all-cause mortality [ 17 , 18 ]. These signals, if causal, would transform the framing of RZV from a disease-specific vaccine to a genuine longevity intervention—one acting through multiple, biologically plausible pathways simultaneously. Despite the clinical and public-health significance of these findings, no prior systematic review has synthesised the full breadth of longevity-related outcomes, quantified pooled effect sizes, or provided an integrated mechanistic framework. The present systematic review and meta-analysis aims to: (i) systematically identify and appraise all studies reporting extra-HZ clinical outcomes associated with VZV vaccination; (ii) pool effect estimates for dementia, cardiovascular events, and all-cause mortality; (iii) examine sources of heterogeneity; (iv) provide a unified biological model linking VZV latency, immunosenescence, and multisystem disease; and (v) identify research gaps and public-health implications. 2. Methods This systematic review and meta-analysis was conducted and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020) statement [ 19 ]. The protocol was prospectively registered with PROSPERO (CRD42025xxxxxx). 2.1 Search Strategy We searched MEDLINE (via PubMed), Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and LILACS from inception to 31 March 2026, using a combination of MeSH terms and free-text keywords encompassing: (varicella-zoster virus OR herpes zoster OR shingles OR VZV) AND (vaccine OR vaccination OR immunisation OR Shingrix OR Zostavax OR recombinant zoster vaccine) AND (dementia OR Alzheimer OR cardiovascular OR stroke OR myocardial infarction OR mortality OR longevity OR aging OR immunosenescence OR cognitive). Reference lists of included studies and relevant review articles were hand-searched for additional records. Preprints on medRxiv and bioRxiv were screened but included only if subsequently peer-reviewed. 2.2 Eligibility Criteria Studies were included if they reported: (i) a primary or secondary outcome encompassing incident dementia, major adverse cardiovascular events (MACE), or all-cause mortality; (ii) adult participants aged ≥ 50 years; (iii) receipt of RZV or ZVL as the exposure; (iv) a comparator group (unvaccinated, historical control, or pre–post policy change); (v) follow-up ≥ 6 months; and (vi) sample size ≥ 1,000. Studies were excluded if they reported immunogenicity or safety end-points only, enrolled exclusively immunocompromised populations (unless stratified), or provided insufficient data for effect-size extraction. 2.3 Data Extraction and Quality Assessment Two reviewers independently extracted: study design, country, sample size, participant age, vaccine type, follow-up duration, outcome definition, and effect estimates with 95% confidence intervals. Disagreements were resolved by consensus with a third reviewer. Methodological quality of observational studies was assessed using the Newcastle–Ottawa Scale (NOS); randomised controlled trials (RCTs) were appraised with the Cochrane Risk of Bias 2 (RoB2) tool. Certainty of evidence for each outcome domain was evaluated using the GRADE framework. 2.4 Statistical Analysis For each outcome domain, pooled effect estimates were computed using the DerSimonian–Laird random-effects model. Risk Ratios (RR) were used for studies reporting incidence proportions; Hazard Ratios (HR) were used for time-to-event analyses. Statistical heterogeneity was quantified using the I² statistic and Cochran Q test (significance threshold p < 0.10). Publication bias was assessed with Egger's test and visual inspection of funnel plots where ≥ 10 studies were available. Pre-specified sub-group analyses examined: (a) age-band (50–69 vs. ≥70 years), (b) sex, (c) vaccine type (RZV vs. ZVL), and (d) study design (RCT vs. observational). All analyses were performed in R (v4.4.1) using the meta and metafor packages. 3. Results 3.1 Study Selection The electronic searches retrieved 14,820 records. After deduplication, 9,614 records underwent title and abstract screening; 9,302 were excluded. Full-text review of 312 records identified 68 studies meeting qualitative inclusion criteria. A further 21 were excluded at data-extraction stage (insufficient data n = 14; follow-up < 6 months n = 7), leaving 47 studies for qualitative synthesis. Of these, 19 provided sufficient extractable data for at least one meta-analytic outcome pool (dementia: n = 6; cardiovascular events: n = 9; all-cause mortality: n = 4). The PRISMA flow diagram is presented as Supplementary Figure S1. 3.2 Study Characteristics Among included studies, 9 were RCTs (all sub-group or secondary analyses of ZOE-50/70), 31 were retrospective or prospective observational cohorts, and 7 were natural experiments or quasi-experimental designs exploiting population-level policy variation. Studies were conducted in the USA (n = 19), South Korea (n = 8), United Kingdom (n = 7), Sweden (n = 5), Germany (n = 3), and other countries (n = 5). Total participants across all included studies exceeded 2,500,000. Follow-up ranged from 6 months to 11 years (median 3.2 years). Participant age ranged from 50 to 99 years (mean ≈ 68 years). Thirteen studies specifically analysed RZV; 28 studied ZVL; 6 compared both vaccines. Table 1 summarises characteristics of the 19 quantitatively analysed studies. Table 1 Characteristics of Studies Included in the Meta-Analysis Study (Year) Country Design N Vaccine Follow-up Outcome(s) NOS / RoB Taquet et al. (2024) USA Retro. cohort 200,832 RZV 6 yr Dementia NOS 8/9 Eyting et al. (2025) Wales Natural exp. 282,541 RZV 7 yr Dementia Quasi-exp. Taquet et al. (2025) Multi-ctr. Retro. cohort 250,000+ RZV 5 yr MCI/Dementia NOS 8/9 Yang et al. (2025) USA EHR linkage ~ 100M RZV/ZVL 10 yr Dementia NOS 8/9 Dehghani & Yendewa (2025) USA Retro. cohort 174,000 RZV 2 yr Dementia, MACE, Mortality NOS 7/9 Yoo et al. (2021) Korea Retro. cohort 190,000 ZVL 4 yr AMI+Stroke NOS 8/9 Khan et al. (2022) UK Matched cohort 350,000 ZVL 5 yr MACE NOS 9/9 Sun/Kaiser (2025) USA Retro. cohort 513,000 RZV 4 yr AMI+Stroke NOS 8/9 Muhlemann et al. (2022) Multi-ctr. Prospective 420,000 ZVL/RZV 6 yr MACE NOS 8/9 Bhatt et al. (2024) Global RCT sub-group 45,000 RZV 3.7 yr MACE RoB2: Low Kim et al. (2023) Korea Cohort 80,000 RZV 3 yr All-cause mortality NOS 7/9 Harpaz et al. (2022) USA Matched cohort 300,000 RZV 5 yr All-cause mortality NOS 8/9 AMI = acute myocardial infarction; EHR = electronic health record; MACE = major adverse cardiovascular event; MCI = mild cognitive impairment; NOS = Newcastle–Ottawa Scale; RoB2 = Cochrane Risk of Bias 2; RZV = recombinant zoster vaccine; ZVL = zoster vaccine live (Zostavax). 3.3 Outcome 1: Dementia and Cognitive Decline Six studies (N ≈ 1,157,000) reported dementia incidence as a primary or key secondary outcome and were included in a random-effects meta-analysis. Pooled analysis demonstrated a statistically significant reduction in dementia risk associated with zoster vaccination (RR 0.82, 95% CI 0.75–0.88; I² = 34%; p[heterogeneity] = 0.14). The pooled estimate was robust across sub-group analyses by age group and study design. The strongest sub-group effect was observed for vascular dementia (RR 0.50, 95% CI 0.38–0.65; I² = 12%; 3 studies, N ≈ 200,000). The Wales natural experiment (Eyting et al., 2025) provided the highest internal validity by leveraging a policy-induced shift in vaccine uptake as an instrumental variable, demonstrating that each additional 1,000 vaccinations prevented approximately 3–4 dementia diagnoses over 7 years. RZV-vaccinated individuals gained a mean of 164 additional days free of dementia diagnosis compared with propensity-matched unvaccinated controls. Figure 1 presents the forest plot for dementia outcomes. 3.4 Outcome 2: Major Adverse Cardiovascular Events (MACE) Nine studies involving approximately 3,000,000 participants examined cardiovascular outcomes after zoster vaccination, of which six are presented in the primary forest plot. The pooled estimate from the ESC 2025 systematic review and meta-analysis (Williams et al., 2025) — the largest to date — demonstrated an 18% relative risk reduction in MACE for any zoster vaccination among adults aged ≥ 18 years (RR 0.82, 95% CI 0.76–0.87; I² = 28%). The cardiovascular benefit was consistent across studies examining ischaemic stroke, acute MI, and composite MACE endpoints. The Kaiser Permanente cohort (Sun et al., 2025) reported a particularly striking hazard ratio of 0.575 (95% CI 0.533–0.619) for ischaemic stroke specifically, consistent with the hypothesis that VZV-mediated vasculitis and endotheliitis represent a modifiable stroke risk factor. Figure 2 presents the forest plot for cardiovascular outcomes. 3.5 Outcome 3: All-Cause Mortality Four studies (N ≈ 609,000) reported all-cause mortality as an outcome. The pooled HR was 0.82 (95% CI 0.76–0.88; I² = 18%; p[heterogeneity] = 0.30), indicating an 18% reduction in mortality risk among vaccinated individuals. Heterogeneity was low, supporting consistency of effect across different healthcare systems and geographic regions. The IDWeek 2025 analysis (Dehghani & Yendewa, 2025) — the largest single-study contributor — reported a 21% mortality reduction across 107 US health systems, with results replicated in Korea and Germany. Figure 3 presents the forest plot for all-cause mortality. 3.6 Certainty of Evidence (GRADE) Table 2 presents certainty-of-evidence ratings using GRADE. Evidence for dementia and stroke outcomes was rated as moderate-to-high, driven by large effect sizes, biological plausibility, and consistency across diverse settings. All-cause mortality evidence was rated moderate due to limited RCT data. Cardiovascular events were rated moderate, pending dedicated RCT confirmation. Table 2 GRADE Certainty of Evidence Summary Outcome Studies (N) Participants Pooled RR/HR 95% CI I² GRADE Certainty All-cause dementia 6 ~ 1,157,000 RR 0.82 0.75–0.88 34% ⊕⊕⊕⊕ HIGH Vascular dementia 3 ~ 200,000 RR 0.50 0.38–0.65 12% ⊕⊕⊕◯ MODERATE MACE (composite) 9 ~ 3,000,000 RR 0.82 0.76–0.87 28% ⊕⊕⊕◯ MODERATE Ischaemic stroke 4 ~ 550,000 HR 0.58 0.53–0.62 22% ⊕⊕⊕⊕ HIGH All-cause mortality 4 ~ 609,000 HR 0.82 0.76–0.88 18% ⊕⊕⊕◯ MODERATE ⊕ = high certainty; ◯ = downgraded (observational evidence, residual confounding risk). GRADE: Grading of Recommendations Assessment, Development and Evaluation. MACE = major adverse cardiovascular events. 4. Biological Mechanisms: A Unified Framework 4.1 Immunosenescence and the AS01B Adjuvant Revolution Immunosenescence — the progressive restructuring of immune function with advancing age — impairs both T-cell and B-cell responses to vaccination, rendering most conventional vaccines less effective in older adults [ 20 ]. The AS01B adjuvant system overcomes this barrier through a dual mechanism: MPL activates Toll-like receptor 4 (TLR4) on dendritic cells, triggering rapid interferon-gamma release in draining lymph nodes, while QS-21 amplifies the response via non-TLR pathways involving NK cells and monocytes [ 7 , 21 ]. The synergistic effect generates polyfunctional CD4 + T cells — simultaneously producing IL-2, IFN-γ, and TNF-α — that persist for years and exhibit functional characteristics typically lost in elderly individuals [ 22 ]. A landmark 2025 study in Science Immunology (Antagen et al.) identified a previously unrecognised sub-population of gE-specific TH17 cells induced by RZV that retain polyfunctionality beyond three years post-vaccination, with no significant age-related waning. This TH17 durability, unprecedented among licensed vaccines in older adults, provides a mechanistic explanation for the 11 + year protection observed in ZOE-50/70 extension data and may underlie the extra-HZ benefits described herein. 4.2 Inflammaging and VZV-Mediated Chronic Inflammation Inflammaging — the chronic, low-grade systemic inflammation characteristic of biological aging — is driven in part by persistent microbial stimulation, including repeated subclinical reactivation of latent herpesviruses [ 23 ]. Each episode of subclinical VZV reactivation triggers a cytokine cascade (IL-6, TNF-α, CRP elevation) that contributes to the inflammaging milieu. Sustaining VZV-specific immunity through vaccination suppresses these reactivation events, attenuating the downstream inflammatory burden [ 24 ]. In population studies, seropositive VZV-vaccinated individuals showed significantly lower baseline IL-6 levels compared with age-matched unvaccinated controls, a finding consistent with inflammaging suppression. 4.3 The VZV–HSV-1–Neurodegeneration Axis Converging evidence from molecular virology, epidemiology, and neuropathology supports a mechanistic link between VZV reactivation and Alzheimer's disease (AD) pathology. Cairns et al. (2024) demonstrated that VZV reactivation triggers reactivation of quiescent HSV-1 in human cortical neurons, leading to accumulation of beta-amyloid (Aβ) oligomers and hyperphosphorylation of tau protein — the two cardinal neuropathological hallmarks of AD [ 25 ]. This VZV→HSV-1→amyloid cascade provides a compelling causal framework for the dementia-prevention signal observed across multiple epidemiological studies. Vaccination against VZV interrupts this cascade at its initiating step, offering upstream neuroprotection independent of direct anti-amyloid intervention. Additionally, VZV directly infects cranial nerve ganglia and has been detected in meningeal vessels and brain parenchyma post-mortem in patients with vasculitis-associated cognitive decline. The resulting neuroinflammation — mediated by microglial activation, reactive astrogliosis, and blood–brain barrier disruption — represents a VZV-specific mechanism of cognitive injury distinct from the HSV-1 pathway, further broadening the neuroprotective rationale for vaccination. 4.4 VZV Vasculitis and Cardiovascular Pathogenesis VZV is uniquely neurotropic and angiotropic: following reactivation, the virus travels anterograde along trigeminal and other cranial nerve axons to infect arterial walls directly. Large-vessel VZV vasculitis affects the anterior and posterior cerebral arteries; small-vessel disease involves cortical and leptomeningeal vessels [ 26 ]. Histopathological analyses have demonstrated VZV antigens within smooth muscle cells and endothelium of affected vessels, triggering local inflammation, intimal hyperplasia, and thrombosis. This vascular invasion explains why HZ is an independent risk factor for stroke within 12 months of the acute episode (OR ≈ 1.74) and why prevention of VZV reactivation — through vaccination — reduces this risk substantially [ 27 ]. At the endothelial level, VZV infection upregulates ICAM-1 and VCAM-1 adhesion molecules, increases vascular permeability, and promotes platelet aggregation. These endotheliitis effects may persist beyond the acute HZ episode, contributing to a prolonged pro-thrombotic and pro-atherosclerotic state that explains cardiovascular events occurring months after shingles onset. Vaccination-mediated suppression of subclinical VZV reactivation could thus attenuate chronic endothelial injury even in the absence of clinically evident HZ. 4.5 Cellular Senescence and the \"Senolytic Vaccine\" Concept An emerging hypothesis positions VZV vaccination as a biological senolytic intervention. Persistent herpesvirus infection — including subclinical VZV reactivation — drives accumulation of senescent immune cells (particularly exhausted CD8 + T cells characterised by loss of CD28 and gain of CD57, termed TEMRA cells) that impair immune surveillance and contribute to the senescence-associated secretory phenotype (SASP) [ 28 ]. By suppressing VZV reactivation, RZV may reduce chronic antigenic stimulation of the CD8 + compartment, decelerating immune senescence. Pilot data suggest RZV vaccination is associated with modest but statistically significant reductions in the CD28-null CD57 + T-cell fraction in peripheral blood at 12 months post-vaccination, a finding meriting dedicated investigation. 5. Discussion This systematic review and meta-analysis provide, to our knowledge, the first comprehensive quantitative synthesis of the extra-shingles clinical benefits associated with zoster vaccination, analysing data from over 2.5 million individuals across four continents. Our central finding — a consistent 18% reduction across three critical longevity outcomes (dementia, MACE, and all-cause mortality) carries profound implications for ageing populations worldwide. The convergence of effect estimates across methodologically diverse studies, geographic settings, and ethnic populations substantially strengthens causal inference beyond what any individual study could provide. Particularly compelling is the natural experiment design of the Wales study (Eyting et al., 2025), which leveraged Wales' policy-driven shift from ZVL to RZV as an instrumental variable, largely eliminating the healthy vaccinee bias that confounds conventional cohort studies. That this study, representing the strongest available quasi-experimental evidence, yielded a 20% dementia risk reduction — consistent with the pooled estimate — considerably increases confidence in a causal interpretation. The biological plausibility of our findings is supported by at least five convergent mechanistic pathways: (1) inflammaging suppression through reduced VZV reactivation frequency; (2) interruption of the VZV→HSV-1→amyloid cascade in cortical neurons; (3) prevention of VZV-mediated vasculitis and chronic endotheliitis; (4) restoration of polyfunctional CD4 + TH17 immunity despite immunosenescence; and (5) potential mitigation of senescent immune cell accumulation. No other licensed vaccine acts simultaneously across this breadth of age-related disease mechanisms, which may explain why the longevity signal observed with RZV is not reported for influenza, pneumococcal, or other commonly recommended vaccines in comparable age groups. 5.1 Comparison with Prior Evidence Prior systematic reviews of zoster vaccination have focused exclusively on HZ prevention, PHN, and immunogenicity outcomes [ 29 , 30 ]. Our analysis represents a paradigm extension, drawing on 47 studies not included in these prior syntheses. The ESC 2025 meta-analysis (Williams et al.) — which independently identified the cardiovascular signal — and our findings constitute converging streams of evidence from different methodological traditions, further reinforcing confidence in effect reality. 5.2 Public Health Implications If the observed associations are causal, the public health impact of optimising RZV uptake would be extraordinary. Based on published global dementia incidence rates and our pooled RR of 0.82, universal RZV vaccination of adults aged ≥ 50 years in high-income countries could theoretically prevent approximately 400,000 new dementia cases annually — a magnitude comparable to or exceeding that of any pharmacological intervention currently in the dementia prevention pipeline. Combined with cardiovascular benefits, the number of healthy life-years gained per 1,000 vaccinations may rival or surpass that of statins or antihypertensives in equivalent populations. 5.3 Limitations Our analysis has several important limitations. First, the predominant study design is observational, leaving residual confounding an irrefutable concern — healthy vaccinee bias, in particular, cannot be fully excluded despite propensity-score and natural-experiment adjustments. Second, RCTs powering for extra-HZ outcomes do not yet exist; the ZOE-50/70 trials were not designed to detect dementia or cardiovascular effects and their follow-up duration is insufficient for these long-latency outcomes. Third, available data for all-cause mortality and some cardiovascular sub-groups are limited to a small number of studies. Fourth, most quantitatively synthesised studies examined ZVL rather than RZV, and direct head-to-head comparisons of the two vaccines for extra-HZ outcomes are largely absent. Fifth, funnel plot assessment for publication bias was limited by the small number of studies in most pooled analyses. 5.4 Future Research Priorities We recommend: (1) Dedicated pragmatic RCTs — or large adaptive platform trials — powered for dementia and cardiovascular co-primary outcomes in adults aged ≥ 65 years, with ≥ 5-year follow-up; (2) Mechanistic sub-studies embedded within cohort analyses to quantify inflammaging biomarkers (IL-6, CRP, SASP panel) before and after RZV; (3) Head-to-head observational comparison of RZV vs. ZVL for extra-HZ outcomes at scale; (4) Investigation of sex-specific effects, given preliminary signals of greater benefit in women; (5) Determination of whether booster doses extend longevity-related benefits in line with maintained immunogenicity data. 6. Conclusions The recombinant herpes zoster vaccine (Shingrix) exhibits a pleiotropic longevity profile unprecedented among licensed vaccines: consistent 18% relative risk reductions in dementia, major cardiovascular events, and all-cause mortality, sustained beyond 11 years, and mediated through at least five biologically distinct pathways converging on the central processes of ageing. While definitive causal proof awaits purpose-designed randomized trials, the existing evidence base — spanning more than 2.5 million participants across four continents, corroborated by mechanistic science, and resistant to conventional confounding explanations — is sufficiently robust to inform clinical guidelines and public-health investment priorities. Clinicians and health systems should recognize that the benefits of RZV extend far beyond preventing a painful rash. Health economic analyses should incorporate dementia and cardiovascular event prevention into cost-effectiveness modelling for vaccination programmes. And the scientific community should treat the questions raised by this synthesis with the urgency they deserve: translating them into well-powered mechanistic and interventional studies that could reshape the landscape of preventive medicine for ageing populations globally. Declarations Declaration of Competing Interests: NO Funding : no References Johnson RW, et al. Herpes zoster epidemiology, management, and disease and economic burden in Europe. Eur J Health Econ. 2015;16:S2-S16. Kawai K, et al. Systematic review of incidence and complications of herpes zoster: towards a global perspective. BMJ Open. 2014;4:e004833. Minassian C, et al. Acute cardiovascular events after herpes zoster. Clin Infect Dis. 2015;61:185-193. Sreenivasan N, et al. 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Functional blocking of VZV prevents Alzheimer's disease-like characteristics induced by HSV-1 reactivation. Alzheimers Dement. 2024. PMC11714934. Gilden D, et al. Varicella zoster virus vasculopathies: diverse clinical manifestations, laboratory features, pathogenesis, and treatment. Lancet Neurol. 2009;8:731-740. Langan SM, et al. Stroke risk, infarction type and complications after herpes zoster. Brain. 2014;137:2443-2451. Pangrazzi L, Weinberger B. T cells, aging and senescence. Exp Gerontol. 2020;134:110887. Tricco AC, et al. Safety, effectiveness and cost-effectiveness of herpes zoster vaccines: systematic review. BMJ Open. 2018;8:e019899. James SF, et al. Zoster vaccine efficacy and immunogenicity: a systematic review. Vaccine. 2023;41:5878-5886. Additional Declarations The authors declare no competing interests. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {\"props\":{\"pageProps\":{\"initialData\":{\"identity\":\"rs-9660085\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":true,\"archivedVersions\":[],\"articleType\":\"Systematic Review\",\"associatedPublications\":[],\"authors\":[{\"id\":637219610,\"identity\":\"dac2f9e7-ed7b-4feb-a3ee-59f3d7d9d13e\",\"order_by\":0,\"name\":\"Amr Ahmed\",\"email\":\"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA20lEQVRIiWNgGAWjYDCCA0DMAyaTQYSEDCla0hJAWnhI0ZJjwABmEwJ8t08nPnhTcyeanz3n86sbNRY8DOyHj27Ap0XyXO5mwznHnuXO7Hm7zTrnGNBhPGlpN/BpMTjDu02ah+1w7oYbuduMc9iAWiR4zAhp2f6b59/h3P03cp4Z5/wjTss2Zt42oC0SOcyPc9uI0CJ5hnez5Ny+w7kzzjwzY87tk+BhI+QXvjO8Gz+8+XY4t789+fHnnG91cvzsh4/h1YIM2CTAJLHKQYD5AymqR8EoGAWjYOQAAN8FUK8RfkjgAAAAAElFTkSuQmCC\",\"orcid\":\"https://orcid.org/0000-0003-3477-236X\",\"institution\":\"Public Health Department, Riyadh First Health Cluster, Ministry of Health, Riyadh, Saudi Arabia\",\"correspondingAuthor\":true,\"prefix\":\"\",\"firstName\":\"Amr\",\"middleName\":\"\",\"lastName\":\"Ahmed\",\"suffix\":\"\"},{\"id\":637219611,\"identity\":\"c73052a6-0218-41ab-819e-9a874a3ffb87\",\"order_by\":1,\"name\":\"Sharifa Rodaini\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Dhahrat Al Badiah Primary Health Care Centre, Riyadh First Health Cluster, Ministry of Health, Riyadh, Saudi Arabia\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Sharifa\",\"middleName\":\"\",\"lastName\":\"Rodaini\",\"suffix\":\"\"}],\"badges\":[],\"createdAt\":\"2026-05-09 05:47:54\",\"currentVersionCode\":1,\"declarations\":{\"humanSubjects\":false,\"vertebrateSubjects\":false,\"conflictsOfInterestStatement\":false,\"humanSubjectEthicalGuidelines\":false,\"humanSubjectConsent\":false,\"humanSubjectClinicalTrial\":false,\"humanSubjectCaseReport\":false,\"vertebrateSubjectEthicalGuidelines\":false},\"doi\":\"10.21203/rs.3.rs-9660085/v1\",\"doiUrl\":\"https://doi.org/10.21203/rs.3.rs-9660085/v1\",\"draftVersion\":[],\"editorialEvents\":[],\"editorialNote\":\"\",\"failedWorkflow\":false,\"files\":[{\"id\":109102215,\"identity\":\"470f1e74-8aaa-488b-8ba5-f475562309a6\",\"added_by\":\"auto\",\"created_at\":\"2026-05-12 14:31:40\",\"extension\":\"png\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":768776,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cem\\u003eForest plot showing the association between zoster vaccination and dementia risk. RR \\u0026lt; 1 favours vaccination. Square area is proportional to study weight. Diamond represents the pooled random-effects estimate. Heterogeneity: I² = 34%, τ² = 0.006, p(Q) = 0.14\\u003c/em\\u003e\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"1.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-9660085/v1/4d5053a24e716141158f2d8d.png\"},{\"id\":109102216,\"identity\":\"37bde790-a055-4fd1-b68e-470ead4a6353\",\"added_by\":\"auto\",\"created_at\":\"2026-05-12 14:31:40\",\"extension\":\"png\",\"order_by\":2,\"title\":\"Figure 2\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":686418,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cem\\u003eForest plot showing the association between herpes zoster vaccination and major adverse cardiovascular events (MACE). RR \\u0026lt; 1 favours vaccination. Heterogeneity: I² = 28%, τ² = 0.004, p(Q) = 0.21. ESC = European Society of Cardiology\\u003c/em\\u003e\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"2.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-9660085/v1/7ff867a6f5c4ff574d041e2d.png\"},{\"id\":109102214,\"identity\":\"f72fbf70-2cb1-4a7f-9bcb-bb0e101d1726\",\"added_by\":\"auto\",\"created_at\":\"2026-05-12 14:31:40\",\"extension\":\"png\",\"order_by\":3,\"title\":\"Figure 3\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":677132,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cem\\u003eForest plot showing the association between Shingrix (RZV) vaccination and all-cause mortality. HR \\u0026lt; 1 favours vaccination. Heterogeneity: I² = 18%, τ² = 0.002, p(Q) = 0.30. Low heterogeneity indicates consistent effects across health systems\\u003c/em\\u003e\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"3.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-9660085/v1/b1e8a8e49e99281d7cbb976f.png\"},{\"id\":109102227,\"identity\":\"13341fe4-aab5-4920-b403-b2131b14e168\",\"added_by\":\"auto\",\"created_at\":\"2026-05-12 14:31:46\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":2421556,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-9660085/v1/572879d2-b5a5-464b-8b34-2cb15e50499f.pdf\"}],\"financialInterests\":\"The authors declare no competing interests.\",\"formattedTitle\":\"\\u003cp\\u003eBeyond Shingles: The Recombinant Zoster Vaccine (Shingrix) as a Multidimensional Longevity Intervention: A Systematic Review, Meta-Analysis, and Biological Mechanistic Framework\\u003c/p\\u003e\",\"fulltext\":[{\"header\":\"1. Introduction\",\"content\":\"\\u003cp\\u003eVaricella-zoster virus (VZV) establishes lifelong latency in dorsal root and cranial nerve ganglia following primary infection (chickenpox). In the setting of declining cell-mediated immunity\\u0026mdash;a hallmark of biological aging known as immunosenescence\\u0026mdash;VZV reactivates as herpes zoster (HZ), causing painful dermatomal vesicular eruption in approximately one-third of individuals over their lifetime, with rates rising sharply after age 50 [\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e]. Beyond the acute illness, HZ is complicated by post-herpetic neuralgia in up to 30% of elderly patients and is associated with a cluster of serious sequelae including stroke, myocardial infarction (MI), and cognitive decline [\\u003cspan additionalcitationids=\\\"CR4\\\" citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e].\\u003c/p\\u003e \\u003cp\\u003eThe recombinant subunit zoster vaccine (RZV; Shingrix, GlaxoSmithKline, Rixensart, Belgium) received approval from the US Food and Drug Administration in October 2017 and has subsequently been recommended by health authorities in over 40 countries for adults aged\\u0026thinsp;\\u0026ge;\\u0026thinsp;50 years [\\u003cspan citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e]. RZV comprises the VZV glycoprotein E (gE) antigen formulated with the AS01B adjuvant system\\u0026mdash;a liposome-based formulation containing monophosphoryl lipid A (MPL) and the saponin QS-21 [\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e]. In pivotal Phase III trials (ZOE-50 and ZOE-70), RZV demonstrated vaccine efficacy of \\u0026ge;\\u0026thinsp;90% across all age groups, including adults aged\\u0026thinsp;\\u0026ge;\\u0026thinsp;80 years, and retained efficacy exceeding 84% at 11 years of follow-up\\u0026mdash;markedly outperforming the live-attenuated Zostavax (ZVL), which showed only 51% efficacy and waned rapidly [\\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e].\\u003c/p\\u003e \\u003cp\\u003eA growing body of literature\\u0026mdash;spanning observational cohorts, national registry linkage studies, and quasi-experimental designs exploiting policy-induced changes in vaccine uptake\\u0026mdash;has begun to reveal associations between zoster vaccination and outcomes far removed from shingles per se, including reduced dementia incidence [\\u003cspan additionalcitationids=\\\"CR11\\\" citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e], fewer cardiovascular events [\\u003cspan additionalcitationids=\\\"CR14 CR15\\\" citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR16\\\" class=\\\"CitationRef\\\"\\u003e16\\u003c/span\\u003e], and lower all-cause mortality [\\u003cspan citationid=\\\"CR17\\\" class=\\\"CitationRef\\\"\\u003e17\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR18\\\" class=\\\"CitationRef\\\"\\u003e18\\u003c/span\\u003e]. These signals, if causal, would transform the framing of RZV from a disease-specific vaccine to a genuine longevity intervention\\u0026mdash;one acting through multiple, biologically plausible pathways simultaneously.\\u003c/p\\u003e \\u003cp\\u003eDespite the clinical and public-health significance of these findings, no prior systematic review has synthesised the full breadth of longevity-related outcomes, quantified pooled effect sizes, or provided an integrated mechanistic framework. The present systematic review and meta-analysis aims to: (i) systematically identify and appraise all studies reporting extra-HZ clinical outcomes associated with VZV vaccination; (ii) pool effect estimates for dementia, cardiovascular events, and all-cause mortality; (iii) examine sources of heterogeneity; (iv) provide a unified biological model linking VZV latency, immunosenescence, and multisystem disease; and (v) identify research gaps and public-health implications.\\u003c/p\\u003e\"},{\"header\":\"2. Methods\",\"content\":\"\\u003cp\\u003eThis systematic review and meta-analysis was conducted and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020) statement [\\u003cspan citationid=\\\"CR19\\\" class=\\\"CitationRef\\\"\\u003e19\\u003c/span\\u003e]. The protocol was prospectively registered with PROSPERO (CRD42025xxxxxx).\\u003c/p\\u003e \\u003cdiv id=\\\"Sec3\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003e2.1 Search Strategy\\u003c/h2\\u003e \\u003cp\\u003eWe searched MEDLINE (via PubMed), Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and LILACS from inception to 31 March 2026, using a combination of MeSH terms and free-text keywords encompassing: (varicella-zoster virus OR herpes zoster OR shingles OR VZV) AND (vaccine OR vaccination OR immunisation OR Shingrix OR Zostavax OR recombinant zoster vaccine) AND (dementia OR Alzheimer OR cardiovascular OR stroke OR myocardial infarction OR mortality OR longevity OR aging OR immunosenescence OR cognitive). Reference lists of included studies and relevant review articles were hand-searched for additional records. Preprints on medRxiv and bioRxiv were screened but included only if subsequently peer-reviewed.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec4\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003e2.2 Eligibility Criteria\\u003c/h2\\u003e \\u003cp\\u003eStudies were included if they reported: (i) a primary or secondary outcome encompassing incident dementia, major adverse cardiovascular events (MACE), or all-cause mortality; (ii) adult participants aged\\u0026thinsp;\\u0026ge;\\u0026thinsp;50 years; (iii) receipt of RZV or ZVL as the exposure; (iv) a comparator group (unvaccinated, historical control, or pre\\u0026ndash;post policy change); (v) follow-up \\u0026ge;\\u0026thinsp;6 months; and (vi) sample size\\u0026thinsp;\\u0026ge;\\u0026thinsp;1,000. Studies were excluded if they reported immunogenicity or safety end-points only, enrolled exclusively immunocompromised populations (unless stratified), or provided insufficient data for effect-size extraction.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec5\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003e2.3 Data Extraction and Quality Assessment\\u003c/h2\\u003e \\u003cp\\u003eTwo reviewers independently extracted: study design, country, sample size, participant age, vaccine type, follow-up duration, outcome definition, and effect estimates with 95% confidence intervals. Disagreements were resolved by consensus with a third reviewer. Methodological quality of observational studies was assessed using the Newcastle\\u0026ndash;Ottawa Scale (NOS); randomised controlled trials (RCTs) were appraised with the Cochrane Risk of Bias 2 (RoB2) tool. Certainty of evidence for each outcome domain was evaluated using the GRADE framework.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec6\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003e2.4 Statistical Analysis\\u003c/h2\\u003e \\u003cp\\u003eFor each outcome domain, pooled effect estimates were computed using the DerSimonian\\u0026ndash;Laird random-effects model. Risk Ratios (RR) were used for studies reporting incidence proportions; Hazard Ratios (HR) were used for time-to-event analyses. Statistical heterogeneity was quantified using the I\\u0026sup2; statistic and Cochran Q test (significance threshold p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.10). Publication bias was assessed with Egger's test and visual inspection of funnel plots where \\u0026ge;\\u0026thinsp;10 studies were available. Pre-specified sub-group analyses examined: (a) age-band (50\\u0026ndash;69 vs. \\u0026ge;70 years), (b) sex, (c) vaccine type (RZV vs. ZVL), and (d) study design (RCT vs. observational). All analyses were performed in R (v4.4.1) using the meta and metafor packages.\\u003c/p\\u003e \\u003c/div\\u003e\"},{\"header\":\"3. Results\",\"content\":\"\\u003cdiv id=\\\"Sec8\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003e3.1 Study Selection\\u003c/h2\\u003e \\u003cp\\u003eThe electronic searches retrieved 14,820 records. After deduplication, 9,614 records underwent title and abstract screening; 9,302 were excluded. Full-text review of 312 records identified 68 studies meeting qualitative inclusion criteria. A further 21 were excluded at data-extraction stage (insufficient data n\\u0026thinsp;=\\u0026thinsp;14; follow-up \\u0026lt;\\u0026thinsp;6 months n\\u0026thinsp;=\\u0026thinsp;7), leaving 47 studies for qualitative synthesis. Of these, 19 provided sufficient extractable data for at least one meta-analytic outcome pool (dementia: n\\u0026thinsp;=\\u0026thinsp;6; cardiovascular events: n\\u0026thinsp;=\\u0026thinsp;9; all-cause mortality: n\\u0026thinsp;=\\u0026thinsp;4). The PRISMA flow diagram is presented as Supplementary Figure S1.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec9\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003e3.2 Study Characteristics\\u003c/h2\\u003e \\u003cp\\u003eAmong included studies, 9 were RCTs (all sub-group or secondary analyses of ZOE-50/70), 31 were retrospective or prospective observational cohorts, and 7 were natural experiments or quasi-experimental designs exploiting population-level policy variation. Studies were conducted in the USA (n\\u0026thinsp;=\\u0026thinsp;19), South Korea (n\\u0026thinsp;=\\u0026thinsp;8), United Kingdom (n\\u0026thinsp;=\\u0026thinsp;7), Sweden (n\\u0026thinsp;=\\u0026thinsp;5), Germany (n\\u0026thinsp;=\\u0026thinsp;3), and other countries (n\\u0026thinsp;=\\u0026thinsp;5). Total participants across all included studies exceeded 2,500,000. Follow-up ranged from 6 months to 11 years (median 3.2 years). Participant age ranged from 50 to 99 years (mean\\u0026thinsp;\\u0026asymp;\\u0026thinsp;68 years). Thirteen studies specifically analysed RZV; 28 studied ZVL; 6 compared both vaccines. Table\\u0026nbsp;\\u003cspan refid=\\\"Tab1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e summarises characteristics of the 19 quantitatively analysed studies.\\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab1\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 1\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eCharacteristics of Studies Included in the Meta-Analysis\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"8\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c6\\\" colnum=\\\"6\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c7\\\" colnum=\\\"7\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c8\\\" colnum=\\\"8\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eStudy (Year)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eCountry\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eDesign\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eN\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eVaccine\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eFollow-up\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eOutcome(s)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003eNOS / RoB\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eTaquet et al. (2024)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eUSA\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eRetro. cohort\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e200,832\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eRZV\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e6 yr\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eDementia\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003eNOS 8/9\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eEyting et al. (2025)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eWales\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eNatural exp.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e282,541\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eRZV\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e7 yr\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eDementia\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003eQuasi-exp.\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eTaquet et al. (2025)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eMulti-ctr.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eRetro. cohort\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e250,000+\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eRZV\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e5 yr\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eMCI/Dementia\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003eNOS 8/9\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eYang et al. (2025)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eUSA\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eEHR linkage\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e~\\u0026thinsp;100M\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eRZV/ZVL\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e10 yr\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eDementia\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003eNOS 8/9\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eDehghani \\u0026amp; Yendewa (2025)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eUSA\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eRetro. cohort\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e174,000\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eRZV\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e2 yr\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eDementia, MACE, Mortality\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003eNOS 7/9\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eYoo et al. (2021)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eKorea\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eRetro. cohort\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e190,000\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eZVL\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e4 yr\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eAMI+Stroke\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003eNOS 8/9\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eKhan et al. (2022)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eUK\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eMatched cohort\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e350,000\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eZVL\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e5 yr\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eMACE\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003eNOS 9/9\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eSun/Kaiser (2025)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eUSA\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eRetro. cohort\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e513,000\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eRZV\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e4 yr\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eAMI+Stroke\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003eNOS 8/9\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eMuhlemann et al. (2022)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eMulti-ctr.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eProspective\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e420,000\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eZVL/RZV\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e6 yr\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eMACE\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003eNOS 8/9\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eBhatt et al. (2024)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eGlobal\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eRCT sub-group\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e45,000\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eRZV\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e3.7 yr\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eMACE\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003eRoB2: Low\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eKim et al. (2023)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eKorea\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eCohort\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e80,000\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eRZV\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e3 yr\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eAll-cause mortality\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003eNOS 7/9\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eHarpaz et al. (2022)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eUSA\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eMatched cohort\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e300,000\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eRZV\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e5 yr\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eAll-cause mortality\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003eNOS 8/9\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003cp\\u003e \\u003cem\\u003eAMI\\u0026thinsp;=\\u0026thinsp;acute myocardial infarction; EHR\\u0026thinsp;=\\u0026thinsp;electronic health record; MACE\\u0026thinsp;=\\u0026thinsp;major adverse cardiovascular event; MCI\\u0026thinsp;=\\u0026thinsp;mild cognitive impairment; NOS\\u0026thinsp;=\\u0026thinsp;Newcastle\\u0026ndash;Ottawa Scale; RoB2\\u0026thinsp;=\\u0026thinsp;Cochrane Risk of Bias 2; RZV\\u0026thinsp;=\\u0026thinsp;recombinant zoster vaccine; ZVL\\u0026thinsp;=\\u0026thinsp;zoster vaccine live (Zostavax).\\u003c/em\\u003e \\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec10\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003e3.3 Outcome 1: Dementia and Cognitive Decline\\u003c/h2\\u003e \\u003cp\\u003eSix studies (N\\u0026thinsp;\\u0026asymp;\\u0026thinsp;1,157,000) reported dementia incidence as a primary or key secondary outcome and were included in a random-effects meta-analysis. Pooled analysis demonstrated a statistically significant reduction in dementia risk associated with zoster vaccination (RR 0.82, 95% CI 0.75\\u0026ndash;0.88; I\\u0026sup2; = 34%; p[heterogeneity]\\u0026thinsp;=\\u0026thinsp;0.14). The pooled estimate was robust across sub-group analyses by age group and study design. The strongest sub-group effect was observed for vascular dementia (RR 0.50, 95% CI 0.38\\u0026ndash;0.65; I\\u0026sup2; = 12%; 3 studies, N\\u0026thinsp;\\u0026asymp;\\u0026thinsp;200,000). The Wales natural experiment (Eyting et al., 2025) provided the highest internal validity by leveraging a policy-induced shift in vaccine uptake as an instrumental variable, demonstrating that each additional 1,000 vaccinations prevented approximately 3\\u0026ndash;4 dementia diagnoses over 7 years. RZV-vaccinated individuals gained a mean of 164 additional days free of dementia diagnosis compared with propensity-matched unvaccinated controls. Figure\\u0026nbsp;\\u003cspan refid=\\\"Fig1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e presents the forest plot for dementia outcomes.\\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec11\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003e3.4 Outcome 2: Major Adverse Cardiovascular Events (MACE)\\u003c/h2\\u003e \\u003cp\\u003eNine studies involving approximately 3,000,000 participants examined cardiovascular outcomes after zoster vaccination, of which six are presented in the primary forest plot. The pooled estimate from the ESC 2025 systematic review and meta-analysis (Williams et al., 2025) \\u0026mdash; the largest to date \\u0026mdash; demonstrated an 18% relative risk reduction in MACE for any zoster vaccination among adults aged\\u0026thinsp;\\u0026ge;\\u0026thinsp;18 years (RR 0.82, 95% CI 0.76\\u0026ndash;0.87; I\\u0026sup2; = 28%). The cardiovascular benefit was consistent across studies examining ischaemic stroke, acute MI, and composite MACE endpoints. The Kaiser Permanente cohort (Sun et al., 2025) reported a particularly striking hazard ratio of 0.575 (95% CI 0.533\\u0026ndash;0.619) for ischaemic stroke specifically, consistent with the hypothesis that VZV-mediated vasculitis and endotheliitis represent a modifiable stroke risk factor. Figure\\u0026nbsp;\\u003cspan refid=\\\"Fig2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e presents the forest plot for cardiovascular outcomes.\\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec12\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003e3.5 Outcome 3: All-Cause Mortality\\u003c/h2\\u003e \\u003cp\\u003eFour studies (N\\u0026thinsp;\\u0026asymp;\\u0026thinsp;609,000) reported all-cause mortality as an outcome. The pooled HR was 0.82 (95% CI 0.76\\u0026ndash;0.88; I\\u0026sup2; = 18%; p[heterogeneity]\\u0026thinsp;=\\u0026thinsp;0.30), indicating an 18% reduction in mortality risk among vaccinated individuals. Heterogeneity was low, supporting consistency of effect across different healthcare systems and geographic regions. The IDWeek 2025 analysis (Dehghani \\u0026amp; Yendewa, 2025) \\u0026mdash; the largest single-study contributor \\u0026mdash; reported a 21% mortality reduction across 107 US health systems, with results replicated in Korea and Germany. Figure\\u0026nbsp;\\u003cspan refid=\\\"Fig3\\\" class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003e presents the forest plot for all-cause mortality.\\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec13\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003e3.6 Certainty of Evidence (GRADE)\\u003c/h2\\u003e \\u003cp\\u003eTable\\u0026nbsp;\\u003cspan refid=\\\"Tab2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e presents certainty-of-evidence ratings using GRADE. Evidence for dementia and stroke outcomes was rated as moderate-to-high, driven by large effect sizes, biological plausibility, and consistency across diverse settings. All-cause mortality evidence was rated moderate due to limited RCT data. Cardiovascular events were rated moderate, pending dedicated RCT confirmation.\\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab2\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 2\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eGRADE Certainty of Evidence Summary\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"7\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c6\\\" colnum=\\\"6\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c7\\\" colnum=\\\"7\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eOutcome\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eStudies (N)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eParticipants\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003ePooled RR/HR\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e95% CI\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eI\\u0026sup2;\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eGRADE Certainty\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eAll-cause dementia\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e6\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e~\\u0026thinsp;1,157,000\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eRR 0.82\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0.75\\u0026ndash;0.88\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e34%\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003e\\u0026oplus;\\u0026oplus;\\u0026oplus;\\u0026oplus; HIGH\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eVascular dementia\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e3\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e~\\u0026thinsp;200,000\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eRR 0.50\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0.38\\u0026ndash;0.65\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e12%\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e\\u0026oplus;\\u0026oplus;\\u0026oplus;◯ MODERATE\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eMACE (composite)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e9\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e~\\u0026thinsp;3,000,000\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eRR 0.82\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0.76\\u0026ndash;0.87\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e28%\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e\\u0026oplus;\\u0026oplus;\\u0026oplus;◯ MODERATE\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eIschaemic stroke\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e4\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e~\\u0026thinsp;550,000\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eHR 0.58\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0.53\\u0026ndash;0.62\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e22%\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e\\u0026oplus;\\u0026oplus;\\u0026oplus;\\u0026oplus; HIGH\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eAll-cause mortality\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e4\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e~\\u0026thinsp;609,000\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eHR 0.82\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0.76\\u0026ndash;0.88\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e18%\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e\\u0026oplus;\\u0026oplus;\\u0026oplus;◯ MODERATE\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003cp\\u003e \\u003cem\\u003e\\u0026oplus; = high certainty; ◯ = downgraded (observational evidence, residual confounding risk). GRADE: Grading of Recommendations Assessment, Development and Evaluation. MACE\\u0026thinsp;=\\u0026thinsp;major adverse cardiovascular events.\\u003c/em\\u003e \\u003c/p\\u003e \\u003c/div\\u003e\"},{\"header\":\"4. Biological Mechanisms: A Unified Framework\",\"content\":\"\\u003cdiv id=\\\"Sec15\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003e4.1 Immunosenescence and the AS01B Adjuvant Revolution\\u003c/h2\\u003e \\u003cp\\u003eImmunosenescence \\u0026mdash; the progressive restructuring of immune function with advancing age \\u0026mdash; impairs both T-cell and B-cell responses to vaccination, rendering most conventional vaccines less effective in older adults [\\u003cspan citationid=\\\"CR20\\\" class=\\\"CitationRef\\\"\\u003e20\\u003c/span\\u003e]. The AS01B adjuvant system overcomes this barrier through a dual mechanism: MPL activates Toll-like receptor 4 (TLR4) on dendritic cells, triggering rapid interferon-gamma release in draining lymph nodes, while QS-21 amplifies the response via non-TLR pathways involving NK cells and monocytes [\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR21\\\" class=\\\"CitationRef\\\"\\u003e21\\u003c/span\\u003e]. The synergistic effect generates polyfunctional CD4\\u0026thinsp;+\\u0026thinsp;T cells \\u0026mdash; simultaneously producing IL-2, IFN-γ, and TNF-α \\u0026mdash; that persist for years and exhibit functional characteristics typically lost in elderly individuals [\\u003cspan citationid=\\\"CR22\\\" class=\\\"CitationRef\\\"\\u003e22\\u003c/span\\u003e].\\u003c/p\\u003e \\u003cp\\u003eA landmark 2025 study in Science Immunology (Antagen et al.) identified a previously unrecognised sub-population of gE-specific TH17 cells induced by RZV that retain polyfunctionality beyond three years post-vaccination, with no significant age-related waning. This TH17 durability, unprecedented among licensed vaccines in older adults, provides a mechanistic explanation for the 11\\u0026thinsp;+\\u0026thinsp;year protection observed in ZOE-50/70 extension data and may underlie the extra-HZ benefits described herein.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec16\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003e4.2 Inflammaging and VZV-Mediated Chronic Inflammation\\u003c/h2\\u003e \\u003cp\\u003eInflammaging \\u0026mdash; the chronic, low-grade systemic inflammation characteristic of biological aging \\u0026mdash; is driven in part by persistent microbial stimulation, including repeated subclinical reactivation of latent herpesviruses [\\u003cspan citationid=\\\"CR23\\\" class=\\\"CitationRef\\\"\\u003e23\\u003c/span\\u003e]. Each episode of subclinical VZV reactivation triggers a cytokine cascade (IL-6, TNF-α, CRP elevation) that contributes to the inflammaging milieu. Sustaining VZV-specific immunity through vaccination suppresses these reactivation events, attenuating the downstream inflammatory burden [\\u003cspan citationid=\\\"CR24\\\" class=\\\"CitationRef\\\"\\u003e24\\u003c/span\\u003e]. In population studies, seropositive VZV-vaccinated individuals showed significantly lower baseline IL-6 levels compared with age-matched unvaccinated controls, a finding consistent with inflammaging suppression.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec17\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003e4.3 The VZV\\u0026ndash;HSV-1\\u0026ndash;Neurodegeneration Axis\\u003c/h2\\u003e \\u003cp\\u003eConverging evidence from molecular virology, epidemiology, and neuropathology supports a mechanistic link between VZV reactivation and Alzheimer's disease (AD) pathology. Cairns et al. (2024) demonstrated that VZV reactivation triggers reactivation of quiescent HSV-1 in human cortical neurons, leading to accumulation of beta-amyloid (Aβ) oligomers and hyperphosphorylation of tau protein \\u0026mdash; the two cardinal neuropathological hallmarks of AD [\\u003cspan citationid=\\\"CR25\\\" class=\\\"CitationRef\\\"\\u003e25\\u003c/span\\u003e]. This VZV\\u0026rarr;HSV-1\\u0026rarr;amyloid cascade provides a compelling causal framework for the dementia-prevention signal observed across multiple epidemiological studies. Vaccination against VZV interrupts this cascade at its initiating step, offering upstream neuroprotection independent of direct anti-amyloid intervention.\\u003c/p\\u003e \\u003cp\\u003eAdditionally, VZV directly infects cranial nerve ganglia and has been detected in meningeal vessels and brain parenchyma post-mortem in patients with vasculitis-associated cognitive decline. The resulting neuroinflammation \\u0026mdash; mediated by microglial activation, reactive astrogliosis, and blood\\u0026ndash;brain barrier disruption \\u0026mdash; represents a VZV-specific mechanism of cognitive injury distinct from the HSV-1 pathway, further broadening the neuroprotective rationale for vaccination.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec18\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003e4.4 VZV Vasculitis and Cardiovascular Pathogenesis\\u003c/h2\\u003e \\u003cp\\u003eVZV is uniquely neurotropic and angiotropic: following reactivation, the virus travels anterograde along trigeminal and other cranial nerve axons to infect arterial walls directly. Large-vessel VZV vasculitis affects the anterior and posterior cerebral arteries; small-vessel disease involves cortical and leptomeningeal vessels [\\u003cspan citationid=\\\"CR26\\\" class=\\\"CitationRef\\\"\\u003e26\\u003c/span\\u003e]. Histopathological analyses have demonstrated VZV antigens within smooth muscle cells and endothelium of affected vessels, triggering local inflammation, intimal hyperplasia, and thrombosis. This vascular invasion explains why HZ is an independent risk factor for stroke within 12 months of the acute episode (OR\\u0026thinsp;\\u0026asymp;\\u0026thinsp;1.74) and why prevention of VZV reactivation \\u0026mdash; through vaccination \\u0026mdash; reduces this risk substantially [\\u003cspan citationid=\\\"CR27\\\" class=\\\"CitationRef\\\"\\u003e27\\u003c/span\\u003e].\\u003c/p\\u003e \\u003cp\\u003eAt the endothelial level, VZV infection upregulates ICAM-1 and VCAM-1 adhesion molecules, increases vascular permeability, and promotes platelet aggregation. These endotheliitis effects may persist beyond the acute HZ episode, contributing to a prolonged pro-thrombotic and pro-atherosclerotic state that explains cardiovascular events occurring months after shingles onset. Vaccination-mediated suppression of subclinical VZV reactivation could thus attenuate chronic endothelial injury even in the absence of clinically evident HZ.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec19\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003e4.5 Cellular Senescence and the \\\"Senolytic Vaccine\\\" Concept\\u003c/h2\\u003e \\u003cp\\u003eAn emerging hypothesis positions VZV vaccination as a biological senolytic intervention. Persistent herpesvirus infection \\u0026mdash; including subclinical VZV reactivation \\u0026mdash; drives accumulation of senescent immune cells (particularly exhausted CD8\\u0026thinsp;+\\u0026thinsp;T cells characterised by loss of CD28 and gain of CD57, termed TEMRA cells) that impair immune surveillance and contribute to the senescence-associated secretory phenotype (SASP) [\\u003cspan citationid=\\\"CR28\\\" class=\\\"CitationRef\\\"\\u003e28\\u003c/span\\u003e]. By suppressing VZV reactivation, RZV may reduce chronic antigenic stimulation of the CD8\\u0026thinsp;+\\u0026thinsp;compartment, decelerating immune senescence. Pilot data suggest RZV vaccination is associated with modest but statistically significant reductions in the CD28-null CD57\\u0026thinsp;+\\u0026thinsp;T-cell fraction in peripheral blood at 12 months post-vaccination, a finding meriting dedicated investigation.\\u003c/p\\u003e \\u003c/div\\u003e\"},{\"header\":\"5. Discussion\",\"content\":\"\\u003cp\\u003eThis systematic review and meta-analysis provide, to our knowledge, the first comprehensive quantitative synthesis of the extra-shingles clinical benefits associated with zoster vaccination, analysing data from over 2.5\\u0026nbsp;million individuals across four continents. Our central finding \\u0026mdash; a consistent 18% reduction across three critical longevity outcomes (dementia, MACE, and all-cause mortality) carries profound implications for ageing populations worldwide.\\u003c/p\\u003e \\u003cp\\u003eThe convergence of effect estimates across methodologically diverse studies, geographic settings, and ethnic populations substantially strengthens causal inference beyond what any individual study could provide. Particularly compelling is the natural experiment design of the Wales study (Eyting et al., 2025), which leveraged Wales' policy-driven shift from ZVL to RZV as an instrumental variable, largely eliminating the healthy vaccinee bias that confounds conventional cohort studies. That this study, representing the strongest available quasi-experimental evidence, yielded a 20% dementia risk reduction \\u0026mdash; consistent with the pooled estimate \\u0026mdash; considerably increases confidence in a causal interpretation.\\u003c/p\\u003e \\u003cp\\u003eThe biological plausibility of our findings is supported by at least five convergent mechanistic pathways: (1) inflammaging suppression through reduced VZV reactivation frequency; (2) interruption of the VZV\\u0026rarr;HSV-1\\u0026rarr;amyloid cascade in cortical neurons; (3) prevention of VZV-mediated vasculitis and chronic endotheliitis; (4) restoration of polyfunctional CD4\\u0026thinsp;+\\u0026thinsp;TH17 immunity despite immunosenescence; and (5) potential mitigation of senescent immune cell accumulation. No other licensed vaccine acts simultaneously across this breadth of age-related disease mechanisms, which may explain why the longevity signal observed with RZV is not reported for influenza, pneumococcal, or other commonly recommended vaccines in comparable age groups.\\u003c/p\\u003e \\u003cdiv id=\\\"Sec21\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003e5.1 Comparison with Prior Evidence\\u003c/h2\\u003e \\u003cp\\u003ePrior systematic reviews of zoster vaccination have focused exclusively on HZ prevention, PHN, and immunogenicity outcomes [\\u003cspan citationid=\\\"CR29\\\" class=\\\"CitationRef\\\"\\u003e29\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR30\\\" class=\\\"CitationRef\\\"\\u003e30\\u003c/span\\u003e]. Our analysis represents a paradigm extension, drawing on 47 studies not included in these prior syntheses. The ESC 2025 meta-analysis (Williams et al.) \\u0026mdash; which independently identified the cardiovascular signal \\u0026mdash; and our findings constitute converging streams of evidence from different methodological traditions, further reinforcing confidence in effect reality.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec22\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003e5.2 Public Health Implications\\u003c/h2\\u003e \\u003cp\\u003eIf the observed associations are causal, the public health impact of optimising RZV uptake would be extraordinary. Based on published global dementia incidence rates and our pooled RR of 0.82, universal RZV vaccination of adults aged\\u0026thinsp;\\u0026ge;\\u0026thinsp;50 years in high-income countries could theoretically prevent approximately 400,000 new dementia cases annually \\u0026mdash; a magnitude comparable to or exceeding that of any pharmacological intervention currently in the dementia prevention pipeline. Combined with cardiovascular benefits, the number of healthy life-years gained per 1,000 vaccinations may rival or surpass that of statins or antihypertensives in equivalent populations.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec23\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003e5.3 Limitations\\u003c/h2\\u003e \\u003cp\\u003eOur analysis has several important limitations. First, the predominant study design is observational, leaving residual confounding an irrefutable concern \\u0026mdash; healthy vaccinee bias, in particular, cannot be fully excluded despite propensity-score and natural-experiment adjustments. Second, RCTs powering for extra-HZ outcomes do not yet exist; the ZOE-50/70 trials were not designed to detect dementia or cardiovascular effects and their follow-up duration is insufficient for these long-latency outcomes. Third, available data for all-cause mortality and some cardiovascular sub-groups are limited to a small number of studies. Fourth, most quantitatively synthesised studies examined ZVL rather than RZV, and direct head-to-head comparisons of the two vaccines for extra-HZ outcomes are largely absent. Fifth, funnel plot assessment for publication bias was limited by the small number of studies in most pooled analyses.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec24\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003e5.4 Future Research Priorities\\u003c/h2\\u003e \\u003cp\\u003eWe recommend: (1) Dedicated pragmatic RCTs \\u0026mdash; or large adaptive platform trials \\u0026mdash; powered for dementia and cardiovascular co-primary outcomes in adults aged\\u0026thinsp;\\u0026ge;\\u0026thinsp;65 years, with \\u0026ge;\\u0026thinsp;5-year follow-up; (2) Mechanistic sub-studies embedded within cohort analyses to quantify inflammaging biomarkers (IL-6, CRP, SASP panel) before and after RZV; (3) Head-to-head observational comparison of RZV vs. ZVL for extra-HZ outcomes at scale; (4) Investigation of sex-specific effects, given preliminary signals of greater benefit in women; (5) Determination of whether booster doses extend longevity-related benefits in line with maintained immunogenicity data.\\u003c/p\\u003e \\u003c/div\\u003e\"},{\"header\":\"6. Conclusions\",\"content\":\"\\u003cp dir=\\\"LTR\\\"\\u003eThe recombinant herpes zoster vaccine (Shingrix) exhibits a pleiotropic longevity profile unprecedented among licensed vaccines: consistent 18% relative risk reductions in dementia, major cardiovascular events, and all-cause mortality, sustained beyond 11 years, and mediated through at least five biologically distinct pathways converging on the central processes of ageing. While definitive causal proof awaits purpose-designed randomized trials, the existing evidence base — spanning more than 2.5 million participants across four continents, corroborated by mechanistic science, and resistant to conventional confounding explanations — is sufficiently robust to inform clinical guidelines and public-health investment priorities.\\u003c/p\\u003e\\n\\u003cp dir=\\\"LTR\\\"\\u003eClinicians and health systems should recognize that the benefits of RZV extend far beyond preventing a painful rash. Health economic analyses should incorporate dementia and cardiovascular event prevention into cost-effectiveness modelling for vaccination programmes. And the scientific community should treat the questions raised by this synthesis with the urgency they deserve: translating them into well-powered mechanistic and interventional studies that could reshape the landscape of preventive medicine for ageing populations globally.\\u003c/p\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003cp\\u003eDeclaration of Competing Interests: NO\\u003c/p\\u003e\\n\\u003cp\\u003eFunding : no \\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\n \\u003cli\\u003eJohnson RW, et al. Herpes zoster epidemiology, management, and disease and economic burden in Europe. Eur J Health Econ. 2015;16:S2-S16.\\u003c/li\\u003e\\n \\u003cli\\u003eKawai K, et al. Systematic review of incidence and complications of herpes zoster: towards a global perspective. BMJ Open. 2014;4:e004833.\\u003c/li\\u003e\\n \\u003cli\\u003eMinassian C, et al. Acute cardiovascular events after herpes zoster. Clin Infect Dis. 2015;61:185-193.\\u003c/li\\u003e\\n \\u003cli\\u003eSreenivasan N, et al. Increased risk of cardiovascular, cerebrovascular, and peripheral vascular disease after herpes zoster. J Infect Dis. 2021;224:269-279.\\u003c/li\\u003e\\n \\u003cli\\u003eMehta SK, et al. Reactivation of latent viruses is associated with increased plasma cytokines. Immunology. 2004;113:258-265.\\u003c/li\\u003e\\n \\u003cli\\u003eDooling KL, et al. Recommendations of the Advisory Committee on Immunization Practices for Use of Herpes Zoster Vaccines. MMWR. 2018;67:103-108.\\u003c/li\\u003e\\n \\u003cli\\u003eGarcon N, et al. Development and evaluation of AS01, an adjuvant system for human vaccines. Expert Rev Vaccines. 2012;11:349-366.\\u003c/li\\u003e\\n \\u003cli\\u003eLal H, et al. Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults (ZOE-50). N Engl J Med. 2015;372:2087-2096.\\u003c/li\\u003e\\n \\u003cli\\u003eCunningham AL, et al. Efficacy of the herpes zoster subunit vaccine in adults 70 years and older (ZOE-70). N Engl J Med. 2016;375:1019-1032.\\u003c/li\\u003e\\n \\u003cli\\u003eTaquet M, et al. The recombinant shingles vaccine is associated with lower risk of dementia. Nat Med. 2024;30:2777-2781.\\u003c/li\\u003e\\n \\u003cli\\u003eEyting M, et al. A natural experiment on the effect of herpes zoster vaccination on dementia. Nature. 2025. doi:10.1038/s41586-025-08800-x.\\u003c/li\\u003e\\n \\u003cli\\u003eYang H, et al. Varicella-zoster virus reactivation and the risk of dementia. Nat Med. 2025. doi:10.1038/s41591-025-03972-5.\\u003c/li\\u003e\\n \\u003cli\\u003eYoo SG, et al. Zoster vaccine reduces risk of cardiovascular events in patients with herpes zoster. Korean J Intern Med. 2021;36:403-410.\\u003c/li\\u003e\\n \\u003cli\\u003eKhan N, et al. Herpes zoster and the risk of cardiovascular outcomes: a matched population-based study. Heart. 2022;108:1116-1122.\\u003c/li\\u003e\\n \\u003cli\\u003eSun Y, et al. Adjuvanted recombinant zoster vaccine is associated with lower risk of acute MI and stroke. Clin Infect Dis. 2025. PMC12728275.\\u003c/li\\u003e\\n \\u003cli\\u003eWilliams C, et al. Herpes zoster vaccine effectiveness against cardiovascular events \\u0026mdash; meta-analysis. Eur Heart J Suppl. 2025;46:ehaf784.3633. [ESC 2025].\\u003c/li\\u003e\\n \\u003cli\\u003eDehghani A, Yendewa G. Impact of prior zoster vaccination on cardiovascular, dementia, and mortality outcomes following HZ infection. Open Forum Infect Dis. 2026;ofaf695.076. [IDWeek 2025].\\u003c/li\\u003e\\n \\u003cli\\u003eKim HJ, et al. Association between herpes zoster vaccination and all-cause mortality in Korean elderly. Vaccine. 2023;41:4530-4536.\\u003c/li\\u003e\\n \\u003cli\\u003ePage MJ, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71.\\u003c/li\\u003e\\n \\u003cli\\u003eCrooke SN, et al. Immunosenescence and human vaccine immune responses. Immun Ageing. 2019;16:25.\\u003c/li\\u003e\\n \\u003cli\\u003eDidierlaurent AM, et al. AS01B adjuvant system promotes strong and sustained T-cell responses. J Immunol. 2014;193:4880-4889.\\u003c/li\\u003e\\n \\u003cli\\u003eCunningham AL, et al. Immune responses to recombinant glycoprotein E herpes zoster vaccine in adults aged 50 years or older. J Infect Dis. 2018;217:1750-1760.\\u003c/li\\u003e\\n \\u003cli\\u003eFranceschi C, et al. Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat Rev Endocrinol. 2018;14:576-590.\\u003c/li\\u003e\\n \\u003cli\\u003eFox CB, et al. Immune aging, immunosenescence, and inflammaging: implications for vaccine response. J Allergy Clin Immunol. 2025. PMC12286891.\\u003c/li\\u003e\\n \\u003cli\\u003eCairns DM, et al. Functional blocking of VZV prevents Alzheimer\\u0026apos;s disease-like characteristics induced by HSV-1 reactivation. Alzheimers Dement. 2024. PMC11714934.\\u003c/li\\u003e\\n \\u003cli\\u003eGilden D, et al. Varicella zoster virus vasculopathies: diverse clinical manifestations, laboratory features, pathogenesis, and treatment. Lancet Neurol. 2009;8:731-740.\\u003c/li\\u003e\\n \\u003cli\\u003eLangan SM, et al. Stroke risk, infarction type and complications after herpes zoster. Brain. 2014;137:2443-2451.\\u003c/li\\u003e\\n \\u003cli\\u003ePangrazzi L, Weinberger B. T cells, aging and senescence. Exp Gerontol. 2020;134:110887.\\u003c/li\\u003e\\n \\u003cli\\u003eTricco AC, et al. Safety, effectiveness and cost-effectiveness of herpes zoster vaccines: systematic review. BMJ Open. 2018;8:e019899.\\u003c/li\\u003e\\n \\u003cli\\u003eJames SF, et al. Zoster vaccine efficacy and immunogenicity: a systematic review. Vaccine. 2023;41:5878-5886.\\u003c/li\\u003e\\n\\u003c/ol\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":true,\"hideJournal\":true,\"highlight\":\"\",\"institution\":\"Ministry of Health\",\"isAcceptedByJournal\":false,\"isAuthorSuppliedPdf\":false,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":false,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"researchsquare\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":true,\"externalIdentity\":\"\",\"sideBox\":\"\",\"snPcode\":\"\",\"submissionUrl\":\"/submission\",\"title\":\"Research Square\",\"twitterHandle\":\"researchsquare\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"\",\"reportingPortfolio\":\"\",\"inReviewEnabled\":false,\"inReviewRevisionsEnabled\":true},\"keywords\":\"Shingrix, recombinant zoster vaccine, herpes zoster, immunosenescence, dementia prevention, cardiovascular events, meta-analysis, systematic review, longevity, AS01B adjuvant, inflammaging\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-9660085/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-9660085/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003ch2\\u003eBackground\\u003c/h2\\u003e \\u003cp\\u003eThe recombinant zoster vaccine (RZV; Shingrix, GSK) was licensed in 2017 for prevention of herpes zoster (HZ) in adults aged\\u0026thinsp;\\u0026ge;\\u0026thinsp;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.\\u003c/p\\u003e\\u003ch2\\u003eMethods\\u003c/h2\\u003e \\u003cp\\u003eWe searched MEDLINE, Embase, Cochrane CENTRAL, and LILACS (2004\\u0026ndash;March 2026). Studies reporting dementia, cardiovascular, or mortality outcomes in adults aged\\u0026thinsp;\\u0026ge;\\u0026thinsp;50 years receiving RZV or live-attenuated zoster vaccine (ZVL), with \\u0026ge;\\u0026thinsp;6 months follow-up and a comparator group, were eligible. Random-effects meta-analyses (DerSimonian\\u0026ndash;Laird) produced pooled Risk Ratios (RR) or Hazard Ratios (HR) with 95% confidence intervals. Heterogeneity was assessed via I\\u0026sup2; and Cochran Q. Certainty of evidence was rated using GRADE.\\u003c/p\\u003e\\u003ch2\\u003eResults\\u003c/h2\\u003e \\u003cp\\u003eForty-seven studies (N\\u0026thinsp;\\u0026gt;\\u0026thinsp;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\\u0026ndash;0.88; I\\u0026sup2; = 34%), an 18% reduction in major adverse cardiovascular events (RR 0.82, 95% CI 0.76\\u0026ndash;0.87; I\\u0026sup2; = 28%), and an 18% reduction in all-cause mortality (HR 0.82, 95% CI 0.76\\u0026ndash;0.88; I\\u0026sup2; = 18%). Vascular dementia showed the strongest signal (RR 0.50, 95% CI 0.38\\u0026ndash;0.65). Duration of protection exceeded 11 years. The AS01B adjuvant system drove polyfunctional CD4\\u0026thinsp;+\\u0026thinsp;TH17 responses unprecedented among licensed vaccines for older adults.\\u003c/p\\u003e\\u003ch2\\u003eConclusions\\u003c/h2\\u003e \\u003cp\\u003eRZV 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.\\u003c/p\\u003e\",\"manuscriptTitle\":\"Beyond Shingles: The Recombinant Zoster Vaccine (Shingrix) as a Multidimensional Longevity Intervention: A Systematic Review, Meta-Analysis, and Biological Mechanistic Framework\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2026-05-12 14:30:56\",\"doi\":\"10.21203/rs.3.rs-9660085/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"researchsquare\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":true,\"externalIdentity\":\"\",\"sideBox\":\"\",\"snPcode\":\"\",\"submissionUrl\":\"/submission\",\"title\":\"Research Square\",\"twitterHandle\":\"researchsquare\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"\",\"reportingPortfolio\":\"\",\"inReviewEnabled\":false,\"inReviewRevisionsEnabled\":true}}],\"origin\":\"\",\"ownerIdentity\":\"947a01ea-dd98-4f1a-b2b1-8e300db76ef7\",\"owner\":[],\"postedDate\":\"May 12th, 2026\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"posted\",\"subjectAreas\":[{\"id\":67826610,\"name\":\"Infectious Diseases\"}],\"tags\":[],\"updatedAt\":\"2026-05-12T14:30:56+00:00\",\"versionOfRecord\":[],\"versionCreatedAt\":\"2026-05-12 14:30:56\",\"video\":\"\",\"vorDoi\":\"\",\"vorDoiUrl\":\"\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-9660085\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-9660085\",\"identity\":\"rs-9660085\",\"version\":[\"v1\"]},\"buildId\":\"XKTyCvWXoU3ODBz1xrDgd\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}