---
title: "Recombinant shingles vaccine associated with reduced risk of cardiovascular events in older adults"
id: "nature-2-recombinant-shingles-vaccination-and-the-risk-of-cardiovascular-events"
canonical_url: "https://medichelpline.com/clinical-feed/nature-2-recombinant-shingles-vaccination-and-the-risk-of-cardiovascular-events"
content_type: "clinical_feed_article"
specialty: "Cardiology"
source_name: "Nature Medicine"
source_url: "https://www.nature.com/articles/s41591-026-04606-0"
published_at: "2026-08-26T10:31:44.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Recombinant shingles vaccine associated with reduced risk of cardiovascular events in older adults
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/nature-2-recombinant-shingles-vaccination-and-the-risk-of-cardiovascular-events
- **Specialty:** [Cardiology](https://medichelpline.com/clinical-feed/cardiology.md)
- **Primary Source:** Nature Medicine
- **Source URL:** [Original Journal Publication](https://www.nature.com/articles/s41591-026-04606-0)
- **Published At:** 2026-08-26T10:31:44.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- A natural-experiment study used the rapid US switch from the live attenuated to the **recombinant shingles vaccine** after October 2017 to reduce confounding seen in vaccinated-versus-unvaccinated comparisons. - The analysis compared adults aged ≥60 vaccinated April–September 2017 (predominantly live vaccine) with those vaccinated April–September 2018 (predominantly recombinant vaccine), with 36,460 individuals in each matched cohort. - Primary outcome was a composite cardiovascular endpoint: **ischemic heart disease**, ischemic stroke and **heart failure** within 7 years of vaccination. - The recombinant vaccine group had a 9% decrease in cardiovascular burden over 7 years (RMTL ratio = 0.91, 95% CI: 0.88–0.95; P < 0.001), corresponding to more time lived diagnosis-free. - Significant associations were observed for ischemic heart disease (RMTL ratio = 0.90, 95% CI: 0.87–0.94) and heart failure (RMTL ratio = 0.88, 95% CI: 0.83–0.93) in both sexes, and for ischemic stroke in males (RMTL ratio = 0.88, 95% CI: 0.78–0.98). - Atrial fibrillation incidence was also lower (RMTL = 0.93, 95% CI: 0.88–0.98); no associations were found for myocarditis, peripheral arterial disease, hemorrhagic stroke or transient ischemic attack; STEMI showed a similar magnitude but was not statistically significant. - The association attenuated over time, being stronger in the first half of follow-up and diminishing in the latter half. - Several sensitivity and secondary analyses supported robustness: competing risk adjustment for death, pre-COVID follow-up only, matched follow-up time, alternative covariate windows, and negative control comparisons (TDaP vaccination) produced consistent findings. - The authors report an E value of 1.42, indicating that an unmeasured confounder would need a modest association and imbalance to fully explain the result. - The study authors conclude these observational results support the need for clinical trials and mechanistic studies to investigate potential cardioprotective effects of shingles vaccines.
## Clinical Analysis & Structured Key Points
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[brief communications](https://www.nature.com/nm/articles?type=brief-communication) 4. article Recombinant shingles vaccination and the risk of cardiovascular events [ Download PDF ](https://www.nature.com/articles/s41591-026-04606-0.pdf) [ Download PDF ](https://www.nature.com/articles/s41591-026-04606-0.pdf) * Brief Communication * [Open access](https://www.springernature.com/gp/open-science/about/the-fundamentals-of-open-access-and-open-research) * Published: 26 August 2026 # Recombinant shingles vaccination and the risk of cardiovascular events * [Fabiana Corsi-Zuelli](https://www.nature.com/articles/s41591-026-04606-0#auth-Fabiana-Corsi_Zuelli-Aff1)[1](https://www.nature.com/articles/s41591-026-04606-0#Aff1), * [Fang Li](https://www.nature.com/articles/s41591-026-04606-0#auth-Fang-Li-Aff1)[1](https://www.nature.com/articles/s41591-026-04606-0#Aff1), * [Rachel Upthegrove](https://www.nature.com/articles/s41591-026-04606-0#auth-Rachel-Upthegrove-Aff1-Aff2-Aff3-Aff4)[1](https://www.nature.com/articles/s41591-026-04606-0#Aff1),[2](https://www.nature.com/articles/s41591-026-04606-0#Aff2),[3](https://www.nature.com/articles/s41591-026-04606-0#Aff3),[4](https://www.nature.com/articles/s41591-026-04606-0#Aff4), * [John A. Todd](https://www.nature.com/articles/s41591-026-04606-0#auth-John_A_-Todd-Aff5)[5](https://www.nature.com/articles/s41591-026-04606-0#Aff5), * [Betty Raman](https://www.nature.com/articles/s41591-026-04606-0#auth-Betty-Raman-Aff6-Aff7) [ORCID: orcid.org/0000-0002-1239-9608](https://orcid.org/0000-0002-1239-9608)[6](https://www.nature.com/articles/s41591-026-04606-0#Aff6),[7](https://www.nature.com/articles/s41591-026-04606-0#Aff7), * [Paul J. Harrison](https://www.nature.com/articles/s41591-026-04606-0#auth-Paul_J_-Harrison-Aff1-Aff4) [ORCID: orcid.org/0000-0002-6719-1126](https://orcid.org/0000-0002-6719-1126)[1](https://www.nature.com/articles/s41591-026-04606-0#Aff1),[4](https://www.nature.com/articles/s41591-026-04606-0#Aff4) & * … * [Maxime Taquet](https://www.nature.com/articles/s41591-026-04606-0#auth-Maxime-Taquet-Aff1-Aff4) [ORCID: orcid.org/0000-0002-8987-952X](https://orcid.org/0000-0002-8987-952X)[1](https://www.nature.com/articles/s41591-026-04606-0#Aff1),[4](https://www.nature.com/articles/s41591-026-04606-0#Aff4) Show authors [_Nature Medicine_](https://www.nature.com/nm) (2026) [Cite this article](https://www.nature.com/articles/s41591-026-04606-0#citeas) [ Save article ](https://www.nature.com/articles/s41591-026-04606-0/save-research?_csrf=IGjRCbAs87Uke8XG1hXDqhdfmBQbF1sX) [ View saved research ](https://www.nature.com/saved-research) ## Abstract The recombinant herpes zoster (shingles) vaccine may reduce risks of cardiovascular disease. However, existing studies have compared vaccine recipients with non-recipients and, thus, are susceptible to confounding. To mitigate these biases, we conducted a natural experiment created by the rapid transition from the live attenuated to the recombinant shingles vaccine in the United States. We compared incidences of a composite cardiovascular endpoint (ischemic heart disease, heart failure or ischemic stroke) among adults aged ≥60 years vaccinated immediately before versus immediately after this transition. The recombinant vaccine was associated with a 9% decrease in cardiovascular burden over 7 years (restricted mean time lost (RMTL) ratio = 0.91, 95% confidence interval (CI): 0.88−0.95). The association attenuated over time and was significant for ischemic heart disease (10% decrease in burden; RMTL ratio = 0.90, 95% CI: 0.87−0.94) and heart failure (12% decrease in burden; RMTL ratio = 0.88, 95% CI: 0.83−0.93) in both sexes and ischemic stroke in males (12% decrease; RMTL ratio = 0.88, 95% CI: 0.78−0.98). An association was also seen for atrial fibrillation (7% decrease in burden; RMTL = 0.93, 95% CI: 0.88−0.98) but not other cardiac, peripheral and cerebrovascular outcomes. Results were consistent in secondary analyses. These results justify clinical trials and mechanistic studies to investigate potential cardioprotective effects of shingles vaccines. ## Main Herpes zoster (shingles) is a painful condition caused by reactivation of latent varicella-zoster virus (that causes chickenpox)[1](https://www.nature.com/articles/s41591-026-04606-0#ref-CR1 "Schmader, K. Herpes zoster. Ann. Intern. Med. 169, ITC19–ITC31 \(2018\)."). Shingles vaccination is recommended in many countries to mitigate the deleterious consequences of the infection in older adults. There has been recent interest in the possibility that the recombinant shingles vaccine may reduce the risk of cardiovascular disease[2](https://www.nature.com/articles/s41591-026-04606-0#ref-CR2 "Rayens, E. et al. Adjuvanted recombinant zoster vaccine is effective against herpes zoster ophthalmicus, and is associated with lower risk of acute myocardial infarction and stroke in adults aged ≥50 years. Clin. Infect. Dis. 81, e441–e445 \(2025\)."),[3](https://www.nature.com/articles/s41591-026-04606-0#ref-CR3 "Xu, X., Ray, I., Tang, E., Arnold, B. F. & Acharya, N. R. Protective effects of recombinant zoster vaccine and antiviral therapy against cardiovascular disease following herpes zoster infection. J. Infect. Dis. 232, 465–473 \(2025\)."),[4](https://www.nature.com/articles/s41591-026-04606-0#ref-CR4 "Parameswaran, G. I. et al. Increased stroke risk following herpes zoster infection and protection with zoster vaccine. Clin. Infect. Dis. 76, e1335–e1340 \(2023\)."). However, existing studies have relied on comparisons between vaccinated and unvaccinated individuals. This design is prone to ‘healthy-vaccinee’ bias because people who choose to get vaccinated differ systematically from those who choose not to in ways that are not measured in the data and cannot be accounted for in the analysis. Here we used a natural experiment arising from the rapid uptake of the recombinant vaccine and the concurrent discontinuation of the live attenuated vaccine after October 2017 (Fig. [1a](https://www.nature.com/articles/s41591-026-04606-0#Fig1)). Because there is no obvious reason for systematic differences between people who were vaccinated on either side of this time cutoff, this design mitigates biases that affect conventional cohort studies. By comparing cohorts of individuals who have both chosen to be vaccinated against shingles (with the live vaccine serving as a control given its lack of association with cardiovascular outcomes[5](https://www.nature.com/articles/s41591-026-04606-0#ref-CR5 "Pomirchy, M. et al. Herpes zoster vaccination and dementia occurrence. JAMA 333, 2083–2092 \(2025\).")), this study design also eliminates the healthy-vaccinee bias. Using a similar design, we previously provided evidence that recombinant shingles vaccination may lower the risk of dementia[6](https://www.nature.com/articles/s41591-026-04606-0#ref-CR6 "Taquet, M., Dercon, Q., Todd, J. A. & Harrison, P. J. The recombinant shingles vaccine is associated with lower risk of dementia. Nat. Med. 30, 2777–2781 \(2024\)."). **Fig. 1: Association between recombinant shingles vaccine and risk of cardiovascular outcomes within 7 years of vaccination.** ![Fig. 1: Association between recombinant shingles vaccine and risk of cardiovascular outcomes within 7 years of vaccination.](https://media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41591-026-04606-0/MediaObjects/41591_2026_4606_Fig1_HTML.png) [Full size image](https://www.nature.com/articles/s41591-026-04606-0/figures/1) **a** , Proportion (in %) of vaccine type received, showing the step change that occurred in October 2017. The exposure windows used in the primary analysis are shown in gray. **b** , Kaplan−Meier curves of the cumulative incidence for the cardiovascular composite endpoint within 7 years of vaccination between those vaccinated in April−September 2017 (predominantly live vaccine) and those vaccinated in April−September 2018 (predominantly recombinant vaccine) (_n_ = 36,460 in each cohort). Shaded areas represent 95% CIs of the cumulative incidence. Solid lines show the Kaplan−Meier estimate of the cumulative incidence (the measure of center). Between-cohort differences were assessed using the RMTL ratio with a two-sided _z_ -test (survRM2 R package), without adjustment for multiple comparisons. **c** , Temporal evolution of risk for the individual components of the composite cardiovascular endpoint after shingles vaccination in 2018 compared to 2017—differences in cumulative incidence over time (top panel) and piecewise constant hazard ratios (HRs) for the first and last 3.5 years of follow-up (bottom panels) (_n_ = 36,460 in each cohort). In the top panel, the line shows the difference in Kaplan−Meier cumulative incidence between cohorts (the measure of center) and the shaded band its 95% CI; in the bottom panels, points show the piecewise constant HR (the measure of center) and error bars its 95% CI. _P_ values are two-sided. Apr, April; IHD, ischemic heart disease; Sep, September. We compared cardiovascular outcomes among adults ≥60 years of age vaccinated against shingles within the 6 months preceding the transition from live to recombinant shingles vaccination (1 April to 30 September 2017) and the same period (to eliminate seasonal effects[7](https://www.nature.com/articles/s41591-026-04606-0#ref-CR7 "Stewart, S., Keates, A. K., Redfern, A. & McMurray, J. J. V. Seasonal variations in cardiovascular disease. Nat. Rev. Cardiol. 14, 654–664 \(2017\).")) a year later (1 April to 30 September 2018) when the recombinant shingles vaccine was predominantly used (Fig. [1a](https://www.nature.com/articles/s41591-026-04606-0#Fig1)). Our primary outcome was a composite cardiovascular endpoint comprising ischemic heart disease, ischemic stroke and heart failure. We used propensity score matching to further control for drifts in the characteristics of the vaccinated population. A total of 36,460 individuals who received their shingles vaccine between April and September 2018 (93.5% received the recombinant vaccine) were propensity score matched to 36,460 individuals who received their shingles vaccine between April and September 2017 (98.6% received the live vaccine) (Supplementary Table [1](https://www.nature.com/articles/s41591-026-04606-0#MOESM1)). Individuals in the group who predominantly received the recombinant vaccine were at a lower risk of cardiovascular events over the next 7 years than those in the group who predominantly received the live vaccine: RMTL ratio = 0.91, 95% CI: 0.88−0.95, _P_ < 0.001, translating into 9% more time lived diagnosis free (Fig. [1b](https://www.nature.com/articles/s41591-026-04606-0#Fig1) and Table [1](https://www.nature.com/articles/s41591-026-04606-0#Tab1)). The _E_ value was 1.42, indicating that an unmeasured confounder would need to be 1.42 times more common in those vaccinated in 2017 than in those vaccinated in 2018 and to be associated with a 1.42-fold increased risk of cardiovascular outcomes after matching for all other covariates to have a chance to explain away our finding. The association was found to hold in both females and males (Table [1](https://www.nature.com/articles/s41591-026-04606-0#Tab1) and Extended Data Fig. [1](https://www.nature.com/articles/s41591-026-04606-0#Fig2)) with no moderation by sex (permutation test: _P_ = 0.53; Supplementary Table [2](https://www.nature.com/articles/s41591-026-04606-0#MOESM1)). **Table 1 Summary of results** [ Full size table](https://www.nature.com/articles/s41591-026-04606-0/tables/1) Those who predominantly received the recombinant shingles vaccine had lower incidences of the composite of cardiovascular events or death, ischemic heart disease and heart failure, with males also having a lower risk of ischemic stroke (Table [1](https://www.nature.com/articles/s41591-026-04606-0#Tab1) and Extended Data Fig. [2](https://www.nature.com/articles/s41591-026-04606-0#Fig3)). Those who predominantly received the recombinant vaccine were also at a lower risk of atrial fibrillation but not myocarditis, peripheral arterial disease, hemorrhagic stroke or transient ischemic attack; association with ST-elevation myocardial infarction (STEMI) was of similar magnitude as for ischemic heart disease and heart failure but did not reach statistical significance (Table [1](https://www.nature.com/articles/s41591-026-04606-0#Tab1) and Extended Data Fig. [3](https://www.nature.com/articles/s41591-026-04606-0#Fig4)). The association remained similar when accounting for death as a competing risk (and there was no association with non-cardiovascular death; Table [1](https://www.nature.com/articles/s41591-026-04606-0#Tab1) and Supplementary Table [3](https://www.nature.com/articles/s41591-026-04606-0#MOESM1)); when the follow-up period was entirely before the COVID-19 pandemic (Supplementary Table [4](https://www.nature.com/articles/s41591-026-04606-0#MOESM1)); when the amount of follow-up time was matched between cohorts (Supplementary Table [5](https://www.nature.com/articles/s41591-026-04606-0#MOESM1)); and when different time windows were used to ascertain covariates (Table [1](https://www.nature.com/articles/s41591-026-04606-0#Tab1)). In the year before vaccination, the two cohorts did not differ in preventive healthcare use or in the risk of cardiovascular events (Supplementary Table [6](https://www.nature.com/articles/s41591-026-04606-0#MOESM1)). Likewise, there was no significant difference between cohorts during follow-up in terms of preventive health indicators (Supplementary Table [7](https://www.nature.com/articles/s41591-026-04606-0#MOESM1)). As expected, individuals who predominantly received the recombinant vaccine were at a lower risk of shingles and a similar risk of negative control outcome than those who predominantly received the live vaccine (Table [1](https://www.nature.com/articles/s41591-026-04606-0#Tab1) and Extended Data Fig. [4](https://www.nature.com/articles/s41591-026-04606-0#Fig5)). There was no sign that secular trends in diagnostic rates confounded the results: those who received the tetanus, diphtheria and pertussis (TDaP) vaccine in April−September 2018 had a very similar risk of recorded cardiovascular events as those who received it during the same months in 2017 (Table [1](https://www.nature.com/articles/s41591-026-04606-0#Tab1)). The protective association against ischemic heart disease and heart failure was found to be present in the first half of follow-up (as seen in Fig. [1c](https://www.nature.com/articles/s41591-026-04606-0#Fig1) by hazard ratios below 1 and an increasing difference in cumulative incidences) before attenuating in the second half (as seen in Fig. [1c](https://www.nature.com/articles/s41591-026-04606-0#Fig1) by hazard ratios that are no longer significant and plateauing differences in cumulative incidence). The recombinant shingles vaccine was also associated with a lower risk of the primary endpoint and each of its components, when compared to the influenza and TDaP vaccines (Extended Data Fig. [5](https://www.nature.com/articles/s41591-026-04606-0#Fig6) and Supplementary Table [8](https://www.nature.com/articles/s41591-026-04606-0#MOESM1)), although this was based on conventional m
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