Recombinant Shingles Vaccine Linked to Lower CV Burden

Key Takeaways

• Among US adults aged 60 years or older vaccinated during the transition from live attenuated to recombinant shingles vaccination, the recombinant vaccine was associated with an 9% lower 7-year burden of major cardiovascular diagnoses.
• Subgroup and secondary analyses suggested lower burdens for ischemic heart disease and heart failure in both sexes, lower ischemic stroke burden in males, and lower atrial fibrillation burden.
• The association weakened over time, and investigators said the findings support clinical trials and mechanistic studies rather than proving causality.

Shingles vaccination is routine preventive care for adults aged 60 years or older, a group with substantial baseline risk for myocardial and cerebrovascular events. Earlier studies often compared vaccinated people with nonrecipients, leaving concern that healthier people were more likely to be vaccinated. The rapid US shift after October 2017 from a live attenuated product to a recombinant zoster vaccine created a vaccinated-versus-vaccinated comparison that let investigators examine whether vaccine platform tracked with later cardiovascular burden.

In a Nature Medicine study of recombinant versus live shingles vaccination and cardiovascular events, investigators used the TriNetX US Collaborative Network electronic health record (EHR) dataset, which covered approximately 60 healthcare organizations and more than 100 million patients. They compared adults receiving their first shingles vaccine dose at age 60 years or older during April 1 to September 30, 2017, with those vaccinated in the same months of 2018, matching 36,460 individuals in each cohort. The 2018 cohort was 93.5% recombinant vaccinated and the 2017 cohort was 98.6% live vaccinated. The primary endpoint was a composite of ischemic heart disease, ischemic stroke, or heart failure 7 years after vaccination. Propensity score matching covered 83 covariates, with vaccination timing treated within an instrumental-variable framework, so the design compared adjacent vaccinated cohorts rather than vaccinated people with nonrecipients.

Over 7 years, the predominantly recombinant cohort had a lower risk of the composite primary endpoint, with a restricted mean time lost (RMTL) ratio of 0.91 (95% confidence interval [CI], 0.88-0.95; P < 0.001), corresponding to a 9% lower cardiovascular burden. Component analyses also favored recombinant vaccination for ischemic heart disease, with an RMTL ratio of 0.90 (95% CI, 0.87-0.94) or a 10% decrease in burden, and for heart failure, with an RMTL ratio of 0.88 (95% CI, 0.83-0.93) or a 12% decrease in burden. Atrial fibrilllation was also lower, with an RMTL ratio of 0.93 (95% CI, 0.88-0.98) or a 7% decrease in burden, and ischemic-stroke reached statistical significance only among males, with an RMTL ratio of 0.88 (95% CI, 0.78-0.98).

Sex did not significantly moderate the primary endpoint, and myocarditis, peripheral arterial disease, hemorrhagic stroke, and transient ischemic attack were not associated. Secondary and sensitivity analyses, including pre-vaccination trajectory checks and tetanus, diphtheria and pertussis (TDaP) period comparisons, were directionally consistent, and earlier separation in ischemic heart disease and heart failure attenuated later in follow-up.

Because this was an observational natural experiment using recorded diagnoses in electronic health record data, undiagnosed events and residual confounding could still influence the association despite matching and supportive control analyses. Socioeconomic and lifestyle factors were incompletely captured, the design did not compare recombinant vaccination with no vaccination, and multiple doses were not assessed. The authors presented biologic explanations as hypotheses only, with the waning association over time fitting the possibility of time-limited immune or endothelial effects.

The investigators reported that recombinant shingles vaccination was associated with lower long-term cardiovascular burden than live attenuated vaccination in older US adults, with the clearest signals in ischemic heart disease and heart failure, while the ischemic-stroke association reached statistical significance only in males. They said the findings support clinical trials and mechanistic studies rather than establish causality.

Clinician Questions

Which patients were included in the recombinant versus live shingles vaccine cardiovascular comparison?

The comparison included US adults who received their first shingles vaccine dose at age 60 years or older during April 1 to September 30, 2017, or the same months in 2018.

How was the primary cardiovascular endpoint defined after shingles vaccination?

The primary endpoint was a composite of ischemic heart disease, ischemic stroke, or heart failure recorded from 1 day to 7 years after vaccination in the matched vaccinated cohorts. Because outcomes came from recorded diagnoses in EHR data, the endpoint reflects documented clinical events rather than adjudicated outcomes or undetected disease.

What questions remain unresolved about recombinant shingles vaccination and cardiovascular risk?

The authors said the observational natural experiment does not establish causality, and residual unmeasured confounding remains possible. The study also did not compare recombinant vaccination with no vaccination, did not assess multiple doses, and did not determine the mechanisms behind the observed association.