Recombinant Shingles Vaccine May Lower Cardiovascular Risk

Adults who received the recombinant shingles vaccine had a 9% lower cardiovascular burden over 7 years than those who received the discontinued live-attenuated vaccine, according to a study published August 26, 2026, in Nature Medicine.¹

Researchers from the University of Oxford and the University of Birmingham used a natural experiment created by the rapid US transition from the live vaccine to the recombinant vaccine, comparing adults 60 years and older vaccinated in the 6 months immediately before the October 2017 switch with those vaccinated in the same calendar months of the following year. The recombinant vaccine is marketed as Shingrix, and the live vaccine it replaced, zoster vaccine live (Zostavax), has not been available in the United States since November 18, 2020, according to the Centers for Disease Control and Prevention (CDC).²

Comparing Two Vaccine Eras

The study drew on electronic health record data from the TriNetX US Collaborative Network, which includes approximately 60 health care organizations and data from more than 100 million patients.¹

The researchers identified 36,460 individuals who received their first shingles vaccine dose between April and September 2018, when 93.5% of recipients received the recombinant vaccine, and propensity-score matched them 1:1 to 36,460 individuals vaccinated between April and September 2017, when 98.6% of recipients received the live vaccine.¹

The primary outcome was a composite cardiovascular end point comprising ischemic heart disease (IHD), ischemic stroke, and heart failure occurring within 7 years of vaccination. Because the researchers anticipated that follow-up durations would violate the proportional hazard assumption, differences between the 2 cohorts were summarized using a restricted mean time lost (RMTL) ratio, which represents how much longer, on average, an individual lived free of the outcome during the follow-up period.¹

The recombinant vaccine cohort had an RMTL ratio of 0.91 (95% CI, 0.88-0.95; P = 3.2×10⁻⁷) for the composite endpoint, equating to 9% more time lived diagnosis-free than the live-vaccine cohort. The association attenuated as follow-up continued.¹

Effects Varied by Outcome and Sex

The protective association was strongest for cardiac-specific outcomes. IHD showed a 10% decrease in burden (RMTL ratio, 0.90; 95% CI, 0.87-0.94; P = 6.0×10⁻⁷), significant in both females (RMTL ratio, 0.91; 95% CI, 0.85-0.96) and males (RMTL ratio, 0.92; 95% CI, 0.88-0.97).¹

Heart failure showed a 12% decrease in burden (RMTL ratio, 0.88; 95% CI, 0.83-0.93; P = 7.4×10⁻⁶), also significant in both females (RMTL ratio, 0.84; 95% CI, 0.77-0.91) and males (RMTL ratio, 0.91; 95% CI, 0.84-0.98).¹

Ischemic stroke did not reach significance overall (RMTL ratio, 0.95; 95% CI, 0.87-1.03; P = .18), but a 12% decrease in burden was significant in men (RMTL ratio, 0.88; 95% CI, 0.78-0.98; P = .02) and not in women (RMTL ratio, 0.92; 95% CI, 0.82-1.03; P = .16). Among secondary outcomes, atrial fibrillation showed a 7% decrease in burden (RMTL ratio, 0.93; 95% CI, 0.88-0.98; P = .0072).¹

No significant differences emerged between the 2 vaccine groups for myocarditis, peripheral arterial disease, transient ischemic attack, or hemorrhagic stroke. ST-elevation myocardial infarction showed a similar magnitude of association (RMTL ratio, 0.88; 95% CI, 0.75-1.04) but did not reach statistical significance (P = .13).¹

As a check against unmeasured confounding, the researchers calculated an E value of 1.42 for the primary outcome, meaning an unmeasured confounder would need to be 1.42 times more common in the 2017 cohort and associated with a 1.42-fold increased risk of cardiovascular outcomes to fully explain the finding.¹

A positive-control analysis found the recombinant vaccine was associated with a substantially lower risk of a shingles diagnosis itself (RMTL ratio, 0.73; 95% CI, 0.65-0.82; P = 5.2×10⁻⁸), and a negative-control composite of unrelated acute conditions showed no significant difference between cohorts (RMTL ratio, 1.07; 95% CI, 0.97-1.17; P = .16), which the authors said argued against systematic bias between the groups.¹

"The observed reduction of risk is clinically meaningful," the study authors wrote, noting that a confirmed 0.8% absolute difference in cumulative incidence of IHD and heart failure among adults older than 60 years "would translate into hundreds of thousands of cases prevented in the United States alone."¹

Possible Biological Mechanism

The authors wrote that the pattern of results argues against shingles prevention alone explaining the cardiovascular association. The absolute difference in shingles cases between the 2 vaccine groups was less than 0.5% at mid-follow-up, compared with a 1.5% reduction in IHD, and the cardiovascular divergence between cohorts appeared early rather than accumulating gradually, as would be expected if fewer shingles cases were driving the effect.¹

A more plausible explanation, they wrote, is that the recombinant vaccine may induce immune and endothelial changes that are independently cardioprotective—for instance, the AS01 adjuvant it contains has been shown to trigger sustained epigenetic and functional reprogramming of monocytes, including reduced interleukin-6 (IL-6) responses to Toll-like receptor activation, and IL-6 inhibition has separately been causally linked to lower cardiovascular risk.¹

A separate study published in The Journals of Gerontology examined shingles vaccination and biological aging using data from the Health and Retirement Study, a nationally representative US cohort. Because its biological data were collected in 2016, before Shingrix was introduced in 2017, the study's authors noted that the shingles vaccination captured in their analysis was assumed to reflect receipt of the earlier live vaccine, not the recombinant vaccine.³

Among adults 70 years and older (N = 3884), shingles vaccination in that cohort was associated with lower inflammation scores (b = -0.14; P = .0027), slower epigenetic aging (b = -0.17; P = .0001), slower transcriptomic aging (b = -0.19; P < .0001), and a lower composite biological aging score (b = -0.18; P = .0002), with epigenetic and transcriptomic improvements most pronounced within 3 years of vaccination.³

That study did not evaluate the recombinant vaccine and does not confirm the same biological pathway proposed in the Nature Medicine analysis, but it adds to a broader body of research linking shingles vaccination to favorable immune and inflammatory profiles.³

What This Means for Pharmacists

The CDC recommends Shingrix for adults 50 years and older and for adults 19 years and older with weakened immune systems due to disease or therapy, given as a 2-dose series spaced 2 to 6 months apart for immunocompetent adults. The agency reports Shingrix is more than 90% effective at preventing shingles and postherpetic neuralgia in adults 50 years and older with healthy immune systems, with 97% effectiveness in adults 50 to 69 years old and 91% effectiveness in those 70 years and older.²

Pharmacists are well positioned to field questions about the new data. A review published in the Journal of the American College of Clinical Pharmacy notes that the majority of adult vaccines in the United States are now administered in pharmacy-based settings, and 89% of Americans live within 5 miles of a community-based pharmacy.⁴

Pharmacist authority to administer vaccines, including zoster vaccines, is granted under varying state mechanisms. Montana's statute, for example, specifically authorizes pharmacists to independently prescribe and administer shingles vaccines to patients of all ages pursuant to CDC guidance, according to the review's summary of state authority as of January 2025.⁴

Limitations and Next Steps

The authors cautioned that although their design mitigates the "healthy-vaccinee" bias that affects conventional cohort studies comparing vaccinated with unvaccinated people, it does not establish causality. Electronic health record data carry their own limitations, including unvalidated diagnoses and limited socioeconomic and lifestyle data, and because the natural experiment framework required assuming vaccination timing rather than vaccine receipt itself as the source of comparison, the study could not compare the recombinant vaccine with no vaccination at all. Outcomes were also based on recorded diagnoses, so undiagnosed cases were not captured.¹

"In summary, receiving the recombinant shingles vaccine is associated with a reduced risk of cardiovascular events compared to the live attenuated vaccine," the authors wrote.¹ "Given the global burden of cardiovascular disease, these findings, if confirmed in clinical trials and mechanistic studies, would have important implications for public health."

REFERENCES

1. Corsi-Zuelli F, Li F, Upthegrove R, et al. Recombinant shingles vaccination and the risk of cardiovascular events. Nat Med. Published online August 26, 2026. doi:10.1038/s41591-026-04606-0

2. Centers for Disease Control and Prevention. Shingles vaccination. Accessed August 27, 2026. https://www.cdc.gov/shingles/vaccines/index.html

3. Kim JK, Crimmins EM. Association between shingles vaccination and slower biological aging: evidence from a US population-based cohort study. J Gerontol A Biol Sci Med Sci. 2026;81(3):glag008. doi:10.1093/gerona/glag008

4. Goode JR, Rothholz MC, Foster SL, Brody ER, Gräbenstein JD. Pharmacy-Based Immunization Delivery: A Comprehensive History and Current Challenges. J Am Coll Clin Pharm. 2026;9(6):e70219. doi:10.1002/jac5.70219