ENGLAND — The study analyzed electronic health records from the TriNetX network covering 72,920 vaccinated adults aged 60 and older. Researchers used propensity score matching to create 36,460 pairs for comparison between those vaccinated in April–September 2017, when Zostavax was predominant, and April–September 2018, when Shingrix was predominant.

A reduction in ischemic stroke was statistically significant in men (RMTL ratio 0.88, 95% CI 0.78-0.98) but not in women. An association was observed for atrial fibrillation (RMTL 0.93, 95% CI 0.88-0.98) but not for other cardiac, peripheral, or cerebrovascular outcomes.

Maxime Taquet, an associate professor of psychiatry at the University of Oxford, provided context on the findings. If confirmed, Shingrix could prevent hundreds of thousands of cardiovascular events in the USA alone, and may be the first vaccine that protects the heart and the brain, Taquet said. He noted that the study provides high-quality observational evidence supporting a cardioprotective effect, though randomized trials are needed for confirmation.

This study remains observational, even though it’s a natural experiment, and so we are keen to see results from randomized controlled trials. And one of them is underway, Taquet said. The DAN ZOSTER study of about 162,000 people in Denmark is underway, with first results anticipated in 2027.

Ian Jones, a virologist, suggested broader implications for immune health. The data amplify the obvious benefit of the shingles vaccination, but it also suggests there may be an immune dimension to a number of age-related conditions and that focusing on boosting immunity could be generally beneficial, Jones said.

Why It Matters

The scale of shingles vaccination means that even small individual benefits can have substantial public health impacts. Although the benefits are relatively small on an individual basis, millions of people receive shingles vaccination, meaning that even a small cardiovascular benefit could translate into a substantial number of cardiovascular events prevented at a population level, said Mark Russell, a clinical senior lecturer.

The regulatory history of the vaccines provides context for the shift in clinical practice. Shingrix is a recombinant subunit vaccine by GSK, while Zostavax is a live attenuated vaccine against shingles by Merck. The recombinant shingles vaccine (Shingrix) was approved in the U.S. in October 2017 for adults ages 50 and older.

The CDC's Advisory Committee on Immunization Practices issued a preferential recommendation for Shingrix over the live shingles vaccine in 2018. The live-attenuated shingles vaccine (Zostavax) officially left the U.S. market in 2020.

Timeline

A separate study published in Annals of Internal Medicine found that older adults who received the Shingrix vaccine had a 24% lower risk of dementia over four years compared to unvaccinated peers.

What's New

Kaley Hayes, an assistant professor at Brown University's School of Public Health, commented on the neurological findings. This was really the next question everyone was wondering about. There’s been some evidence, but very conflicting evidence on whether this vaccine has cardioprotective effects as well as potential neuroprotective effects, Hayes said.

She also noted the connection between physical and cognitive health: "Our cognition is so tied to our overall health and what happens to us physically. It’s really amazing to see that something that’s supposed to prevent a physical ailment can also help keep our brain healthy, too." Regarding the dementia study, Hayes stated, "This translates to about one in 17 dementia cases potentially being prevented." Fabiana Corsi-Zuelli, a research fellow, offered a potential mechanism for the cardiovascular findings: "The recombinant vaccine may induce trained immunity. That means changes in cells of our immune system." Betty Raman, an associate professor, explained the biological link between inflammation and vascular health: Ischemic heart disease and vascular diseases tend to be linked to an inflammatory response. So the cytokines essentially activate cells within the tissue that can promote atherosclerosis, which is basically deposition of fat in the wall, and that in turn can lead to vascular events like a blockage in the arteries.

How Sources Differ

Sources presented different metrics regarding the risk reduction associated with Shingrix. Nature Medicine reported that recipients of the recombinant vaccine (Shingrix) had a lower risk of composite cardiovascular outcomes over seven years compared to recipients of the live vaccine (Zostavax), with a restricted mean time lost ratio of 0.91 (95% CI 0.88-0.95). In contrast, Annals of Internal Medicine reported that a separate study found that older adults who received the Shingrix vaccine had a 24% lower risk of dementia over four years compared to unvaccinated peers.

The specific outcomes measured also varied across reports. Annals of Internal Medicine focused on a 24% lower risk of dementia over four years compared to unvaccinated peers. Nature Medicine reported that the study found a reduced risk of ischemic heart disease among Shingrix recipients (RMTL ratio 0.90, 95% CI 0.87-0.94). Another finding from Nature Medicine indicated a reduced risk of heart failure among Shingrix recipients (RMTL ratio 0.88, 95% CI 0.83-0.93).

Interpretations of the clinical significance differed in emphasis. Study authors characterized the observed reduction of risk as clinically meaningful, noting that if confirmed in clinical trials, a 0.8% absolute difference in cumulative incidences of ischemic heart disease and heart failure among adults over 60 years of age would translate into hundreds of thousands of cases prevented in the United States alone.

The need for further verification was showed by differing perspectives on current evidence. Hugo Pedder stated that a randomized trial would be the best way to confidently answer whether recombinant vaccines do provide the benefits seen here versus live vaccines, but until such a trial is done this study provides some of the best quality observational evidence supporting an effect of recombinant versus live vaccines for cardiovascular outcomes.

Approval criteria and study populations were described differently across sources.

These results justify clinical trials and mechanistic studies.