Newer shingles vaccine linked to lower heart disease risk, Oxford study finds

Older adults who received the newer shingles vaccine Shingrix had significantly lower rates of heart attack, stroke and heart failure over the following seven years than those who received the vaccine it replaced, according to a study of more than 70,000 people published this week in Nature Medicine. The findings, from a team at the University of Oxford, add cardiovascular disease to a growing list of conditions in which the recombinant shingles shot appears to offer protection beyond its intended target, the painful skin rash caused by reactivation of the chickenpox virus.

The researchers took advantage of a natural experiment created when Shingrix replaced the older vaccine Zostavax in the United States in October 2017. Using anonymized electronic health records from the TriNetX network, they compared more than 36,000 adults aged 60 and older who were vaccinated with Shingrix against a matched group of similar age and health status who had received Zostavax in the months before the switch, then tracked both groups for seven years.

What the data showed

People who received Shingrix spent 9% more time free of any cardiovascular diagnosis than those who received Zostavax, according to the University of Oxford's Medical Sciences Division. Broken down by condition, Shingrix recipients had a 10% lower rate of ischemic heart disease and a 12% lower rate of heart failure. Stroke risk was 12% lower among men who received Shingrix, though the difference was not statistically significant for women, and atrial fibrillation was 7% less common. In absolute terms the gap was modest — roughly one percentage point fewer cardiovascular events over the full seven years — but researchers noted that shingles vaccination is already recommended for tens of millions of older adults.

The natural-experiment design was intended to address a longstanding problem in vaccine research known as the "healthy vaccinee" effect, in which people who choose to get vaccinated tend to be healthier or more health-conscious than those who do not, which can make a vaccine look more protective than it really is. Because almost everyone getting a shingles shot around the 2017 switchover received whichever vaccine was on the shelf that month rather than choosing between the two, the researchers argue the comparison is less vulnerable to that bias than earlier observational work. Even so, the authors acknowledged that some differences between the groups, including how consistently each was followed up in the health records, could not be fully ruled out.

A vaccine with a longer reach than expected

Shingles, caused by reactivation of the dormant varicella-zoster virus, affects roughly one in three people during their lifetime and becomes more common and more severe with age. Shingrix, a recombinant subunit vaccine paired with a novel adjuvant, replaced the live-attenuated Zostavax after trials showed it prevented shingles far more effectively, and the Centers for Disease Control and Prevention now recommends two doses for immunocompetent adults 50 and older.

Interest in effects beyond shingles prevention has been building for several years. The same Oxford group previously reported that Shingrix recipients had a lower incidence of dementia than those who received Zostavax, a finding a separate Brown University analysis of more than 500,000 nursing-home residents reinforced this year, reporting a 24% lower rate of dementia diagnosis among those vaccinated with Shingrix. The new cardiovascular findings, researchers say, point toward a shared explanation: the adjuvant in Shingrix, known as AS01B, may provoke a broader and longer-lasting recalibration of the immune system than a conventional vaccine.

"The recombinant vaccine may induce trained immunity. That means changes in cells of our immune system," said Fabiana Corsi-Zuelli, a research fellow in psychiatry at Oxford and a co-author of the study. Because chronic low-grade inflammation is already established as a driver of artery disease, a vaccine that dampens it could plausibly lower cardiovascular risk as a side effect. "Ischemic heart disease and vascular diseases tend to be linked to an inflammatory response," said Betty Raman, an associate professor of cardiovascular medicine at Oxford. "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."

The population most directly affected is the same one already targeted by shingles vaccination guidance: adults 50 and older, along with younger adults who are immunocompromised and at elevated risk of both shingles and its complications. Cardiovascular disease remains the leading cause of death among older Americans, so even a small proportional reduction in heart attacks, strokes and heart failure, applied across the tens of millions of people already eligible for the vaccine, could add up to a meaningful number of prevented events if the association proves causal. Researchers cautioned, however, that the vaccine has not been tested, and is not approved, as a treatment or preventive measure for heart disease itself.

Reaction and caveats

Outside researchers welcomed the results while stressing that an observational study, even one built around a natural experiment, cannot prove the vaccine itself caused the lower cardiovascular rates. "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 and consultant rheumatologist at King's College London who was not involved in the work.

Kaleen Hayes, associate director of pharmacoepidemiology at Brown University, said the study answers a question researchers have been circling for years but leaves the underlying biology unresolved. "There's been some evidence, but very conflicting evidence on whether this vaccine has cardioprotective effects as well as potential neuroprotective effects," she said, adding that it remains unclear "whether it's the actual AS01 versus just in general, it's an effective vaccine and our immune system gets keyed up."

"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," said Maxime Taquet, an associate professor of psychiatry at Oxford who led the study.

What comes next

Taquet was careful to note the limits of the current evidence. "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," he said. That trial, known as DAN-ZOSTER, is following roughly 162,000 participants in Denmark and is expected to report results in 2027, potentially offering the first randomized evidence on whether the vaccine directly reduces cardiovascular events rather than merely correlating with lower rates of them.

Shingrix was approved by the Food and Drug Administration in 2017 for adults 50 and older, and the CDC recommends two doses spaced two to six months apart regardless of prior shingles history. Researchers involved in the new study said the findings should not change that guidance, at least for now. "If these findings and the findings we provided for dementia help sort of nudge that, then that's great," Taquet said. "But they should get it for the shingles protection in the first instance." If the cardiovascular association holds up in trials, Hayes said, it could also point toward new ways of using vaccine-triggered immune activation as a therapeutic strategy in its own right, beyond the diseases vaccines are designed to prevent.