A vaccine researchers didn't expect to be doing this much

Two years ago, Oxford researchers reported something odd: people who got the newer shingles vaccine seemed to develop dementia less often than people who got the older one. That finding alone was strange enough to warrant follow-up. Now the same research team has gone looking for a second effect, and found it. A study published Wednesday in Nature Medicine reports that people who received Shingrix, the recombinant shingles vaccine introduced in 2017, had meaningfully lower rates of cardiovascular disease than people who received its discontinued predecessor, Zostavax.

If a vaccine built to prevent a painful skin condition turns out to protect both the heart and the brain, that's not a small footnote. It's the kind of finding that reshapes how researchers think about what vaccines can plausibly do beyond their original target.

How you prove it wasn't just healthier people getting vaccinated

The obvious problem with any study like this is confounding. People who bother getting vaccinated tend to be more health-conscious and have better healthcare access than people who don't, so of course they'd show better outcomes regardless of what's actually in the shot. The Oxford team built their study specifically to rule that explanation out. Rather than comparing vaccinated people to unvaccinated people, they compared two groups who had both chosen to get a shingles vaccine, just on opposite sides of a specific date: October 2017, when Shingrix was approved in the U.S. and began displacing Zostavax, the older live vaccine.

That design turns a messy observational question into something closer to a natural experiment. Both groups sought out vaccination, saw a doctor, and made the same health decision. The only meaningful difference is which of the two available vaccines happened to be on the market when they went in for their shot. Using TriNetX electronic health records covering 60 health systems, the researchers matched roughly 72,000 vaccinated people aged 60 and older into comparable groups on either side of that approval date and tracked them for seven years.

What the numbers actually showed

After seven years of follow-up, people who received Shingrix had a 9% lower overall cardiovascular burden than those who got Zostavax, a composite measure spanning coronary heart disease, heart failure, and stroke. Broken down further, coronary heart disease was reduced by 10% and heart failure by 12% in the Shingrix group. Stroke risk fell 12% among men, though the reduction wasn't statistically significant among women, and atrial fibrillation was 7% lower across both sexes. In absolute terms, that relative risk reduction works out to roughly 1% fewer cardiovascular events after seven years, a modest number per person but one that compounds meaningfully across a population.

Mark Russell, a clinical senior lecturer and consultant rheumatologist at King's College London who wasn't involved in the study, put that population math plainly in a statement shared by the Science Media Centre: "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."

Why researchers think the two vaccines behave so differently

The obvious next question is mechanism, and here the researchers are candid that they're working from hypothesis rather than proof. One clue comes from what's actually different between the two shots. Zostavax was a live vaccine; Shingrix is a recombinant vaccine paired with an adjuvant called AS01, a chemical compound designed to boost the immune response, that Zostavax never contained. Study co-author Maxime Taquet, an associate professor of psychiatry at Oxford, said the cardiovascular data strengthens the case for the adjuvant specifically: "We've got a bit more stronger hypothesis that this has to do with the adjuvant, because we haven't seen any protection of Zostavax vaccines for cardiovascular disease, and the natural experiments have not found any effect on cardiovascular outcome."

The leading biological theory involves what researchers call trained immunity. Fabiana Corsi-Zuelli, a research fellow in psychiatry at Oxford and study co-author, explained that the recombinant vaccine may durably alter immune cell behavior in ways a live vaccine doesn't. Betty Raman, an Oxford associate professor of cardiovascular medicine and another co-author, connected that mechanism to specific vascular biology: heightened inflammatory activity from cytokines can promote atherosclerosis, the fatty buildup inside artery walls that eventually causes blockages and vascular events. If Shingrix is dialing down that inflammatory cascade more effectively than its predecessor did, a cardiovascular benefit would follow naturally, alongside whatever it's doing to reduce dementia risk through a related pathway of immune and inflammatory changes in the brain, not unlike research showing the brain's resident immune cells undergo their own substantial turnover starting around age 50.

The caveats the researchers themselves are raising

To their credit, the study authors are not overselling this. Taquet was explicit that despite the clever natural-experiment design, the study remains observational, and a randomized controlled trial is the only way to establish that Shingrix actually causes the reduced cardiovascular risk rather than merely correlating with it. One such trial, called DAN ZOSTER, is already underway in Denmark, enrolling roughly 162,000 participants, with first results expected in 2027. Kaleen Hayes, an associate director of pharmacoepidemiology at Brown University who led the earlier dementia study but wasn't involved in this new one, called the cardiovascular question "really the next question everyone was wondering about," while noting that evidence in this space has so far been genuinely mixed.

Hayes also offered a more measured alternative explanation worth taking seriously: rather than the AS01 adjuvant specifically, the effect could simply reflect that Shingrix triggers a more robust immune response in general, since it is a notably more effective vaccine at preventing shingles itself. Sorting out which explanation is correct matters for more than academic tidiness. If the effect really is adjuvant-specific, that points directly toward how future vaccines might be engineered, a design question with implications well beyond shingles, including in fields like Alzheimer's research already searching for biomarkers that predict which patients respond to which interventions.

What this means before any trial finishes

Taquet didn't shy away from the scale of what's potentially at stake. "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," he said. But he and Raman were also clear that shingles vaccines remain approved only for middle-aged and older adults for now, and that expanding eligibility would require its own dedicated research rather than assumption. For anyone already eligible, Taquet's closing advice cuts through the uncertainty cleanly: get vaccinated for shingles protection first, and treat any cardiovascular or cognitive benefit as a welcome bonus that stronger trials still need to confirm.