Best Evidence Yet That Shingles Vaccine Is Cardioprotective

The idea that herpes zoster (shingles) vaccination may have cardiovascular benefits was backed by the results of a natural experiment, researchers found.

Investigators saw clear differences in patient outcomes between those vaccinated in the 2017 season dominated by the live-attenuated shingles vaccine (Zostavax) and those vaccinated in 2018 mostly using the recombinant herpes zoster vaccine (Shingrix), reported Maxime Taquet, MSc, BMBCh, PhD, of University of Oxford and Oxford Health NHS Foundation Trust in England, and colleagues.

The newer, more effective recombinant vaccine was associated with drops over the next 7 years in terms of:

• Composite cardiovascular outcomes (restricted mean time lost [RMTL] ratio 0.91, 95% CI 0.88-0.95)
• Ischemic heart disease (RMTL ratio 0.90, 95% CI 0.87-0.94)
• Heart failure (RMTL ratio 0.88, 95% CI 0.83-0.93)

“The observed reduction of risk is clinically meaningful: 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,” study authors wrote in Nature Medicine.

“These results justify clinical trials and mechanistic studies to investigate potential cardioprotective effects of shingles vaccines,” they concluded.

The rapid transition from the live-attenuated to the recombinant shingles vaccine in the U.S. occurred as a result of evidence of the latter’s much higher effectiveness and safety for immunocompromised people.

The recombinant vaccine was approved in October 2017 for adults ages 50 and older. In 2018, it received a preferential recommendation by the CDC’s Advisory Committee on Immunization Practices over the live shingles vaccine, which officially left the market in 2020.

To explain how shingles vaccination would be beneficial to the heart, Taquet and colleagues said they favored the hypothesis that the vaccine causes immune and endothelial changes that could be cardioprotective.

Virologist Ian Jones, PhD, of the University of Reading in England, expounded on the plausibility of the immune system hypothesis.

“The vaccine works by generating antibodies to a single virus protein that block or reduce virus entry, giving protection against shingles, the re-awakened form of chickenpox. While the antibodies are specific to the virus, the vaccine also includes chemicals to kick-start the immune system and it is possible that this immune jolt also clears up low-level persistent inflammation which would otherwise build to later clinical disease, including neuronal and cardiovascular disease,” he wrote in comments posted to the Science Media Centre (SMC) website.

“The data amplify the obvious benefit of the shingles vaccination,” Jones continued, “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.”

Importantly, for their study, Taquet and colleagues sought to eliminate the conventional biases that possibly affected older cohort studies suggesting a link between recombinant shingles vaccine and reduced cardiovascular risk.

They relied on electronic health records in comparing the outcomes of adults age ≥60 years vaccinated in April 2017-September 2017 (when 98.6% of people received the live vaccine) to those vaccinated in April 2018-September 2018 (when 93.5% of people received the recombinant vaccine).

Propensity score matching created 36,460 pairs for comparison.

Any apparent cardioprotective effects of shingles vaccination were attenuated in the second half of follow-up. However, associations did persist in various secondary analyses, such as accounting for death as a competing risk.

Additionally, reduction in ischemic stroke was statistically significant in men (RMTL ratio 0.88, 95% CI 0.78-0.98) but not women.

As for secondary outcomes, an association was also seen for atrial fibrillation (RMTL 0.93, 95% CI 0.88-0.98) but not other cardiac, peripheral, and cerebrovascular outcomes.

Taquet’s team acknowledged several study limitations, including the lack of adjustment for multiple vaccine doses and the inability of the observational study to determine whether associations are causal.

“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,” according to another SMC commentary by Hugo Pedder, MSc, a statistician at the University of Bristol in England.

Of note, the same researchers had previously reported another natural study showing that recombinant shingles vaccination may lower the risk of dementia.