Influenza Vaccine May Offer Much More Than Flu Prevention

The influenza vaccine is linked to a significantly lower risk of ischemic stroke, with the reduced risk apparent at a population level even outside of flu season, in new findings that suggest the vaccine itself, and not just avoidance of the virus, may be beneficial.

“We postulate that influenza vaccination may have a protective effect against stroke that may be partly independent of influenza prevention,” study investigator Francisco J. de Abajo, MD, PhD, MPH, of the University of Alcalá in Madrid, Spain, told Medscape Medical News.

“Although the study is observational and this finding can also be explained by unmeasured confounding factors, we feel that a direct biological effect of vaccine cannot be ruled out and this finding opens new avenues for investigation.”

The study was published online September 7 in Neurology.

Not a Spurious Association

While there is a well-established link between seasonal influenza and increased ischemic stroke risk, the role of flu vaccination in stroke prevention is unclear.

In the nested case-control study, researchers evaluated data from primary care practices in Spain between 2001 and 2015. They identified 14,322 patients with first-time ischemic stroke. Of these, 9542 had noncardioembolic stroke and 4780 had cardioembolic stroke.

Each case was matched with five controls from the population of age- and sex-matched controls without stroke (n = 71,610).

Those in the stroke group had a slightly higher rate of flu vaccination than controls, at 41.4% vs 40.5% (odds ratio [OR], 1.05).

Adjusted analysis revealed those who received flu vaccination were less likely to experience ischemic stroke within 15 to 30 days of vaccination (OR, 0.79) and, to a lesser degree, over up to 150 days (OR, 0.92).

The reduced risk associated with the flu vaccine was observed with both types of ischemic stroke and appeared to offer stroke protection outside of flu season.

The reduced risk was also found in subgroup comparisons in men, women, those over and under 65 years of age, and those with intermediate and high vascular risk.

Importantly, a separate analysis of pneumococcal vaccination did not show a similar reduction in stroke risk (adjusted OR, 1.08).

“The lack of protection found with the pneumococcal vaccine actually reinforces the hypothesis that the protection of influenza vaccine is not a spurious association, as both vaccines might share the same biases and confounding factors,” de Abajo said.

Anti-Inflammatory Effect?

Influenza infection is known to induce a systemic inflammatory response that “can precipitate atheroma plaque rupture mediated by elevated concentrations of reactive proteins and cytokines,” the investigators note, and so, avoiding infection could prevent those effects.

The results are consistent with other studies that have shown similar findings, including recent data from the INTERSTROKE trial. However, the reduced risk observed in the current study even in years without a flu epidemic expands on previous findings.

“This finding suggests that other mechanisms different from the prevention of influenza infection — eg, a direct biological effect — could account for the risk reduction found,” the investigators write.

In terms of the nature of that effect, de Abajo noted that “at this stage, we can only speculate.”

“Having said that, there are some pieces of evidence that suggest influenza vaccination may release anti-inflammatory mediators that can stabilize the atheroma plaque. This is an interesting hypothesis that should be addressed in the near future,” he added.

More Than Just Flu Prevention

In an accompanying editorial, Dixon Yang, MD, and Mitchell S.V. Elkind, MD, agree that the findings point to intriguing potential unexpected benefits of the vaccine.

“This case-control study…importantly suggests the influenza vaccine is more than just about preventing the flu,” they write.

Elkind told Medscape Medical News that the mechanism could indeed involve an anti-inflammatory effect.

“There is some evidence that antibiotics also have anti-inflammatory properties that might reduce risk of stroke or the brain damage from a stroke,” he noted. “So, it is plausible that some of the effect of the vaccine on reducing risk of stroke may be through a reduction in inflammation.”

Elkind noted that the magnitude of the reduction observed with the vaccine, though not substantial, is important.

“The magnitude of effect for any one individual may be modest, but it is in the ballpark of the effect of other commonly used approaches to stroke prevention, such as taking an aspirin a day, which reduces risk of stroke by about 20%.”

“But because influenza is so common, the impact of even a small effect for an individual can have a large impact at the population level. So, the results are of public health significance.”

The study received support from the Biomedical Research Foundation of the Prince of Asturias University Hospital and the Institute of Health Carlos III in Madrid, Spain. Elkind has reported receiving ancillary funding but no personal compensation from Roche for a federally funded trial of stroke prevention.

Neurology. Published online September 7, 2022. Abstract, Editorial

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