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Investigation of an early signal for stroke associated with COVID-19 bivalent vaccines turned into suspicion of high-dose or adjuvanted flu shots instead, based on a large U.S. population-based study.

When researchers inspected a large Medicare database, they found no evidence of a significantly elevated risk for stroke at 1-21 days or 22-42 days after vaccination with either of the mRNA COVID vaccines distributed for the 2022-2023 respiratory season when compared with the 43-90 day control window, reported researchers led by Yun Lu, PhD, a statistician of the FDA in Silver Spring, Maryland.

There was a significant excess of nonhemorrhagic stroke for people with concomitant administration of Pfizer-BioNTech's bivalent vaccine plus a high-dose or adjuvanted influenza vaccine during the 22-42 days risk window (risk difference of 3.13 out of 100,000 doses); and a significant excess of transient ischemic attack for people with concomitant administration of Moderna's bivalent COVID vaccine plus a high-dose or adjuvanted influenza vaccine during the 1-21 days risk window (risk difference of 3.33 out of 100,000 doses).

But the researchers found that people with administration of a high-dose or adjuvanted influenza vaccine alone (without concomitant COVID vaccination) had an elevated risk for the combined outcome of nonhemorrhagic stroke or transient ischemic attack in both the 1-21 days risk window (risk difference of 1.65 per 100,000 doses) and 22-42 days risk window (risk difference of 1.60 per 100,000 doses).

"This finding suggests that the observed association between vaccination and stroke in the concomitant subgroup was likely driven by a high-dose or adjuvanted influenza vaccination," the investigators .

COVID-19 bivalent vaccines were made to blend protection against the ancestral COVID strain and the Omicron BA.4/5 subvariants. They were not as widely adopted as the original vaccines but still remained on the market until they were replaced in September 2023 with monovalent vaccines targeting the XBB.1.5 Omicron subvariant alone for the 2023-2024 respiratory virus season.

Lu and colleagues conducted their study as a follow-up to the CDC and FDA's January 2023 warning of an early signal of nonhemorrhagic stroke in older adults who had received Pfizer-BioNTech's bivalent COVID-19 vaccine. That preliminary notice had been based on reports to the Vaccine Safety Datalink during the immediate period after vaccination, though later analyses also suggested a connection with concomitant flu vaccination.

Regarding these now-retired bivalent COVID vaccines, the present data are "reassuring" and consistent with reports from France and Israel, according to vaccine researchers Kathryn Edwards, MD, and Marie Griffin, MD, MPH, both of Vanderbilt University in Nashville, Tennessee.

Edwards and Griffin emphasized the small magnitude of the stroke risk associated with high-dose influenza vaccination identified by Lu's team.

"From a population health perspective, a risk of serious outcomes of 1 per 100,000 vaccinated individuals would be more than balanced by the benefits of most recommended vaccines. For example, influenza virus results in thousands of potentially preventable illnesses, medical care visits, hospitalizations, and deaths among persons aged 65 years or older in the U.S. annually and missed days from school and work in younger persons," they commented in .

The duo nevertheless cautioned that the risk-benefit calculus of these vaccines may not be so favorable for some relatively healthy older adults who are at an extremely low risk of serious influenza complications.

"It is encouraging that the current U.S. vaccine safety system can identify small vaccine risks on the order of 1 per 100,000. Importantly, public health professionals should be prepared to effectively communicate the level of certainty about potential risks," Edwards and Griffin urged. "The study by Lu et al illustrates the value of a timely, well-designed analysis and has provided reassurance about the COVID-19 boosters. Ongoing monitoring of influenza vaccines marketed for older adults will provide additional data on stroke risk."

For their study, the authors relied on a large representative database that identified over 5.3 million Medicare beneficiaries (median age 74 years, 56% women) who got either mRNA bivalent COVID vaccine starting from Aug. 31, 2022, the emergency use authorization date for these products, to Feb. 4, 2023. Excluded were people with a recent prior stroke, residents of long-term care facilities, and those in hospice care.

There were ultimately 11,001 individuals recorded as having a stroke after getting a COVID-19 bivalent vaccine. Approximately 10-15% of this case population had a COVID-19 diagnosis claim in the months prior to stroke, and 34-45% had had a concomitant high-dose or adjuvanted influenza vaccination.

"Because the framework of the current self-controlled case series study does not compare the populations who were vaccinated vs those who were unvaccinated, it does not account for the reduced rate of severe influenza after vaccination," Lu's group wrote. "More studies are needed to better understand the association between high-dose or adjuvanted influenza vaccination and stroke."

The study authors also acknowledged that they likely did not capture all cases of SARS-CoV-2 infection among participants due to non-reported at-home tests.

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