A primary concern addressed in a recent JAMA study was whether the risk of stroke was elevated immediately after administration of either brand of a COVID-19 bivalent vaccine compared with a later time period.
In a self-controlled case series that included 11,001 Medicare beneficiaries who experienced stroke after administration of either brand of the COVID-19 bivalent vaccine, FDA researchers and colleagues found that the risk of stroke was not significantly elevated during the 1- to 21-day or 22- to 42-day risk window after vaccination compared with the 43- to 90-day control window.
The recipients who had strokes were among 5.4 million vaccinated individuals. The study period was August 31, 2022, through February 4, 2023.
The investigation followed the announcement in January 2023 by the CDC, and the FDA noted a safety concern for ischemic stroke among adults aged 65 years or older who received the Pfizer-BioNTech BNT162b2 or the WT/OMI BA.4/BA.5 COVID-19 bivalent vaccine from Moderna.
The study team sought to evaluate stroke risk after administration of 1) either brand of the COVID-19 bivalent vaccine; 2) either brand of the COVID-19 bivalent plus a high-dose or adjuvanted influenza vaccine on the same day (concomitant administration); and 3) a high-dose or adjuvanted influenza vaccine.
For the study, exposures included receipt of either brand of the COVID-19 bivalent vaccine (primary), or secondarily, a high-dose or adjuvanted influenza vaccine. The researchers were monitoring for the risk of nonhemorrhagic stroke, transient ischemic attack, a combined outcome of nonhemorrhagic stroke or transient ischemic attack, or hemorrhagic stroke during the 1- to 21-day or 22- to 42-day risk window after vaccination versus the 43- to 90-day control window.
Medicare beneficiaries who received either brand of the COVID-19 bivalent vaccine had a median age of 74 years, and 56% were women, according to the study. Among the 11,001 beneficiaries who experienced stroke after receiving either brand of the COVID-19 bivalent vaccine, no statistically significant associations were identified between either brand of the COVID-19 bivalent vaccine and the outcomes of nonhemorrhagic stroke, transient ischemic attack, nonhemorrhagic stroke or transient ischemic attack, or hemorrhagic stroke during the 1- to 21-day or 22- to 42-day risk window versus the 43- to 90-day control window (incidence rate ratio [IRR] range, 0.72-1.12).
Among the 4,596 beneficiaries who experienced stroke after concomitant administration of either brand of the COVID-19 bivalent vaccine plus a high-dose or adjuvanted influenza vaccine, a statistically significant association between vaccination and nonhemorrhagic stroke was noted during the 22- to 42-day risk window for the Pfizer-BioNTech BNT162b2; WT/OMI BA.4/BA.5 COVID-19 bivalent vaccine (IRR, 1.20 [95% CI, 1.01-1.42]; risk difference/100,000 doses, 3.13 [95% CI, 0.05-6.22]). In addition, the authors point out that “a statistically significant association between vaccination and transient ischemic attack during the 1- to 21-day risk window for the Moderna mRNA-1273.222 COVID-19 bivalent vaccine (IRR, 1.35 [95% CI, 1.06-1.74]; risk difference/100,000 doses, 3.33 [95% CI, 0.46-6.20])” was found.
The study added that among the 21,345 beneficiaries who experienced stroke after administration of a high-dose or adjuvanted influenza vaccine, a statistically significant association between vaccination and nonhemorrhagic stroke was pinpointed during the 22- to 42-day risk window (IRR, 1.09 [95% CI, 1.02-1.17]; risk difference/100,000 doses, 1.65 [95% CI, 0.43-2.87]).
“Among Medicare beneficiaries aged 65 years or older who experienced stroke after receiving either brand of the COVID-19 bivalent vaccine, there was no evidence of a significantly elevated risk for stroke during the days immediately after vaccination,” the researchers concluded.
The age subgroup analysis found no consistent associations across ages, outcomes, risk windows, or vaccines, but that does not mean elevated risk of stroke did not occur in some situations. Thes study showed that the COVID-19 bivalent BNT162b2; WT/OMI BA.4/BA.5 vaccine was associated with an elevated rate of nonhemorrhagic stroke and the combined outcome of nonhemorrhagic stroke or transient ischemic attack during the 1- to 21-day risk window after vaccination among the oldest age group, defined as those aged 85 years or older. “However, this study also identified associations between the COVID-19 bivalent mRNA-1273.222 vaccine and the combined outcome of nonhemorrhagic stroke or transient ischemic attack during the 22- to 42-day risk window after vaccination in the youngest age group (65-74 years),” the authors wrote.
There were inconsistent associations about the concomitant administration of either brand of the COVID-19 bivalent vaccine and a high-dose or adjuvanted influenza vaccine. “For example, after concomitant administration of a high-dose or adjuvanted influenza vaccine and a COVID-19 bivalent vaccine, the elevated rate of nonhemorrhagic stroke was detected during the 22- to 42-day risk window with the BNT162b2; WT/OMI BA.4/BA.5 vaccine, whereas the elevated rate of transient ischemic attack was detected with the mRNA-1273.222 vaccine during the 1- to 21-day risk window,” the study team explained. “Although a recent multicenter randomized clinical trial did not report elevated risk with concomitant vaccine administration, reports to the [Vaccine Safety Datalink] did identify a small increased risk of stroke after concomitant administration of the COVID-19 bivalent vaccine and a high-dose or adjuvanted influenza vaccine.”
An association that was small in magnitude between stroke and administration of a high-dose or adjuvanted influenza vaccine when the vaccine was administered without concomitant administration of either brand of the COVID-19 bivalent vaccine was also discussed in the report. “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,” according to the authors. “Although a few studies with self-reported data detail the safety profile of high-dose influenza vaccines, to our knowledge, there are no studies that report an association between receipt of a high-dose or adjuvanted influenza vaccine and risk of stroke.”
Overall, the researchers emphasized the need to understand the clinical significance of the risk of stroke after vaccination together “with the significant benefits of receiving an 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. More studies are needed to better understand the association between high-dose or adjuvanted influenza vaccination and stroke.”
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