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 US population-based study, according to researchers.
When they 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.
The team, led by Yun Lu, PhD, a statistician of the US Food & Drug Administration (FDA) in Maryland, found a significant excess of non-haemorrhagic stroke for people with concomitant administration of Pfizer-BioNTech’s bivalent vaccine plus a high-dose or adjuvanted flu vaccine during the 22-42 days risk window (risk difference of 3.13 out of 100 000 doses); and a significant excess of transient ischaemic 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 those who had a high-dose or adjuvanted influenza shot alone (without concomitant Covid vaccination) had an elevated risk for the combined outcome of non-haemorrhagic stroke or transient ischaemic 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 the observed association between vaccination and stroke in the concomitant subgroup was possibly driven by a high-dose or adjuvanted flu vaccination,” reported the investigators in JAMA Network.
Covid-19 bivalent vaccines were made to blend protection against the ancestral Covid strain and the Omicron BA.4/5 subvariants, reports Medpage Today. They were not as widely adopted as the original shots 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 warning earlier this year of an early signal of non-haemorrhagic stroke in older people who had received Pfizer-BioNTech’s bivalent shot.
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 jabs.
Regarding these now-retired Covid vaccines, the present data are “reassuring” and consistent with reports from France and Israel, said vaccine researchers Kathryn Edwards, MD, and Marie Griffin, MD, MPH, both of Vanderbilt University in Tennessee.
They emphasised 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, the flu virus results in thousands of potentially preventable illnesses, medical care visits, hospitalisations, and deaths of over 65s annually, and missed days from school and work in younger people,” they commented in an accompanying editorial.
The duo nevertheless cautioned that the risk-benefit calculus of these vaccines may not be so favourable for some relatively healthy older people who are at an extremely low risk of serious flu complications.
They said “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 people will provide additional data on stroke risk.”
For their study, the authors relied on a large representative database that identified more than 5.3m Medicare beneficiaries (median age 74 years, 56% women) who got either mRNA bivalent Covid vaccine between 31 August 2022 and 4 February 2023.
Excluded were people with a recent prior stroke, residents of long-term care facilities, and those in hospice care.
Ultimately, 11 001 individuals recorded as having a stroke after getting a Covid-19 bivalent vaccine. About 10%-15% of this case population had a Covid-19 diagnosis claim in the months before the stroke, and 34%-45% had had a concomitant high-dose or adjuvanted flu 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 flu after vaccination,” Lu’s group wrote.
“More studies are needed to better understand the association between high-dose or adjuvanted flu vaccination and stroke.”
Study details
Stroke risk after Covid-19 bivalent vaccination among US older adults
Yun Lu, Kathryn Matuska, Gita Nadimpalli, et al
Published in JAMA Network on 19 March 2024
Abstract
Importance
In January 2023, the US Centres for Disease Control and Prevention and the US Food and Drug Administration noted a safety concern for ischaemic stroke among adults aged 65 or older who received the Pfizer-BioNTech BNT162b2; WT/OMI BA.4/BA.5 Covid-19 bivalent vaccine.
Objective
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.
Design, Setting, and Participants
Self-controlled case series including 11 001 Medicare beneficiaries aged 65 years or older who experienced stroke after receiving either brand of the Covid-19 bivalent vaccine (among 5 397 278 vaccinated individuals). The study period was August 31, 2022 to February 4, 2023.
Exposures
Receipt of (1) either brand of the Covid-19 bivalent vaccine (primary) or (2) a high-dose or adjuvanted influenza vaccine (secondary).
Main Outcomes and Measures
Stroke risk (non-haemorrhagic stroke, transient ischaemic attack, combined outcome of non-haemorrhagic stroke or transient ischemic attack, or haemorrhagic stroke) during the 1- to 21-day or 22- to 42-day risk window after vaccination vs the 43- to 90-day control window.
Results
There were 5 397 278 Medicare beneficiaries who received either brand of the Covid-19 bivalent vaccine (median age, 74 years [IQR, 70-80 years]; 56% were women). Among the 11 001 beneficiaries who experienced stroke after receiving either brand of the Covid-19 bivalent vaccine, there were no statistically significant associations between either brand of the Covid-19 bivalent vaccine and the outcomes of non-haemorrhagic stroke, transient ischemic attack, non-haemorrhagic stroke or transient ischemic attack, or haemorrhagic stroke during the 1- to 21-day or 22- to 42-day risk window vs the 43- to 90-day control window (incidence rate ratio [IRR] range, 0.72-1.12). Among the 4596 beneficiaries who experienced stroke after concomitant administration of either brand of the COVID-19 bivalent vaccine plus a high-dose or adjuvanted influenza vaccine, there was a statistically significant association between vaccination and non-haemorrhagic stroke 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]) and a statistically significant association between vaccination and transient ischaemic 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]). Among the 21 345 beneficiaries who experienced stroke after administration of a high-dose or adjuvanted influenza vaccine, there was a statistically significant association between vaccination and non-haemorrhagic stroke 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]).
Conclusions and Relevance
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.
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