Abstract
This study investigates the association between bivalent COVID-19 vaccines and ischemic stroke, as well as the effect of simultaneous influenza vaccination on the association.
In January 2023, the US Centers for Disease Control and Prevention (CDC) reported a signal for ischemic stroke in people aged 65 years and older who received the BNT162b2 vaccine (Pfizer-BioNTech), bivalent (BA.4/BA.5).1 Relative risk 1 to 21 days postvaccination vs 22 to 42 days postvaccination was 1.47 (95% CI, 1.11-1.95).2 The increase may have been related to concurrent administration of high-dose or adjuvanted influenza vaccine.2 Other assessments in the US have not validated this signal and no signal was observed with the mRNA-1273 vaccine (Moderna), bivalent (BA.4/BA.5).1
In the UK, the COVID-19 autumn 2022 booster campaign for persons aged 50 years or older also used bivalent BNT162b2 and mRNA-1273 vaccines but containing BA.1 rather than BA.4/BA.5 strains. We investigated the association between these vaccines and ischemic stroke and the effect of simultaneous influenza vaccination on the association.
Methods
National Health Service (NHS) hospital admissions in England from September 5, 2022, to December 4, 2022, for ischemic stroke (including transient ischemic attack) or hemorrhagic stroke (for comparison) in individuals aged 50 years and older on August 31, 2022, were linked to the National Immunisation Management System3 via NHS number. The ICD-10 discharge coding and exclusions applied are shown in the eTable in Supplement 1. Admissions with a linked COVID-19 booster vaccine record were retained for analysis together with information on influenza vaccine given on the same day (eAppendix 1 in Supplement 1). With the self-controlled case-series method,4 the incidence of ischemic or hemorrhagic stroke in the 1 to 21 days postvaccination relative to a control period from 22 days postvaccination until the end of the study period was calculated using conditional Poisson models (eAppendix 2 in Supplement 1). Statistical significance was based on the lower bound of the 95% CI for the relative incidence (RI) exceeding 1.0.
Analyses were done separately for BNT162b2 and mRNA-1273 vaccines in patients aged 50 years and older and 65 years and older; a further analysis was conducted for patients aged 65 years and older given simultaneous influenza vaccine. The UK Health Security Agency has approval to process confidential patient data for health protection purposes without explicit consent under The Health Service (Control of Patient Information) Regulations 2002.
Results
In the study period, 14.6 million doses of a bivalent mRNA vaccine were given to persons aged 50 years and older and there were 6882 cases of ischemic stroke and 1510 of hemorrhagic stroke after the booster (Table 1). Of these patients, 983 (11.7%) had received simultaneous influenza vaccine; for 822 (94.6%) of those aged 65 years and older, the product was adjuvanted.
Table 1. Vaccine Type Received and Demographic Features of 8332 Individuals Admitted to the Hospital With Ischemic or Hemorrhagic Stroke After a Bivalent COVID-19 Booster Dosea.
| Ischemic stroke, No. (%) (n = 6882) | Hemorrhagic stroke, No. (%) (n = 1510) | |
|---|---|---|
| Bivalent vaccine | ||
| mRNA-1273 | 4677 (68.0) | 1020 (67.5) |
| BNT162b2 | 2205 (32.0) | 490 (32.5) |
| Sex | ||
| Male | 3519 (51.1) | 755 (50.0) |
| Female | 3363 (48.9) | 755 (50.0) |
| Age, y | ||
| 50-64 | 688 (10.0) | 174 (11.5) |
| 65-74 | 1557 (22.6) | 362 (24.0) |
| 75-84 | 2658 (38.6) | 588 (38.9) |
| ≥85 | 1979 (28.8) | 386 (25.6) |
Abbreviations: BNT162b2, Pfizer-BioNTech COVID-19 vaccine bivalent (BA.1); mRNA-1273, Moderna COVID-19 vaccine bivalent (BA.1).
From September 5, 2022, to December 4, 2022, in England. Table excludes 27 individuals with ischemic stroke and 6 with hemorrhagic stroke admitted on the day of vaccination.
Table 2 shows the number of cases in the 1- to 21-day postvaccination risk period and the control period for each analysis, along with the RI estimates. The median length of the control period was 51 days (IQR, 43-58 days) for individuals receiving mRNA-1273 and 29 days (IQR, 19-36 days) for those receiving BNT162b2. For individuals aged 65 years and older and receiving BNT162b2, the mean person-days in the risk interval were 20.9 vs 26.3 in the control interval (RI for ischemic stroke, 0.90; 95% CI, 0.76-1.05). For patients aged 65 years and older and also receiving influenza vaccine, the mean person-days in the risk interval were 21.0 vs 25.4 in the control interval (RI for ischemic stroke, 0.79; 95% CI, 0.50-1.23). Results were similar for individuals aged 50 years and older, receiving mRNA-1273 vaccine, or with hemorrhagic stroke. The lower bound of the 95% CI for all RI estimates was below 1.
Table 2. Assessment of the Relative Incidence of Stroke in the Risk Period 1 to 21 Days After COVID-19 Vaccination Compared With the Control Period From 22 Days After COVID-19 Vaccinationa.
| Type of stroke | Age, y | Bivalent vaccine (BA.1) | Cases in risk interval/cases in control interval | Mean person-days in case/control intervals | Relative incidence (95% CI) |
|---|---|---|---|---|---|
| Ischemic | ≥50 | BNT162b2 | 1068/1137 | 20.8/25.4 | 0.91 (0.79-1.06) |
| mRNA-1273 | 1371/3306 | 21.1/48.3 | 0.94 (0.84-1.04) | ||
| Both (BNT162b2 and mRNA-1273) | 2439/4443 | 21.0/40.9 | 0.93 (0.86-1.01) | ||
| ≥65 | BNT162b2 | 847/959 | 20.9/26.3 | 0.90 (0.76-1.05) | |
| mRNA-1273 | 1274/3114 | 21.1/28.7 | 0.93 (0.83-1.04) | ||
| Both (BNT162b2 and mRNA-1273) | 2121/4073 | 21.0/42.2 | 0.92 (0.85-1.01) | ||
| ≥65 | BNT162b2 and influenza vaccine | 111/122 | 21.0/25.4 | 0.79 (0.50-1.23) | |
| mRNA-1273 and influenza vaccine | 142/350 | 21.1/45.1 | 0.90 (0.65-1.27) | ||
| Both and influenza vaccine | 253/472 | 21.1/37.3 | 0.88 (0.69-1.14) | ||
| Hemorrhagic | ≥50 | BNT162b2 | 214/276 | 21.0/25.1 | 0.86 (0.63-1.18) |
| mRNA-1273 | 293/727 | 21.1/48.5 | 0.96 (0.75-1.22) | ||
| Both (BNT162b2 and mRNA-1273) | 507/1003 | 21.1/39.5 | 0.86 (0.72-1.02) | ||
| ≥65 | BNT162b2 | 159/224 | 20.9/26.2 | 0.84 (0.59-1.20) | |
| mRNA-1273 | 270/683 | 21.0/49.1 | 0.99 (0.77-1.27) | ||
| Both (BNT162b2 and mRNA-1273) | 429/907 | 21.0/41.0 | 0.86 (0.71-1.05) |
Abbreviations: BNT162b2, Pfizer-BioNTech COVID-19 vaccine bivalent (BA.1); mRNA-1273, Moderna COVID-19 vaccine bivalent (BA.1).
From September 5, 2022, to December 4, 2022, in England.
Discussion
This analysis showed no evidence of an increased risk of stroke in the 21 days immediately after vaccination with either of the 2 mRNA COVID-19 bivalent BA.1 vaccines in England, with similar results for ischemic and hemorrhagic stroke and for the subset aged 65 years and older given influenza vaccine on the same day as the bivalent COVID-19 vaccine. For ischemic stroke, the upper bounds of CIs for the RI were all below the point estimate reported by CDC of a relative risk of 1.47. The findings align with those reported for ischemic and hemorrhagic stroke after a bivalent BA.4/BA.5 booster in a French study,5 which did not examine the effect of influenza vaccination. Study limitations include inability to assess the BA.4/BA.5 vaccine used in the US, the relatively small percentage with influenza vaccine given on the same day, and the assumption that any risk is acute, allowing a control period from 21 days postvaccination.
Section Editors: Jody W. Zylke, MD, Deputy Editor; Kristin Walter, MD, Senior Editor.
eTable. Selection of Study Participants
eAppendix 1. Influenza Vaccine Eligibility and Types of Vaccine Used
eAppendix 2. Statistical Methods
Data Sharing Statement
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eTable. Selection of Study Participants
eAppendix 1. Influenza Vaccine Eligibility and Types of Vaccine Used
eAppendix 2. Statistical Methods
Data Sharing Statement