Letters
RESEARCH LETTER Table 1. Vaccine Type Received and Demographic Features
BA.1 Bivalent COVID-19 Vaccine Use and Stroke
in England
In January 2023, the US Centers for Disease Control and Pre-
vention (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
Supplemental content
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 assess-
ments in the US have not validated this signal and no signal
was observed with the mRNA-1273 vaccine (Moderna), biva-
lent (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 is-
chemic stroke (including transient ischemic attack) or hemor-
rhagic stroke (for comparison) in individuals aged 50 years and
older on August 31, 2022, were linked to the National Immuni-
sation Management System3 via NHS number. The ICD-10 dis-
charge 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 infor-
mation 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 calcu-
lated using conditional Poisson models (eAppendix 2 in Supple-
ment 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 confiden-
tial patient data for health protection purposes without ex-
plicit consent under The Health Service (Control of Patient In-
formation) 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%)
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of 8332 Individuals Admitted to the Hospital With Ischemic
or Hemorrhagic Stroke After a Bivalent COVID-19 Booster Dosea
Ischemic stroke, No. (%) Hemorrhagic stroke, No.
(n = 6882) (%) (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).
a
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.
had received simultaneous influenza vaccine; for 822 (94.6%)
of those aged 65 years and older, the product was adjuvanted.
Table 2 shows the number of cases in the 1- to 21-day post-
vaccination risk period and the control period for each analy-
sis, along with the RI estimates. The median length of the con-
trol 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 in-
terval were 20.9 vs 26.3 in the control interval (RI for ische-
mic 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 con-
trol 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.
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 influ-
enza vaccine on the same day as the bivalent COVID-19 vac-
cine. For ischemic stroke, the upper bounds of CIs for the RI
were all below the point estimate reported by CDC of a rela-
tive risk of 1.47. The findings align with those reported for is-
chemic 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
(Reprinted) JAMA Published online June 15, 2023 E1
 Letters

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 Bivalent Cases in risk interval/ Mean person-days Relative incidence
of stroke Age, y vaccine (BA.1) cases in control interval in case/control intervals (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 2439/4443 21.0/40.9 0.93 (0.86-1.01)
and mRNA-1273)
≥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 2121/4073 21.0/42.2 0.92 (0.85-1.01)
and mRNA-1273)
≥65 BNT162b2 111/122 21.0/25.4 0.79 (0.50-1.23)
and influenza vaccine
mRNA-1273 142/350 21.1/45.1 0.90 (0.65-1.27)
and influenza vaccine
Both and influenza 253/472 21.1/37.3 0.88 (0.69-1.14)
vaccine
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 507/1003 21.1/39.5 0.86 (0.72-1.02)
and mRNA-1273) Abbreviations: BNT162b2,
≥65 BNT162b2 159/224 20.9/26.2 0.84 (0.59-1.20) Pfizer-BioNTech COVID-19 vaccine
bivalent (BA.1); mRNA-1273, Moderna
mRNA-1273 270/683 21.0/49.1 0.99 (0.77-1.27) COVID-19 vaccine bivalent (BA.1).
Both (BNT162b2 429/907 21.0/41.0 0.86 (0.71-1.05) a
From September 5, 2022, to
and mRNA-1273)
December 4, 2022, in England.

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 pe-
riod from 21 days postvaccination.
Nick Andrews, PhD
Conflict of Interest Disclosures: Dr Ramsay reported that the Immunisation
Department in her directorate provides vaccine manufacturers (including
Pfizer) with postmarketing surveillance reports about pneumococcal and
meningococcal disease, which the companies are required to submit to
the UK Licensing authority in compliance with their risk management
strategy. A cost recovery charge is made for these reports. No other
disclosures were reported.

Julia Stowe, PhD Funding/Support: This work was funded by the UK Health Security Agency.

Elizabeth Miller, MBBS
Mary Ramsay, MBBS
Author Affiliations: Immunisation Division, UK Health Security Agency,
London, United Kingdom (Andrews, Stowe, Ramsay); London School of
Hygiene and Tropical Medicine, London, United Kingdom (Miller).
Accepted for Publication: May 24, 2023.
Published Online: June 15, 2023. doi:10.1001/jama.2023.10123
Corresponding Author: Nick Andrews, PhD, Immunisation Division,
UK Health Security Agency, 61 Colindale Ave, London NW9 5EQ,
United Kingdom (nick.andrews@ukhsa.gov.uk).
Author Contributions: Dr Andrews had full access to all of the data in the study
and takes responsibility for the integrity of the data and the accuracy of the data
analysis.
Concept and design: Andrews, Stowe, Miller, Ramsay.
Acquisition, analysis, or interpretation of data: Andrews, Stowe, Ramsay.
Drafting of the manuscript: Andrews, Stowe, Miller.
Critical revision of the manuscript for important intellectual content: Andrews,
Stowe, Miller, Ramsay.
Statistical analysis: Andrews.
Administrative, technical, or material support: Andrews, Stowe, Miller.
Supervision: Andrews.
Role of the Funder/Sponsor: Via their employment the authors played a role in
the design and conduct of the study; collection, management, analysis, and
interpretation of the data; preparation, review, or approval of the manuscript;
and decision to submit the manuscript for publication.
Data Sharing Statement: See Supplement 2.
1. CDC & FDA identify preliminary COVID-19 vaccine safety signal for persons
aged 65 years and older. Centers for Disease Control and Prevention. Accessed
March 15, 2023. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/
safety/bivalent-boosters.html
2. US Food and Drug Administration. COVID-19 mRNA bivalent booster vaccine
safety: Vaccines and Related Biological Products Advisory Committee meeting.
Accessed May 2, 2023. https://www.fda.gov/media/164811/download
3. Tessier E, Edelstein M, Tsang C, et al. Monitoring the COVID-19 immunisation
programme through a national immunisation management system—England’s
experience. Int J Med Inform. 2023;170:104974. doi:10.1016/j.ijmedinf.2022.
104974
4. Whitaker HJ, Farrington CP, Spiessens B, Musonda P. Tutorial in biostatistics:
the self-controlled case series method. Stat Med. 2006;25(10):1768-1797. doi:
10.1002/sim.2302
5. Jabagi MJ, Bertrand M, Botton J, et al. Stroke, myocardial infarction, and
pulmonary embolism after bivalent booster. N Engl J Med. 2023;388(15):1431-
1432. doi:10.1056/NEJMc2302134

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