National Center for Emerging and Zoonotic Infectious Diseases

mRNA COVID-19 bivalent booster vaccine 

safety update

Advisory Committee on Immunization Practices (ACIP) meeting

April 19, 2023

Tom T. Shimabukuro, MD, MPH, MBA

Director, Immunization Safety Office

Division of Healthcare Quality Promotion 

Centers for Disease Control and Prevention (CDC)
Topics

▪ Describe current data on ischemic stroke following 

mRNA COVID-19 bivalent booster vaccination 

• CDC’s Vaccine Safety Datalink (VSD) Rapid Cycle Analysis (RCA) 

signal assessment for ischemic stroke after Pfizer-BioNTech 

COVID-19 mRNA bivalent booster dose vaccination in the age 

group ≥65 years old

• Vaccine Adverse Event Reporting System (VAERS) data on 

ischemic stroke following mRNA COVID-19 bivalent booster 

dose vaccination

2
VSD COVID-19 Rapid Cycle Analysis: 

Analyses of Ischemic Stroke after PfizerBioNTech Bivalent Booster Dose

Prepared by:

Kaiser Permanente Northern California Vaccine Study Center

Presented by Tom Shimabukuro, MD, MPH, MBA

Centers for Disease Control and Prevention

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Vaccine Safety Datalink (VSD)

▪ Established in 1990

▪ Collaborative project between CDC and 9 integrated healthcare organizations

▪ Includes electronic health record data on ~12.5 million individuals across all sites 4
VSD RCA for bivalent boosters

▪ Pre-specified outcomes were assessed during weekly sequential 

monitoring after COVID-19 bivalent booster vaccination*

• Risk of pre-specified outcomes 1–21 days following a bivalent vaccination 

compared with bivalent vaccinated individuals who were 22–42 days 

following the bivalent dose (vaccinated concurrent comparator method)

• All analyses adjusted for age, sex, race/ethnicity, VSD site, calendar time 

(days) and seasonality (time)

• Signal if p-value <0.01 (1-sided)

* Rapid Cycle Analysis (RCA) to monitor the safety of COVID-19 vaccines in near real-time within the Vaccine Safety Datalink. Available at: 

Rapid Cycle Analysis (RCA) to monitor the safety of COVID-19 vaccines in near real-time within the Vaccine Safety Datalink (cdc.gov) 5
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VSD COVID-19 vaccine RCA prespecified surveillance outcomes

Prespecified outcomes Settings

Acute disseminated encephalomyelitis Emergency dept, Inpatient

Acute myocardial infarction Emergency dept, Inpatient

Acute respiratory distress syndrome Emergency dept, Inpatient

Anaphylaxis* Emergency dept, Inpatient

Appendicitis Emergency dept, Inpatient

Bell’s palsy Emergency dept, Inpatient, Outpatient

Cerebral venous sinus thrombosis Emergency dept, Inpatient

Disseminated intravascular coagulation Emergency dept, Inpatient

Encephalitis / myelitis / encephalomyelitis Emergency dept, Inpatient

Guillain-Barré syndrome Emergency dept, Inpatient

Immune thrombocytopenia Emergency dept, Inpatient, Outpatient

Kawasaki disease Emergency dept, Inpatient

Multisystem inflammatory syndrome in children/adults (MIS-C/MIS-A) Emergency dept, Inpatient

Myocarditis / pericarditis* Emergency dept, Inpatient

Narcolepsy / cataplexy Emergency dept, Inpatient, Outpatient

Pulmonary embolism Emergency dept, Inpatient

Seizures/Convulsions (including 0-7 days for youngest ages) Emergency dept, Inpatient

Stroke, hemorrhagic Emergency dept, Inpatient

Stroke, ischemic Emergency dept, Inpatient

Thrombosis with thrombocytopenia syndrome Emergency dept, Inpatient

Thrombotic thrombocytopenic purpura Emergency dept, Inpatient

Transverse myelitis Emergency dept, Inpatient

Venous thromboembolism Emergency dept, Inpatient, Outpatient

*All outcomes are first ever in the ICD-10 era, except anaphylaxis which is first in 7 days, and myocarditis/pericarditis which is first in 60 days

▪ In COVID-19 bivalent booster vaccine monitoring, VSD RCA detected a statistical signal for ischemic stroke after 

Pfizer-BioNTech bivalent booster vaccination in the age group 65 years and older

▪ No other VSD RCA pre-specified surveillance outcomes have signaled in any age groups for either of the mRNA 

COVID-19 bivalent booster vaccines or when data for the two mRNA vaccine types are combined/pooled
VSD investigations of an RCA signal to assess whether it 

reflects a real effect of vaccination on an outcome

▪ Data quality assessment for errors, anomalies, or missing/late-arriving data

▪ Analyses using different comparators than primary concurrent (e.g., un-boosted, 

unvaccinated or “historical” comparators) to supplement our primary analyses

▪ Additional investigations to provide context (e.g., background rates, etc.)

▪ Graphic displays of outcome incidence day by day after vaccination, using temporal scan 

statistics to assess apparent clustering

• Examine the temporal clustering of outcome events in subgroups defined by demographics, site or 

simultaneous exposure (e.g., flu vaccine)

▪ If the signal is driven by a strong association in one subgroup or VSD site, further 

analyses by site or subgroup as appropriate

▪ Chart review to confirm cases and collect additional data (e.g., date of symptom onset). 

▪ Consider epidemiologic studies to further investigate surveillance findings

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Rapid Cycle Analysis (RCA) to monitor the safety of COVID-19 vaccines in near real-time within the Vaccine Safety Datalink. Available at: Rapid 

Cycle Analysis (RCA) to monitor the safety of COVID-19 vaccines in near real-time within the Vaccine Safety Datalink (cdc.gov)
VSD COVID-19 RCA analyses: 

Ischemic stroke after Pfizer-BioNTech 

bivalent booster among people ≥65 

years of age
COVID-19 bivalent booster doses and influenza vaccine doses 

administered over time among persons aged ≥65 years, by vaccine type

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VSD RCA ischemic stroke definition

ICD-10 CODES TO FIND INCIDENT 

CASES 

ICD-10 CODES FOR LOOKBACK TO ADJUST 

ONSET DATE (in all settings)

ICD-10 CODES - TO DETECT PREVALENCE 

(history of, in all settings) ICD-10 CODES - OTHER CAUSE EXCLUSIONS (in all settings) 

Stroke, ischemic 

(settings = Emergency, Inpatient)

Codes to adjust Stroke, ischemic onset 

(if seen within 1 day before case) Stroke, ischemic - Review for Prevalence - 1ST EVER Other possible causes of Stroke, ischemic

G45.8 Other transient cerebral 

ischemic attacks and 

related syndromes Adjust onset date if occurs in the 1 day prior to 

incident case: Exclude if occurs EVER prior to incident case:

Exclude if COVID-19 in the last 30 days prior to incident case (not 

including same day): 

G45.9 Transient cerebral 

ischemic attack, 

unspecified

COVID-19 DIAGNOSIS 

I63.* Cerebral infarction Z92.82 Status post administration of tPA

(rtPA) in a different facility within 

the last 24 hours prior to admission 

to current facility

Z86.73 Personal history of transient ischemic 

attack (TIA), and cerebral infarction 

without residual deficits

OR

COVID-19 POSITIVE LAB TEST

R51.* Headache I69.* Sequelae of cerebrovascular disease Exclude if occurs in the time period noted prior to incident case 

(not including same day):

R47.* Speech disturbances, not 

elsewhere classified I48.*

Atrial fibrillation and flutter (if seen EVER prior to 

incident case)

R29.810 Facial weakness I21.* Acute myocardial infarction (if seen within 28 days prior 

to incident case)

R53.1 Weakness

S15.*

Injury of blood vessels at neck level (if seen within 1 day 

prior to incident case)

R42.* Dizziness and giddiness

I74.*

Arterial embolism and thrombosis (if seen within 1 day 

prior to incident case)

R41.82 Altered mental status, unspecified D57.* Sickle-cell disorders (if seen EVER prior to incident case)

R40.4 Transient alternation of awareness

D68.5*

Primary thrombophilia (if seen EVER prior to incident 

case)

G81.9* Hemiplegia, unspecified

H53.9 Unspecified visual disturbance

H53.13* Sudden visual loss

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Bivalent RCA concurrent comparator analyses of

ischemic strokes during a 1–21-day Risk Interval versus 

a 22–42-day Comparison Interval (data through April 8, 2023) 

Nominal analysis Sequential analysis

Age group 

(years) Vaccine Risk events (N)

Comp 

events (N)

Adjusted 

Rate Ratio

95% 

Confidence 

Interval

1-sided

p-value

Signal this 

week? 

1-sided 

p <0.01

18–64

Pfizer 49 52 1.09 0.73–1.63 0.372 No

Moderna 18 32 0.56 0.30–1.01 0.981 No

65+ Pfizer 158 145 1.26 0.99–1.60 0.032 No

Moderna 80 77 1.21 0.87–1.68 0.142 No

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Ischemic stroke after Pfizer-BioNTech bivalent booster, age ≥65 

years, counts and adjusted rate ratios (Oct 16, 2022–April 8, 2023)

12 Red dot represents sequential signal: p-value <0.01 (1-sided)

RR= 1.26 (95% CI 0.99–1.60)
Age group 

(years)

Interval 

(days) Comparators Vaccine Riskevents (N)

Comp

events (N)

Adjusted 

Rate Ratio

95% 

Confidence 

Interval

P-value

(2-sided)

65+ 1–21 Not bivalent

boosted Pfizer 168 2536 1.01 0.86–1.19 0.907

* Analyses only included outcomes through April 8, 2023. 

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Supplemental RCA analyses:

Ischemic strokes during the 1–21-day interval comparing bivalent boosted 

vs. un-boosted concurrent comparators (but eligible for bivalent booster)

*
Analytic population

Cases in 1–21-day

Risk Interval

(N=139)

Cases in 22–42-day

Comparison Interval

(N=108)

Adjusted

Rate Ratio**

(95% CI)

P-value 

Bivalent Pfizer + same-day

high-dose or adjuvanted flu 

vaccine

43 27 1.59 (0.99–2.61) 0.06

Bivalent Pfizer + same day

standard dose flu vaccine 8 11 0.73 (0.28–1.83) 0.50

Bivalent Pfizer without any

same day flu vaccine 107 99 1.08 (0.82– 1.42) 0.58

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* Analyses only include vaccination data through January 14, 2023, and stroke outcome data through Feb 25, 2023

** Adjusted by 5-year age groups

Post-signal analyses*:

Ischemic stroke incidence during days 1–21 compared with days 22–42, 

among ≥65 years with and without simultaneous influenza vaccination
Ischemic stroke following bivalent Pfizer-BioNTech mRNA 

COVID-19 booster vaccination in people ages 65+ years

▪ Statistical signal 

• The statistical signal persisted during the November 2022–January 2023 timeframe 

• The rate ratio has slowly attenuated from 1.92 to 1.26 and has not met signaling 

criteria during the past 10 weekly analyses 

▪ Additional signal investigation analyses

• Supplemental analyses using un-boosted concurrent comparators showed a rate ratio 

RR=1.01 (95% CI 0.86–1.19; p-value 0.907)

• Analyses evaluating simultaneous high-dose or adjuvanted flu vaccine showed a rate 

ratio RR=1.59 (95% CI 0.99–2.61; p-value 0.06)

‒ Separate analyses did not detect an elevated RR for stroke after flu vaccine alone (data not shown)

• Supplemental analyses suggest comparison interval (22–42 days) rates were lower 

than expected (data previously presented to ACIP February 24, 2023*)

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* ACIP Meeting COVID-19 mRNA bivalent booster vaccine safety--February 24, 2023 (cdc.gov)
Vaccine Adverse Event Reporting System 

(VAERS)
VAERS is the nation’s early warning system for vaccine safety

+

Vaccine Adverse Event 

Reporting System

http://vaers.hhs.gov

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U.S. reports to VAERS following bivalent booster COVID-19 mRNA 

vaccination among ages ≥5 years*(as of April 2, 2023) (N=28,363)

▪ Distribution by age, sex, and serious status similar regardless of manufacturer

• Most reports (93%) were non-serious

Manufacturer

Median 

Age (IQR), 

years

Male†

N (%)

Female†

N (%)

Non-serious

N (%)£

Serious 

N (%)

Doses

admin‡ 

Pfizer-BioNTech 56 (35–69) 6,599 (38) 10,580 (61) 16,124 (93) 1,307 (8) 35,256,444

Moderna 62 (45–71) 4,159 (38) 6,620 (61) 10,209 (93) 725 (7) 19,900,255

Total 59 (39–70) 10,758 (38) 17,198 (61) 26,331 (93) 2,032 (7) 55,156,699

* Includes reports after Moderna bivalent booster among ages ≥6 years

† Excludes 407 (1%) reports where sex was not reported

£ 2 reports documented receipt of Moderna and Pfizer Bivalent, they are counted in each group but only counted once total

‡ Doses administered among children ages 5–11 years vaccinated during October 18, 2022–March 29, 2023 18
Reports to VAERS of ischemic stroke/transient ischemic attack (TIA) after 

bivalent COVID-19 mRNA vaccination in people ages ≥18 years

(as of April 2, 2023)

▪ 149 verified reports of ischemic stroke/TIA

• Ischemic stroke (110), TIA (35), ischemic stroke + TIA (4)

• Pfizer-BioNTech bivalent (112), Moderna bivalent (37)

• Median age: 72 years (IQR: 66–79 years)

• Median time to onset: 13 days (IQR: 4–29 days)

• 68 males, 81 females

• All verified reports (149, 100%) had at least one risk 

factor for ischemic stroke

‒ The most common was hypertension (89, 60%)

• Simultaneous influenza vaccination

‒ 18–64 years: standard dose (6)

‒ ≥65 years: high-dose (10), adjuvanted (3), standard dose (2), 

unknown type (1)

Preliminary reports of ischemic 

stroke/TIA (N=252)

Under review*

(n=34)

Excluded based 

upon chart 

review (n=9)

Verified ischemic stroke/TIA by

* Awaiting medical records and/or healthcare provider interview; some still processing chart review (n=149)

19

Non-ischemic stroke 

verified by chart review 

(n=60)
VAERS reports and reporting rates of ischemic stroke/TIA in the 3 weeks after 

mRNA COVID-19 bivalent vaccination in people ages 18–39, 40–64, and ≥65 years 

(as of April 2, 2023)

* Doses administered as of April 5, 2023

† Ramirez et al. Trends in Transient Ischemic Attack Hospitalizations in the United States. J Am Heart Assoc. 2016;5(9):e004026. (Estimated expected cases based upon observed annual incidence in 2010 for 

ages 25–44, 45–54, and 65–84 years, adjusted for period corresponding to 3 weeks after vaccination). 20

Chart-verified reports Chart-verified reports

+ reports under review

Background

Age group

(years) Vaccine Obsreports

Doses

admin*

Reporting rate

(per million

doses admin)

Obs

reports

Doses

admin*

Reporting rate

(per million

doses admin)

Exp

cases†

18–39 Pfizer-BioNTech 3 6,334,671 0.5 3 6,334,671 0.5 88

18–39 Moderna 0 3,048,913 0 1 3,048,913 0.3 42

40–64 Pfizer-BioNTech 13 12,419,399 1.0 17 12,419,399 1.4 1,168

40–64 Moderna 4 7,028,873 0.6 5 7,028,873 0.7 661

≥65 Pfizer-BioNTech 51 13,693,161 3.7 60 13,693,161 4.4 4,993

≥65 Moderna 19 9,622,716 2.0 23 9,622,716 2.4 3,509
VAERS monitoring: COVID-19 mRNA bivalent booster 

vaccination and ischemic stroke 

▪ No unusual or unexpected reporting patterns observed, and no 

evidence of a safety concern detected for ischemic stroke with either 

mRNA COVID-19 bivalent boosters in VAERS monitoring 

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Summary
COVID-19 mRNA bivalent booster vaccination safety – data 

from other monitoring systems and programs*

▪ FDA monitoring in the CMS data and Department of Veterans Affairs monitoring in the VA 

system have not detected any safety signals for ischemic stroke following COVID-19 

mRNA bivalent boosters using historical comparator designs 

▪ Surveillance conducted by international regulatory and public health partners has not 

detected a safety concern for ischemic stroke following bivalent COVID-19 mRNA booster 

vaccination 

▪ No evidence of a safety signal for ischemic stroke in Pfizer’s global monitoring of bivalent 

COVID-19 mRNA booster vaccination

▪ No safety signals were detected for ischemic stroke for primary series or monovalent 

boosters for Pfizer-BioNTech or Moderna COVID-19 vaccines in U.S. and global monitoring

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* These surveillance activities did not include analyses to evaluate the effect of simultaneous flu vaccination; different 

formulations of COVID-19 mRNA bivalent booster vaccinations were used globally
Further evaluation and key next steps

Further evaluation

▪ Consult with other surveillance systems to better understand: 

• Possible role of simultaneous high-dose or adjuvanted flu vaccination with COVID-19 

vaccination

• Possible decreased rate of stroke observed in VSD in the 3–6 weeks following vaccination

▪ In the process of chart reviewing a random sample of 100 cases across VSD sites

▪ Continue monitoring in VAERS

Key next steps

▪ CDC continues to recommend that everyone eligible for a COVID-19 mRNA 

bivalent booster or a flu vaccine get vaccinated

▪ CDC and FDA are engaged in epidemiologic analyses regarding simultaneous 

vaccination with COVID-19 mRNA bivalent booster and flu vaccines

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Acknowledgements

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▪ CDC Immunization Safety Office

• VAERS Team

• V-safe Team

• Clinical Immunization Safety Assessment 

(CISA) Project

• Vaccine Safety Datalink (VSD) Team

▪ COVID-19 Vaccine Task Force Data Monitoring 

and Reporting Group

▪ Kaiser Permanente Northern California (VSD)

▪ Marshfield Clinic Research Institute (VSD)

▪ VSD sites

• HealthPartners Institute, Minneapolis, MN

• Kaiser Permanente Colorado, Denver, CO

• Kaiser Permanente Northwest, Portland, OR

• Kaiser Permanente Southern California, Los Angeles, CA

• Kaiser Permanente Washington, Seattle, WA

• Denver Health, Denver, CO
Disclaimer/disclosures

▪ The findings and conclusions in this presentation are those of the presenters and 

do not necessarily represent the official position of the CDC

▪ Mention of a product or company name is for identification purposes only and 

does not constitute endorsement by CDC

▪ Dr. Nicola Klein reports research support from Pfizer for COVID-19 vaccine clinical 

trials and from Pfizer, GlaxoSmithKline, Merck and Sanofi Pasteur for unrelated 

studies

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For more information, contact CDC

1-800-CDC-INFO (232-4636)

TTY: 1-888-232-6348 www.cdc.gov

The findings and conclusions in this report are those of the authors and do not necessarily represent the 

official position of the Centers for Disease Control and Prevention.

Photo credit: James Gathany

(https://phil.cdc.gov/Details.

aspx?pid=8876) 
Extra Slides
Ischemic stroke by day after Pfizer-BioNTech bivalent 

boosters, people ages ≥65 Years*

* Data cutoff 2/28/2023

Cluster days 13–22, 

p-value = .0637

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