Document text
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 Pfizer -
BioNTech 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
3
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. Av ailable 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
6VSD 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
7Rapid Cycle Analysis (RCA) to monitor the safety of COVID -19 vaccines in near real -time within the Vaccine Safety Datalink. Avai lable 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
9
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,
unspecifiedCOVID -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 facilityZ86.73 Personal history of transient ischemic
attack (TIA), and cerebral infarction
without residual deficitsOR
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
10
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)VaccineRisk
events (N)Comp
events (N)Adjusted
Rate Ratio95%
Confidence
Interval1-sided
p-valueSignal thi
week?
1-sided
p <0.01s
18–64Pfizer
Moderna49
1852
321.09
0.560.73–1.63
0.30–1.010.372
0.981No
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
11
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)
95% Age group
(years)Interval
(days)Comparators VaccineRisk
events (N)Comp
events (N)Adjusted
Rate RatioConfidence
IntervalP-value
(2-sided)
Not bivalent65+ 1–21 Pfizer 168 2536 1.01 0.86–1.19 0.907boosted
* Analyses only included outcomes through April 8, 2023.
13Supplemental RCA analyses:
Ischemic strokes during the 1–21-day interval comparing bivalent boosted
vs. un -boosted concurrent comparators (but eligible for bivalent booster )*
Cases in 1 –21-day Cases in 22 –42-day Adjusted
Analytic population Risk Interval Comparison Interval Rate Ratio** P-value
(N=139) (N=108) (95% CI)
Bivalent Pfizer + same -day
high-dose or adjuvanted flu 43 27 1.59 (0.99 –2.61) 0.06
vaccine
Bivalent Pfizer + same day8 11 0.73 (0.28 –1.83) 0.50standard dose flu vaccine
Bivalent Pfizer without any107 99 1.08 (0.82 –1.42) 0.58same day flu vaccine
14* Analyses only include vaccination data through January 14, 2023 , and stroke outcome data through Feb 25, 2023
** Adjusted by 5 -year age groupsPost-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*)
15*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
17
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 -seriousManufacturerMedian
Age (IQR),
yearsMale†
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: 66–79years)
•Median time to onset: 13 days (IQR: 4 –29 days)
•68males, 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
chart review (n= 149) *Awaiting medical records and/or healthcare provider interview; some still processing
19Non -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)
Chart -verified reports Chart -verified reports Background + reports under review
Reporting rate Reporting rate Age group Obs Doses Obs Doses ExpVaccine (per million (per million † (years) reports admin* reports admin* cases doses admin) doses admin)
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
* 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
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
21
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
23*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
24
Acknowledgements
25▪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
26
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://wwwn.cdc.gov/phil/
Details.aspx?pid=8876 )
Extra Slides
Ischemic stroke by day after Pfizer -BioNTech bivalent
boosters, people ages ≥65 Years*
*Data cutoff 2/28/2023Cluster days 13 –22,
p-value = .0637
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