Update on Original COVID-19 Vaccine and COVID-19 

Vaccine, Bivalent Safety

Richard Forshee

Deputy Director, FDA/CBER/OBPV

Advisory Committee on Immunization Practices

February 24, 2023 
2

• CBER Active Surveillance Program (BEST Initiative)

• Bivalent COVID-19 mRNA Vaccines Safety Surveillance

• Conclusion

Outline
3

*Data lag varies based on data source, ranges from a few days to a few months.

BEST Initiative Data Sources
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Claims Data Source Age (years) Population Enrolled 

(million)

CMS Medicare 65+ 36

DP 1

0-4

5-17

18-64

1.2

3.1

14.8

DP 2

0-4

5-17

18-64

1.0

2.6 

11.6 

DP 3

0-4

5-17

18-64

1.4

3.7

17.1

Rapid Cycle Analysis (RCA) Data Sources
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• Confidential, population-based, computerized 

databases that record immunization doses 

administered by participating providers to persons 

in U.S. public health jurisdictions 

• Supplements claims-based COVID-19 vaccine 

administration data

• Undercapture of COVID-19 vaccines in claims 

databases due to vaccines administered without 

insurance reimbursement

Immunization Information Systems (IIS)
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Descriptive Monitoring provides descriptive statistics of 

vaccine doses and selected adverse events.

Signal Detection performs sequential testing, while 

vaccine doses accumulate, to identify potential safety 

risks early; does not prove causal relationship.

Signal Evaluation uses more robust study designs to 

evaluate potential safety signals.

Phases of Vaccine Active Surveillance
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• CBER Active Surveillance Program (BEST Initiative)

• Bivalent COVID-19 mRNA Vaccines Safety Surveillance

• Conclusion

Outline
8

COVID-19 Bivalent mRNA Vaccines Rapid Cycle Analyses 

Administered Doses By Age Group

1. Data cuts: CVS data through 10/2022, HealthCore data through 11/2022, Optum data through 12/2022 

2. Data cuts: CMS data through 12/2022

Age Groups 

(years)

BNT162b2 

(# vaccinations)

mRNA-1273 

(# vaccinations)

Total 

(# vaccinations)

5/6-171 196,992 13,016 210,008

18-351 442,870 211,694 654,564

36-641 1,248,430 654,220 1,902,650

65+2 4,265,244 3,042,074 7,307,318
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• FDA Study Design: Rapid Cycle Analysis (RCA) near real-time 

surveillance 

• No causal association established

• Population: 6 month-4/5 years, 5/6-17 years, 18-64 years*, ≥65 

years

• Exposure: mRNA-1273.222 and BNT162b2 COVID-19 vaccines

• Bivalent booster: original SARS-CoV-2 virus and Omicron 

variants BA.4 and BA.5.

• Statistical Method: MaxSPRT

• Comparator: Historical rates 

*For the myocarditis/pericarditis outcome, the study population was additionally split into 18-35 and 36-64 year age groups.

COVID-19 Bivalent mRNA Vaccines Safety Monitoring
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Adverse Events Monitored in Adult and Pediatric Populations

Acute Myocardial Infarction Hemorrhagic Stroke 

Anaphylaxis Immune Thrombocytopenia 

Appendicitis Multisystem Inflammatory Syndrome 

Bell’s Palsy Myocarditis/Pericarditis (Myo-/Pericarditis)*

Common Site Thrombosis with 

Thrombocytopenia Narcolepsy 

Disseminated Intravascular Coagulation Non-hemorrhagic Stroke 

Deep Vein Thrombosis Pulmonary Embolism 

Encephalitis/Encephalomyelitis Transverse Myelitis 

Guillain-Barre Syndrome Unusual Site Thrombosis (Broad) with 

Thrombocytopenia

*This includes 4 myo-/pericarditis outcome definitions varying care settings (all settings vs. IP/OP-ED) and risk windows (1-7 vs. 1-21 days)

These AEs have not been associated with COVID-19 vaccines based on available pre-licensure evidence.

Adverse Events Monitored in

Pediatric Populations Only

Seizure/Febrile Seizure

Kawasaki Disease

Multisystem Inflammatory Syndrome in children 

(MIS-C) 

FDA Adverse Events Monitored 
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Adverse Event (AE) Medicare Population1

(Ages 65+)

Adult Population2

(Ages 18-64)

Pediatric Population2

(Ages 5-17/6-17)

Acute Myocardial Infarction No No Descriptive Only

Anaphylaxis No No No

Appendicitis No No No

Disseminated Intravascular Coagulation No No No

Deep Vein Thrombosis No No No

Bell’s Palsy No No No

Encephalomyelitis/Encephalitis No No No

Guillain-Barré Syndrome No No Descriptive Only

Hemorrhagic Stroke No No Descriptive Only

Myocarditis/Pericarditis No BNT162b2 Bivalent 

(18-35) No

Common Site Thrombosis with 

Thrombocytopenia No No No

Uncommon Site Thrombosis with 

Thrombocytopenia Syndrome No No Descriptive Only

Narcolepsy No No No

Non-Hemorrhagic Stroke No No No

Pulmonary Embolism No No No

Transverse Myelitis No No Descriptive Only

Immune Thrombocytopenia No No No

Febrile Seizures N/A N/A Descriptive Only

Seizures/Convulsions N/A N/A No

Kawasaki disease N/A N/A Descriptive Only

Multisystem Inflammatory Syndrome Descriptive Only Descriptive Only Descriptive Only

1. Data cuts: CMS 12/2022

2. Data cuts: CVS Health data through 10/2022; HealthCore data through 11/2022, Optum data through 12/2022

AEs and the associated vaccine brand with a safety signal are noted. 

N/A indicates neither descriptive monitoring nor sequential testing is being conducted in the indicated age group for a given AE. NO indicates that a safety signal has 

not been detected. Descriptive Only indicates sequential testing is not being conducted in the indicated age group for a given AE.

Signals Detected
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Adverse Event (AE) Ages 65+ years

Acute Myocardial Infarction BNT162b2, mRNA-1273

Deep Vein Thrombosis BNT162b2, mRNA-1273

Bell’s Palsy BNT162b2

Common Site Thrombosis with 

Thrombocytopenia BNT162b2

Non-Hemorrhagic Stroke BNT162b2, mRNA-1273

Pulmonary Embolism BNT162b2

Adverse Events that Completed Surveillance Period
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Risk Ratio Non-hemorrhagic Stroke for Pfizer

Bivalent Compared to Historical Rates (2019)

We reached the maximum length of surveillance without a signal
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• Approximately 4.25 million doses of the Pfizer-BioNTech bivalent vaccine have 

been administered in the CMS database in individuals 65 years and older

• 38% of the Medicare recipients who received a Pfizer bivalent COVID-19 

booster received a seasonal influenza vaccination on the same day

• 78% received a seasonal influenza vaccination within +/- 42 days 

• Further work to be done to segment out the different influenza vaccine types 

administered with the COVID-19 vaccines

• No signal seen at this time for non-hemorrhagic stroke

Concomitant Influenza Vaccination
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• This is a large-scale signal detection study of two COVID-19 mRNA bivalent 

vaccines conducted in multiple claims databases. 

• RCA surveillance detected a signal for myocarditis/pericarditis following 

BNT162b2 bivalent vaccine doses among 18-35 year olds.

• Among adults 65 years and older, several AEs have completed the 

surveillance period. 

• Signal detection studies do not establish a causal relationship and further 

evaluation of signals is required in more robust studies.

• Surveillance is ongoing and expanded to < 5 year olds. 

COVID-19 Bivalent mRNA Vaccines RCA

Summary
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1) No excess reports of stroke from VAERS

2) CMS database with about 4.25 million doses shows no increase in stroke

3) VA database run shows no increase in stroke on preliminary query

4) Various countries in Europe as well as Israel indicate no increased risk of stroke in 

their surveillance systems

5) Pfizer notes no increase in signal in their global safety database or when 

comparing the monovalent to bivalent vaccines

In any case, a formal epidemiologic study is being initiated by FDA to 

prepare for potential vaccine coadministration in 2023-2024

Data Suggesting Absence of Safety Risk for the 

Bivalent Boosters in Age 65y+
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Acknowledgements

• Steven A. Anderson

• CBER Surveillance Team: Azadeh Shoaibi, Hui-Lee Wong, Tainya C. Clarke, 

Joyce Obidi, Joann F. Gruber, Patricia C. Lloyd, Sylvia Cho

• CBER OBPV

• Federal Partners: CMS, VA, CDC

• FDA Partners: Acumen, Blue Health Intelligence, CVS Health, HealthCore, 

IBM, IQVIA, OHDSI, Optum, RTI Health Solutions

www.bestinitiative.org