NON-INTERVENTIONAL INTERIM STUDY REPORT 5

C4591021
BNT162b2 (COMIRNATY, Pfizer-BioNTech COVID-19 vaccine)
12 March 2024

NON-INTERVENTIONAL (NI) STUDY

INTERIM REPORT 5

PASS information

Title Post Conditional Approval Active

Surveillance Study Among Individuals in
Europe Receiving the Pfizer-BioNTech
Coronavirus Disease 2019 (COVID-19)
Vaccine

Protocol number C4591021

Version identifier of the interim study V1.0

report

Date 12 March 2024

EU Post Authorization Study (PAS) EUPAS41623

register number
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

Active substance BNT162b2

Medicinal product COVID-19 messenger ribonucleic acid

(mRNA) vaccine is a nucleoside-modified
ribonucleic acid (modRNA) encoding the
viral spike glycoprotein S of severe acute
respiratory syndrome coronavirus 2 (SARS-
CoV-2)

Marketing Authorization Holder (MAH) BioNTech Manufacturing GmbH

Joint PASS No

Research question and objectives The research question addressed by this

study is: Is there an increased risk of select
adverse events of special interest (AESI)
after being vaccinated with the Pfizer-
BioNTech COVID-19 vaccine?

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Objectives

Primary study objective

To determine whether an increased risk of

prespecified AESI exists following the
administration of at least one dose of the
Pfizer-BioNTech COVID-19 vaccine using
two approaches: (a) a cohort design
comparing risk in vaccinated and
unvaccinated individuals and (b) a self-
controlled risk interval (SCRI) design.

Secondary study objectives

 To estimate the incidence rates of

prespecified AESI among individuals
who receive at least one dose of the
Pfizer-BioNTech COVID-19 vaccine
using a cohort study design.
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 To describe the incidence rates and

determine whether an increased risk of
prespecified AESI exists following the
administration of at least one dose of the
Pfizer-BioNTech COVID-19 vaccine
compared with a matched comparator
group with no COVID-19 vaccination
within subcohorts of interest (i.e.,
individuals who are
immunocompromised, individuals who
are frail and have comorbidities,
individuals diagnosed with previous
COVID-19 infection, and age-specific
groups) in Europe using a cohort study
design and/or a SCRI design.

 To determine whether an increased risk

of prespecified AESI exists following the
administration of at least one dose of the
Pfizer-BioNTech COVID-19 vaccine
compared with no COVID-19
vaccination, in pregnant people and their
neonates using a cohort study design.

To characterise utilisation patterns of Pfizer-

BioNTech COVID-19 vaccine among
individuals within Europe, including
estimating the proportion of individuals

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receiving the vaccine; two-dose vaccine

completion rate and distribution of time gaps
between the first and second doses; and
demographics and clinical characteristics of
recipients, overall and among subcohorts of
interest, such as individuals who are
immunocompromised, elderly, or have
specific comorbidities.

Country(-ies) of study The Netherlands (NL), Norway (NO), Italy

(IT), Spain (ES), United Kingdom (UK)

Author 4.1(b)
4.1(b)
University Medical Center Utrecht
AND
4.1(b)
4.1(b)
RTI Health Solutions
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

On behalf of the Vaccine Monitoring

Collaboration for Europe (VAC4EU)
Consortium research team

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Marketing Authorization Holder(s)

Marketing Authorization Holder(s) BioNTech Manufacturing GmbH

An der Goldgrube 12
55131 Mainz
Germany

MAH contact person 4.1(b)

This document contains confidential information belonging to Pfizer. Except as otherwise agreed to in writing,
by accepting or reviewing this document, you agree to hold this information in confidence and not copy or
disclose it to others (except where required by applicable law) or use it for unauthorized purposes. In the
event of any actual or suspected breach of this obligation, Pfizer must be promptly notified.
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

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TABLE OF CONTENTS
LIST OF IN-TEXT TABLES ...................................................................................................8
LIST OF IN-TEXT FIGURES ...............................................................................................12
1. ABSTRACT (STAND-ALONE DOCUMENT) ...................................................................16
2. LIST OF ABBREVIATIONS .............................................................................................16
3. INVESTIGATORS ...........................................................................................................19
4. OTHER RESPONSIBLE PARTIES .................................................................................21
5. MILESTONES .................................................................................................................22
6. RATIONALE AND BACKGROUND .................................................................................23
7. RESEARCH QUESTION AND OBJECTIVES .................................................................23
7.1. Objectives ...........................................................................................................23
7.1.1. Primary study objective ...........................................................................23
7.1.2. Secondary study objectives ....................................................................24
8. AMENDMENTS AND UPDATES.....................................................................................24
9. RESEARCH METHODS..................................................................................................30
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9.1. Study design .......................................................................................................30

9.1.1. Retrospective cohort design....................................................................32
9.1.2. Self-controlled risk interval design...........................................................33
9.2. Setting.................................................................................................................34
9.2.1. Data sources...........................................................................................34
9.2.2. Study period and follow-up......................................................................35
9.3. Subjects ..............................................................................................................36
9.3.1. Inclusion criteria ......................................................................................36
9.4. Variables.............................................................................................................37
9.4.1. Exposure definition .................................................................................37
9.4.2. Definition of outcomes.............................................................................39
9.4.3. Covariate definition .................................................................................41
9.5. Data sources and measurement .........................................................................45
9.6. Bias.....................................................................................................................46
9.7. Study Size...........................................................................................................48
9.8. Data transformation.............................................................................................49
9.9. Statistical methods ..............................................................................................49
9.9.1. Main summary measures........................................................................49

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9.9.2. Main statistical methods..........................................................................50

9.9.3. Baseline exchangeability and negative control outcome .........................51
9.9.4. Missing values ........................................................................................53
9.9.5. Sensitivity analyses.................................................................................53
9.9.6. Amendments to the statistical analysis plan ............................................53
9.10. Quality control ...................................................................................................57
9.10.1. Pedianet................................................................................................58
9.10.2. PHARMO (NL) ......................................................................................58
9.10.3. NHR (University of Oslo) (NO) ..............................................................58
9.10.4. EpiChron (ES).......................................................................................58
9.10.5. SIDIAP (ES)..........................................................................................59
9.10.6. CPRD Aurum (UK) ................................................................................59
9.11. Protection of human subjects ............................................................................59
10. RESULTS......................................................................................................................60
10.1. Participating data sources .................................................................................60
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10.1.1. Vaccinated cohort .................................................................................62

10.1.2. Matched cohorts ...................................................................................77
10.2. Main results.....................................................................................................111
10.2.1. Results from negative control..............................................................111
10.2.2. Incidence rates and hazard ratios for AESIs .......................................117
10.2.3. Detailed results for 11 AESIs of specific interest .................................127
10.3. Other analyses ................................................................................................207
10.4. Adverse events / adverse reactions.................................................................207
11. DISCUSSION..............................................................................................................207
11.1. Key results ......................................................................................................207
11.1.1. Important information on data sources ................................................208
11.1.2. Total vaccinated population and vaccination patterns .........................209
11.1.3. Matched cohorts .................................................................................210
11.1.4. Negative control ..................................................................................211
11.1.5. Incidence rates and hazard ratios for AESIs .......................................211
11.2. Limitations.......................................................................................................219
11.3. Interpretation...................................................................................................221
11.4. Generalisability................................................................................................221

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12. OTHER INFORMATION..............................................................................................221

13. CONCLUSIONS ..........................................................................................................221
14. REFERENCES............................................................................................................223
15. LIST OF SOURCE TABLES AND FIGURES...............................................................226
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LIST OF IN-TEXT TABLES

Table 1. Amendments to the protocol..................................................................24
Table 2. List of selected adverse events of special interest.................................31
Table 3. Date of administration of first dose of Pfizer-BioNTech COVID-19
vaccine and dates of data collection for this report ................................36
Table 4. Comorbidities and related medicinal products with evidence of
being at high risk for developing severe COVID-19 ...............................45
Table 5. Number of individuals needed to detect different risk ratios for
selected adverse events of special interest for a range of
background rates ..................................................................................48
Table 6. Summary of amendments to the statistical analysis plan.......................53
Table 7. Attrition table for the Pfizer-BioNTech COVID-19 vaccinated cohort
(before matching) by data source*.........................................................63
Table 8. Pfizer-BioNTech COVID‑19 vaccine doses received (n, %) and
timing (in weeks) by data source*..........................................................65
Table 9. PART 1: Baseline demographics, lifestyle variables and healthcare
utilisation at the time of the first and third Pfizer-BioNTech COVID-
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19 vaccine doses in the Pfizer-BioNTech vaccinated cohort, by

data source*..........................................................................................69
Table 10. Attrition table for the matched cohort by data source* ...........................78
Table 11. Cohort follow-up and reasons for censoring by vaccination status
(matched cohort design), by data source...............................................80
Table 12. Part 1: Baseline demographics, lifestyle variables and health
resources utilisation for vaccinated and unvaccinated cohorts with
absolute standardised difference (ASD) by data source ........................82
Table 13. Part 1: Baseline comorbidities at time zero (past 10 years) by
exposure group (matched cohort design) by data source ......................91
Table 14. Part 1: Baseline comedications at time zero by exposure group
(matched cohort design) by data source..............................................100
Table 15. Part 1: Prior adverse events of special interest (AESIs) within one
year of time zero (outcome-specific exclusion criteria) by exposure
group by data source...........................................................................105
Table 16. Summary of number of events, person-years (PY), and incidence
rates for each AESI in the vaccinated and unvaccinated cohorts
and the adjusted hazard ratio (HR) and rate difference (RD) by
data source .........................................................................................118
Table 17. Risk estimates (95% CI) per 10,000 person-years (PY) for acute
cardiovascular injury among individuals who received at least one
dose of Pfizer-BioNTech COVID-19 vaccine and matched
unvaccinated individuals by data source (risk window: 365 days
after dose 1)........................................................................................128

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Table 18. Matched and adjusted hazard ratios (HRs) and matched and
adjusted risk differences (RDs) per 10,000 person-years and their
95% CIs for acute cardiovascular injury among individuals who
received at least one dose of Pfizer-BioNTech COVID-19 vaccine
and matched unvaccinated individuals by data source (risk
window: 365 days after dose 1)...........................................................134
Table 19. Risk estimates (95% CI) per 10,000 person-years (PY) for
arrhythmia among individuals who received at least one dose of
Pfizer-BioNTech COVID-19 vaccine and matched unvaccinated
individuals by data source (risk window: 365 days after dose 1)..........136
Table 20. Matched and adjusted hazard ratios (HRs) and matched and
adjusted risk differences (RDs) per 10,000 person-years and their
95% CIs for arrhythmia among individuals who received at least
one dose of Pfizer-BioNTech COVID-19 vaccine and matched
unvaccinated individuals by data source (risk window: 365 days
after dose 1)........................................................................................142
Table 21. Risk estimates (95% CI) per 10,000 person-years (PY) for heart
failure among individuals who received at least one dose of Pfizer-
BioNTech COVID-19 vaccine and matched unvaccinated
individuals by data source (risk window: 365 days after dose 1)..........144
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Table 22. Matched and adjusted hazard ratios (HRs) and matched and
adjusted risk differences (RDs) per 10,000 person-years and their
95% CIs for heart failure among individuals who received at least
one dose of Pfizer-BioNTech COVID-19 vaccine and matched
unvaccinated individuals by data source (risk window: 365 days
after dose 1)........................................................................................149
Table 23. Risk estimates (95% CI) per 10,000 person-years (PY) for stress
cardiomyopathy among individuals who received at least one dose
of Pfizer-BioNTech COVID-19 vaccine and matched unvaccinated
individuals by data source (risk window: 365 days after dose 1)..........151
Table 24. Matched and adjusted hazard ratios (HRs) and matched and
adjusted risk differences (RDs) per 10,000 person-years and their
95% CIs for stress cardiomyopathy among individuals who
received at least one dose of Pfizer-BioNTech COVID-19 vaccine
and matched unvaccinated individuals by data source (risk
window: 365 days after dose 1)...........................................................156
Table 25. Risk estimates (95% CI) per 10,000 person-years (PY) for
coronary artery disease among individuals who received at least
one dose of Pfizer-BioNTech COVID-19 vaccine and matched
unvaccinated individuals by data source (risk window: 365 days
after dose 1)........................................................................................158

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Table 26. Matched and adjusted hazard ratios (HRs) and matched and
adjusted risk differences (RDs) per 10,000 person-years and their
95% CIs for coronary artery disease among individuals who
received at least one dose of Pfizer-BioNTech COVID-19 vaccine
and matched unvaccinated individuals by data source (risk
window: 365 days after dose 1)...........................................................164
Table 27. Risk estimates (95% CI) per 10,000 person-years (PY) for
myocarditis within 21 days after start of follow-up among
individuals who received at least one dose of Pfizer-BioNTech
COVID-19 vaccine and matched unvaccinated individuals by data
source .................................................................................................166
Table 28. Matched and adjusted hazard ratios (HRs) and matched and
adjusted risk differences (RDs) per 10,000 person-years and their
95% CIs for myocarditis within 21 days after start of follow-up
among individuals who received at least one dose of Pfizer-
BioNTech COVID-19 vaccine and matched unvaccinated
individuals by data source ...................................................................172
Table 29. Risk estimates (95% CI) per 10,000 person-years (PY) for cerebral
venous sinus thrombosis within 28 days after start of follow-up
among individuals who received at least one dose of Pfizer-
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BioNTech COVID-19 vaccine and matched unvaccinated

individuals by data source ...................................................................174
Table 30. Matched and adjusted hazard ratios (HRs) and matched and
adjusted risk differences (RDs) per 10,000 person-years and their
95% CIs for cerebral venous sinus thrombosis within 28 days after
start of follow-up among individuals who received at least one dose
of Pfizer-BioNTech COVID-19 vaccine and matched unvaccinated
individuals by data source ...................................................................180
Table 31. Risk estimates (95% CI) per 10,000 person-years (PY) for
10.2.3.7. glomerulonephritis within 365 days after start of follow-up
among individuals who received at least one dose of Pfizer-
BioNTech COVID-19 vaccine and matched unvaccinated
individuals by data source ...................................................................182
Table 32. Matched and adjusted hazard ratios (HRs) and matched and
adjusted risk differences (RDs) per 10,000 person-years and their
95% CIs for glomerulonephritis within 365 days after start of follow-
up among individuals who received at least one dose of Pfizer-
BioNTech COVID-19 vaccine and matched unvaccinated
individuals by data source ...................................................................185
Table 33. Risk estimates (95% CI) per 10,000 person-years (PY) for Bell’s
palsy within 42 days after start of follow-up among individuals who
received at least one dose of Pfizer-BioNTech COVID-19 vaccine
and matched unvaccinated individuals by data source ........................187

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Table 34. Matched and adjusted hazard ratios (HRs) and matched and
adjusted risk differences (RDs) per 10,000 person-years and their
95% CIs for Bell’s Palsy within 42 days after start of follow-up
among individuals who received at least one dose of Pfizer-
BioNTech COVID-19 vaccine and matched unvaccinated
individuals by data source ...................................................................192
Table 35. Risk estimates (95% CI) per 10,000 person-years (PY) for
secondary amenorrhoea within 183 days after start of follow-up
among individuals who received at least one dose of Pfizer-
BioNTech COVID-19 vaccine and matched unvaccinated
individuals by data source ...................................................................194
Table 36. Matched hazard ratios (HRs) and matched risk differences (RDs)
per 10,000 person-years and their 95% CIs for secondary
amenorrhoea within 183 days after start of follow-up among
individuals who received at least one dose of Pfizer-BioNTech
COVID-19 vaccine and matched unvaccinated individuals by data
source .................................................................................................200
Table 37. Risk estimates (95% CI) per 10,000 person-years (PY) for
hypermenorrhea within 183 days after start of follow-up among
individuals who received at least one dose of Pfizer-BioNTech
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COVID-19 vaccine and matched unvaccinated individuals by data

source .................................................................................................202
Table 38. Matched and adjusted hazard ratios (HRs) and matched and
adjusted risk differences (RDs) per 10,000 person-years and their
95% CIs for hypermenorrhoea within 183 days after start of follow-
up among individuals who received at least one dose of Pfizer-
BioNTech COVID-19 vaccine and matched unvaccinated
individuals by data source ...................................................................206
Table 39. Comparison of adjusted hazard ratios in interim reports 4 and 5 for
selected AESIs....................................................................................217

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LIST OF IN-TEXT FIGURES

Figure 1. Self-controlled risk interval design .........................................................34
Figure 2. Map showing location and number of active individuals in each
data source ...........................................................................................35
Figure 3. Study period and follow-up ...................................................................36
Figure 4. Overview of proposed analytical approach to assess baseline
exchangeability in the retrospective matched cohort study....................52
Figure 5. Cumulative incidence of COVID-19 disease in the first 12 days
after start of follow-up among individuals who received at least one
dose of Pfizer-BioNTech COVID-19 vaccine and matched
unvaccinated individuals by data source .............................................112
Figure 6. Cumulative incidence of acute cardiovascular injury among
individuals who received at least one dose of Pfizer-BioNTech
COVID-19 vaccine and matched unvaccinated individuals by data
source (risk window: 365 days after dose 1)........................................129
Figure 7. Forest plot showing incidence rates and 95% confidence intervals
for acute cardiovascular injury among individuals who received at
least one dose of Pfizer-BioNTech COVID-19 vaccine and
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matched unvaccinated individuals by data source and by age

groups (risk window: 365 days after dose 1) .......................................131
Figure 8. Cumulative incidence of arrhythmia among individuals who
received at least one dose of Pfizer-BioNTech COVID-19 vaccine
and matched unvaccinated individuals by data source (risk
window: 365 days after dose 1)...........................................................137
Figure 9. Forest plot showing incidence rates and 95% confidence intervals
for arrhythmia among individuals who received at least one dose of
Pfizer-BioNTech COVID-19 vaccine and matched unvaccinated
individuals by data source and by age groups (risk window: 365
days after dose 1) ...............................................................................139
Figure 10. Cumulative incidence of heart failure among individuals who
received at least one dose of Pfizer-BioNTech COVID-19 vaccine
and matched unvaccinated individuals by data source (risk
window: 365 days after dose 1)...........................................................145
Figure 11. Forest plot showing incidence rates and 95% confidence intervals
for heart failure among individuals who received at least one dose
of Pfizer-BioNTech COVID-19 vaccine and matched unvaccinated
individuals by data source and by age groups (risk window: 365
days after dose 1) ...............................................................................147
Figure 12. Cumulative incidence of stress cardiomyopathy among individuals
who received at least one dose of Pfizer-BioNTech COVID-19
vaccine and matched unvaccinated individuals by data source (risk
window: 365 days after dose 1)...........................................................152

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Figure 13. Forest plot showing incidence rates and 95% confidence intervals
for stress cardiomyopathy among individuals who received at least
one dose of Pfizer-BioNTech COVID-19 vaccine and matched
unvaccinated individuals by data source and by age groups (risk
window: 365 days after dose 1)...........................................................154
Figure 14. Cumulative incidence of coronary artery disease among individuals
who received at least one dose of Pfizer-BioNTech COVID-19
vaccine and matched unvaccinated individuals by data source (risk
window: 365 days after dose 1)...........................................................159
Figure 15. Forest plot showing incidence rates and 95% confidence intervals
for coronary artery disease among individuals who received at
least one dose of Pfizer-BioNTech COVID-19 vaccine and
matched unvaccinated individuals by data source and by age
groups (risk window: 365 days after dose 1) .......................................161
Figure 16. Cumulative incidence of myocarditis within 21 days after start of
follow-up among individuals who received at least one dose of
Pfizer-BioNTech COVID-19 vaccine and matched unvaccinated
individuals by data source ...................................................................167
Figure 17. Forest plot showing incidence rates and 95% confidence intervals
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for myocarditis within 21 days after start of follow-up among

individuals who received at least one dose of Pfizer-BioNTech
COVID-19 vaccine and matched unvaccinated individuals by data
source and by age groups ...................................................................169
Figure 18. Cumulative incidence of cerebral venous sinus thrombosis within
28 days after start of follow-up among individuals who received at
least one dose of Pfizer-BioNTech COVID-19 vaccine and
matched unvaccinated individuals by data source...............................175
Figure 19. Forest plot showing incidence rates and 95% confidence intervals
for cerebral venous sinus thrombosis within 28 days after start of
follow-up among individuals who received at least one dose of
Pfizer-BioNTech COVID-19 vaccine and matched unvaccinated
individuals by data source and by age groups .....................................177
Figure 20. Cumulative incidence of glomerulonephritis within 365 days after
start of follow-up among individuals who received at least one dose
of Pfizer-BioNTech COVID-19 vaccine and matched unvaccinated
individuals by data source ...................................................................183
Figure 21. Forest plot showing incidence rates and 95% confidence intervals
for glomerulonephritis within 365 days after start of follow-up
among individuals who received at least one dose of Pfizer-
BioNTech COVID-19 vaccine and matched unvaccinated
individuals by data source and by age groups .....................................184
Figure 22. Cumulative incidence of Bell’s palsy within 42 days after start of
follow-up among individuals who received at least one dose of
Pfizer-BioNTech COVID-19 vaccine and matched unvaccinated
individuals by data source ...................................................................188

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Figure 23. Forest plot showing incidence rates and 95% confidence intervals
for Bell’s palsy within 42 days after start of follow-up among
individuals who received at least one dose of Pfizer-BioNTech
COVID-19 vaccine and matched unvaccinated individuals by data
source and by age groups ...................................................................190
Figure 24. Cumulative incidence of secondary amenorrhoea within 183 days
after start of follow-up among individuals who received at least one
dose of Pfizer-BioNTech COVID-19 vaccine and matched
unvaccinated individuals by data source .............................................195
Figure 25. Forest plot showing incidence rates and 95% confidence intervals
for secondary amenorrhoea within 183 days after start of follow-up
among individuals who received at least one dose of Pfizer-
BioNTech COVID-19 vaccine and matched unvaccinated
individuals by data source and by age groups.....................................197
Figure 26. Cumulative incidence of hypermenorrhoea within 183 days after
start of follow-up among individuals who received at least one dose
of Pfizer-BioNTech COVID-19 vaccine and matched unvaccinated
individuals by data source ...................................................................203
Figure 27. Forest plot showing incidence rates and 95% confidence intervals
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for hypermenorrhoea within 183 days after start of follow-up among

individuals who received at least one dose of Pfizer-BioNTech
COVID-19 vaccine and matched unvaccinated individuals by data
source and by age groups ...................................................................204

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Annex 1. List of stand-alone documents

Appendix 1. SIGNATURES

Appendix 2. PROTOCOL

Appendix 3. INVESTIGATORS AND CORRESPONDING INDEPENDENT ETHICS

COMMITTEES (IECs) OR INSTITUTIONAL REVIEW BOARDS (IRBs)

Refer to Section 3 Investigators and Section 5 Milestones

Appendix 3.1. List of Investigators by Country

Refer to Section 3 Investigators

Appendix 3.2. List of Independent Ethics Committee (IEC) or Institutional Review Board
(IRB) and Corresponding Protocol Approval Dates

Refer to Section 5 Milestones

Appendix 4. STATISTICAL ANALYSIS PLAN

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Appendix 5. SAMPLE CASE REPORT FORM (CRF) / DATA COLLECTION TOOL (DCT)

Not applicable.

Appendix 6. SAMPLE STANDARD SUBJECT INFORMATION SHEET AND INFORMED

CONSENT DOCUMENT (ICD)

Not applicable.

Appendix 7. LIST OF SUBJECT DATA LISTINGS

Not applicable.

Appendix 8. ADDITIONAL DOCUMENTS

Not applicable.

Annex 2. Additional information

Annex 2: Detailed results for all AESIs (Standalone)

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1. ABSTRACT (STAND-ALONE DOCUMENT)

2. LIST OF ABBREVIATIONS
Abbreviation Definition
ACCESS project vACcine Covid-19 monitoring readinESS
AESI Adverse event of special interest
ARS Toscana Agenzia Regionale di Sanita’ della Toscana (a
research institute of the Tuscany region of Italy)
ATC Anatomical Therapeutic Chemical (classification
system)
BDU User database at EpiChron
BIFAP Base de Datos para la Investigación
Farmacoepidemiológica en Atención Primària (a data
resource for pharmacoepidemiology in Spain)
CDM Common data model
CHESS COVID-19 Hospitalisation in England Surveillance
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System (UK)
CI Confidence interval
COVID-19 Coronavirus disease 2019
CPRD Aurum Clinical Practice Research Datalink Aurum
DAP Database access provider
DRE Digital Research Environment (NL)
DSRU Drug Safety Research Unit (UK)
DTP Diphtheria, tetanus, and pertussis vaccine
EMA European Medicines Agency
ENCePP European Network of Centres for
Pharmacoepidemiology and Pharmacovigilance
EpiChron EpiChron Research Group on Chronic Diseases at
the Aragon Health Sciences Institute (Spain)
ES Spain
ETL Extraction, transformation, and loading (a process for
putting data into a common data model)
EU PAS Register European Union electronic register of post-
authorisation studies
EU European Union
FDA Food and Drug Administration

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Abbreviation Definition
GP General practitioner
GPP Good Pharmacoepidemiology Practices
GVP Good Pharmacovigilance Practices
HSD Health Search Database (Italy)
ICD International Classification of Diseases
ICD-9-CM International Classification of Diseases, 9th Revision,
Clinical Modification
ICD-10 International Classification of Diseases, 10th Revision
ICNARC Intensive Care National Audit and Research Centre
ICPC International Classification of Primary Care
IR Incidence rate
ISPE International Society for Pharmacoepidemiology
IT Italy
KM Kaplan-Meier
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MAH Marketing authorisation holder

MBRN Medical Birth Registry of Norway
mRNA Messenger RNA
MSIS Norwegian Surveillance System for Communicable
Diseases
NHS National Health Service (UK)
NIPH Norwegian Institute of Health
NL Netherlands
NO Norway
NPR National Patient Register (Norway)
ONS Office for National Statistics
PASS Post-authorisation safety study
PHARMO PHARMO Institute for Drug Outcomes Research or
PHARMO Data Network (Netherlands)
PHE Public Health England
PMR postmarketing requirement
PS Propensity score
QC Quality control

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Abbreviation Definition
RTI-HS RTI Health Solutions
SAP Statistical analysis plan
SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2
(cause of COVID-19 disease)
SCRI Self-controlled risk interval (study design)
SIDIAP Sistema d’Informació per el Desenvolupament de la
Investigació en Atenció Primària [Information System
for the Improvement of Research in Primary Care]
(Spain)
SQL Structured Query Language
SSB Statistics Norway
SGSS Second Generation Surveillance System
SYSVAK National, electronic immunisation register
TMS Task management system
UK United Kingdom
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UMCU University Medical Center Utrecht

USA United States of America
VAC4EU Vaccine monitoring Collaboration for Europe
VV Varicella zoster virus
WHO World Health Organization

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3. INVESTIGATORS
Principal Investigator(s) of the Protocol

Name, degree(s) Job Title Affiliation

4.1(b) 4.1(b) Pfizer, Inc.

Daniel Weibel, PhD Assistant Professor University Medical Center

Utrecht

Alejandro Arana, MD, MPH Senior Director, Epidemiology RTI Health Solutions

4.1(b) 4.1(b) University Medical Center

Utrecht

4.1(b) 4.1(b) RTI Health Solutions

4.1(b) 4.1(b) RTI Health Solutions

4.1(b) 4.1(b) RTI Health Solutions

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4.1(b) 4.1(b) RTI Health Solutions

4.1(b) 4.1(b) RTI Health Solutions

Lead Country Investigator(s) of the Protocol

Name, degree(s) Title Affiliation

Rosa Gini, PhD Head Pharmacoepidemiology Agenzia regionale di sanità

Unit della Toscana

Francesco Lapi PhD Director Health Search Research

4.1(b) 4.1(b) PHARMO Institute for Drug

Outcomes Research
Jetty Overbeek, PhD Head of PHARMO Research

4.1(b) 4.1(b)
4.1(b) 4.1(b)
4.1(b) 4.1(b)
Carlo Giaquinto, MD President Fondazione Penta ETS

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Name, degree(s) Title Affiliation

Saad Shakir, MB ChB, Director Drug Safety Research Unit

LRCP&S, FRCP, FFPM, (DSRU)
FISPE, MRCGP

4.1(b) 4.1(b)

4.1(b) 4.1(b)
4.1(b) 4.1(b)

4.1(b) 4.1(b)
4.1(b) 4.1(b)
Antonio Gimeno-Miguel, MPH, Researcher EpiChron Research Group.
PhD Instituto Aragonés de Ciencias
de la Salud
4.1(b) 4.1(b)
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Felipe Villalobos, MD, PhD Researcher IDIAP-Jordi Gol

4.1(b) 4.1(b)
4.1(b) 4.1(b)
4.1(b) 4.1(b)
Angela Lupattelli, PhD Professor University of Oslo

4.1(b) 4.1(b)
4.1(b) 4.1(b)
4.1(b) 4.1(b)

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4. OTHER RESPONSIBLE PARTIES

Responsible Party Name and Affiliation Role in the study

Vaccine Monitoring Collaboration for Coordination of VAC4EU study framework
Europe (VAC4EU) and network across VAC4EU studies;
contracting SAB;
Support for:
 contract templates; negotiations, and
contract amendments;
 archiving of study documents; support
quality system oversight and
implementation
Support and implementation of tools (e.g.,
DRE, TMS, ETL specifications; CDM,
Catalogue);
Scientific review

4.1(b) , National Taiwan Scientific Advisory Board member

University Children’s Hospital, Taipei,
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Taiwan

4.1(b) London School of Scientific Advisory Board member

Hygiene and Tropical Medicine, United
Kingdom

4.1(b) , BioNTech Manufacturing MAH contact person

GmbH

4.1(b) , Teamit Institute Programme Manager

S.L

4.1(b) , Teamit Institute S.L Study Manager

4.1(b) , MediCom Consult Medical Writer

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5. MILESTONES

Milestone Planned date Actual date Comments

Date of independent institutional review 05 October
board (IRB) approval of protocol 2021
Registration in the EU PAS register 25 June 2021 25 June 2021
Start of data collection 30 September 30 September
2021 2021
End of study data collection 31 March 2024
Study progress report 1 30 September 27 September
2021 2021
Interim report I 31 March 2022 23 March 2022
Interim report 2 30 September 15 September
2022 2022
Interim report 3 31 March 2023 20 March 2023
Interim report 4 30 September 15 September
2023 2023
Interim report 5 31 March 2024 12 March 2024
Final study report2 20 December
2024
1 Data were not provided in the progress report
2 Pending approval from EMA
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6. RATIONALE AND BACKGROUND

The novel coronavirus, SARS-CoV-2, the cause of COVID-19, has resulted in a global
pandemic. The Pfizer-BioNTech COVID-19 vaccine, tozinameran (Comirnaty®) a novel
mRNA-based vaccine, has been authorised for use in several countries, including those in
the European Union (EU), for the prevention of COVID-19. Because of the relatively short
prelicensure period and limited number of participants in clinical studies, efficient and timely
monitoring of the safety of the vaccine will be needed in European countries.

The safety of the Pfizer-BioNTech COVID-19 vaccine has been investigated in clinical
studies conducted in the United States, Europe, Turkey, South Africa, and South America
and included over 43,000 patients aged 16 years and older. The overall safety profile of the
vaccine was found to be favourable in the trial setting. Reported adverse reactions from
unblinded data (i.e., from the overall trial population) on participants aged 16 years and
older who received two doses of Pfizer-BioNTech COVID-19 vaccine 21 days apart after 2
months of follow-up included pain at the injection site (84.1%), fatigue (62.9%), headache
(55.1%), muscle pain (38.3%), chills (31.9%), joint pain (23.6%), fever (14.2%), injection site
swelling (10.5%), injection site redness (9.5%), nausea (1.1%), malaise (0.5%), and
lymphadenopathy (0.3%). The safety database revealed an imbalance of cases of Bell’s
palsy (four in the vaccine group and none in the placebo group).[1] Severe allergic reactions
have been reported following receipt of the Pfizer-BioNTech COVID-19 vaccine in mass
vaccination campaigns outside clinical trials in various countries. Additional safety events
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may become evident with more widespread use in the general population.

Public health authorities identified priority populations for vaccination based on health care
or essential worker status, comorbidities, and age and therefore the vaccine was initially
provided to vulnerable groups at higher risk for COVID-19 infection and COVID-19
complications.[2] As recommendations for vaccination were updated over time, the
characteristics of vaccine recipients varied over time.

This non-interventional study was designated as a Post-Authorization Safety Study (PASS)

and is a commitment to EMA and a postmarketing requirement to the Food and Drug
Administration.

7. RESEARCH QUESTION AND OBJECTIVES

Research question: Is there an increased risk of select adverse events of special interest
(AESI) after being vaccinated with the Pfizer-BioNTech COVID-19 vaccine?

7.1. Objectives
7.1.1. Primary study objective
 To determine whether an increased risk of prespecified AESI exists following the
administration of at least one dose of the Pfizer-BioNTech COVID-19 vaccine using
two approaches: (a) a matched cohort design comparing risk in vaccinated and
unvaccinated individuals and (b) a self-controlled risk interval (SCRI) design.

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7.1.2. Secondary study objectives

 To estimate the incidence rates of prespecified AESI among individuals who receive
at least one dose of the Pfizer-BioNTech COVID-19 vaccine using a cohort study
design.

 To describe the incidence rates and determine whether an increased risk of

prespecified AESI exists following the administration of at least one dose of the
Pfizer-BioNTech COVID-19 vaccine compared with no COVID-19 vaccination within
sub-cohorts of interest (i.e., individuals who are immunocompromised, individuals
who are frail and have comorbidities, individuals diagnosed with previous COVID-19
infection, and age-specific groups) in Europe using a cohort study design and/or a
SCRI design.

 To determine whether an increased risk of prespecified AESI exists following the

administration of at least one dose of the Pfizer-BioNTech COVID-19 vaccine
compared with no COVID-19 vaccination, in pregnant people and their neonates
using a cohort study design.

 To characterise utilisation patterns of Pfizer-BioNTech COVID-19 vaccine among

individuals within Europe, including estimating the proportion of individuals receiving
the vaccine; two-dose vaccine completion rate and distribution of time gaps between
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the first and second doses; and demographics and clinical characteristics of
recipients, overall and among sub-cohorts of interest, such as individuals who are
immunocompromised, elderly, or have specific comorbidities.

 To assess the effectiveness of the Direct Healthcare Professional Communication

(DHPC) about the risk of myocarditis and pericarditis associated with COVID-19
mRNA vaccine use, and describe the rate of cardiac imaging use for vaccinated and
unvaccinated individuals in this study population each calendar month during the
study period, before and after distribution of the DHPC.

8. AMENDMENTS AND UPDATES

A summary of the protocol amendments is provided in Table 1 below.

Table 1. Amendments to the protocol

Amendment Date Section of Summary of Reason
number protocol amendment/update
changed
4 18 4. Abstract Extended final study report Moved 3 months forward to
October and 6. timeline to 20 December avoid overlap with the
2023 Milestones 2024 production of study 1038
(Natural history of myocarditis)
final report and 1052 (safety of
the bivalent PFE vaccine) first
interim report. These 3 studies
share resources and avoiding
overlap will impact positively in
the quality of the report.

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Table 1. Amendments to the protocol

Amendment Date Section of Summary of Reason
number protocol amendment/update
changed
4 18 9.3.2.1 Safety New AESIs added to Table Request from European
October Outcomes 2: myositis, Medicines Agency (EMA) and
2023 hypermenorrhoea, to align AESIs with Pfizer-
glomerulonephritis and BioNTech COVID-19 bivalent
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thrombosis
4 18 9.3.2.1 Safety VAED changed to severe Updated to provide clarity
October Outcomes COVID-19 defined as either
2023 COVID-19 hospitalisation or
death
4 18 9.3.2.1 Safety Risk windows modified to Updated for accuracy and
October Outcomes remove 1 clarity
2023 Table 2
4 18 9.3.3 The covariates, race and/or These covariates are not
October Covariate ethnicity, residency in a long- available in any of the study
2023 Definitions term care facility, healthcare data sources
work or essential worker
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status, skilled nursing facility,

nursing home, or extended
care facility stay, wheelchair
use, home hospital bed,
home oxygen, rehabilitation
care were removed
4 18 9.3.3 The covariate, CDC at-risk This covariate is employed as a
October Covariate groups was added matching variable
2023 Definitions
4 18 9.3.3 Paragraph on at-risk medical This covariate was added to the
October Covariate conditions for developing list of covariates and is
2023 Definitions severe COVID-19 was added employed as a matching
to define the covariate, CDC variable
at-risk groups
4 18 9.5 Study Size VAED in study size Updated for consistency with
October calculations changed to AESI definitions in Table 2
2023 severe COVID-19
4 18 9.7.1 Cohort Sections; Comparison with Updated to provide clarity
October design and historical comparators, and
2023 9.7.2 Time trends in AESI in pre-
Comparison pandemic, post-pandemic,
with historical and post-vaccination periods
comparators have been further developed
and clarified
Section on age-standardised
outcome measures removed
from the Cohort design
section
4 18 9.7.4 Stratification by age of Request from European
October reporting of cardiac MRI and Medicines Agency (EMA)
2023

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Table 1. Amendments to the protocol

Amendment Date Section of Summary of Reason
number protocol amendment/update
changed
echocardiogram by age
added
Discussion of the
interpretation of results and
conclusions on effectiveness
of DHCP letter added
3 11 April General Administrative, formatting, Updated to provide clarity and
2023 and typographical corrections to be consistent with remainder
have been made of protocol
3 11 April 3 Responsible Updated degree(s) and Added missing degree
2023 parties added Other Responsible information and missing Other
Parties Contributing to the Responsible Parties
Protocol
3 11 April 7 Rationale Add new secondary Request from EMA
2023 and objective: To describe the
background rate of cardiac imaging use
8.2 Objectives among vaccinated and
unvaccinated individuals
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9.2 Setting each calendar month of the

9.7 Data study period, before and after
analysis distribution of the DHPC
letter
3 11 April 9.4.1 Update sources of data for Some COVID-19 specific
2023 Exposure CPRD databases linked to CPRD
were identified as not
definitionerr
necessary to obtain study
9.5 CPRD variables based on recent
experience in the study
3 11 April 9.3.2.1 Safety New AESI added: secondary Request from European
2023 outcomes amenorrhoea Medicines Agency (EMA)
3 11 April 9.3.2.1 Safety COVID-19 disease removed COVID-19 disease is not an
2023 outcomes as a safety outcome AESI and COVID-19 testing is
not systematically performed in
the healthcare systems of the
study data sources
3 11 April 9.3.2.1 Safety Table 1, AESI These three events are
2023 outcomes ‘Thrombocytopenia with equivalent and have the same
venous thromboembolism’ definition, but TTS is the
was removed and the AESI preferred name
‘Heparin-induced
thrombocytopenia (HIT)-like
event’ was renamed
‘Thrombosis
thrombocytopenia syndrome
(TTS)’
3 11 April 9.3.2.2 Add description of the This was previously combined
2023 Outcome validation process for HSD with the description for
identification Pedianet

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Table 1. Amendments to the protocol

Amendment Date Section of Summary of Reason
number protocol amendment/update
changed
and validation,
by data source
3 11 April 9.3.2.3 Cardiac imaging defined Needed for the added
2023 Cardiac secondary objective.
imaging
3 11 April 9.4.3 Covariate definition will be These categories were chosen
2023 Covariate updated to the following age to align with age groups as
definition groups: 0-1, 2-4, 5-11, 12-15, authorized and prioritized
16-17,18-29, 30-39, 40-49, during vaccine rollout
50-59, 60-64, 65-69, 70-79, indications of the vaccine in
and 80+ years. children younger than 16 years
old
3 11 April 9.4 Data Re-ordered data sources to Consistency
2023 sources be consistent with order in
other studies
3 11 April 9.4.4 Update sources of data for Outpatient Pharmacy Database
2023 PHARMO PHARMO will not be used
2 31 6 Milestones Added study end date of 31 To clarify that the last date of
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March December 2023 data available will be 31

2022 December 2023, which differs
from the end of data collection
date that takes into account lag
times
2 31 9.1.1.1 Added that one individual will To clarify how multiple matches
March Matching be randomly selected if will be handled
2022 process multiple individuals match a
vaccinated individual
2 31 9.2.2.1 Cohort Removed the exclusion Request from EMA
March and SCRI criterion, ‘Have contact with
2022 designs the healthcare system in the
7 days before time zero’
2 31 9.2.3 Added a sensitivity analysis Request from EMA to remove
March Sensitivity excluding individuals who from main analysis and add as
2022 analysis have had contact with the a sensitivity analysis
healthcare system in the 7
days before time zero
2 31 9.2.5 Study Added 2018-2019 as a To assess time trends in health
March period historical period seeking behaviour
2022
2 31 9.3.2.1 Safety Added an additional risk Request from EMA
March outcomes window of 1-21 days for
2022 myocarditis and pericarditis
2 31 9.3.2.1 Safety Added thrombocytopenia This outcome is an important
March outcomes with venous AESI to include in the study
2022 thromboembolism

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Table 1. Amendments to the protocol

Amendment Date Section of Summary of Reason
number protocol amendment/update
changed
2 31 9.3.2.1 Safety Modified risk intervals and To align with the latest version
March outcomes preferred study design for of the SAP
2022 various outcomes
2 31 9.3.3 Combined the age category To align with the latest version
March Covariate of 18-19 years with the adult of the SAP
2022 definitions age category, yielding a
category 18-29 years
2 31 9.3.3 Removed ‘batch of vaccine This variable will not be
March Covariate received’ from the list of informative for the planned
2022 definitions covariates analyses because only the
effect of the vaccine as a
whole, and not by batches, is
being investigated
2 31 9.7.1.5 Age- Added quarterly calculation To include a calculation of
March standardised of crude and age- background rates of AESIs in
2022 outcome standardised incidence rates each data source
measures of AESIs in a historical period
of 2018-2019 and during the
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post-vaccination follow-up
period; rates in these periods
will be compared
2 31 10.4 Ethical Removed Good Guidelines no longer available
March conduct of the Epidemiological Practice
2022 study guidelines issued by the
International Epidemiological
Association
2 31 11 Updated name of training To reflect current training name
March Management
2022 and reporting
of adverse
events /
adverse
reactions
2 31 General Minor administrative, Updated to provide clarity and
March formatting, and typographical be consistent with remainder of
2022 changes have been made protocol
1 16 3 Responsible Updated Pfizer principal New principal investigator for
Decemb Parties investigator study
er 2021

1 16 6 Milestones Updated end of data Incorrect date in initial protocol

Decemb collection date
er 2021
1 16 9.1.1.1 Updated figure The “V” to symbolise time of
Decemb Matching Figure 1 vaccination was moved to be
er 2021 process consistent with the timeline in
the figure. Also the label
“patient” was changed to

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Table 1. Amendments to the protocol

Amendment Date Section of Summary of Reason
number protocol amendment/update
changed
“person” in the figure to align
with the description that
appears below the figure
1 16 9.3.1.1 Cohort Inclusion of addition Request from Center for
Decemb design sensitivity analysis to assess Biologics Evaluation and
er 2021 AESIs after 2 nd and 3 rd doses Research (CBER) to include
dose stratification
1 16 9.3.2 Outcome Inclusion of Request from EMA/CBER to
Decemb definitions myocarditis/pericarditis as include myocarditis and
er 2021 outcome pericarditis as an outcome
separate from the
cardiovascular composite
endpoint
1 16 9.3.3 Additional stratification of age In anticipation of future
Decemb Covariate group 0-19 years indications of the vaccine in
er 2021 definitions children younger than 16 years
old
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1 16 9.5 Study size Update of the sample size The matching ratio was
Decemb calculation to the matching changed from 1:4 to 1:1, and
er 2021 ratio 1:1 the sample size section was
inadvertently not updated
1 16 General Minor administrative, Updated to provide clarity and
Decemb formatting, and typographical be consistent with remainder of
er 2021 changes have been made protocol
1 16 9.1.1.1 The following matching Such a criterion was used in an
Decemb Matching criterion was added: observational study with the
er 2021 process Socioeconomic same objective and design as
status/education level (as the current one
available, exact matching)
1 16 9.1.1.1 Matching without To address the anticipated
Decemb Matching replacement has been limited number of unvaccinated
er 2021 process changed to matching with individuals in certain intervals of
replacement. the study period
1 16 9.2.1.1 Cohort Changed inclusion criterion Inclusion criterion was
Decemb design from “No history of incorrect.
er 2021 vaccination with a non–
Pfizer-BioNTech COVID-19
vaccine before time zero” to
“No history of vaccination
with a COVID-19 vaccine
before time zero”
1 16 9.2.2.1 Cohort Added the following two New evidence has been
Decemb and SCRI inclusion criteria: published recommending these
er 2021 designs Having contact with the two inclusion criteria
healthcare system within 7
days before time zero (as an
indicator of a health event not

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Table 1. Amendments to the protocol

Amendment Date Section of Summary of Reason
number protocol amendment/update
changed
related to subsequent
vaccination that could reduce
the probability of receiving
the vaccine)
Having a diagnosis of the
specific AESI under study
within 1 year before time zero
(to distinguish the recording
of previous events from true
new events) and at any time
before time zero for diabetes
type 1.
1 16 9.9 Limitations Added an additional To add the fact that the
Decemb of the paragraph on the limitations resulting matching process
er 2021 research of the matching process produces estimates that are the
methods average causal effect in
vaccinated. If further
adjustment via inverse
probability weighting is applied,
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because the weights are

estimated and applied to the
matched population, the
estimated effect will still be the
causal effect in a population
that has the distribution of
matching variables of the
vaccinated.

Following final assessment of the fourth interim report by PRAC, anosmia, ageusia and
severe COVID-19 have been removed from the list of AESIs reported in this fifth interim
report because they are no longer considered as an important potential risk after exposure
to the Pfizer-BioNTech COVID-19 vaccine. These changes will be included in the next
protocol and SAP amendments.

9. RESEARCH METHODS
Full details of the research methods used can be found in the protocol (Standalone
Appendix 2) and are summarised here.

9.1. Study design

This post-authorisation active surveillance study of safety events of interest associated with
the Pfizer-BioNTech COVID-19 vaccine used a retrospective cohort design involving
multiple databases (Table 2).

In addition to the cohort analysis, for a subset of the study endpoints (see Table 2), the
SCRI design was also used to assess risk. The SCRI design was used to sequentially
monitor the occurrence of AESIs while controlling for time-invariant confounders (such as
sex, race, chronic illness, and health state).

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Table 2. List of selected adverse events of special interest

Body system/ Adverse event of special Estimated risk Analytic Approach
classification interest window (days)*
Autoimmune Guillain-Barré syndrome a 42[3] Cohort/SCRI
diseases Acute disseminated 42[3] Cohort/SCRI
encephalomyelitis
Narcolepsy a 42 b Cohort/SCRI
Acute aseptic arthritis 42 c Cohort/SCRI
Diabetes mellitus type I 365 Cohort
(Idiopathic) thrombocytopenia a 42[4] Cohort/SCRI
Thrombosis thrombocytopenia 15[3] Cohort/SCRI
syndrome (TTS) a
Myositis 365 Cohort
Cardiovascular Acute cardiovascular injury 365d Cohort
system Arrhythmia 365 Cohort
Heart failure 365 Cohort
Stress cardiomyopathy 365 Cohort
Coronary artery disease 365 Cohort
Myocarditis a 21 after each dose Cohort/SCRI
Pericarditis a 14 after each dose
Myocarditis and pericarditis a 7 after each dose
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Circulatory Coagulation disorders: 28[3] Cohort/SCRI

system thromboembolism, haemorrhage
Single organ cutaneous 28 e Cohort/SCRI
vasculitis
Cerebral venous sinus 28 Cohort/SCRI
thrombosis
Hepato- Acute liver injury 365 Cohort
gastrointestinal Acute kidney injury 365 Cohort
and renal Acute pancreatitis 365 Cohort
system Rhabdomyolysis 365 Cohort
Glomerulonephritis 365 Cohort
Nerves and Generalised convulsion 42[3] Cohort/SCRI
central nervous Meningoencephalitis 42[3] Cohort/SCRI
system Transverse myelitis a 42[3] Cohort/SCRI
Bell’s palsy 42[3] Cohort/SCRI
Respiratory Acute respiratory distress 365 Cohort
system syndrome
Skin and Erythema multiforme 42 f Cohort
mucous Chilblain-like lesions 42 e Cohort
membrane,
bone and joints
system
Reproductive Secondary amenorrhoea 183 Cohort
system Hypermenorrhoea 183 Cohort
Other system Anaphylaxis a 1[3] Cohort/SCRI
Multisystem inflammatory 42 g Cohort
syndrome
Death (any causes) 365 Cohort
Subacute thyroiditis 365 c Cohort

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Table 2. List of selected adverse events of special interest

Body system/ Adverse event of special Estimated risk Analytic Approach
classification interest window (days)*
Sudden death 365 Cohort
Pregnancy Gestational diabetes Any time pregnancy Subcohort
outcome, Preeclampsia After 20 weeks Subcohort
maternal gestation
Maternal death Any time pregnancy Subcohort
Pregnancy Foetal growth restriction Any time pregnancy Subcohort
outcome, Spontaneous abortions At termination Subcohort
neonates. Stillbirth At birth Subcohort
Define design Preterm birth At preterm birth Subcohort
taking trimester Major congenital anomalies a 1 year after birth Subcohort
into account Microcephaly At birth Subcohort
Neonatal death At birth Subcohort
Termination of pregnancy for At termination Subcohort
foetal anomaly

Notes:
* Time zero corresponds to the day of vaccination (ie, a 42-day risk interval means that individuals
are followed from the day of vaccination to the 41st day).
a This AESI will undergo clinical validation.
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b Published risk and control intervals for demyelinating diseases and cranial disorders were applied
to TM and narcolepsy/cataplexy.
c Published risk and control intervals for autoimmune disorders were applied to similar autoimmune
rheumatic conditions (ie, fibromyalgia and autoimmune thyroiditis).
d Published risk and control intervals for myocarditis and pericarditis were applied to other
cardiovascular conditions (ie, heart failure and cardiogenic shock, stress cardiomyopathy, CAD,
arrhythmia, AMI).
e Similar risk and control intervals were applied to all cardiovascular and haematological disorders
characterised by damage to the blood vessels and/or arteries and clotting (ie, microangiopathy,
DVT, pulmonary embolus, limb ischaemia, haemorrhagic disease, DIC, chilblain-like lesions). The
published risk and control intervals for KD were applied to vasculitides given that KD is a type of
medium and small-vessel vasculitis.
f Published risk and control intervals for non-anaphylactic allergic reactions were applied to
hypersensitivity disorders (i.e., erythema multiforme).
9.1.1. Retrospective cohort design
A retrospective cohort design was used to estimate the incidence of AESI after receipt of the
vaccine. Incidence rates of prespecified AESIs among individuals who receive at least one
dose of the Pfizer-BioNTech COVID 19 vaccine were calculated.

The primary objective was addressed in comparative analyses of these incidences with
those the AESI incidences occurring in an unvaccinated matched comparator group.

In this retrospective cohort design, time zero was defined as the time at which the exposure
status was assigned, when inclusion and exclusion criteria were applied and when study
outcomes started to be counted.[5-8] Time zero in the exposed groups (i.e., vaccine
recipients) was the day the first vaccination dose was received. Time zero in the unexposed
group was the day when they had not received a Pfizer-BioNTech COVID-19 vaccine dose.
This day was chosen by calendar matching to the time zero of the corresponding exposed

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group; at each calendar day when an individual was vaccinated, those individuals who were
not vaccinated that same day (time zero) or before were assigned to the unexposed group,
and they were matched to the vaccinated individuals by age, sex, geographical region,
previous identified COVID-19 infection, previous influenza vaccination at time zero,
pregnancy, immunocompromised, CDC risk criteria and socioeconomic status/education
level. Matched pair were censored if the vaccinated individual received a non-Pfizer-
BioNTech COVID-19 vaccine or if the unvaccinated individual received any COVID-19
vaccine.

Despite matching for potentially relevant confounders, residual confounding can remain.
Symptomatic SARS-CoV-2 infection was used as a negative control outcome, under the
assumption that confounders for symptomatic SARS-CoV-2 were equally relevant for
developing adverse clinical conditions. We, therefore, used the difference in the cumulative
incidence of symptomatic SARS-CoV-2 infection at day 12 in the matched vaccinated and
unvaccinated cohorts as a negative control (Section 9.9.3) to check baseline
exchangeability.

9.1.2. Self-controlled risk interval design

As an additional and complementary approach for a subset of study outcomes that were
acute and meet other necessary assumptions, a SCRI design will be used in the final
analysis. These assumptions will include that the outcome has an acute onset and short
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latency and has relatively well-known risk intervals; the design is less suited to study
outcomes that affect the probability of exposure, but this potential bias was reduced by the
use of a post-vaccination control interval.

Vaccine exposure is known to be challenging to measure, particularly in a pandemic setting

where vaccines may be administered outside the usual health care system. Often, this
results in under-ascertainment of exposure and the inclusion of exposed persons in the
unexposed cohort. This under ascertainment of exposure could result in a bias towards the
null if the vaccine does increase the risk of an event. As the SCRI design includes only
people with known vaccine exposure, it is not subject to this bias.

The SCRI design will compare the risk of each outcome during a prespecified period
following each dose during which there is a hypothetical increased risk of the outcome (‘risk
interval’) with a self-matched control interval, used to assess the baseline risk of the
outcome.

The SCRI design will be performed in the overall vaccinated population, including among
vaccinated individuals not included in the retrospective cohort analysis because a matching
comparator was not found. This design will serve as a sensitivity analysis and will enable the
evaluation of the exclusion of unmatched pairs from the analysis.

The AESIs for which a SCRI analysis is a valid approach and their risk windows are
indicated in Table 2.

A prespecified post-vaccination control interval will be used for each outcome. This
approach will minimise bias because of outcomes affecting the probability of exposure (e.g.,
the outcome is a contraindication for exposure or delayed exposure). For individuals who

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received more than one dose of the vaccine, the risk interval will be extended beyond each
dose.

For outcomes with short risk intervals, for each dose, the control interval occurred temporally
close to the risk interval associated with that dose and before the next dose was given. For
outcomes with risk intervals longer than the gap between doses, the control interval for each
dose occurred after the risk interval of the second dose (Figure 1).

Figure 1. Self-controlled risk interval design

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T = time measured in days.

Note: Example with a risk period of 42 days and a control period of 42 days.

9.2. Setting
The study planned to use data from eight European electronic health care databases in
Italy, the Netherlands, Norway, Spain and the UK.

9.2.1. Data sources

The following European electronic health care databases and two-letter country codes were
planned to be used as data sources (Figure 2):

 ARS Toscana (Agenzia Regionale di Sanita’ della Toscana) [a research institute of the
Tuscany region of Italy] (IT)]1

 Pedianet (IT)

 Health Search Database (HSD) (IT)2

1 Due to an ongoing review of the data protection law and the secondary use of the Tuscany administrative

data, the research team at ARS Toscana have to suspend research temporarily.
2 Due to concerns about the accuracy of the vaccination status of ‘unvaccinated’ individuals no data from

HSD have been included in this report

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 PHARMO (PHARMO Data Network) (NL)

 NHR (The Norwegian health registers) (NO)

 EpiChron (EpiChron Research Group on Chronic Diseases at the Aragon Health

Sciences Institute) (ES)

 SIDIAP (Sistema d’Informació per el Desenvolupament de la Investigació en Atenció

Primària) [Information System for the Improvement of Research in Primary Care] (ES)

 CPRD (Clinical Practice Research Datalink) Aurum (UK)

Figure 2. Map showing location and number of active individuals in each data
source
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9.2.2. Study period and follow-up

The study period for both the cohort and SCRI designs started on the date of administration
of the first dose of the Pfizer-BioNTech COVID-19 vaccine in each country participating in
the study (Table 3) and will end on the date of the latest data availability. Follow-up will last
for two years for AESIs. Differences in follow-up for acute and non-acute events are
described in the statistical analysis plan (SAP) (Standalone Appendix 4). Pregnancy
outcomes will be followed up for an additional year in women who become pregnant during
the two years of follow-up; the results will be reported in the final report (Figure 3).

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Table 3. Date of administration of first dose of Pfizer-BioNTech COVID-19 vaccine

and dates of data collection for this report
Country (data Date of first dose Data source start and end date
source) administrated for use of data
Italy (Pedianet) 31 May 2021 31 May 2021 – 31 Dec 2022
The Netherlands 06 January 2021 GP data: 6 January 2021 – 30
(PHARMO) June 2023
Hospital data: 6 January 2021 –
31 Dec 2022
Norway (NHR) 27 December 2020 1 January 2021 – 31 December
2022
Spain (EpiChron, 27 December 2020 EpiChron: 27 December 2020 –
SIDIAP) 31 Jul 2023
SIDIAP: 01 January 2021 – 30
Jun 2023
UK (CPRD Aurum) 08 December 2020 08 December 2020 – 21 March
2022

Figure 3. Study period and follow-up

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9.3. Subjects
The source population for both cohort and SCRI designs was all individuals registered in the
health care data sources listed in Section 9.2.1.

9.3.1. Inclusion criteria

9.3.1.1. Cohort design
Individuals had to meet all the following inclusion criteria to be eligible for inclusion in the
cohort study:

 Have a minimum of 12 months (or from birth if enrolled in the data source at birth) of
active enrolment and history in one of the participating data sources to ensure
adequate characterisation of medical history; this criterion had to be met after the
start of the study period.

 No history of vaccination with a COVID-19 vaccine before time zero.

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At any time, vaccinated individuals may differ from the remaining population in
characteristics that may determine their risk of AESI. Measured baseline differences were
adjusted for in the analyses (Section 9.9.3).

For the study of pregnancy outcomes, the cohort was restricted to pregnant women. Details
of the differences from the main cohort approach are described in the SAP (Standalone
Appendix 4).

9.3.1.2. Self-controlled risk interval design

For analyses of outcomes assessed with the SCRI design, the criteria below will have to be
met. Note that the study population for each outcome-specific analysis will therefore be
different.

 Have received at least one dose of the Pfizer-BioNTech COVID-19 vaccine.

 Have experienced an event during the risk or control interval.

 Have full accrual of data used to define the event in the risk and control intervals
combined, taking into account the data lag and timing of data extraction.

9.3.1.3. Exclusion criteria for cohort and self-controlled risk interval designs
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 Have had contact with the health care system in the seven days before time zero (as
an indicator of a health event not related to subsequent vaccination that could
reduce the probability of receiving the vaccine). It is planned to assess this exclusion
criterion in a sensitivity analysis.[9]

 Have had a diagnosis of the specific AESI under study within 1 year before time zero
(to distinguish the recording of previous events from true new events) and at any
time before time zero for diabetes type 1.

Individuals having any specified contraindication to vaccination or being part of a group not
recommended for vaccination in the jurisdiction of the study will be analysed separately in
the final report.

9.4. Variables
9.4.1. Exposure definition
Exposure definitions differed by data source and were based on recorded prescription,
dispensing, or administration of the Pfizer-BioNTech COVID-19 vaccine as described in
Section 9.5. The main exposure of interest was the receipt of at least one dose of the Pfizer-
BioNTech COVID-19 vaccine. Cohorts of individuals exposed to a third dose of the Pfizer-
BioNTech COVID-19 vaccine were also analysed.

9.4.1.1. Cohort design

The vaccination categories for the different exposure groups were defined as follows:

1. Receipt of at least one dose of the Pfizer-BioNTech COVID-19 vaccine, followed or

not by a second dose or booster of the Pfizer-BioNTech COVID-19 vaccine.

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Individuals were censored if and when they received a non–Pfizer-BioNTech COVID-

19 vaccine during follow-up.

2. The vaccination category for the matched unexposed group was defined as not
receiving a COVID-19 vaccine of any brand during the study period. Individuals were
censored when they received a dose of any COVID-19 vaccine during follow-up.

The following sensitivity analyses were implemented for the cohort design:

1. A vaccination category consisting of the receipt of two vaccination doses, per the
recommended primary vaccination schedule was studied (i.e., receipt of a first dose
of the Pfizer-BioNTech COVID-19 vaccine, followed by a second dose by week 4
after the first dose in the absence of an adverse event, and having never received a
non–Pfizer-BioNTech COVID-19 vaccine). For this specific sensitivity analysis, but
not for the main analysis, individuals were censored if they did not receive the
second dose of the Pfizer-BioNTech COVID-19 vaccine by week 6 after the first dose
in the absence of an adverse event or if they received a non–Pfizer-BioNTech
COVID-19 vaccine during follow-up. The operationalisation of these exposure
strategies is described in Section 9.5.

2. The risks for AESIs following a second or subsequent dose were estimated as
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follows:

 Risk of AESIs following a second dose of the Pfizer-BioNTech COVID-19

vaccine. In this sensitivity analysis, the study population were individuals who
received a second dose of the Pfizer-BioNTech COVID-19 vaccine, and
follow-up started on the day the second dose was received. The risk of AESIs
were estimated using the same estimators used in the main analysis.

 The risk of AESIs following subsequent doses of the Pfizer-BioNTech

COVID-19 vaccine were estimated in a similar way. In these sensitivity
analyses, the study population was individuals who received a subsequent
dose of the Pfizer-BioNTech COVID-19 vaccine, and follow-up started the
day the subsequent dose was received. The risks of AESIs were estimated
using the same estimators used in the main analysis (i.e., incidence rates
(IRs), hazard rations (HRs), risk differences (RDs).

Individuals who received a first dose (population studied in the main analysis) may be
different from the individuals who received a second dose and they may also be different
from the individuals receiving subsequent doses (populations studied in this sensitivity
analysis). These differences could be due to both the national vaccination policies
concerning dosing recommendations (i.e., a third dose was indicated for specific at-risk
individuals) and the fact that individuals who received subsequent doses were survivors who
had not suffered any serious adverse reactions (e.g., an anaphylactic reaction to a first
dose) that would have contraindicated the continuation of the vaccination schedule. We
were only able to identify that a third dose was given without being able to distinguish if it
was the third dose in a 2+1 vaccination primary schedule or a booster dose.

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9.4.1.2. Self-controlled risk interval design

As per the protocol and SAP, the results from the SCRI study are not reported in this interim
report. For the SCRI design, for each dose, person-time in the risk interval will be
considered as ‘exposed’, while person-time in the control interval will be considered
‘unexposed’. Risk intervals are specific to the outcome of interest and will be defined to
reflect the length of post-vaccine exposure that an incident post-vaccine event was expected
to occur. The risk windows for events after vaccination were not well known for COVID-19
vaccines when the study protocol and SAP were drafted, so these were defined based on
prior post-marketing studies of other vaccines (where applicable), clinical trial data (where
applicable), and passive post-marketing surveillance activities (as they became available).
An acute event, while time-limited in duration, does not necessarily have a defined risk
window if there is no known time-limited window after vaccine exposure that the acute event
would be expected to occur post-vaccination.

Outcome-specific control intervals will also be defined. For outcomes with short risk
intervals, the control interval occurs relatively close in time to the risk interval for each dose.
For outcomes with long risk intervals, among individuals receiving two or more doses, the
control interval for both the first and second doses occurs after the risk interval of the
second or subsequent dose and do not overlap with the risk interval of the following dose. A
sensitivity analysis will be performed, where the exposed group of vaccinees will be
restricted to those who were vaccinated as per the recommended schedule, (i.e., two doses
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of the Pfizer-BioNTech COVID-19 vaccine per the Pfizer-BioNTech recommended dosing

schedule).3

9.4.2. Definition of outcomes

9.4.2.1. Safety outcomes
Outcomes were defined homogeneously across the data sources to the fullest extent
possible. Selected AESIs currently included in the study are listed in Table 2 and were
based on those proposed by the ACCESS project (vACcine COVID-19 monitoring
readinESS), which was funded by the EMA to ensure that a European infrastructure is in
place to effectively monitor COVID-19 vaccines in the real world, once the vaccines are
authorised- in the EU (http://www.encepp.eu/encepp/viewResource.htm?id=37274.).
Additional outcomes were added following discussions and requests from EMA: Thrombotic
thrombocytopenia syndrome (TTS) and myocarditis and pericarditis, with 1 to 7, 1 to 14 and
1 to 21-day risk windows individually and as a combined event.

Outcomes were identified in EHR databases with algorithms based on codes for diagnoses,
procedures, and treatments. Definitions, codes, and proposed algorithms for all AESI
incorporated definitions developed by the ACCESS project

3 This refers to the original 2-dose schedule.

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(https://zenodo.org/communities/vac4eu/?page=1&size=20) and are described in more

detail in the SAP (Standalone Appendix 4).

a. Outcome identification and validation, by data source

AESIs were identified based on patient profile review of electronic medical records by health
care professionals. In addition, for selected outcomes listed in Table 2 and others (if
considered necessary in a future evaluation of results), manual review of patient charts
conducted by clinicians blinded to COVID-19 vaccine exposure will be performed starting in
2023, when possible, and the results will be included in the final report. Confirmation of an
event diagnosis will be classified using the levels of certainty in existing Brighton
Collaboration definitions and those currently being developed.

Standard algorithms for each outcome definition were applied to participant data sources,
based on the results of the ACCESS project. Algorithms were tailored to the data source to
take into consideration the nature of the records that identified the outcome, e.g., primary
care, access to hospital care, and access to emergency care.[10] Multiple algorithms for the
same outcome were included in the analysis, to assess the potential impact of differential
misclassification.

Pedianet (IT): A validation mechanism, including individual linkage with the electronic
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regional immunisation registry, will be in place. The validation process will include review by
clinicians of the individual EHRs, which contain information from primary care reports.

PHARMO (NL): In the Netherlands, for the validation study, information on selected
endpoints from patient medical records were abstracted by local medical professionals
employed at PHARMO, provided that medical chart review was approved by the ethics
committee and other local and/or national governing bodies.

NHR (NO): In Norway, the validation process was based on the manual review of hospital
charts for a subsample of individuals with the AESI, compared with registered diagnoses in
the Patient Registry of Norway.

EpiChron (ES): In Aragon (Spain), the proposed validation process was based on a review
of the individuals’ electronic medical records by clinicians from the research team who are
blinded to COVID-19 vaccination status. These records included information from primary
care reports, hospital discharge reports (including hospital emergency rooms), and results of
diagnostic tests and laboratory tests.

SIDIAP (ES): In Catalonia (Spain), the validation process was part of the data quality
control. Validation was based on a review of the electronic medical record information
(ECAP) by members of the SIDIAP research group who were blinded to COVID-19
vaccination status.

CPRD Aurum (UK): In the United Kingdom (UK), validation was conducted by a review of
electronic medical record information for selected endpoints by clinicians who were blinded
to COVID-19 vaccination status.

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9.4.3. Covariate definition

The following variables were assessed at time zero (for the cohort design) or the date of
initial vaccine dose (for the SCRI design) to define patient populations of special interest or
priority vaccination groups, to define subgroups of interest for secondary analyses, or to
control for confounding. The AESIs may have different sets of risk factors, and outcome-
specific analyses therefore could contain different covariate sets. Potential covariates could
include the following information, as available in each data source:

 Demographics

 Age at time zero (used to define subgroups for secondary analyses)

 Age in categories, in line with published background incidence rates from

ACCESS (0-17, 18-29, 30-39, 40-49, 50-59, 60-64, 65-69, 70-79, 80+ years)

 The age group 0-17 years was further categorised, when feasible, as follows:
0-1, 2-4, 5-11, 12-15, 16-17

 Sex

 Pregnancy status and pregnancy trimester at time zero

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 Geographic region, as appropriate in each country

 Socioeconomic status, as available in each country (including housing,

employment, and income, if available)

 Date of vaccination (categorised in trimesters)

 COVID-19 history, as available in each data source (used to define subgroups of

interest)

 Previous diagnosis of COVID-19

 Positive test result for COVID-19

 Personal lifestyle characteristics

 Smoking status (if available)

 Body mass index (if available)

 Comorbidities

 History of anaphylaxis

 History of allergies

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 Diabetes mellitus (types 1 and 2)

 Hypertension

 Cardiovascular disease

 Cerebrovascular disease

 Chronic respiratory disease

 Chronic kidney disease

 Chronic liver disease

 Cancer

 Autoimmune disorders

 Influenza infection or other respiratory infections

 Charlson Comorbidity Index (reported as individual items and as a composite

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score)

 CDC at risk groups

 Immunocompromising conditions (used to define subgroups for secondary analyses)

 Immunodeficiencies

 Immunosuppressant medication use

 Human immunodeficiency virus and other immunosuppressing conditions

 Comedication use during the year before time zero (prescriptions or dispensing, no
over-the-counter medication use). For this report, comedication use was assessed
for ten years prior to time zero, but this will be corrected in the next interim report.

 Analgesics

 Antibiotics

 Antiviral medications

 Corticosteroids

 Non-steroidal anti-inflammatory drugs

 Psychotropics

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 Statins

 Novel oral anticoagulants

 Warfarin

 Health care utilisation in the year before time zero and in the 2 weeks before time
zero

 Number of hospitalisations

 Number of emergency department visits

 Primary care utilisation

 Cancer screening

 Other preventive health services, as appropriate

 COVID-19 tests
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 Other vaccinations

 Influenza

 Pneumococcal

 DTP (diphtheria, tetanus, and pertussis)

 TPV (polio)

 TV (MMR) (measles, mumps and rubella)

 Hib (Haemophilus influenzae type b)

 HB (hepatitis B virus)

 VV (varicella zoster virus)

 HZ (herpes-zoster virus)

 HPV (human papillomavirus)

 Meningococcal

 Rotavirus

 Surrogates of frailty

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 Paralysis

 Parkinson’s disease

 Skin ulcer

 Weakness

 Stroke/brain injury

 Ambulance transport

 Dementia

 Difficulty walking

 Psychiatric illness

 Sepsis

 Heart failure
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 Podiatric care

 Bladder incontinence

 Diabetes complications

 Arthritis

 Coagulation deficiencies

 Vertigo

 Lipid abnormalities.

The CDC at risk groups will be defined based on at-risk medical conditions for developing
severe COVID-19 and will be reported as baseline characteristics for vaccinated and non-
vaccinated individuals. These will be defined based on scientific evidence available on the
US Centers for Disease Control and Prevention website and the UK National Health
Services digital website.[11, 12] Those websites are updated regularly and provide a
classification based on levels of evidence.

At-risk medical conditions that are considered as at higher risk to develop severe COVID-19
are summarised in Table 4. Medicinal products that can be considered as proxies for these
conditions are also listed. At-risk Subgroups will be identified using medical codes and
associated dates for at-risk medical conditions characterising at-risk groups for developing
severe COVID-19 as well as prescription and/or dispensing records for drug exposures
which may be used as proxies for their identification. At-risk subgroups will be created for

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each of the at-risk medical conditions listed in Table 4. Multimorbidity, i;e., individuals in
more than one at-risk subgroup will be included in each subgroup.

Table 4. Comorbidities and related medicinal products with evidence of being at

high risk for developing severe COVID-19
At-risk medical conditions identified by Medicinal product proxy(ies) (ATC code)
diagnosis codes
Cancer (with chemo/immuno/radiotherapy, Alkylating agents (L01A)
cancer treatment, immunosuppressant; Antimetabolites (L01B)
targeted cancer treatment (such as protein Plant alkaloids and other natural products (L01C)
kinase inhibitors or PARP inhibitors); blood or Cytotoxic antibiotics and related substances
bone marrow cancer (such as leukaemia, (L01D)
lymphoma, myeloma) Other antineoplastic agents (L01X)
Hormones and related agents (L02A)
Hormone antagonists and related agents (L02B)
Immunostimulants (L03)
Immunosuppressants (L04)
Type 1& 2 Diabetes Blood glucose lowering drugs A10A & A10B
Obesity (BMI > 30) Peripherally acting anti-obesity products (A08AB)
Centrally acting anti-obesity products (A08AA)
Cardiovascular disease/ Serious heart Antiarrhythmics, class I and III (C01B)
conditions including heart failure, coronary Cardiac stimulants excl. Cardiac glycosides
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artery disease, cardiomyopathies (C01C)

Vasodilators used in cardiac diseases (C01D)
Other cardiac preparations (C01E)
Antithrombotic agents (B01A)
Chronic lung disease including COPD, Drugs for obstructive airway diseases (R03)
asthma, bronchiectasis, interstitial lung Lung surfactants (R07AA)
disease, cystic fibrosis, tuberculosis. Respiratory stimulants (R07AB)
Chronic kidney disease Erythropoietin (B03XA01)
HIV Protease inhibitors (J05AE)
Combinations to treat HIV (J05AR)
NRTI (J05AF)
NNRTI (J05AG)
Immunosuppression Immunosuppressants (L04A)
Corticosteroids (H02)
Sickle cell disease Hydroxyurea (L01XX05)
Other haematologic agents (B06AX)
Hypertension anti-hypertensive drugs (C02, C03, C07, C08,
C09)

9.5. Data sources and measurement

Exposure was based on recorded prescription, dispensing, or administration data for the
Pfizer-BioNTech COVID-19 vaccine. Vaccine receipt and date of vaccination was obtained
from all possible sources that capture COVID-19 vaccination, such as pharmacy dispensing
records, general practice records, immunisation registers, vaccination records, medical
records, or other secondary data sources. Depending on the data source, vaccines were
identified via nationally-used product codes and included batch numbers, where possible.
The main exposure of interest was the receipt of at least one dose of the Pfizer-BioNTech

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COVID-19 vaccine. The source of exposure was as described below for the six data sources
that contributed to this interim report.

Pedianet (IT): Information on COVID-19 vaccine included date of immunisation, type of

vaccine, vaccine batch number, and dose. Information on COVID-19 immunisation was
retrieved via a direct linkage with the regional immunization registry. The family care
physicians synchronise the data every trimester.

PHARMO (NL): Information on vaccination, obtained from PHARMO’s General Practitioner

(GP) database, included Anatomical Therapeutic Chemical (ATC) code, brand, batch, and
date of application.

NHR (NO): All vaccinations, including COVID-19 vaccinations, are subject to notification to
SYSVAK and are registered without obtaining patient consent. The following data were
registered: individual personal identifier, vaccine name and ATC code, vaccine batch
number, date of vaccination, and the centre where the vaccine was administered.

EpiChron (ES): The Aragon Health System (Aragon, Spain) implemented a specific
vaccination register embedded in the electronic health record (EHR) system. The COVID-19
vaccination was systematically registered in this register by health care professionals. This
register collected all the relevant information regarding the vaccination process, such as
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patient’s identifier; date of administration and due date for next dose, when applicable;
centre of administration; injection site; name of the vaccine; brand (laboratory); batch
number; dose; and vaccination criteria (risk group to which the patient belongs). There was
also a free-text section in which health professionals included their observations (e.g.,
presence or not of an allergic reaction).

SIDIAP (ES): For all 8 million individuals of the Catalan Institute of Health–Primary Care
teams, SIDIAP has information available on the administration of COVID-19 vaccines to
individuals linked to a unique and anonymous identifier. The information is originated from
the electronic medical records. For each patient, SIDIAP has date and centre of
administration, dose, brand, reasons for vaccination (e.g., risk group), and other information
related to vaccination.

CPRD Aurum (UK): Information on COVID-19 vaccination in the CPRD Aurum data source
included the brand of COVID-19 vaccine administered, the date that the vaccine was
administered to the patient, and the date that the record of vaccination was entered in the
primary care medical record. In the UK, the majority of COVID-19 vaccines were
administered at local immunisation centres or pharmacies in the community. Details of the
vaccination were systematically entered by healthcare professionals into a national
database at the time of administration, which was linked with primary care health records via
the patient’s NHS number. This information is now available to researchers as anonymised
primary healthcare records via CPRD Aurum.

9.6. Bias
This study is subject to limitations related to both the study design and use of secondary
health care data. A data-related limitation of this study is the reliance on the accuracy of
codes and algorithms to identify outcomes. Outcomes and their dates of occurrence were
validated, but the extent of validation may be limited because medical records were used for

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validation, and these could be incomplete. Exposure identification could be based on

pharmacy dispensing records, general practice records, immunisation registers, medical
records, or other secondary data sources. The ability to identify specific COVID-19 vaccine
products and dates of vaccination in these data sources is detailed in Section 9.5. It is
possible that vaccination of individuals outside the health care system was not recorded in
secondary EHR databases, thereby leading to potential bias because of exposure
misclassification for the cohort study. It is also possible that some AESIs are the result of
immunisation errors occurring during the administration of the Pfizer-BioNTech COVID-19
vaccine. This information was not collected regularly and could not be taken into account
with the current protocol.

A study design-related limitation of both the cohort and SCRI designs is that any uncertainty
regarding risk periods will lead to misclassification and attenuation of risk estimates. A
limitation of the cohort design is the potential for residual or unmeasured confounding, as it
is unlikely that the data sources will have information on all potential confounders. To
address potential confounding, the SCRI, which automatically adjusts for time-invariant
confounders, was used as a secondary approach. However, the SCRI is not well suited to
study outcomes with gradual onset, long latency, or risk periods that are not well known. It
also may be subject to bias for outcomes that affect the probability of exposure. The SCRI
design was complementary to the cohort design for prespecified AESI with defined risk
intervals.
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In addition, in Italy, the COVID-19 vaccination campaign started in December 2020 with
each of the 20 regions having adopted different vaccination strategies involving hubs and/or
general practices. The primary care setting was actively involved in the vaccination
campaign only at the beginning of April 2021, and only certain age categories and/or types
of vaccines were available for direct administration by GPs. Thus, for the period between
January and March 2021, Italian GPs have likely recorded vaccine injections according to
three main pathways: a) some regions automatically informed GPs regarding their patients’
COVID-19 vaccination status; b) GPs referred patients to a specific hub to register their
vaccination status there; and c) patients autonomously reported their vaccination to their
GPs. For the first six months of 2021, HSD expects to find complete data for certain age
categories, while in the first three months and for some other age categories, they will only
find incomplete data for some regions. In HSD, after preliminary evaluation of data
completeness, the study design (e.g., self-controlled or cohort design) will be chosen for the
specific objectives.

The matching procedure in the cohort analysis produced a study population (i.e., a set of
matched pairs) with a distribution of matching variables representative of the vaccinated
individuals by matching unvaccinated individuals to vaccinated individuals based on a
prespecified set of baseline variables. Therefore, the cohort analysis estimated the average
causal effect in the vaccinated population i.e., in a population that had the distribution of
matching variables of the vaccinated. When further adjustment via inverse probability
weighting was applied, the estimated effect remained the causal effect in a population that
had the distribution of matching variables with the vaccinated cohort because the weights
were estimated and applied to the matched population. The average causal effect in the
treated and untreated populations differed only if any baseline variable modified the effect,
in addition to random variation. This will have to be considered when comparing effect
estimates with other studies.

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The main analysis for both the cohort and SCRI analysis pooled together the population
used to estimate the effect of a first dose of the Pfizer-BioNTech COVID-19 vaccine and the
population used to estimate the effect of subsequent doses of the same vaccine. This
pooling was done to gain statistical precision, under the assumption that the effect of a first
or second dose in both populations is homogeneous. If this assumption is inaccurate, e.g.,
because receiving a first dose sensitises the immune system to react against a second
dose, the estimates of the main analysis will be biased.

9.7. Study Size

The study is conducted in a source population of 38.9 million individuals captured in the
electronic health care data sources.

Table 5 shows the sample size calculations for AESIs with different assumptions for the risk
ratios. For example, assuming a two-sided alpha of 0.95, power of 80%, and a ratio of 1 to 1
exposed to unexposed, to detect a risk ratio of 2 for Guillain-Barré syndrome, 22,340,153
exposed and 22,340,153 unexposed individuals would need to be included.

Table 5. Number of individuals needed to detect different risk ratios for selected
adverse events of special interest for a range of background rates
Sample sizea
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AESI Background rate Risk Exposed Unexposed

during risk ratio
window
Anaphylaxis 1/40,000 5 25,164,513 25,164,513
Anaphylaxis 1/40,000 7 15,147,759 15,147,759
Anaphylaxis 1/40,000 10 9,341,969 9,341,969
Anaphylaxis 1/40,000 50 1,081,289 1,081,289
Guillain-Barré 1/100,000 2 22,340,153 22,340,153
syndrome
Guillain-Barré 1/100,000 3 7,725,193 7,725,193
syndrome
Guillain-Barré 1/100,000 5 2,997,860 2,997,860
syndrome
Guillain-Barré 1/100,000 10 1,112,913 1,112,913
syndrome
AESI = adverse event of special interest; Severe COVID-19 defined as COVID-19-related
hospitalisation or death.
a Assuming a two-sided alpha = 0.95, power of 80%, and a ratio of 1:1 exposed to
unexposed.
Background incidence rate (IR) taking into account the risk window (source:
https://doi.org/10.1093/infdis/jiab628):
Anaphylaxis 1/40,000; (1/40,000)/365 * risk window (risk window 2 days) = <0.010000137
Guillain-Barré syndrome 1/100,000; (1/100,000)/365 * risk window (risk window 42 days)
= <0.01000115

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9.8. Data transformation

Detailed methodology for data transformations, particularly complex transformations (e.g.,
many raw variables used to derive an analytic variable), are documented in the statistical
analysis plan (SAP), which is dated, filed and maintained by the sponsor (Standalone
Appendix 4).

9.9. Statistical methods

9.9.1. Main summary measures
In this Interim Report (IR) #5, all individuals vaccinated with at least a first dose of the Pfizer-
BioNTech COVID-19 vaccine and satisfying the inclusion criteria during the time periods
below were included. The main summary measures reported for the unmatched vaccinated
cohort were:

 Attrition table for the Pfizer-BioNTech COVID-19 vaccinated cohort.

 Counts and proportions of administered Pfizer-BioNTech COVID-19 vaccine doses

patterns by age groups and sex. This table was repeated for immunocompromised,
elderly and individuals who have specific comorbidities.

 Population description at the time of first and third dose.

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 Prior AESI (outcome-specific exclusion criteria) at time zero.

 Cohort follow-up duration and censoring reasons.

For the matched cohort design, matched on a subset of variables:

 Age: age of vaccinated individuals categorised into 2-year age groups (exact
matching);

 Sex: male, female (exact matching);

 Previous COVID-19 diagnosis at time 0 (exact matching);

 Place of residence: at the level of neighbourhood, small town or at GP practice level

(exact matching);

 At least one influenza vaccine in the last five years (yes/no) (not recorded is
considered as not vaccinated) (exact matching);

 Pregnancy status yes, no (exact matching):

o Among pregnant women, matching will take a ‘greedy matching’ approach, in

which a matched will be first sought by last menstrual period (LMP) within 7
days of each other; if no matches are found, the period will be extended to 30
days;

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 Immunocompromised yes, no (exact matching):

o At least one of the following in the last 10 years: immunodeficiencies,

immunosuppressant medication use, human immunodeficiency virus and
other immunosuppressing conditions

 Number of pre-existing conditions considered by the Centers for Disease Control and
Prevention (CDC) as risk factors:

o Cancer, type 1& 2 diabetes, obesity (BMI > 30), cardiovascular disease/
serious heart conditions (heart failure, coronary artery disease,
cardiomyopathies), chronic lung disease including COPD, asthma, chronic
kidney disease, HIV, immunosuppression, sickle cell disease, hypertension

o CDC at risk group 0 = none of the conditions above

o CDC at risk group 1 = 1 of the conditions above

o CDC at risk group 2 ≥ 1 of the conditions above

 Socioeconomic status/education level (as available, exact matching)

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The main summary measures reported for the matched vaccinated and unvaccinated
cohorts were::

 Attrition table for matched cohort design.

 The matching statistics (number of Pfizer-BioNTech vaccinated patients excluded,

included and matched by calendar and age).

 Population description at time zero by exposure group.

 Prior AESI at time zero (exclusion criteria for the AESI-specific analysis).

 Cohort follow-up and reasons for censoring.

 Population description at time zero by cohort (age groups, sex, age groups by sex,
influenza vaccination, COVID-19 infection, history of AESI – exclusion criteria with
prior history within one year – documented for the previous 10 years).

9.9.2. Main statistical methods

 The IR of all AESIs by different time windows after dose 1.

 The IR of all AESIs within the risk windows after dose 1, dose 2, and dose 3.

 The number of cases, and risk estimates (IR, Kaplan-Meier (KM) for all AESI
(identified electronically) in each matched exposure group, overall and by subgroups.

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 The crude cumulative incidence (1- KM) curves for each AESI by exposure group
taking risk windows in consideration.

 Cumulative incidence curves (1 - KM) for the negative control outcome, starting from
the day of administration of the first dose of vaccine.

9.9.3. Baseline exchangeability and negative control outcome

Despite matching for potentially relevant confounders, baseline exchangeability may not be
achieved and residual confounding may remain. An observational study of the effectiveness
of the Pfizer-BioNTech COVID-19 vaccine used the cumulative incidence of symptomatic
SARS-CoV-2 infections at day 12 as a negative control, and a difference of approximately
0.06% was considered as proof of non-relevant residual confounding.[13] Similarly,
symptomatic SARS-CoV-2 infection was used as a negative control outcome, under the
assumption that confounders for symptomatic SARS-CoV-2 were equally relevant for
developing adverse clinical conditions. More details are available in the statistical analysis
plan.

We, therefore, used the difference in the cumulative incidence of symptomatic SARS-CoV-2
infection at day 12 in the matched vaccinated and unvaccinated cohorts as a negative
control, calculated using a 1-KM estimator (Figure 4). It was established a priori that, if the
12-day risk difference of symptomatic SARS-CoV-2 infection was ≤0.10%, the matching
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would be considered to be sufficient to achieve baseline exchangeability and if it was >0.1%,

the matching would be considered not sufficient to achieve baseline exchangeability. In the
latter case, inverse probability of treatment weighting (IPTW), a form of propensity score
(PS) method, would be used to adjust the estimates using PS methods. PS methods are
appropriate when there is a small number of events for each outcome, which is the case in
this study.

The PS was defined as the probability of receiving the Pfizer-BioNTech COVID-19 vaccine
at baseline in the matched population, conditional on the matching variables and on any
baseline variables with an ASD ≥0.1. This probability was estimated using a logistic
regression model including all the matching variables, all variables with an ASD ≥0.1, prior
history for each AESI and age (i.e., 0-5, 6-11, 12-17, 18-29, 30-39, 40-49, 50-59, 60-64, 65-
69, 70-79, ≥80 years), as independent variables. Geographic region was excluded from the
model to avoid complete separation between groups. The analyses did not use any specific
statistical technique for handling missing values and the only restriction was not including
any variables with more than 30% of missing values.

One single PS model was estimated in the eligible population without selection on the
outcome, and used to adjust all outcome estimators. Variables highly correlated with
exposure (i.e., OR<0.1 or OR>10 and prevalence >2%) were excluded from the model in
order to avoid complete separation of the curves of the PS.

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The stabilised weights were calculated as:

Where PS is the propensity score and A is the vaccination status at baseline (vaccinated:
A=1, unvaccinated: A=0), i.e., the weight for the vaccinated cohort was 0.5/PS and for the
unvaccinated cohort it was 0.5/(1-PS). Since, by design, the marginal probability of being
exposed is ½, the weights were stabilized by multiplying by 0.5.

The distribution of the weights was assessed using min, max, P1, P99, median, mean, and
standard deviation. We described the distribution of assessed weights and truncated the
weights at the 1st and 99th percentile of the distribution of weights in each group to avoid
undue influence of extreme weights.

Adjusted HRs and 95% CIs were estimated via weighted Cox proportional hazard
regression model with robust estimation of the variance. Adjusted cumulative incidence (1-
KM) differences were obtained by subtracting 1-KM, weighted using the IPTW, estimated at
the end of the risk window for each AESI.

In this report, regardless of the result of the 12-day risk difference to achieve baseline
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exchangeability we calculated PS adjusted estimates which are reported here.

Figure 4. Overview of proposed analytical approach to assess baseline

exchangeability in the retrospective matched cohort study

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9.9.4. Missing values

Patients with missing data for the matching variables and those with missing exposure
status or any of the outcome data were not included in the analyses. We assumed that the
absence of information on clinical events meant that the event did not occur.

9.9.5. Sensitivity analyses

The sensitivity analyses described in Section 9.4.1.1 above were tested and, for
completeness, the tables are included in on-line supplementary data available on request.
These will be further refined and reported in subsequent reports.

9.9.6. Amendments to the statistical analysis plan

A summary of the amendments that have been made to the SAP is provided in Table 6.

Table 6. Summary of amendments to the statistical analysis plan

Amendment Date Section of Summary of Reason
number SAP amendment/update
changed
3 March 2.1 Update list of outcomes Request by EMA
2024 to exclude ‘severe because vaccine-
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COVID-19 disease’ associated enhanced

disease/vaccine-
associated enhanced
respiratory disease
(VAED/VAERD) is
longer considered as
an important potential
risk
3 March 2.1 Update list of outcomes Request by EMA
2024 to include ‘cerebral
venous sinus thrombosis’
and ‘glomerulonephritis’
3 March 7.2.8 Updated section on Request by EMA
2024 description of cardiac
imaging use before and
after the issue of the
direct healthcare
professional
communication letter to
be consistent with
changes to protocol V5.0,
section 9.3.2.1

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Table 6. Summary of amendments to the statistical analysis plan

Amendment Date Section of Summary of Reason
number SAP amendment/update
changed
2 28 Jun 2 Updated introduction To describe new
2023 objective i.e.,
assessment of the
effectiveness of the
direct healthcare
professional
communication
(DHPC) letter
2 28 Jun 2.1 Update list of outcomes Request by EMA
2023 to include myositis,
secondary amenorrhoea
and hypermenorrhoea to
be consistent with
changes to protocol V5.0,
section 9.3.2.1
2 28 Jun 2.2.6.3 Removed ‘verified’ from
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2023 AESIs in Table 3

2 28 Jun 2.4.2 Added new secondary Included in European
2023 objective described in risk management plan
protocol V5.0, section as an additional risk
8.2: to assess the minimization measure
effectiveness of the direct
healthcare professional
communication (DHPC)
letter by describing the
rate of cardiac imaging
use for vaccinated and
unvaccinated individuals
each calendar month of
the study period, before
and after distribution of
the DHPC letter
2 28 Jun 5.2.1 Added
2023 myocarditis/pericarditis to
Table 6
2 28 Jun 5.3 Added cardiac imaging Inclusion of endpoints
2023 as additional endpoint for new objective
described above
related to DHPC

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Table 6. Summary of amendments to the statistical analysis plan

Amendment Date Section of Summary of Reason
number SAP amendment/update
changed
2 28 Jun 5.4.1 Demographic variables DAPs have confirmed
2023 removed from list: these variables are not
 race/ethnicity available.
 residency in long-
term care facility
 healthcare worker or
essential worker
status
2 28 Jun 5.4.4 Added additional
2023 conditions to the CDC at
risk-groups
2 28 Jun 5.4.7 Healthcare use variable DAPs confirmed
2023 deleted variable not available
 skilled nursing facility
2 28Jun 5.4.12 Added additional
2023 respiratory conditions in
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Table 8
2 28 Jun 7.2.5 Added section in Final Include analysis of new
2023 Report objective related to
DHPC
2 28 Jun 7.2.8 Added section on Analysis of new
2023 Description of cardiac objective related to
imaging use before and DHPC
after the issue of the
direct healthcare
professional
communication letter
2 28 Jun Updated sections The comparison with
2023 2.2.5  Comparison with historical periods will
4.1 historical controls, be made via the
7.2.5  Study period matched historical
7.2.7  Analysis. Final comparators analysis
Report
 Comparison with
historical
comparators.
2 28 Jun 5.4.1 Protocol V4.0, section To be consistent with
2023 Demographi 9.3.3: age categories the change in age
cs have been modified; categories that has
been communicated to
regulatory authorities
via an administrative
change letter

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Table 6. Summary of amendments to the statistical analysis plan

Amendment Date Section of Summary of Reason
number SAP amendment/update
changed
1 15- 2.1 Study Renamed the AESI, ‘HIT- These three names
Apr- Design; like event’ to ‘thrombotic refer to the same
2022 5.2.1 thrombocytopenia event, so there was a
Identificatio syndrome (TTS)’ and duplication in the list.
n and deleted The current name in
validation of ‘thrombocytopenia, common use for the
outcome in venous syndrome potentially
each data thromboembolism’ from associated with
source; 8.3 the list of AESIs COVID-19 vaccination
Events has been selected
1 15- 7.2.6.8 Revised age To align with vaccine
Apr- Subgroup categorisations authorization schedule
2022 analyses; and distribution rollout
7.2.8.2
Measures of
association
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1 15- 7.2.1 Added study end date of To clarify that the last
Apr- Analysis 31 December 2023 and date of data available
2022 timelines changed end of data will be 31 December
collection to 31 March 2023, which differs
2024 from the end of data
collection date that
takes into account lag
times.
1 15- 7.2.6.10 Added a sensitivity Request from EMA to
Apr- Sensitivity analysis for the cohort remove from main
2022 Analyses; design excluding analysis and add as a
7.2.4 Interim individuals who have had sensitivity analysis
Reports 2-5 contact with the
healthcare system in the
seven days before time
zero
1 15- 2.2.2.4.1. Added the variable To align with the latest
Apr- Matching ‘Immunocompromised version of the study
2022 process (yes/no) – exact protocol
matching’ to the list of
matching variables
1 15- 2.2.2.2 Removed exclusion Request from EMA
Apr- Exclusion criteria, ‘have had been in
2022 criteria; contact with the
2.2.6.2. healthcare system in the
Exclusion 7 days before time 0’
criteria

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Table 6. Summary of amendments to the statistical analysis plan

Amendment Date Section of Summary of Reason
number SAP amendment/update
changed
1 15- 2.2.2.1 Removed inclusion The criterion is implicit
Apr- Inclusion criterion, ‘live in an area and will be met by
2022 criteria where COVID-19 every participant given
vaccination is under way the data sources used
at baseline’ for the study
1 15- 2.1 Study Added an additional risk Request from EMA
Apr- design window of 1-21 days for
2022 myocarditis and
pericarditis
1 15- 2.1 Study Modified risk intervals For clarity and to align
Apr- design and preferred study with the latest version
2022 design for various of the protocol
outcomes
1 15-Apr 7.2.7 Added an analysis to Request from CBER
2022 Comparison describe time trends in
with AESI during the pre-
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historical pandemic, post-

comparators pandemic, and post-
vaccination periods
The changes to the statistical analysis documented in the amended protocols and described
in the amended SAPs have been implemented:

9.10. Quality control

Rigorous quality control (QC) has been used for all deliverables. Data transformation into
the CDM was conducted by each subcontracted research partner from its associated
database, using the processes described below. Standard operating procedures or internal
process guidance at each research centre were used to guide the conduct of the study.
These included rules for secure and confidential data storage, backup, and recovery;
methods to maintain and archive project documents; QC procedures for programming;
standards for writing analysis plans; and requirements for scientific review by senior staff.

At UMCU, as the scientific coordinating centre responsible for central data management and
analysis and scientific coleader centre, all documents underwent QC review and senior
scientific review. Data management and statistical analysis followed standard operating
procedures. All statistical analysis programmes were double-coded.

At RTI Health Solutions (RTI-HS), as the project coordinating centre and scientific coleader
centre, the study protocol underwent QC review, senior scientific review, and editorial
review. Senior reviewers with expertise in the appropriate subject matter area provided
advice on the design of research study approaches and the conduct of the study and
reviewed results, reports, and other key study documents.

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9.10.1. Pedianet
Pedianet data processing included QC steps to verify the correspondence between a
diagnostic code and its open-text descriptor, conducted through manual validation of clinical
histories, in addition to standardised procedures in SQL and Microsoft Access to extract
data from database. Quality control checks of patient general data were conducted through
the detection of outlier values and validation rules; grouping of diseases; and regular
monitoring of aggregate clinical and drug data. All transformations in the data were logged in
R scripts. To ensure code reliability, double programming in R and Stata or Python was
used for all scripts. The study is being conducted according to the Guidelines for Good
Pharmacoepidemiology Practices (GPP)[14] and the ENCePP Code of Conduct.[15]

9.10.2. PHARMO (NL)

PHARMO adhered to high standards throughout the research process based on robust
methodologies, transparency, and scientific independence, in accordance with the ENCePP
Guide on Methodological Standards in Pharmacoepidemiology[16] and the ENCePP Code of
Conduct.[15] PHARMO is ISO 9001:2015 certified. Standard operating procedures, work
instructions, and checklists were used to guide the conduct of this study. These procedures
and documents include internal quality audits, rules for secure and confidential data storage,
methods to maintain and archive project documents, rules and procedures for execution and
QC of SAS programming, standards for writing protocols and reports, and requirements for
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senior scientific review of key study documents.

9.10.3. NHR (University of Oslo) (NO)

The University of Oslo had centralised information security policies in place to preserve the
confidentiality, integrity and availability of the organisation’s systems and data. All data are
stored and analyzed within the TSD platform, a service for sensitive data at the University of
Oslo (https://www.uio.no/english/services/it/research/sensitive-data/). Only authorized
researchers can access and handle the data within TSD. A two-step authentication process
is in place to access TSD. The study was conducted according to the Guidelines for Good
Pharmacoepidemiology Practices (GPP)[16] and the ENCePP Code of Conduct.[15] Data
quality is a high priority at the Norwegian Health Registries; updated data are released
regularly for research purposes after centralized quality control. The University of Oslo has
rules for secure and confidential data storage and analysis, as well as rules for data
cleaning, linkage, and programming.

9.10.4. EpiChron (ES)

The EpiChron Cohort is built from the BIGAN platform which integrates a technical
infrastructure and a data lake gathering individual patient data from the regional health
service information systems. The completion of the hospital CMBD register and the drug
dispensation database, is systematic, uniform, and normative, in compliance with legal
requirements. Specific on-line training and chart documentation on the use of EHR software
was regularly provided to physicians and nurses in Aragon. The BIGAN platform includes
several processes to control and improve the quality of its data, mainly in the extraction,
transformation, and loading (ETL) processes of capture and persistence in the data lake.
Among these mechanisms, there are validation rules (for example, for dates and time
intervals) or cross-checks with master tables, requiring that certain coded data exist in a
standardised dictionary. Analysis of the distribution of variables is also carried out

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periodically, in search of ‘outliers’ that identify errors in the data capture or transformation
processes. As a rule, records that do not validate QA procedures are kept in a ‘holding area
to be reviewed and discarded or reprocessed. The resulting databases are pseudonymised
to encrypt individual-level identification codes, protecting individuals’ privacy and complying
with data protection laws, and they are stored on a central computer server, with restricted
access by members of the research group, using a double-entry password. The research
group was a multidisciplinary qualified team including public health specialists,
epidemiologists, clinicians, pharmacists, statisticians, and data managers, who were all
trained in data management and patient data protection.

9.10.5. SIDIAP (ES)

Data quality processes were implemented at each phase of the data flow cycle. Quality
control checks were performed at the extraction and uploading steps. The elements present
were described by geographical areas, registering physician, time and the distribution
function of values to assess data completeness. Correctness was assessed by validity
checks on outliers, out of range values, formatting errors and logical date incompatibilities.
Completeness and correctness measures were used to inform decisions on the required
transformations to improve data quality (e.g., harmonisation, normalisation, and clean-up)
and the fitness of the data for the purpose of this specific research project.

9.10.6. CPRD Aurum (UK)

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The DSRU has information security policies in place to preserve the confidentiality, integrity
and availability of the organisation’s systems and data. These include ensuring that the
premises provide suitable physical and environmental security, all equipment is secure and
protected against malicious software, the network can be accessed only by authorised staff,
telecommunication lines to the premises are protected from interception by being routed
overhead or underground, and personnel receive training regarding security awareness. The
study will be conducted according to the International Society for Pharmacoepidemiology
Guidelines for Good Pharmacoepidemiology Practices (GPP)[16] and according to the
ENCePP Code of Conduct.[15] Data quality is a high priority at the DSRU and is assured
through a number of methods based on staff training, validated systems, error prevention,
data monitoring, data cleaning, and documentation, including the following:

 Staff training on data processing standard operating procedures

 Data management plan for every research study outlining the legal basis for
data collection, data flows, data access rights, data retention periods, etc.

 Routine data cleaning to screen for errors, missing values, and extreme
values and diagnose their cause

 System process logs to document staff access, etc.

9.11. Protection of human subjects

Subject information and consent

Not Applicable.

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Independent Ethics Committee (IEC)/Institutional Review Board (IRB)

The final protocol, any amendments, and informed consent documentation were reviewed
and approved by an IRB for each site participating in the study, in compliance with local
requirements and policies (Standalone Appendix 3).

The final protocol, any amendments, and informed consent documentation were reviewed
and approved by a local data protection agency for each site participating in the study.

Ethical conduct of the study

The study was conducted in accordance with legal and regulatory requirements, as well as
with scientific purpose, value and rigor and followed generally accepted research practices
described in the Guidelines for Good Pharmacoepidemiology Practices (GPP)[16] and
according to the ENCePP Code of Conduct.[15]

10. RESULTS
10.1. Participating data sources
Six of the eight data sources contributed data for this interim report (Section 9.2.1):

 Pedianet (IT)
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 PHARMO (NL)

 NHR (NO)

 EpiChron (ES)

 SIDIAP (ES)

 CPRD Arum (UK).

The study period for this fifth interim report started in each country with the first Pfizer-
BioNTech COVID-19 vaccinations between 27 December 2020 in EpiChron (Spain) and 6
January 2021 in PHARMO (The Netherlands) (Table 3). Data collection started on 31 May
2021 in Pedianet (Italy) because vaccination in children started later. The end dates for data
extraction for this interim report are summarised in Table 3.

Pedianet is an Italian paediatric general practice research database that includes children
until the age of 14, after which they are transferred to general practitioners. The vaccination
campaign for children in Italy started on 31 May 2021, which is reflected by the different
calendar time of first vaccination. AESIs are based on diagnoses in the paediatricians’
record, which may include information from hospitalisation, when it is reported back to them,
but this may not be complete, which is why Pedianet could not contribute data for all AESIs.

The data in this interim report from PHARMO were extracted from GP records up to 30 June
2023 and hospital records up to 31 December 2022. Data on pregnancy status were not
available from PHARMO for this interim report. The International Classification of Primary

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Care (ICPC) coding system is used in the PHARMO databases. This is not as granular as
International Classification of Diseases (ICD) coding, and therefore identification of AESIs
was supplemented with free-text searching. The identification algorithms for free text
searches were based on commonly used, internally developed algorithms at PHARMO
tailored to this study. These algorithms enable additional cases to be classified and thus will
improve sensitivity of AESI identification. The algorithms were not formally validated for this
study. Substantial efforts were made to improve the ETL script for the events, which has led
to increases in rates, and rates that are more aligned with other data sources.

The NHR data source provided GP data from the Norway Control and Payment of Primary
Health Care Refunds (KUHR) and hospital data from the Norwegian Patient Registry up to
31 December 2022 for this report. The KUHR GP data source is at max 4 digits for ICPC2
codes because more details digits are not used in the KUHR GP data source. This can lead
to a less specific identification of events resulting in higher event and incident numbers from
Norway.

The EpiChron data sources included diagnostic codes from general practitioners and from
hospital discharge records up to 31 July 2023 for this interim report.

The SIDIAP data source included diagnostic codes from general practitioners and from
hospital discharge records up to 30 June 2023 in this interim report #5. However, because
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of differences in lag times in different data bases within SIDAP and delays in notifications
about hospitalisations data for the end of the follow-up period, may be incomplete.

The CPRD Aurum data source included diagnostic codes from general practitioners up to 21
March 2022 for this interim report.

All the matching criteria were used except pregnancy in PHARMO, CPRD and Pedianet,
socio-economic indicator in CPRD, and influenza vaccination in NHR and the balance
between the matched vaccinated and unvaccinated cohorts was verified. We have also
included data for those who received a third and fourth (booster) dose of the Pfizer-
BioNTech COVID-19 vaccine, which was implemented in many countries in the fall of 2022.
In addition, PS adjusted risk estimates were included. Pregnancy data were not available for
this interim report.

Two data sources, ARS and HSD from Italy, could not contribute data to this interim report:

 Data from ARS were reported in the first and second interim reports, but due to an
ongoing review of the data protection law and the secondary use of the Tuscany
administrative data, the research team at ARS have to suspend research
temporarily.

 Data on COVID-19 vaccination were missing for a high percentage of individuals in

HSD (Italian GP databases) and it was, therefore, not considered to be fit-for-
purpose. In Italy, GPs were involved in the COVID-19 vaccination campaign in March
2021 only for their patients aged 80 or older. There was no automated system to
collect data on patients' vaccination status, and recording this information depended
entirely on the efforts of the GPs. Since it is mandatory for Italian GPs to collect
vaccine-related information for their own electronic dossiers, the accuracy of vaccine

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registration is expected to improve over the coming months. However, we cannot

exclude the possibility that recording of vaccine brand may be selective. We will
monitor vaccine uptake data in HSD to assess whether data are fit-for-purpose.

10.1.1. Vaccinated cohort

From among the 17,677,132 individuals who received ≥1 dose of the Pfizer-BioNTech
COVID-19 vaccine, application of the inclusion criteria of being enrolled at least 12 months
in the database and not having received a prior non-Pfizer COVID-19 vaccination yielded a
total of 12,613,349 (71.35%) eligible individuals (Table 7). These individuals were from Italy
(Pedianet 10,547 (0.08% of the total eligible population); the Netherlands (PHARMO
1,091,265 (8.65%)), Norway (NHR 3,587,702 (28.44%)), Spain (EpiChron 735,237 (5.83%)
and SIDIAP 3,089,610 (24.50%)) and the UK (CPRD Aurum 4,098,988 (32.50%). The main
reason for exclusion was the receipt of a COVID-19 vaccine other than Pfizer-BioNTech; the
highest exclusion rate was in CPRD Aurum (47.26%) and the lowest in NHR (10.37%). A
total of 26,980 pregnant women who had received at least one dose of the Pfizer-BioNTech
COVID-19 vaccine were included.
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Table 7. Attrition table for the Pfizer-BioNTech COVID-19 vaccinated cohort (before matching) by data source*
Pedianet NHR PHARMO EpiChron SIDIAP CPRD
n (%) n (%) n (%) n (%) n (%) Aurum
n (%)
Received a first dose of Pfizer- 12,046 (100) 4,002,649 1,230,629 887,188 3,772,034 7,772,586
BioNTech COVID-19 vaccine (100) (100) (100) (100) (100)
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Had ≥12 months continuous 11,284 3,962,140 1,222,172 871,425 3,699,954 6,764,107
enrolmenta AND received a Pfizer- (93.67) (98.99) (99.31) (98.22) (98.09) (87.03)
BioNTech vaccine
Received no prior COVID-19 10,547 3,587,702 1,091,265 735,237 3,089,610 4,098,988
vaccination, other than Pfizer- (87.56) (89.63) (88.68) (82.87) (81.91) (52.74)
BioNTech vaccine, AND had ≥12
months continuous enrolment AND
received a Pfizer-BioNTech vaccine
Total Pfizer-BioNTech COVID-19 10,547 3,587,702 1,091,265 735,237 3,089,610 4,098,988
b
vaccinated cohort (87.56) (89.63) (88.68) (82.87) (81.91) (52.74)
Pregnant women vaccinated with 0 13,708 (0.34) 0 3,225 (0.36) 10,047 (0.27) 0
1st dose Pfizer-BioNTech
vaccinated included**
a ≥12 months continuous enrolment before t0 (time of vaccination) or lifetime enrolment if age <12 months
b ≥12 months continuous enrolment AND no prior COVID-19 vaccination
*Refer to Table 3 for information on time periods for data; ** Pedianet only has data for a paediatric population, and pregnancy
data for PHARMO and CPRD Aurum will be available for the final report and pregnancy outcomes will be reported

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10.1.1.1. Number and timing of doses in the vaccinated cohort before matching
The number of Pfizer-BioNTech COVID 19 vaccine doses and the timing of vaccination (in
weeks) by data source are summarized in Table 8. Overall as a total of all data sources,
10,665,306 persons received a second dose (84.6%). The interval between the first and
second doses was longer than 6 weeks for 16.6% of these individuals in all data sources
except CPRD Aurum. In CPRD Aurum 81.27% were vaccinated with the second dose
outside the 6-week window. This 6-week interval is based on the recommended 4-week
scheme, with an additional 2-week security margin, except in the UK, where the
recommendation was for a 3-month interval. The number of individuals who received a
second dose within 6 weeks after the 1st dose varied from 53.9% in NHR to 90.0% in
EpiChron. In the paediatric data source, Pedianet, 83.1% of the children received their
second dose within six weeks, at the time of database lock.

At the time of database lock (Table 3), a total of 4,642,445 individuals received a third dose
of the Pfizer-BioNTech COVID 19 vaccine, which is 36.8% of the individuals included who
had received the 1st dose. The interval between doses 2 and 3 varied between data
sources with medians that ranged from 21 weeks (Pedianet) to 31 weeks (SIDIAP). The
current EMA guidelines recommend 28 days between 2nd and 3rd dose for individuals older
than 5 years and at least 3 months for the booster dose (i.e., Comirnaty 30 micrograms)
after primary vaccination for individuals older than 12 years.[17] In Spain (EpiChron and
SIDIAP) individuals aged 18 years and older were recommended to receive a first booster
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(i.e., third dose) five months after the last dose of the complete vaccination schedule. In the
Netherlands (PHARMO) individuals older than 11 years were recommended to receive
repeated vaccinations after at least 3 months after the last vaccination. In Italy (Pedianet)
and Norway (NHR) specific recommendations are for at special risk population only.

A total of 1,021,555 individuals received a fourth dose (8.1%) and 7,801 (0.1%) a fifth dose
at the time of database lock.

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Table 8. Pfizer-BioNTech COVID‑19 vaccine doses received (n, %) and timing (in weeks) by data source*
Pedianet NHR PHARMO EpiChron SIDIAP CPRD Aurum
Total first dose COVID- 10,547 (100) 3,587,702 (100) 1,091,265 (100) 735,237 (100) 3,089,610 (100) 4,098,988 (100)
19 vaccine received, N
Second dose COVID-19
vaccine received
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

Within 6 weeks 8,762 (83.08) 1,935,334 (53.94) 722,638 (66.22) 657,921 (89.48) 2,601,256 (84.19) 229,496 (5.60)
(completion rate) after 1st
dose, n (%)
>6 weeks after 1st dose, n 247 (2.34) 816,101 (22.75) 123,462 (11.31) 27,749 (3.77) 211,158 (6.83) 3,331,182 (81.27)
(%)
Total second dose 9,009 (85.42) 2,751,435 (76.69) 846,100 (77.53) 685,670 (93.26) 2,812,414 (91.03) 3,560,678 (86.87)
received, n (%)
Interval between first
and second dose COVID-
19 vaccine (weeks)
Median (Q1, Q3) 3.14 (3.00, 3.86) 6.00 (5.86, 7.29) 5.00 (5.00, 5.14) 3.00 (3.00, 3.00 (3.00,3.29) 10.57 (8.43, 11.29)
(weeks) 3.00)
Minimum, maximum [2.29-45.86] [2.14-93.86] [2.14-106.71] [2.29-111.14] [2.14-107] [2.14-64.43]
(weeks)
< 2 weeks, n (%) 0 0 0 0 0 0
2-4 weeks, n (%) 7,975 (88.52) 530,109 (19.27) 133,231 (15.75) 654,635 (95.47) 2,566,260 (91.25) 130,728 (3.67)
5-6 weeks, n (%) 787 (8.74) 1,405,225 (51.07) 589,407 (69.66) 3,286 (0.48) 34,996 (1.24) 98,768 (2.77)
7-8 weeks, n (%) 25 (0.28) 414,419 (15.06) 10,032 (1.19) 1,317 (0.19) 80,327 (2.86) 833,971 (23.42)
9-12 weeks, n (%) 9 (0.10) 278,706 (10.13) 8,359 (0.99) 1,605 (0.23) 54,794 (1.95) 2,028,717 (56.98)
13-18 weeks, n (%) 24 (0.27) 37,409 (1.36) 7,315 (0.86) 2,113 (0.31) 23,125 (0.82) 275,106 (7.73)
>18 weeks, n (%) 189 (2.10) 85,567 (3.11) 97,756 (11.55) 22,714 (3.31) 52,912 (1.88) 193,388 (5.43)
Third dose COVID-19 1,230 (11.66) 1,782,452 (49.68) 222,344 (20.37) 237,270 (32.27) 489,483 (15.84) 1,909,666 (46.59)
vaccine received
Interval between second
and third dose COVID-19
vaccine (weeks)
Median (Q1, Q3) 21.43 (19.14, 26.14 (21.86, 29.14) 26.14 (22.86, 33.86) 29.86 (27.43, 31 (27.43, 43.14) 27.29 (24.43,
(weeks) 24.86) 35.00) 29.29)
Minimum, maximum [14.14-55.57] [13-99] [13-108] [19.43-129.43] [13-123.43] [13-62]
(weeks)

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Table 8. Pfizer-BioNTech COVID‑19 vaccine doses received (n, %) and timing (in weeks) by data source*
Pedianet NHR PHARMO EpiChron SIDIAP CPRD Aurum
<12 weeks, n (%) 0 0 0 0 0 0
12-24 weeks, n (%) 925 (75.20) 718,926 (40.33) 97,687 (43.94) 12,506 (5.27) 19,005 (3.88) 498,500 (26.10)
25-37 weeks, n (%) 277 (22.52) 915,451 (51.36) 83,918 (37.74) 173,256 (73.02) 320,713 (65.52) 1,344,468 (70.40)
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

38-50 weeks, n (%) 24 (1.95) 128,686 (7.22) 28,293 (12.72) 24,114 (10.16) 75,538 (15.43) 66,135 (3.46)
>50 weeks, n (%) 4 (0.33) 19,389 (1.09) 12,446 (5.60) 27,394 (11.55) 74,227 (15.16) 563 (0.03)
Fourth dose COVID-19 16 (0.15) 641,085 (17.87) 27,488 (2.52) 67,799 (9.22) 256,834 (8.31) 28,333 (0.69)
vaccine received
Interval between third
and fourth dose COVID-
19 vaccine (weeks)
Median (Q1, Q3) 41.43 (40.61, 40.71 (37.57, 44.71) 40.57 (25.00, 43.57) 49.00 (47.14, 49.86 (47.71, 16.00 (14.14,
(weeks) 44.25) 51.43) 52.57) 18.43)
Minimum, maximum [32.57-45.86] [13-78.57] [13-84.29] [19.43-87.29] [13-90] [13-37.14]
(weeks)
<12 weeks, n (%) 0 0 0 0 0 0
12-24 weeks, n (%) 0 18,672 (2.91) 6,832 (24.85) 652 (0.96) 2,225 (0.87) 28,181 (99.46)
25-37 weeks, n (%) 2 (12.50) 156,815 (24.46) 3,982 (14.49) 2,408 (3.55) 6,361 (2.48) 152 (0.54)
38-50 weeks, n (%) 14 (87.50) 428,152 (66.79) 15,273 (55.56) 44,965 (66.32) 148,333 (57.75) 0
>50 weeks, n (%) 0 37,446 (5.84) 1,401 (5.10) 19,774 (29.17) 99,915 (38.90) 0
Fifth dose COVID-19 0 5,259 (0.15) 2,248 (0.21) 60 (0.01) 234 (0.01) 0
vaccine received
Interval between third and
fourth dose COVID-19
vaccine (weeks)
Median (Q1, Q3) NA 32.00 (23.14, 38.14) 25.00 (18.43, 28.14) 28.07 (22.82, 26.86 (22.00, NA
(weeks) 31.21) 29.82)
Minimum, maximum NA [13-56.14] [13-50.43] [19.86-49.14] [13.29-54] NA
(weeks)
<12 weeks, n (%) 0 0 0 0 0 0
12-24 weeks, n (%) 0 1,489 (28.31) 1,085 (48.27) 22 (36.67) 91 (38.89) 0
25-37 weeks, n (%) 0 2,394 (45.52) 1,089 (48.44) 37 (61.67) 123 (52.56) 0

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Table 8. Pfizer-BioNTech COVID‑19 vaccine doses received (n, %) and timing (in weeks) by data source*
Pedianet NHR PHARMO EpiChron SIDIAP CPRD Aurum
38-50 weeks, n (%) 0 1,370 (26.05) 74 (3.29) 1 (1.67) 17 (7.26) 0
>50 weeks, n (%) 0 6 (0.11) 0 0 3 (1.28) 0
*Refer to Table 3 for information on time periods for data
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

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10.1.1.2. Baseline characteristics of vaccinated cohort (before matching)

The baseline characteristics of those who received at least one dose and three doses of the
Pfizer-BioNTech COVID-19 vaccine in the vaccinated cohort are summarised in Table 9.
The median age of the vaccinated cohort at first dose ranged from 36 years in CPRD Aurum
to 49 years in PHARMO and EpiChron. The median age at first dose in Pedianet, that
contains data for children only, was 10 years. The percentage of females among those who
received a 1st dose varied from 49.10% in Pedianet to 52.70% in CPRD Aurum (Table 9).

A maximum (i.e., with masking of numbers under five) of 162 children under 5 years of age
received a first dose of the Pfizer-BioNTech COVID-19 vaccine.

A total of 9,234 pregnant women received their first dose during their first trimester of
pregnancy and 9,763 during their second trimester.

Most individuals received their first dose in the second quarter of 2021, except in CPRD
Aurum, where it was the first quarter 2021, and Pedianet where the first dose was mainly
received in the last quarter of 2021 and the first quarter of 2022, since paediatric vaccination
began in Italy on 31 May 2021. The third dose was most frequently received in the fourth
quarter of 2021, except in PHARMO where it was received in the first quarter 2022.

The median age of individuals who received a third dose ranged from 36 years in PHARMO
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

to 74 years in SIDIAP. The percentages of females among those who received a third dose
ranged from 49.43% in Pedianet to 56.75% in SIDIAP.

Information on long-term care facility residency and healthcare or essential worker status
was not available in the databases. Only limited Information on personal lifestyle variables
was available: smoking status was only available in PHARMO, EpiChron, and SIDIAP, but
not for all individuals, and although BMI was available in Pedianet, PHARMO, EpiChron,
and SIDIAP the level of missing data was high. Available data for personal lifestyle variables
showed that between 5-10% of those who received dose 1 and dose 3 were current
smokers in EpiChron and SIDIAP and between 1-5% in PHARMO. BMI data indicated
overweight and obesity of below 5% of dose 1 and 3 vaccinated in PHARMO, around 5% in
EpiChron, and between 10-20% in SIDIAP. In SIDIAP 14.95% of those who received dose 1
and 21.04% of those who received dose 3 had been diagnosed as obese. In the other data
sources the percentages were below 8% for both doses. Between 61.72% in PHARMO and
81.39% in EpiChron of those vaccinated had used primary care at least twice in the year
prior to their 1st dose. In the year prior to vaccination, between 0.84% in Pedianet and
2.96% in NHR of those who had received a first dose had been hospitalised at least two
times.

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Table 9. PART 1: Baseline demographics, lifestyle variables and healthcare utilisation at the time of the first and third
Pfizer-BioNTech COVID-19 vaccine doses in the Pfizer-BioNTech vaccinated cohort, by data source*

(SEE PART 2 BELOW)

Pedianet NHR PHARMO
Baseline characteristics 1st dose 3rd dose 1st dose 3rd dose 1st dose 3rd dose
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

Total, n (%) 10,547 1,230 3,587,702 1,782,452 1,091,265 222,344

Demographics
Age (years)
Mean (SD) 9.40 (2.48) 12.76 (0.66) 46.95 (21.06) 58.04 (18.89) 48.66 (21.74) 42.30 (20.09)
Median (Q1, Q3) 10 (7, 12) 13 (12, 13) 47 (29, 64) 61 (46, 73) 49 (30, 69) 36 (27,56)
Age groups (years), n (%)
0-1 0 0 5 (<0.01) 0 <5 0
2-4 17 (0.16) 0 6 (<0.01) 0 78 (0.01) 0
5-11 7,757 (73.55) 0 10,287 (0.29) 16 (<0.01) 10,086 (0.92) 11 (<0.01)
12-15 2,773 (26.29) 1,230 (100) 209,840 (5.85) 290 (0.02) 62,493 (5.73) 3,584 (1.61)
16-17 NA NA 119,437 (3.33) 1,053 (0.06) 36,286 (3.33) 3,795 (1.71)
18-29 NA NA 578,954 (16.14) 196,287 (11.01) 150,513 (13.79) 60,957 (27.42)
30-39 NA NA 490,131 (13.66) 141,347 (7.93) 141,492 (12.97) 59,349 (26.69)
40-49 NA NA 516,944 (14.41) 204,150 (11.45) 147,143 (13.48) 27,489 (12.36)
50-59 NA NA 551,359 (15.37) 303,446 (17.02) 185,075 (16.96) 20,250 (9.11)
60-64 NA NA 244,051 (6.80) 160,737 (9.02) 15,071 (1.38) 4,733 (2.13)
65-69 NA NA 241,396 (6.73) 205,416 (11.52) 90,180 (8.26) 7,663 (3.45)
70-79 NA NA 411,663 (11.47) 372,108 (20.88) 177,166 (16.23) 20,303 (9.13)
80+ NA NA 213,629 (5.95) 197,602 (11.09) 75,680 (6.94) 14,210 (6.39)
Female, n (%) 5,179 (49.10) 608 (49.43) 1,780,147 (49.62) 928,599 (52.10) 557,320 (51.07) 115,032 (51.74)
Females aged 14 to 50 years, 0 0 884,364 (49.68) 302,171 (32.54) 256,091 (45.95) 77,731 (67.57)
n (%)
Pregnancy status, n (%)

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Table 9. PART 1: Baseline demographics, lifestyle variables and healthcare utilisation at the time of the first and third
Pfizer-BioNTech COVID-19 vaccine doses in the Pfizer-BioNTech vaccinated cohort, by data source*

(SEE PART 2 BELOW)

Pedianet NHR PHARMO
Baseline characteristics 1st dose 3rd dose 1st dose 3rd dose 1st dose 3rd dose
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

First trimester 0 0 4,871 (35.57) 1,721 (28.13) NA NA

Second trimester 0 0 4,654 (33.98) 3,148 (51.46) NA NA
Third trimester 0 0 4,171 (30.45) 1,248 (20.40) NA NA
Date of vaccination, n (%)
1 Oct–31 Dec 2020 0 0 10,495 (0.29) 0 7 (<0.01) 0
1 Jan–31 Mar 2021 <5 0 499,803 (13.93) 0 117,235 (10.74) 0
1 Apr–30 Jun 2021 198 (1.88) 0 1,681,233 (46.86) 47 (<0.01) 548,206 (50.24) 113 (0.05)
1 Jul–30 Sep 2021 1,679 (15.92) 0 1,240,266 (34.57) 13,090 (0.73) 312,169 (28.61) 289 (0.13)
1 Oct–31 Dec 2021 3,326 (31.54) <5 111,749 (3.11) 1,167,113 (65.48) 58,228 (5.34) 47,491 (21.36)
1 Jan–31 Mar 2022 5,133 (48.67) 1,087 (88.37) 34,715 (0.97) 548,321 (30.76) 38,966 (3.57) 138,306 (62.20)
1 Apr–30 Jun 2022 139 (1.32) 92 (7.48) 6,317 (0.18) 25,152 (1.41) 4,248 (0.39) 12,424 (5.59)
1 Jul–30 Sep 2022 57 (0.54) 29 (2.36) 2,000 (0.06) 17,591 (0.99) 3,413 (0.31) 6,905 (3.11)
1 Oct–31 Dec 2022 14 (0.13) 19 (1.54) 1,124 (0.03) 11,138 (0.62) 8,263 (0.76) 15,372 (6.91)
Personal lifestyle
characteristics
Smoking status, n (%)
Current NA NA NA NA 46,496 (4.26) 7,310 (3.29)
Former NA NA NA NA 96,172 (8.81) 11,538 (5.19)
Never NA NA NA NA 150,747 (13.81) 23,952 (10.77)
Never or former NA NA NA NA 0 0
Unknown NA NA NA NA 797,850 (73.11) 179,544 (80.75)
Body Mass Index, n (%)**
Underweight (BMI < 20 kg/m2) 6,121 (58.04) 571 (46.42) NA NA 1,792 (0.16) 416 (0.19)

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Table 9. PART 1: Baseline demographics, lifestyle variables and healthcare utilisation at the time of the first and third
Pfizer-BioNTech COVID-19 vaccine doses in the Pfizer-BioNTech vaccinated cohort, by data source*

(SEE PART 2 BELOW)

Pedianet NHR PHARMO
Baseline characteristics 1st dose 3rd dose 1st dose 3rd dose 1st dose 3rd dose
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

Normal weight (BMI 20 to < 1,306 (12.38) 278 (22.60) NA NA 16,620 (1.52) 3,749 (1.69)
25 kg/m2)
Overweight (BMI 25 to < 30 267 (2.53) 67 (5.45) NA NA 32,051 (2.94) 6,784 (3.05)
kg/m2)
Obese (BMI ≥ 30 kg/m2) 51 (0.48) 20 (1.63) NA NA 22,843 (2.09) 5,031 (2.26)
BMI missing 2,802 (26.57) 294 (23.90) NA NA 1,017,959 (93.28) 206,364 (92.81)
Obesity diagnosis or obesity 581 (5.51) 90 (7.32) 121,186 (3.38) 75,473 (4.23) 13,743 (1.26) 2,966 (1.33)
surgery
Healthcare utilisation
Number of hospitalisations, n
(%)
0 10,159 (96.32) 1,184 (96.26) 3,221,921 (89.80) 1,554,994 (87.24) NA NA
1 299 (2.83) 39 (3.17) 259,653 (7.24) 152,648 (8.56) NA NA
2+ 89 (0.84) 7 (0.57) 106,128 (2.96) 74,810 (4.20) NA NA
Number of emergency
department visits, n (%)
0 9,304 (88.21) 1,073 (87.24) NA NA NA NA
1 984 (9.33) 122 (9.92) NA NA NA NA
2+ 259 (2.46) 35 (2.85) NA NA NA NA
Skilled nursing facility, nursing
home, extended care facility, n
(%)
0 NA NA NA NA NA NA
1 NA NA NA NA NA NA
2+ NA NA NA NA N!a NA
Primary care utilisation, n visits
(%)

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Table 9. PART 1: Baseline demographics, lifestyle variables and healthcare utilisation at the time of the first and third
Pfizer-BioNTech COVID-19 vaccine doses in the Pfizer-BioNTech vaccinated cohort, by data source*

(SEE PART 2 BELOW)

Pedianet NHR PHARMO
Baseline characteristics 1st dose 3rd dose 1st dose 3rd dose 1st dose 3rd dose
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

0 1,296 (12.29) 136 (11.06) 509,272 (14.19) 226,088 (12.68) 259,808 (23.81) 53,716 (24.16)
1 1,746 (16.55) 201 (16.34) 367,341 (10.24) 147,512 (8.28) 157,964 (14.48) 32,927 (14.81)
2+ 7,505 (71.16) 893 (72.60) 2,711,089 (75.57) 1,408,852 (79.04) 673,493 (61.72) 135,701 (61.03)
Cancer screening, n (%)
0 NA NA NA NA NA NA
1 NA NA NA NA NA NA
2+ NA NA NA NA NA NA
COVID-19 tests, n (%)***
0 2,964 (28.10) 173 (14.07) NA NA NA NA
1-2 6,521 (61.83) 836 (67.97) NA NA NA NA
3-4 976 (9.25) 203 (16.50) NA NA NA NA
5+ 86 (0.82) 18 (1.46) NA NA NA NA
*Refer to Table 3 for information on time periods for data; ** Child-specific BMI algorithm is pending validation; ***NHR only records positive COVID-19 test
results so the number of tests performed is not available
NA: not applicable

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Table 9. PART 2: Baseline demographics, lifestyle variables and healthcare utilisation at the time of the first and third
Pfizer-BioNTech COVID-19 vaccine doses in the Pfizer-BioNTech vaccinated cohort, by data source

(SEE PART 1 ABOVE)

EpiChron SIDIAP CPRD Aurum
Baseline characteristics 1st dose 3rd dose 1st dose 3rd dose 1st dose 3rd dose
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

Total, n (%) 735,237 237,270 3,089,610 489,483 4,098,988 1,909,666

Demographics
Age (years)
Mean (SD) 50.56 (21.68) 59.99 (19.75) 45.06 (22.62) 63.34 (23.06) 42.36 (22.63) 54.73 (21.73)
Median (Q1, Q3) 49 (35, 70) 58 (46.00, 76) 45 (27, 58) 74 (44, 81) 36 (24, 61) 56 (35, 74)
Age groups (years), n (%)
0-1 0 0 <5 0 <5 0
2-4 0 0 33 (<0.01) <5 8 (<0.01) 0
5-11 2,651 (0.36) 0 190,872 (6.18) 255 (0.05) 7,539 (0.18) <5
12-15 36,900 (5.02) 920 (0.39) 197,402 (6.39) 2,680 (0.55) 337,861 (8.24) 882 (0.05)
16-17 17,685 (2.41) 1,856 (0.78) 98,269 (3.18) 3,651 (0.75) 194,075 (4.73) 17,805 (0.93)
18-29 81,355 (11.07) 14,038 (5.92) 349,245 (11.30) 54,134 (11.06) 938,760 (22.90) 282,772 (14.81)
30-39 93,222 (12.68) 20,799 (8.77) 402,647 (13.03) 41,382 (8.45) 856,638 (20.90) 328,394 (17.20)
40-49 144,299 (19.63) 39,676 (16.72) 610,817 (19.77) 50,159 (10.25) 354,007 (8.64) 186,534 (9.77)
50-59 125,143 (17.02) 48,013 (20.24) 516,261 (16.71) 42,287 (8.64) 338,352 (8.25) 224,484 (11.76)
60-64 13,581 (1.85) 5,182 (2.18) 40,503 (1.31) 7,156 (1.46) 168,489 (4.11) 123,983 (6.49)
65-69 33,854 (4.60) 12,781 (5.39) 43,728 (1.42) 4,961 (1.01) 168,959 (4.12) 127,872 (6.70)
70-79 104,985 (14.28) 48,424 (20.41) 387,065 (12.53) 128,235 (26.20) 373,129 (9.10) 311,740 (16.32)
80+ 81,562 (11.09) 45,581 (19.21) 252,766 (8.18) 154,579 (31.58) 361,168 (8.81) 305,198 (15.98)
Female, n (%) 383,543 (52.17) 125,765 (53.01) 1,604,257 (51.92) 277,783 (56.75) 2,159,983 (52.70) 1,068,133 (55.93)
Females aged 14 to 50 years, 179,872 (46.90) 41,722 (33.17) 780,629 (48.66) 81,714 (29.42) 1,272,611 (58.92) 467,770 (43.79)
n (%)
Pregnancy status, n (%)

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Table 9. PART 2: Baseline demographics, lifestyle variables and healthcare utilisation at the time of the first and third
Pfizer-BioNTech COVID-19 vaccine doses in the Pfizer-BioNTech vaccinated cohort, by data source

(SEE PART 1 ABOVE)

EpiChron SIDIAP CPRD Aurum
Baseline characteristics 1st dose 3rd dose 1st dose 3rd dose 1st dose 3rd dose
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

First trimester 921 (28.60) 83 (22.68) 3,442 (34.31) 334 (34.90) NA NA

Second trimester 1,383 (42.95) 175 (47.81) 3,726 (37.14) 364 (38.04) NA NA
Third trimester 916 (28.45) 108 (29.51) 2,864 (28.55)) 259 (27.06) NA NA
Date of vaccination, n (%)
1 Oct–31 Dec 2020 2,297 (0.31) 0 3,401 (0.11) 0 192,811 (4.70) 0
1 Jan–31 Mar 2021 106,096 (14.43) 0 365,417 (11.83) 0 1,591,029 (38.82) 0
1 Apr–30 Jun 2021 379,460 (51.61) 0 1,588,038 (51.40) 8 (<0.01) 1,223,197 (29.84) 42 (<0.01)
1 Jul–30 Sep 2021 224,287 (30.51) 11,418 (4.81) 855,425 (27.69) 20,952 (4.28) 512,769 (12.51) 138,511 (7.25)
1 Oct–31 Dec 2021 16,365 (2.23) 101,746 (42.88) 168,924 (5.47) 273,618 (55.90) 447,894 (10.93) 1,538,451 (80.56)
1 Jan–31 Mar 2022 4,726 (0.64) 81,254 (34.25) 91,825 (2.97) 43,745 (8.94) 131,288 (3.20) 232,662 (12.18)
1 Apr–30 Jun 2022 604 (0.08) 11,614 (4.89) 8,177 (0.26) 64,122 (13.10) NA NA
1 Jul–30 Sep 2022 437 (0.06) 12,228 (5.15) 4,142 (0.13) 49,251 (10.06) NA NA
1 Oct–31 Dec 2022 586 (0.08) 12,953 (5.46) 2,526 (0.08) 26,343 (5.38) NA NA
Personal lifestyle
characteristics
Smoking status, n (%)
Current 49,706 (6.76) 16,164 (6.81) 268,594 (8.69) 27,891 (5.70) NA NA
Former 0 0 89,577 (2.90) 19,790 (4.04) NA NA
Never 0 0 1,025,000 (33.18) 243,772 (49.80) NA NA
Never or former 135,119 (18.38) 55,506 (23.39) 0 0 NA NA
Unknown 550,412 (74.86) 165,600 (69.79) 1,706,439 (55.23) 198,030 (40.46) NA NA
Body Mass Index, n (%)

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Table 9. PART 2: Baseline demographics, lifestyle variables and healthcare utilisation at the time of the first and third
Pfizer-BioNTech COVID-19 vaccine doses in the Pfizer-BioNTech vaccinated cohort, by data source

(SEE PART 1 ABOVE)

EpiChron SIDIAP CPRD Aurum
Baseline characteristics 1st dose 3rd dose 1st dose 3rd dose 1st dose 3rd dose
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Underweight (BMI < 20 18,529 (2.52) 2,288 (0.96) 242,023 (7.83) 10,554 (2.16) NA NA
kg/m2)
Normal weight (BMI 20 to < 44,307 (6.03) 11,245 (4.74) 378,352 (12.25) 69,809 (14.26) NA NA
25 kg/m2)
Overweight (BMI 25 to < 30 44,365 (6.03) 16,789 (7.08) 469,428 (15.19) 121,042 (24.73) NA NA
kg/m2)
Obese (BMI ≥ 30 kg/m2) 33,299 (4.53) 14,200 (5.98) 350,983 (11.36) 87,386 (17.85) NA NA
BMI missing 594,737 (80.89) 192,748 (81.24) 1,648,824 (53.37) 200,692 (41) NA NA
Obesity diagnosis or obesity 47,873 (6.51) 17,665 (7.45) 461,774 (14.95) 102,999 (21.04) 177,831 (4.34) 113,375 (5.94)
surgery
Healthcare utilisation
Number of hospitalisations, n
(%)
0 675,629 (91.89) 213,464 (89.97) 2,868,988 (92.86) 425,078 (86.84) 4,020,290 (98.08) 1,861,773 (97.49)
1 47,532 (6.46) 18,130 (7.64) 176,813 (5.72) 46,656 (9.53) 60,831 (1.48) 36,642 (1.92)
2+ 12,076 (1.64) 5,676 (2.39) 43,809 (1.42) 17,749 (3.63) 17,867 (0.44) 11,251 (0.59)
Number of emergency
department visits, n (%)
0 594,158 (80.81) 188,645 (79.51) NA NA 3,648,640 (89.01) 1,678,366 (87.89)
1 95,611 (13) 32,562 (13.72) NA NA 306,897 (7.49) 154,567 (8.09)
2+ 45,468 (6.18) 16,063 (6.77) NA NA 143,451 (3.50) 76,733 (4.02)
Skilled nursing facility, nursing
home, extended care facility,
n (%)
0 NA NA NA NA 4,094,595 (99.89) 1,907,419 (99.88)
1 NA NA NA NA 3,071 (0.07) 1,630 (0.09)
2+ NA NA NA NA 1,322 (0.03) 617 (0.03)

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Table 9. PART 2: Baseline demographics, lifestyle variables and healthcare utilisation at the time of the first and third
Pfizer-BioNTech COVID-19 vaccine doses in the Pfizer-BioNTech vaccinated cohort, by data source

(SEE PART 1 ABOVE)

EpiChron SIDIAP CPRD Aurum
Baseline characteristics 1st dose 3rd dose 1st dose 3rd dose 1st dose 3rd dose
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

Primary care utilisation, n

visits (%)
0 84,598 (11.51) 16,016 (6.75) 400,364 (12.96) 21,726 (4.44) NA NA
1 52,260 (7.11) 13,792 (5.81) 235,349 (7.62) 15,840 (3.24) NA NA
2+ 598,379 (81.39) 207,462 (87.44) 2,453,897 (79.42) 451,917 (92.33) NA NA
Cancer screening, n (%)
0 NA NA NA NA 3,601,937 (87.87) 1,440,630 (75.44)
1 NA NA NA NA 287,783 (7.02) 206,013 (10.79)
2+ NA NA NA NA 209,268 (5.11) 263,023 (13.77)
COVID-19 tests, n (%)
0 518,190 (70.48) 132,574 (55.87) 1,368,977 (44.31) 170,171 (34.77) 2,697,394 (65.81) 1,084,754 (56.80)
1-2 217,047 (29.52) 104,696 (44.13) 1,209,464 (39.15) 181,381 (37.06) 1,095,722 (26.73) 563,293 (29.50)
3-4 0 0 346,542 (11.22) 71,857 (14.68) 188,843 (4.61) 138,670 (7.26)
5+ 0 0 164,627 (5.33) 66,074 (13.50) 117,029 (2.86) 122,949 (6.44)
*Refer to Table 3 for information on time periods for data
NA: not applicable

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10.1.2. Matched cohorts

The attrition data for the matched vaccinated and unvaccinated cohorts are summarised by
data source in Table 10. From a total of 12,613,349 vaccinated individuals included,
12,400,847 (98.32%) could be matched with an unvaccinated individual at time zero (Table
10). Unvaccinated individuals were eligible to be matched until they received any COVID-19
vaccine. Although each unvaccinated individual could be matched several times, the median
number of times was one in each of the data sources.
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Table 10. Attrition table for the matched cohort by data source*
Pedianet NHR PHARMO EpiChron SIDIAP CPRD Aurum
Vaccinated cohort
Received a Pfizer-BioNTech 12,046 (100) 4,002,649 (100) 1,230,629 (100) 887,188 (100) 3,772,034 (100) 7,772,586 (100)
vaccine, n (%)
Total vaccinated included, n 10,547 (87.56) 3,587,702 (89.63) 1,091,265 (88.68) 735,237 (82.87) 3,089,610 (81.91) 4,098,988 (52.74)
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

(%)a
Pregnant women vaccinated, 0 13,708 (0.34) NA 3,225 (0.36) 10,047 (0.27) NA
n (%)
Matched cohort
Vaccinees matched, n (%) 10,500 (87.17) 3,584,238 (89.55) 992,144 (80.62) 627,972 (70.78) 3,087,124 (81.84) 4,098,869 (52.73)
Served as control before 3,061 (29.15) 2,474,628 (69.04) 380,302 (38.33) 298,505 (47.53) 1,657,254 (53.68) 1,347,172 (32.87)
vaccination, n (%)
Unvaccinated, n 10,500 3,584,238 992,144 627,972 3,087,124 4,098,869
Unique unvaccinated 8,022 (76.40) 2,082,345 (58.10) 706,102 (71.17) 394,137 (62.76) 1,962,666 (63.58) 3,059,568 (74.64)
matched included, n (%)
Mean number of times a 1.31 1.72 1.41 1.59 1.57 1.34
comparator selected for
matching
Median (Q1–Q3) 1 (1.00–1.00) 1 (1.00–2.00) 1 (1.00–2.00) 1 (1.00–2.00) 1 (1.00–2.00) 1 (1.00–2.00)
Min, Max 1 (6) 1 (15) 1 (10) 1 (23) 1 (15) 1 (12)
1, n (%) 6,084 (75.84) 1,187,374 (57.02) 496,100 (70.26) 248,034 (62.93) 1,233,234 (62.83) 2,268,076 (55.33)
2, n (%) 1,506 (18.77) 524,128 (25.17) 152,871 (21.65) 91,510 (23.22) 470,593 (23.98) 599,347 (14.62)
3, n (%) 342 (4.26) 223,978 (10.76) 42,753 (6.05) 34,322 (8.71) 170,468 (8.69) 148,607 (3.63)
4, n (%) 75 (0.93) 90,669 (4.35) 10,845 (1.54) 12,519 (3.18) 57,842 (2.95) 34,048 (0.83)
5 or more, n (%) 15 (0.19) 56,196 (2.70) 3,533 (0.50) 7,752 (1.97) 30,529 (1.56) 9,490 (0.23)
a ≥12 months continuous enrolment AND no prior COVID-19 vaccination, other than Pfizer-BioNTech vaccine
*Refer to Table 3 for information on time periods for data;

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The median months of follow up from first dose until censoring ranged from 0.9 months in
NHR to 11.3 months in Pedianet. The follow-up time was short in all data sources, but was
similar for vaccinated and unvaccinated cohorts since the censoring date was the same for
both (Table 11).

A total of 6,217,296 (50.14%) matched unvaccinated individuals were censored because of

receipt of a COVID-19 vaccine (Pfizer-BioNTech COVID-19 vaccine or a non-Pfizer-
BioNTech COVID-19 vaccine) (Table 11). The percentages of individuals censored for
exiting the data sources or end of data availability ranged from 0.4% in the vaccinated
cohort in EpiChron to 36.7% in unvaccinated cohort in CPRD Aurum.
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Table 11. Cohort follow-up and reasons for censoring by vaccination status (matched cohort design), by data source
Pedianet NHR PHARMO
Vac Unvac Vac Unvac Vac Unvac
Total, N 10,500 10,500 3,584,238 3,584,238 992,144 992,144
Person-months of follow-up
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Median (Q1, Q3) (months) 11.30 (1.90, 11.90) 11.30 (1.90, 11.90) 0.90 (0.40, 2.60) 0.90 (0.40, 2.50) 5.90 (0.60, 16.40) 5.60 (0.70, 15.10)
Min, max (months) 0.10, 22.10 0, 22.10 0, 24.30 0, 24.30 0, 29.70 0, 29.70
Reasons for censoring, n (%)
Non-Pfizer-BioNTech vaccine 8 (0.10) 322 (3.10) 288,041 (8) 322,446 (9) 165,165 (16.60) 87,027 (8.80)
received
Unvaccinated received Pfizer or NA 3,086 (29.40) NA 2,426,459 (67.70) NA 422,533 (42.60)
non-Pfizer COVID-19 vaccine
Exit from data sourcea 738 (7.00) 665 (6.30) 551,997 (15.40) 552,043 (15.40) 126,410 (12.70) 195,907 (19.70)

EpiChron SIDIAP CPRD Aurum

Vac Unvac Vac Unvac Vac Unvac
Total, N 627,972 627,972 3,087,124 3,087,124 4,098,869 4,098,869
Person-months of follow-up
Median (Q1, Q3) (months) 1 (0.30, 7.60) 1 (0.30, 7.60) 1.20 (0.30, 7.10) 1.20 (0.30, 7.10) 2.20 (0.60, 6.70) 2.10 (0.60, 6.50)
Min, max (months) 0, 31.20 0, 31.20 0.10, 30.0 0.10, 30.0 0, 15.40 0, 15.40
Reasons for censoring, n (%)
Non-Pfizer-BioNTech vaccine 38,763 (6.20) 79,088 (12.60) 267,231 (8.70) 568,186 (18.40) 166,538 (4.10) 1,102,616 (26.90)
received
Unvaccinated received Pfizer or NA 368,991 (58.80) NA 1,655,969 (53.60) NA 1,340,258 (32.70)
non-Pfizer COVID-19 vaccine
Exit from data sourcea 2,488 (0.40) 3,212 (0.50) 0 0 1,505,360 (36.70) 1,499,323 (36.60)
a Administrative end of follow-up or death; NA not applicable

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10.1.2.1. Baseline characteristics

The prevalence of the baseline characteristics in the vaccinated and unvaccinated cohorts,
and their absolute standardised differences (ASDs) for each data source are summarised in
Table 12. The median age at first dose in the vaccinated and unvaccinated cohorts ranged
from 36 years in CPRD Aurum to 49 years in PHARMO. The median age at first dose in
Pedianet, was 10 years. The percentage of females (in both cohorts since they were
matched on sex) who had received a 1st dose from 49.08% in Pedianet to 52.70% in CPRD
Aurum (Table 12). Most first doses of the Pfizer-BioNTech COVID-19 vaccine were
administered in the second quarter of 2021, except in CPRD Aurum in the first quarter of
2021 and in the paediatric population in Pedianet and in CPRD Aurum when this was in the
first quarter of 2022, due to the later starting date for paediatric vaccination.

Pregnancy information at time zero was collected in NHR, EpiChron and SIDIAP. Pregnant
women were more frequently vaccinated in the second trimester in EpiChron and SIDIAP
and in the first trimester in NHR. Information on long-term care facility residency and
healthcare worker or essential worker status could not be identified in the data sources.

Smoking status was missing for Pedianet, NHR and CPRD Aurum. Among those with data,
around 4% were current smokers in PHARMO and between 5 and 9% in EpiChron and
SIDIAP, respectively. BMI data were missing for about 27% of individuals in Pedianet, 53%
of individuals in SIDIAP, about 80% of individuals in EpiChron and about 95% of individuals
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

in PHARMO; BMI data were not available in NHR. The percentages of individuals with an
obesity diagnosis or obesity surgery were similar between the vaccinated and unvaccinated
cohorts.

More unvaccinated individuals had no primary care visits, with 37% of unvaccinated
individuals compared with 25% of vaccinated individuals in PHARMO, 23% of unvaccinated
individuals versus 13% of vaccinated individuals in EpiChron, and 13% of unvaccinated
individuals versus 18% of vaccinated individuals in SIDIAP. Also, more unvaccinated
individuals did not have any COVID-19 tests, with the most notable differences in SIDIAP
(52% of unvaccinated individuals compared with 44% of vaccinated individuals) and CPRD
Aurum (74% of unvaccinated individuals versus 66% of vaccinated individuals). Other
healthcare utilisation outcomes, such as hospitalisation, were similar between vaccinated
and unvaccinated individuals across data sources.

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Table 12. Part 1: Baseline demographics, lifestyle variables and health resources utilisation for vaccinated and
unvaccinated cohorts with absolute standardised difference (ASD) by data source

(SEE PART 2 BELOW)

Pedianet NHR PHARMO
Vac Unvac ASD Vac Unvac ASD Vac Unvac ASD
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Total, N 10,500 10,500 3,584,238 3,584,238 992,144 992,144

Demographics
Age (years) 0.09 0.004 0.002
Mean (SD) 9.40 (2.48) 9.17 (2.46) 46.94 (21.05) 46.87 (21.05) 48.31 (21.64) 48.26 (21.63)
Median (Q1, Q3) 10 (7.00, 12.00) 10 (7.00, 11.00) 47 (29.00, 64.00) 47 (29.00, 64.00) 49 (30.00, 68.00) 49 (30.00, 68.00)
Age groups (years), n (%) 0.301 0.105 0.071
0-1 0 0 5 <5 <5 <5
2-4 17 (0.16) 357 (3.40) 6 260 (0.01) 73 (0.01) 271 (0.03)
5-11 7,733 (73.65) 8,205 (78.14) 10,273 (0.29) 41,151 (1.15) 9,446 (0.95) 14,299 (1.44)
12-15 2,750 (26.19) 1,938 (18.46) 209,744 (5.85) 193,192 (5.39) 58,519 (5.90) 54,215 (5.46)
16-17 NA NA 119,332 (3.33) 119,234 (3.33) 33,644 (3.39) 34,065 (3.43)
18-29 NA NA 578,529 (16.14) 563,690 (15.73) 138,134 (13.92) 137,071 (13.82)
30-39 NA NA 489,811 (13.67) 492,387 (13.74) 129,445 (13.05) 129,077 (13.01)
40-49 NA NA 516,547 (14.41) 516,082 (14.40) 133,389 (13.44) 133,575 (13.46)
50-59 NA NA 550,997 (15.37) 551,472 (15.39) 170,375 (17.17) 166,430 (16.77)
60-64 NA NA 243,827 (6.80) 250,854 (7) 12,585 (1.27) 18,546 (1.87)
65-69 NA NA 241,138 (6.73) 235,984 (6.58) 82,555 (8.32) 81,295 (8.19)
70-79 NA NA 411,192 (11.47) 410,834 (11.46) 160,688 (16.20) 162,199 (16.35)
80+ NA NA 212,837 (5.94) 209,096 (5.83) 63,289 (6.38) 61,099 (6.16)
Female, n (%) 5,153 (49.08) 5,153 (49.08) 0 1,778,272 (49.61) 1,778,272 (49.61) 0 506,601 (51.06) 506,601 (51.06) 0
Females aged 14 to 50 0 0 883,609 (49.69) 879,819 (49.48) 233,578 (46.11) 233,234 (46.04)
years, n (%)
Pregnancy status, n (%) 0

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Table 12. Part 1: Baseline demographics, lifestyle variables and health resources utilisation for vaccinated and
unvaccinated cohorts with absolute standardised difference (ASD) by data source

(SEE PART 2 BELOW)

Pedianet NHR PHARMO
Vac Unvac ASD Vac Unvac ASD Vac Unvac ASD
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First trimester NA NA 4,787 (35.46) 3,463 (26.05) NA NA

Second trimester NA NA 4,605 (34.11) 4,209 (26.05) NA NA
Third trimester NA NA 4,108 (30.43) 5,624 (42.30) NA NA
Date of vaccination or 0 0 0
matching, n (%)
1 Oct–31 Dec 2020 0 0 10,467 (0.29) 10,467 (0.29) 6 6
1 Jan–31 March 2021 <5 <5 499,170 (13.93) 499,170 (13.93) 105,029 (10.59) 105,029 (10.59)
1 Apr–30 Jun 2021 197 (1.88) 197 (1.88) 1,680,167 (46.88) 1,680,167 (46.88) 504,483 (50.85) 504,483 (50.85)
1 Jul–30 Sep 2021 1,667 (15.88) 1,667 (15.88) 1,239,193 (34.57) 1,239,193 (34.57) 287,879 (29.02) 287,879 (29.02)
1 Oct–31 Dec 2021 3,315 (31.57) 3,315 (31.57) 111,312 (3.11) 111,312 (3.11) 49,299 (4.97) 49,299 (4.97)
1 Jan–31 Mar 2022 5,115 (48.71) 5,115 (48.71) 34,530 (0.96) 34,530 (0.96) 32,788 (3.30) 32,788 (3.30)
1 Apr–30 Jun 2022 137 (1.30) 137 (1.30) 6,306 (0.18) 6,306 (0.18) 3,463 (0.35) 3,463 (0.35)
1 Jul–30 Sep 2022 54 (0.51) 54 (0.51) 1,980 (0.06) 1,980 (0.06) 2,650 (0.27) 2,650 (0.27)
1 Oct–31 Dec 2022 14 (0.13) 14 (0.13) 1,113 (0.03) 1,113 (0.03) 6,181 (0.62) 6,181 (0.62)
Personal lifestyle
characteristics
Smoking status 0.123
Current NA NA NA NA 41,307 (4.16) 40,572 (4.09)
Former NA NA NA NA 85,675 (8.64) 66,740 (6.73)
Never NA NA NA NA 134,784 (13.59) 105,582 (10.64)
Never or former NA NA NA NA 0 0
Unknown NA NA NA NA 730,378 (73.62) 779,250 (78.54)
BMI, n (%)* 0.041 0.054

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Table 12. Part 1: Baseline demographics, lifestyle variables and health resources utilisation for vaccinated and
unvaccinated cohorts with absolute standardised difference (ASD) by data source

(SEE PART 2 BELOW)

Pedianet NHR PHARMO
Vac Unvac ASD Vac Unvac ASD Vac Unvac ASD
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Underweight (BMI 6,093 (58.03) 6,029 (57.42) NA NA 1,593 (0.16) 1,549 (0.16)
<20kg/m2)
Normal weight (BMI 20 to 1,296 (12.34) 1,229 (11.70) NA NA 14,902 (1.50) 11,944 (1.20)
<25kg/m2)
Overweight (BMI 25 to 265 (2.52) 234 (2.23) NA NA 28,814 (2.90) 22,556 (2.27)
<30kg/m2)
Obese (BMI ≥30kg/m2) 51 (0.49) 47 (0.45) NA NA 20,496 (2.07) 17,281 (1.74)
BMI missing 2,795 (26.62) 2,961 (28.20) 3,584,238 (100) 3,584,238 (100) 926,339 (93.37) 938,814 (94.62)
Obesity diagnosis or 578 (5.50) 524 (4.99) 121,103 (3.38) 103,663 (2.89) 11,413 (1.15) 12,144 (1.22)
obesity surgery
Healthcare utilisation
Number of hospitalisations, 0.006 0.002
n (%)
0 10,114 (96.32) 10,122 (96.40) 3,219,179 (89.81) 3,219,132 (89.81) NA NA
1 297 (2.83) 294 (2.80) 259,206 (7.23) 260,313 (7.26) NA NA
2+ 89 (0.85) 84 (0.80) 105,853 (2.95) 104,793 (2.92) NA NA
Number of emergency 0.017
department visits, n (%)
0 9,265 (88.24) 9,312 (88.69) NA NA NA NA
1 976 (9.30) 952 (9.07) NA NA NA NA
2+ 259 (2.47) 236 (2.25) NA NA NA NA
Skilled nursing facility,
nursing home, or extended
care facility stay, n (%)
0 NA NA NA NA NA NA
1 NA NA NA NA 0 NA
2+ NA NA NA NA 0 NA

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Table 12. Part 1: Baseline demographics, lifestyle variables and health resources utilisation for vaccinated and
unvaccinated cohorts with absolute standardised difference (ASD) by data source

(SEE PART 2 BELOW)

Pedianet NHR PHARMO
Vac Unvac ASD Vac Unvac ASD Vac Unvac ASD
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

Primary care utilisation, n 0.035 0.097 0.272

(%)
0 1,294 (12.32) 1,403 (13.36) 508,912 (14.20) 632,646 (17.65) 244,890 (24.68) 368,551 (37.15)
1 1,745 (16.62) 1,787 (17.02) 367,102 (10.24) 374,005 (10.43) 146,021 (14.72) 121,939 (12.29)
2+ 7,461 (71.06) 7,310 (69.62) 2,708,224 (75.56) 2,577,587 (71.91) 601,233 (60.60) 501,654 (50.56)
Cancer screening, n (%)
0 NA NA NA NA NA NA
1 NA NA NA NA NA NA
2+ NA NA NA NA NA NA
COVID-19 tests, n (%) 0.085 0.001
0 2,958 (28.17) 3,319 (31.61) 3,508,985 (97.90) 3,508,681 (97.89) NA NA
1-2 6,489 (61.80) 6,291 (59.91) 75,251 (2.10) 75,555 (2.11) NA NA
3-5 967 (9.21) 826 (7.87) <5 <5 NA NA
5+ 86 (0.82) 64 (0.61) 0 0 NA NA
ASD: absolute standardised difference; NR: not reportable; Vac: vaccinated cohort; Unvac: unvaccinated cohort; NA: not available
* Child-specific BMI algorithm is pending validation

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Table 12. Part 2: Baseline demographics, lifestyle variables and health resources utilisation for vaccinated and
unvaccinated cohorts with absolute standardised difference (ASD) by data source

(SEE PART 1 ABOVE)

EpiChron SIDIAP CRPD Aurum
Vac Unvac ASD Vac Unvac ASD Vac Unvac ASD
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

Total, N 627,972 627,972 3,087,124 3,087,124 4,098,869 4,098,869

Demographics
Age (years) 0.005 0.004 0.003
Mean (SD) 49.60 (21.31) 49.49 (21.27) 45.05 (22.61) 44.96 (22.58) 42.36 (22.63) 42.30 (22.65)
Median (Q1, Q3) 48(34.00,69.00) 48(34.00,68.00) 45(27.00,58.00) 45(27.00,58.00) 36(24.00,61.00) 36(24.00,61.00)
Age groups (years), n (%) 0.065 0.085 0.137
0-1 0 0 <5 <5 <5 <5
2-4 0 0 33 (<0.01) 8,053 (0.26) 8 (<0.01) 168 (<0.01)
5-11 2,359 (0.38) 5,169 (0.82) 190,826 (6.18) 207,210 (6.71) 7,539 (0.18) 55,274 (1.35)
12-15 32,535 (5.18) 30,985 (4.93) 197,309 (6.39) 181,315 (5.87) 337,854 (8.24) 308,831 (7.53)
16-17 15,602 (2.48) 14,860 (2.37) 98,219 (3.18) 88,587 (2.87) 194,067 (4.73) 191,220 (4.67)
18-29 72,157 (11.49) 71,887 (11.45) 348,959 (11.30) 351,451 (11.38) 938,744 (22.90) 924,479 (22.55)
30-39 81,333 (12.95) 81,879 (13.04) 402,401 (13.03) 404,437 (13.10) 856,627 (20.90) 850,910 (20.76)
40-49 129,303 (20.59) 129,898 (20.69) 610,549 (19.78) 612,716 (19.85) 353,997 (8.64) 356,638 (8.70)
50-59 108,495 (17.28) 106,539 (16.97) 516,017 (16.72) 504,880 (16.35) 338,341 (8.25) 340,973 (8.32)
60-64 10,537 (1.68) 11,046 (1.76) 40,440 (1.31) 45,703 (1.48) 168,483 (4.11) 173,654 (4.24)
65-69 27,290 (4.35) 29,954 (4.77) 43,663 (1.41) 50,501 (1.64) 168,955 (4.12) 170,790 (4.17)
70-79 86,404 (13.76) 86,409 (13.76) 386,748 (12.53) 392,338 (12.71) 373,119 (9.10) 376,369 (9.18)
80+ 61,957 (9.87) 59,346 (9.45) 251,958 (8.16) 239,931 (7.77) 361,132 (8.81) 349,561 (8.53)
Female, n (%) 325,995 (51.91) 325,995 (51.91) 0 1,602,861 (51.92) 1,602,861 (51.92) 0 2,159,944 (52.70) 2,159,944 (52.70) 0
Females aged 14 to 50 157,179 (48.22) 157,386 (48.28) 780,072 (48.67) 778,035 (48.54) 1,272,597 (58.92) 1,268,839 (58.74)
years, n (%)
Pregnancy status, n (%) 0 0 0

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Table 12. Part 2: Baseline demographics, lifestyle variables and health resources utilisation for vaccinated and
unvaccinated cohorts with absolute standardised difference (ASD) by data source

(SEE PART 1 ABOVE)

EpiChron SIDIAP CRPD Aurum
Vac Unvac ASD Vac Unvac ASD Vac Unvac ASD
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

First trimester 388 (29.57) 352 (0.22) 3,366 (34.38) 2,984 (30.74) NA NA
Second trimester 553 (42.15) 494 (37.60) 3,636 (37.13) 3,302 (34.02) NA NA
Third trimester 371 (28.28) 468 (35.62) 2,790 (28.49) 3,421 (35.24) NA NA
Date of vaccination or 0 0 2.085
matching, n (%)
1 Oct–31 Dec 2020 1,914 (0.30) 1,914 (0.30) 3,390 (0.11) 3,390 (0.11) 192,806 (4.70) 192,806 (4.70)
1 Jan–31 March 2021 90,082 (14.34) 90,082 (14.34) 365,000 (11.82) 365,000 (11.82) 1,590,992 (38.82) 1,590,992 (38.82)
1 Apr–30 Jun 2021 326,134 (51.93) 326,134 (51.93) 1,587,152 (51.41) 1,587,152 (51.41) 1,223,173 (29.84) 1,223,173 (29.84)
1 Jul–30 Sep 2021 193,267 (30.78) 193,267 (30.78) 854,613 (27.68) 854,613 (27.68) 512,743 (12.51) 512,743 (12.51)
1 Oct–31 Dec 2021 11,741 (1.87) 11,741 (1.87) 168,650 (5.46) 168,650 (5.46) 447,871 (10.93) 447,871 (10.93)
1 Jan–31 Mar 2022 3,525 (0.56) 3,525 (0.56) 91,786 (2.97) 91,786 (2.97) 131,284 (3.20) 131,284 (3.20)
1 Apr–30 Jun 2022 448 (0.07) 448 (0.07) 8,168 (0.26) 8,168 (0.26) 0 0
1 Jul–30 Sep 2022 304 (0.05) 304 (0.05) 4,134 (0.13) 4,134 (0.13) 0 0
1 Oct–31 Dec 2022 297 (0.05) 297 (0.05) 2,505 (0.08) 2,505 (0.08) 0 0
Personal lifestyle
characteristics
Smoking status 0.042 0.032
Current 42,056 (6.70) 39,551 (6.30) 268,452 (8.70) 284,305 (9.21) NA NA
Former 0 0 89,495 (2.90) 81,470 (2.64) NA NA
Never 0 0 1,023,895 (33.17) 991,306 (32.11) NA NA
Never or former 111,199 (17.71) 102,607 (16.34) 0 0 NA NA
Unknown 474,717 (75.60) 485,814 (77.36) 1,705,282 (55.24) 1,730,043 (56.04) 4,098,869 (100) 4,098,869 (100)
BMI, n (%) 0.042 0.019

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Table 12. Part 2: Baseline demographics, lifestyle variables and health resources utilisation for vaccinated and
unvaccinated cohorts with absolute standardised difference (ASD) by data source

(SEE PART 1 ABOVE)

EpiChron SIDIAP CRPD Aurum
Vac Unvac ASD Vac Unvac ASD Vac Unvac ASD
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

Underweight (BMI 16,234 (2.59) 13,922 (2.22) 241,878 (7.84) 245,048 (7.94) NA NA
<20kg/m2)
Normal weight (BMI 20 to 37,463 (5.97) 33,214 (5.29) 377,833 (12.24) 363,715 (11.78) NA NA
<25kg/m2)
Overweight (BMI 25 to 36,338 (5.79) 34,490 (5.49) 468,918 (15.19) 457,009 (14.80) NA NA
<30kg/m2)
Obese (BMI ≥30kg/m2) 26,959 (4.29) 26,879 (4.28) 350,764 (11.36) 354,932 (11.50) NA NA
BMI missing 510,978 (81.37) 519,467 (82.72) 1,647,731 (53.37) 1,666,420 (53.98) 4,098,869 (100) 4,098,869 (100)
Obesity diagnosis or 38,148 (6.07) 38,588 (6.14) 461,540 (14.95) 465,994 (15.09) 177,827 (4.34) 183,067 (4.47)
obesity surgery
Healthcare utilisation
Number of hospitalisations, 0.014 0.006 0.016
n (%)
0 583,439 (92.91) 584,736 (93.11) 2,866,870 (92.87) 2,862,986 (92.74) 4,020,179 (98.08) 4,012,630 (97.90)
1 36,079 (5.75) 34,283 (5.46) 176,526 (5.72) 178,480 (5.78) 60,824 (1.48) 64,253 (1.57)
2+ 8,454 (1.35) 8,953 (1.43) 43,728 (1.42) 45,658 (1.48) 17,866 (0.44) 21,986 (0.54)
Number of emergency 0.025 0.021
department visits, n (%)
0 514,931 (82) 520,123 (82.83) NA NA 3,648,548 (89.01) 3,656,162 (89.20)
1 78,097 (12.44) 73,002 (11.63) NA NA 306,880 (7.49) 288,678 (7.04)
2+ 34,944 (5.56) 34,847 (5.55) NA NA 143,441 (3.50) 154,029 (3.76)
Skilled nursing facility, 0.006
nursing home, or extended
care facility stay, n (%)
0 NA NA NA NA 4,094,478 (99.89) 4,093,713 (99.87)
1 NA NA NA NA 3,070 (0.07) 3,733 (0.09)
2+ NA NA NA NA 1,321 (0.03) 1,423 (0.03)

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Table 12. Part 2: Baseline demographics, lifestyle variables and health resources utilisation for vaccinated and
unvaccinated cohorts with absolute standardised difference (ASD) by data source

(SEE PART 1 ABOVE)

EpiChron SIDIAP CRPD Aurum
Vac Unvac ASD Vac Unvac ASD Vac Unvac ASD
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

Primary care utilisation, n 0.264 0.153 0

(%)
0 80,867 (12.88) 143,472 (22.85) 400,309 (12.97) 570,263 (18.47) NA NA
1 47,953 (7.64) 45,942 (7.32) 235,283 (7.62) 232,983 (7.55) NA NA
2+ 499,152 (79.49) 438,558 (69.84) 2,451,532 (79.41) 2,283,878 (73.98) NA NA
Cancer screening, n (%) 0.041
0 NA NA NA NA 3,601,837 (87.87) 3,655,938 (89.19)
1 NA NA NA NA 287,776 (7.02) 257,800 (6.29)
2+ NA NA NA NA 209,256 (5.11) 185,131 (4.52)
COVID-19 tests, n (%) 0.089 0.175 0.185
0 459,117 (73.11) 483,174 (76.94) 1,368,338 (44.32) 1,606,662 (52.04) 2,697,349 (65.81) 3,032,105 (73.97)
1-2 168,855 (26.89) 144,798 (23.06) 1,208,357 (39.14) 1,099,113 (35.60) 1,095,676 (26.73) 864,685 (21.10)
3-5 0 0 346,123 (11.21) 282,407 (9.15) 188,833 (4.61) 137,063 (3.34)
5+ 0 0 164,306 (5.32) 98,942 (3.20) 117,011 (2.85) 65,016 (1.59)
ASD: absolute standardised difference; NR: not reportable; Vac: vaccinated cohort; Unvac: unvaccinated cohort; NA: not available

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10.1.2.2. Baseline comorbidities

The prevalence of baseline comorbidities in the 10 years prior to time zero in the vaccinated
and unvaccinated cohorts with absolute standardised differences (ASDs) are summarised
by data source in Table 13. About 7 to 12% of individuals had a history of either a positive
COVID-19 test or a COVID-19 diagnosis. Both NHR and PHARMO reported <2.1%, which is
likely to be underestimated due to registration practices in Norway and The Netherlands.
History of anaphylaxis was rare, as expected. Cardiovascular disease, hypertension,
allergies and chronic respiratory disease were the most prevalent comorbidities.

Although the prevalence rates of the baseline comorbidities varied between data sources,
the comparison between the vaccinated and unvaccinated cohorts showed a good balance
since the ASDs were small for each of the variables (Table 13).
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

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Table 13. Part 1: Baseline comorbidities at time zero (past 10 years) by exposure group (matched cohort design) by data
source

(SEE PART 2 BELOW)

Pedianet NHR PHARMO
Vac Unvac ASD Vac Unvac ASD Vac Unvac ASD
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

Total, n (%) 10,500 (100) 10,500 (100) 3,584,238 (100) 3,584,238 (100) 992,144 (100) 992,144 (100)
COVID-19 history, n (%)
Previous diagnosis of 0 0 5,224 (0.15) 4,830 (0.13) 0.003 17,340 (1.75) 17,344 (1.75) 0
COVID-19
Positive test result for 1,054 (10.04) 1,054 (10.04) 0 75,253 (2.10) 75,557 (2.11) 0.001 0 0
COVID-19
Comorbidities, n (%)
History of anaphylaxis 81 (0.77) 83 (0.79) 0.002 56,354 (1.57) 55,829 (1.56) 0.001 6,081 (0.61) 5,994 (0.60) 0.001
History of allergies 1,709 (16.28) 1,720 (16.38) 0.003 79,798 (2.23) 78,642 (2.19) 0.002 20,685 (2.08) 18,542 (1.87) 0.016
Diabetes mellitus (types 1 28 (0.27) 37 (0.35) 0.015 266,517 (7.44) 244,053 (6.81) 0.024 59,496 (6) 61,841 (6.23) 0.01
and 2)
Hypertension <5 9 (0.09) 0.024 761,684 (21.25) 751,950 (20.98) 0.007 70,035 (7.06) 71,509 (7.21) 0.006
Cardiovascular disease 442 (4.21) 399 (3.80) 0.021 1,570,275 (43.81) 1,567,711 (43.74) 0.001 324,586 (32.72) 320,397 (32.29) 0.009
Chronic respiratory 6,177 (58.83) 6,241 (59.44) 0.012 821,902 (22.93) 810,372 (22.61) 0.008 122,414 (12.34) 121,610 (12.26) 0.002
disease
Chronic kidney disease <5 <5 0.008 7,331 (0.20) 5,630 (0.16) 0.011 16,098 (1.62) 14,148 (1.43) 0.016
Chronic liver disease <5 <5 0 26,774 (0.75) 33,426 (0.93) 0.02 932 (0.09) 1,605 (0.16) 0.019
Cancer 67 (0.64) 61 (0.58) 0.007 268,230 (7.48) 248,275 (6.93) 0.022 56,854 (5.73) 61,063 (6.15) 0.018
Autoimmune disorders 250 (2.38) 221 (2.10) 0.019 707,068 (19.73) 677,030 (18.89) 0.021 47,287 (4.77) 45,795 (4.62) 0.007
Influenza infection or other 6,233 (59.36) 6,252 (59.54) 0.004 758,790 (21.17) 731,272 (20.40) 0.019 41,354 (4.17) 39,177 (3.95) 0.011
respiratory infections
Charlson Comorbidity 0.009 0.028 0.055
Index Score, n (%)
0 or 1 10,329 (98.37) 10,329 (98.37) 2,881,286 (80.39) 2,920,591 (81.48) 924,198 (93.15) 914,735 (92.20)
2 147 (1.40) 151 (1.44) 317,963 (8.87) 300,744 (8.39) 37,566 (3.79) 36,910 (3.72)
3 24 (0.23) 20 (0.19) 384,989 (10.74) 362,903 (10.12) 30,380 (3.06) 40,499 (4.08)

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Table 13. Part 1: Baseline comorbidities at time zero (past 10 years) by exposure group (matched cohort design) by data
source

(SEE PART 2 BELOW)

Pedianet NHR PHARMO
Vac Unvac ASD Vac Unvac ASD Vac Unvac ASD
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

Myocardial infarct 8 (0.08) <5 (0.04) 0.016 76,688 (2.14) 74,243 (2.07) 0.005 14,152 (1.43) 15,903 (1.60) 0.014
Congestive heart failure <5 <5 0 90,226 (2.52) 89,534 (2.50) 0.001 8,042 (0.81) 11,482 (1.16) 0.035
Cerebrovascular disease 79 (0.75) 73 (0.70) 0.007 153,658 (4.29) 147,079 (4.10) 0.009 15,949 (1.61) 18,208 (1.84) 0.018
Peripheral vascular 51 (0.49) 48 (0.46) 0.004 226,202 (6.31) 215,936 (6.02) 0.012 31,272 (3.15) 29,502 (2.97) 0.01
disease
Mild to moderate kidney <5 <5 0.008 5,458 (0.15) 3,638 (0.10) 0.014 3,330 (0.34) 5,642 (0.57) 0.035
disease
Severe kidney disease <5 0 0.014 19,073 (0.53) 18,359 (0.51) 0.003 2,969 (0.30) 5,072 (0.51) 0.033
Mild liver disease <5 0 0.02 7,191 (0.20) 8,621 (0.24) 0.009 259 (0.03) 421 (0.04) 0.009
Moderate or severe liver 0 0 11,738 (0.33) 11,898 (0.33) 0.001 454 (0.05) 492 (0.05) 0.002
disease
Malignant tumour 51 (0.49) 47 (0.45) 0.006 239,356 (6.68) 219,230 (6.12) 0.023 30,122 (3.04) 36,018 (3.63) 0.033
Metastasic solid tumour 0 0 25,195 (0.70) 22,349 (0.62) 0.01 4,034 (0.41) 9,413 (0.95) 0.066
HIV/AIDS 6 (0.06) <5 (0.02) 0.02 7,267 (0.20) 7,911 (0.22) 0.004 955 (0.10) 954 (0.10) 0
Diabetes with 0 0 32,248 (0.90) 25,704 (0.72) 0.02 3,561 (0.36) 4,585 (0.46) 0.016
complications
Diabetes no complications 7 (0.07) 9 (0.09) 0.007 112,700 (3.14) 94,455 (2.64) 0.03 3,185 (0.32) 3,667 (0.37) 0.008
Dementia 0 0 40,021 (1.12) 27,409 (0.76) 0.036 6,095 (0.61) 9,078 (0.91) 0.035
Skin ulcer <5 <5 0 31,827 (0.89) 34,724 (0.97) 0.008 2,123 (0.21) 2,490 (0.25) 0.008
Hemiplegia 10 (0.10) 10 (0.10) 0 11 (<0.01) 7 (<0.01) 0.001 1,648 (0.17) 2,702 (0.27) 0.023
Connective tissue disease 151 (1.44) 154 (1.47) 0.002 266,555 (7.44) 253,955 (7.09) 0.014 9,210 (0.93) 7,746 (0.78) 0.016
CDC at-risk groups, n 0.008 0.014 0.001
(%) a
Group 0 (no conditions) 3,443 (32.79) 3,443 (32.79) 1,285,288 (35.86) 1,285,288 (35.86) 531,509 (53.57) 531,509 (53.57)
Group 1 (1 condition) 3,839 (36.56) 3,804 (36.23) 912,928 (25.47) 932,388 (26.01) 228,126 (22.99) 228,604 (23.04)

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Table 13. Part 1: Baseline comorbidities at time zero (past 10 years) by exposure group (matched cohort design) by data
source

(SEE PART 2 BELOW)

Pedianet NHR PHARMO
Vac Unvac ASD Vac Unvac ASD Vac Unvac ASD
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

Group 2 (>1 condition) 3,218 (30.65) 3,253 (30.98) 1,386,022 (38.67) 1,366,562 (38.13) 232,509 (23.44) 232,031 (23.39)
Immunocompromising 3,056 (29.10) 3,056 (29.10) 0 752,857 (21) 752,857 (21) 0 130,937 (13.20) 130,937 (13.20) 0
conditions, n (%)
Surrogates of frailty, n
(%)
Wheelchair use NA NA NA NA NA NA
Home hospital bed NA NA NA NA NA NA
Paralysis 6 (0.06) <5 0.02 7,339 (0.20) 7,072 (0.20) 0.002 2,984 (0.30) 3,906 (0.39) 0.016
Parkinson’s disease NA NA 13,183 (0.37) 11,029 (0.31) 0.01 2,267 (0.23) 2,438 (0.25) 0.004
Weakness 0 <5 (0.01) 0.014 685,153 (19.12) 671,155 (18.73) 0.01 60,221 (6.07) 51,482 (5.19) 0.038
Stroke/brain injury 77 (0.73) 73 (0.70) 0.005 153,658 (4.29) 147,079 (4.10) 0.009 15,902 (1.60) 18,164 (1.83) 0.018
Ambulance transport NA NA NA NA NA NA
Difficulty walking 61 (0.58) 61 (0.58) 0 NA NA 862 (0.09) 1,345 (0.14) 0.015
Home oxygen NA NA NA NA NA NA
Rehabilitation care NA NA NA NA NA NA
Psychiatric illness 351 (3.34) 312 (2.97) 0.021 580,456 (16.19) 629,441 (17.56) 0.036 41,846 (4.22) 42,011 (4.23) 0.001
Sepsis <5 <5 0.019 96,661 (2.70) 93,084 (2.60) 0.006 11,799 (1.19) 10,940 (1.10) 0.008
Podiatric care NA NA NA NA NA NA
Bladder incontinence 202 (1.92) 197 (1.88) 0.003 158,193 (4.41) 150,323 (4.19) 0.011 13,576 (1.37) 12,171 (1.23) 0.013
Arthritis 376 (3.58) 332 (3.16) 0.023 865,330 (24.14) 842,663 (23.51) 0.015 65,869 (6.64) 55,680 (5.61) 0.043
Coagulation deficiencies 82 (0.78) 72 (0.69) 0.011 22,935 (0.64) 22,339 (0.62) 0.002 2,441 (0.25) 2,645 (0.27) 0.004
Vertigo 59 (0.56) 38 (0.36) 0.029 496,447 (13.85) 488,261 (13.62) 0.007 51,708 (5.21) 42,179 (4.25) 0.045
Lipid abnormalities 0 <5 0.024 314,205 (8.77) 301,407 (8.41) 0.013 22,837 (2.30) 18,656 (1.88) 0.029

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Table 13. Part 1: Baseline comorbidities at time zero (past 10 years) by exposure group (matched cohort design) by data
source

(SEE PART 2 BELOW)

Pedianet NHR PHARMO
Vac Unvac ASD Vac Unvac ASD Vac Unvac ASD
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

ASD: absolute standardised difference; NR: not reportable; Vac: vaccinated cohort; Unvac: unvaccinated cohort; NA not available
a CDC at-risk groups conditions: cancer, type 1 and 2 diabetes, obesity (BMI > 30), cardiovascular disease/ serious heart conditions (heart failure, coronary artery
disease, cardiomyopathies), chronic lung disease including COPD, asthma, chronic kidney disease, HIV, immunosuppression, sickle cell disease, hypertension.

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Table 13. Part 2: Baseline comorbidities at time zero (past 10 years) by exposure group (matched cohort design) by data
source

(SEE PART 1 ABOVE)

EpiChron SIDIAP CPRD Aurum
Vac Unvac ASD Vac Unvac ASD Vac Unvac ASD
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

Total, n (%) 627,972 (100) 627,972 (100) 3,087,124 (100) 3,087,124 (100) 4,098,869 (100) 4,098,869 (100)
COVID-19 history, n (%)
Previous diagnosis of 3,309 (0.53) 3,759 (0.60) 0.01 378,481 (12.26) 375,307 (12.16) 0.003 378,053 (9.22) 378,042 (9.22) 0
COVID-19
Positive test result for 45,030 (7.17) 45,036 (7.17) 0 326,332 (10.57) 337,630 (10.94) 0.012 <5 <5 0
COVID-19
Comorbidities, n (%)
History of anaphylaxis 3,205 (0.51) 2,951 (0.47) 0.006 18,611 (0.60) 16,441 (0.53) 0.009 4,096 (0.10) 4,914 (0.12) 0.006
History of allergies 154,899 (24.67) 140,957 (22.45) 0.052 443,433 (14.36) 436,753 (14.15) 0.006 499,265 (12.18) 469,116 (11.45) 0.023
Diabetes mellitus (types 1 55,982 (8.91) 59,047 (9.40) 0.017 248,941 (8.06) 259,530 (8.41) 0.012 429,936 (10.49) 423,633 (10.34) 0.005
and 2)
Hypertension 102,476 (16.32) 104,635 (16.66) 0.009 419,615 (13.59) 418,422 (13.55) 0.001 736,474 (17.97) 742,289 (18.11) 0.004
Cardiovascular disease 235,599 (37.52) 228,910 (36.45) 0.022 980,910 (31.77) 966,456 (31.31) 0.01 444,043 (10.83) 431,504 (10.53) 0.01
Chronic respiratory 80,287 (12.79) 80,245 (12.78) 0 813,274 (26.34) 813,291 (26.34) 0 700,099 (17.08) 708,414 (17.28) 0.005
disease
Chronic kidney disease 23,300 (3.71) 22,957 (3.66) 0.003 121,257 (3.93) 118,967 (3.85) 0.004 197,480 (4.82) 193,589 (4.72) 0.004
Chronic liver disease 2,360 (0.38) 2,633 (0.42) 0.007 83,897 (2.72) 89,892 (2.91) 0.012 13,968 (0.34) 14,738 (0.36) 0.003
Cancer 25,095 (4.00) 25,424 (4.05) 0.003 111,646 (3.62) 111,274 (3.60) 0.001 197,963 (4.83) 180,981 (4.42) 0.02
Autoimmune disorders 45,253 (7.21) 44,214 (7.04) 0.006 190,360 (6.17) 190,000 (6.15) 0 321,187 (7.84) 286,480 (6.99) 0.032
Influenza infection or 104,944 (16.71) 98,177 (15.63) 0.029 888,500 (28.78) 862,667 (27.94) 0.019 353,730 (8.63) 338,293 (8.25) 0.014
other respiratory
infections
Charlson Comorbidity 0.006 0.007 0.026
Index Score, n (%)
0 or 1 531,266 (84.60) 529,970 (84.39) 2,581,358 2,573,413 (83.36) 3,097,537 3,102,884 (75.70)
(83.62) (75.57)
2 53,994 (8.60) 54,836 (8.73) 264,974 (8.58) 270,201 (8.75) 387,927 (9.46) 360,935 (8.81)

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Table 13. Part 2: Baseline comorbidities at time zero (past 10 years) by exposure group (matched cohort design) by data
source

(SEE PART 1 ABOVE)

EpiChron SIDIAP CPRD Aurum
Vac Unvac ASD Vac Unvac ASD Vac Unvac ASD
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

3 42,712 (6.80) 43,166 (6.87) 240,792 (7.80) 243,510 (7.89) 613,405 (14.97) 635,050 (15.49)
Myocardial infarct 6,103 (0.97) 6,620 (1.05) 0.008 28,799 (0.93) 29,788 (0.96) 0.003 45,711 (1.12) 44,880 (1.09) 0.002
Congestive heart failure 13,908 (2.21) 14,519 (2.31) 0.007 57,982 (1.88) 58,306 (1.89) 0.001 49,858 (1.22) 52,404 (1.28) 0.006
Cerebrovascular disease 12,804 (2.04) 12,247 (1.95) 0.006 68,564 (2.22) 66,319 (2.15) 0.005 94,586 (2.31) 96,753 (2.36) 0.004
Peripheral vascular 10,568 (1.68) 10,641 (1.69) 0.001 85,509 (2.77) 85,461 (2.77) 0 22,847 (0.56) 23,560 (0.57) 0.002
disease
Mild to moderate kidney 23,437 (3.73) 23,105 (3.68) 0.003 120,597 (3.91) 118,244 (3.83) 0.004 172,322 (4.20) 168,248 (4.10) 0.005
disease
Severe kidney disease 859 (0.14) 922 (0.15) 0.003 4,712 (0.15) 3,589 (0.12) 0.01 15,294 (0.37) 15,834 (0.39) 0.002
Mild liver disease 2,141 (0.34) 2,224 (0.35) 0.002 19,569 (0.63) 20,642 (0.67) 0.004 48,447 (1.18) 42,907 (1.05) 0.013
Moderate or severe liver 561 (0.09) 703 (0.11) 0.007 1,679 (0.05) 2,001 (0.06) 0.004 43,382 (1.06) 59,407 (1.45) 0.035
disease
Malignant tumour 21,897 (3.49) 22,245 (3.54) 0.003 87,396 (2.83) 88,875 (2.88) 0.003 197,632 (4.82) 180,712 (4.41) 0.02
Metastasic solid tumour 1,896 (0.30) 2,272 (0.36) 0.01 9,006 (0.29) 10,391 (0.34) 0.008 2,961 (0.07) 2,639 (0.06) 0.003
HIV/AIDS 291 (0.05) 434 (0.07) 0.009 0 0 161 (<0.01) 197 (<0.01) 0.001
Diabetes with 4,958 (0.79) 5,253 (0.84) 0.005 48,558 (1.57) 50,045 (1.62) 0.004 153,916 (3.76) 154,302 (3.76) 0
complications
Diabetes no 9,085 (1.45) 9,866 (1.57) 0.01 45,505 (1.47) 47,076 (1.52) 0.004 250,334 (6.11) 232,885 (5.68) 0.018
complications
Dementia 7,377 (1.17) 5,693 (0.91) 0.026 42,641 (1.38) 35,072 (1.14) 0.022 51,271 (1.25) 65,337 (1.59) 0.029
Skin ulcer 2,754 (0.44) 2,940 (0.47) 0.004 15,239 (0.49) 15,655 (0.51) 0.002 44,610 (1.09) 41,430 (1.01) 0.008
Hemiplegia 2,363 (0.38) 2,241 (0.36) 0.003 14,439 (0.47) 12,604 (0.41) 0.009 2,498 (0.06) 2,411 (0.06) 0.001
Connective tissue 83,354 (13.27) 74,220 (11.82) 0.044 207,031 (6.71) 202,750 (6.57) 0.006 111,929 (2.73) 98,789 (2.41) 0.02
disease
CDC at-risk groups, n 0.002 0.001 0
(%) a

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Table 13. Part 2: Baseline comorbidities at time zero (past 10 years) by exposure group (matched cohort design) by data
source

(SEE PART 1 ABOVE)

EpiChron SIDIAP CPRD Aurum
Vac Unvac ASD Vac Unvac ASD Vac Unvac ASD
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

Group 0 (no conditions) 299,702 (47.73) 299,702 (47.73) 1,347,940 1,347,940 (43.66) 2,164,699 2,164,699 (52.81)
(43.66) (52.81)
Group 1 (1 condition) 116,320 (18.52) 116,789 (18.60) 692,041 (22.42) 690,984 (22.38) 1,060,268 1,060,002 (25.86)
(25.87)
Group 2 (>1 condition) 211,950 (33.75) 211,481 (33.68) 1,047,143 1,048,200 (33.95) 873,902 (21.32) 874,168 (21.33)
(33.92)
Immunocompromising 37,581 (5.98) 37,581 (5.98) 0 615,371 (19.93) 615,371 (19.93) 0 26,800 (0.65) 26,800 (0.65) 0
conditions, n (%)
Surrogates of frailty, n
(%)
Wheelchair use NA NA NA NA 876 (0.02) 1,302 (0.03) 0.006
Home hospital bed NA NA NA NA 0 6 (<0.01) 0.002
Paralysis 3,356 (0.53) 3,152 (0.50) 0.005 16,280 (0.53) 14,232 (0.46) 0.009 6,195 (0.15) 6,456 (0.16) 0.002
Parkinson’s disease 2,923 (0.47) 2,483 (0.40) 0.011 10,461 (0.34) 9,374 (0.30) 0.006 10,854 (0.26) 12,266 (0.30) 0.006
Weakness 5,622 (0.90) 5,747 (0.92) 0.002 204,925 (6.64) 209,865 (6.80) 0.006 112,879 (2.75) 100,789 (2.46) 0.019
Stroke/brain injury 8,601 (1.37) 8,504 (1.35) 0.001 68,209 (2.21) 65,957 (2.14) 0.005 96,639 (2.36) 99,120 (2.42) 0.004
Ambulance transport NA NA NA NA 1,073 (0.03) 1,319 (0.03) 0.004
Difficulty walking 1,670 (0.27) 1,534 (0.24) 0.004 30,347 (0.98) 28,257 (0.92) 0.007 26,674 (0.65) 30,690 (0.75) 0.012
Home oxygen NA NA NA NA 612 (0.01) 777 (0.02) 0.003
Rehabilitation care NA NA NA NA 3,305 (0.08) 2,658 (0.06) 0.006
Psychiatric illness 164,147 (26.14) 156,167 (24.87) 0.029 833,439 (27) 847,693 (27.46) 0.01 540,468 (13.19) 501,776 (12.24) 0.028
Sepsis 3,513 (0.56) 3,502 (0.56) 0 18,246 (0.59) 18,388 (0.60) 0.001 28,483 (0.69) 31,794 (0.78) 0.009
Podiatric care NA NA NA NA 38,065 (0.93) 36,323 (0.89) 0.004
Bladder incontinence 32,304 (5.14) 29,815 (4.75) 0.018 149,846 (4.85) 139,438 (4.52) 0.016 89,488 (2.18) 90,426 (2.21) 0.002
Arthritis 232,249 (36.98) 215,220 (34.27) 0.057 787,715 (25.52) 782,386 (25.34) 0.004 592,694 (14.46) 554,027 (13.52) 0.027

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Table 13. Part 2: Baseline comorbidities at time zero (past 10 years) by exposure group (matched cohort design) by data
source

(SEE PART 1 ABOVE)

EpiChron SIDIAP CPRD Aurum
Vac Unvac ASD Vac Unvac ASD Vac Unvac ASD
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

Coagulation deficiencies 15,009 (2.39) 14,935 (2.38) 0.001 10,622 (0.34) 10,240 (0.33) 0.002 15,938 (0.39) 13,852 (0.34) 0.008
Vertigo 9,522 (1.52) 9,226 (1.47) 0.004 399,542 (12.94) 393,198 (12.74) 0.006 425,173 (10.37) 391,336 (9.55) 0.028
Lipid abnormalities 34,119 (5.43) 33,759 (5.38) 0.003 267,836 (8.68) 264,658 (8.57) 0.004 69,963 (1.71) 65,840 (1.61) 0.008
ASD: absolute standardised difference; NR: not reportable; Vac: vaccinated cohort; Unvac: unvaccinated cohort; NA not available
a CDC at-risk groups conditions: cancer, type 1 and 2 diabetes, obesity (BMI > 30), cardiovascular disease/ serious heart conditions (heart failure, coronary artery
disease, cardiomyopathies), chronic lung disease including COPD, asthma, chronic kidney disease, HIV, immunosuppression, sickle cell disease, hypertension.

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10.1.2.3. Baseline comedications

Comedication use for 1 year prior to time zero is summarised (with ASDs) in the vaccinated
and unvaccinated cohorts by data source in Table 14. We observed higher use of
antibiotics, non-steroidal anti-inflammatory drugs (NSAIDs), and psychotropics in NHR,
EpiChron and SIDIAP compared with PHARMO, where the results are based on GP
prescriptions only. Data for most vaccines were not available in PHARMO as these data are
not provided by GPs. The ASDs for the comparison of prevalence of comedication variables
show no imbalance between the vaccinated and unvaccinated cohorts.
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

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Table 14. Part 1: Baseline comedications at time zero by exposure group (matched cohort design) by data source

(SEE PART 2 BELOW)

Pedianet NHR PHARMO
Vac Unvac ASD Vac Unvac ASD Vac Unvac ASD
Total, n (%) 10,500 (100) 10,500 (100) 3,584,238 (100) 3,584,238 (100) 992,144 (100) 992,144 (100)
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

Comedications, n (%)
Analgesics 19 (0.18) 25 (0.24) 0.012 793,145 (22.13) 767,156 (21.40) 0.018 59,272 (5.97) 53,827 (5.43) 0.024
Antibiotics 1,050 (10) 1,173 (11.17) 0.038 610,097 (17.02) 587,087 (16.38) 0.017 86,788 (8.75) 75,590 (7.62) 0.041
Antiviral medications 25 (0.24) 29 (0.28) 0.008 46,181 (1.29) 44,012 (1.23) 0.005 2,491 (0.25) 2,292 (0.23) 0.004
Corticosteroids 329 (3.13) 362 (3.45) 0.018 178,331 (4.98) 170,758 (4.76) 0.01 26,755 (2.70) 24,647 (2.48) 0.013
Non-steroidal anti-inflammatory 113 (1.08) 160 (1.52) 0.04 654,868 (18.27) 618,214 (17.25) 0.027 58,192 (5.87) 49,088 (4.95) 0.041
drugs
Psychotropics 61 (0.58) 73 (0.70) 0.014 511,711 (14.28) 524,431 (14.63) 0.01 46,850 (4.72) 42,808 (4.31) 0.02
Statins 0 0 515,691 (14.39) 478,758 (13.36) 0.03 99,722 (10.05) 80,924 (8.16) 0.066
Novel oral anticoagulants <5 5 (0.05) 0.023 436,567 (12.18) 418,277 (11.67) 0.016 76,799 (7.74) 64,574 (6.51) 0.048
Warfarin <5 <5 0.008 25,112 (0.70) 23,825 (0.66) 0.004 <5 <5 0.001
Immunosuppressant medications 336 (3.20) 367 (3.50) 0.016 221,595 (6.18) 204,472 (5.70) 0.02 34,235 (3.45) 30,766 (3.10) 0.02
Other vaccines, n (%)
Influenza 3,843 (36.60) 3,907 (37.21) 0.013 NA NA 712 (0.07) 1,090 (0.11) 0.013
Pneumococcal 5,275 (50.24) 5,246 (49.96) 0.006 300,445 (8.38) 280,018 (7.81) 0.021 NA NA
DTP (diphtheria, tetanus, and 2,696 (25.68) 2,491 (23.72) 0.045 68,326 (1.91) 72,708 (2.03) 0.009 NA NA
pertussis)
TPV (polio) 8,684 (82.70) 8,505 (81) 0.044 127,540 (3.56) 130,561 (3.64) 0.005 NA NA
TV (MMR) (measles, mumps and 7 (0.07) 9 (0.09) 0.007 NA NA NA NA
rubella)
Hib (Haemophilus influenzae type b) 4,609 (43.90) 4,729 (45.04) 0.023 25,319 (0.71) 31,347 (0.87) 0.019 NA NA
HepB (hepatitis B virus) 54 (0.51) 172 (1.64) 0.109 382,001 (10.66) 335,808 (9.37) 0.043 NA NA
VZV (varicella-zoster virus) 8,311 (79.15) 7,935 (75.57) 0.086 5,068 (0.14) 4,283 (0.12) 0.006 NA NA
HPV (human papillomavirus) 98 (0.93) 53 (0.50) 0.051 443,426 (12.37) 401,980 (11.22) 0.036 NA NA

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Table 14. Part 1: Baseline comedications at time zero by exposure group (matched cohort design) by data source

(SEE PART 2 BELOW)

Pedianet NHR PHARMO
Vac Unvac ASD Vac Unvac ASD Vac Unvac ASD
Meningitis 5,523 (52.60) 5,261 (50.10) 0.05 267,482 (7.46) 212,928 (5.94) 0.061 NA NA
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

Rotavirus 496 (4.72) 495 (4.71) 0 2,013 (0.06) 2,036 (0.06) 0 NA NA

ASD: absolute standardised difference, NR: not reportable; Vac: vaccinated cohort; Unvac: unvaccinated cohort

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Table 14. Part 2: Baseline comedications at time zero by exposure group (matched cohort design) by data source
(SEE PART 1 ABOVE)
EpiChron SIDIAP CPRD Aurum
Vac Unvac ASD Vac Unvac ASD Vac Unvac ASD
Total, n (%) 627,972 627,972 3,087,124 3,087,124 4,098,869 4,098,869
(100) (100) (100) (100) (100) (100)
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

Comedications, n (%)
Analgesics 185,986 172,280 0.048 753,688 745,272 0.006 529,937 517,062 0.009
(29.62) (27.43) (24.41) (24.14) (12.93) (12.61)
Antibiotics 118,641 105,391 0.055 459,540 444,042 0.014 553,564 499,256 0.04
(18.89) (16.78) (14.89) (14.38) (13.51) (12.18)
Antiviral medications 3,997 (0.64) 3,751 (0.60) 0.005 18,546 16,842 0.007 36,632 31,372 0.014
(0.60) (0.55) (0.89) (0.77)
Corticosteroids 23,984 24,300 0.003 110,059 110,583 0.001 NA NA
(3.82) (3.87) (3.57) (3.58)
Non-steroidal anti-inflammatory 164,579 143,204 0.079 565,245 548,693 0.014 231,241 202,597 0.031)
drugs (26.21) (22.80) (18.31) (17.77) (5.64) (4.94)
Psychotropics 136,657 122,193 0.057 470,100 439,520 0.028 206,312 202,810 0.004
(21.76) (19.46) (15.23) (14.24) (5.03) (4.95)
Statins 117,606 111,322 0.026 348,087 328,745 0.02 605,446 560,929 0.031
(18.73) (17.73) (11.28) (10.65) (14.77) (13.68)
Novel oral anticoagulants 57,079 55,689 0.008 214,285 208,275 0.008 253,412 245,216 0.008
(9.09) (8.87) (6.94) (6.75) (6.18) (5.98)
Warfarin 216 (0.03) 203 (0.03) 0.001 4,108 (0.13) 4,206 (0.14) 0.001 NA NA
Immunosuppressant 25,587 25,863 0.002 117,775 117,833 0 NA NA
medications (4.07) (4.12) (3.82) (3.82)
Other vaccines, n (%)
Influenza 179,815 179,815 0 820,081 820,081 0 1,730,281 1,730,281 0
(28.63) (28.63) (26.56) (26.56) (42.21) (42.21)
Pneumococcal 32,710 27,925 0.036 291,231 283,469 0.009 NA NA
(5.21) (4.45) (9.43) (9.18)
DTP (diphtheria, tetanus, and 140,418 122,617 0.07 384,332 381,256 0.003 1,352,988 1,151,025 0.107
pertussis) (22.36) (19.53) (12.45) (12.35) (33.01) (28.08)
TPV (polio) 1,136 (0.18) 1,489 (0.24) 0.012 115,598 120,137 0.008 1,205,327 1,007,190 0.109
(3.74) (3.89) (29.41) (24.57)
TV (MMR) (measles, mumps 24,970 20,196 0.041 252,531 269,560 0.02 325,690 323,350 0.002
and rubella) (3.98) (3.22) (8.18) (8.73) (7.95) (7.89)

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Table 14. Part 2: Baseline comedications at time zero by exposure group (matched cohort design) by data source
(SEE PART 1 ABOVE)
EpiChron SIDIAP CPRD Aurum
Vac Unvac ASD Vac Unvac ASD Vac Unvac ASD
Hib (Haemophilus influenzae 702 (0.11) 664 (0.11) 0.002 105,405 105,779 0.001 34,413 46,015 0.029
type b) (3.41) (3.43) (0.84) (1.12)
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

HepB (hepatitis B virus) 6,606 (1.05) 5,822 (0.93) 0.013 107,762 110,447 0.005 156,815 118,806 0.051
(3.49) (3.58) (3.83) (2.90)
VZV (varicella-zoster virus) 10,553 8,831 (1.41) 0.022 <5 <5 0.001 4,671 4,427 0.002
(1.68) (0.11) (0.11)
HPV (human papillomavirus) 34,816 27,623 0.053 23 (<0.01) 16 (<0.01) 0.001 324,287 251,301 0.07
(5.54) (4.40) (7.91) (6.13)
Meningitis 63,163 49,606 0.076 459,496 423,655 0.033 597,739 465,682 0.096
(10.06) (7.90) (14.88) (13.72) (14.58) (11.36)
Rotavirus 20 (<0.01) 14 (<0.01) 0.002 28,157 20,275 0.029 2,592 2,724 0.001
(0.91) (0.66) (0.06) (0.07)
ASD: absolute standardised difference, NR: not reportable; Vac: vaccinated cohort; Unvac: unvaccinated cohort

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10.1.2.4. Censoring due to prior events of special interest

Prior AESIs (outcome-specific exclusion criteria) in the year prior to receiving their first
Pfizer-BioNTech COVID-19 vaccine dose the Pfizer-BioNTech vaccinated cohort and the
matched unvaccinated cohort by data source are summarized in Table 15. As only low
numbers of individuals experienced AESI-specific events in the year prior to receiving their
first Pfizer-BioNTech COVID-19 vaccine dose, the AESI-specific exclusion criteria of having
experienced that specific AESI prior to the first dose of Pfizer-BioNTech COVID-19 vaccine
had very little impact on the analyses (Table 15).
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

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Table 15. Part 1: Prior adverse events of special interest (AESIs) within one year of time zero (outcome-specific exclusion
criteria) by exposure group by data source

(SEE PART 2 BELOW)

Pedianet NHR PHARMO
Vac Unvac ASD Vac Unvac ASD Vac Unvac ASD
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

Total, n (%) 10,500 (100) 10,500 (100) 3,584,238 (100) 3,584,238 (100) 992,144 (100) 992,144 (100)
Autoimmune diseases, n (%)
Guillain-Barré syndrome <5 (0.02) 6 (0.06) 0.020 148 (<0.01) 118 (<0.01) 0.001 10 (<0.01) 10 (<0.01) <0.001
Acute disseminated NA NA 28 (<0.01) 26 (<0.01) <0.001 <5 0 0.001
encephalomyelitis
Narcolepsy 0 0 <0.001 369 (0.01) 476 (0.01) 0.003 <5 <5 0.001
Acute aseptic arthritis 44 (0.42) 38 (0.36) 0.009 28,323 (0.79) 27,223 (0.76) 0.004 511 (0.05) 484 (0.05) 0.001
Diabetes mellitus type 1 14 (0.13) 18 (0.17) 0.010 49,714 (1.39) 39,943 (1.11) 0.025 1,642 (0.17) 1,596 (0.16) 0.001
(Idiopathic) thrombocytopenia 0 0 <0.001 659 (0.02) 658 (0.02) <0.001 19 (<0.01) 33 (<0.01) 0.003
Thrombotic thrombocytopenia NA NA 174 (<0.01) 179 (<0.01) <0.001 12 (<0.01) 29 (<0.01) 0.004
syndrome (TTS)
Myositis NA NA 880 (0.02) 843 (0.02) 0.001 5 (<0.01) 17 (<0.01) 0.004
Cardiovascular system, n (%)
Acute cardiovascular injurya 31 (0.30) 19 (0.18) 0.023 238,308 (6.65) 229,449 (6.40) 0.010 11,203 (1.13) 11,124 (1.12) 0.001
Arrhythmia 22 (0.21) 18 (0.17) 0.009 166,532 (4.65) 161,814 (4.51) 0.006 8,890 (0.90) 8,813 (0.89) 0.001
Heart failure NA NA 40,065 (1.12) 40,848 (1.14) 0.002 1,383 (0.14) 1,678 (0.17) 0.008
Stress cardiomyopathy NA NA 18 (<0.01) 29 (<0.01) 0.001 7 (<0.01) 6 (<0.01) <0.001
Coronary artery disease NA NA 70,122 (1.96) 65,757 (1.83) 0.009 2,225 (0.22) 2,131 (0.21) 0.002
Myocarditis 6 (0.06) 0 0.034 387 (0.01) 440 (0.01) 0.001 11 (<0.01) 14 (<0.01) 0.001
Pericarditis <5 0 0.020 1,001 (0.03) 948 (0.03) 0.001 25 (<0.01) 33 (<0.01) 0.001
Circulatory system, n (%)
Coagulation disorders: 6 (0.06) <5 (0.03) 0.014 29,837 (0.83) 29,476 (0.82) 0.001 1,142 (0.12) 1,323 (0.13) 0.005
thromboembolism, haemorrhage
Single organ cutaneous vasculitis NA NA 337 (0.01) 368 (0.01) 0.001 <5 10 (<0.01) 0.003
Cerebral venous sinus thrombosis 0 0 <0.001 130 (<0.01) 127 (<0.01) <0.001 8 (<0.01) 12 (<0.01) 0.001

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Table 15. Part 1: Prior adverse events of special interest (AESIs) within one year of time zero (outcome-specific exclusion
criteria) by exposure group by data source

(SEE PART 2 BELOW)

Pedianet NHR PHARMO
Vac Unvac ASD Vac Unvac ASD Vac Unvac ASD
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

Hepato-gastrointestinal and renal

system, n (%)
Acute liver injury 0 0 <0.001 514 (0.01) 543 (0.02) 0.001 8 (<0.01) 14 (<0.01) 0.002
Acute kidney injury 0 0 <0.001 10,005 (0.28) 10,693 (0.30) 0.004 461 (0.05) 705 (0.07) 0.010
Acute pancreatitis NA NA 2,446 (0.07) 2,498 (0.07) 0.001 176 (0.02) 209 (0.02) 0.002
Rhabdomyolysis NA NA 9 (<0.01) <5 0.002 10 7 (<0.01) 0.001
Glomerulonephritis 0 0 <0.001
Nerves and central nervous system, n
(%)
Generalised convulsion 23 (0.22) 36 (0.34) 0.023 24,681 (0.69) 21,548 (0.60) 0.011 311 (0.03) 426 (0.04) 0.006
Meningoencephalitis 0 0 <0.001 1,018 (0.03) 811 (0.02) 0.004 30 33 (<0.01) 0.001
Transverse myelitis <5 0 0.014 42 (<0.01) 25 (<0.01) 0.002 0 <5 0.001
Bell’s palsy <5 0 0.014 2,710 (0.08) 2,796 (0.08) 0.001 160 (0.02) 165 (0.02) <0.001
Respiratory system
Acute respiratory distress syndrome NA NA 183 (0.01) 191 (0.01) <0.001 5 (<0.01) 8 (<0.01) 0.001
Skin and mucous membrane, bone,
and joints system, n (%)
Erythema multiforme <5 (0.01) <5 (0.01) <0.001 141 (<0.01) 145 (<0.01) <0.001 <5 <5 <0.001
Chilblain-like lesions <5 (0.03) <5 (0.01) 0.014 8 (<0.01) 6 (<0.01) <0.001 119 (0.01) 91 (0.01) 0.003
Reproductive system, n (%)
Secondary amenorrhoea <5 0 0.014 1,127 (0.03) 1,046 (0.03) 0.001 <5 <5 0.001
Hypermenorrhoea 14 (0.13) 7 (0.07) 0.021 NA NA 22 (<0.01) 25 (<0.01) 0.001
Other systems, n (%)
Anaphylaxis 13 (0.12) 14 (0.13) 0.003 1,612 (0.04) 1,591 (0.04) <0.001 23 (<0.01) 31 (<0.01) 0.002
Multisystem inflammatory syndrome NA NA 2,205 (0.06) 2,270 (0.06) 0.001 12 (<0.01) 12 (<0.01) <0.001
Subacute thyroiditis NA NA 162 (<0.01) 148 (<0.01) 0.001 0 0 <0.001

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Table 15. Part 1: Prior adverse events of special interest (AESIs) within one year of time zero (outcome-specific exclusion
criteria) by exposure group by data source

(SEE PART 2 BELOW)

Pedianet NHR PHARMO
Vac Unvac ASD Vac Unvac ASD Vac Unvac ASD
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

ASD: absolute standardised difference; NR: not reportable; Vac: vaccinated cohort; Unvac: unvaccinated cohort
a including microangiopathy ASD: Absolute standardised difference

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Table 15. Part 2: Prior adverse events of special interest (AESIs) within one year of time zero (outcome-specific exclusion
criteria) by exposure group by data source

(SEE PART 1 ABOVE)

EpiChron SIDIAP CPRD Aurum
Vac Unvac ASD Vac Unvac ASD Vac Unvac ASD
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

Total, n (%) 627,972 (100) 627,972 (100) 3,087,124 (100) 3,087,124 (100) 4,098,869 (100) 4,098,869 (100)
Autoimmune diseases, n (%)
Guillain-Barré syndrome 16 (0.01) 24 (<0.01) 0.002 135 (<0.01) 150 (<0.01) 0.001 319 (0.01) 310 (0.01) <0.001
Acute disseminated 0 <5 0.002 9 (<0.01) 6 (<0.01) 0.001 <5 <5 <0.001
encephalomyelitis
Narcolepsy 9 (<0.01) <5 0.002 48 (<0.01) 43 (<0.01) <0.001 126 (<0.01) 114 (<0.01) 0.001
Acute aseptic arthritis 3,731 (0.59) 3,486 (0.56) 0.005 15,008 (0.49) 14,687 (0.48) 0.002 21,549 (0.53) 19,035 (0.46) 0.009
Diabetes mellitus type 1 4,064 (0.65) 4,356 (0.69) 0.006 7,742 (0.25) 8,003 (0.26) 0.002 493 (0.01) 318 (0.01) 0.004
(Idiopathic) thrombocytopenia 34 (0.01) 51 (0.01) 0.003 276 (0.01) 306 (0.01) 0.001 419 (0.01) 384 (0.01) 0.001
Thrombotic thrombocytopenia 28 (<0.01) 43 (0.01) 0.003 192 (0.01) 218 (0.01) 0.001 28 (<0.01) 32 (<0.01) <0.001
syndrome (TTS)
Myositis 29 (<0.01) 32 (0.01) 0.001 408 (0.01) 411 (0.01) <0.001 298 (0.01) 290 (0.01) <0.001
Cardiovascular system, n (%)
Acute cardiovascular injurya 14,421 (2.30) 14,771 (2.35) 0.004 60,950 (1.97) 61,356 (1.99) 0.001 79,955 (1.95) 75,119 (1.83) 0.009
Arrhythmia 11,310 (1.80) 11,440 (1.82) 0.002 49,121 (1.59) 49,372 (1.60) 0.001 43,962 (1.07) 40,982 (1) 0.007
Heart failure 4,249 (0.68) 4,607 (0.73) 0.007 14,705 (0.48) 15,328 (0.50) 0.003 16,250 (0.40) 16,956 (0.41) 0.003
Stress cardiomyopathy 32 (0.01) 25 (<0.01) 0.002 193 (0.01) 224 (0.01) 0.001 146 (<0.01) 112 (<0.01) 0.001
Coronary artery disease 1,617 (0.26) 1,801 (0.29) 0.006 7,071 (0.23) 7,532 (0.24) 0.003 23,133 (0.56) 20,962 (0.51) 0.007
Myocarditis 27 (<0.01) 22 (<.010) 0.001 124 (<0.01) 123 (<0.01) <0.001 231 (0.01) 189 (<0.01) 0.001
Pericarditis 120 (0.02) 111 (0.02) 0.001 746 (0.02) 803 (0.03) 0.001 534 (0.01) 518 (0.01) <0.001
Circulatory system, n (%)
Coagulation disorders: 4,073 (0.65) 4,364 (0.69) 0.006 12,416 (0.40) 13,394 (0.43) 0.005 13,520 (0.33) 13,647 (0.33) 0.001
thromboembolism, haemorrhage
Single organ cutaneous vasculitis 6 (<0.01) 5 (<0.01) 0.001 50 (<0.01) 62 (<0.01) 0.001 64 (<0.01) 40 (<0.01) 0.002
Cerebral venous sinus thrombosis 8 (<0.01) 7 (<0.01) <0.001 34 (<0.01) 45 (<0.01) 0.001 92 (<0.01) 97 (<0.01) <0.001

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Table 15. Part 2: Prior adverse events of special interest (AESIs) within one year of time zero (outcome-specific exclusion
criteria) by exposure group by data source

(SEE PART 1 ABOVE)

EpiChron SIDIAP CPRD Aurum
Vac Unvac ASD Vac Unvac ASD Vac Unvac ASD
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

Hepato-gastrointestinal and renal

system, n (%)
Acute liver injury 178 (0.03) 208 (0.03) 0.003 449 (0.01) 545 (0.02) 0.002 264 (0.01) 246 (0.01) 0.001
Acute kidney injury 2,052 (0.33) 2,421 (0.39) 0.010 13,290 (0.43) 14,267 (0.46) 0.005 9,235 (0.23) 9,817 (0.24) 0.003
Acute pancreatitis 453 (0.07) 508 (0.08) 0.003 2,011 (0.07) 2,202 (0.07) 0.002 1,301 (0.03) 1,148 (0.03) 0.002
Rhabdomyolysis 127 (0.02) 162 (0.03) 0.004 527 (0.02) 580 (0.02) 0.001 199 (<0.01) 345 (0.01) 0.004
Glomerulonephritis 68 (0.01) 75 (0.01) 0.001 568 (0.02) 494 (0.02) 0.002 575 (0.01) 523 (0.01) 0.001
Nerves and central nervous system,
n (%)
Generalised convulsion 1,123 (0.18) 965 (0.15) 0.006 4,355 (0.14) 4,191 (0.14) 0.001 9,459 (0.23) 9,225 (0.23) 0.001
Meningoencephalitis 45 (0.01) 52 (0.01) 0.001 176 (0.01) 170 (0.01) <0.001 178 (<0.01) 180 (<0.01) <0.001
Transverse myelitis <5 0 0.003 16 (<0.01) 10 (<0.01) 0.001 86 (<0.01) 79 (<0.01) <0.001
Bell’s palsy 375 (0.06) 473 (0.08) 0.006 2,561 (0.08) 2,671 (0.09) 0.001 1,599 (0.04) 1,525 (0.04) 0.001
Respiratory system, n (%)
Acute respiratory distress syndrome 108 (0.02) 186 (0.03) 0.008 1,055 (0.03) 1,508 (0.05) 0.007 130 (<0.01) 153 (<0.01) 0.001
Skin and mucous membrane, bone,
and joints system, n (%)
Erythema multiforme 29 (<0.01) 26 (<0.01) 0.001 140 (<0.01) 141 (<0.01) <0.001 202 (<0.01) 165 (<0.01) 0.001
Chilblain-like lesions 282 (0.04) 242 (0.04) 0.003 1,782 (0.06) 1,713 (0.06) 0.001 1,768 (0.04) 1,222 (0.03) 0.007
Reproductive system, n (%)
Secondary amenorrhoea 1,041 (0.17) 962 (0.15) 0.003 7,630 (0.25) 8,366 (0.27) 0.005 14,781 (0.36) 11,548 (0.28) 0.014
Hypermenorrhoea 3,208 (0.51) 2,915 (0.46) 0.007 12,311 (0.40) 12,579 (0.41) 0.001 NA NA
Other systems, n (%)
Anaphylaxis 314 (0.05) 372 (0.06) 0.004 451 (0.01) 457 (0.01) <0.001 558 (0.01) 664 (0.02) 0.002
Multisystem inflammatory syndrome 104 (0.02) 146 (0.02) 0.005 55 (<0.01) 62 (<0.01) 0.001 0 8 (<0.01) 0.002
Subacute thyroiditis <5 <5 0.001 11 (<0.01) 10 (<0.01) <0.001 30 (<0.01) 24 (<0.01) 0.001

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Table 15. Part 2: Prior adverse events of special interest (AESIs) within one year of time zero (outcome-specific exclusion
criteria) by exposure group by data source

(SEE PART 1 ABOVE)

EpiChron SIDIAP CPRD Aurum
Vac Unvac ASD Vac Unvac ASD Vac Unvac ASD
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

ASD: absolute standardised difference; NR: not reportable; Vac: vaccinated cohort; Unvac: unvaccinated cohort
a including microangiopathy ASD: Absolute standardised difference

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10.1.2.5. Outcome data in the unmatched vaccinated cohort

Incidence rates (95% CI) for AESIs among individuals who receive a first dose of the Pfizer-
BioNTech COVID-19 vaccine (before matching) in the pre-specified time windows defined in
Table 2 by data source were calculated (available in an online repository and accessible on
request).

Incidence rates (95% CI) for AESIs in Pfizer-BioNTech vaccinated population after a first,
second, or third dose (before matching by data source) are provided in Tables 15.9.1-7
(available in an online repository and accessible on request).

10.2. Main results

The main results for this interim report #5 are those for the following two secondary
analyses:

 Estimated incidence rates of prespecified AESI among individuals who receive at least
one dose of the Pfizer-BioNTech COVID19 vaccine compared with individuals in a
matched comparator unvaccinated cohort using a cohort study design.

 Description of incidence rates and assessment of a potential increased risk of

prespecified AESI following the administration of at least one dose of the Pfizer-
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

BioNTech COVID-19 vaccine compared with a matched comparator group with no

COVID-19 vaccination in Europe using a cohort study design.

In this fifth interim report, regardless of the results from the negative control, baseline
imbalances were adjusted using IPTW to challenge the assumption that confounders for
symptomatic SARS-CoV-2 infections are equally relevant for all AESIs (SAP section 2.2.2.6,
SAP Figure 6). Individuals following each vaccination category under study may have
different characteristics that may determine their risk for any AESI. To account for such
potential confounding, PS methods were used to estimate the adjusted risk ratios and 95%
CIs. PS represent the probability of being vaccinated at any calendar time given a set of
baseline covariates.

The results are summarized for each data source, per AESI, in the following tables and
figures. The data for COVID-19 disease in the first 12 days after vaccination were used for
the negative control (see Section 10.2.1 below).

10.2.1. Results from negative control

To assess baseline exchangeability, the incidences of COVID-19 in the first 12 days after
vaccination in the vaccinated and unvaccinated cohorts were compared. In NHR, PHARMO,
EpiChron and SIDIAP the differences between the incidences were less than 1 per 1000
cases, which was the a-priori set threshold for baseline exchangeability (Figure 5). In
Pedianet, the difference between the incidences of COVID-19 disease in the first 12 days
was 2 per 1000 cases (see Figure 5). Cumulative incidence curves for vaccinated and
unvaccinated cohorts increase similarly in the first 12 days after time zero. In Pedianet the
background incidence of COVID-19 disease in the first 12 days was higher (350 per 10,000
individuals) than those in the other data sources (around 40 per 10,000 individuals) but this
is not suggestive of confounding. Although we considered that the matching process
achieved the required balance between the cohorts, the analyses were performed in the

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matched cohorts with additional control for confounding to evaluate the effect of the PS
adjustment.

Figure 5. Cumulative incidence of COVID-19 disease in the first 12 days after start
of follow-up among individuals who received at least one dose of Pfizer-
BioNTech COVID-19 vaccine and matched unvaccinated individuals by
data source
Pedianet
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Figure 5. Cumulative incidence of COVID-19 disease in the first 12 days after start
of follow-up among individuals who received at least one dose of Pfizer-
BioNTech COVID-19 vaccine and matched unvaccinated individuals by
data source
NHR
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Figure 5. Cumulative incidence of COVID-19 disease in the first 12 days after start
of follow-up among individuals who received at least one dose of Pfizer-
BioNTech COVID-19 vaccine and matched unvaccinated individuals by
data source
PHARMO
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

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Figure 5. Cumulative incidence of COVID-19 disease in the first 12 days after start
of follow-up among individuals who received at least one dose of Pfizer-
BioNTech COVID-19 vaccine and matched unvaccinated individuals by
data source
EpiChron
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Figure 5. Cumulative incidence of COVID-19 disease in the first 12 days after start
of follow-up among individuals who received at least one dose of Pfizer-
BioNTech COVID-19 vaccine and matched unvaccinated individuals by
data source
SIDIAP
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Figure 5. Cumulative incidence of COVID-19 disease in the first 12 days after start
of follow-up among individuals who received at least one dose of Pfizer-
BioNTech COVID-19 vaccine and matched unvaccinated individuals by
data source
CPRD Aurum
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

10.2.2. Incidence rates and hazard ratios for AESIs

The overall results for each AESI by data source are summarised in Table 16. More
complete results can be found in Standalone Annex 2. More complete results for AESIs of
specific interest are provided in Section 10.2.3.

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Table 16. Summary of number of events, person-years (PY), and incidence rates for each AESI in the vaccinated and
unvaccinated cohorts and the adjusted hazard ratio (HR) and rate difference (RD) by data source
Vaccinated Unvaccinated Adjusted HRa Adjusted
Adverse event of special interest Events (n) PY Incidence rate (95% CI) Events (n) PY Incidence rate (95% CI) RDa
Autoimmune diseases
Guillain-Barre syndrome
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

Pedianet 0 1,036 0 (0, NC) 0 1,036 0 (0, NC) 0 0

NHR 7 257,572 0.27 (0.11, 0.56) 5 257,243 0.19 (0.07, 0.55) 1.40 (0.43, 4.58) 0.01
PHARMO 0 87,418 0 (0, 0.42) <5 NR 0.23 (0.03, 1.62) NA -0.02
EpiChron 0 43,902 0 (0, 0.84) <5 NR 0.46 (0.06, 3.24) NA -0.07
SIDIAP 7 230,053 0.30 (0.12, 0.63) 9 230,053 0.39 (0.16, 0.96) 0.76 (0.24, 2.43) -0.01
CPRD Aurum 14 349,149 0.40 (0.22, 0.67) 14 347,825 0.40 (0.22, 0.75) 0.98 (0.43, 2.25) -0.01
Acute disseminated encephalomyelitis
Pedianet NA NA NA NA NA NA NA NA
NHR <5 NR 0.12 (0.02, 0.34) 0 257,259 0 (0, NC) NA 0.02
PHARMO 0 87,420 0 (0, NC) 0 87,590 0 (0, NC) NA 0
EpiChron 0 43,906 0 (0, 0.84) <5 NR 0.46 (0.06, 3.24) NA -0.06
SIDIAP <5 NR 0.04 (0, 0.24) 0 230,072 0 (0, NC) NA 0
CPRD Aurum 0 349,188 0 (0, 0.11) 0 347,863 0 (0, NC) NA 0
Narcolepsy
Pedianet 0 1,037 0 (0, NC) 0 1,037 0 (0, NC) NA 0
NHR 21 257,522 0.82 (0.50, 1.25) 11 257,194 0.43 (0.21, 0.85) 1.89 (0.86, 4.17) 0.04
PHARMO 0 87,420 0 (0, NC) 0 87,590 0 (0, NC) NA 0
EpiChron 0 43,905 0 (0, NC) 0 43,859 0 (0, NC) NA 0
SIDIAP <5 NR 0.09 (0.01, 0.31) 8 230,066 0.35 (0.17, 0.70) 0.24 (0.06, 0.96) -0.03
CPRD Aurum 7 349,166 0.20 (0.08, 0.41) 8 347,841 0.23 (0.12, 0.46) 0.94 (0.34, 2.60) 0
Acute aseptic arthritis
Pedianet <5 NR 38.91 (10.60, 99.61) 5 1,029 48.61 (20.23, 116.77) 0.79 (0.21, 2.94) -1.28
NHR 1,360 254,051 53.53 (50.72, 56.46) 1,285 253,740 50.64 (47, 54.57) 1.05 (0.96, 1.15) 0.27
PHARMO 39 87,336 4.47 (3.18, 6.10) 51 87,506 5.83 (4.16, 8.17) 0.72 (0.45, 1.15) -0.18
EpiChron 306 43,445 70.43 (62.76, 78.79) 274 43,403 63.13 (53.22, 74.88) 1.05 (0.86, 1.29) 0.38
SIDIAP 1,000 228,262 43.81 (41.14, 46.61) 1,007 228,259 44.12 (40.45, 48.12) 0.95 (0.85, 1.05) -0.18
CPRD Aurum 1,121 346,656 32.34 (30.47, 34.29) 886 345,371 25.65 (23.73, 27.73) 1.23 (1.11, 1.35) 0.74
Diabetes mellitus type 1
Pedianet 0 6,974 0 (0, NC) 0 6,998 0 (0, NC) 0 0
NHR 476 836,725 5.69 (5.19, 6.22) 385 825,721 4.66 (4.01, 5.43) 1.21 (1.02, 1.45) 0.63
PHARMO 65 479,264 1.36 (1.05, 1.73) 61 473,634 1.29 (0.94, 1.76) 1.04 (0.70, 1.55) 0.07
EpiChron 52 206,385 2.52 (1.88, 3.30) 72 205,385 3.51 (2.39, 5.15) 0.71 (0.45, 1.13) -1.12
SIDIAP 369 999,903 3.69 (3.32, 4.09) 385 999,919 3.85 (3.29, 4.51) 0.92 (0.76, 1.11) -0.15
CPRD Aurum 245 1,284,669 1.91 (1.68, 2.16) 204 1,254,734 1.63 (1.37, 1.93) 1.20 (0.97, 1.48) 0.34
(Idiopathic) thrombocytopenia

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Table 16. Summary of number of events, person-years (PY), and incidence rates for each AESI in the vaccinated and
unvaccinated cohorts and the adjusted hazard ratio (HR) and rate difference (RD) by data source
Vaccinated Unvaccinated Adjusted HRa Adjusted
Adverse event of special interest Events (n) PY Incidence rate (95% CI) Events (n) PY Incidence rate (95% CI) RDa
Pedianet 0 1,037 0 (0, NC) 0 1,037 0 (0, NC) 0 0
NHR 25 257,490 0.97 (0.63, 1.43) 40 257,161 1.56 (1, 2.41) 0.62 (0.36, 1.09) -0.07
PHARMO <5 NR 0.23 (0.03, 0.83) <5 NR 0.34 (0.11, 1.06) 0.60 (0.10, 3.57) -0.02
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

EpiChron <5 NR 0.46 (0.06, 1.65) 9 43,853 2.05 (0.79, 5.30) 0.23 (0.04, 1.23) -0.23
SIDIAP 22 230,030 0.96 (0.60, 1.45) 27 230,029 1.17 (0.71, 1.93) 0.77 (0.40, 1.47) -0.03
CPRD Aurum 26 349,128 0.74 (0.49, 1.09) 18 347,805 0.52 (0.31, 0.86) 1.40 (0.74, 2.67) 0.03
Thrombotic thrombocytopenia
syndrome
Pedianet NA NA NA NA NA NA NA NA
NHR 6 123,793 0.48 (0.18, 1.05) 7 123,744 0.57 (0.24, 1.31) 0.85 (0.27, 2.71) 0
PHARMO 0 35,681 0 (0, 1.03) <5 NR 0.28 (0.04, 1.98) NA -0.01
EpiChron <5 NR 0.99 (0.12, 3.57) <5 NR 0.49 (0.07, 3.51) 1.72 (0.15, 19.10) 0.01
SIDIAP <5 NR 0.39 (0.11, 0.99) 6 103,019 0.58 (0.26, 1.30) 0.63 (0.18, 2.25) -0.01
CPRD Aurum <5 NR 0.07 (0, 0.37) <5 NR 0.13 (0.03, 0.54) 0.55 (0.05, 6.09) 0
Myositis
Pedianet NA NA NA NA NA NA NA NA
NHR 153 854,133 1.79 (1.52, 2.10) 134 842,594 1.59 (1.22, 2.07) 1.12 (0.83, 1.52) 0.32
PHARMO 5 480,853 0.10 (0.03, 0.24) 6 475,212 0.13 (0.03, 0.54) 0.74 (0.13, 4.38) -0.09
EpiChron 9 208,240 0.43 (0.20, 0.82) <5 NR 0.19 (0.04, 0.91) 1.87 (0.34, 10.19) 0.05
SIDIAP 181 1,004,091 1.80 (1.55, 2.09) 187 1,004,106 1.86 (1.51, 2.30) 0.88 (0.68, 1.14) -0.27
CPRD Aurum 50 1,284,805 0.39 (0.29, 0.51) 52 1,254,861 0.41 (0.29, 0.59) 0.91 (0.58, 1.42) 0.12
Cardiovascular system
Acute cardiovascular injury including
microangiopathy
Pedianet 28 6,951 40.28 (26.77, 58.22) 20 6,977 28.67 (17.07, 48.16) 1.38 (0.73, 2.61) 10.12
NHR 20,167 772,035 261.22 (257.63, 264.85) 19,669 764,487 257.28 (251.86, 262.82) 1.01 (0.99, 1.04) 2.20
PHARMO 5,626 469,832 119.74 (116.64, 122.92) 3,766 465,082 80.97 (77.64, 84.46) 1.38 (1.31, 1.45) 33.31
EpiChron 3,446 201,712 170.84 (165.18, 176.64) 2,870 201,406 142.50 (134.71, 150.74) 1.10 (1.03, 1.18) 18.26
SIDIAP 11,569 979,663 118.09 (115.95, 120.26) 11,132 980,277 113.56 (110.25, 116.97) 0.99 (0.96, 1.03) 3.01
CPRD Aurum 10,041 1,258,613 79.78 (78.23, 81.35) 7,796 1,232,960 63.23 (61.38, 65.14) 1.23 (1.18, 1.27) 27.28
Arrhythmia
Pedianet 25 6,959 35.92 (23.25, 53.03) 14 6,987 20.04 (11.44, 35.08) 1.75 (0.88, 3.49) 13.68
NHR 17,200 793,320 216.81 (213.58, 220.08) 16,543 784,864 210.78 (205.87, 215.80) 1.03 (1, 1.05) 5.25
PHARMO 4,696 471,867 99.52 (96.69, 102.41) 3,158 466,955 67.63 (64.58, 70.83) 1.36 (1.29, 1.44) 26.84
EpiChron 2,840 203,033 139.88 (134.78, 145.12) 2,305 202,602 113.77 (106.79, 121.21) 1.12 (1.04, 1.21) 16.77
SIDIAP 9,527 984,283 96.79 (94.86, 98.75) 9,146 984,781 92.87 (89.88, 95.97) 0.99 (0.96, 1.03) 2.84
CPRD Aurum 6,337 1,269,791 49.91 (48.68, 51.15) 4,735 1,242,440 38.11 (36.66, 39.62) 1.27 (1.21, 1.33) 21.25
Heart failure

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Table 16. Summary of number of events, person-years (PY), and incidence rates for each AESI in the vaccinated and
unvaccinated cohorts and the adjusted hazard ratio (HR) and rate difference (RD) by data source
Vaccinated Unvaccinated Adjusted HRa Adjusted
Adverse event of special interest Events (n) PY Incidence rate (95% CI) Events (n) PY Incidence rate (95% CI) RDa
Pedianet NA NA NA NA NA NA NA NA
NHR 3,885 838,216 46.35 (44.90, 47.83) 4,930 827,927 59.55 (56.84, 62.38) 0.77 (0.73, 0.82) -13.33
PHARMO 780 479,288 16.27 (15.15, 17.46) 593 473,758 12.52 (11.20, 13.99) 1.29 (1.13, 1.47) 4.01
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

EpiChron 983 206,512 47.60 (44.67, 50.67) 1,035 205,745 50.30 (45.61, 55.49) 0.90 (0.80, 1.01) -4.60
SIDIAP 2,569 998,769 25.72 (24.74, 26.74) 2,739 998,818 27.42 (25.73, 29.22) 0.89 (0.82, 0.96) -1.19
CPRD Aurum 2,462 1,278,995 19.25 (18.50, 20.03) 2,299 1,250,241 18.39 (17.37, 19.47) 1.02 (0.95, 1.09) 5.23
Stress cardiomyopathy
Pedianet NA NA NA NA NA NA NA NA
NHR 7 854,493 0.08 (0.03, 0.17) 10 842,940 0.12 (0.04, 0.37) 0.69 (0.18, 2.67) 0.02
PHARMO 6 480,858 0.12 (0.05, 0.27) <5 NR 0.08 (0.03, 0.28) 1.49 (0.33, 6.69) 0
EpiChron 6 208,241 0.29 (0.11, 0.63) 6 207,207 0.29 (0.09, 0.90) 0.85 (0.21, 3.47) -0.05
SIDIAP 35 1,004,330 0.35 (0.24, 0.48) 21 1,004,339 0.21 (0.11, 0.39) 1.51 (0.75, 3.04) 0.14
CPRD Aurum 14 1,284,916 0.11 (0.06, 0.18) 11 1,254,967 0.09 (0.04, 0.18) 1.30 (0.53, 3.20) 0.06
Coronary artery disease
Pedianet NA NA NA NA NA NA NA NA
NHR 5,593 831,346 67.28 (65.52, 69.06) 5,541 820,893 67.50 (64.71, 70.41) 0.99 (0.94, 1.04) 0.43
PHARMO 893 478,964 18.64 (17.44, 19.91) 579 473,477 12.23 (10.99, 13.60) 1.49 (1.31, 1.69) 6.17
EpiChron 379 207,469 18.27 (16.47, 20.20) 371 206,465 17.97 (15.33, 21.06) 0.97 (0.80, 1.17) 0.57
SIDIAP 1,542 1,001,458 15.40 (14.64, 16.19) 1,464 1,001,552 14.62 (13.44, 15.90) 1 (0.91, 1.10) 0.52
CPRD Aurum 2,651 1,277,998 20.74 (19.96, 21.55) 1,804 1,249,224 14.44 (13.58, 15.36) 1.40 (1.30, 1.50) 7.83
Myocarditis (7 days)
Pedianet 0 197 0 (0, NC) 0 197 0 (0, NC) 0 0
NHR 6 64,453 0.93 (0.34, 2.03) 9 64,442 1.40 (0.73, 2.68) 0.67 (0.24, 1.88) -0.01
PHARMO <5 NR 0.56 (0.01, 3.11) 0 17,936 0 (0, NC) 0 0.01
EpiChron <5 NR 0.91 (0.02, 5.08) 0 10,976 0 (0, NC) 0 0.02
SIDIAP 0 54,205 0 (0, NC) <5 NR 0.55 (0.18, 1.72) NA -0.01
CPRD Aurum 10 74,891 1.34 (0.64, 2.46) <5 74,845 0.13 (0.02, 0.95) 9.70 (1.24, 0.02
75.97)**
Myocarditis (14 days)
Pedianet 0 380 0 (0, NC) 0 380 0 (0, NC) 0 0
NHR 13 117,067 1.11 (0.59, 1.90) 12 117,024 1.03 (0.56, 1.89) 1.09 (0.48, 2.46) 0.01
PHARMO <5 NR 0.60 (0.07, 2.15) <5 NR 0.59 (0.08, 4.22) 0.81 (0.07, 8.92) -0.01
EpiChron <5 NR 1.04 (0.13, 3.77) <5 NR 0.52 (0.07, 3.70) 1.84 (0.17, 20.30) 0.02
SIDIAP 6 97,369 0.62 (0.23, 1.34) 5 97,369 0.51 (0.21, 1.23) 1.09 (0.33, 3.62) 0.01
CPRD Aurum 14 140,114 1 (0.55, 1.68) 8 139,949 0.57 (0.26, 1.24) 1.74 (0.68, 4.44) 0.01
Myocarditis (21 days)
Pedianet 0 553 0 (0, NC) 0 553 0 (0, NC) 0 0
NHR 16 160,598 1 (0.57, 1.62) 17 160,505 1.06 (0.62, 1.80) 0.94 (0.46, 1.94) 0

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12 March 2024

Table 16. Summary of number of events, person-years (PY), and incidence rates for each AESI in the vaccinated and
unvaccinated cohorts and the adjusted hazard ratio (HR) and rate difference (RD) by data source
Vaccinated Unvaccinated Adjusted HRa Adjusted
Adverse event of special interest Events (n) PY Incidence rate (95% CI) Events (n) PY Incidence rate (95% CI) RDa
PHARMO <5 NR 0.62 (0.13, 1.82) <5 NR 0.42 (0.06, 2.95) 1.23 (0.13, 11.84) 0.01
EpiChron <5 NR 1.53 (0.42, 3.92) <5 NR 0.38 (0.05, 2.72) 3.64 (0.41, 32.53) 0.07
SIDIAP 8 134,968 0.59 (0.26, 1.17) 7 134,968 0.52 (0.22, 1.20) 1.05 (0.35, 3.16) 0
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

CPRD Aurum 18 198,641 0.91 (0.54, 1.43) 8 198,282 0.40 (0.19, 0.88) 2.30 (0.94, 5.66) 0.03
Pericarditis (7 days)
Pedianet <5 NR 50.83 (1.29, 283.23) 0 197 0 (0, NC) 0 0.95
NHR 16 64,433 2.48 (1.42, 4.03) 24 64,422 3.73 (2.35, 5.91) 0.66 (0.34, 1.30) -0.02
PHARMO 0 17,887 0 (0, NC) <5 NR 0.56 (0.08, 3.96) NA -0.01
EpiChron <5 NR 3.64 (0.99, 9.33) 5 10,973 4.56 (1.62, 12.85) 0.83 (0.20, 3.45) -0.01
SIDIAP 19 54,182 3.51 (2.11, 5.48) 18 54,182 3.32 (1.67, 6.61) 0.96 (0.42, 2.17) 0
CPRD Aurum 12 74,880 1.60 (0.83, 2.80) 11 74,834 1.47 (0.77, 2.79) 1.10 (0.47, 2.58) 0
Pericarditis (14 days)
Pedianet <5 NR 26.28 (0.67, 146.40) 0 381 0 (0, NC) 0 0.95
NHR 36 117,030 3.08 (2.15, 4.26) 39 116,988 3.33 (2.24, 4.97) 0.92 (0.55, 1.54) 0
PHARMO <5 NR 0.30 (0.01, 1.66) <5 NR 0.30 (0.04, 2.11) 1.44 (0.09, 22.95) 0.01
EpiChron 6 19,166 3.13 (1.15, 6.81) 7 19,160 3.65 (1.44, 9.25) 0.84 (0.25, 2.87) -0.02
SIDIAP 36 97,329 3.70 (2.59, 5.12) 34 97,329 3.49 (1.97, 6.18) 0.95 (0.49, 1.83) -0.01
CPRD Aurum 22 140,094 1.57 (0.98, 2.38) 16 139,928 1.14 (0.68, 1.92) 1.36 (0.71, 2.61) 0.02
Pericarditis (21 days)
Pedianet <5 NR 18.06 (0.46, 100.64) 0 554 0 (0, NC) 0 0.95
NHR 55 160,548 3.43 (2.58, 4.46) 50 160,456 3.12 (2.14, 4.54) 1.10 (0.69, 1.73) 0.03
PHARMO <5 NR 0.21 (0.01, 1.16) <5 NR 0.21 (0.03, 1.47) 1.44 (0.09, 22.95) 0.01
EpiChron 6 26,098 2.30 (0.84, 5) 8 26,084 3.07 (1.23, 7.67) 0.74 (0.22, 2.49) -0.05
SIDIAP 43 134,911 3.19 (2.31, 4.29) 38 134,912 2.82 (1.66, 4.77) 1.02 (0.56, 1.88) 0.01
CPRD Aurum 38 198,611 1.91 (1.35, 2.63) 24 198,253 1.21 (0.79, 1.86) 1.49 (0.87, 2.54) 0.04
Myocarditis or pericarditis (7 days)
Pedianet <5 NR 50.86 (1.29, 283.39) 0 197 0 (0, NC) 0 0.95
NHR 21 64,421 3.26 (2.02, 4.98) 32 64,410 4.97 (3.37, 7.32) 0.65 (0.37, 1.17) -0.03
PHARMO <5 NR 0.56 (0.01, 3.12) <5 NR 0.56 (0.08, 3.96) 1.10 (0.07, 17.58) 0
EpiChron 5 10,974 4.56 (1.48, 10.63) 5 10,973 4.56 (1.62, 12.85) 1.02 (0.26, 3.93) 0.01
SIDIAP 18 54,178 3.32 (1.97, 5.25) 20 54,178 3.69 (1.96, 6.97) 0.81 (0.37, 1.75) -0.01
CPRD Aurum 22 74,873 2.94 (1.84, 4.45) 12 74,827 1.60 (0.87, 2.95) 1.80 (0.86, 3.76) 0.02
Myocarditis or pericarditis (14 days)
Pedianet <5 NR 26.29 (0.67, 146.48) 0 380 0 (0, NC) 0 0.95
NHR 48 117,008 4.10 (3.02, 5.44) 49 116,965 4.19 (2.98, 5.90) 0.98 (0.63, 1.52) 0.01
PHARMO <5 NR 0.89 (0.18, 2.61) <5 NR 0.89 (0.21, 3.84) 0.98 (0.15, 6.58) 0
EpiChron 8 19,165 4.17 (1.80, 8.22) 8 19,159 4.18 (1.79, 9.76) 0.97 (0.33, 2.89) 0
SIDIAP 39 97,322 4.01 (2.85, 5.48) 38 97,322 3.90 (2.32, 6.57) 0.92 (0.50, 1.68) -0.01

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CT24-WI-GL15-RF02 3.0 Non-Interventional/Low-Interventional Study Type 1 Study Report Template
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BNT162b2 (COMIRNATY, Pfizer-BioNTech COVID-19 vaccine)
12 March 2024

Table 16. Summary of number of events, person-years (PY), and incidence rates for each AESI in the vaccinated and
unvaccinated cohorts and the adjusted hazard ratio (HR) and rate difference (RD) by data source
Vaccinated Unvaccinated Adjusted HRa Adjusted
Adverse event of special interest Events (n) PY Incidence rate (95% CI) Events (n) PY Incidence rate (95% CI) RDa
CPRD Aurum 36 140,080 2.57 (1.80, 3.56) 24 139,915 1.72 (1.11, 2.64) 1.49 (0.87, 2.53) 0.03
Myocarditis or pericarditis (21 days)
Pedianet <5 NR 18.07 (0.46, 100.70) 0 553 0 (0, NC) 0 0.95
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

NHR 68 160,517 4.24 (3.29, 5.37) 64 160,424 3.99 (2.90, 5.48) 1.06 (0.71, 1.58) 0.03
PHARMO <5 NR 0.83 (0.23, 2.13) <5 NR 0.62 (0.14, 2.68) 1.29 (0.21, 7.90) 0.01
EpiChron 10 26,097 3.83 (1.84, 7.05) 9 26,083 3.45 (1.48, 8.02) 1.07 (0.38, 3.03) 0.02
SIDIAP 48 134,902 3.56 (2.62, 4.72) 44 134,902 3.26 (2.04, 5.23) 0.99 (0.57, 1.72) 0.01
CPRD Aurum 56 198,592 2.82 (2.13, 3.66) 32 198,235 1.61 (1.11, 2.35) 1.68 (1.06, 2.66) 0.07
Circulatory system
Coagulation disorders:
thromboembolism
Pedianet 0 719 0 (0, 51.32) <5 NR 13.91 (1.96, 98.77) NA -0.95
NHR 1,278 194,519 65.70 (62.15, 69.40) 1,359 194,372 69.92 (65.31, 74.86) 0.94 (0.86, 1.02) -0.29
PHARMO 94 61,625 15.25 (12.33, 18.67) 88 61,748 14.25 (11.08, 18.34) 1.03 (0.75, 1.42) 0.03
EpiChron 222 32,012 69.35 (60.53, 79.10) 242 31,991 75.65 (63.66, 89.89) 0.88 (0.71, 1.09) -0.71
SIDIAP 624 167,788 37.19 (34.33, 40.23) 861 167,776 51.32 (46.93, 56.12) 0.67 (0.60, 0.76) -1.28
CPRD Aurum 643 250,854 25.63 (23.69, 27.69) 849 250,239 33.93 (31.45, 36.60) 0.74 (0.66, 0.82) -0.70
Single organ cutaneous vasculitis
Pedianet
NHR 13 197,648 0.66 (0.35, 1.12) 7 197,491 0.35 (0.15, 0.82) 1.85 (0.68, 5.02) 0.02
PHARMO 0 61,781 0 (0, NC) <5 NR 0.16 (0.02, 1.15) NA -0.01
EpiChron <5 NR 0.31 (0.01, 1.72) 0 32,389 0 (0, NC) 0 0.03
SIDIAP 5 169,107 0.30 (0.10, 0.69) <5 NR 0.06 (0.01, 0.42) 4.67 (0.54, 39.99) 0.02
CPRD Aurum 5 252,286 0.20 (0.06, 0.46) 7 251,664 0.28 (0.11, 0.70) 0.72 (0.20, 2.58) -0.01
Cerebral venous sinus thrombosis
Pedianet 0 719 0 (0, NC) 0 719 0 (0, NC) 0 0
NHR 7 197,673 0.35 (0.14, 0.73) 11 197,515 0.56 (0.28, 1.11) 0.63 (0.23, 1.74) -0.01
PHARMO <5 NR 0.16 (0, 0.90) 0 61,904 0 (0, NC) 0 0.01
EpiChron <5 NR 0.31 (0.01, 1.72) <5 NR 0.31 (0.04, 2.19) 0.90 (0.06, 14.09) 0.01
SIDIAP <5 NR 0.12 (0.01, 0.43) <5 NR 0.18 (0.06, 0.55) 0.68 (0.11, 4.20) 0
CPRD Aurum 5 252,280 0.20 (0.06, 0.46) 11 251,658 0.44 (0.23, 0.83) 0.43 (0.14, 1.27) -0.02
Hepato-gastrointestinal and renal system
Acute liver injury
Pedianet 0 6,991 0 (0, NC) 0 7,014 0 (0, NC) 0 0
NHR 125 854,201 1.46 (1.22, 1.74) 167 842,663 1.98 (1.53, 2.57) 0.73 (0.54, 1) -0.53
PHARMO 12 480,849 0.25 (0.13, 0.44) 7 475,208 0.15 (0.06, 0.34) 1.76 (0.65, 4.79) 0.09
EpiChron 68 208,124 3.27 (2.54, 4.14) 69 207,101 3.33 (2.23, 4.98) 0.91 (0.56, 1.46) -0.11
SIDIAP 119 1,004,116 1.19 (0.98, 1.42) 160 1,004,106 1.59 (1.25, 2.03) 0.64 (0.47, 0.88) -0.49

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Table 16. Summary of number of events, person-years (PY), and incidence rates for each AESI in the vaccinated and
unvaccinated cohorts and the adjusted hazard ratio (HR) and rate difference (RD) by data source
Vaccinated Unvaccinated Adjusted HRa Adjusted
Adverse event of special interest Events (n) PY Incidence rate (95% CI) Events (n) PY Incidence rate (95% CI) RDa
CPRD Aurum 68 1,284,804 0.53 (0.41, 0.67) 70 1,254,863 0.56 (0.42, 0.75) 0.92 (0.63, 1.34) 0.07
Acute kidney injury
Pedianet 0 6,991 0 (0, NC) 0 7,014 0 (0, NC) 0 0
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

NHR 2,480 849,109 29.21 (28.07, 30.38) 3,577 838,010 42.68 (40.29, 45.22) 0.68 (0.63, 0.73) -14.55
PHARMO 340 480,188 7.08 (6.35, 7.87) 297 474,581 6.26 (5.36, 7.30) 1.11 (0.92, 1.34) 1.04
EpiChron 701 207,210 33.83 (31.37, 36.43) 703 206,336 34.07 (30.19, 38.45) 0.92 (0.80, 1.06) -1.09
SIDIAP 3,069 997,291 30.77 (29.69, 31.88) 3,452 997,268 34.61 (32.82, 36.51) 0.82 (0.77, 0.87) -3.83
CPRD Aurum 1,765 1,280,435 13.78 (13.15, 14.44) 1,977 1,251,085 15.80 (14.89, 16.77) 0.84 (0.78, 0.90) -0.45
Acute pancreatitis
Pedianet NA NA NA NA NA NA NA NA
NHR 474 853,262 5.56 (5.07, 6.08) 533 841,748 6.33 (5.53, 7.25) 0.87 (0.74, 1.03) -0.63
PHARMO 86 480,661 1.79 (1.43, 2.21) 74 475,027 1.56 (1.13, 2.14) 1.08 (0.73, 1.58) 0.26
EpiChron 105 207,993 5.05 (4.13, 6.11) 84 206,971 4.06 (2.93, 5.62) 1.14 (0.78, 1.66) 0.68
SIDIAP 455 1,003,340 4.53 (4.13, 4.97) 513 1,003,342 5.11 (4.49, 5.83) 0.82 (0.70, 0.96) -0.72
CPRD Aurum 271 1,284,267 2.11 (1.87, 2.38) 260 1,254,360 2.07 (1.77, 2.42) 0.99 (0.81, 1.21) 0.07
Rhabdomyolysis
Pedianet NA NA NA NA NA NA NA NA
NHR 5 854,499 0.06 (0.02, 0.14) 7 842,942 0.08 (0.02, 0.38) 0.71 (0.12, 4.05) -0.01
PHARMO 7 480,852 0.15 (0.06, 0.30) <5 NR 0.06 (0.02, 0.20) 2.20 (0.56, 8.63) 0.07
EpiChron 47 208,172 2.26 (1.66, 3) 51 207,135 2.46 (1.34, 4.52) 0.86 (0.44, 1.68) 0.02
SIDIAP 135 1,004,110 1.34 (1.13, 1.59) 215 1,004,093 2.14 (1.71, 2.68) 0.60 (0.46, 0.80) -0.68
CPRD Aurum 63 1,284,795 0.49 (0.38, 0.63) 82 1,254,853 0.65 (0.49, 0.87) 0.74 (0.51, 1.08) -0.04
Glomerulonephritis
Pedianet 0 6,991 0 (0, NC) 0 7,014 0 (0, NC) 0 0
NHR NA NA NA NA NA NA NA NA
PHARMO NA NA NA NA NA NA NA NA
EpiChron 12 208,226 0.58 (0.30, 1.01) 18 207,187 0.87 (0.40, 1.88) 0.59 (0.22, 1.55) -0.28
SIDIAP 105 1,004,201 1.05 (0.86, 1.27) 73 1,004,208 0.73 (0.53, 1) 1.29 (0.88, 1.87) 0.29
CPRD Aurum 137 1,284,652 1.07 (0.90, 1.26) 150 1,254,718 1.20 (0.96, 1.48) 0.88 (0.67, 1.16) -0.23
Nerves and central nervous system
Generalised convulsion
Pedianet 0 1,031 0 (0, NC) <5 NR 19.40 (4.85, 77.53) NA -2.46
NHR 696 254,063 27.39 (25.40, 29.51) 688 253,745 27.11 (24.50, 30.01) 1.01 (0.89, 1.14) 0.05
PHARMO 38 87,350 4.35 (3.08, 5.97) 27 87,521 3.08 (2.06, 4.62) 1.37 (0.82, 2.31) 0.14
EpiChron 94 43,751 21.49 (17.36, 26.29) 73 43,707 16.70 (12.52, 22.28) 1.17 (0.83, 1.66) 0.59
SIDIAP 325 229,410 14.17 (12.67, 15.79) 348 229,408 15.17 (13.18, 17.45) 0.85 (0.71, 1.02) -0.22
CPRD Aurum 628 347,581 18.07 (16.68, 19.54) 633 346,267 18.28 (16.73, 19.97) 0.97 (0.86, 1.09) -0.03
Meningoencephalitis

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Table 16. Summary of number of events, person-years (PY), and incidence rates for each AESI in the vaccinated and
unvaccinated cohorts and the adjusted hazard ratio (HR) and rate difference (RD) by data source
Vaccinated Unvaccinated Adjusted HRa Adjusted
Adverse event of special interest Events (n) PY Incidence rate (95% CI) Events (n) PY Incidence rate (95% CI) RDa
Pedianet 0 1,037 0 (0, NC) 0 1,037 0 (0, NC) 0 0
NHR 46 257,455 1.79 (1.31, 2.38) 43 257,127 1.67 (1.14, 2.46) 1.07 (0.68, 1.69) 0.02
PHARMO <5 NR 0.34 (0.07, 1) 6 87,584 0.69 (0.27, 1.73) 0.49 (0.11, 2.14) -0.04
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

EpiChron <5 NR 0.91 (0.25, 2.33) <5 NR 0.23 (0.03, 1.62) 3.29 (0.37, 29.20) 0.09
SIDIAP 12 230,048 0.52 (0.27, 0.91) 17 230,048 0.74 (0.35, 1.57) 0.69 (0.27, 1.79) -0.03
CPRD Aurum 9 349,160 0.26 (0.12, 0.49) 22 347,835 0.63 (0.35, 1.14) 0.40 (0.16, 0.96) -0.05
Transverse myelitis
Pedianet 0 1,036 0 (0, NC) 0 1,037 0 (0, NC) 0 0
NHR <5 NR 0.08 (0.01, 0.28) <5 NR 0.08 (0.01, 0.55) 0.99 (0.09, 10.88) 0
PHARMO 0 87,420 0 (0, NC) 0 87,590 0 (0, NC) 0 0
EpiChron <5 NR 0.46 (0.06, 1.65) 0 43,860 0 (0, NC) 0 0.05
SIDIAP <5 NR 0.13 (0.03, 0.38) <5 NR 0.09 (0.01, 0.62) 1.18 (0.12, 11.36) 0
CPRD Aurum 6 349,174 0.17 (0.06, 0.37) 6 347,849 0.17 (0.08, 0.38) 0.91 (0.29, 2.87) 0
Bell's palsy
Pedianet 0 1,036 0 (0, NC) 0 1,037 0 (0, NC) 0 0
NHR 166 257,184 6.45 (5.51, 7.51) 144 256,858 5.61 (4.49, 7.01) 1.15 (0.88, 1.50) 0.11
PHARMO 10 87,393 1.14 (0.55, 2.10) 14 87,563 1.60 (0.91, 2.80) 0.65 (0.28, 1.51) -0.08
EpiChron 31 43,848 7.07 (4.80, 10.04) 34 43,803 7.76 (3.30, 18.25) 0.84 (0.34, 2.09) -0.22
SIDIAP 167 229,708 7.27 (6.21, 8.46) 167 229,708 7.27 (5.96, 8.88) 0.96 (0.75, 1.24) -0.01
CPRD Aurum 114 348,927 3.27 (2.70, 3.92) 116 347,605 3.34 (2.72, 4.09) 0.99 (0.75, 1.29) -0.01
Respiratory system
Acute respiratory distress syndrome
Pedianet NA NA NA NA NA NA NA NA
NHR 56 854,397 0.66 (0.50, 0.85) 284 842,801 3.37 (2.76, 4.11) 0.19 (0.14, 0.27) -3.27
PHARMO <5 NR 0.04 (0.01, 0.15) 6 475,213 0.13 (0.05, 0.32) 0.30 (0.06, 1.63) -0.12
EpiChron 26 208,169 1.25 (0.82, 1.83) 147 207,106 7.10 (5.55, 9.08) 0.16 (0.10, 0.25) -6.22
SIDIAP 82 1,003,633 0.82 (0.65, 1.01) 579 1,003,438 5.77 (5.09, 6.54) 0.13 (0.10, 0.17) -4.63
CPRD Aurum 18 1,284,870 0.14 (0.08, 0.22) 56 1,254,915 0.45 (0.31, 0.64) 0.31 (0.17, 0.55) -0.29
Skin and musous membrane bone and
joints
Erythema multiforme
Pedianet 0 1,036 0 (0, NC) 0 1,037 0 (0, NC) NA 0
NHR <5 NR 0.12 (0.02, 0.34) 7 257,242 0.27 (0.12, 0.63) 0.43 (0.10, 1.74) -0.01
PHARMO 0 87,419 0 (0, NC) 0 87,590 0 (0, NC) NA 0
EpiChron <5 NR 0.68 (0.14, 2) <5 NR 0.23 (0.03, 1.62) 3.18 (0.32, 31.35) 0.03
SIDIAP 10 230,051 0.43 (0.21, 0.80) 11 230,051 0.48 (0.24, 0.95) 0.82 (0.35, 1.96) -0.02
CPRD Aurum 7 349,155 0.20 (0.08, 0.41) 11 347,830 0.32 (0.15, 0.66) 0.55 (0.18, 1.65) -0.02
Chilblain-like lesions

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Table 16. Summary of number of events, person-years (PY), and incidence rates for each AESI in the vaccinated and
unvaccinated cohorts and the adjusted hazard ratio (HR) and rate difference (RD) by data source
Vaccinated Unvaccinated Adjusted HRa Adjusted
Adverse event of special interest Events (n) PY Incidence rate (95% CI) Events (n) PY Incidence rate (95% CI) RDa
Pedianet <5 NR 19.30 (2.34, 69.73) 0 1,037 0 (0, NC) NA 2.22
NHR 0 257,590 0 (0, NC) 0 257,262 0 (0, NC) NA 0
PHARMO 5 87,403 0.57 (0.19, 1.34) <5 NR 0.34 (0.11, 1.06) 1.51 (0.36, 6.38) 0.01
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

EpiChron 5 43,871 1.14 (0.37, 2.66) 13 43,824 2.97 (1.65, 5.32) 0.36 (0.12, 1.05) -0.23
SIDIAP 59 229,814 2.57 (1.95, 3.31) 89 229,812 3.87 (2.94, 5.09) 0.65 (0.45, 0.94) -0.15
CPRD Aurum 121 348,931 3.47 (2.88, 4.14) 98 347,607 2.82 (2.29, 3.48) 1.18 (0.89, 1.55) 0.06
Reproductive system
Secondary amenorrhoea
Pedianet <5 NR 2.57 (0.07, 14.33) 0 3,902 0 (0, NC) NA 1.11
NHR 136 141,726 9.60 (8.05, 11.35) 147 139,920 10.51 (8.34, 13.24) 0.91 (0.69, 1.21) -0.55
PHARMO <5 NR 0.13 (0, 0.73) <5 NR 0.13 (0.02, 0.94) 0.77 (0.05, 11.99) 0
EpiChron 270 38,227 70.63 (62.46, 79.58) 141 38,189 36.92 (29.89, 45.61) 1.71 (1.34, 2.18) 14.62
SIDIAP 1,663 176,273 94.34 (89.86, 98.99) 1,582 175,905 89.93 (84.11, 96.16) 0.99 (0.91, 1.07) 0.08
CPRD Aurum 4,484 986,853 45.44 (44.12, 46.79) 3,326 974,615 34.13 (32.70, 35.61) 1.25 (1.18, 1.31) 3.24
Hypermenorrhea
Pedianet <5 NR 5.15 (0.62, 18.62) <5 NR 7.70 (1.79, 33.20) 0.62 (0.08, 4.66) -0.87
NHR NA NA NA NA NA NA NA NA
PHARMO 6 76,532 0.78 (0.29, 1.71) 5 75,683 0.66 (0.23, 1.86) 1.18 (0.31, 4.47) 0.04
EpiChron 858 37,157 230.91 (215.72, 246.89) 535 37,166 143.95 (128.81, 160.87) 1.40 (1.23, 1.60) 33.57
SIDIAP 2,502 175,111 142.88 (137.34, 148.59) 2,285 174,773 130.74 (123.61, 138.29) 1.02 (0.95, 1.09) 2.94
CPRD Aurum NA NA NA NA NA NA NA NA
Other
Anaphylaxis*
Pedianet 0 NA 0 (0, NC) 0 NA 0 (0, NC) NA NA
NHR 64 NA 0.18 (0.14, 0.23) <5 NA 0.01 (0, 0.02) 31.95 (7.82, NA
130.52)
PHARMO <5 NA 0.01 (0, NC) 0 NA 0 (0, NC) NA NA
EpiChron <5 NA 0.05 (0.02, 0.14) <5 NA 0.02 (0, 0.11) 3.01 (0.31, 29.00) NA
SIDIAP 5 NA 0.02 (0.01, 0.04) <5 NA 0.01 (0, 0.03) 1.62 (0.39, 6.78) NA
CPRD Aurum <5 NA 0.03 (0.02, 0.05) 8 NA 0.02 (0.01, 0.04) 1.40 (0.58, 3.40) NA
Multisystem inflammatory syndrome
Pedianet NA NA NA NA NA NA NA NA
NHR 183 257,260 7.11 (6.12, 8.22) 233 256,935 9.07 (7.57, 10.86) 0.78 (0.62, 0.98) -0.21
PHARMO <5 NR 0.11 (0, 0.64) <5 NR 0.11 (0.02, 0.81) 1.20 (0.08, 19.01) 0.01
EpiChron 17 43,889 3.87 (2.26, 6.20) 9 43,843 2.05 (0.94, 4.50) 1.84 (0.74, 4.61) 0.27
SIDIAP 8 230,064 0.35 (0.15, 0.69) 7 230,064 0.30 (0.13, 0.70) 1.19 (0.40, 3.58) 0.01
CPRD Aurum <5 NR 0.09 (0.02, 0.25) <5 NR 0.03 (0, 0.20) 3.36 (0.35, 32.30) 0.01
Death (any causes)

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Table 16. Summary of number of events, person-years (PY), and incidence rates for each AESI in the vaccinated and
unvaccinated cohorts and the adjusted hazard ratio (HR) and rate difference (RD) by data source
Vaccinated Unvaccinated Adjusted HRa Adjusted
Adverse event of special interest Events (n) PY Incidence rate (95% CI) Events (n) PY Incidence rate (95% CI) RDa
Pedianet <5 NR 1.43 (0.04, 7.97) 0 7,014 0 (0, NC) NA 1.38
NHR 6,855 854,504 80.22 (78.33, 82.14) 14,385 842,949 170.65 (165.72, 175.72) 0.47 (0.45, 0.48) -83.15
PHARMO 2,079 480,866 43.23 (41.40, 45.13) 2,855 475,224 60.08 (56.98, 63.34) 0.66 (0.62, 0.71) -11.55
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

EpiChron 1,531 208,255 73.52 (69.88, 77.29) 2,494 207,218 120.36 (112.60, 128.65) 0.58 (0.54, 0.63) -40.13
SIDIAP NA NA NA NA NA NA NA NA
CPRD Aurum 5,062 1,284,949 39.39 (38.32, 40.50) 15,617 1,254,994 124.44 (121.70, 127.24) 0.29 (0.28, 0.30) -78.73
Subacute thyroiditis
Pedianet NA NA NA NA NA NA NA NA
NHR 39 854,417 0.46 (0.32, 0.62) 22 842,870 0.26 (0.15, 0.45) 1.75 (0.93, 3.30) 0.15
PHARMO 0 480,866 0 (0, NC) 0 475,224 0 (0, NC) 0 0
EpiChron <5 NR 0.10 (0.01, 0.35) <5 NR 0.10 (0.01, 0.69) 0.92 (0.08, 10.11) 0.02
SIDIAP 5 1,004,405 0.05 (0.02, 0.12) <5 NR 0.02 (0, 0.08) 2.14 (0.41, 11.09) 0.03
CPRD Aurum 12 1,284,929 0.09 (0.05, 0.16) <5 NR 0.03 (0.01, 0.08) 2.98 (0.96, 9.25) 0.06
Sudden death
Pedianet NA NA NA NA NA NA NA NA
NHR 93 854,481 1.09 (0.88, 1.33) 190 842,924 2.25 (1.78, 2.86) 0.48 (0.35, 0.65) -1.28
PHARMO <5 NR 0.04 (0.01, 0.15) <5 NR 0.06 (0.01, 0.27) 0.75 (0.10, 5.51) -0.04
EpiChron 0 208,255 0 (0, NC) 0 207,218 0 (0, NC) 0 0
SIDIAP NA NA NA NA NA NA NA NA
CPRD Aurum 6 1,284,948 0.05 (0.02, 0.10) 9 1,254,993 0.07 (0.03, 0.19) 0.65 (0.18, 2.33) -0.01
NA: not available; NC: not calculable; NR: not reportable due to obligation to mask number of events when less than 5.
a see Section 9.3.33; * as risk window is one day, the prevalence was calculated per 10,000 persons; **Outlier, to be confirmed for final report.

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10.2.3. Detailed results for 11 AESIs of specific interest

Detailed results are given for the following 11 AESIs either at the request of EMA and for the
recently added AESIs.

10.2.3.1. Acute cardiovascular injury

Acute cardiovascular injury is a composite event consisting of microangiopathy, heart
failure, stress cardiomyopathy, coronary artery disease, and arrhythmia. Acute
cardiovascular injury was observed in both the vaccinated and unvaccinated cohorts in all
data sources. The incidence rates in the vaccinated cohorts ranged from 40.28 per 10,000
person-years (95% CI: 26.77, 58.22) in Pedianet to 261.22 per 10,000 person-years (95%
CI: 257.63, 264.85) in NHR and in the unvaccinated cohorts these ranged from 28.67 per
10,000 person-years (95% CI 17.07, 48.16) in Pedianet to 257.28 per 10,000 person-years
(95% CI: 251.86, 262.82) in NHR.

The incidence of acute cardiovascular injury was higher in the older age groups in all data
sources, in both the vaccinated and non-vaccinated cohorts during the 365-day risk interval.
The matched HRs were 1.41 (95% CI: 0.74, 2.66) in Pedianet, 1.02 (95% CI: 0.99, 1.04) in
NHR, 1.48 (95% CI: 1.41, 1.55) in PHARMO, 1.20 (95% CI: 1.12, 1.28) in EpiChron, 1.04
(95% CI: 1.00, 1.08) in SIDIAP, and 1.26 (95% CI: 1.21, 1.30) in CPRD Aurum. The
adjusted HRs were 1.38 (95% CI: 0.73, 2.61) in Pedianet, 1.01 (95% CI: 0.99, 1.04) in NHR,
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

1.38 (95% CI: 1.31, 1.45) in PHARMO, 1.10 (95% CI: 1.03, 1.18) in EpiChron, 0.99 (95% CI:
0.96, 1.03) in SIDIAP, and 1.23 (95% CI: 1.18, 1.27) in CPRD Aurum. The matched and
adjusted HR and CIs were >1 in PHARMO, EpiChron, and CPRD Aurum. The HRs for acute
cardiovascular injury were primarily driven by arrhythmia.

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Table 17. Risk estimates (95% CI) per 10,000 person-years (PY) for acute cardiovascular injury among individuals who
received at least one dose of Pfizer-BioNTech COVID-19 vaccine and matched unvaccinated individuals by data
source (risk window: 365 days after dose 1)
Vaccinated Unvaccinated
Data source Events Cumulative Person-years Incidence rate Events Cumulative Person-years Incidence rate
(n) incidence (95% CI) (PY) (95% CI) (n) incidence (95% CI) (PY) (95% CI)
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

Pedianet 28 39.55 (24.84, 54.24) 6,951 40.28 (26.77, 20 28.67 (13.85, 43.46) 6,977 28.67 (17.07,
58.22) 48.16)
NHR 20,167 237.70 (234.04, 772,035 261.22 (257.63, 19,669 234.23 (228.47, 764,487 257.28 (251.86,
241.35) 264.85) 239.99) 262.82)
PHARMO 5,626 116.87 (113.70, 469,832 119.74 (116.64, 3,766 76.98 (73.65, 80.31) 465,082 80.97 (77.64,
120.04) 122.92) 84.46)
EpiChron 3,446 157.44 (151.89, 201,712 170.84 (165.18, 2,870 126.57 (118.91, 201,406 142.50 (134.71,
162.98) 176.64) 134.21) 150.74)
SIDIAP 11,569 107.47 (105.35, 979,663 118.09 (115.95, 11,132 99.88 (96.67, 980,277 113.56 (110.25,
109.60) 120.26) 103.08) 116.97)
CPRD Aurum 10,041 95.83 (92.89, 98.77) 1,258,613 79.78 (78.23, 7,796 66.95 (63.62, 70.28) 1,232,960 63.23 (61.38,
81.35) 65.14)
Note: Estimation of confidence intervals differs between vaccinated and unvaccinated, since the unvaccinated estimate is a generalised estimating equation (GEE)
estimates (to account for individuals who were matched to more than one vaccinated individual). When NA (not-assessable) is listed for the 1-KM it means that
there is no estimate for the duration of follow-up specified as risk interval, meaning that there was not any patient who reached the end of the risk window. The
vaccinated and unvaccinated cohorts were matched on age, sex, geographical region, prior identified COVID-19 infection, prior influenza vaccination, pregnancy,
immunocompromised and number of pre-existing conditions considered by the Centers for Disease Control and Prevention (CDC) as risk criteria (0, 1, 2, 3, 4+).

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Figure 6. Cumulative incidence of acute cardiovascular injury among individuals

who received at least one dose of Pfizer-BioNTech COVID-19 vaccine
and matched unvaccinated individuals by data source (risk window: 365
days after dose 1)
Pedianet NHR
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PHARMO EpiChron

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Figure 6. Cumulative incidence of acute cardiovascular injury among individuals

who received at least one dose of Pfizer-BioNTech COVID-19 vaccine
and matched unvaccinated individuals by data source (risk window: 365
days after dose 1)
SIDIAP CPRD Aurum
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Cumulative incidence curves (1 – Kaplan–Meier risk) starting from the day of administration
of the first dose of vaccine up to 365 days. Dotted lines represent 95% confidence intervals.
The number at risk at each time point and the cumulative number of events during the 365-
day risk window are also shown for each time point. The numerical data correspond to the
days indicated by the tick marks on the x-axis.

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Figure 7. Forest plot showing incidence rates and 95% confidence intervals for
acute cardiovascular injury among individuals who received at least one
dose of Pfizer-BioNTech COVID-19 vaccine and matched unvaccinated
individuals by data source and by age groups (risk window: 365 days
after dose 1)
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Figure 7. Forest plot showing incidence rates and 95% confidence intervals for
acute cardiovascular injury among individuals who received at least one
dose of Pfizer-BioNTech COVID-19 vaccine and matched unvaccinated
individuals by data source and by age groups (risk window: 365 days
after dose 1)
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Figure 7. Forest plot showing incidence rates and 95% confidence intervals for
acute cardiovascular injury among individuals who received at least one
dose of Pfizer-BioNTech COVID-19 vaccine and matched unvaccinated
individuals by data source and by age groups (risk window: 365 days
after dose 1)
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Figure 7. Forest plot showing incidence rates and 95% confidence intervals for
acute cardiovascular injury among individuals who received at least one
dose of Pfizer-BioNTech COVID-19 vaccine and matched unvaccinated
individuals by data source and by age groups (risk window: 365 days
after dose 1)
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Table 18. Matched and adjusted hazard ratios (HRs) and matched and adjusted risk
differences (RDs) per 10,000 person-years and their 95% CIs for acute
cardiovascular injury among individuals who received at least one dose of
Pfizer-BioNTech COVID-19 vaccine and matched unvaccinated individuals
by data source (risk window: 365 days after dose 1)
Matched HR (95% Adjusted HR (95% Matched RD Adjusted RD
CI) CI)
Pedianet 1.41 (0.74, 2.66) 1.38 (0.73, 2.61) 10.88 10.12
NHR 1.02 (0.99, 1.04) 1.01 (0.99, 1.04) 3.47 2.20
PHARMO 1.48 (1.41, 1.55) 1.38 (1.31, 1.45) 39.89 33.31
EpiChron 1.20 (1.12, 1.28) 1.10 (1.03, 1.18) 30.87 18.26
SIDIAP 1.04 (1.00, 1.08) 0.99 (0.96, 1.03) 7.60 3.01
CPRD Aurum 1.26 (1.21, 1.30) 1.23 (1.18, 1.27) 28.88 27.28
NA: not assessable due to zero cases in the vaccinated or unvaccinated cohorts for HR or in
both cohorts for RD

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10.2.3.2. Arrhythmia
Arrhythmia was observed in the vaccinated and unvaccinated cohorts in all data sources.
The incidence rates ranged from 35.92 per 10,000 person-years (95% CI: 23.25, 53.03) in
Pedianet (children only) to 216.81 per 10,000 person-years (95% CI: 213.58, 220.08) in
NHR in the vaccinated cohorts and from 20.04 per 10,000 person-years (95% CI: 11.44,
35.08) in Pedianet to 210.78 per 10,000 person-years (95% CI: 205.87, 215.80) in NHR in
the unvaccinated cohorts. The cumulative incidences during the 365-day risk window
ranged from 35.53 per 10,000 individuals (95% CI: 21.56, 49.48) in Pedianet to 199.30 per
10,000 person-years (95% CI: 195.98, 202.62) in NHR in the vaccinated cohorts and from
21.13 per 10,000 person-years (95% CI 9.15, 33.10) in Pedianet to 193.12 per 10,000
person-years (95% CI: 187.85, 198.38) in NHR in the unvaccinated cohorts.

The incidence rates were higher in the older age groups. The matched HRs were 1.79 (95%
CI: 0.91, 3.55) in Pedianet, 1.03 (95% CI: 1, 1.06) in NHR, 1.47 (95% CI: 1.39, 1.55) in
PHARMO, 1.23 (95% CI: 1.14, 1.32) in EpiChron, 1.04 (95% CI: 1, 1.08) in SIDIAP, and
1.31 (95% CI: 1.25, 1.37) in CPRD Aurum. The adjusted HRs were 1.75 (95% CI: 0.88,
3.49) in Pedianet, 1.03 (95% CI: 1, 1.05) in NHR, 1.36 (95% CI: 1.29, 1.44) in PHARMO,
1.12 (95% CI: 1.04, 1.21) in EpiChron, 0.99 (95% CI: 0.96, 1.03) in SIDIAP, and 1.27 (95%
CI: 1.21, 1.33) in CPRD Aurum. In NHR, PHARMO, EpiChron, and CPRD Aurum the
adjusted HRs and CIs were above 1.
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Table 19. Risk estimates (95% CI) per 10,000 person-years (PY) for arrhythmia among individuals who received at least
one dose of Pfizer-BioNTech COVID-19 vaccine and matched unvaccinated individuals by data source (risk
window: 365 days after dose 1)
Vaccinated Unvaccinated
Data source Events Cumulative Person-years Incidence rate Events Cumulative Person-years Incidence rate
(n) incidence (95% (PY) (95% CI) (n) incidence (95% (PY) (95% CI)
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

CI) CI)
Pedianet 25 35.53 (21.56, 6,959 35.92 (23.25, 14 21.13 (9.15, 33.10) 6,987 20.04 (11.44,
49.48) 53.03) 35.08)
NHR 17,200 199.30 (195.98, 793,320 216.81 (213.58, 16,543 193.12 (187.85, 784,864 210.78 (205.87,
202.62) 220.08) 198.38) 215.80)
PHARMO 4,696 97.57 (94.67, 471,867 99.52 (96.69, 3,158 64.56 (61.49, 466,955 67.63 (64.58,
100.47) 102.41) 67.62) 70.83)
EpiChron 2,840 128.94 (123.93, 203,033 139.88 (134.78, 2,305 101.19 (94.34, 202,602 113.77 (106.79,
133.95) 145.12) 108.05) 121.21)
SIDIAP 9,527 88.46 (86.53, 984,283 96.79 (94.86, 9,146 81.49 (78.59, 984,781 92.87 (89.88,
90.39) 98.75) 84.39) 95.97)
CPRD Aurum 6,337 60.53 (58.21, 1,269,791 49.91 (48.68, 4,735 38.24 (35.76, 1,242,440 38.11 (36.66,
62.84) 51.15) 40.72) 39.62)
Note: Estimation of confidence intervals differs between vaccinated and unvaccinated, since the unvaccinated estimate is a generalised estimating
equation (GEE) estimates (to account for individuals who were matched to more than one vaccinated individual). When NA (not-assessable) is
listed for the 1-KM it means that there is no estimate for the duration of follow-up specified as risk interval, meaning that there was not any patient
who reached the end of the risk window. The vaccinated and unvaccinated cohorts were matched on age, sex, geographical region, prior identified
COVID-19 infection, prior influenza vaccination, pregnancy, immunocompromised and number of pre-existing conditions considered by the
Centers for Disease Control and Prevention (CDC) as risk criteria (0, 1, 2, 3, 4+).

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Figure 8. Cumulative incidence of arrhythmia among individuals who received at

least one dose of Pfizer-BioNTech COVID-19 vaccine and matched
unvaccinated individuals by data source (risk window: 365 days after
dose 1)
Pedianet NHR
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PHARMO EpiChron

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Figure 8. Cumulative incidence of arrhythmia among individuals who received at

least one dose of Pfizer-BioNTech COVID-19 vaccine and matched
unvaccinated individuals by data source (risk window: 365 days after
dose 1)
SIDIAP CPRD Aurum
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Cumulative incidence curves (1 – Kaplan–Meier risk) starting from the day of administration
of the first dose of vaccine. Dotted lines represent 95% confidence intervals. The number at
risk at each time point and the cumulative number of events during the 365-day risk window
are also shown for each time point. The numerical data correspond to the days indicated by
the tick marks on the x-axis.

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Figure 9. Forest plot showing incidence rates and 95% confidence intervals for
arrhythmia among individuals who received at least one dose of Pfizer-
BioNTech COVID-19 vaccine and matched unvaccinated individuals by
data source and by age groups (risk window: 365 days after dose 1)
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Figure 9. Forest plot showing incidence rates and 95% confidence intervals for
arrhythmia among individuals who received at least one dose of Pfizer-
BioNTech COVID-19 vaccine and matched unvaccinated individuals by
data source and by age groups (risk window: 365 days after dose 1)
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Figure 9. Forest plot showing incidence rates and 95% confidence intervals for
arrhythmia among individuals who received at least one dose of Pfizer-
BioNTech COVID-19 vaccine and matched unvaccinated individuals by
data source and by age groups (risk window: 365 days after dose 1)
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Table 20. Matched and adjusted hazard ratios (HRs) and matched and adjusted risk
differences (RDs) per 10,000 person-years and their 95% CIs for arrhythmia
among individuals who received at least one dose of Pfizer-BioNTech
COVID-19 vaccine and matched unvaccinated individuals by data source
(risk window: 365 days after dose 1)
Matched HR (95% Adjusted HR (95% Matched RD Adjusted RD
CI) CI)
Pedianet 1.79 (0.91, 3.55) 1.75 (0.88, 3.49) 14.40 13.68
NHR 1.03 (1.00, 1.06) 1.03 (1.00, 1.05) 6.18 5.25
PHARMO 1.47 (1.39, 1.55) 1.36 (1.29, 1.44) 33.01 26.84
EpiChron 1.23 (1.14, 1.32) 1.12 (1.04, 1.21) 27.75 16.77
SIDIAP 1.04 (1.00, 1.08) 0.99 (0.96, 1.03) 6.97 2.84
CPRD Aurum 1.31 (1.25, 1.37) 1.27 (1.21, 1.33) 22.28 21.25
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10.2.3.3. Heart failure

Heart failure was observed in the vaccinated and unvaccinated cohorts in all data sources,
except Pedianet. The incidence rates of heart failure ranged from 16.27 per 10,000 person-
years (95% CI: 15.15, 17.46) in PHARMO to 47.60 per 10,000 person-years (95% CI: 44.67,
50.67) in EpiChron in the vaccinated cohorts and from 12.52 per 10,000 person-years (95%
CI: 11.20, 13.99) in PHARMO to 59.55 per 10,000 person-years (95% CI: 56.84, 62.38) in
NHR in the unvaccinated cohorts. The cumulative incidence of heart failure during the 365-
day risk window showed differences between vaccinated and non-vaccinated in PHARMO
and CPRD Aurum in the progression of follow-up time.

The incidence of heart failure was higher in the older age groups in all data sources. The
matched HRs were 0.78 (95% CI: 0.74, 0.82) in NHR, 1.30 (95% CI: 1.14, 1.48) in
PHARMO, 0.95 (95% CI: 0.84, 1.06) in EpiChron, 0.94 (95% CI: 0.87, 1.01) in SIDIAP, and
1.04 (95% CI: 0.97, 1.12) in CPRD Aurum. The adjusted HRs were 0.77 (95% CI: 0.73,
0.82) in NHR, 1.29 (95% CI: 1.13, 1.47) in PHARMO, 0.90 (95% CI: 0.80, 1.01) in EpiChron,
0.89 (95% CI: 0.82, 0.96) in SIDIAP, and 1.02 (95% CI: 0.95, 1.09) in CPRD Aurum.
Differences were observed for the incidence of heart failure between the vaccinated and
unvaccinated cohorts during the 365-day risk window in PHARMO.
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Table 21. Risk estimates (95% CI) per 10,000 person-years (PY) for heart failure among individuals who received at least
one dose of Pfizer-BioNTech COVID-19 vaccine and matched unvaccinated individuals by data source (risk
window: 365 days after dose 1)
Vaccinated Unvaccinated
Data source Events Cumulative Person-years Incidence rate Events Cumulative Person-years Incidence rate
(n) incidence (95% (PY) (95% CI) (n) incidence (95% (PY) (95% CI)
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

CI) CI)
Pedianet NA NA NA NA NA NA NA NA
NHR 3,885 43.91 (42.36, 838,216 46.35 (44.90, 4,930 56.79 (53.75, 827,927 59.55 (56.84,
45.45) 47.83) 59.83) 62.38)
PHARMO 780 15.93 (14.76, 479,288 16.27 (15.15, 593 11.77 (10.42, 473,758 12.52 (11.20,
17.09) 17.46) 13.11) 13.99)
EpiChron 983 42.49 (39.65, 206,512 47.60 (44.67, 1,035 44.07 (39.20, 205,745 50.30 (45.61,
45.32) 50.67) 48.94) 55.49)
SIDIAP 2,569 23.53 (22.53, 998,769 25.72 (24.74, 2,739 23.54 (21.90, 998,818 27.42 (25.73,
24.53) 26.74) 25.19) 29.22)
CPRD Aurum 2,462 24.79 (23.26, 1,278,995 19.25 (18.50, 2,299 19.30 (17.36, 1,250,241 18.39 (17.37,
26.32) 20.03) 21.24) 19.47)
NA: Not available
Note: Estimation of confidence intervals differs between vaccinated and unvaccinated, since the unvaccinated estimate is a generalised estimating
equation (GEE) estimates (to account for individuals who were matched to more than one vaccinated individual). When NA (not-assessable) is
listed for the 1-KM it means that there is no estimate for the duration of follow-up specified as risk interval, meaning that there was not any patient
who reached the end of the risk window. The vaccinated and unvaccinated cohorts were matched on age, sex, geographical region, prior identified
COVID-19 infection, prior influenza vaccination, pregnancy, immunocompromised and number of pre-existing conditions considered by the
Centers for Disease Control and Prevention (CDC) as risk criteria (0, 1, 2, 3, 4+).

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Figure 10. Cumulative incidence of heart failure among individuals who received at
least one dose of Pfizer-BioNTech COVID-19 vaccine and matched
unvaccinated individuals by data source (risk window: 365 days after
dose 1)
NHR PHARMO
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EpiChron SIDIAP

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Figure 10. Cumulative incidence of heart failure among individuals who received at
least one dose of Pfizer-BioNTech COVID-19 vaccine and matched
unvaccinated individuals by data source (risk window: 365 days after
dose 1)
CPRD Aurum
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Cumulative incidence curves (1 – Kaplan–Meier risk) starting from the day of administration
of the first dose of vaccine. Dotted lines represent 95% confidence intervals. The number at
risk at each time point and the cumulative number of events during the 365-day risk window
are also shown for each time point. The numerical data correspond to the days indicated by
the tick marks on the x-axis.

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Figure 11. Forest plot showing incidence rates and 95% confidence intervals for
heart failure among individuals who received at least one dose of Pfizer-
BioNTech COVID-19 vaccine and matched unvaccinated individuals by
data source and by age groups (risk window: 365 days after dose 1)
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Figure 11. Forest plot showing incidence rates and 95% confidence intervals for
heart failure among individuals who received at least one dose of Pfizer-
BioNTech COVID-19 vaccine and matched unvaccinated individuals by
data source and by age groups (risk window: 365 days after dose 1)
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Figure 11. Forest plot showing incidence rates and 95% confidence intervals for
heart failure among individuals who received at least one dose of Pfizer-
BioNTech COVID-19 vaccine and matched unvaccinated individuals by
data source and by age groups (risk window: 365 days after dose 1)
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

Table 22. Matched and adjusted hazard ratios (HRs) and matched and adjusted risk
differences (RDs) per 10,000 person-years and their 95% CIs for heart
failure among individuals who received at least one dose of Pfizer-
BioNTech COVID-19 vaccine and matched unvaccinated individuals by
data source (risk window: 365 days after dose 1)
Matched HR (95% CI) Adjusted HR (95% CI) Matched RD Adjusted RD
Pedianet NA NA NA NA
NHR 0.78 (0.74, 0.82) 0.77 (0.73, 0.82) -12.89 -13.33
PHARMO 1.30 (1.14, 1.48) 1.29 (1.13, 1.47) 4.16 4.01
EpiChron 0.95 (0.84, 1.06) 0.90 (0.80, 1.01) -1.58 -4.60
SIDIAP 0.94 (0.87, 1.01) 0.89 (0.82, 0.96) -0.01 -1.19
CPRD Aurum 1.04 (0.97, 1.12) 1.02 (0.95, 1.09) 5.49 5.23
NA: not assessable due to zero cases in the vaccinated or unvaccinated cohorts for HR or in
both cohorts for RD

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10.2.3.4. Stress cardiomyopathy

Stress cardiomyopathy was a rare event but could be identified in all data sources except
Pedianet. The incidence rates for stress cardiomyopathy ranged from 0.08 per 10,000
person-years (95% CI: 0.03, 0.17) in NHR to 0.35 per 10,000 person-years (95% CI: 0.24,
0.48) in SIDIAP in the vaccinated cohorts and from 0.08 (0.03, 0.28) per 10,000 person-
years (95% CI: 0.03, 0.28) in PHARMO to 0.29 per 10,000 person-years (95% CI: 0.09,
0.90) in EpiChron in the unvaccinated cohorts. The cumulative incidence during the 365-day
risk window was less than 0.5 per 10,000 person-years in both cohorts in all three data
sources.

The incidence of stress cardiomyopathy was higher in age groups over 40 years of age. The
matched HRs for stress cardiomyopathy were 0.69 (95% CI: 0.18, 2.70) in NHR, 1.49 (95%
CI: 0.35, 6.31) in PHARMO, 0.99 (95% CI: 0.25, 3.98) in EpiChron, 1.67 (95% CI: 0.82,
3.38) in SIDIAP, 1.25 (95% CI: 0.51, 3.07) in CPRD Aurum. The adjusted HRs were 0.69
(95% CI: 0.18, 2.67) in NHR, 1.49 (95% CI: 0.33, 6.69) in PHARMO, 0.85 (95% CI: 0.21,
3.47) in EpiChron, 1.51 (95% CI: 0.75, 3.04) in SIDIAP, 1.30 (95% CI: 0.53, 3.20) in CPRD
Aurum. No differences were observed for the incidence of stress cardiomyopathy between
the vaccinated and unvaccinated cohorts during the 365-day risk window.
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Table 23. Risk estimates (95% CI) per 10,000 person-years (PY) for stress cardiomyopathy among individuals who
received at least one dose of Pfizer-BioNTech COVID-19 vaccine and matched unvaccinated individuals by data
source (risk window: 365 days after dose 1)
Vaccinated Unvaccinated
Data source Events Cumulative Person-years Incidence Events Cumulative Person-years Incidence
(n) incidence (95% (PY) rate (95% CI) (n) incidence (95% (PY) rate (95% CI)
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

CI) CI)
Pedianet NA NA NA NA NA NA NA NA
NHR 7 0.09 (0.02, 0.16) 854,493 0.08 (0.03, 10 0.07 (0, 0.14) 842,940 0.12 (0.04,
0.17) 0.37)
PHARMO 6 0.11 (0.02, 0.20) 480,858 0.12 (0.05, <5 0.10 (0, 0.23) NR 0.08 (0.03,
0.27) 0.28)
EpiChron 6 0.30 (0.06, 0.54) 208,241 0.29 (0.11, 6 0.29 (0, 0.65) 207,207 0.29 (0.09,
0.63) 0.90)
SIDIAP 35 0.33 (0.21, 0.45) 1,004,330 0.35 (0.24, 21 0.18 (0.02, 0.33) 1,004,339 0.21 (0.11,
0.48) 0.39)
CPRD Aurum 14 0.11 (0.04, 0.19) 1,284,916 0.11 (0.06, 11 0.06 (0.01, 0.11) 1,254,967 0.09 (0.04,
0.18) 0.18)
NA: Not available
Note: Estimation of confidence intervals differs between vaccinated and unvaccinated, since the unvaccinated estimate is a
generalised estimating equation (GEE) estimates (to account for individuals who were matched to more than one vaccinated
individual). When NA (not-assessable) is listed for the 1-KM it means that there is no estimate for the duration of follow-up specified
as risk interval, meaning that there was not any patient who reached the end of the risk window. The vaccinated and unvaccinated
cohorts were matched on age, sex, geographical region, prior identified COVID-19 infection, prior influenza vaccination, pregnancy,
immunocompromised and number of pre-existing conditions considered by the Centers for Disease Control and Prevention (CDC) as
risk criteria (0, 1, 2, 3, 4+).

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Figure 12. Cumulative incidence of stress cardiomyopathy among individuals who

received at least one dose of Pfizer-BioNTech COVID-19 vaccine and
matched unvaccinated individuals by data source (risk window: 365
days after dose 1)
NHR PHARMO
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EpiChron SIDIAP

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Figure 12. Cumulative incidence of stress cardiomyopathy among individuals who

received at least one dose of Pfizer-BioNTech COVID-19 vaccine and
matched unvaccinated individuals by data source (risk window: 365
days after dose 1)
CPRD Aurum
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Cumulative incidence curves (1 – Kaplan–Meier risk) starting from the day of administration
of the first dose of vaccine. Dotted lines represent 95% confidence intervals. The number at
risk at each time point and the cumulative number of events during the 365-day risk window
are also shown for each time point. The numerical data correspond to the days indicated by
the tick marks on the x-axis.

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Figure 13. Forest plot showing incidence rates and 95% confidence intervals for
stress cardiomyopathy among individuals who received at least one
dose of Pfizer-BioNTech COVID-19 vaccine and matched unvaccinated
individuals by data source and by age groups (risk window: 365 days
after dose 1)
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Figure 13. Forest plot showing incidence rates and 95% confidence intervals for
stress cardiomyopathy among individuals who received at least one
dose of Pfizer-BioNTech COVID-19 vaccine and matched unvaccinated
individuals by data source and by age groups (risk window: 365 days
after dose 1)
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Figure 13. Forest plot showing incidence rates and 95% confidence intervals for
stress cardiomyopathy among individuals who received at least one
dose of Pfizer-BioNTech COVID-19 vaccine and matched unvaccinated
individuals by data source and by age groups (risk window: 365 days
after dose 1)
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Table 24. Matched and adjusted hazard ratios (HRs) and matched and adjusted risk
differences (RDs) per 10,000 person-years and their 95% CIs for stress
cardiomyopathy among individuals who received at least one dose of
Pfizer-BioNTech COVID-19 vaccine and matched unvaccinated individuals
by data source (risk window: 365 days after dose 1)
Matched HR (95% Adjusted HR (95% Matched RD Adjusted RD
CI) CI)
Pedianet NA NA NA NA
NHR 0.69 (0.18, 2.70) 0.69 (0.18, 2.67) 0.02 0.02
PHARMO 1.49 (0.35, 6.31) 1.49 (0.33, 6.69) 0 0
EpiChron 0.99 (0.25, 3.98) 0.85 (0.21, 3.47) 0 -0.05
SIDIAP 1.67 (0.82, 3.38) 1.51 (0.75, 3.04) 0.15 0.14
CPRD Aurum 1.25 (0.51, 3.07) 1.30 (0.53, 3.20) 0.05 0.06
NA: not assessable due to zero cases in the vaccinated or unvaccinated cohorts for HR or in
both cohorts for RD

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10.2.3.5. Coronary artery disease

Coronary artery disease was observed in the vaccinated and unvaccinated cohorts in all
data sources, except Pedianet. The incidence rates ranged from 15.40 per 10,000 person-
years (95% CI: 14.64, 16.19) in SIDIAP to 67.28 per 10,000 person-years (95% CI: 65.52,
69.06) in NHR in the vaccinated cohorts and from 12.23 per 10,000 person-years (95% CI:
10.99, 13.60) in PHARMO to 67.50 per 10,000 person-years (95% CI: 64.71, 70.41) in NHR
in the unvaccinated cohorts. The incidence of coronary artery disease was higher in higher
age groups in all data sources in the vaccinated and unvaccinated cohorts.

The matched HRs of coronary artery disease were 1.00 (95% CI: 0.95, 1.05) in NHR, 1.53
(95% CI: 1.35, 1.73) in PHARMO, 1.02 (95% CI: 0.84, 1.23) in EpiChron, 1.05 (95% CI:
0.96, 1.16) in SIDIAP, 1.43 (95% CI: 1.33, 1.54) in CPRD Aurum. The adjusted HRs were
0.99 (95% CI: 0.94, 1.04) in NHR, 1.49 (95% CI: 1.31, 1.69) in PHARMO, 0.97 (95% CI:
0.80, 1.17) in EpiChron, 1.00 (95% CI: 0.91, 1.10) in SIDIAP, 1.40 (95% CI: 1.30, 1.50) in
CPRD Aurum. In PHARMO and CPRD Aurum were HR above 1 and the lower limits of the
95% CI for the adjusted HRs were >1.
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Table 25. Risk estimates (95% CI) per 10,000 person-years (PY) for coronary artery disease among individuals who
received at least one dose of Pfizer-BioNTech COVID-19 vaccine and matched unvaccinated individuals by data
source (risk window: 365 days after dose 1)
Vaccinated Unvaccinated
Data source Events Cumulative Person-years Incidence Events Cumulative Person-years Incidence
(n) incidence (95% (PY) rate (95% CI) (n) incidence (95% (PY) rate (95% CI)
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

CI) CI)
Pedianet NA NA NA NA NA NA NA NA
NHR 5,593 60.35 (58.55, 831,346 67.28 (65.52, 5,541 59.38 (56.38, 820,893 67.50 (64.71,
62.14) 69.06) 62.39) 70.41)
PHARMO 893 17.91 (16.69, 478,964 18.64 (17.44, 579 11.41 (10.15, 473,477 12.23 (10.99,
19.13) 19.91) 12.66) 13.60)
EpiChron 379 17.28 (15.43, 207,469 18.27 (16.47, 371 15.75 (13.16, 206,465 17.97 (15.33,
19.12) 20.20) 18.34) 21.06)
SIDIAP 1,542 14.23 (13.46, 15) 1,001,458 15.40 (14.64, 1,464 13.01 (11.83, 1,001,552 14.62 (13.44,
16.19) 14.19) 15.90)
CPRD Aurum 2,651 25.69 (24.16, 1,277,998 20.74 (19.96, 1,804 17.52 (15.70, 1,249,224 14.44 (13.58,
27.23) 21.55) 19.33) 15.36)
NA: Not available
Note: Estimation of confidence intervals differs between vaccinated and unvaccinated, since the unvaccinated estimate is a
generalised estimating equation (GEE) estimates (to account for individuals who were matched to more than one vaccinated
individual). When NA (not-assessable) is listed for the 1-KM it means that there is no estimate for the duration of follow-up specified
as risk interval, meaning that there was not any patient who reached the end of the risk window. The vaccinated and unvaccinated
cohorts were matched on age, sex, geographical region, prior identified COVID-19 infection, prior influenza vaccination, pregnancy,
immunocompromised and number of pre-existing conditions considered by the Centers for Disease Control and Prevention (CDC) as
risk criteria (0, 1, 2, 3, 4+).

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Figure 14. Cumulative incidence of coronary artery disease among individuals who
received at least one dose of Pfizer-BioNTech COVID-19 vaccine and
matched unvaccinated individuals by data source (risk window: 365
days after dose 1)
NHR PHARMO
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EpiChron SIDIAP

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Figure 14. Cumulative incidence of coronary artery disease among individuals who
received at least one dose of Pfizer-BioNTech COVID-19 vaccine and
matched unvaccinated individuals by data source (risk window: 365
days after dose 1)
CPRD Aurum
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Cumulative incidence curves (1 – Kaplan–Meier risk) starting from the day of administration
of the first dose of vaccine. Dotted lines represent 95% confidence intervals. The number at
risk at each time point and the cumulative number of events during the 365-day risk window
are also shown for each time point. The numerical data correspond to the days indicated by
the tick marks on the x-axis.

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Figure 15. Forest plot showing incidence rates and 95% confidence intervals for
coronary artery disease among individuals who received at least one
dose of Pfizer-BioNTech COVID-19 vaccine and matched unvaccinated
individuals by data source and by age groups (risk window: 365 days
after dose 1)
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Figure 15. Forest plot showing incidence rates and 95% confidence intervals for
coronary artery disease among individuals who received at least one
dose of Pfizer-BioNTech COVID-19 vaccine and matched unvaccinated
individuals by data source and by age groups (risk window: 365 days
after dose 1)
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Figure 15. Forest plot showing incidence rates and 95% confidence intervals for
coronary artery disease among individuals who received at least one
dose of Pfizer-BioNTech COVID-19 vaccine and matched unvaccinated
individuals by data source and by age groups (risk window: 365 days
after dose 1)
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Table 26. Matched and adjusted hazard ratios (HRs) and matched and adjusted risk
differences (RDs) per 10,000 person-years and their 95% CIs for coronary
artery disease among individuals who received at least one dose of Pfizer-
BioNTech COVID-19 vaccine and matched unvaccinated individuals by
data source (risk window: 365 days after dose 1)
Matched HR (95% Adjusted HR (95% Matched RD Adjusted RD
CI) CI)
Pedianet NA NA NA NA
NHR 1.00 (0.95, 1.05) 0.99 (0.94, 1.04) 0.96 0.43
PHARMO 1.53 (1.35, 1.73) 1.49 (1.31, 1.69) 6.50 6.17
EpiChron 1.02 (0.84, 1.23) 0.97 (0.80, 1.17) 1.52 0.57
SIDIAP 1.05 (0.96, 1.16) 1.00 (0.91, 1.10) 1.22 0.52
CPRD Aurum 1.43 (1.33, 1.54) 1.40 (1.30, 1.50) 8.18 7.83
NA: not assessable due to zero cases in the vaccinated or unvaccinated cohorts for HR or in
both cohorts for RD
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10.2.3.6. Myocarditis (21-day risk window)

Myocarditis events were identified in all data sources. During the 21-day risk window after
the start of follow-up, the incidence rates ranged from 0.83 per 10,000 person-years (95%
CI: 0.23, 2.13) in PHARMO to 18.07 per 10,000 person-years (95% CI: 0.46, 100.70) in
PEDIANET in the vaccinated cohorts and from 0.62 per 10,000 person-years in (95% CI:
0.14, 2.68) in PHARMO to 3.99 per 10,000 person-years (95% CI: 2.90, 5.48) in NHR in the
unvaccinated cohorts. The cumulative incidence was below 1 per 10,000 individuals in both
cohorts in each data source. There were no differences in the incidence of myocarditis in a
21-day risk window across age groups.

The matched HRs were 0.94 (95% CI: 0.46, 1.93) in NHR, 1.50 (95% CI: 0.16, 14.45) in
PHARMO, 4.00 (95% CI: 0.45, 35.77) in EpiChron, 1.14 (95% CI: 0.38, 3.40) in SIDIAP, and
2.25 (95% CI: 0.91, 5.54) in CPRD Aurum. The adjusted HRs were 0.94 (95% CI: 0.46,
1.94) in NHR, 1.23 (95% CI: 0.13, 11.84) in PHARMO, 3.64 (95% CI: 0.41, 32.53) in
EpiChron, 1.05 (95% CI: 0.35, 3.16) in SIDIAP, and 2.30 (95% CI: 0.94, 5.66) in CPRD
Aurum. The lower limits of the CIs in the HRs for myocarditis assessed in a risk window of
21 days are below 1.
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Table 27. Risk estimates (95% CI) per 10,000 person-years (PY) for myocarditis within 21 days after start of follow-up
among individuals who received at least one dose of Pfizer-BioNTech COVID-19 vaccine and matched
unvaccinated individuals by data source
Vaccinated Unvaccinated
Data source Events Cumulative Person- Incidence rate Events Cumulative Person- Incidence rate
(n) incidence (95% years (PY) (95% CI) (n) incidence (95% years (PY) (95% CI)
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

CI) CI)
Pedianet <5 0.98 (0, 2.89) NR 18.07 (0.46, 0 0 (0, NC) 553 0 (0, NC)
100.70)
NHR 68 0.25 (0.19, 0.31) 160,517 4.24 (3.29, 64 0.22 (0.15, 0.29) 160,424 3.99 (2.90,
5.37) 5.48)
PHARMO <5 0.05 (0, 0.10) NR 0.83 (0.23, <5 0.03 (0, 0.09) NR 0.62 (0.14,
2.13) 2.68)
EpiChron 10 0.22 (0.08, 0.35) 26,097 3.83 (1.84, 9 0.19 (0.03, 0.35) 26,083 3.45 (1.48,
7.05) 8.02)
SIDIAP 48 0.21 (0.15, 0.26) 134,902 3.56 (2.62, 44 0.18 (0.10, 0.27) 134,902 3.26 (2.04,
4.72) 5.23)
CPRD Aurum 56 0.16 (0.12, 0.21) 198,592 2.82 (2.13, 32 0.09 (0.06, 0.13) 198,235 1.61 (1.11,
3.66) 2.35)
NA: Not available; NR: not reportable due to masking of numbers of events <5; NC: Not calculable
Note: Estimation of confidence intervals differs between vaccinated and unvaccinated, since the unvaccinated estimate is a
generalised estimating equation (GEE) estimates (to account for individuals who were matched to more than one vaccinated
individual). When NA (not-assessable) is listed for the 1-KM it means that there is no estimate for the duration of follow-up specified
as risk interval, meaning that there was not any patient who reached the end of the risk window. The vaccinated and unvaccinated
cohorts were matched on age, sex, geographical region, prior identified COVID-19 infection, prior influenza vaccination, pregnancy,
immunocompromised and number of pre-existing conditions considered by the Centers for Disease Control and Prevention (CDC) as
risk criteria (0, 1, 2, 3, 4+).

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Figure 16. Cumulative incidence of myocarditis within 21 days after start of follow-
up among individuals who received at least one dose of Pfizer-BioNTech
COVID-19 vaccine and matched unvaccinated individuals by data source
NHR PHARMO
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EpiChron SIDIAP

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Figure 16. Cumulative incidence of myocarditis within 21 days after start of follow-
up among individuals who received at least one dose of Pfizer-BioNTech
COVID-19 vaccine and matched unvaccinated individuals by data source
CPRD Aurum
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

Cumulative incidence curves (1 – Kaplan–Meier risk) starting from the day of administration
of the first dose of vaccine. Dotted lines represent 95% confidence intervals. The number at
risk at each time point and the cumulative number of events during the 21-day risk window
are also shown for each time point. The numerical data correspond to the days indicated by
the tick marks on the x-axis.

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Figure 17. Forest plot showing incidence rates and 95% confidence intervals for
myocarditis within 21 days after start of follow-up among individuals
who received at least one dose of Pfizer-BioNTech COVID-19 vaccine
and matched unvaccinated individuals by data source and by age
groups
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Figure 17. Forest plot showing incidence rates and 95% confidence intervals for
myocarditis within 21 days after start of follow-up among individuals
who received at least one dose of Pfizer-BioNTech COVID-19 vaccine
and matched unvaccinated individuals by data source and by age
groups
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Figure 17. Forest plot showing incidence rates and 95% confidence intervals for
myocarditis within 21 days after start of follow-up among individuals
who received at least one dose of Pfizer-BioNTech COVID-19 vaccine
and matched unvaccinated individuals by data source and by age
groups
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Table 28. Matched and adjusted hazard ratios (HRs) and matched and adjusted risk
differences (RDs) per 10,000 person-years and their 95% CIs for
myocarditis within 21 days after start of follow-up among individuals who
received at least one dose of Pfizer-BioNTech COVID-19 vaccine and
matched unvaccinated individuals by data source
Matched HR (95% Adjusted HR (95% Matched RD Adjusted RD
CI) CI)
Pedianet NA NA NA NA
NHR 0.94 (0.46, 1.93) 0.94 (0.46, 1.94) 0 0
PHARMO 1.50 (0.16, 14.45) 1.23 (0.13, 11.84) 0.01 0.01
EpiChron 4.00 (0.45, 35.77) 3.64 (0.41, 32.53) 0.07 0.07
SIDIAP 1.14 (0.38, 3.40) 1.05 (0.35, 3.16) 0.01 0
CPRD Aurum 2.25 (0.91, 5.54) 2.30 (0.94, 5.66) 0.03 0.03
NA: not assessable due to zero cases in the vaccinated or unvaccinated cohorts for HR or in
both cohorts for RD
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10.2.3.7. Cerebral venous sinus thrombosis

Cerebral venous sinus thrombosis (CVST) was observed in both the vaccinated and
unvaccinated cohorts in all data sources, except Pedianet. The incidence rates in the
vaccinated cohorts ranged from 0.12 per 10,000 person-years (95% CI: 0.01, 0.43) in
SIDIAP to 0.35 per 10,000 person-years (95% CI: 0.14, 0.73) in NHR and in the
unvaccinated cohorts these ranged from 0.18 per 10,000 person-years (95% CI: 0.06, 0.55)
in SIDIAP to 0.56 per 10,000 person-years (95% CI: 0.28, 1.11) in NHR.

There was no difference of the incidence of CVST observed between age groups in all data
sources, in both the vaccinated and non-vaccinated cohorts, during the 28-day risk interval.
The matched HRs were 0.64 (95% CI: 0.23, 1.75) in NHR, 1 (95% CI: 0.06, 15.96) in
EpiChron, 0.67 (95% CI: 0.11, 3.99) in 0.45 (95% CI: 0.15, 1.35) in CPRD Aurum. The
adjusted HRs were 10.63 (95% CI: 0.23, 1.74) in NHR, 0.90 (95% CI: 0.06, 14.09) in
EpiChron, 0.68 (95% CI: 0.11, 4.20) in SIDIAP, 0.43 (95% CI: 0.14, 1.27) in CPRD Aurum.
No differences between vaccinated and unvaccinated were observed for CVST.
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Table 29. Risk estimates (95% CI) per 10,000 person-years (PY) for cerebral venous sinus thrombosis within 28 days after
start of follow-up among individuals who received at least one dose of Pfizer-BioNTech COVID-19 vaccine and
matched unvaccinated individuals by data source
Vaccinated Unvaccinated
Data source Events Cumulative Person- Incidence rate Events Cumulative Person- Incidence rate
(n) incidence (95% years (PY) (95% CI) (n) incidence (95% years (PY) (95% CI)
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CI) CI)
Pedianet 0 0 (0, NC) 719 0 (0, 51.28) 0 0 (0, 0) 719 0 (0, NC)
NHR 7 0.03 (0.01, 0.05) 197,673 0.35 (0.14, 11 0.04 (0.01, 0.07) 197,515 0.56 (0.28,
0.73) 1.11)
PHARMO <5 0.01 (0, 0.03) NR 0.16 (0, 0.90) 0 0 (0, 0) 61,904
EpiChron <5 0.03 (0, 0.09) NR 0.31 (0.01, <5 0.02 (0, 0.05) NR 0.31 (0.04,
1.72) 2.19)
SIDIAP <5 0.01 (0, 0.02) NR 0.12 (0.01, <5 0.01 (0, 0.03) NR 0.18 (0.06,
0.43) 0.55)
CPRD Aurum 5 0.01 (0, 0.03) 252,280 0.20 (0.06, 11 0.03 (0.01, 0.05) 251,658 0.44 (0.23,
0.46) 0.83)
NA: Not available; NR: not reportable due to masking of events <5; NC: not calculable
Note: Estimation of confidence intervals differs between vaccinated and unvaccinated, since the unvaccinated estimate is a generalised estimating equation (GEE)
estimates (to account for individuals who were matched to more than one vaccinated individual). When NA (not-assessable) is listed for the 1-KM it means that
there is no estimate for the duration of follow-up specified as risk interval, meaning that there was not any patient who reached the end of the risk window. The
vaccinated and unvaccinated cohorts were matched on age, sex, geographical region, prior identified COVID-19 infection, prior influenza vaccination, pregnancy,
immunocompromised and number of pre-existing conditions considered by the Centers for Disease Control and Prevention (CDC) as risk criteria (0, 1, 2, 3, 4+).

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Figure 18. Cumulative incidence of cerebral venous sinus thrombosis within 28

days after start of follow-up among individuals who received at least one dose of
Pfizer-BioNTech COVID-19 vaccine and matched unvaccinated individuals by data
source
NHR PHARMO
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EpiChron SIDIAP

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Figure 18. Cumulative incidence of cerebral venous sinus thrombosis within 28

days after start of follow-up among individuals who received at least one dose of
Pfizer-BioNTech COVID-19 vaccine and matched unvaccinated individuals by data
source
CPRD Aurum
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Cumulative incidence curves (1 – Kaplan–Meier risk) starting from the day of administration
of the first dose of vaccine. Dotted lines represent 95% confidence intervals. The number at
risk at each time point and the cumulative number of events during the 365-day risk window
are also shown for each time point. The numerical data correspond to the days indicated by
the tick marks on the x-axis.

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Figure 19. Forest plot showing incidence rates and 95% confidence intervals for
cerebral venous sinus thrombosis within 28 days after start of follow-up
among individuals who received at least one dose of Pfizer-BioNTech
COVID-19 vaccine and matched unvaccinated individuals by data source
and by age groups
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Figure 19. Forest plot showing incidence rates and 95% confidence intervals for
cerebral venous sinus thrombosis within 28 days after start of follow-up
among individuals who received at least one dose of Pfizer-BioNTech
COVID-19 vaccine and matched unvaccinated individuals by data source
and by age groups
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Figure 19. Forest plot showing incidence rates and 95% confidence intervals for
cerebral venous sinus thrombosis within 28 days after start of follow-up
among individuals who received at least one dose of Pfizer-BioNTech
COVID-19 vaccine and matched unvaccinated individuals by data source
and by age groups
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Table 30. Matched and adjusted hazard ratios (HRs) and matched and adjusted risk
differences (RDs) per 10,000 person-years and their 95% CIs for cerebral
venous sinus thrombosis within 28 days after start of follow-up among
individuals who received at least one dose of Pfizer-BioNTech COVID-19
vaccine and matched unvaccinated individuals by data source

Matched HR (95% Adjusted HR (95% Matched RD Adjusted RD

CI) CI)

NA NA NA NA
Pedianet
0.64 (0.23, 1.75) 0.63 (0.23, 1.74) -0.01 -0.01
NHR
NA NA 0.01 0.01
PHARMO
1 (0.06, 15.96) 0.90 (0.06, 14.09) 0.01 0.01
EpiChron
0.67 (0.11, 3.99) 0.68 (0.11, 4.20) 0 0
SIDIAP
0.45 (0.15, 1.35) 0.43 (0.14, 1.27) -0.02 -0.02
CPRD Aurum
NA: not assessable due to zero cases in the vaccinated or unvaccinated cohorts for HR or in both
cohorts for RD
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10.2.3.8. Glomerulonephritis
Glomerulonephritis events could be identified in all data sources, except NHR and
PHARMO. Pedianet did not detect any events within the risk window. During the 21-day risk
window after the start of follow-up, the incidence rates ranged from 0.58 per 10,000 person-
years (95% CI: 0.30, 1.01) in EpiChron to 1.07 per 10,000 person-years (95% CI: 0.90,
1.26) in CPRD Aurum in the vaccinated cohorts and from 0.73 per 10,000 person-years in
(95% CI: 0.53, 1.00) in SIDIAP to 1.20 per 10,000 person-years (95% CI: 0.96, 1.48) in
CPRD Aurum in the unvaccinated cohorts. The cumulative incidence was around 1 per
10,000 individuals in both cohorts in each data source. The incidence of glomerulonephritis
in a 365-day risk window is increasing with age.

The matched HRs were 0.66 (95% CI: 0.26, 1.73) in EpiChron, 1.44 (95% CI: 0.99, 2.08) in
SIDIAP, and 0.89 (95% CI: 0.68, 1.17) in CPRD Aurum. The adjusted HRs were 0.59 (95%
CI: 0.22, 1.55) in EpiChron, 1.29 (95% CI: 0.88, 1.87) in SIDIAP, 0.88 (95% CI: 0.67, 1.16)
in CPRD Aurum. The lower limits of the CIs in the HRs for glomerulonephritis assessed in a
risk window of 365 days are below 1.
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Table 31. Risk estimates (95% CI) per 10,000 person-years (PY) for 10.2.3.7. glomerulonephritis within 365 days after start
of follow-up among individuals who received at least one dose of Pfizer-BioNTech COVID-19 vaccine and
matched unvaccinated individuals by data source
Vaccinated Unvaccinated
Data source Events Cumulative Person-years Incidence rate Events Cumulative Person-years Incidence rate
(n) incidence (95% (PY) (95% CI) (n) incidence (95% (PY) (95% CI)
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

CI) CI)
Pedianet 0 0 (0, NC) 6,991 0 (0, NC) 0 0 (0, NC) 7,014 0 (0, NC)
NHR NA NA NA NA NA NA NA NA
PHARMO NA NA NA NA NA NA NA NA
EpiChron 12 0.53 (0.21, 0.85) 208,226 0.58 (0.30, 18 0.72 (0.15, 1.30) 207,187 0.87 (0.40,
1.01) 1.88)
SIDIAP 105 0.99 (0.78, 1.19) 1,004,201 1.05 (0.86, 73 0.61 (0.41, 0.82) 1,004,208 0.73 (0.53,
1.27) 1.00)
CPRD Aurum 137 1.14 (0.84, 1.44) 1,284,652 1.07 (0.90, 150 1.35 (0.96, 1.75) 1,254,718 1.20 (0.96,
1.26) 1.48)
NA: Not available; NR: not reportable due to masking of numbers of events <5; NC: not calculable
Note: Estimation of confidence intervals differs between vaccinated and unvaccinated, since the unvaccinated estimate is a
generalised estimating equation (GEE) estimates (to account for individuals who were matched to more than one vaccinated
individual). When NA (not-assessable) is listed for the 1-KM it means that there is no estimate for the duration of follow-up specified
as risk interval, meaning that there was not any patient who reached the end of the risk window. The vaccinated and unvaccinated
cohorts were matched on age, sex, geographical region, prior identified COVID-19 infection, prior influenza vaccination, pregnancy,
immunocompromised and number of pre-existing conditions considered by the Centers for Disease Control and Prevention (CDC) as
risk criteria (0, 1, 2, 3, 4+).

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Figure 20. Cumulative incidence of glomerulonephritis within 365 days after start of
follow-up among individuals who received at least one dose of Pfizer-
BioNTech COVID-19 vaccine and matched unvaccinated individuals by
data source
EpiChron SIDIAP
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CPRD Aurum

Cumulative incidence curves (1 – Kaplan–Meier risk) starting from the day of administration
of the first dose of vaccine. Dotted lines represent 95% confidence intervals. The number at
risk at each time point and the cumulative number of events during the 21-day risk window
are also shown for each time point. The numerical data correspond to the days indicated by
the tick marks on the x-axis.

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Figure 21. Forest plot showing incidence rates and 95% confidence intervals for
glomerulonephritis within 365 days after start of follow-up among
individuals who received at least one dose of Pfizer-BioNTech COVID-19
vaccine and matched unvaccinated individuals by data source and by
age groups
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Figure 21. Forest plot showing incidence rates and 95% confidence intervals for
glomerulonephritis within 365 days after start of follow-up among
individuals who received at least one dose of Pfizer-BioNTech COVID-19
vaccine and matched unvaccinated individuals by data source and by
age groups
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Table 32. Matched and adjusted hazard ratios (HRs) and matched and adjusted risk
differences (RDs) per 10,000 person-years and their 95% CIs for
glomerulonephritis within 365 days after start of follow-up among
individuals who received at least one dose of Pfizer-BioNTech COVID-19
vaccine and matched unvaccinated individuals by data source
Matched HR (95% Adjusted HR (95% Matched RD Adjusted RD
CI) CI)
Pedianet NA NA NA NA
NHR NA NA NA NA
PHARMO NA NA NA NA
EpiChron 0.66 (0.26, 1.73) 0.59 (0.22, 1.55) -0.19 -0.28
SIDIAP 1.44 (0.99, 2.08) 1.29 (0.88, 1.87) 0.38 0.29
CPRD Aurum 0.89 (0.68, 1.17) 0.88 (0.67, 1.16) -0.21 -0.23
NA: not assessable due to zero cases in the vaccinated or unvaccinated cohorts for HR or in
both cohorts for RD

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10.2.3.9. Bell’s palsy

Bell’s palsy events could be identified in all data sources, except in Pedianet, where no
Bell’s palsy events were identified within the risk window. The incidence rates ranged from
1.14 per 10,000 person-years (95% CI: 0.55, 2.10) in PHARMO to 7.27 per 10,000 person-
years (95% CI: 6.21, 8.46) in SIDIAP in the vaccinated cohorts. In the unvaccinated cohorts
these ranged from 1.60 per 10,000 person-years (95% CI: 0.91, 2.80) in PHARMO to 7.76
per 10,000 person-years (95% CI: 3.30, 18.25) in EpiChron. The cumulative incidence was
below 1 per 10,000 individuals in both cohorts in all data sources except in the unvaccinated
cohort in EpiChron where the cumulative incidence was 1.01 per 10,000 individuals (95%
CI: 0.13, 1.89). The incidence was similar in the different age groups.

The matched HRs were 1.15 (95% CI: 0.88, 1.50) in NHR, 0.72 (95% CI: 0.31, 1.65) in
PHARMO, 0.91 (95% CI: 0.36, 2.30) in EpiChron, 1.00 (95% CI: 0.78, 1.28) in SIDIAP, and
0.98 (95% CI: 0.75, 1.28) in CPRD Aurum. The adjusted HRs were 1.15 (95% CI: 0.88,
1.50) in NHR, 0.65 (95% CI: 0.28, 1.51) in PHARMO, 0.84 95% CI: (95% CI: 0.34, 2.09) in
EpiChron, 0.96 (95% CI: 0.75, 1.24) in SIDIAP, and 0.99 (95% CI: 0.75, 1.29) in CPRD
Aurum. The lower limits of the 95% CIs for the HRs were above 1 in the matched and
adjusted results for Bells’s palsy assessed within a risk window of 42 days.
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Table 33. Risk estimates (95% CI) per 10,000 person-years (PY) for Bell’s palsy within 42 days after start of follow-up
among individuals who received at least one dose of Pfizer-BioNTech COVID-19 vaccine and matched
unvaccinated individuals by data source
Vaccinated Unvaccinated
Data source Events Cumulative Person- Incidence rate Events Cumulative Person- Incidence rate
(n) incidence (95% years (PY) (95% CI) (n) incidence (95% years (PY) (95% CI)
090177e1a02df15c\Approved\Approved On: 14-Mar-2024 23:12 (GMT)

CI) CI)
Pedianet 0 0 (0, NC) 1,036 0 (0, NC) 0 0 (0, NC) 1,037 0 (0, NC)
NHR 166 0.74 (0.63, 0.86) 257,184 6.45 (5.51, 144 0.63 (0.49, 0.78) 256,858 5.61 (4.49,
7.51) 7.01)
PHARMO 10 0.12 (0.05, 0.20) 87,393 1.14 (0.55, 14 0.19 (0.08, 0.30) 87,563 1.60 (0.91,
2.10) 2.80)
EpiChron 31 0.86 (0.55, 1.17) 43,848 7.07 (4.80, 34 1.01 (0.13, 1.89) 43,803 7.76 (3.30,
10.04) 18.25)
SIDIAP 167 0.82 (0.69, 0.95) 229,708 7.27 (6.21, 167 0.80 (0.64, 0.97) 229,708 7.27 (5.96,
8.46) 8.88)
CPRD Aurum 114 0.37 (0.30, 0.44) 348,927 3.27 (2.70, 116 0.38 (0.30, 0.46) 347,605 3.34 (2.72,
3.92) 4.09)
NC: not calculable
Note: Estimation of confidence intervals differs between vaccinated and unvaccinated, since the unvaccinated estimate is a
generalised estimating equation (GEE) estimates (to account for individuals who were matched to more than one vaccinated
individual). When NA (not-assessable) is listed for the 1-KM it means that there is no estimate for the duration of follow-up specified
as risk interval, meaning that there was not any patient who reached the end of the risk window. The vaccinated and unvaccinated
cohorts were matched on age, sex, geographical region, prior identified COVID-19 infection, prior influenza vaccination, pregnancy,
immunocompromised and number of pre-existing conditions considered by the Centers for Disease Control and Prevention (CDC) as
risk criteria (0, 1, 2, 3, 4+).

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Figure 22. Cumulative incidence of Bell’s palsy within 42 days after start of follow-
up among individuals who received at least one dose of Pfizer-BioNTech
COVID-19 vaccine and matched unvaccinated individuals by data source
NHR PHARMO
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EpiChron SIDIAP

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Figure 22. Cumulative incidence of Bell’s palsy within 42 days after start of follow-
up among individuals who received at least one dose of Pfizer-BioNTech
COVID-19 vaccine and matched unvaccinated individuals by data source
CPRD Aurum
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Cumulative incidence curves (1 – Kaplan–Meier risk) starting from the day of administration
of the first dose of vaccine. Dotted lines represent 95% confidence intervals. The number at
risk at each time point and the cumulative number of events during the 42-day risk interval
are also shown for each time point. The numerical data correspond to the days indicated by
the tick marks on the x-axis.

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Figure 23. Forest plot showing incidence rates and 95% confidence intervals for
Bell’s palsy within 42 days after start of follow-up among individuals
who received at least one dose of Pfizer-BioNTech COVID-19 vaccine
and matched unvaccinated individuals by data source and by age
groups
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Figure 23. Forest plot showing incidence rates and 95% confidence intervals for
Bell’s palsy within 42 days after start of follow-up among individuals
who received at least one dose of Pfizer-BioNTech COVID-19 vaccine
and matched unvaccinated individuals by data source and by age
groups
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Figure 23. Forest plot showing incidence rates and 95% confidence intervals for
Bell’s palsy within 42 days after start of follow-up among individuals
who received at least one dose of Pfizer-BioNTech COVID-19 vaccine
and matched unvaccinated individuals by data source and by age
groups
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Table 34. Matched and adjusted hazard ratios (HRs) and matched and adjusted risk
differences (RDs) per 10,000 person-years and their 95% CIs for Bell’s
Palsy within 42 days after start of follow-up among individuals who
received at least one dose of Pfizer-BioNTech COVID-19 vaccine and
matched unvaccinated individuals by data source
Matched HR (95% Adjusted HR (95% Matched RD Adjusted RD
CI) CI)
Pedianet NA NA 0 0
NHR 1.15 (0.88, 1.50) 1.15 (0.88, 1.50) 0.11 0.11
PHARMO 0.72 (0.31, 1.65) 0.65 (0.28, 1.51) -0.07 -0.08
EpiChron 0.91 (0.36, 2.30) 0.84 (0.34, 2.09) -0.15 -0.22
SIDIAP 1.00 (0.78, 1.28) 0.96 (0.75, 1.24) 0.02 -0.01
CPRD Aurum 0.98 (0.75, 1.28) 0.99 (0.75, 1.29) -0.01 -0.01
NA: not assessable due to zero cases in the vaccinated or unvaccinated cohorts for HR or in
both cohorts for RD

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10.2.3.10. Secondary amenorrhoea

Secondary amenorrhoea events were identified in all data sources, with a low number of
events in Pedianet and PHARMO. In NHR, EpiChron, SIDIAP and CPRD Aurum, the
incidence rates ranged from 9.60 per 10,000 person-years (95% CI: 8.05, 11.35) in NHR to
117.52 per 10,000 person-years (95% CI: 114.02, 121.10) in CPRD Aurum in the vaccinated
cohorts. In the unvaccinated cohorts in NHR, EpiChron, SIDIAP and CPRD Aurum these
ranged from 5.24 per 10,000 person-years (95% CI: 3.88, 6.60) in NHR to 44.50 per 10,000
person-years (95% CI: 42.47, 46.53) in CPRD Aurum. The cumulative incidence varied
between 4.71 per 10,000 individuals (95% CI: 3.82, 5.59) in NHR and 56.19 per 10,000
individuals (95% CI: 54.44, 57.93) in CPRD Aurum in the vaccinated cohorts and between
5.24 per 10,000 individuals (95% CI: 3.88, 6.60) in NHR and 44.50 per 10,000 individuals
(95% CI: 42.47, 46.53) in CPRD Aurum in the unvaccinated cohorts. The cumulative
incidence curves of vaccinated and unvaccinated diverged in EpiChron and CPRD Aurum
during follow up.

The matched HRs were in 0.91 (95% CI: 0.69, 1.22) in NHR, 0.99 (95% CI: 0.06, 15.60) in
PHARMO, 1.91 (95% CI: 1.50, 2.43) in EpiChron, 1.05 (95% CI: 0.97, 1.14) in SIDIAP, and
1.32 (95% CI: 1.25, 1.39) in CPRD Aurum. The adjusted HRs were 0.91 (95% CI: 0.69,
1.21) in NHR, 0.77 (95% CI: 0.05, 11.99) in PHARMO, 1.71 (95% CI: 1.34, 2.18) in
EpiChron, 0.99 (95% CI: 0.91, 1.07) in SIDIAP, and 1.24 (95% CI: 1.17, 1.30) in CPRD
Aurum. Differences were observed in the incidence of secondary amenorrhoea between the
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Table 35. Risk estimates (95% CI) per 10,000 person-years (PY) for secondary amenorrhoea within 183 days after start of
follow-up among individuals who received at least one dose of Pfizer-BioNTech COVID-19 vaccine and matched
unvaccinated individuals by data source
Vaccinated Unvaccinated
Data source Events Cumulative Person- Incidence rate Events Cumulative Person- Incidence rate
(n) incidence (95% years (PY) (95% CI) (n) incidence (95% years (PY) (95% CI)
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CI) CI)
Pedianet <5 1.23 (0, 3.65) NR 2.57 (0.07, 0 0 (0, NC) 3,902 0 (0, NC)
14.33)
NHR 136 4.71 (3.82, 5.59) 141,726 9.60 (8.05, 147 5.24 (3.88, 6.60) 139,920 10.51 (8.34,
11.35) 13.24)
PHARMO <5 0.07 (0, 0.21) NR 0.13 (0, 0.73) <5 0.06 (0, 0.17) NR 0.13 (0.02,
0.94)
EpiChron 270 34.82 (30.59, 38,227 70.63 (62.46, 141 17.68 (13.81, 38,189 36.92 (29.89,
39.05) 79.58) 21.55) 45.61)
SIDIAP 1,663 47.15 (44.82, 176,273 94.34 (89.86, 1,582 44.39 (41.32, 175,905 89.93 (84.11,
49.49) 98.99) 47.46) 96.16)
CPRD Aurum 4,257 56.19 (54.44, 362,239 117.52 3,174 44.50 (42.47, 356,406 89.06 (85.25,
57.93) (114.02, 46.53) 93.04)
121.10)
NR: not reportable due to masking of numbers of events <5; NC: not calculable
Note: Estimation of confidence intervals differs between vaccinated and unvaccinated, since the unvaccinated estimate is a
generalised estimating equation (GEE) estimates (to account for individuals who were matched to more than one vaccinated
individual). When NA (not-assessable) is listed for the 1-KM it means that there is no estimate for the duration of follow-up specified
as risk interval, meaning that there was not any patient who reached the end of the risk window. The vaccinated and unvaccinated
cohorts were matched on age, sex, geographical region, prior identified COVID-19 infection, prior influenza vaccination, pregnancy,
immunocompromised and number of pre-existing conditions considered by the Centers for Disease Control and Prevention (CDC) as
risk criteria (0, 1, 2, 3, 4+).

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Figure 24. Cumulative incidence of secondary amenorrhoea within 183 days after
start of follow-up among individuals who received at least one dose of
Pfizer-BioNTech COVID-19 vaccine and matched unvaccinated
individuals by data source
Pedianet NHR
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PHARMO EpiChron

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Figure 24. Cumulative incidence of secondary amenorrhoea within 183 days after
start of follow-up among individuals who received at least one dose of
Pfizer-BioNTech COVID-19 vaccine and matched unvaccinated
individuals by data source
SIDIAP CPRD Aurum
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Cumulative incidence curves (1 – Kaplan–Meier risk) starting from the day of administration
of the first dose of vaccine. Dotted lines represent 95% confidence intervals. The number at
risk at each time point and the cumulative number of events during the 183-day risk window
are also shown for each time point. The numerical data correspond to the days indicated by
the tick marks on the x-axis.

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Figure 25. Forest plot showing incidence rates and 95% confidence intervals for
secondary amenorrhoea within 183 days after start of follow-up among
individuals who received at least one dose of Pfizer-BioNTech COVID-19
vaccine and matched unvaccinated individuals by data source and by
age groups
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Figure 25. Forest plot showing incidence rates and 95% confidence intervals for
secondary amenorrhoea within 183 days after start of follow-up among
individuals who received at least one dose of Pfizer-BioNTech COVID-19
vaccine and matched unvaccinated individuals by data source and by
age groups
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Figure 25. Forest plot showing incidence rates and 95% confidence intervals for
secondary amenorrhoea within 183 days after start of follow-up among
individuals who received at least one dose of Pfizer-BioNTech COVID-19
vaccine and matched unvaccinated individuals by data source and by
age groups
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Table 36. Matched hazard ratios (HRs) and matched risk differences (RDs) per
10,000 person-years and their 95% CIs for secondary amenorrhoea within
183 days after start of follow-up among individuals who received at least
one dose of Pfizer-BioNTech COVID-19 vaccine and matched unvaccinated
individuals by data source
Matched HR (95% Adjusted HR (95% Matched RD Adjusted RD
CI) CI)
Pedianet NA NA 1.23 1.11
NHR 0.91 (0.69, 1.22) 0.91 (0.69, 1.21) -0.54 -0.55
PHARMO 0.99 (0.06, 15.60) 0.77 (0.05, 11.99) 0.01 0
EpiChron 1.91 (1.50, 2.43) 1.71 (1.34, 2.18) 17.14 14.62
SIDIAP 1.05 (0.97, 1.14) 0.99 (0.91, 1.07) 2.76 0.08
CPRD Aurum 1.32 (1.25, 1.39) 1.24 (1.17, 1.30) 11.69 8.39
NA: not assessable due to zero cases in the vaccinated or unvaccinated cohorts for HR or in
both cohorts for RD
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10.2.3.11. Hypermenorrhoea
Hypermenorrhoea events were identified in Pedianet, EpiChron, and SIDIAP. The incidence
rates were 5.15 per 10,000 person-years (95% CI: 0.62, 18.62) in Pedianet, 142.88 per
10,000 person-years (95% CI: 137.34, 148.59) in SIDIAP, and 230.91 per 10,000 person-
years (95% CI: 215.72, 246.89) in EpiChron in the vaccinated cohorts. In the unvaccinated
cohorts the incidence rates were 7.70 per 10,000 person-years (95% CI: 1.79, 33.20) in
Pedianet, 130.74 per 10,000 person-years (95% CI: 123.61, 138.29) in SIDIAP, and 143.95
per 10,000 person-years (95% CI: 128.81, 160.87) in EpiChron. In PHARMO, incidence
rates were below 1 with very few cases identified in both cohorts. The cumulative incidence
varied between 2.57 per 10,000 individuals (95% CI: 0, 6.15) in Pedianet and 114.59 per
10,000 individuals (95% CI: 106.80, 122.37) in EpiChron in the vaccinated cohorts and
between 3.21 per 10,000 individuals (95% CI: 0, 7.99) in Pedianet and 69.56 per 10,000
individuals (95% CI: 61.61, 77.50) in EpiChron in the unvaccinated cohorts. The cumulative
incidence curves for the vaccinated and unvaccinated cohorts diverged during follow up in
EpiChron and SIDIAP.

The matched HRs were 0.67 (95% CI: 0.09, 5.01) in Pedianet, 1.60 (95% CI: 1.41, 1.83) in
EpiChron, and 1.09 (95% CI: 1.02, 1.17) in SIDIAP. The adjusted HRs were 0.62 (95% CI:
0.08, 4.66) in Pedianet, 1.40 (95% CI: 1.23, 1.60) in EpiChron, and 1.02 (95% CI: 0.95,
1.09) in SIDIAP. In EpiChron the adjusted HRs were above 1 and the lower limits of the 95%
Cis were >1.
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Table 37. Risk estimates (95% CI) per 10,000 person-years (PY) for hypermenorrhea within 183 days after start of follow-up
among individuals who received at least one dose of Pfizer-BioNTech COVID-19 vaccine and matched
unvaccinated individuals by data source
Vaccinated Unvaccinated
Data source Events Cumulative Person-years Incidence rate Events Cumulative Person-years Incidence rate
(n) incidence (95% (PY) (95% CI) (n) incidence (PY) (95% CI)
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CI) (95% CI)

Pedianet <5 2.57 (0, 6.15) NR 5.15 (0.62, <5 3.21 (0, 7.99) NR 7.70 (1.79,
18.62) 33.20)
NHR NA NA NA NA NA NA NA NA
PHARMO 6 0.37 (0.07, 0.68) 76,532 0.78 (0.29, 5 0.34 (0, 0.70) 75,683 0.66 (0.23,
1.71) 1.86)
EpiChron 858 114.59 (106.80, 37,157 230.91 535 69.56 (61.61, 37,166 143.95
122.37) (215.72, 77.50) (128.81,
246.89) 160.87)
SIDIAP 2,502 70.96 (68.09, 175,111 142.88 2,285 63.45 (59.74, 174,773 130.74
73.83) (137.34, 67.15) (123.61,
148.59) 138.29)
CPRD NA NA NA NA NA NA NA NA
Aurum
NA: not available; NR: not reportable due to masking numbers of events <5
Note: Estimation of confidence intervals differs between vaccinated and unvaccinated, since the unvaccinated estimate is a
generalised estimating equation (GEE) estimates (to account for individuals who were matched to more than one vaccinated
individual). When NA (not-assessable) is listed for the 1-KM it means that there is no estimate for the duration of follow-up specified
as risk interval, meaning that there was not any patient who reached the end of the risk window. The vaccinated and unvaccinated
cohorts were matched on age, sex, geographical region, prior identified COVID-19 infection, prior influenza vaccination, pregnancy,
immunocompromised and number of pre-existing conditions considered by the Centers for Disease Control and Prevention (CDC) as
risk criteria (0, 1, 2, 3, 4+).

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Figure 26. Cumulative incidence of hypermenorrhoea within 183 days after start of
follow-up among individuals who received at least one dose of Pfizer-
BioNTech COVID-19 vaccine and matched unvaccinated individuals by
data source
Pedianet PHARMO
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EpiChron SIDIAP

Cumulative incidence curves (1 – Kaplan–Meier risk) starting from the day of administration
of the first dose of vaccine. Dotted lines represent 95% confidence intervals. The number at
risk at each time point and the cumulative number of events during the 183-day risk window
are also shown for each time point. The numerical data correspond to the days indicated by
the tick marks on the x-axis.

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Figure 27. Forest plot showing incidence rates and 95% confidence intervals for
hypermenorrhoea within 183 days after start of follow-up among
individuals who received at least one dose of Pfizer-BioNTech COVID-19
vaccine and matched unvaccinated individuals by data source and by
age groups
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Figure 27. Forest plot showing incidence rates and 95% confidence intervals for
hypermenorrhoea within 183 days after start of follow-up among
individuals who received at least one dose of Pfizer-BioNTech COVID-19
vaccine and matched unvaccinated individuals by data source and by
age groups
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Figure 27. Forest plot showing incidence rates and 95% confidence intervals for
hypermenorrhoea within 183 days after start of follow-up among
individuals who received at least one dose of Pfizer-BioNTech COVID-19
vaccine and matched unvaccinated individuals by data source and by
age groups
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Table 38. Matched and adjusted hazard ratios (HRs) and matched and adjusted risk
differences (RDs) per 10,000 person-years and their 95% CIs for
hypermenorrhoea within 183 days after start of follow-up among
individuals who received at least one dose of Pfizer-BioNTech COVID-19
vaccine and matched unvaccinated individuals by data source
Matched HR (95% Adjusted HR (95% Matched RD Adjusted RD
CI) CI)
Pedianet 0.67 (0.09, 5.01) 0.62 (0.08, 4.66) -0.64 -0.87
NHR NA NA NA NA
PHARMO 1.19 (0.32, 4.41) 1.18 (0.31, 4.47) 0.04 0.04
EpiChron 1.60 (1.41, 1.83) 1.40 (1.23, 1.60) 45.03 33.57
SIDIAP 1.09 (1.02, 1.17) 1.02 (0.95, 1.09) 7.52 2.94
CPRD Aurum NA NA NA NA
NA: not assessable due to zero cases in the vaccinated or unvaccinated cohorts for HR or in
both cohorts for RD

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10.3. Other analyses

None.

10.4. Adverse events / adverse reactions

No adverse events (AEs), other than those reported in aggregated data, were observed
during study.

This study involves a combination of existing structured data and unstructured data, which
were converted to structured form during the implementation of the protocol solely by a
computer using automated algorithmic methods, such as natural language processing.

In these data sources, it is not possible to link (i.e., identify a potential association between)
a particular product and medical event for any individual. Thus, the minimum criteria for
reporting an AE (i.e., identifiable patient, identifiable reporter, a suspect product, and event)
cannot be met.

11. DISCUSSION
11.1. Key results
This fifth interim report provides updated results on the estimated incidence rates (IRs) and
hazard ratios (HRs) for the 37 prespecified AESIs (Table 16) in a vaccinated cohort of
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individuals who received at least one dose of the Pfizer-BioNTech COVID-19 vaccine and in
a matched unvaccinated comparator cohort. Results are reported for two recently added
AESIs, i.e., glomerulonephritis and cerebral venous sinus thrombosis (CVST).

These results are based on data from six data sources in five countries: Pedianet in Italy,
PHARMO in the Netherlands, NHR in Norway, EpiChron and SIDIAP in Spain and CPRD
Aurum in the UK. No data from ARS (IT) could be extracted and analysed for this fifth
interim report because of national and regional reassessment of their ability to provide public
data for PASS. Results from HSD (IT) have also not been included because of data validity
concerns regarding misclassification of exposure due to Pfizer-BioNTech COVID-19 vaccine
registration practices among GP practices in the data source coverage area.

In this report we included data up to 31 December 2022 from Pedianet, 30 June 2023 (i.e.,
GP data) and 31 December 2022 (i.e., hospital data) from PHARMO, 30 June 2023 from
SIDIAP, 31 July 2023 from EpiChron, 31 December 2022 from NHR, and 21 March 2022
from CPRD Aurum. The period covered in the analysed data included months when
participants could receive up to five doses of the Pfizer-BioNTech COVID-19 vaccine, which
was implemented in many countries end of summer 2022. Hence, data for individuals who
had received up to three booster doses of the Pfizer-BioNTech COVID-19 vaccine have also
been included.

In this fifth interim report, we have used all matching criteria except pregnancy for CPRD
and PHARMO for reasons of ongoing pregnancy data and script validations and for
PEDIANET which is a paediatric database only, socio-economic status for CPRD, and
influenza vaccination for NHR. The balance between the matched vaccinated and
unvaccinated cohorts was verified. Matching on pregnancy status was done using a
pregnancy algorithm developed by the ConcePTION project.[18] We used a negative control
outcome, i.e., COVID-19 in the first 12 days after time zero and the results are compatible
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with the absence of relevant baseline residual confounding. Because the use of this
negative control outcome assumes that the confounders for COVID-19 disease are equally
relevant for all AESIs, effect estimates were additionally adjusted via IPT weighting, since
similar estimates with and without IPT weighting would support this assumption. This was
what we observed, thus our matching process generated comparable cohorts.

These results should be considered as the last interim results from a long-term safety
surveillance study. Limitations from prior reports have been identified and issues have been
corrected, such as the inclusion of IPT adjusted results, improved algorithms to clean the
vaccination information, refined and more specific disease code lists, and performance of
matching based on all matching variables, including socio-economic status. We will continue
to work on resolving outstanding issues for the final report.

11.1.1. Important information on data sources

Two data sources, ARS and HSD from Italy, could not contribute data to this fifth interim
report:

 Data from ARS were reported in interim reports 1 and 2, but since then data have not
been re-extracted due to national and regional reassessment of their ability to
provide public data for PASS studies.
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 Data on COVID-19 vaccination were missing for a high percentage of individuals in

the HSD data source (Italian GP databases), and it was, therefore, not considered as
fit for purpose. In Italy, GPs were involved in the COVID-19 vaccination campaign
only for their patients aged 80 years and older in March 2021. There was no
automated system to collect data on patients' vaccination status, and recording this
information depended entirely on the efforts of the GPs. Since it is mandatory for
Italian GPs to collect vaccine-related information for their own electronic dossiers,
the accuracy of vaccine registration is expected to improve over time. However, we
cannot exclude the possibility that recording of the vaccine brand may be selective.
We will continue to monitor data on vaccine uptake in HSD to assess whether they
are fit for purpose.

In the other data sources, data for events can originate from different data sources (i.e., GP,
emergency visits, hospital discharge data sources, outpatient specialist diagnoses). This
may have an impact on the estimates for the incidence rates as shown in a recent study.[19]

Pedianet is an Italian paediatric general practice research database that includes children
until the age of 14, after which they are transferred to general practitioners. The vaccination
campaign for children in Italy started on 31 May 2021, which is reflected by the different
calendar time of first vaccination. AESIs are based on diagnoses in the paediatricians’
record, which may include information from hospitalisation, when it is reported back to them,
but this may not be complete, which is why Pedianet could not contribute data for all AESIs.

The data from PHARMO in this fifth interim report were extracted from GP records up to 30
June 2023 and from hospital records up to 31 December 2022. The coding system used in
the PHARMO GP databases is ICPC, which is not as granular as ICD coding. Additional
AESI events were identified using free text searching. Although substantial improvements in
the free text identification and the ETL script for variables and AESIs have been made, the

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number of events and event rates tend to be lower in this GP data source compared with the
other data sources, that also include data from secondary care settings.

The EpiChron data source included diagnosis codes from general practitioners and from
hospital discharges up to 31 July 2023 for this fifth interim report.

The SIDIAP data source included data from general practitioner and hospital discharge
records up to 30 June 2023 for this report.

The NHR data source provided GP data from the Norway Control and Payment of Primary
Health Care Refunds (KUHR) and hospital data from the Norwegian Patient Registry up to
31 December 2022 for this report. The KUHR GP data source is at max 4 digits for ICPC2
codes because more details digits are not used in the KUHR GP data source. This can lead
to a less specific identification of events resulting in higher event and incident numbers from
Norway.

The CPRD Aurum data source provided data from primary care medical records up to 21
March 2022 for this report. Only information which has been coded in the medical records,
including information from hospital discharge letters, can be used. A coding system specific
to CPRD Aurum is used to determine event diagnoses, prescriptions, and vaccine
administration (MedCodeID for diagnoses and ProdCodeID for medicinal products). No free
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text is available.

11.1.2. Total vaccinated population and vaccination patterns

The number of individuals who received a first dose of Pfizer-BioNTech COVID-19 vaccine
and were included in this fifth report was 12,613,349. A total of 10,665,306 (84.6%)
individuals received a second dose of the Pfizer-BioNTech COVID-19 vaccine. The second
dose was mainly administered within six weeks after the first dose; 16.6% individuals had an
interval of more than six weeks between the first and second doses in all data sources,
except CPRD Aurum where 81.27% were vaccinated with the second dose outside the 6-
week window. This longer interval between the doses in the UK is explained by The higher
percentage of individuals with a longer interval between the first and second doses in the
UK (CPRD Aurum) is because the Joint Committee on Vaccination and Immunisation (JCVI)
recommended a 12-week interval between the first and second doses in order to prioritised
the administration of first doses to a large percentage of the population, before administering
the second dose.[20] In other data sources the percentage of individuals who had an interval
longer than six weeks between the first and second doses varied from 2.34% in Pedianet to
22.75% in PHARMO.

A total of 26,980 pregnant women in the NHR, EpiChron and SIDIAP data sources received
a first dose of the Pfizer-BioNTech COVID-19 vaccine and satisfied the inclusion criteria.
Among these women 9,234 (34.23%) received the dose during their first trimester of
pregnancy and 9,763 (36.19%) in their second trimester. Pregnancy data were not available
from PHARMO or CPRD Aurum for this report, but they are expected to be available for the
final report.

Overall, 4,642,445 individuals had a recorded third dose of the Pfizer vaccine which is
36.81% of those who received a 1st dose. The mean age of these individuals was higher
than those who had received at least a first dose (except in PHARMO), reflecting the

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targeted roll out of booster doses to elderly individuals first. The interval between the second
and third doses varied between data sources with the median interval ranging from 21
weeks in Pedianet to 31 weeks in SIDIAP.

At the time of database lock, 1,021,555 (8.10%) individuals had received a fourth dose and
7,801 (0.06%) a fifth dose of the Pfizer-BioNTech COVID-19 vaccine.

11.1.3. Matched cohorts

In this fifth interim report, individuals were matched in each data source on the following pre-
specified matching variables: calendar date of time zero, age, sex, prior COVID-19
diagnosis, place of residence, at least one influenza vaccine (not in NHR), pregnancy (not in
PHARMO, CPRD Aurum, and Pedianet), immunocompromised status, pre-existing
conditions considered as risk factors for severe COVID-19 by the Centers for Disease
Control and Prevention (CDC) and socio-economic status (not in CPRD).

From a total of 12,613,349 individuals who received a first dose of the Pfizer-BioNTech
COVID-19 vaccine and were included in the study, 12,400,847 (98.32%) could be matched
with an unvaccinated individual. The median follow-up time after the first dose varied from
0.9 months in NHR to 11.3 months in Pedianet. Censoring of follow-up was mostly due to
unvaccinated individuals being vaccinated with a COVID-19 vaccine, which also resulted in
the censoring of the matched vaccinated individual.
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Many individuals who were initially included in the matched unvaccinated cohort
subsequently received a Pfizer-BioNTech COVID-19 vaccine. A total of 6,217,296 (50.14%)
matched unvaccinated individuals were censored because of receipt of a COVID-19 vaccine
(Pfizer-BioNTech COVID-19 vaccine or a non-Pfizer-BioNTech COVID-19 vaccine) When
this occurred, the follow-up of the unvaccinated individual was censored (as was that for the
matched vaccinated individual), and the unvaccinated individual entered the vaccinated
cohort with time zero as the date of vaccination if an unvaccinated individual could be
matched to them. This had an impact on the duration of follow-up, especially for events with
long risk windows. However, this is inevitable since COVID-19 vaccination uptake rates are
high in the participating countries.

The median age of matched vaccinated individuals was highest in PHARMO (49 years),
followed by EpiChron (48 years), NHR (47 years), SIDIAP (45 years), and CPRD Aurum (36
years). The median age in Pedianet, a paediatric database, was 10 years, with only a few
children aged under 5 years captured. We assessed lifestyle factors, healthcare use,
prevalence of comorbidity and comorbidity summary scores, as well as the use of
comedications and vaccines prior to time zero. Information on long-term care facility
residency and healthcare worker or essential worker status could not be identified in the
data sources. The lifestyle indicators (i.e., smoking status and BMI), which were available
from PHARMO for about 26% and 21% of the vaccinated and unvaccinated cohorts,
respectively, EpiChron for about 24% and 23% of the vaccinated and unvaccinated cohorts,
respectively and SIDIAP for about 55% and 54% of the vaccinated and unvaccinated
cohorts, respectively. This should be interpreted cautiously because of the high percentage
of missing data for these variables. The healthcare use indicators showed a similar
distribution between the vaccinated and unvaccinated cohorts.

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PHARMO had missing data on almost all other vaccines, as these vaccinations are not
registered by the GPs in the Netherlands. Despite the differences in prevalence of
covariates between data sources, which may be explained by the type of data source, the
age of the population and experience with using ETL, the assessment of the absolute
standardised differences (ASDs) between the vaccinated and unvaccinated cohorts within
each data source for the prevalence of baseline demographic characteristics, comorbidities
and comedications did not show differences or imbalance.

There are now more than 12 million vaccinated individuals and 12 million unvaccinated
individuals in the study, which, in the pooled analysis that is planned for the final report,
would be sufficient to detect a risk ratio of 3 for Guillain-Barré syndrome (incidence rate of 1
in 100,000 person-years and a risk window of 42 days), assuming a two-sided alpha of 0.95
and a power of 80%.

11.1.4. Negative control

A difference in the cumulative incidence of symptomatic SARS-CoV-2 infections at day 12 of
approximately 0.1% was considered as proof of non-relevant residual confounding based on
an observational study of the effectiveness of the Pfizer-BioNTech COVID-19 vaccine in
adults.[13]. We compared the incidences of COVID-19 in the first 12 days after vaccination in
the vaccinated and unvaccinated cohorts to assess baseline exchangeability. In NHR,
PHARMO, EpiChron SIDIAP and CPRD Aurum the differences for the incidences were less
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than 1 per 1,000 individuals. In Pedianet the difference between the incidences of COVID-
19 in the first 12 days was 2 per 1,000 cases but this is not suggestive of confounding as
incidence rates in the pediatric population were 10 times those in the adult population and
the Kaplan-Meier curves showed similar increases in vaccinated and unvaccinated.
Consequently, we considered that the matching process achieved the required balance
between the cohorts. Regardless of the negative control results, as we are dealing with
outcomes that have long risk windows, the analyses were performed in the matched cohorts
with PS adjustments to control for the effect of potential confounding.

11.1.5. Incidence rates and hazard ratios for AESIs

Since the analyses in previous interim reports, the AESIs code lists have been re-reviewed
by clinical epidemiologists within VAC4EU, and tags for specific and sensitive codes were
assessed per descendant code, instead of at the concept level. This may have led to
changes in some of the event rates.

The following 11 AESIs, are discussed below either at the request of EMA or because they
have been recently included in the list of AESIs.

11.1.5.1. Acute cardiovascular injury

Acute cardiovascular injury (ACI) was defined as a composite endpoint. The definition is
based on American College of Cardiology/American Heart Association Task Force definition,
i.e., acute cardiovascular injury is an acute illness that is physician-diagnosed as a
cardiovascular injury.[21] Acute cardiovascular injury refers to a broad spectrum of cardiac
pathology including microangiopathy, heart failure, stress cardiomyopathy, coronary artery
disease, myocarditis, pericarditis and cardiac arrhythmias, usually associated with
abnormalities on ECG, echocardiography or cardiac MRI, and elevated biochemical
markers. The study variable is operationalised as an algorithm including diagnostic codes

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identifying microangiopathy, acute myocardial infarction, stress cardiomyopathy, heart

failure, coronary artery disease, myocarditis, pericarditis, and arrhythmia.

In this report, the adjusted HRs and the lower limits of the 95% CIs for ACI were above 1 in
PHARMO with a HR of 1.38 (95% CI: 1.31, 1.45), in EpiChron with a HR of 1.10 (95% CI:
1.03, 1.18), and in CPRD Aurum with a HR of 1.23 (95% CI: 1.18, 1.27) in CPRD Aurum. In
CPRD Aurum and EpiChron the cumulative incidence showed divergence between
vaccinated and unvaccinated from around day 80 within the 365 days risk window and in
PHARMO from around day 30.

In PHARMO the identification of ACI was mainly driven by events identified with the ICPC
GP symptom code ‘palpitations’ (K04) and ICD10 hospital code for atrial fibrillation and atrial
flutter unspecified (I489), and acute subendocardial myocardial infarction (I214), followed by
ICD10 heart failure unspecified (I509), and ICPC code for acute myocardial infarction (K75)
and atrial fibrillation/flutter (K78). In CPRD Aurum the highest code counts were for
MedCodelds for atrial fibrillation (MedCodeld 82343012) and ischaemic heart disease
(MedCodeld 2534664018). In EpiChron, ACI was mainly identified through the ICD9CM
codes for atrial fibrillation (427.31) and tachycardia unspecified (785.0) followed by
ICD10CM codes for heart failure unspecified (I50.9) and unspecified atrial fibrillation (I48.91)
and ICD9CM codes for acute myocardial infarction of unspecified site episode of care
unspecified (410.90), and heart failure unspecified (428.9).
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Some of these events may have presented with mild symptoms that did not require
immediate medical attention, and healthcare may have been sought in a delayed manner.
The differences in incidence between vaccinated and unvaccinated could be partly due to
vaccinated individuals seeking medical attention more frequently than those who were
unvaccinated.

Another plausible explanation is the difference in the composition of the unvaccinated cohort
as follow-up increases. Follow-up for unvaccinated individuals is censored in the
unvaccinated cohort if they are vaccinated and they are then followed up from that time
point in the vaccinated cohort. Therefore, long term follow-up in the unvaccinated cohort is
restricted to individuals who are never vaccinated and who are possibly less likely to seek
medical attention if not urgently needed. This difference between the vaccinated and
unvaccinated individuals may be minimal in the earlier periods of follow-up after vaccination,
during which time proportionally more unvaccinated persons intend to be vaccinated. The
Kaplan-Meier curves show that, generally, the differences between vaccinated and
unvaccinated cohorts are driven by the divergence in cumulative incidence over time,
particularly for AESIs with a long follow up time of 365 days. We will further assess the
numbers of individuals switching from the unvaccinated to vaccinated cohorts in relation to
follow up time. Also, we plan to analyse differences in baseline characteristics between
those unvaccinated that remain in the unvaccinated cohort for a long follow up period (e.g.,
at day 100, 200, 300, and 365) and the unvaccinated that get vaccinated during follow up
period at different time points at the same timepoints. In addition, a negative control event,
with the characteristics of cardiovascular disease, will be identified and analysed to explore
the behaviour of the incidence rate in relation to follow-up time.

Another reason that may explain the divergence, could be that cardiovascular events occur
due to COVID-19, which is considered to be a risk factor for cardiovascular events. As
COVID-19 infection is only assessed at baseline at the time of vaccination there is no
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information about COVID-19 infections occurring during the 365 day follow up that
potentially could trigger cardiovascular events in vaccinated or unvaccinated individuals
within 365 days after the first dose.

11.1.5.2. Arrhythmia
In this report, the adjusted HRs and the lower limits of the 95% CIs for arrhythmia were
above 1 in NHR, PHARMO, EpiChron, and CPRD Aurum with a HR of 1.03 (95% CI: 1,
1.05) in NHR, 1.36 (95% CI: 1.29, 1.44) in PHARMO, 1.12 (95% CI: 1.04, 1.21) in EpiChron,
and 1.27 (95% CI: 1.21, 1.33) in CPRD Aurum. In all data sources the cumulative incidence
showed divergence between vaccinated and unvaccinated from around day 60 within the
365 days risk window. Arrythmia is the main driver of results for acute cardiovascular injury
and all the discussion points mentioned above apply specifically to this AESI.

In NHR and PHARMO the identification of arrhythmia was mainly driven through ICPC GP
codes for atrial fibrillation/flutter (K78) and ‘palpitations (K04), and ICD10 code for atrial
fibrillation and atrial flutter unspecified (I489). In EpiChron arrhythmia was identified mainly
through ICD9CM codes for atrial fibrillation 427.3, and tachycardia unspecified 785.0, and
the ICD10CM code for unspecified atrial fibrillation (I48.91). In CPRD Aurum the MedCodeld
82343012 for atrial fibrillation was the most frequent code.

These results show higher cumulative incidence rates of arrhythmia in vaccinated cohorts
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compared with those in unvaccinated cohorts, increasing with time since vaccination. The
matched HRs were higher in CPRD Aurum than in the other data sources.

In all data sources except NHR, adjustment (PS control of confounding) resulted in a
lowering of the HR. suggesting some residual confounding present in the matched HRs.
Vaccinated and unvaccinated individuals may be different in their frequency of use of
healthcare services (i.e., a healthy vaccinee effect) (i.e., a healthy vaccinee effect). It is
possible that vaccinated individuals were more likely to seek health care than unvaccinated
individuals, and thus have this condition diagnosed.

The EMA COVID Vaccine Monitoring (CVM) final report showed background incidence rates
in unvaccinated individuals comparable to those found in this fifth interim report with
diagnoses more frequently originating from primary care.[22]

11.1.5.3. Heart failure

Heart failure was part of the acute cardiovascular injury composite event but was also
analysed separately.

In this report, the adjusted HRs and the lower limits of the 95% CIs for heart failure were
above 1 in PHARMO with a HR of 1.29 (95% CI: 1.13, 1.47) and showed a divergence
between vaccinated and unvaccinated from around day 60 within the 365 days risk window.

Heart failure in PHARMO was mainly identified by ICD10 hospital codes for heart failure
unspecified (I509) and left ventricular failure (I501) followed by ICPC GP codes
decompensation of the heart (K77). In PHARMO hospital codes are being added to
complete the primary care ICPC GP codes and will be further investigated for the final
report.

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11.1.5.4. Stress cardiomyopathy

Stress cardiomyopathy was part of the acute cardiovascular injury composite event, but was
also analysed separately.

No differences were observed for the incidence of stress cardiomyopathy between the
vaccinated and unvaccinated cohorts during the 365-day risk window.

ACCESS data showed that the incidence was underestimated when relying on GP data
only.

11.1.5.5. Coronary artery disease

Coronary artery disease is part of the acute cardiovascular injury composite event, but was
also analysed separately.

In this report, the adjusted HRs and the lower limits of the 95% CIs for coronary artery
disease were above 1 in PHARMO with a HR of 1.49 (95% CI: 1.31, 1.69) and in CPRD
Aurum with a HR of 1.40 (95% CI: 1.30, 1.50). The cumulative incidence showed a
divergence between vaccinated and unvaccinated cohorts from around day 30 in PHARMO
and CPRD within the 365 days risk window. The potentials reasons for these results are
discussed above in Section 11.1.5.1.
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Coronary artery disease in PHARMO was mainly identified with ICD10 hospital codes for
angina pectoris unspecified (I209) and acute subendocardial myocardial infarction (I214),
Unstable angina (I200), Acute transmural myocardial infarction of inferior wall (I211) and
with ICPC codes for Acute myocardial infarction (K75), and angina pectoris (K74). In CPRD
Aurum the main codes identifying CAD were Ischaemic heart disease (MedCodeld
2534664018) and angina pectoris (MedCodeld 299757012).

11.1.5.6. Myocarditis (21-day risk window)

The lower limits of the 95% CIs for the myocarditis HRs occurring in a risk window of 21
days were below 1. There were no differences observed for myocarditis between vaccinated
and unvaccinated in a 21-day risk window.

Myocarditis has been associated with COVID-19 mRNA vaccines in several studies in young
adults, after the second dose of the vaccine.[23] This second dose is typically administered
28 days after the first dose, and therefore was not observed in the during the 21-day risk
window analysed here.

11.1.5.7. Cerebral venous sinus thrombosis

Cerebral venous sinus thrombosis (CVST) has been added to the list of AESIs for this fifth
interim report. CVST had been operationalised as cerebral venous thrombosis (CVT) in the
prior interim reports. No differences between vaccinated and unvaccinated have been
observed for CVST.

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11.1.5.8. Glomerulonephritis
The lower limits of the CIs for the glomerulonephritis HRs assessed in a risk window of 365
days were below 1. There were no differences observed for glomerulonephritis between the
vaccinated and unvaccinated cohorts.

Glomerulonephritis has been added for the first time for this fifth interim report as an AESI.
No glomerulonephritis events were identified in Pedianet, NHR, or PHARMO. In PHARMO,
the use of a single ICD-10 code only capturing hospital-based diagnoses, may explain the
lack of glomerulonephritis events identified since PHARMO predominantly contributed GP
data. This and other potential causes for the lack of results from NHR and PHARMO for
glomerulonephritis are under investigation and will be reported in the final report. This will be
done by reviewing definitions, algorithms and diagnostic ICD10 and ICPC codes.
Additionally, the impact of partial ICD10 hospital registration coverage in PHARMO will be
assessed, as glomerulonephritis is more likely to be detected in hospital settings. As
glomerulonephritis is more likely to be detected in hospital settings and in adults, we did not
expect to identify glomerulonephritis events in Pedianet.

11.1.5.9. Bell’s palsy

In this interim report 5 we did not observe any differences between the vaccinated and
unvaccinated cohorts for Bell’s palsy assessed in a risk window of 42 days. The adjusted
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HR was 0.65 (95% CI: 0.28, 1.51). The lower limits of the 95% CIs for the HRs were all
below 1. This is different from interim report 4, for PHARMO where the lower limits of the
95% CIs for the HRs were above 1, with an adjusted HR of 3.08 (95% CI: 1.24, 7.62). In
interim report 4, there were 24 and 7 events within the 42 days risk window in the
vaccinated and unvaccinated cohorts, respectively in PHARMO compared with 10 and 14,
respectively, in interim report 5. We compared the code lists and did not detect any changes
in diagnostic codes between interim report 4 and interim report 5. However, the reduction of
cases identified could be due to an improved case identification algorithm introduced in
interim report 5 or due to the continued efforts of PHARMO to clean COVID-19 vaccine
exposure registration in removing potential duplicate vaccination entries originating from
different data bases.

11.1.5.10. Secondary amenorrhoea

Secondary amenorrhoea events were identified in EpiChron, SIDIAP, and CPRD Aurum.
Pedianet, which covers a paediatric population, is not suitable for the assessment of
secondary amenorrhoea. Detection of this event may have been limited overall since codes
did not include the underlying diseases to which amenorrhoea could be secondary; Codes
for these underlying diseases were not included in the definition because it was felt they
were not only specific for secondary amenorrhoea. PHARMO and NHR had low numbers of
cases. The lack of GP-based ICPC codes to define secondary amenorrhoea for these
countries, where this event is likely to be managed primarily by GPs, may explain the low
numbers of events.

In this report, the adjusted HRs and the lower limits of the 95% CIs for secondary
amenorrhoea within 183 days were above 1 in EpiChron with an adjusted HR of 1.71 (95%
CI: 1.34, 2.18) and in CPRD Aurum with an adjusted HR of 1.24 (95% CI: 1.17, 1.30). The
cumulative incidence showed a divergence between vaccinated and unvaccinated from

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around day 15 in EpiChron and CPRD Aurum within the 183 days risk window. However,
the observed occurrence of a menstrual disorder event as early as 15 days after vaccination
does not appear to be biologically plausible and this is currently being investigated. The
inclusion of biologically plausible lag time in the risk window from start of follow up after
vaccination is needed.

Menstrual problems are mainly identified in GP practices and the ICPC codes in NHR and
PHARMO are not granular enough to separate secondary amenorrhoea from amenorrhoea
or even hypermenorrhoea. The codes available usually cover unspecified menstrual
problems. Additionally, in the case of secondary amenorrhoea, the more specific underlying
diagnosis will be coded in hospital settings. A possible next step would be to broaden the
definition with a more sensitive definition for the identification of ‘menstrual problems’ in
general. This is also partly reflected in some inconsistent published reports about the
association of COVID-19 vaccines and menstrual disorders.[23-26]. Similar to the
cardiovascular events, the differences between the vaccinated and unvaccinated cohorts
could be explained by different healthcare seeking behaviour. In light of this and the
limitations described above, the apparent differences in the incidences of secondary
amenorrhoea in vaccinated and unvaccinated cohorts is inconclusive. Further investigations
will be carried out and presented in the final report.

11.1.5.11. Hypermenorrhoea
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Hypermenorrhoea events were identified in EpiChron, and SIDIAP. No events were

identified in CPRD Aurum as there are no MedCodeld codes. As a limitation in this interim
report 5, the incidence rates and HRs were assessed in the overall population and not
restricted to only females in age groups considered to be of child-bearing potential. Pedianet
(restricted to a paediatric population) is not suitable for the assessment of
hypermenorrhoea.

In this report, the adjusted HR and the lower limits of the 95% CIs for hypermenorrhoea
within 183 days were above 1 in EpiChron with a HR of 1.60 (95% CI: 1.41, 1.83). The
cumulative incidence showed a divergence between vaccinated and unvaccinated from
around day 30 in EpiChron. This observed occurrence of a menstrual disorder event
beginning 30 days after vaccination seems too early to be biological plausible associated
with the vaccine and is being investigated further. The inclusion of biologically plausible lag
time in the risk window from start of follow up after vaccination is needed.

Recent publications suggest that menstrual problems have been observed following COVID-
19 vaccination but further longitudinal studies are needed to confirm the causal relationship
between COVID-19 vaccination and menstrual irregularities.[23-26] The definition used for
hypermenorrhoea was very specific, with very few codes in each dictionary. For instance,
only one ICD10 code -N92.1 (Excessive and frequent menstruation with irregular cycle) was
used for hypermenorrhoea. amenorrhoea This is an inconsistent finding since the higher risk
of hypermenorrhoea in the vaccinated cohort was only observed in EpiChron; this will be
further investigated and discussed in the final report.

11.1.5.12. Comparison of adjusted hazard ratios between interim reports 4 and 5

Higher adjusted HRs were observed in interim report 5 than in interim report 4 for acute
cardiovascular injury, including microangiopathy in NHR, PHARMO, EpiChron and SIDIAP
(Table 39). This is most likely to be due to an adaptation of the identification algorithm. In
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interim 4 this algorithm included stress cardiomyopathy, heart failure, coronary artery
disease, other thromboembolic venous events, and cardiogenic shock. In interim report 5
the algorithm included microangiopathy, acute myocardial infarction, stress cardiomyopathy,
heart failure, coronary artery disease, myocarditis, pericarditis, and arrhythmia. This
adaptation was based on the definition from the American College of Cardiology/American
Heart Association Task Force, stating that acute cardiovascular injury is an acute illness that
is physician-diagnosed as a cardiovascular injury. [21] Acute cardiovascular injury refers to a
broad spectrum of cardiac pathology including microangiopathy, heart failure, stress
cardiomyopathy, coronary artery disease, myocarditis, pericarditis and cardiac arrhythmias,
usually associated with abnormalities on ECG, echocardiography or cardiac MRI, and
elevated biochemical markers.”

The adjusted HRs for arrhythmia, heart failure, stress cardiomyopathy, coronary artery
disease, and myocarditis were similar for the interim reports 4 and 5 and are consistent
across all data sources.

Cerebral venous sinus thrombosis and glomerulonephritis included for the first time in this
interim report 5, so no comparisons with interim report 4 are possible.

No consistent differences in the adjusted HRs for Bell’s palsy between interim reports 4 and
5 were observed. More specific identification codes were used in the algorithm in PHARMO
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which may have led to the lower adjusted HR, but this is under investigation for the final
report.

No differences in the adjusted HRs for secondary amenorrhoea and between interim reports
4 and 5 were observed, except in EpiChron for secondary amenorrhoea and PHARMO for
hypermenorrhoea. The adjusted HR in interim report 4 for secondary amenorrhoea in
EpiChron was lower than that observed in SIDIAP and in interim report 5 the adjusted HR
was higher than in SIDIAP. The adjusted HR for hypermenorrhoea in PHARMO in interim
report 4 was higher than those observed in the other data sources, but in interim report 5 the
adjusted HR is similar to those seen in the other data sources. The case identification
algorithm that includes ICPC and ICD10 codes for these menstrual events will be further
refined for the final report.

Table 39. Comparison of adjusted hazard ratios in interim reports 4 and 5 for
selected AESIs
Interim report 4 Interim report 5
Acute cardiovascular injury including
microangiopathy
Pedianet NA 1.38 (0.73, 2.61)
NHR 0.94 (0.90, 0.98) 1.01 (0.99, 1.04)
PHARMO 1.20 (1.08, 1.33) 1.38 (1.31, 1.45)
EpiChron 0.91 (0.82, 1.00) 1.10 (1.03, 1.18)
SIDIAP 0.93 (0.89, 0.99) 0.99 (0.96, 1.03)
CPRD Aurum NA 1.23 (1.18, 1.27)
Arrhythmia
Pedianet 1.73 (0.79, 3.78) 1.75 (0.88, 3.49)
NHR 1.04 (1.00, 1.07) 1.03 (1.00, 1.05)

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Table 39. Comparison of adjusted hazard ratios in interim reports 4 and 5 for
selected AESIs
Interim report 4 Interim report 5
PHARMO 1.28 (1.19, 1.38) 1.36 (1.29, 1.44)
EpiChron 1.07 (0.98, 1.17) 1.12 (1.04, 1.21)
SIDIAP 1.02 (0.98, 1.06) 0.99 (0.96, 1.03)
CPRD Aurum NA 1.27 (1.21, 1.33)
Heart failure
Pedianet NA NA
NHR 0.80 (0.75, 0.85) 0.77 (0.73, 0.82)
PHARMO 1.13 (0.97, 1.31) 1.29 (1.13, 1.47)
EpiChron 0.88 (0.78, 0.99) 0.90 (0.80, 1.01)
SIDIAP 0.87 (0.81, 0.93) 0.89 (0.82, 0.96)
CPRD Aurum NA 1.02 (0.95, 1.09)
Stress cardiomyopathy
Pedianet NA NA
NHR NA 0.69 (0.18, 2.67)
PHARMO 1.34 (0.23, 7.82) 1.49 (0.33, 6.69)
EpiChron 3.12 (0.38, 25.82) 0.85 (0.21, 3.47)
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SIDIAP 1.55 (0.82, 2.91) 1.51 (0.75, 3.04)

CPRD Aurum NA NA
Coronary artery disease
Pedianet NA NA
NHR 0.99 (0.94, 1.05) 0.99 (0.94, 1.04)
PHARMO 1.36 (1.15, 1.60) 1.49 (1.31, 1.69)
EpiChron 0.84 (0.69, 1.02) 0.97 (0.80, 1.17)
SIDIAP 1.06 (0.97, 1.16) 1.00 (0.91, 1.10)
CPRD Aurum NA 1.40 (1.30, 1.50)
Myocarditis (21 days)
Pedianet NA 0
NHR 0.91 (0.35, 2.38) 0.94 (0.46, 1.94)
PHARMO NA 1.23 (0.13, 11.84)
EpiChron 2.82 (0.29, 27.15) 3.64 (0.41, 32.53)
SIDIAP 2.71 (0.71, 10.30) 1.05 (0.35, 3.16)
CPRD Aurum NA 2.30 (0.94, 5.66)
Cerebral venous sinus thrombosis
Pedianet NA 0
NHR NA 0.63 (0.23, 1.74)
PHARMO NA NA
EpiChron NA 0.90 (0.06, 14.09)
SIDIAP NA 0.68 (0.11, 4.20)
CPRD Aurum NA 0.43 (0.14, 1.27)
Glomerulonephritis
Pedianet NA 0
NHR NA NA
PHARMO NA NA

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Table 39. Comparison of adjusted hazard ratios in interim reports 4 and 5 for
selected AESIs
Interim report 4 Interim report 5
EpiChron NA 0.59 (0.22, 1.55)
SIDIAP NA 1.29 (0.88, 1.87)
CPRD Aurum NA 0.88 (0.67, 1.16)
Bell's palsy
Pedianet NA 0
NHR 1.01 (0.76, 1.35) 1.15 (0.88, 1.50)
PHARMO 3.08 (1.24, 7.62) 0.65 (0.28, 1.51)
EpiChron 0.89 (0.40, 2.00) 0.84 (0.34, 2.09)
SIDIAP 0.91 (0.71, 1.16) 0.96 (0.75, 1.24)
CPRD Aurum NA 0.99 (0.75, 1.29)
Secondary amenorrhoea
Pedianet 1.78 (0.16, 19.84) NA
NHR NA 0.91 (0.69, 1.21)
PHARMO NA 0.77 (0.05, 11.99)
EpiChron 0.34 (0.07, 1.76) 1.71 (1.34, 2.18)
SIDIAP 1.07 (0.99, 1.16) 0.99 (0.91, 1.07)
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CPRD Aurum NA 1.24 (1.17, 1.30)

Hypermenorrhoea
Pedianet 0.33 (0.08, 1.42) 0.62 (0.08, 4.66)
NHR NA NA
PHARMO 6.62 (0.80, 54.62) 1.18 (0.31, 4.47)
EpiChron 1.38 (1.21, 1.57) 1.40 (1.23, 1.60)
SIDIAP 1.09 (1.03, 1.16) 1.02 (0.95, 1.09)
CPRD Aurum NA NA
NA: not available

11.2. Limitations
Vaccination data and coverage were consistent with ECDC coverage data in Pedianet and
EpiChron, SIDIAP (https://vaccinetracker.ecdc.europa.eu/public/extensions/covid-
19/vaccine-tracker.html#uptake-tab). Information on the COVID-19 vaccine brand was
considerably missing in NHR. Data from PHARMO showed lower than expected estimates
of vaccine uptake, they are improving.

The contributing data sources, differed in the point of care from where they sampled their
populations (GP, emergency visits, hospital discharge data bases) which could have an
impact on the estimates for the incidence rates as shown in a recent study.[19]

Pedianet is a paediatric general practice research database, that includes children until the
age of 14, after which they are transferred to general practitioners. Vaccination of children
started later in 2021, which is reflected by the different calendar time of first vaccination.
AESIs were based on diagnoses in the paediatricians’ records, which may include
information from hospitalisation when it is reported back to them. However, this reporting
may not be complete, which is why Pedianet could not contribute data for all AESIs.

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In PHARMO, data on COVID-19 vaccinations were entered in the GP medical record

through various routes, including directly by the GPs who administered the vaccine or
occasionally by manual linkage of information from a nationwide vaccination registry (CIMS)
maintained by public health institutes, for individuals vaccinated at a public health institute.
Registering vaccines administered at public health institutes in the GP EHR was not
mandatory. Additionally, the requirements for the supply chain for the Pfizer-BioNTech
COVID-19 vaccine such as refrigeration made it unsuitable for use in GP practices.
Together, these factors could have resulted in underestimated numbers of individuals
vaccinated with the Pfizer-BioNTech COVID-19 vaccine, or in duplicate entries. Throughout
the duration of this study the registration of vaccination improved in the GP EHR, possibly
due to delays in GPs obtaining nationwide vaccination registry data, or delayed entry into
the EHR, if any central information was obtained at all. Correspondingly, vaccine uptake
rates for the Netherlands are more in line with national data. A direct link between the
PHARMO Data Network with the nationwide vaccination registry in the Netherlands could
not be established.

Data from NHR were available up to the end of 2022. Since the previous interim reports,
NHR have continuously updated previously missing COVID-19 vaccine brand information.
Additionally, hospital event information has been included, in addition to the primary care
data. Previously, events were not identified with full ICD10 codes. Full ICD10 codes are now
available with the new data extraction conducted in 2023 and are included in this fifth interim
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report. However, the KUHR GP data source only has a maximum of 4 digits for ICPC2
codes because more detailed digits are not used in this data source. This could lead to less
specific identification of events resulting in higher event counts and incident rates from
Norway for events identified mainly in the GP setting using ICPC2 codes.

Risk differences were provided without an estimation of their precision which is a limitation.
Bootstrapping methods for the calculation of the risk difference are being tested and will be
implemented in future analysis.

The missing data for death (any cause) in SIDIAP are under investigation and will be
corrected in the next draft of this fifth interim report.

As stated previously in the discussion section, further investigations into diagnostic codes
and case definitions, differential baseline characteristics in unvaccinated individuals,
compared with vaccinated individuals, at longer follow time points, differential healthcare
seeking patterns and adherence, (i.e., cardiovascular acute injury, arrhythmia,
glomerulonephritis, secondary amenorrhoea, and hypermenorrhoea) will be undertaken and
the findings will be discussed in the final report.

Definition of AESIs

AESIs were identified through diagnostic codes, which can be tagged as narrow (specific)
and possible (sensitive). In this fifth interim report, we used only narrow (specific) codes. For
the final comparative analyses, AESIs cases will be validated. The provenance of the
diagnostic codes also differs. In Pedianet and partly in PHARMO, where only a minority of
the study population had linked hospital data, AESIs were coded in primary care. Patients
with severe events may not have consulted their GP, or, if they did, the GP may not have
included the codes for the final diagnoses that were determined in the hospital setting. Also,
feedback from hospital records into the GP record may not be complete, or easily accessible
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in the GP databases. This could be the reason why rates are lower for some rare events
that require hospitalisation in these data sources. SIDIAP and EpiChron contain inpatient
and outpatient diagnoses. The NHR results are based on primary care (GP), hospital and
outpatient specialist data. Registers, codes and PCR testing were used for COVID-19
diagnoses and tests. PHARMO and Pedianet used additional free text searching for COVID-
19 as well as for other events. CPRD Aurum used only primary care coded records.

11.3. Interpretation
These analyses were performed on data from more than 12 million individuals who had
received at least one dose of the Pfizer-BioNTech COVID-19 vaccine (vaccinated cohorts)
and from an equal number of matched unvaccinated individuals (unvaccinated cohorts). The
matching was successful, both in terms of the identification of an appropriately matched pair
as well as minimised confounding. In this fifth interim report, follow-up has been extended
which has had a positive impact on the detection of AESIs, particularly for those with longer
risk windows.

11.4. Generalisability
The distribution of age and sex of the data source populations were compatible with the
national statistics in each country. The study population for this fifth interim report included a
large percentage of all individuals who received the Pfizer-BioNTech COVID-19 vaccine, in
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the setting of vaccination programmes that began with elderly and frail individuals in very
late 2020 and early 2021 and expanded to younger, healthier individuals later in 2021. This
report includes all individuals.

12. OTHER INFORMATION

Not Applicable.

13. CONCLUSIONS
The results in this fifth interim report describe the characteristics and incidence rates for the
37 AESIs (Table 16) in more than 12 million vaccinated individuals and 12 million matched
unvaccinated controls.

The data were analysed by data source and were not pooled in this report. The incidence
rates of AESIs were generally very low in the risk intervals studied and were comparable
with available published background incidence rates from previous studies in unvaccinated
cohorts.

Among the 11 AESIs that were highlighted for further discussion, the divergence in
cumulative incidence observed for several of the cardiovascular events with long risk
windows (eg. 365 days) resulted in small increases in risk in some of the data sources.
These increases could be explained by a number of factors. Some of these events have
presented with mild symptoms that did not require immediate medical attention, and
vaccinated individuals may have sought medical attention more frequently than those who
were unvaccinated (healthy vaccinee effect). Another plausible explanation is differences in
the composition of the unvaccinated cohort as follow-up progresses. Unvaccinated
individuals were censored in the unvaccinated cohort if they were vaccinated and were then
followed up in the vaccinated cohort from that time point. Hence, the individuals who
remained in the unvaccinated cohort were those who were never vaccinated and who were
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possibly less likely seek medical attention at all if it was not urgently needed. These
differences may have been minimal earlier in follow-up, but may have become more
pronounced as follow-up progressed.

Results for CVST, Bell’s Palsy and glomerulonephritis all showed no evidence of an
increased risk in the vaccinated cohort based on adjusted HRs. Adjusted HRs for secondary
amenorrhea were slightly elevated in EpiChron and CPRD Aurum. For hypermenorhea,
only the adjusted HR in Epichron was slightly elevated. These events, along with the
cardiovascular events described above, will continue to be monitored and further refined for
inclusion in the final study report.
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[26] Nazir M, Asghar S, Rathore MA, Shahzad A, Shahid A, Ashraf Khan A, et al.
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15. LIST OF SOURCE TABLES AND FIGURES

Not applicable.
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4.1(b) 4.1(b) 4.1(b)

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