019736 S596 M5 5354 c4591014 protocol amendment2 track

Document text

BNT162b2 
C4591014 NON -INTERVENTIONAL STUDY PROTOCOL
Version 2.0, 01Oct 3 01 D ecember 2021
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 2.0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
15-Aug-2018
Page 1 of 48NON -INTER VENTIONAL  (NI) STUDY  PROT OCOL
This document contains confidential information belonging to Pfizer.  Except as otherw ise agreed to in w rit-
ing, 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 obligatio n, Pfizer must be promptly notified.
090177e198c0ac48\Approved\Approved On: 02-Dec-2021 13:28 (GMT)
FDA-CBER-2022-5812-0236110
BNT162b2 
C4591014 NON -INTERVENTIONAL STUDY PROTOCOL
Version 2.0, 01Oct 3 01 D ecember 2021
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 2 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
15-Aug-2018
Page 2of 48Study information
Title Pfizer-BioNTech COVID -19 BNT162b2 Vac-
cine Effectiveness Study -Kaiser Perma-
nente Southern California 
Protocol number C4591014
Protocol version identifier Version 1.02.0
Date 22 March 24 May 3 01 December 2021
Research question and objectives The primary  objective of this study  is to esti-
mate vaccine effectiveness (VE) of 2 -doses 
of Pfizer’s BNT162b2 (fully  vaccinated) 
against acute respiratory  illness requiring 
hospitalization due to SARS -CoV -2 infec-
tion among KPSC members eligible for vac-
cination16 12 years of age .  Secondary  
and exploratory  objectives will examine VE 
for 1 dose vaccination, at least 1 dose, more 
than 2 dose sas well as against emergency  
department ( ED) admission, specific variants 
and other populations of interest. 
To assess vaccine effectiveness (VE), we 
propose a large retrospective database stud y 
using two parallel study  designs:  a test -neg-
ative case -control design and a retrospective 
cohort design .  We will conduct additional
analyses of VE estimates by  various patient 
characteristicsstrata and strain ty pe. 
Author Sara Y. Tartof, PhD MPH
Kaiser Permanente Southern California De-
partment of Research & Evaluation
[email protected]
(626)564 -3001
Heidi Fischer, PhD MS
Kaiser Permanente Southern California De-
partment of Research & Evaluation
[email protected]
(626)564 -3290
Jeff Slezak, MS
090177e198c0ac48\Approved\Approved On: 02-Dec-2021 13:28 (GMT)
FDA-CBER-2022-5812-0236111
BNT162b2 
C4591014 NON -INTERVENTIONAL STUDY PROTOCOL
Version 2.0, 01Oct 3 01 D ecember 2021
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 2 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
15-Aug-2018
Page 3of 48Kaiser Permanente Southern California De-
partment of Research & Evaluation
[email protected]
(626)564 -3477
John M. McLaughlin, PhD
Pfizer Vaccines
Medical Development and Scientific/Clini-
cal Aff airs
[email protected]
Fred Angulo, DVM PhD
Laura Puzniak, PhD, MPH
Pfizer Vaccines
Medical Development and Scientific/Clini-
cal Affairs
[email protected]
090177e198c0ac48\Approved\Approved On: 02-Dec-2021 13:28 (GMT)
FDA-CBER-2022-5812-0236112
BNT162b2 
C4591014 NON -INTERVENTIONAL STUDY PROTOCOL
Version 2.0, 01Oct 3 01 D ecember 2021
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 2 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
15-Aug-2018
Page 4of 481.TABLE OF CONTENTS
1. TABLE OF CONTENTS ................................ ................................ ................................ .......4
2. LIST OF ABBREVIAT IONS ................................ ................................ ................................ 6
3. RESPONSIBLE PARTI ES................................ ................................ ................................ ....8
4. ABSTRACT ................................ ................................ ................................ ........................... 8
5. AMENDMENTS AND UP DATES ................................ ................................ ..................... 10
6. MILESTONES ................................ ................................ ................................ ..................... 13
7. RATIONALE AND BAC KGROUND ................................ ................................ ................ 14
8. RESEARCH QUESTION AND OBJECTI VES ................................ ................................ .15
9. RESEARCH METHODS ................................ ................................ ................................ ....20
9.1. Research Setting ................................ ................................ ................................ ......20
9.2. Study  design ................................ ................................ ................................ ............ 22
9.2.1. I nclusion criteria ................................ ................................ ......................... 23
9.2.2. Exclusion criteria ................................ ................................ ........................ 24
9.3. Variables ................................ ................................ ................................ .................. 24
9.3.1. Test Negative Design Outcomes and Exposures ................................ ........ 24
9.3.2. Full Cohort Design Outcome and Exposures ................................ ............. 25
9.3.3. Test -Negative and Full Cohort Designs –Outside Vaccinati ons ............... 27
9.3.4. Test -Negative and Full Cohort Designs -Covariates ................................ .28
9.4. Data sources ................................ ................................ ................................ ............ 28
9.5. Study  size ................................ ................................ ................................ ................ 29
9.6. Data management ................................ ................................ ................................ ....34
9.6.1. Electronic data records ................................ ................................ ............... 34
9.6.2. Record retention ................................ ................................ .......................... 34
9.7. Data analy sis................................ ................................ ................................ ........... 35
9.7.1. Test Ne gative Design Analyses ................................ ................................ ..35
9.7.1.1. Descriptive Analyses ................................ ................................ .35
9.7.1.2. Estimated Crude (Unadjusted) VE ................................ ............ 35
9.7.1.3. Estimating Adjusted VE ................................ ............................ 36
9.7.1.4. Sensitivity  Analyses ................................ ................................ ..36
090177e198c0ac48\Approved\Approved On: 02-Dec-2021 13:28 (GMT)
FDA-CBER-2022-5812-0236113
BNT162b2 
C4591014 NON -INTERVENTIONAL STUDY PROTOCOL
Version 2.0, 01Oct 3 01 D ecember 2021
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 2 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
15-Aug-2018
Page 5of 489.7.1.5. Exploratory  analy ses estimating VE for health care 
workers and other high risk populations ................................ ........... 37
9.7.2. Full Cohort Design Analy ses................................ ................................ ......38
9.7.2.1. Descriptive Analyses ................................ ................................ .38
9.7.2.2. Estimated Crude (Unadjusted) VE ................................ ............ 39
9.7.2.3. Estimating Adjusted VE ................................ ............................ 39
9.7.2.4. Sensitivity  Analyses ................................ ................................ ..39
9.7.2.5. Exploratory  analy ses estimating VE for health care 
workers and other high risk populations ................................ ........... 39
9.7.3. Additional Analy tic Elements for Test Negative and Full Cohort 
Design ................................ ................................ ................................ .............. 40
9.8. Quality  control ................................ ................................ ................................ ......... 41
9.9. L imitations of the research m ethods ................................ ................................ .......42
9.10. Other aspects ................................ ................................ ................................ ......... 42
10. PROTECTI ON OF HU MAN SUBJECTS ................................ ................................ ........ 43
10.1. Patient information................................ ................................ ................................ 43
10.2. Patient consent ................................ ................................ ................................ .......43
10.3. I nstitutional Re view Board (IRB)/Independent Ethics Committee (I EC)............ 43
10.4. Ethical conduct of the study ................................ ................................ .................. 43
11. MANAGEMENT AND R EPORTI NG OF ADVERSE EVENTS/ADVERSE 
REACTI ONS ................................ ................................ ................................ ...................... 44
12. PL ANS FOR DI SSEM INATING AND COMMUNI CATING STUDY RESUL TS........ 44
13. REFERENCES ................................ ................................ ................................ .................. 45
14. LIST OF TABLES ................................ ................................ ................................ ............. 46
15. LIST OF FIGURES ................................ ................................ ................................ ........... 46
16. ANNEX 1. L IST OF STAND ALONE D OCUMENTS ................................ ................... 46
17. ANNEX 2. ADDITIO NAL INFORMATION ................................ ................................ ...46
090177e198c0ac48\Approved\Approved On: 02-Dec-2021 13:28 (GMT)
FDA-CBER-2022-5812-0236114
BNT162b2 
C4591014 NON -INTERVENTIONAL STUDY PROTOCOL
Version 2.0, 01Oct 3 01 D ecember 2021
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 2 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
15-Aug-2018
Page 6of 482. LIST OF ABBREVIATIONS
Abbreviation Definition
AE adverse event
ARI Acute Respiratory  Infection
BMI body  mass index
CAIR California Immunization Registry
CHIP Children’s Health Insurance Program
CI confidence interval
CLIA Clinical L aboratory  Improvement Amendments of 
1988
COPD Chronic Obstructive Pulmonary  Disease
COVID -19 coronavirus Disease 2019
CSR Clinical Study  Report
ED emergency  department
EHR electronic health record 
EUA Emergency  Use Authorization
FDA United States Foo d and Drug Administration
GEE generalized estimating equations
HCW health care worker
HR hazard ratio
ICD International Classification of Diseases
ICMJE International Committee of Medical Journal Editors
ICU Intensive Care Unit
IEC Independent Ethics Committee
IRB Institutional Review Board
KP Kaiser Permanente
KPSC Kaiser Permanente Southern California
LOS length of stay
LTCF long term care facility
mRNA modified ribonucleic acid
NI Non-interventional
NIS non-interventional study
NLP Natural Language Processing
OR odds ratio
PCR polymerase chain reaction
PHI protected health information
RSV Respiratory  Syncytial Virus
RT-PCR Reverse Transcriptase Pol ymerase Chain Reaction
SAE serious adverse event
SAP Statistical Analy sis Plan
SARS -CoV -2 Severe Acute Respiratory S yndrome Coronavirus 2
090177e198c0ac48\Approved\Approved On: 02-Dec-2021 13:28 (GMT)
FDA-CBER-2022-5812-0236115
BNT162b2 
C4591014 NON -INTERVENTIONAL STUDY PROTOCOL
Version 2.0, 01Oct 3 01 D ecember 2021
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 2 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
15-Aug-2018
Page 7of 48Abbreviation Definition
SAS Statistical Analy sis Software
SDIR San Diego Immunization Registry
SOC Standard of Care
TND test-negative design
US United States
VE vaccine effectiveness
WGS whole genome sequencing
090177e198c0ac48\Approved\Approved On: 02-Dec-2021 13:28 (GMT)
FDA-CBER-2022-5812-0236116
BNT162b2 
C4591014 NON -INTERVENTIONAL STUDY PROTOCOL
Version 2.0, 01Oct 3 01 D ecember 2021
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 2 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
15-Aug-2018
Page 8of 483.RESPONSIBLE PARTIES
Principal Investigator(s) of the Protocol
Nam e, degree(s) Job Title Affiliation Address
Sara Y. Tartof, PhD, 
MPHResearch Scientist Department of Research 
and Evaluation
Kaiser Permanente,
Southern California100 South Los Robles, 
2nd Floor
Pasadena, CA 91101 
USA
Heidi Fischer, PhD, MS Research Scientist Bio-
statisticianDepartment of Research 
and Evaluation
Kaiser Permanente, 
Southern California100 South Los Robles, 
6th Floor
Pasadena, CA 91101 
USA
Jeff Slezak, MS Research Scientist Bio-
statisticianDepartment of Research 
and Evaluation
Kaiser Permanente, 
Southern California100 South Los Robles, 
6th Floor
Pasadena, CA 91101 
USA
Fred Angulo, DVM 
PhDLaura Puzniak, PhD, 
MPHEpidemiologist Medical Development 
and Scientific/Clinical 
Affairs, Pfizer Vaccines500 Arcola Rd, Col-
legeville, PA 19426
USA
John McLaughlin, PhD Epidemiologist Medical Development 
and Scientific/Clinical 
Affairs, Pfizer Vaccines500 Arcola Rd., Col-
legeville, PA 19426
USA
4.ABSTRACT
BNT162b2 is a modified RNA (mRNA) vaccine administered as 2 doses 21 day s apart that 
encodes the full -length, membrane -anchored S gly coprotein of SARS -CoV -2 with two intro-
duced proline mutations to lock it in the prefusion conformation. It w as co -developed b y Bi-
oNTech SE and Pfizer, Inc. The vaccine showed an acceptable safet y profile in a Phase 1/2 
study1and was tolerable and demonstrated a 95% clinical efficacy  >7 day s after the second 
dose against COVID -19 in persons without current or prior SARS- CoV -2 infection in a 
Phase 3 trial2. Pfizer -BioNTech COVID -19 Vaccine is approved authorized for use under an 
Emergency  Use Authorization (EUA) for active immunization to prevent coron avirus disease 
2019 (COVID -19) caused by  severe acute respiratory  syndrome coronavirus 2 (SARS -CoV -
2) in individuals 1616 12years of age and older , authorized for use under an Emergency  Use 
Authorization (EUA) for individuals 5- 15 and for booster dose for individuals 18 and over. .
Data confirming the effectiveness of the vaccine outside of the clinical setting are needed.
The primary  objective of this study  is to estimate the vaccine effectiveness (VE) of 2 -doses 
of Pfizer’s BNT162b2 (fully  vaccinated) vaccine against acute respiratory  illness requiring 
hospitalization due to SARS -CoV -2 infection among KPSC members eligible for vaccination
16 years of age . Secondary  and exploratory  objectives will may examine VE for 1 dose 
vaccination, at least 1 dose, > 2 doses , as well as against emergency  department (ED) admis-
sion, specific variants , mixed dosing schedules, durability , age cutoffs to align with regula-
tory authorizations/approvals and other population s of interest. 
090177e198c0ac48\Approved\Approved On: 02-Dec-2021 13:28 (GMT)
FDA-CBER-2022-5812-0236117
BNT162b2 
C4591014 NON -INTERVENTIONAL STUDY PROTOCOL
Version 2.0, 01Oct 3 01 D ecember 2021
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 2 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
15-Aug-2018
Page 9of 48To assess VE, we propose a large retrospective database stud y using two parallel stud y de-
signs:  a test -negative case -control design and a retrospective cohort design.  The test- nega-
tive design (TND) will assess VE against COVID -19 hospital ization (primary endpoint) and 
EDadmission. The retrospective cohort anal ysis will may assess VE against COVID -19 hos-
pitalization (primary ), intensive care unit ( ICU)admission, death, ED admission, and outpa-
tient disease (with no subsequent hospitalization within 14 day s). We will may further con-
duct additional analyses of VE estimates by  various patient characteristics and strain ty pe. 
This study  will be conducted at Kaiser Permanente Southern California (KPSC), an inte-
grated health care organization comprising one of the largest health insurance plans in the 
United States ( US), a hospital sy stem, and >7,600 phy sicians and 27,000 nurses located 
throughout 9 counties of Southern California. For the TND, the stud y population will include 
all KPSC patients 16 years or older eligible for vaccination who are admitted to the hospital 
or present to the ED with acute respiratory  infection (ARI) after 14 December 2020 (date of 
first vaccinations at KPSC), and who receive a polymerase chain reaction ( PCR) test for 
SARS -CoV -2. For the Full Cohort Design, the study  population will include all KPSC mem-
bers as of 14 December 2020 (date of first Pfizer vaccination at KPSC) eligible for vaccina-
tion.aged 16 and older.  
Vaccine exposure for both study  designs include theinitial 2 -dose series fully  vaccinated ,de-
fined as 2 doses of BNT162b2 received with ≥7 day s between receipt of the 2nddose and the 
event date (e.g., admission) ;partially  vaccinated ,defined as 1 dose (onl y) of BNT162b2 re-
ceived with ≥14 day s between the receipt of the 1stdose and the event date; and ever vac-
cinated, defined as ≥1dose of BNT162b2 received with ≥14days between the receipt of the 
1stdose and the event date and >2 doses, defined as >2 doses of BNT162b2 received with 
≥14 days between receipt of the lastdose(s) and the event date (e.g., admission) . The unex-
posed group will include individuals with no record of COVID- 19 vaccination at the time of 
the event and will serve as the reference group in all most VE analy ses. An additional com-
parison will may be made among thos e individuals receiving a 2 -dose series compared to >2
doses or mixed dosing schedules. All data will be collected from KPSC electronic health rec-
ords (EHRs) .
090177e198c0ac48\Approved\Approved On: 02-Dec-2021 13:28 (GMT)
FDA-CBER-2022-5812-0236118
BNT162b2 
C4591014 NON -INTERVENTIONAL STUDY PROTOCOL
Version 2.0, 01Oct 3 01 D ecember 2021
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 2 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
15-Aug-2018
Page 10of 485.AMENDMENTS AND UPDAT ES
Amendment 1:  
1.Due to approval of BNT 162b2 granted b y the United States Food and Drug Admin-
istration ( FDA ) on 23 August 2021, the protocol amendment reflects updated registra-
tion language.
2.Due to EUA for ages 12 -15 granted b y the FDA on 10 May 2021 and for 5 -11 on 11 
Novembe r 2021 and the potential for additional authorizations related to age , the pro-
tocol amendment reflects inclusion of all KP SC members meeting vaccination eligi-
bility  to allow anal ysesbased on evolving age requirements .
3.Due to EUA for a booster dose of BNT162b2 among individuals over 18, the protocol 
amendment reflects inclusion of anal yses for vaccine effectiveness among individual 
with greater than 2 doses of BNT162b2 and deletes reference to being “fully vac-
cinated” with a two dose series due to the evolving evidence regarding schedules, par-
ticularly  among those with immunocompromising conditions.
4.Due to EUA of heterologous booster dosing, the protocol widened inclusion criteria 
to individuals receiving any  dose of BNT162b2 in their vaccination series, however 
BNT162b2 onl y vaccination series will be used to meet the regulatory  requirement 
objectives. 
5. Due to FDA request, methods were updated to delete automated model creation and 
the inclusion of all measured covariates in the development of adjusted models.
6. Due to FDA request, milestones associated with regulatory  requirements were final-
ized and updated in the protocol.
Amendment 
numberDate Protocol      
section(s) 
changedSummary of            
amendment(s)Reason
1 31December 
30Nov2021Section 6 Update milestones 
and timeframe for 
completionAlignment with regula-
tory commitment
Section 7 Update authoriza-
tion and approvals 
of BNT162b2Alignment with evolv-
ing regulatory  authori-
zations and approvals 
over time
090177e198c0ac48\Approved\Approved On: 02-Dec-2021 13:28 (GMT)
FDA-CBER-2022-5812-0236119
BNT162b2 
C4591014 NON -INTERVENTIONAL STUDY PROTOCOL
Version 2.0, 01Oct 3 01 D ecember 2021
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 2 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
15-Aug-2018
Page 11of 48Amendment 
numberDate Protocol      
section(s) 
changedSummary of            
amendment(s)Reason
Section 7, 
8, 9Expanded age in-
clusion to 
BNT162b2 vac-
cine eligibleEligibility  updated 
based on regulatory  au-
thorizations and ap-
provals over time
Section 7, 
8, 9Inclusion of objec-
tives and anal yses 
to assess VE 
among individuals 
receiving >2 dosesAllow VE evaluations  
of additional doses in 
accordance with regu-
latory authorization and 
approvals and include 
comparison to individ-
uals receiving 2doses.
Section 9 Updating exclu-
sion criteria to in-
dividuals only  re-
ceiving another 
COVID -19 vac-
cineAllow heterologous 
vaccination analy ses 
that includes 
BNT162b2 within the 
study  population
Section 9 Updated censoring 
description in co-
hort anal ysisThe time periods ini-
tially  mentioned as be-
ing censored are inher-
ently  included in the 
separate vaccine expo-
sure categories.
Section 9 Extended length of 
membership in 
KPSC to 1 y ear 
from 6 months Updated in cohort de-
sign to allow accurate 
classification of comor-
bid conditions
Section 9 Updated control 
definition to in-
clude same 
timeframe for 
identification as 
casesRequest from regul a-
tory authority  to assure 
time frame for cases 
and controls equivalent
090177e198c0ac48\Approved\Approved On: 02-Dec-2021 13:28 (GMT)
FDA-CBER-2022-5812-0236120
BNT162b2 
C4591014 NON -INTERVENTIONAL STUDY PROTOCOL
Version 2.0, 01Oct 3 01 D ecember 2021
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 2 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
15-Aug-2018
Page 12of 48Amendment 
numberDate Protocol      
section(s) 
changedSummary of            
amendment(s)Reason
Section 9 Updated levels of 
exposure: took out 
reference to “full y 
vaccinated” asso-
ciated with two 
dose series, added 
>2 doses as expo-
sure, added mixed 
dosing and up-
dated definition of 
“not vaccinated”Due to the recommen-
dation for an additional 
dose among immuno-
compromised popula-
tion, refere nce to “full y 
vaccinated” is evolving 
and updated to broaden 
the definition. Due to 
updated authorizations 
for both boosters and 
heterologous dosing, 
exposure categories 
were updated. Clarifi-
cation of the compari-
son group, which was 
initially  categorized a s 
“not vaccinated” was 
updated to “unvac-
cinated” to clarify  that 
person and person time 
included is in relation 
to index event date.   
1 31Dec21
30Nov2021Section 9 Updated method-
ology  for anal yses In response to regula-
tory request, eliminated 
backwards stepwise re-
gression as methodol-
ogy to select variables 
and added updated co-
variateselection meth-
odology  and methods
090177e198c0ac48\Approved\Approved On: 02-Dec-2021 13:28 (GMT)
FDA-CBER-2022-5812-0236121
BNT162b2 
C4591014 NON -INTERVENTIONAL STUDY PROTOCOL
Version 2.0, 01Oct 3 01 D ecember 2021
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 2 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
15-Aug-2018
Page 13of 486.MILESTONES
Milestone Planned date
Start of data collection 01April15 May 2021
Final SAP 3110December2021 27 May 
2021
Interim Data Anal ysis/Report 1 30 June 2021
Final Study  Report on Primary  Data Collection 30 July  2022
Secondary and exploratory  data collection 30 July  2023
Final Clinical Study  Report (CSR) Submission June 2023 01 January 2024
Submit Manuscript for Publication 15 March 2024
090177e198c0ac48\Approved\Approved On: 02-Dec-2021 13:28 (GMT)
FDA-CBER-2022-5812-0236122
BNT162b2 
C4591014 NON -INTERVENTIONAL STUDY PROTOCOL
Version 2.0, 01Oct 3 01 D ecember 2021
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 2 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
15-Aug-2018
Page 14of 487.RATIONALE AND BACKGR OUND
The outbreak of the 2019 novel coronavirus disease (COVID -19), which is caused b y severe 
acute respiratory  syndrome -related coronavirus 2 (SARS -CoV -2), is still apandemic threat to 
global public health. Although the epicenter of the COVID -19 outbreak in December of 2019 
was in Wuhan, China, the World Health Organization reports over 259 million confirmed 
casas and over 5 million deaths glob ally as of November 26, 2021. the disease has spread to 
more than 200 countries with more than 117million confirmed cases and 2. 6million con
firmed deaths worldwide as of 09 March 2019 . In addition, essentially  every one’s lives have 
been affected as a result of mandatory  isolation and quarantine measures. The ripple effect of 
the COVID -19 outbreak has brought major challenges to health sy stems across the world and 
has had far -reaching impacts on the global economy . So far, public health experts have 
largely only been able to employ  nonpharmaceutical intervention strategies to mitigate and 
control the spread of the virus. Now that safe and effective vaccines areavailable, further 
evaluation of their effectiveness outside of the clinical trial setting are needed following their 
introduction into the general population.
BNT162b2 is a modified RNA vaccine recommended as 2 doses 21 day s apart that encodes 
the full -length, membrane -anchored S gl ycoprotein of SARS -CoV -2 with two introduced 
proline mutations to lock it in the prefusion conformation. It was co- developed by  BioNTech 
SE and Pfizer, I nc. The vaccine showed an acceptable safety profile in a Phase 1/2 study1. In 
a Phase 3 trial, the vaccine was tolerable and demonstrated 95% efficacy  >7 day s after sec-
ond dose against COVID -19 in persons without current or prior SARS- CoV -2 infection2.
The vaccine is currentl y authorized approved for used  u nder an Emergency  Use Authoriza
tion (EUA) by the FDA for active immunization to prevent coronavirus disease 2019 
(COVID -19) caused b y severe acute respiratory  syndrome coronavirus 2 ( SARS -CoV -2)in 
individuals 16 12 years of age and older (updated with the 12 15 age group per agreement 
with the agencies 10Ma y2021 )and authorized for use among persons aged 5- 11 and for an 
additional dose (bey ond initial 2 -dose series) under an EUA for active immunization to pre-
vent coronavirus disease 2019 (COVID -19) caused by  SARS -CoV -2 among individuals with 
immunocompromising or select high risk conditions. and older and Ddata confirming the ef-
fectiveness of the vaccine outside of the clinical setting are needed .
As such, this study  will be conducted in Kaiser Permanente Southern California (KPSC) , a 
large inte grated healthcare organization with over 4.7 million members who comprise a soci-
oeconomicall y dive rse and broadly  representative population that reflects of the racial/ethnic 
groups living in Southern California. As of 23 February  2021 , KPSC has had over 4 41,000 
COVID -19 cases and approximately  29,000 confirmed patients admitted to the hospital and 
has vaccinated more than 311,000 individuals. KPSC has 2 Regional Laboratories that pro-
cess COVID -19 and other specimens. The central reference laboratories rece ive more than 
50,000 specimens per day  from the local laboratories and perform over 29 million tests annu-
ally. All laboratories undergo routine qualit y checks to meet or surpass accrediting bod y 
specifications.
090177e198c0ac48\Approved\Approved On: 02-Dec-2021 13:28 (GMT)
FDA-CBER-2022-5812-0236123
BNT162b2 
C4591014 NON -INTERVENTIONAL STUDY PROTOCOL
Version 2.0, 01Oct 3 01 D ecember 2021
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 2 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
15-Aug-2018
Page 15of 488.RESEARCH QUESTION AN D OBJECTIVES
The primar y objective of the study  is to estimate vaccine effectiveness (VE) of 2 doses of 
Pfizer’s BNT162b2 vaccine (i.e., fully vaccinated) against acute respiratory  illness (ARI) re-
quiring hospitalization due to SARS -CoV -2 infection among KPSC members eligible fo r vac-
cination16 years of age .VE will be evaluated using a test -negative design (TND), including 
all KPSC patients 16  or older eligible for vaccination who are admitted to the hospital with
acute respiratory  infection (ARI ) after 14 December 2020 (date of first vaccinations at KPSC), 
and who receive a PCR test for SARS -CoV -2.Secondary  and exploratory  objectives will may 
examine VE for 1 dose vaccination, at least 1 dose, >2 dose sas well as against ED admission, 
specific variants ,mixed dosing schedules , durability , age cutoffs to align with regulatory  au-
thorizations/ approvals and other populations of interest. Additionally, we will estimate VE us-
ing a full cohort design, including all KPSC members eligible for vaccination 16 years or older . 
Table 1and Table 2outline all primary , secondary  and exploratory  objectives for the current 
study  for the TND and full cohort designs, respectively . Additional sensitivity  analyses are not 
described below, but rather are outlined in the subsequent Anal ysis section.
To assess VE, we propose a large retrospective database stud y using two parallel stud y de-
signs:  a test -negative case -control design and a retrospective cohort design.  The testnega
tive design ( TND ) will assess VE against COVID- 19 hospitalization (primary endpoint) and 
EDadmission. The retrospective cohort anal ysis will may assess VE against COVID -19 hos-
pitalization (primary ), ICU admission, death, ED admission, and outpatient disease (with no 
subsequent hospitalization within 14 day s). We will may furthe r conduct additional analy ses 
of VE estimates b y various patient characteristics and strain ty pe. 
Table 1.TND Study Design Proposed Objectives
Test- Negative Design
Objectives Endpoints
Primary: Primary: 
1.To estimate the effectiveness of 2 doses of 
BNT162b2 (i.e., fully vaccinated) against 
hospitalization for ARI due to SARS -CoV- 2 
infection.VE calculated as 1 minus the odds ratio ( OR)com-
paring the odds of being fullyvaccinated (with 2 
doses )with BNT162b2 for hospitalized cases and 
controls, multiplied by 100%.
Secondary: Secondary: 
1.To estimate the effectiveness of 2 doses of 
BNT162b2 (i.e., fully vaccinated) against 
ED admission (without subsequent hospital-
ization) for ARI due to SARS -CoV-2 infec-
tion.VE calculated as 1 minus the OR comparing the odds 
of being fully vaccinated with (2 doses )BNT162b2 
for ED cases and controls, multiplied by 100%.
2.To describe the effectiveness of only 1 dose 
of BNT162b2 (i.e., partially vaccinated) 
against hospitalization for ARI due to 
SARS -CoV -2 infection.VE calculated as 1 minus the OR comparing the odds 
of being partially vaccinated with BNT162b2 (only 1 
dose) for hospitalized cases and controls, multiplied 
by 100%.
090177e198c0ac48\Approved\Approved On: 02-Dec-2021 13:28 (GMT)
FDA-CBER-2022-5812-0236124
BNT162b2 
C4591014 NON -INTERVENTIONAL STUDY PROTOCOL
Version 2.0, 01Oct 3 01 D ecember 2021
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 2 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
15-Aug-2018
Page 16of 48Table 1.TND Study Design Proposed Objectives
Test- Negative Design
3.To describe the effectiveness of only 1 dose 
of BNT162b2 (i.e., partially vaccinated) 
against ED admission (without subsequent 
hospitalization) for ARI due to SARS -CoV -
2 infection.VE calculated as 1 minus the OR comparing the odds 
of being partially vaccinated with BNT162b2 (only 1 
dose) for ED cases and controls, multiplied by 100%.
4.To describe the effectiveness of ≥1 dose of 
BNT162b2 (i.e., ever vaccinated) against 
hospitalization for ARI due to SARS -CoV- 2 
infection.VE calculated as 1 minus the OR comparing the odds 
of ever being vaccinated ( ≥1 dose) w ith BNT162b2 
for hospitalized cases and controls, multiplied by 
100%.
5.To describe the effectiveness of ≥1 dose of 
BNT162b2 (i.e., ever vaccinated) against 
ED admission (without subsequent hospital-
ization) for ARI due to SARS -CoV- 2 infec-
tion.VE calculated as 1 minus the OR comparing the odds 
of ever being vaccinated ( ≥1 dose) w ith BNT162b2 
for ED cases and controls, multiplied by 100%.
6.To describe the effectiveness of >2 doses of 
BNT162b2 against hospitalization for ARI 
due to SARS -CoV -2 infection.VE calculated as 1 minus the OR comparing the odds 
of >2 doses with BNT162b2 f or hospitalized cases 
and controls, multiplied by 100%.
7.To des cribe the effectiveness of >2 doses of 
BNT162b2 against ED admission (w ithout 
subsequent hospitalization) for ARI due to 
SARS -CoV -2 infection.VE calculated as 1 minus the OR comparing the odds 
of >2 doses with BNT162b2 f or ED cases and con-
trols, multiplie d by 100%.
6.8.To further describe the effectiveness of 
BNT162b2 against hospitalization and ED 
admission stratified by prevalent or im-
portant viral strainsBNT162b2 VE estimates stratified by virus variant 
(as determined by genome sequencing) and select de-
scriptive analyses described above by number of 
doses received
7.9.To evaluate the effectiveness of BNT162b2 
against severe hospitalization -related out-
comes (e.g., ICU admission, mechanical 
ventilation, and death)BNT162b2 VE estimates against severe outcom es in-
cluding ICU admission, mechanical ventilation, and 
death by number of doses received .
10.To evaluate overall and variant -specific ef-
fectiveness of BNT162b2 against SARS -
CoV- 2 infections and COVID -19 related 
hospital admissions by time since vaccina-
tion (by month)Monthly VE estimates between variants of interest
using independent Z tests of log hazard ratio s.
Tertiary/Exploratory: Tertiary/Exploratory: 
1. Com pare VE of models stratified by rele-
vant vaccination phase time periods to un-
derstand how VE may change as vaccinated 
patient risk profiles or variants change over 
time.BNT162b2 VE estimates by vaccination phase
2.To estimate the effectiveness of 1, ≥1, or2 
or >2 doses of BNT162b2 (i.e., fully vac
cinated) against hospitalization or ED for 
ARI due to SARS -CoV -2 infection.VE calculated as 1 minus the OR comparing the odds 
of have >2, 2, 1, or ≥1 doses of BNT162b2 for hospi-
talized and ED cases and controls, multiplied by 
100%.
090177e198c0ac48\Approved\Approved On: 02-Dec-2021 13:28 (GMT)
FDA-CBER-2022-5812-0236125
BNT162b2 
C4591014 NON -INTERVENTIONAL STUDY PROTOCOL
Version 2.0, 01Oct 3 01 D ecember 2021
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 2 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
15-Aug-2018
Page 17of 48Table 1.TND Study Design Proposed Objectives
Test- Negative Design
3.To further describe the effectiveness of 
BNT162b2 against hospitalization and ED 
admission stratified by various patient char-
acteristics ( e.g., age, sex , race/ethnicity ,
chronic medical conditions , history  of SARS -
CoV -2 infection, long -term care facility  resi-
dence, pregnancy  status, and receipt of influ-
enza vaccine ).BNT162b2 VE estimates by age group 
BNT162b2 VE estimates by sex 
BNT162b2 VE estimates by  presence of chronic medi-
cal conditions , history  of SARS -CoV -2 infection, preg-
nancy  status
BNT162b2 VE estimates by  race/ethnicity
BNT162b2 VE estimates by receipt of influenza vac-
cine in the last year
BNT162b2 VE estimates among long -term care fa-
cility residents (hospital outcome only)
BNT162b2 VE estimates by time since vaccination
BNT162b2 VE estimates by time between first and 
second dose among those who received 2 doses
4.To describe the proportion of hospitalized 
and ED patients with ARI where SARS -
CoV -2 was identified.Proportion of ARI hospitalizations where SARS -
CoV- 2 is identified.
5.To summarize the proportion of patients 
who receive 0, 1, or 2, or>2doses of 
BNT162b2 among hospitalized and ED pa-
tients. 
6. To summarize the time between admin-
istration of the first and second dose of 
BNT162b2 among patients who received 2 
doses and betw een the second and third 
dose of BNT162b2 among patients who re-
ceived 3doses
7.To summarize the time since vaccination 
with BNT162b2 (most -recent dose) since 
vaccinations at KPSC beganProp ortion of patients who receive 0, 1, and 2,or
>2doses of BNT162b2
Average and median time between receipt of the 
first and second dose BNT162b2 among patients 
who received tw o doses and betw een seco nd and 
third dose BNT162b2 among patients who re-
ceived 3doses .
Average and median time between 14 December 
2020 and receipt of last dose among patients re-
ceiving BNT162b2 stratified by total number of 
doses received .
8. To describe demographic , clinical , and la-
boratory characteristics (i.e., viral strain) 
and disease severity of any BNT162b2 vac-
cine failuresDescribe age, gender, race/ethnicity, clinical 
characteristics, and severity (ICU admission, 
ventilator, death) of any patients who received 
BNT162b2 and test positive for SARS -CoV -2
stratified by total num ber of doses received
9. To describe COVID -19 disease severity for 
vaccinated and unvaccinated cases in the 
TND designDescribe disease severity for vaccinated and un-
vaccinated cases (e.g., average hospital length of 
stay ( LOS ), 30-day readm ission, the proportion 
requiring ICU admission or mechanical ventila-
tion, death) stratified by total number of doses re-
ceived
Table 2.Full Cohort Study Design Proposed Objectives
Cohort Design
Objectives Endpoints
090177e198c0ac48\Approved\Approved On: 02-Dec-2021 13:28 (GMT)
FDA-CBER-2022-5812-0236126
BNT162b2 
C4591014 NON -INTERVENTIONAL STUDY PROTOCOL
Version 2.0, 01Oct 3 01 D ecember 2021
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 2 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
15-Aug-2018
Page 18of 48Table 2.Full Cohort Study Design Proposed Objectives
Cohort Design
Primary: Primary: 
1.To estimate the effectiveness of 2 doses of 
BNT162b2 (i.e., fully vaccinated) against 
hospitalization due to SARS -CoV- 2 infec-
tion.VE calculated as 1 minus the hazard ratio ( HR)
comparing the incidence of being fully vac
cinated ( 2 doses )with BNT162b2 for hospitaliza-
tion due to SARS -CoV -2 infection and not, mul-
tiplied by 100%.
Secondary: Secondary: 
1. To estimate the effectiveness of 2 doses of 
BNT162b2 (i.e., fully vaccinated) against 
ED admission (without subsequent hospital-
ization) ED admission due to SARS -CoV- 2 
infection.VE calculated as 1 minus the HR comparing the inci-
dence of being fully vaccinated ( 2 doses )with 
BNT162b2 for ED admission due to SARS -CoV- 2 
infection and n ot, multiplied by 100%.
2.To estimate the effectiveness of 2 doses of 
BNT162b2 (i.e., fully vaccinated) against 
ICU admission due to SARS -CoV- 2 infec-
tionVE calculated as 1 minus the HR comparing the inci-
dence of being fully vaccinated ( 2 doses )with 
BNT162b2 for ICU admission due to SARS -CoV -2 
infection and not, multiplied by 100%.
3.To estimate the effectiveness of 2 doses of 
BNT162b2 (i.e., fully vaccinated) against 
death due to SARS -CoV -2 infectionVE calculated as 1 minus the HR comparing the inci-
dence of being fully vaccinated (2 doses )with 
BNT162b2 for death due to SARS -CoV -2 infection 
and not, multiplied by 100%.
4.To estimate the effectiveness of 2 doses of 
BNT162b2 (i.e., fully vaccinated) against 
COVID -19 outpatient visits (without subse-
quent hospitalization within 14 days) due to 
SARS -CoV -2 infectionVE calculated as 1 minus the HR comparing the inci-
dence of being fully vaccinated ( 2 doses )with 
BNT162b2 for COVID- 19 outpatient visits (without
subsequent hospitalization within 14 days) due to 
SARS -CoV -2 infection and not, multiplied by 100%.
5.To describe the effectiveness of only 1 dose 
of BNT162b2 (i.e., partially vaccinated) 
against hospitalization, ED admission , ICU
admission, death, and out patient visits 
(without subsequent hospitalization within 
14 days) due to SARS -CoV -2 infection.VE calculated as 1 minus the HR comparing the inci-
dence of only 1 dose of BNT162b2 (i.e., partially 
vaccinated) for hospitalization, ED visit, death, and 
COVID -19 outpatient visits (without subsequent hos-
pitalization within 14 days) due to SARS -CoV -2 in-
fection and not, multiplied by 100%. 
6.To describe the effectiveness of ≥1 dose of 
BNT162b2 (i.e., ever vaccinated) against 
hospitalization, ICU admission , ED admis-
sion, death, and outpatient visits (without 
subsequent hospitalization within 14 days) 
due to S ARS -CoV -2 infection.VE calculated as 1 minus the HR comparing the inci-
dence ≥1 dose of BNT162b2 (i.e., ever vaccinated) 
for hospitalization, ED visit, death, and COVID -19 
outpatient visits (without subsequent hospitalization 
within 14 days) due to SARS -CoV-2 infection and 
not, multiplied by 100%. 
7.To describe the effectiveness of >2doses of 
BNT162b2 against hospitalization, ED ad-
mission , ICU admission , death, and outpa-
tient visits (without subsequent hospitaliza-
tion within 14 days) due to SARS -CoV -2 
infection.VE calculated as 1 minus the HR comparing the inci-
dence of >2doses of BNT162b2 for hospitalization, 
ED visit, death, and COVID -19 outpatient visits 
(without subsequent hospitalization within 14 days) 
due to SARS -CoV- 2 infection ,multiplied by 100%.
Tertiary/Exploratory: Tertiary/Exploratory: 
1. Com pare VE by number of doses received 
of models stratified by relevant vaccination BNT162b2 VE estimates by vaccination phase and 
by month
090177e198c0ac48\Approved\Approved On: 02-Dec-2021 13:28 (GMT)
FDA-CBER-2022-5812-0236127
BNT162b2 
C4591014 NON -INTERVENTIONAL STUDY PROTOCOL
Version 2.0, 01Oct 3 01 D ecember 2021
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 2 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
15-Aug-2018
Page 19of 48Table 2.Full Cohort Study Design Proposed Objectives
Cohort Design
phase time periods to understand how VE 
may change as vaccinated patient risk pro-
files change over time.
2.To further describe the effectiveness of 
BNT162b2 by durability of vaccine effec-
tiveness after receipt of 2 doses by number 
of doses received .VE calculated as 1 minus the HR comparing the inci-
dence of being full y vaccinated at various timepoints 
from vaccination for all outcomes, multiplied by 
100%.
3.To further describe the effectiveness of 
BNT162b2 stratified by various patient 
characteristics (e.g., age, sex, race/ethnicity , 
chronic medical conditions, history  of SARS -
CoV -2 infection, long -term care facility  resi-
dence, pregnancy  status, and receipt of influ-
enza vaccine).BNT162b2 VE estimates by age group 
BNT162b2 VE estimates by sex 
BNT162b2 VE estimates by  presence of chronic medi-
cal conditions, history  of S ARS- CoV -2 infection, preg-
nancy  status
BNT162b2 VE estimates by  race/ethnicity
BNT162b2 VE estimates by receipt of influenza vac-
cine in the last year
BNT162b2 VE estimates among long -term care fa-
cility residents (hospital outcome only)
BNT162b2 VE estimates by time since vaccination
BNT162b2 VE estimates by time between first and 
second dose among those who received 2 doses
BNT162b2 VE estimates by time between second 
and third dose among those that received 3 doses
4.To summarize the proportion of patients who 
receive 0, 1, or 2, >2doses of BNT162b2 
5.To summarize the time betw een adm inistra-
tion of the first and second dose of 
BNT162b2 among patients who received 2 
doses
6.To summarize the time betw een adm inistra-
tion of the second and third dose of 
BNT162b2 among patients who received 3
doses
5.7.To summarize the time since vaccination 
with BNT162b2 (most -recent dose) from 
study enrollment Proportion of patients who receive 0, 1, and 2, >2
doses of BNT162b2
Average and median time between receipt of the first 
and second dose BNT162b2 among patients who re-
ceived tw o doses
Average and median time between receipt of the sec-
ond and third dose BNT162b2 among patients who 
received 3doses
Average and median time between study enrollment 
and receipt of last dose among patients receiving 
BNT162b2
6.8.Estimate overall incidence rates by vaccina-
tion status and by important demographic 
and clinical characteristics Incidence by vaccination status, age, gender, 
race/ethnicity, clinical characteristics outlined further 
below .
7.9.To further describe the effect iveness of 
BNT162b2 stratified by prevalent or im-
portant viral strainsBNT162b2 VE estimates stratified by virus variant 
(as determined by genome sequencing) and all de-
scriptive analyses described above
8.10. To estimate the effectiveness of 2 
doses of BNT162b2 (i.e., fully vaccinated) 
against death during hospitalization due to 
ARI due to SARS -CoV -2 infectionVE calculated as 1 minus the HR comparing the inci-
dence of being fully vaccinated ( 2 doses )with 
BNT162b2 for death during hospitalization due to 
SARS -CoV -2 infection and not, multiplied by 100%.
090177e198c0ac48\Approved\Approved On: 02-Dec-2021 13:28 (GMT)
FDA-CBER-2022-5812-0236128
BNT162b2 
C4591014 NON -INTERVENTIONAL STUDY PROTOCOL
Version 2.0, 01Oct 3 01 D ecember 2021
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 2 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
15-Aug-2018
Page 20of 489. RESEARCH METHODS 
9.1.Research Setting
Kaiser Permanente Southern California (KPSC) is a large integrated healthcare delivery  sys-
tem that covers more than 4.7 million members. KPSC comprises one of the largest health 
insurance plans in the United States ( US), a hospital system, and >7,600 phy sicians and 
27,000 nurses located throughout 9 counties of Southern California. 15 medical centers and 
234 medical offices comprise the KPSC clinical care setting. Kaiser Permanente Southern 
California’s member population is socioeconomically  diverse and bro adly representative of 
the racial/ethnic groups living in Southern California . Our population represents > 260 eth-
nicities and > 150 languages spoken. As of December 2018, the majorit y of current members 
are Hispanic or Latino (43%), followed b y White (35% ), Asian/Pacific Islander (12%), Black 
or African American (9%), and Other (1%). Member retention is very  high, with nearl y 90% 
staying after 1 y ear, 78% remaining after 3 y ears, and 71% remaining after 5 y ears. Members 
enroll through the Kaiser Foundation Health Plan for prepaid health care insurance, including 
pharmaceutical benefits, through group plans, individual plans, Medicare, Medicaid, and 
other low -income programs. As of December 2018, 22% of patients were enrolled through 
Medicare or Medi -Cal and Children’s Health Insurance Program (CHIP ).    
Our pre -paid s ystem is a strong incentive to receive care within KPSC and members rarel y 
seek outside care. KPSC provides care across the entire spectrum of healthcare needs, from 
outpatient, inpatient, ED, urgent care, specialty  care, pharmacy , imaging, laboratory , virtual 
care, health education classes, and other services for our members. When clinical services 
sought outside of our s ystem are captured through claims reimbursement requests. 
Each Kaiser Permanente Southern California member is assigned a unique medical record 
number upon joining the health plan. This number is retained for life, irrespective of leaving 
and rejoining the health plan. This unique number allows for the linkage of different c om-
puter files containing clinical and administrative information. Kaiser Permanente HealthCon-
nect®, our comprehensive electronic health record, is one of the largest private electronic 
health record s ystems in the world. Kaiser Permanente HealthConnect and our integrated 
model securel y connect medical offices and hospitals across the region, providing members, 
physicians, and other authorized health care providers with online access to clinical infor-
mation. Kaiser Permanente HealthConnect is a customized ve rsion of the EPI C electronic 
health record.
The sy stem integrates all aspects of care, including pharmacy and lab services, as well as ap-
pointments, registration, and billing. This information can be used for research purposes. 
Trained research staff have access to Kaiser Permanente HealthConnect through the Kaiser 
Permanente Regional Application Portal. 
Regional Laboratories
The Sherman Way  Regional Reference Laboratories is a clinical laboratory management s ys-
tem that interfaces with Kaiser Permanente’s medical centers and medical office buildings. 
The central reference laboratory  occupies more than 150,000 square feet of laboratory  space 
090177e198c0ac48\Approved\Approved On: 02-Dec-2021 13:28 (GMT)
FDA-CBER-2022-5812-0236129
BNT162b2 
C4591014 NON -INTERVENTIONAL STUDY PROTOCOL
Version 2.0, 01Oct 3 01 D ecember 2021
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 2 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
15-Aug-2018
Page 21of 48and employ s more than 600 employ ees. Services include comprehensive chemistry , microbi-
ology , cellular pathology, cy togenetic testing, and anatomic pathology  services based on 
state-of-the-art instrumentation and methodologies. 
The Chino Hills reference laboratory  occupies more than 120,000 square feet of laboratory  
space and employ s approximately  230 employ ees.  Services cover specimen processing, in-
cluding send -outs, auto- chemistry , endocrinology , limited special chemistry , immunology , 
bacteriology, molecular microbiology , and histology .
The clinical laboratories located in the local medical centers and medical offices e ach rou-
tinely  conduct 2,000 to 3,000 laboratory  tests per day . The central reference laboratory  re-
ceives more than 50,000 specimens per day  from the local laboratories and performs over 29 
million tests annually . All laboratories undergo routine quality  checks to meet or surpass ac-
crediting bod y specifications.
The Regional Reference Laboratories are fully  accredited by  the College of American 
Pathologists. They  are licensed by  the Department of Health and Human Services Centers 
for Medicare and Medicaid Se rvices under the Clinical Laboratory  Improvement Amend-
ments (CLIA) of 1988, by the State of California Department of Public Health to perform 
clinical assay s, and b y the U.S. Food and Drug Administration Bureau of Biologics. They 
are inspected b y the Ameri can Association of Blood Banks for handling of blood compo-
nents.
There is a dedicated Regional Laboratory  Operations team including management and Re-
search Associates that supports research and serves as the liaison between Research & Evalu-
ation and the R egional Laboratory . 
COVID -19 at KPSC
As of 23 February 2021 KPSC, has had over 441,000 COVID -19 cases and approximately  
29,000 confirmed patients admitted to the hospital. We have vaccinated more than 311,000 
individuals as of 23 February  2021 .
At KPSC, diagnostic testing for SARS -CoV -2 is offered free of charge with an order from a 
KPSC phy sician. Prioritization for testing has evolved during the pandemic, with an empha-
sis on individuals with sy mptoms (particularl y high -risk groups) and prior to hospital admis-
sions or certain outpatient procedures. Testing is primarily  conducted by  reverse transcript ase
polymerase chain reaction ( RT-PCR) of nasopharyngeal/oropharyngeal swabs on the Roche 
cobas® 6800 and 8800 analy zers or nasal/orophary ngeal swabs on Hologic Panther® anal yz-
ers. A smaller number of Abbott I DNOW® point -of-care tests are conducted in limited set-
tings (e.g., obstetrics, pulmonary medicine, and infectious disease departments). Testing of 
asymptomatic individuals is also available, lever aging e -visits to place tests orders. Imple-
mentation in November 2020 of saliva testing and a new COVID -19 laboratory  with Thermo 
Fisher Scientific Amplitude Solution instruments has increased testing capacity  to approxi-
mately  46,000 tests per day . 
090177e198c0ac48\Approved\Approved On: 02-Dec-2021 13:28 (GMT)
FDA-CBER-2022-5812-0236130
BNT162b2 
C4591014 NON -INTERVENTIONAL STUDY PROTOCOL
Version 2.0, 01Oct 3 01 D ecember 2021
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 2 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
15-Aug-2018
Page 22of 489.2.Study design 
This is a database onl y study  of existing healthcare data, no patients will be activel y enrolled.
Vaccine exposure for both study  designs include fully  vaccinated, defined asinitial vaccine 
series of 2 doses of BNT162b2 received with ≥7 day s betwee n receipt of the 2nddose and the 
event date (e.g., admission); partially  vaccinated, defined as 1 dose (onl y) of BNT162b2 re-
ceived with ≥14 day s between the receipt of the 1stdose and the event date;  and ever vac-
cinated, defined as ≥1dose of BNT162b2 r eceived with ≥14days between the receipt of the 
1stdose and the event date ; and >2 doses of BNT162b received with ≥14days between last 
dose received and the event date . The unexposed group will include individuals with no rec-
ord of COVID -19 vaccination at the time of the event and will serve as the reference group in 
all most VE analy ses. Additional VE analy ses will compare those individuals receiving 2 
doses to those r eceiving >2 doses. All data will be collected from KPSC electronic health 
records (EHRs).
Study Design(s)
Test Negative Case -Control Design 
A TND study  design will be used to evaluate the primary  objective of this study , to assess ef-
fectiveness of 2 dose s of Pfizer COVI D vaccine > 7 day s after second dose against hospitali-
zation for ARI  due to SARS -CoV -2 infection. It will include all KPSC patients eligible for 
vaccination 16years or older who are admitted to the hospital with acute respiratory  infection 
(ARI) after 14 December 2020 (date of first vaccinations at KPSC), and who receive a PCR 
test for SARS- CoV -2. For secondary  objectives estimating VE against ED admission, the 
TND will include KPSC patients eligible for vaccination 16 years or older who present to 
the ED with acute respiratory  infection (ARI) after 14 December 2020 and who receive a 
PCR test for SARS -CoV -2.These populations will be used to evaluate additional secondary  
and explorato ry objectives outlined in Table 1 and   Table 2above, including VE of 1 dose, 
or ≥1 dose , or>2 doses and VE for important virus variants.
The index date will be defined as the date of hospitalization or ED admission. Patients can 
contribute more than one ARI  event to the study  if a subsequent ARI event for the same pa-
tient occurred >30 day s after the previous event.
Per KPSC clinical protocol, we expect that ED patients with ARI  will be tested for COVID -
19, and in the inpatient setting, all patients with or without ARI  will get tested for COVID-19 
(to be confirmed with preliminary  data). VE will be estimated separatel y for prevention of 
hospitalization (primary  outcome) and for prevention of emergency  department presentation 
without hospitalization (secondary  outcome).
Full Cohort Design
A full cohort design will be used for secondar y objectives to further explore BNT162b2 VE 
in the KPSC population. The cohort stud y will include all KPSC members as of 14 December 
090177e198c0ac48\Approved\Approved On: 02-Dec-2021 13:28 (GMT)
FDA-CBER-2022-5812-0236131
BNT162b2 
C4591014 NON -INTERVENTIONAL STUDY PROTOCOL
Version 2.0, 01Oct 3 01 D ecember 2021
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 2 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
15-Aug-2018
Page 23of 482020 (date of first Pfizer vaccination at KPSC) who are age 16 12 andolder. eligible for vac-
cination . The exposure will be receipt of Pfizer’s COVID- 19 vaccine, with separate relative 
VEs estimated by  number of doses received for those with 2 doses, 1 dose, or ≥1 dose as in 
the TND design above.  In this full cohort design, a patient’s vaccination status, and thus ex-
posure, will change over time, with all patients entering the cohort as unvaccinated. The out-
comes of interest will be COVID -19 associated hospitalization, ED admission, I CU admis-
sion, death, and outpatient COVI D-19 diagnoses (without subsequent hospitalization within 
14 day s).   As with the TND, the main outcome of interest will be hospitalization, and the VE 
of focus will be 2 doses of BNT162b2. The full cohort anal ysis will serve as a secondary  
analysis and will allow for comparability  with TN D study  methodology .  Cohort members 
will be censored if they  disenroll from KPSC, die for reasons not related to COVID- 19 (death 
not within the 30 day s following a positive COVID -19 laboratory  test), receive an y other 
newly  licensed or investigational COV ID-19 vaccine or prophy lactic agent other than 
Pfizer’s COVID -19 vaccin e.,receive >2 Pfizer COVID 19 vaccine doses , experience an out
come  <14 day s after receipt of the 1stPfizer COVID 19 dose, or experience an outcome  <7 
days after receipt of the 2ndPfizer COVI D19 dose.
9.2.1. Inclusion criteria
Patients must meet all of the following inclusion criteria to be eligible for inclusion in the 
study :
Test Negative Design
1.KPSC patients eligible to re ceive BNT162b2 16 years or older who are admitted to the 
hospital (primary objective and some secondary  objectives) with acute respiratory  infec-
tion (ARI ; International Classification of Diseases ( ICD)codes listed in Appendix Table 
1) after 14 December 2020 (date of first vacc inations at KPSC), and who receive a PCR 
test for SARS- CoV -2.
2.For secondary  objectives estimating VE against ED admission, the TND will include 
KPSC patients eligible to receive BNT162b2 16 years or older who present to the ED 
with ARI  after 14 December 2020, and who receive a PCR test for SARS -CoV -2.
3.We will include membership requirement of 6 months 1 yearprior to index date, which is 
defined as the date of hospitalization or ED admission (allowing 31- day administrative 
gap), to facilitate accurate cap ture of comorbid conditions. 
Cohort Design
1.All KPSC members as of 14 December 2020 (date of first Pfizer vaccination at KPSC) 
eligible to receive BNT162b2 who are age 16 and older..
090177e198c0ac48\Approved\Approved On: 02-Dec-2021 13:28 (GMT)
FDA-CBER-2022-5812-0236132
BNT162b2 
C4591014 NON -INTERVENTIONAL STUDY PROTOCOL
Version 2.0, 01Oct 3 01 D ecember 2021
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 2 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
15-Aug-2018
Page 24of 482.For the cohort study , patients must have at least 1 year 6 months of ofmembership (al-
lowing 31- day administrative gap) prior to 14 December 2020 (index date, date vaccina-
tions first began at KPSC) to facilitate accurate capture of comorbid conditions.
9.2.2. Exclusion criteria
Patient s meeting any of the following criteria will not be included in the study cohort :
Test Negative Design 
Patients who receive any only another newl y licensed or investigational SARS -CoV -2 vac-
cine or COVID -19 prophy lactic agent other than Pfizer’s COVID -19 vaccine prior to hospi-
talization (or ED, for secondary  objective) will be excluded from the analysisstudy  popula-
tion. When estimating VE for BNT162b2 vaccination , patients receiving another newl y li-
censed or investigational SARS -CoV -2 vaccine or COVID -19 proph ylactic agent other than 
Pfizer’s COVID -19 vaccine prior to hospitalization or ED will be excluded from the anal ysis.
Patients will also be excluded if the index date is within certain time windows from vaccina-
tion date, outlined further in the exposure section below. 
Cohort Design 
There will be no exclusion criteria for the cohort design, however patients will be censo red 
for receiving an y other newly  licensed or investigational SARS -CoV -2 vaccine or COVID -
19 prophy lactic agent other than Pfizer’s COVID- 19 vaccine. Patients will also be censored 
if the event (hospitalization, ED encounter, etc.) occurs within certain ti me windows from 
vaccination date, outlined further in the exposure section below.
9.3.Variables
9.3.1. Test Negative Design Outcomes and Exposures
Cases : Cases will be defined as those with an y positive KPSC laboratory -confirmed PCR test 
from a sample collected with in 14 day s prior to hospital admission through 3 day s after a 
hospital admission (primary  objective and some secondary ) or ED encounter (secondary  ob-
jective s) with an ARI code ( Appendix Table 1 ). 
Controls: Controls will be defined as those with laboratory  confirmed negative COVID-19 
(negative COVID -19 test collected within 14 days prior to hospital admission through 3 day s 
after a hospital a dmission during first 3 day s of hospitalization for (primary objective and 
some secondary )or ED admiss ionencounter for secondary  objective swith an ARI code (Ap-
pendix Table 1) and no positive COVI D-19 tests within 30 14 days prior to encounter). 
Exposure Definition: The exposure of interest is history  of vaccination with B NT162b2. For 
the primary  objective, patients will be considered vaccinated if they  have documented evi-
dence of receiving the second dose of BNT162b2 ≥7 day s before index date (i.e., defined as 
090177e198c0ac48\Approved\Approved On: 02-Dec-2021 13:28 (GMT)
FDA-CBER-2022-5812-0236133
BNT162b2 
C4591014 NON -INTERVENTIONAL STUDY PROTOCOL
Version 2.0, 01Oct 3 01 D ecember 2021
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 2 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
15-Aug-2018
Page 25of 48the date of hospitalization or ED admission). When evaluating t he effectiveness of 1dose of 
BNT162b2, patients will be considered vaccinated if they  have documented evidence of re
ceiving the first dose of BNT162b2 ≥14 day s before index date. Four Sixlevels of exposure 
variable swill be assessed:
1.Fully vaccinated Initial 2-dose vaccination series defined as 2 doses of BNT162b2 re-
ceived with ≥7 day s between receipt of the 2nddose and the index date . This group will 
serve as the ‘exposed’ group evaluated in the primary  objective. Patients who received 
only 1 dose or 2 doses of BNT162b2 with <7 day s between receipt of the 2nddose and the 
index date will be excluded from analy sis.In sensitivity  anal yses, VE will also be calcu-
lated for 2 doses of BNT162b2 received with ≥14 day s between receipt of the 2nddose 
and the index date .
2.Partially vaccinated defined as 1 dose (only) of BNT162b2 received with ≥14 day s be-
tween receipt of the 1stdose and the index date . This group will serve as the ‘exposed’ 
group as a secondary  endpoint. Patients who received 2 doses or 1 dose of BNT162b2 
with <14 day s between receipt of the 1stdose and the index date will be excluded from 
analysis.
3.Ever vaccinated defined as ≥1 dose of BNT162b2 received with ≥14 days between in-
dex date and receipt of the 1st dose. Patients who received 1 dose of BNT162b2 received 
with <14 days between receipt of the 1stdose and the index date will be excluded from 
analysis
4.Greater than 2 dose sdefine d as receiving >2 doses of BNT162b2 with ≥14 day s be-
tween receipt of the lastdose and the index date .
5.Never Unvaccinated defined as never received BNT162b2 as of index date. This group 
will serve as the reference exposure group (i.e., ‘unexposed’ group) in all most VE anal-
yses.
6. Mixed vaccinated defined as receiving 1 or more doses of BNT162b and any other 
COVID -19 vaccination .
The fully  vaccinated ( 2 2-dose)exposure group will be considered for the primary  objective, 
while the partiall y (1 dose) ,and ever vaccinated ( ≥1 dose) and additional (>2 doses) groups 
will may be considered in secondary objectives. Additional comparisons may be made be-
tween rece iving 2 doses versus >2 doses or mixed dosing schedules . 
9.3.2. Full Cohort Design Outcome and Exposures
Main outcome
090177e198c0ac48\Approved\Approved On: 02-Dec-2021 13:28 (GMT)
FDA-CBER-2022-5812-0236134
BNT162b2 
C4591014 NON -INTERVENTIONAL STUDY PROTOCOL
Version 2.0, 01Oct 3 01 D ecember 2021
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 2 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
15-Aug-2018
Page 26of 48The main outcome of interest will be COVID -19 hospitalization, which will be defined as a 
hospitalization with a positive PCR SARS -CoV -2 test within 1 4 day s prior and 3 day s after 
admission date.
Other outcomes of interest
COVID -19 ICU will be defined as time spent in an intensive care/critical care unit during a 
hospital stay  with COVID -19 admit as defined above.
COVID -19 ED encounter, which will be de fined as an ED encounter with a positive PCR 
SARS -CoV -2 test within 14 day s prior and 3 day s after encounter.
COVID -19 death will be defined as death within the 30 day s following a positive COVI D-19 
laboratory  test. Due to lags in compiling cause of death data in our databases, we will not 
have cause of death data in time for the study . 
Death during hospitalization will also be assessed. 
Laboratory -confirmed SARS -CoV -2 infection identified in the outpatient setting, without a 
hospitalization in the subsequent 14 days. 
Exposures of interest:   The exposure will be receipt of Pfizer’s COVID- 19 vaccine, with sep-
arate relative VEs estimated f or those full y receiving initial (2 dose series) , partially  (1 dose), 
or ever vaccinated ( ≥1 dose ), or > 2dosesdoses as in the TND design above.  In this full co-
hort design, a patient’s vaccination status, and thus exposure, will change over time, so VE 
will be estimated using time -varying exposures, explained in further detail below.
Partially ,and Fully  Initial 2 dose series, and >2 doses Vaccinated :Partial (1 dose) and full in-
itial series (2 dose) and additional dose (>2 doses) vaccination VE will be estimated using 
time-varying exposures, with patients initially  entering the cohort as unvaccinated, then con-
tributing person time to the partial and fully  and initial 2 dose series andadditional dose (s)
vaccinated exposure groups as they  are receiv ingthevaccine over time in the real -world set-
ting. Specifically , a patient will move to the 1 -dose exposure group once 14 -days have passed 
following the first dose, and then to the 2 -dose exposure group once 7 -days have passed fol-
lowing the second dose and then to the >2 dose exposure group once 14-days have passed 
following the lastdose.If a patient experiences an event within 14 day s of the first dose, or 7 
days within the second dose, he or she will be censored at that time .No requirements on the 
timing be tween doses will be applied.   
To explore VE durability after 2 and >2 doses, secondary  models will further refine the expo-
sure categories to include time since receipt of dose 2 and >2 doses . As in the main anal ysis, 
patients will still enter the cohort as unvaccinated on 14 December 2020 (date of first vac-
cinations at KPSC) and will move from unexposed to the partial and full vaccinated (2 or 3 
090177e198c0ac48\Approved\Approved On: 02-Dec-2021 13:28 (GMT)
FDA-CBER-2022-5812-0236135
BNT162b2 
C4591014 NON -INTERVENTIONAL STUDY PROTOCOL
Version 2.0, 01Oct 3 01 D ecember 2021
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 2 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
15-Aug-2018
Page 27of 48or more doses) exposure groups as they  are vaccinated over time. Once the second dose and 
> 2dose is received, we will then code exposure categories as,for example, 30-day months 
since reaching vaccination1 29 day s, 30 89 day s, 90 180 day s, 180 364, and ≥365 day s since
receipt of dose 2 . Each patient will contribute person time to these groups as the allotted 
amount of time passes since their second dose. This will allow us to analy ze the relative VE 
during those different time periods and explore VE durability .  If sam ple size allows, we will 
conduct a similar analy sis looking at only  1dose, where patients will be censored from the 
analyses when they  receive their second dose.  To inform our decisions in choice of cut 
points for both dose models, we will also estimate changes in relative VE continuously  over 
time by  modeling time since vaccination using restricted cubic splines. 
Ever Vaccinated: Relative VE for the Ever Vaccinated ( ≥1 dose) group will be estimated in a 
separate anal ysis also using time vary ing exposure s. Patients will again enter the cohort as 
unvaccinated, then contributing person time to the ever-vaccinated group after receiving dose 
1. They  will remain in this exposure group regardless of receipt of the 2nddose or additional 
doses of the Pfizer COVID -19 vaccine.  
Unexposed:  I ndividuals with no record of BNT162b2 COVID -19 vaccination or person -time 
prior to vaccination among those eventuall y vaccinated.  
9.3.3. Test-Negative and Full Cohort Designs – Outside Vaccinations
To obtain inform ation about vaccination that occurs outside of the KPSC healthcare s ystem, 
we will also take advantage of the recent partnership KPSC established with 7 national phar-
macy  chains as well as data exchange with the California I mmunization Registry  (CAIR). 
This partnership allows for KPSC members to receive influenza and other vaccines outside 
of KPSC pharmacies. Starting 30 December 2020, a bidirectional data exchange was estab-
lished with CAI R, thereby  allowing us to capture vaccinations received outside of KP SC. 
CAIR bidirectionality  brings together a partnership between electronic medical records, the 
public health department, and pharmacies.  Doses administered outside of KPSC are cur-
rently  being recorded in the electronic health record as, for example, “Cov id-19 vaccine, 
Pfizer, external administration.”
One exception to this is that immunization data for San Diego patients is reported into the 
San Diego Immunization Registry  (SDIR), not CAI R.  Because SDI R does not currentl y pro-
vide data to CAI R, complete i mmunization information for San Diego patients is not y et 
available via KP HealthConnect. However, providers can do a manual query in SDIR to up-
date member immunization records.
In California, COVID -19 vaccination providers are required to report COVID -19 doses ad-
ministered within 24 hours of administration to their local immunization registry .
To verify  our exposure data, we propose a validation study  nested in the larger cohort study  
to survey  a random sample of patients in the ‘non- vaccinated’ population to confirm data 
capture in the KPSC EHR (separate protocol). 
090177e198c0ac48\Approved\Approved On: 02-Dec-2021 13:28 (GMT)
FDA-CBER-2022-5812-0236136
BNT162b2 
C4591014 NON -INTERVENTIONAL STUDY PROTOCOL
Version 2.0, 01Oct 3 01 D ecember 2021
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 2 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
15-Aug-2018
Page 28of 489.3.4. Test-Negative and Full Cohort Designs - Covariates
We will consider individual- level and neighborhood-level factors listed in the Table 3 below.  
These are factors that we have either found to be important covariates in previous work, have 
been identified in other risk factor literature, or are variables that may be associated with the 
exposure as well as outc ome (i.e. prior positive SARS -CoV -2 PCR test, etc.)3-8. We will also 
include calendar week time as a covariate in our models to adjust for phase in vaccine 
rollout, testing practice changes, social distancing impacts, surges, and potential changes in 
clinical treatments. 
Table 3. Factors to be considered in models
Dem ographi cs Com orbidities Care utiliza-
tion prior to 
testNeighborhood 
characteristicsCOVID -his-
toryIndividual risk 
indicators
Age Cardiac disease Outpatient en-
countersPopulation den-
sityPrior negative 
PCR testsHealth care 
worker ( HCW )
/ occupation
Sex Organ trans-
plantInpatient en-
countersMedian income Prior positive 
PCR testsLong -term care 
resident
Race/ethnicity Diabetes with 
A1CED encounters Neighborhood 
deprivation in-
dexPrior negative 
serology testsMedical Center
Chronic Ob-
structive Pul-
monary Disease 
(COPD )Influenza vac-
cinationEducation Prior positive 
serology tests
Renal disease Pneumococcal 
vaccinationMedical Center
Body  mass in-
dex ( BMI )Virtual encoun-
ters
Malignancy
Hypertension
Charlson Index
Sedentary vs. 
Active
9.4.Data sources 
All data will be collected from KPSC electronic health records. This is a database analy sis 
study  of existing healthcare data; no patients will be activel y enrolled. We will collect data 
including vaccination status and dates of vaccination, COVID- 19 testing and outcomes, 
090177e198c0ac48\Approved\Approved On: 02-Dec-2021 13:28 (GMT)
FDA-CBER-2022-5812-0236137
BNT162b2 
C4591014 NON -INTERVENTIONAL STUDY PROTOCOL
Version 2.0, 01Oct 3 01 D ecember 2021
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 2 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
15-Aug-2018
Page 29of 48comorbidities, prior healthcare utilization, other vaccinations, demographic data, and other 
data from the EH R. 
All data for research are subjected to a number of quality  checks. The programming teams 
perform range and consistency  checks for all data to be evaluated.  These might include event 
dates after death, procedures coded at facilities that don’t perform them, outly ing laboratory  
values, and other evaluations. All study  data are presented in team meetings on at least a 
weekl y basis and further examinations for potential errors are made b y the scientists and bio-
statisticians. I n addition, at both sites ther e are a number of standard algorithms in place that 
will be used to further subject the data to qualit y control procedures. Aberrant data will be 
examined to determine if they  are due to programming errors, and efforts to resolve s ystem-
atic problems that l ead to errors will occur as soon as possible after they  are discovered and 
will continue until resolution. These quality control procedures will be documented, provid-
ing an auditable trail. 
Once all necessary  data from KPSC have been pulled and have under gone robust quality  con-
trol measures, the databases will be frozen and archival copies of each separate dataset will 
be made. Continuous data quality  assurance and improvement are a top priority . The team 
will be prompt in responding to an y data quality in quiries from Pfizer if and when an y issues 
are discovered. 
All programming and analy ses will be conducted using SAS statistical software, version 9·4 
(Cary , NC), and R (R Core Team 2019, version 3.6.0).
9.5.Study size
The TND anal ysis will be event -driven bas ed on the number of cases identified. Study  sam-
ple size is based on the primary  endpoint (BNT162b2 VE against ARI requiring hospitaliza-
tion where SARS -CoV -2 is identified in the TND study ). The required sample size will de-
pend primaril y on i) the proportion of all -cause ARI  requiring hospitalization caused b y 
SARS -CoV -2 (which determines the number of cases identified and the ratio of cases to con-
trols in the primary  anal ysis), ii) the average uptake of BNT162b2 in the study population 
over the duration of the study , and iii) the assumed VE of the specific COVID- 19 vaccine 
against ARI requiring hospitalization where SARS- CoV -2 is identified. Sample size calcula-
tions were based on the following fixed assumptions:
Two-sided, t ype-I error of 5%
1.90% power 
2.Log(OR) following approximated normal distribution
3.Assumed true BNT162b2 VE vary ing from 70‒90% to prevent ARI requiring hospi-
talization was modeled
090177e198c0ac48\Approved\Approved On: 02-Dec-2021 13:28 (GMT)
FDA-CBER-2022-5812-0236138
BNT162b2 
C4591014 NON -INTERVENTIONAL STUDY PROTOCOL
Version 2.0, 01Oct 3 01 D ecember 2021
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 2 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
15-Aug-2018
Page 30of 484.5% of all -cause ARI episodes requiring hospitalization will test positive for SARS -
CoV -2. A range of 5–30% was also modeled given the attack rate of COVID- 19 may  
vary based on social distancing and shelter -in-place measures, underly ing levels of 
population immunity , and other factors.   
Average BNT162b2 vaccine uptake in controls over the study  period was allowed to vary in 
sample size calculations (range: 10 –90%) and will depend on potential future vaccination up-
take scenarios and timing of the conduct of the study . Final study  enrollment size will also 
depend on the proportion of enrolled patients exclude d from the Per Protocol Population be-
cause i) vaccination records could not be obtained, ii) they  received a newly -licensed or in-
vestigational SARS -CoV -2 vaccine other than BNT162b2 vaccine, or iii) they  received 
BNT162b2 vaccine, but did not receive the f ull 2-dose schedule. 
Table 4 presents sample size calculations for various scenarios of BNT162b2 uptake and the 
proportion of all -cause ARI  where SARS -CoV -2 is identified. Depending on the uptake of 
BNT162b2 and the proportion of ARI  hospitalizations where SARS -CoV -2 is identified at 
the time of the study , approximately  3,000 to 12,000 persons eligible for vaccination ≥16 
years of age will be needed in the TND analy sis. Our study  team will monitor BNT162b2 up-
take among controls and the proportion of all- cause ARI where SARS -CoV -2 is identified to 
inform decisions on the sample size required to reach an effectiveness endpoint. 
For the cohort design, anal ysis will be performed at fixed time points after a specified dura-
tion of follow -up.  Power to detect a given hazard ratio in a Cox model depends primarily  on 
the number of events observed during follow -up, but also varies with the degree of correla-
tion be tween the exposure of interest (vaccination) and the other covariates in the model.  
Given that exposure at any  given time may  be highly  correlated with age or comorbidities, 
we allowed the correlation (r2) to vary  from 0.1 to 0.5, while estimating a VE (1- HR) ranging 
from 30% to 90%.  The power table below shows the total number of events which would 
need to be observed in the cohort to have 90% power at alpha level 0.05 to detect a given VE 
at a given correlation between vaccine exposure and other covaria tes.
Table 4. Total number of events needed to provide 90% power to detect a given VE
Correlation of vaccine exposure with other covariates
VE (1 -HR) 0.1 0.3 0.5
90% 4 5 7
70% 13 17 23
50% 38 49 69
30% 144 185 259
090177e198c0ac48\Approved\Approved On: 02-Dec-2021 13:28 (GMT)
FDA-CBER-2022-5812-0236139
BNT162b2 
C4591014 NON -INTERVENTIONAL STUDY PROTOCOL
Version 2.0, 01Oct 3 01 D ecember 2021
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 2 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
15-Aug-2018
Page 31of 48Requirements for the final anal ysis population to detect BNT162b2 VE >20% assuming true 
VE=70 ‒90% with 90% power and t ype-I error of 5% (2 -sided) under various BNT162b2 up-
take scenarios ( 5to 30% of ARI events requiring hospitalization due to SARS -CoV -2)
090177e198c0ac48\Approved\Approved On: 02-Dec-2021 13:28 (GMT)
FDA-CBER-2022-5812-0236140
BNT162b2 
C4591014 NON -INTERVENTIONAL STUDY PROTOCOL
Version 2.0, 01Oct 3 01 D ecember 2021
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 2 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study 15-Aug-2018
Page 32of 48Table 5.COVID VE Sample Size
5% of ARI is SARS -CoV -2 positive 15% of ARI is SARS -CoV -2 positive 25% of ARI is SARS -CoV -2 positive 30% of ARI is SARS -CoV -2 positive
Assume true VE=70%
BNT162 b2
UptakeCon-
trolscases Tot 
EvalTot En-
roll*Con-
trolscases Tot 
EvalTot En-
roll*Con-
trolscases Tot 
EvalTot En-
roll*Con-
trolscases Tot 
EvalTot En-
roll*
10 6769 356 7125 1187
52104 371 2475 4125 1171 390 1561 2602 938 402 1340 2233
20 3266 172 3438 5730 1022 180 1202 2003 573 191 764 1273 461 198 659 1098
30 2108 111 2219 3698 665 117 782 1303 377 126 503 838 304 130 434 723
40 1540 81 1621 2702 491 87 578 963 281 94 375 625 229 98 327 545
50 1213 64 1277 2128 392 69 461 768 228 76 304 507 187 80 267 445
60 1015 53 1068 1780 335 59 394 657 199 66 265 442 165 71 236 393
70 909 48 957 1595 308 54 362 603 187 62 249 415 157 67 224 373
80 905 48 953 1588 318 56 374 623 200 67 267 445 171 73 244 407
90 1174 62 1236 2060 435 77 512 853 287 96 383 638 251 108 359 598
Assume true VE=80%
BNT162 b2
UptakeCon-
trolscases Tot 
EvalTot En-
roll*Con-
trolscases Tot 
EvalTot En-
roll*Con-
trolscases Tot 
EvalTot En-
roll*Con-
trolscases Tot 
EvalTot En-
roll*
10 4945 260 5205 8675 1518 268 1786 2977 832 277 1109 1848 661 283 944 1573
20 2325 122 2447 4078 717 127 844 1407 396 132 528 880 315 135 450 750
30 1455 77 1532 2553 452 80 532 887 252 84 336 560 201 86 287 478
40 1024 54 1078 1797 321 57 378 630 181 60 241 402 146 63 209 348
50 770 41 811 1352 245 43 288 480 140 47 187 312 114 49 163 272
60 608 32 640 1067 197 35 232 387 115 38 153 255 95 41 136 227
70 505 27 532 887 169 30 199 332 102 34 136 227 85 36 121 202
80 455 24 479 798 160 28 188 313 101 34 135 225 86 37 123 205
90 513 27 540 900 196 35 231 385 132 44 176 293 116 50 166 277
090177e198c0ac48\Approved\Approved On: 02-Dec-2021 13:28 (GMT)
FDA-CBER-2022-5812-0236141
BNT162b2 
C4591014 NON -INTERVENTIONAL STUDY PROTOCOL
Version 2.0, 01Oct 3 01 D ecember 2021
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 2 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study 15-Aug-2018
Page 33of 48Table 5.COVID VE Sample Size
5% of ARI is SARS -CoV -2 positive 15% of ARI is SARS -CoV -2 positive 25% of ARI is SARS -CoV -2 positive 30% of ARI is SARS -CoV -2 positive
Assume true VE=90%
BNT162 b2
UptakeCon-
trolscases Tot 
EvalTot En-
roll*Con-
trolscases Tot 
EvalTot En-
roll*Con-
trolscases Tot 
EvalTot En-
roll*Con-
trolscases Tot 
EvalTot En-
roll*
10 4275 225 4500 7500 1294 228 1522 2537 698 233 931 1552 549 235 784 1307
20 1955 103 2058 3430 594 105 699 1165 322 107 429 715 253 108 361 602
30 1183 62 1245 2075 361 64 425 708 197 66 263 438 155 66 221 368
40 798 42 840 1400 245 43 288 480 135 45 180 300 107 46 153 255
50 568 30 598 997 176 31 207 345 98 33 131 218 78 33 111 185
60 417 22 439 732 132 23 155 258 74 25 99 165 60 26 86 143
70 313 16 329 548 101 18 119 198 59 20 79 132 49 21 70 117
80 241 13 254 423 83 15 98 163 51 17 68 113 43 18 61 102
90 212 11 223 372 82 14 96 160 56 19 75 125 50 21 71 118
*Assumes 40% of enrolled participants will be unevaluable (i.e., excluded from the Per Protocol Population because i) vaccina tion records could not be ob-
tained, ii) they received a newly -licensed or investigational SARS -CoV- 2 vaccine other than COVID -19 vaccine , or iii) they received COVID -19 vaccine , but 
did not receive the full 2 -dose schedule.
090177e198c0ac48\Approved\Approved On: 02-Dec-2021 13:28 (GMT)
FDA-CBER-2022-5812-0236142
BNT162b2 
C4591014 NON -INTERVENTIONAL STUDY PROTOCOL
Version 2.0, 01Oct 3 01 D ecember 2021
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 2 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
15-Aug-2018
Page 34of 489.6.Data management 
Data management activities include sy stem operation and maintenance, security , data specifi-
cation, programming, s ystems and data validation, sequencing of operational steps and 
events, quality  assurance / quality  control, and data backup.  
Thestudy  team will hold weekl y internal meetings with a primary goal surrounding quality  
assurance. The meetings will be a platform for the programmers and anal ysts to report their 
work in progress to the scientist team and to discuss any  potential issues. KPSC will maintain 
internal data management logs to track data manag ement activities and important communi-
cation with internal personnel or Pfizer. 
In general, we will rel y on our internal team meetings to manage tasks. Internal review pro-
cesses and team meetings will be used to monitor performance. Meeting minutes, meeti ng 
agendas, progress reports, meetings, e -mail, and calendar tools will be used to manage and 
ensure qualit y of the project. We will use internal team meetings, e -mail, conference calls, 
the website, and progress reports to communicate. We will develop a d ocument in coordina-
tion with the sponsor that will list all deliverables and expected timelines for deliverables. 
Tracking of project deliverables will be a standing item on meeting agendas. 
Any problems or risks will be brought up at our regular internal team meetings and escalated 
to Pfizer as needed. The leadership team will discuss solutions to problems and way s to miti-
gate risks. We will use e- mail and our progress reports to communicate proactively  with 
Pfizer regarding an y anticipated risks or barri ers to the project.
Once the stud y has begun, if Pfizer changes timelines or increases the scope of the objec-
tives, we will examine all possible means to accommodate the changes within the existing 
budget. If not, we will work closel y with Pfizer to adjust the budget, scope of work, and/or 
timelines.
9.6.1. Electronic data records
All data will be collected from KPSC electronic health records. This is a database analy sis 
study  of existing healthcare data; no patients will be activel y enrolled. Therefore, no case r e-
port forms or data collection tools will be created and submitted to Pfizer.  The investigator 
shall ensure that the electronic data records are securely  stored at the study  site and will have 
limited access. Patient- specific data will not be transferred or reported out to Pfizer.  Aggre-
gate descriptive anal yses will be presented.
9.6.2. Record retention
The final database will be archived and retained in a password -protected location. To enable 
evaluations and/or inspections/audits from regulatory authorities or Pfizer, records, including 
the identity  of all participating patients (sufficient information to link records, e.g., hospital 
records), source documents, detailed records of treatment disposition, and adequate docu-
090177e198c0ac48\Approved\Approved On: 02-Dec-2021 13:28 (GMT)
FDA-CBER-2022-5812-0236143
BNT162b2 
C4591014 NON -INTERVENTIONAL STUDY PROTOCOL
Version 2.0, 01Oct 3 01 D ecember 2021
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 2 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
15-Aug-2018
Page 35of 48mentation of relevant correspondence (e.g ., letters, meeting minutes, and telephone call re-
ports) will be maintained. The records will be retained by  the investigator according to site 
guidelines. The records will be stored securel y for so long as they  are retained.
If the investigator becomes un able for an y reason to continue to retain study records for the 
required period (e.g., retirement, relocation), Pfizer will be prospectivel y notified.  The study 
records must be transferred to a designee acceptable to Pfizer, such as another investigator, 
another institution, or to an independent third party  arranged by  Pfizer. 
Study  records will be kept for a minimum of 15 y ears after completion or discontinuation of 
the study . The investigator will obtain Pfizer's written permission before disposing of a ny 
records, even if retention requirements have been met.
9.7.Data analysis 
Detailed methodology  for summary  and statistical anal yses of data collected in this study will 
be documented in a Statistical Analysis Plan (SAP), which will be dated, filed and main-
tained by  the sponsor.  The SAP may  modify  the plans outlined in the protocol; any  major 
modifications of primary endpoint definitions or their anal yses would be reflected in a proto-
col amendment. 
9.7.1. Test Negative Design Analyses
The anal yses below will be done separatel y for the primary population of hospitalized pa-
tients as well as the secondary  population of patients with ED encounters. Further, they  will 
be stratified b y age groups of interest in alignment with FDA authorizations and approvals
over time. Patients will be included in the analy ses regardless of prior COVID -19 infection 
status.
9.7.1.1. Descriptive Analyses
We will give the proportion of hospitalized and ED patients with ARI  where SARS -CoV -2 
was identified, as well as the proportion of patients who receive 0, 1, and 2, >2doses of 
BNT162b2.  We will provide the average and median time between receipt of the f irst and 
second dose of BNT162b2 among patients who received 2 doses, between receipt of the first 
to second and second to third dose of BNT162b 2among patients who received 3 doses , as 
well as between 14 December 2020 (beginning of vaccinations at KPSC) and receipt of last 
dose of BNT162b2. Finally , we will describe age, gender, race/ethnicity , clinical characteris-
tics, and severit y (ICU admission, ventilator, death), and other characteristics described in 
Table 3 above of an y patients who received BNT162b2 and test positive for SARS- CoV -2.
9.7.1.2. Estimated Crude (Unadjusted) VE
Odds of having received BNT162b2 ( fully initial 2 dose , ever, and partiall y vaccinated and >2 
dose) for cases and test-negative controls will be constructed and compared using ORs and 
95% confidence intervals (CIs). VE will be calculated as 1−OR multiplied by 100%. Corre-
sponding 95% CIs will be calculated using the Wald method.
090177e198c0ac48\Approved\Approved On: 02-Dec-2021 13:28 (GMT)
FDA-CBER-2022-5812-0236144
BNT162b2 
C4591014 NON -INTERVENTIONAL STUDY PROTOCOL
Version 2.0, 01Oct 3 01 D ecember 2021
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 2 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
15-Aug-2018
Page 36of 489.7.1.3. Estimating Adjusted VE 
In addition to constructing crude OR and VE estimates, logistic regression modeling to assess 
BNT162b2 VE after adjustment for potentially  confounding factors will be performed. Find-
ings from the Phase 3studies, expert opinion, and published studies of clinical/biologic factors 
will be used to identify covariates for inclusion in themodel .  These will be assessed for their 
availability  and ability  for adjusting crude results, including an examination of their distribu-
tions and missingness.  Bivariate associations of potential confounders with the outcome, ex-
posure, and each other will be e xamined.  For those with suggestions of imbalance with either 
exposure or outcome, the association between exposure and outcome will be stratified by  cat-
egories of the potential confounder to look for differences across strata (potential effect modi-
fication) and influence on summary  estimates of association (confounding).  The variables will 
ultimately  be selected based on a combination of the a priori decisions and a qualitative assess-
ment of the empirical relationships.  Sensitivity  analyses will assess the robustness of cut-point 
selections and groupings and consider tightly confounded variables and their collinearity.  The 
results of the multivariable model should corroborate the knowledge gained from the stratified 
analyses. A 2 -sided alpha of .05 will be used for logistic regression modelling. Corresponding 
95% CI s will be calculated using the Wald method. A genera lized estimating equations ( GEE)
estimator will be used with a robust sandwich variance estimator to account for clustering in-
troduced b y var iables measured at the neighborhood level. In addition to results from the final 
model, univariate VE results will be presented for each independent variable that is assessed 
for potential confounding, as the results from a fully- adjusted model. 
In addition to constructing crude OR and VE estimates, logistic regression modeling to assess 
BNT162b2 VE after adjustment for potentially  confounding factors will be performed. With 
the exception of variables determined to be of clinical importance, which will be included in 
models regardless, variables described in 8.4.4 will be entered in the logistic regression model 
in backward stepwise manner . Onl y variables that change the estimated OR for BNT162b2 b y 
≥10% (i.e., confounder) will remain in the final VE model. A 2sided alpha of .05 will be used 
for logistic regression modelling. Corresponding 95% CIs will be calculated using the Wald 
method. A generalized estimating equations ( GEE )estimator will be used with a robust sand
wich variance estimator to accou nt for clustering introduced by variables measured at the 
neighborhood level. In addition to results from the final model, univariate VE results will be 
presented for each independent variable that is assessed for potential confounding, as the re
sults from a fully adjusted model. 
9.7.1.4. Sensitivity Analyses
1.It is possible that patients that present with a COVID -19-like illness or a COVID -19 
diagnosis are not tested for SARS- CoV -2 within 3 day s of hospital admission but are 
rather tested later in their hospital st ay. If this were the case, we would want to ex-
pand the requirement of a COVID -19 diagnostic test bey ond 3 day s following admis-
sion. To investigate the possibility  of late testing, we will present data on the distribu-
tion of COVID -19 tests at time since adm ission for those admitted for respiratory  in-
090177e198c0ac48\Approved\Approved On: 02-Dec-2021 13:28 (GMT)
FDA-CBER-2022-5812-0236145
BNT162b2 
C4591014 NON -INTERVENTIONAL STUDY PROTOCOL
Version 2.0, 01Oct 3 01 D ecember 2021
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 2 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
15-Aug-2018
Page 37of 48fections. If we find that a meaningful number of patients are tested >3 day s after hos-
pital admission, we may  include a sensitivity  analy sis to examine VE without time re-
strictions on testing following admission.
2.Use and develop Natural Language Processing (NLP )algorithm to estimate actual 
date of s ymptom onset of COVID -19 s ymptoms. Sy mptom onset will then be consid-
ered to define exposure status at the time of a qualify ing event (or to censor a patient 
if they  experience an event before 14 -days after the first dose of 7 -days after the sec-
ond).
9.7.1.5. Exploratory analyses estimating VE for health care wor kers and other high risk 
populations 
We know that the vaccine roll- out is following a tiered strategy , for example, with healthcare 
workers with direct patient contact being vaccinated first. The logic supporting tiered vaccine 
eligibility  is based on COV ID-19 risk, with highest risk populations prioritized first. To ac-
count for differing risk profiles of vaccinated individuals over time, we will account for cal-
endar week in our model.  To explore whether controlling for calendar week time (length of 
time to be determined by sample size) is sufficient to address possible biases in VE,we will 
explore three options: 
1.Flag healthcare worker, or other sub -population status (gold standard). 
This will require complete and reliable identification of healthcare w orker or other sub-popu-
lation status, for example, long term care facility (LTCF )-resident , in the EHR. This is the 
preferred approach. 
Analy ses will then be stratified so that both cases and controls will come from the same sub -
population.
2.Explore and compare VE of models stratified by  time periods. 
KPSC documentation of the dates of transitions between tiers will be used to create catego-
ries of vaccine distribution by  time ( Healthcare works/L TCF residents onl y, 65+, etc .),
Using these categories, we wi ll perform stratified analy ses for each phase in the vaccine 
rollout and examine any  differences in relative VE between time strata. 
3.If, through our anal yses in part 2 or as the result of additional clinical input, we 
determine our inability  to identify  patients eligible for vaccination during certain 
vaccination tiers will result in unobserved confounding that will materiall y affect 
the reliability  of our VE estimates, we will limit VE anal yses to certain time peri-
ods of interest for which we know vaccina tions were restricted to a particular tier 
–in particular we may  drop anal yses focused on the time period only  healthcare 
workers were vaccinated and focus on time periods were vaccination is more 
widespread. 
090177e198c0ac48\Approved\Approved On: 02-Dec-2021 13:28 (GMT)
FDA-CBER-2022-5812-0236146
BNT162b2 
C4591014 NON -INTERVENTIONAL STUDY PROTOCOL
Version 2.0, 01Oct 3 01 D ecember 2021
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 2 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
15-Aug-2018
Page 38of 48Other Additional Anal yses: 
We will may also perform the following analy ses:
Determine VE against hospitalization and ED admission (combined). 
Provide descriptive statistics and determine VE stratified by viral strains determined 
to be important or prevalent based on sequencing anal yses.
Determine V E of BNT162b2 against hospitalization stratified by  various patient char-
acteristics (e.g., age, sex, race/ethnicity , chronic medical conditions, pregnancy  status, 
receipt of influenza vaccine). See Table 1for full list of stratified anal yses.
Evaluate the effectiveness of BNT162b2 against severe hospitalization -related out-
comes (e.g., ICU admission, mechanical ventilation, and death).
Compare COVID -19 disease severit y between vaccinated and unvaccinated cases.
Evaluate the effectiveness of BNT162b 2as part of a m ixed dosing schedul e.
We may  also consider the impact of co-infections on anal yses. It is possible that agents other 
than SARS -CoV -2 are the primary  drivers causing ARI  symptoms, while SARS -CoV -2 play s 
a less acute role. We may explore this possibility  with descriptive anal ysesof the distribution 
of COVID -19 cases with diagnostic tests for other pathogens, and a sub- analy sis excluding 
all patients with co -infecting respiratory  (influenza or Respiratory  Syncytial Virus [RSV ]) 
pathogens.
9.7.2. Full Cohort Design Analyses
As in the TND, we will include those with and without prior COVID -19 diagnoses. We will 
also stratify  the results by  age groups of interest in alignment with FDA authorizations and 
approvals over time.
9.7.2.1. Descriptive Analyses
We will give the proportion of patients who rec eive 0, 1, and 2, >2doses of BNT162b2 
across all of KPSC during the stud y period.  We will provide the average and median time 
between receipt of the first and second dose of BNT162b2 among patients who received 2 
doses , between receipt of the first and s econd dose and the second and third dose of 
BNT162b 2among patients who received 3 doses, as well as between 14 December 2020 (in-
dex date for cohort study, beginning of vaccinations at KPSC) and receipt of last dose of 
BNT162b2. Overall incidence of the ou tcomes of interest will be calculated by  dividing the 
number of outcome cases by  the total number of person -years. We will also provide inci-
dence estimates by  age, gender, race/ethnicity , clinical characteristics, and other characteris-
tics described in Table 2and Table 3 above. We will additionally  explore changes in the clin-
ical and demographic composition of t he vaccinated and non -vaccinated population over 
090177e198c0ac48\Approved\Approved On: 02-Dec-2021 13:28 (GMT)
FDA-CBER-2022-5812-0236147
BNT162b2 
C4591014 NON -INTERVENTIONAL STUDY PROTOCOL
Version 2.0, 01Oct 3 01 D ecember 2021
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 2 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
15-Aug-2018
Page 39of 48time, as this will also change with vaccine phase integration. Characteristics of those who test 
positive for COVID -19 and those without COVI D-19 will be presented. 
9.7.2.2. Estimated Crude (Unadjusted) VE
VE will be estimated as 1 – [(incidence of outcome among vaccine recipients)/(incidence of 
outcome among unvaccinated)].  The incidence rate ratio will be estimated using the hazard 
ratio from the time- adjusted Cox model, resulting in estimated VE = (1 – adjusted HR) * 
100%. Corresponding 95% CIs will be calculated. Vaccination status will be time -varying as 
described previously  in the Exposures section.
9.7.2.3. Estimating Adjusted VE 
Adjusted hazard ratios (HRs) and 95% CIs will be estimated b y including age, sex, race, and 
other covariates listed in Table 3 in Cox proportional hazards regression models. Potential 
confounders to include in models will be selected based on prior knowledg e and empirical 
findings through the model building process.  Findings from the Phase 3studies, expert 
opinion, and published studies of clinical/biologic factors will be used to identify  covariates 
for the model .The variables will ultimately  be selected based on a combination of the a pri-
ori decisions and a qualitative assessment of the empirical relationships.  Sensitivity  anal yses 
will assess the robustness of cut -point selections and groupings and consider tightl y con-
founded variables and thei r collinearit y.  Covariates of clinical importance will be selected 
for the adjusted anal yses. We will control for calendar week time in all models. Robust vari-
ance will be computed to account for clustering introduced b y neighborhood level variables. 
Vacc ine effectiveness (VE) will be estimated as 1 –[(incidence of outcome among vaccine 
recipients)/(incidence of outcome among unvaccinated)].  The incidence rate ratio will be es-
timated using the hazard ratio from the adjusted the Cox model, resulting in es timated VE = 
(1 –adjusted HR) * 100%.  
9.7.2.4. Sensitivity Analyses
Use and develop NL P algorithm to estimate actual date of s ymptom onset of COVID -19 
symptoms. Sy mptom onset will then be considered to define exposure status at the time of a 
qualify ing event (or to censor a patient if they  experience an event before 14- days after the 
first dose of 7 -days after the second).
9.7.2.5. Exploratory analyses estimating VE for health care workers and other high risk 
populations 
We know that the vaccine roll- out is following a t iered strategy , for example, with healthcare 
workers with direct patient contact being vaccinated first. The logic supporting tiered vaccine 
eligibility  is based on COVID -19 risk, with highest risk populations prioritized first. To ac-
count for differing ri sk profiles of vaccinated individuals over time, we will account for cal-
endar week time in our model.  In the Cox model with time -varying exposure status we will 
use calendar time as the time scale, which effectively  compares vaccinated to unvaccinated 
individuals as of the same date.  To explore whether controlling for calendar week time is 
sufficient to address possible biases in VE, we will explore three options: 
090177e198c0ac48\Approved\Approved On: 02-Dec-2021 13:28 (GMT)
FDA-CBER-2022-5812-0236148
BNT162b2 
C4591014 NON -INTERVENTIONAL STUDY PROTOCOL
Version 2.0, 01Oct 3 01 D ecember 2021
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 2 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
15-Aug-2018
Page 40of 48Flag healthcare worker, or other sub -population status (gold standard). 
oThis will require complete and reliable identification of healthcare worker or 
other sub- population status, for example, L TCF re sident, in the EHR. This is the 
preferred approach. 
oWe will then include an interaction term with healthcare worker and HRs used to 
estimate VE, to determine if VE is meaningfull y different b y these categories.
Explore and compare VE of models by  time per iods. 
oKPSC documentation of the dates of transitions between tiers will be used to cre-
ate categories of vaccine distribution by  time ( Healthcare works/L TCF residents 
only, 65+, etc.), 
oUsing these categories, we will perform stratified analy ses for each p hase in the 
vaccine rollout and examine an y differences in relative VE between time strata. 
If, through our anal yses in part 2 or as the result of additional clinical input, we determine 
our inability  to identify  patients eligible for vaccination during certain vaccination tiers 
will result in unobserved confounding that will materially  affect th e reliability  of our VE 
estimates, we will limit VE anal yses to certain time periods of interest for which we 
know vaccinations were restricted to a particular tier –in particular we may  drop anal yses 
focused on the time period only  healthcare workers wer e vaccinated and focus on time 
periods were vaccination is more widespread. 
9.7.3. Additional Analytic Elements for Test Negative and Full Cohort Design 
Other Anal yses for Both Designs: 
For cohort design, provide descriptive statistics and determine VE stratif ied by  viral 
strains determined to be important or prevalent based on sequencing anal ysesand 
compare between variants of interest .
Determine VE of BNT162b2 stratified by  various patient characteristics (e.g., age, 
sex, chronic medical conditions, receipt of influenza vaccine).  Table 2has the full 
list of proposed stratified anal yses.
Laboratory  Identification of Viral Strains
Residual nasophary ngeal or other respiratory  specimens tested for COVID- 19 as part of 
standard of care (SOC) ,will be collected daily from the two regional laboratories that serve 
the KPSC population.  Specimens will be saved .prior to being discarded for destruction .
Swabs will be retained at the study  site frozen until such time as they  are selected and sent 
for variant determination which may  include PCR and/or whole genome sequencing (WGS).  
090177e198c0ac48\Approved\Approved On: 02-Dec-2021 13:28 (GMT)
FDA-CBER-2022-5812-0236149
BNT162b2 
C4591014 NON -INTERVENTIONAL STUDY PROTOCOL
Version 2.0, 01Oct 3 01 D ecember 2021
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 2 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
15-Aug-2018
Page 41of 48WGS will occur for variants of interest, to identify circulating variants, and to assess VE 
against specific viral strains.  
Missing or Incomplete Data:
Based on extensive prior experience, we expect negligible or no missing data for de-
mographics, comorbidities, utilization, neighborhood characteristics (assessed through resi-
dential address data), COVID history , or societal- level factors. It is possible, however , that 
we will have missing data for occupation and LTCF variables. Regardless of missingness, we 
will present counts and percentages of missing data for all variables. If we find that data for 
variables included in the final models are highl y complete, we will proceed with complete 
case anal yses. If there is a substantial amount of missing data (>10%) for any  variables 
deemed necessary  to include in our final analy ses, sensitivity  anal ysis will be performed us-
ing multiple imputation for missing covariates (under the assumption of missing at random) 
to understand the impact of excluding patients with missing information in adjusted models.
Analysis Timings :
Prior to a final anal ysis, periodic interim anal yses may  be undertaken to understand attributes 
of eme rging variants, to assess preliminary  VE to respond to public health needs or to gauge 
sample size. Due to the observational nature of the study , no alpha adjustment will be ap-
plied. Any  interim anal yses will be described in the SAP.
9.8. Quality control
Data Quality Checks
Range checks and general frequency tables will be produced such that missing values, outli-
ers, and inappropriate or abnormal values will be identified.  Comparisons between date of 
birth, date of death, event dates and vaccination dates will be made.  All data will be checked 
for duplicate records.
A record of data quality  problems and resolutions will be kept through documented meeting 
minutes.  All inconsistencies and/or data quality  issues will be documented.  Revisions will 
be noted in or der to capture the change made, the change date, identification of the individual 
making the change, as well as noting an y further actions to be taken to identify  and/or resolve 
additional data quality  problems of this ty pe.
Select programming will be reviewed by  a second programmer. A report will be created, list-
ing discrepancies, their causes, and an y action taken to resolve them.  If there are discrepan-
cies due to a difference in the date on which the original and validation programs are run, 
both progra ms may  be run again on the same date as a means to eliminate this potential cause 
of discrepancies.
Confidentiality of Data 
090177e198c0ac48\Approved\Approved On: 02-Dec-2021 13:28 (GMT)
FDA-CBER-2022-5812-0236150
BNT162b2 
C4591014 NON -INTERVENTIONAL STUDY PROTOCOL
Version 2.0, 01Oct 3 01 D ecember 2021
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 2 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
15-Aug-2018
Page 42of 48Any research data containing subject protected health information (PHI) is confidential.  
KPSC staff will not discuss research data with an yone other than KPSC personnel. Pfizer 
will only  have access to aggregate data; no PHI will be shared with Pfizer. 
9.9.Limitations of the research methods
If essentiall y all vaccine recipients receive two doses, we would be limited to study ing the 
effect of 1 dose onl y during the time between doses, which could result in insufficient power 
to analy ze the effectiveness of 1dose. The ability to do certain stratified analy ses listed 
above will also be limited by  sample size and outcome rates in each of t hese groups.
Given the vaccine rollout to high-risk groups first and lower- risk groups later, the group who 
receives the vaccine initially  may  be significantly  different from the comparison population.  
In particular, HCW vaccinated during this period woul d primarily  be compared to non- HCW.  
While the rate of infection in HCW is largely  driven by  the rate of infection in the commu-
nity 1, this discrepancy  could result in a biased estimate.  Any  bias caused by  HCW being 
higher risk than the general population will tend to bias the estimate toward lower VE.  We 
will report E -values to quantify  the impact of unmeasured confounding factors.  The E- value 
is defined as the minimum strength of association on the risk ratio scale that an unmeasured 
confounder would n eed to have with both the exposure and the outcome, conditional on the 
measured covariates, to fully  explain away  a specific exposure -outcome association.  We will 
compare the E -value with covariate –outcome associations measured in concurrent literature 
(if available) that may have had data on HCW, employ ment status, or other unmeasured con-
founders and additionally compare the E -value with covariate –outcome associations among 
our measured covariates to determine if an y association is likely  to reach its mag nitude.   If 
we find it is not possible to overcome bias in earl y vaccine recipients using the TND or full 
cohort approach, we will exclude the earl y time period from anal ysis and begin the cohort at 
the time that a greater portion of the general public is able to receive the vaccine, resulting in 
a cohort start date when later batches of Pfizer vaccine are available.
9.10. Other aspects
Not applicable.
090177e198c0ac48\Approved\Approved On: 02-Dec-2021 13:28 (GMT)
FDA-CBER-2022-5812-0236151
BNT162b2 
C4591014 NON -INTERVENTIONAL STUDY PROTOCOL
Version 2.0, 01Oct 3 01 D ecember 2021
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 2 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
15-Aug-2018
Page 43of 4810.PROTECTION OF HUMAN SUBJECTS
10.1. Patient information 
All parties will comply  with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of patient personal data.  Such 
measures will include omitting patient names or other directl y ident ifiable data (PHI) in any  
reports, publications, or other disclosures, except where required b y applicable laws. 
The personal data will be stored at the study  site in encry pted electronic form and will be
password protected to ensure that only  authorized study  staff have access.  The study  site will 
implement appropriate technical and organizational measures to ensure that the personal data 
can be recovered in the event of disaster.  In the event of a potential personal data breach, the 
study  site shall be responsible for determining whether a personal data breach has in fact oc-
curred and, if so, providing breach notifications as required b y site and or/law.
To protect the rights and freedoms of natural persons with regard to the processing of per-
sonal data , , when stud y data are compiled for transfer to Pfizer and other authorized parties, 
patient names will be removed and will be replaced by  a single, specific, numerical code, 
based on a numbering s ystem defined b y Pfizer .  All other identifiable data tran sferred to 
Pfizer or other authorized parties will be identified by  this single, patient -specific code. The 
investigator site will maintain a confidential list of patients who participated in the study , 
linking each patient’s numerical code to his or her actual identity .  In case of data transfer, 
Pfizer will maintain high standards of confidentiality  and protection of patients’ personal data 
consistent with the clinical study agreement and applicable privacy  laws.
10.2. Patient consent
This is a nobservational database anal ysis study  of existing healthcare data; no patients will 
be activel y enrolled.  As this stu dy does not involve data subject to privacy laws according to 
applicable legal requirements, obtaining informed consent from patients b y Pfizer is not re-
quired.  T he site will obtain a waiver for obtaining informed consent from the KPSC I RB.  
10.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)
There must be prospective approval of the study  protocol, protocol amendments, and other 
relevant documents (e.g., informed consent forms if applicable or appropriate waiver for con-
sent) from the rele vant IRBs/IECs.  All correspondence with the IRB/IEC must be retained.  
Copies of I RB/IEC approvals must be forwarded to Pfizer. 
10.4. Ethical conduct of the study
The study  will be conducted in accordance with legal and regulatory  requirements, as well as 
with scientific purpose, value and rigor and follow generall y accepted research practices. 
090177e198c0ac48\Approved\Approved On: 02-Dec-2021 13:28 (GMT)
FDA-CBER-2022-5812-0236152
BNT162b2 
C4591014 NON -INTERVENTIONAL STUDY PROTOCOL
Version 2.0, 01Oct 3 01 D ecember 2021
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 2 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
15-Aug-2018
Page 44of 4811.MANAGEMENT AND REPOR TING OF ADVERSE EVEN TS/ADVERSE REAC-
TIONS
This study  involves electronic health record data that exist as structured data by  the time of 
study  start or a combination of existing structured data and unstructured data, which will be 
converted to structured form during the implementation of the protocol solely b y a computer 
using automated/algorithmic methods, such as natural language processing.
In these data sources, individual patient data are not retrieved or validated, and it is not pos-
sible to link (i.e., identify a potential association between) a particular product and medical 
event for an y individual.  Thus, the minimum criteria for reporting an a dverse event (AE) 
(i.e., identifiable patient, identifiable reporter, a suspect product, and event) cannot be met .
12.PLANS FOR DISSEMINAT ING AND COMMUNICATING STUDY RESULTS
The Investigator will have primary  responsibility  for the expedient preparation, review and 
submission of any  manuscripts, abstracts, press releases or other publications detailing the 
study ’s procedures or findings. The study team will follow the I nternational Committee of 
Medical Journal Editors (ICMJE) criteria to determine authors, and all authors who meet 
these criteria will be offered authorship. We anticipate that as a collaborative project, mem-
bers of each of the study  organizations (KPSC and Pfizer ) will participate. Each organization 
will determine members that meet authorship criteria.  An y publication will include a list of 
investigators, with authors being determined in line with the I CMJE guidelines, as well as an 
acknowledgement of roles of th e study  Sponsor and Funder(s). 
In the event of an y prohibition or restriction imposed (e.g., clinical hold) by an applicable 
competent authorit y in any area of the world, or if the investigator is aware of an y new infor-
mation which might influence the eva luation of the benefits and risks of a Pfizer product, 
Pfizer should be informed immediately .  
090177e198c0ac48\Approved\Approved On: 02-Dec-2021 13:28 (GMT)
FDA-CBER-2022-5812-0236153
BNT162b2 
C4591014 NON -INTERVENTIONAL STUDY PROTOCOL
Version 2.0, 01Oct 3 01 D ecember 2021
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 2 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
15-Aug-2018
Page 45of 4813.REFERENCES
1. Walsh EE, Frenck RW, Jr., Falsey  AR, et al. Safety  and I mmunogenicity of Two 
RNA -Based Covid-19 Vaccine Candidates. N Engl J Med. 2020;383(25):2 439-2450.
2. Polack FP, Thomas SJ, Kitchin N, et al. Safet y and Efficacy of the BNT162b2 mRNA 
Covid -19 Vaccine. N Engl J Med. 2020;383(27):2603-2615.
3. Tartof SY, Qian L, Hong V, et al. Obesit y and Mortality Among Patients Diagnosed 
With COVID -19: Results From an Integrated Health Care Organization. Ann Intern 
Med. 2020;173(10):773 -781.
4. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality  of adult inpa-
tients with COVI D-19 in Wuhan, China: a retrospective cohort study . Lancet. 
2020;3 95(10229):1054- 1062.
5. Webb Hooper M, Napoles AM, Perez -Stable EJ. COVID -19 and Racial/Ethnic Dis-
parities. JAMA. 2020;323(24):2466-2467.
6. Petrilli CM, Jones SA, Yang J, et al. Factors associated with hospital admission and 
critical illness among 5279 pe ople with coronavirus disease 2019 in New York City : 
prospective cohort study . BMJ. 2020;369:m1966.
7. Wu Z, McGoogan JM. Characteristics of and Important Lessons From the Corona-
virus Disease 2019 (COVID -19) Outbreak in China: Summary  of a Report of 72314 
Cases From the Chinese Center for Disease Control and Prevention. JAMA. 
2020;323(13):1239 -1242.
8. Centers for Disease Control and Prevention. COVID -19 and People with Certain 
Medical Conditions. 2021; https://www.cdc.gov/coronavirus/2019 -ncov/need -extra -
precautions/people -with-medical -conditions.html . Accessed March 2, 2021.
090177e198c0ac48\Approved\Approved On: 02-Dec-2021 13:28 (GMT)
FDA-CBER-2022-5812-0236154
BNT162b2 
C4591014 NON -INTERVENTIONAL STUDY PROTOCOL
Version 2.0, 01Oct 3 01 D ecember 2021
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 2 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
15-Aug-2018
Page 46of 4814.LIST OF TABLES
Table 1. TND Study  Design Proposed Objectives ................................ ................. 15
Table 2. Full Cohort Study  Design Proposed Objectives ................................ .......17
Table 3. Factors to be considered in models ................................ ........................... 28
Table 4. Total number of events needed to provide 90% power to det ect a 
given VE ................................ ................................ ................................ ...30
Table 5. COVID VE Sample Size ................................ ................................ .......... 32
15.LIST OF FIGURES
None
16.ANNEX 1. LIST OF STAND ALONE DOCUMENTS
None
17.ANNEX 2. ADDITIONAL INFORMATION
Appendix Table 1:  Acute Respiratory  Infection Diagnosis codes (International Classification 
of Diseases [ICD] codes)
ICD-10 code ICD-10 definition
J12.0 Adenoviral pneumonia
J12.1 Respiratory syncytial virus pneumonia
J12.2 Parainfluenza virus pneumonia
J12.81 Pneumonia due to SARS -associated coronavirus
J12.3 Human metapneumovirus pneumonia
J12.89 Other viral pneumonia
J12.9 Viral pneumonia, unspecified
J13 Pneumonia due to Streptococcus pneumoniae
J18.1 Lobar pneumonia, unspecified organism
J15.0 Pneumonia due to Klebsiella pneumoniae
J15.1 Pneumonia due to Pseudomonas
J14 Pneumonia due to Hemophilus influenzae
J15.4 Pneumonia due to other streptococci
J15.4 Pneumonia due to other streptococci
J15.3 Pneumonia due to streptococcus, group B
090177e198c0ac48\Approved\Approved On: 02-Dec-2021 13:28 (GMT)
FDA-CBER-2022-5812-0236155
BNT162b2 
C4591014 NON -INTERVENTIONAL STUDY PROTOCOL
Version 2.0, 01Oct 3 01 D ecember 2021
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 2 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
15-Aug-2018
Page 47of 48ICD-10 code ICD-10 definition
J15.4 Pneumonia due to other streptococci
J15.20 Pneumonia due to staphylococcus, unspecified
J15.211 Pneumonia due to Methicillin susceptible Staphylococcus aureus
J15.212 Pneumonia due to Methicillin resistant Staphylococcus aureus
J15.29 Pneumonia due to other staphylococcus
J15.8 Pneumonia due to other specified bacteria
J15.5 Pneumonia due to Escherichia coli
J15.6 Pneumonia due to other Gram -negative bacteria
A48.1 Legionnaires' disease
J15.8 Pneumonia due to other specified bacteria
J15.9 Unspecified bacterial pneumonia
J15.7 Pneumonia due to Mycoplasma pneumoniae
J16.0 Chlamydial pneumonia
J16.8 Pneumonia due to other specified infectious organisms
B25.0 Cytomegaloviral pneumonitis
A37.01 Whooping cough due to Bordetella pertussis with pneumonia
A37.11 Whooping cough due to Bordetella parapertussis with pneumonia
A37.81 Whooping cough due to other Bordetella species with pneumonia
A37. 91 Whooping cough, unspecified species with pneumonia
A22.1 Pulmonary anthrax
B44.0 Invasive pulmonary aspergillosis
J17 Pneumonia in diseases classified elsewhere
B77.81 Ascariasis pneumonia
J17 Pneumonia in diseases classified elsewhere
J18.0 Bronchopneumonia, unspecified organism
J18.8 Other pneumonia, unspecified organism
J18.9 Pneumonia, unspecified organism
J10.00 Influenza due to other identified influenza virus with unspecified type of pneu-
monia
J10.01 Influenza due to other identified influenza virus with the same other identified 
influenza virus pneumonia
J10.08 Influenza due to other identified influenza virus with other specified pneumonia
J11.00 Influenza due to unidentified influenza virus with unspecified type of pneu monia
J11.08 Influenza due to unidentified influenza virus with specified pneumonia
J12.9 Viral pneumonia, unspecified
J10.1 Influenza due to other identified influenza virus with other respiratory manifes-
tations
090177e198c0ac48\Approved\Approved On: 02-Dec-2021 13:28 (GMT)
FDA-CBER-2022-5812-0236156
BNT162b2 
C4591014 NON -INTERVENTIONAL STUDY PROTOCOL
Version 2.0, 01Oct 3 01 D ecember 2021
PFIZER CONFIDENTIAL
CT24- WI-GL02 -RF02 2 .0 Non-Interventional Study Protocol Template For Secondary Data Collection Study
15-Aug-2018
Page 48of 48ICD-10 code ICD-10 definition
J11.1 Influenza due to unidentified influenza virus with other respiratory manifesta-
tions
J10.2 Influenza due to other identified influenza virus with gastrointestinal manifesta-
tions
J10.81 Influenza due to other identified influenza virus with encephalopathy
J10.82 Influenza due to other identified influenza virus with myocarditis
J10.83 Influenza due to other identified influenza virus with otitis media
J10.89 Influenza due to other identified influenza virus with other manifestations
J11.2 Influenza due to unidentified influenza virus with gastrointestinal manifestations
J11.81 Influenza due to unidentified influenza virus with encephalopathy
J11.82 Influenza due to unidentified influenza virus with myocarditis
J11.83 Influenza due to unidentified influenza virus with otitis me dia
J11.89 Influenza due to unidentified influenza virus with other manifestations
J09.X1 Influenza due to identified novel influenza A virus with pneumonia
J09.X2 Influenza due to identified novel influenza A virus with other respiratory mani-
festations
J09.X3 Influenza due to identified novel influenza A virus with gastrointestinal manifes-
tations
J09.X9 Influenza due to identified novel influenza A virus with other manifestations
J10.08 Influenza due to other identified influenza virus with other spe cified pneumonia
J10.1 Influenza due to other identified influenza virus with other respiratory manifes-
tations
J09.X9 Influenza due to identified novel influenza A virus with other manifestations
J09.X1 Influenza due to identified novel influenza A virus with pneumonia
J09.X2 Influenza due to identified novel influenza A virus with other respiratory mani-
festations
J09.X3 Influenza due to identified novel influenza A virus with gastrointestinal manifes-
tations
J09.X9 Influenza due to identified novel influenza A virus with other manifestations
090177e198c0ac48\Approved\Approved On: 02-Dec-2021 13:28 (GMT)
FDA-CBER-2022-5812-0236157