A PHASE 1, RANDOMIZED, OPEN-LABEL TRIAL TO EVALUATE THE SAFETY AND IMMUNOGENICITY OF PNEUMOCOCCAL CONJUGATE FORMULATIONS IN HEALTHY ADULTS 18 THROUGH 49 YEARS OF AGE
Phase: PHASE1
Conditions: Pneumococcal Disease
Sponsor: Pfizer

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A PHASE 1, RANDOMIZED, OPEN-LABEL TRIAL TO EVALUATE THE SAFETY 
AND IMMUNOGENICITY OF PNEUMOCOCCAL CONJUGATE 
FORMULATIONS IN HEALTHY ADULTS 18 THROUGH 49 YEARS OF AGE
Study Intervention Number:
Study Intervention Name:
N/A
US IND Number:
TBD
EudraCT/CTIS Number:
N/A
ClinicalTrials.gov ID:
TBD
Pediatric Investigational Plan Number:
N/A
Protocol Number:
C4801001
Phase:
Phase 1
Brief Title: A Phase 1 Study to Evaluate the Safety and Immunogenicity of Pneumococcal 
Conjugate Formulations in Healthy Adults 18 Through 49 Years of Age 
 
 
 
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Document History
Document
Version Date
Original protocol
26 May 2022
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................8
1. PROTOCOL SUMMARY.....................................................................................................9
1.1. Synopsis ....................................................................................................................9
1.2. Schema ....................................................................................................................17
1.3. Schedule of Activities .............................................................................................18
2. INTRODUCTION ...............................................................................................................21
2.1. Study Rationale .......................................................................................................21
2.2. Background .............................................................................................................21
2.3. Benefit/Risk Assessment.........................................................................................23
2.3.1. Risk Assessment.........................................................................................25
2.3.2. Benefit Assessment.....................................................................................27
2.3.3. Overall Benefit/Risk Conclusion................................................................27
3. OBJECTIVES, ENDPOINTS, AND ESTIMANDS ...........................................................27
4. STUDY DESIGN.................................................................................................................28
4.1. Overall Design.........................................................................................................28
4.2. Scientific Rationale for Study Design.....................................................................30
4.2.1. Diversity of Study Population ....................................................................31
4.2.2. Choice of Contraception/Barrier Requirements .........................................32
4.3. Justification for Dose ..............................................................................................32
4.4. End of Study Definition ..........................................................................................32
5. STUDY POPULATION......................................................................................................32
5.1. Inclusion Criteria.....................................................................................................33
5.2. Exclusion Criteria....................................................................................................34
5.3. Lifestyle Considerations..........................................................................................35
5.3.1. Contraception..............................................................................................35
5.4. Screen Failures ........................................................................................................36
5.5. Criteria for Temporarily Delaying 
Enrollment/Randomization/Administration of Study Intervention...........................36
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY.................................36
6.1. Study Intervention(s) Administered........................................................................38
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6.1.1. Administration............................................................................................40
6.1.2. Medical Devices .........................................................................................40
6.2. Preparation, Handling, Storage, and Accountability...............................................40
6.2.1. Preparation and Dispensing........................................................................42
6.3. Assignment to Study Intervention...........................................................................42
6.4. Blinding...................................................................................................................42
6.4.1. Blinding of Participants..............................................................................42
6.4.2. Blinding of Site Personnel..........................................................................42
6.4.3. Blinding of the Sponsor..............................................................................43
6.5. Study Intervention Compliance...............................................................................43
6.6. Dose Modification...................................................................................................43
6.7. Continued Access to Study Intervention After the End of the Study......................43
6.8. Treatment of Overdose............................................................................................43
6.9. Prior and Concomitant Therapy ..............................................................................44
6.9.1. Prohibited During the Study.......................................................................44
6.9.2. Permitted During the Study ........................................................................44
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................44
7.1. Discontinuation of Study Intervention ....................................................................44
7.2. Participant Discontinuation/Withdrawal From the Study.......................................45
7.2.1. Withdrawal of Consent...............................................................................45
7.3. Lost to Follow-Up ...................................................................................................46
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................46
8.1. Administrative Procedures ......................................................................................46
8.2. Efficacy and/or Immunogenicity Assessments .......................................................47
8.2.1. Biological Samples.....................................................................................48
8.3. Safety Assessments .................................................................................................48
8.3.1. Participant Electronic Diary .......................................................................49
8.3.2. Grading Scale for Prompted Events ...........................................................49
8.3.2.1. Local Reactions.........................................................................49
8.3.2.2. Systemic Events ........................................................................50
8.3.3. Physical Examinations................................................................................52
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8.3.4. Vital Signs ..................................................................................................52
8.3.5. Clinical Safety Laboratory Assessments ....................................................52
8.3.6. Pregnancy Testing ......................................................................................52
8.4. Adverse Events, Serious Adverse Events, and Other Safety Reporting .................53
8.4.1. Time Period and Frequency for Collecting AE and SAE Information.......53
8.4.1.1. Reporting SAEs to Pfizer Safety...............................................54
8.4.1.2. Recording Nonserious AEs and SAEs on the CRF...................54
8.4.2. Method of Detecting AEs and SAEs ..........................................................54
8.4.3. Follow-Up of AEs and SAEs......................................................................54
8.4.4. Regulatory Reporting Requirements for SAEs...........................................55
8.4.5. Environmental Exposure, Exposure During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................55
8.4.5.1. Exposure During Pregnancy......................................................55
8.4.5.2. Exposure During Breastfeeding ................................................57
8.4.5.3. Occupational Exposure .............................................................57
8.4.6. Cardiovascular and Death Events...............................................................58
8.4.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................58
8.4.8. Adverse Events of Special Interest.............................................................58
8.4.8.1. Lack of Efficacy........................................................................58
8.4.9. Medical Device Deficiencies......................................................................58
8.4.9.1. Time Period for Detecting Medical Device Deficiencies .........58
8.4.9.2. Follow-Up of Medical Device Deficiencies..............................59
8.4.9.3. Prompt Reporting of Device Deficiencies to the Sponsor ........59
8.4.9.4. Regulatory Reporting Requirements for Device 
Deficiencies .......................................................................................59
8.4.10. Vaccination Errors....................................................................................59
8.5. Pharmacokinetics ....................................................................................................60
8.6. Genetics...................................................................................................................61
8.6.1. Specified Genetics ......................................................................................61
8.6.2. Retained Research Samples for Genetics ...................................................61
8.7. Biomarkers ..............................................................................................................61
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8.8. Immunogenicity Assessments.................................................................................61
8.9. Health Economics ...................................................................................................61
8.10. Study Procedures...................................................................................................61
8.10.1. Visit 1 – Study Intervention Administration – Day 1...............................61
8.10.2. Visit 2 – Follow-Up After Study Intervention Administration – 28 
to 42 Days After Study Intervention Administration.......................................64
8.10.3. Unscheduled Visit for a Grade 3 Systemic Event or Suspected 
Grade 4 Reaction..............................................................................................64
9. STATISTICAL CONSIDERATIONS ................................................................................65
9.1. Statistical Hypothesis ..............................................................................................66
9.1.1. Estimands....................................................................................................66
9.2. Analysis Sets ...........................................................................................................66
9.3. Statistical Analyses .................................................................................................67
9.3.1. General Considerations...............................................................................67
9.3.1.1. Analyses for Binary Data ..........................................................67
9.3.1.2. Analyses for Continuous Data...................................................67
9.3.2. Primary Endpoint(s)/Estimand(s) Analysis ................................................68
9.3.3. Secondary Endpoint(s)/Estimand(s) Analysis............................................68
9.4. Interim Analyses .....................................................................................................69
9.4.1. Analysis Timing..........................................................................................69
9.5. Sample Size Determination.....................................................................................69
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................71
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............71
10.1.1. Regulatory and Ethical Considerations ....................................................71
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................71
10.1.2. Financial Disclosure .................................................................................72
10.1.3. Informed Consent Process ........................................................................72
10.1.4. Data Protection .........................................................................................73
10.1.5. Committees Structure ...............................................................................73
10.1.5.1. Data Monitoring Committee ...................................................73
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10.1.6. Dissemination of Clinical Study Data ......................................................73
10.1.7. Data Quality Assurance ............................................................................75
10.1.8. Source Documents....................................................................................76
10.1.9. Study and Site Start and Closure ..............................................................76
10.1.10. Publication Policy...................................................................................77
10.1.11. Sponsor’s Medically Qualified Individual..............................................78
10.2. Appendix 2: Clinical Laboratory Tests .................................................................79
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting .....................................................................80
10.3.1. Definition of AE .......................................................................................80
10.3.2. Definition of an SAE ................................................................................81
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During 
the Active Collection Period............................................................................83
10.3.4. Reporting of SAEs....................................................................................86
10.4. Appendix 4: Contraceptive and Barrier Guidance ................................................88
10.4.1. Male Participant Reproductive Inclusion Criteria....................................88
10.4.2. Female Participant Reproductive Inclusion Criteria.................................88
10.4.3. Woman of Childbearing Potential ............................................................89
10.4.4. Contraception Methods.............................................................................90
10.5. Appendix 5: Genetics............................................................................................92
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments .......93
10.7. Appendix 7: Kidney Safety Monitoring Guidelines .............................................95
10.7.1. Laboratory Assessment of Change in Kidney Function and 
Detection of Kidney Injury..............................................................................95
10.7.2. Age-Specific Kidney Function Calculation Recommendations...............95
10.7.2.1. Adults (18 Years and Above)—2021 CKD-EPI 
Equations...........................................................................................95
10.7.3. Adverse Event Grading for Kidney Safety Laboratory 
Abnormalities...................................................................................................95
10.8. Appendix 8: AEs, ADEs, SAEs, SADEs, USADEs, and Device 
Deficiencies: Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting in Medical Device Studies .............................................96
10.8.1. Definition of AE and ADE .......................................................................96
10.8.2. Definition of SAE, SADE, and USADE ..................................................96
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10.8.3. Definition of Device Deficiency...............................................................97
10.8.4. Recording/Reporting and Follow-Up of Medical Device 
Deficiencies......................................................................................................97
10.8.5. Reporting of SAEs....................................................................................99
10.8.6. Reporting of SADEs.................................................................................99
10.9. Appendix 9: Abbreviations .................................................................................100
11. REFERENCES ................................................................................................................103
LIST OF TABLES
Table 1.
Study Intervention Groups........................................................................29
Table 2.
Grading Scales for Local Reactions .........................................................50
Table 3.
Grading Scales for Systemic Events.........................................................51
Table 4.
Ranges for Fever.......................................................................................52
Table 5.
Probability of Detecting at Least 1 Adverse Event in a Study Group......70
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1. PROTOCOL SUMMARY 
1.1. Synopsis
Protocol Title: A Phase 1, Randomized, Open-Label Trial to Evaluate the Safety and 
Immunogenicity of Pneumococcal Conjugate Formulations in Healthy Adults 18 Through 
49 Years of Age
Brief Title: A Phase 1 Study to Evaluate the Safety and Immunogenicity of Pneumococcal 
Conjugate Formulations in Healthy Adults 18 Through 49 Years of Age
Regulatory Agency Identification Number(s):
US IND Number:
TBD
[EudraCT/CTIS] Number:
N/A
ClinicalTrials.gov ID:
TBD
Pediatric Investigational Plan Number:
N/A
Protocol Number:
C4801001
Phase:
Phase 1
Rationale:
Streptococcus pneumoniae causes invasive (eg, meningitis, sepsis, bacteremic pneumonia) 
and noninvasive (eg, OM, nonbacteremic pneumonia, sinusitis) disease associated with 
significant healthcare burden, morbidity, and mortality. 13vPnC (Prevnar 13®) was licensed
by the FDA and other countries for use in infants and young children for the prevention of 
pneumococcal disease more than a decade ago. It was subsequently indicated for prevention 
of pneumonia in adults ≥18 years of age. 13vPnC has been introduced into national 
immunization programs for pediatric and adult populations around the world. 20vPnC was 
developed to expand protection against pneumococcal invasive disease and pneumonia and 
has been approved by the FDA and EMA for adults ≥18 years of age. 20vPnC contains the 
identical polysaccharide conjugates and excipients as 13vPnC but with additional conjugate 
polysaccharides for 7 additional serotypes.
 
 
 
 
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This randomized, open-label Phase 1 study is designed to evaluate the safety and 
immunogenicity of
 
Objectives, Endpoints, and Estimands:
Objectives
Endpoints
Estimands
Primary:
Primary:
Primary:
To describe the safety profile of 
candidates in adults 
18 through 49 years of age
•
Prompted local reactions 
(redness, swelling, and pain at 
the injection site)
•
Prompted systemic events 
(fever, headache, fatigue, 
muscle pain, and joint pain)
•
AEs
•
SAEs
In participants receiving the study 
intervention from each group, the 
percentage of participants
reporting:
•
Prompted local reactions 
within 7 days after 
administration
•
Prompted systemic events 
within 7 days after 
administration
•
AEs within 1 month after 
administration
•
SAEs within 1 month after 
administration
Secondary: 
Secondary:
Secondary:
To describe the immune responses 
elicited by the 
candidates
•
OPA titers 
In participants complying with the 
key protocol criteria (evaluable 
participants) from each group:
•
 OPA GMTs 
1 month after administration
Overall Design:
This is a Phase 1, multicenter, randomized, open-label study to evaluate alternative
 This study will be 
conducted at investigator sites in the US. Approximately 405 adults 18 through 49 years of 
age with no history of pneumococcal vaccination will be enrolled. Participants will be 
enrolled and randomized equally to 1 of 9 groups (45 participants per group): 6 groups will 
receive 1 of 6 different 
candidates and 3 groups will receive either
, 
13vPnC, or PCV15 (see Study Intervention Groups table below).
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There are 3 preformulated products that will be administered at 2 different volumes to create 
the 6 different 
candidates
 
 
 
 
All formulations include AlPO4.
The key control group will receive polysaccharide conjugate
 
 contained in 13vPnC (Prevnar 13) and 20vPnC (Prevnar 20™). In addition, 
PCV15 (Vaxneuvance [Merck]) and 13vPnC are both licensed in the US for use in adults and
will be included as supplemental controls.
Study Intervention Groups
Group
Carrier 
Protein 
Chemistry
Polysaccharide 
Dose
Dose Volume
n
45
45
45
45
45
45
45
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Study Intervention Groups
Group
Carrier 
Protein 
Chemistry
Polysaccharide 
Dose
Dose Volume
n
PCV15 (control)
N/A
N/A
0.5 mL
45
13vPnC (control)
CRM197
RAC
0.5 mL
45
Abbreviations: N/A = not applicable; RAC = reductive amination chemistry; 
 
On Day 1 (Visit 1), participants will be assessed for eligibility, have blood drawn for 
immunogenicity assessments, receive a dose of 1 of the 
candidates or controls, be 
observed for 30 minutes after administration, and receive safety follow-up and e-diary 
instructions. The study interventions will be prepared and administered by designated staff.
Local reactions (pain, redness, and swelling) occurring at the injection site and systemic 
events (fever, fatigue, headache, muscle pain, and joint pain) will be prompted for and 
collected daily in an e-diary from Day 1 through Day 7 after administration of study 
intervention, where Day 1 is the day of administration. AEs (including nonserious AEs and 
SAEs) will be assessed for approximately 1 month after study intervention administration 
(through Visit 2).
At Visit 2 (28-42 days after Visit 1), participants will return for follow-up. Information will 
be collected from the participants on AEs and e-diary follow-up (as needed), and blood will 
be drawn for immunogenicity assessments.
Approximately 15 participants from each group will be enrolled at specialty sites that will 
collect 
 
and approximately 20 mL for sera for OPA and IgG measurements. The remaining 
participants enrolled at other sites will have 60 mL of blood drawn for sera for OPA and IgG 
measurements.
Number of Participants:
Approximately 405 participants (approximately 45 per group) will be randomized to study 
intervention.
Study Population:
Key inclusion and exclusion criteria are listed below (for the full set of criteria, 
see Section 5.1 and Section 5.2 of this protocol):
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Inclusion Criteria
Participants must meet the following key inclusion criteria to be eligible for enrollment into 
the study:
1. Male or female participants ≥18 and ≤49 years of age at the time of consent.
2. Adults determined by clinical assessment (including medical history and clinical 
judgment) to be eligible for the study, including adults with preexisting stable disease 
(defined as disease not requiring significant change in therapy or hospitalization for 
worsening disease) within 12 weeks before receipt of study intervention.
3. Female participants of childbearing potential or male participants who are able to 
father children and are willing to use acceptable methods of contraception for at least 
28 days after the dose of study intervention; or female participants not of childbearing 
potential; or male participants not able to father children.
Note: Female participants of nonchildbearing potential must meet the criteria 
described in the WOCBP section of the protocol.
4. Capable of giving signed informed consent, which includes compliance with the
requirements and restrictions listed in the ICD and in this protocol.
Exclusion Criteria 
Participants with any of the following characteristics/conditions will be excluded:
1. History of severe adverse reaction associated with a vaccine and/or severe allergic 
reaction (eg, anaphylaxis) to any component in pneumococcal conjugate vaccines and 
any other diphtheria toxoid–containing vaccine.
2. Serious chronic disorder, including metastatic malignancy, severe COPD requiring 
supplemental oxygen, end-stage renal disease with or without dialysis, cirrhosis of the 
liver, clinically unstable cardiac disease, or any other disorder that in the 
investigator’s opinion would make the participant inappropriate for entry into the 
study.
3. Other medical or psychiatric condition including recent (within the past year) or 
active suicidal ideation/behavior or laboratory abnormality that may increase the risk 
of study participation or, in the investigator’s judgment, make the participant 
inappropriate for the study.
4. Known or suspected immunodeficiency or other conditions associated with 
immunosuppression, including, but not limited to, immunoglobulin class/subclass 
deficiencies, generalized malignancy, HIV infection, leukemia, lymphoma, or organ 
or bone marrow transplant.
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5. Congenital, functional, or surgical asplenia.
6. Current febrile illness (body temperature ≥100.4°F [≥38.0°C]) or other acute illness 
within 48 hours before study intervention administration.
7. Previous vaccination with any licensed or investigational pneumococcal vaccine, or 
planned receipt of any licensed or investigational pneumococcal vaccine through 
study participation.
8. Currently receives treatment with immunosuppressive therapy, including cytotoxic 
agents or systemic corticosteroids, or planned receipt through the last blood draw 
(Visit 2). Participants may not be enrolled if corticosteroids were administered within 
28 days before study intervention administration. Inhaled/nebulized, intra-articular, 
intrabursal, or topical (skin, eyes, or ears) corticosteroids are permitted.
9. Receipt of blood/plasma products or immunoglobulin within the 60 days before study 
intervention administration, or planned receipt during study participation.
10. Receipt of any inactivated or otherwise nonlive vaccine within 14 days or any live 
vaccine within 28 days before administration of study intervention.
11. Participation in other studies involving investigational drugs, investigational vaccines 
(except for investigational pandemic vaccines recommended and authorized in this 
population for emergency use), or investigational devices within 28 days prior to 
study entry and/or during study participation. Participation in purely observational 
studies is acceptable.
Study Arms and Duration:
Each participant will participate in the study for approximately 1 month (Visit 1 through 
Visit 2). The study duration is estimated to be approximately 2 months.
 
 of the controls 
, 13vPnC 
and PCV15) will be administered intramuscularly in the deltoid muscle of the preferably
nondominant arm by a site staff member or designee. The preformulated products and 
controls will be provided to the site by the sponsor.
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Study Intervention(s)
Intervention 
Name
(Formulations)
 
 
 
 
 
 
 
 
 
 
 
13vPnC 
(Prevnar 13)
0.5 mL 
suspension for 
injection
Vaxneuvance
(pneumococcal 
15-valent 
conjugate 
vaccine)
suspension for 
injection
Arm name
(group of 
participants 
receiving a 
specific 
intervention or
no intervention)
 
 
 
 
 
 
 
 
 
13vPnC control 
group
PCV15 control 
group
Dose volume
 
 
 
 
 
 
 
0.5 mL
administered
0.5 mL
administered
Route of 
administration
Intramuscular 
injection
Intramuscular 
injection
Intramuscular 
injection
Intramuscular 
injection
Intramuscular 
injection
Intramuscular 
injection
Intramuscular 
injection
Intramuscular 
injection
Intramuscular 
injection
Use
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Control
Control
Control
IMP or 
NIMP/AxMP
IMP 
IMP 
IMP 
IMP 
IMP
IMP
IMP
NIMP
NIMP
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Statistical Methods:
The study size of this Phase 1 study is not based on any formal hypothesis test for safety or 
immunogenicity results. All statistical analyses will be descriptive.
The primary objective is to describe the safety profile of the 
 candidates; this will be 
done by summary statistics (including counts and percentages of participants and the 
associated 2-sided 95% CIs) for local reactions, systemic events, AEs, and SAEs for each 
study intervention group. With 45 participants per study group, the study will provide a 
greater than 90% chance of observing at least 1 AE in each group if the true rate is at 
least 5%.
The secondary objective will be to describe the pneumococcal immunogenicity of the 
 
candidates by summarizing OPA GMTs approximately 1 month after study intervention 
administration for each group. The corresponding 95% CI for the GMTs will also be 
provided.
Ethical Considerations:
Participants enrolled in this study are in an age group that is not currently covered by the 
indication for vaccines containing 
 conjugate. These participants are relatively 
healthy and therefore are not recommended for pneumococcal conjugate vaccines. Receiving 
the 
candidates or controls will not interfere with the standard of care for these 
participants. For those with risk factors for pneumococcal vaccination, the investigator site 
and ICD will inform participants to seek advice from their healthcare provider regarding the 
need for immunization after the study.
The study will provide the immune impact of
 
 
that could potentially benefit adults and children.
The investigational 
candidates have not yet been evaluated in clinical studies; 
therefore, the initial safety data will be generated in this 
Phase 1 study. 
 
 
 
 
The most common AEs noted in adults after vaccination with 20vPnC 
are primarily related to local reactions (injection site pain, redness, and swelling) and 
systemic events (fever, headache, fatigue, joint pain, and muscle pain). Safety reviews of data 
from the 3 completed Phase 3 adult trials has not revealed any unexpected safety concerns.
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1.3. Schedule of Activities
The SoA table provides an overview of the protocol visits and procedures. Refer to the STUDY ASSESSMENTS AND 
PROCEDURES section of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol.
The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA table, in order to conduct evaluations or 
assessments required to protect the well-being of the participant.
Visit Identifier
Visit 1
Visit 2
Notes
Visit Description 
Study Intervention 
Administration
Follow-Up After Study Intervention 
Administration
Visit Window (Days)
Day 1
28 to 42 Days After IP 
Administration
•
See Section 8.4.3 for follow-up AE and SAE assessments.
Obtain informed consent
X
•
Informed consent should be obtained prior to undergoing any 
study-specific procedures.
•
See Section 10.1.3 for additional information.
Assign participant number 
via the IRT
X
Record demography
X
Perform clinical 
assessment, including 
medical history 
X
Record nonstudy 
vaccinations
X
X
Record concomitant 
medication use for 
treatment of SAEs
X
X
Obtain oral temperature
prior to study intervention
administration
X
Contraception check, if 
applicable
X
X
•
See Section 10.4 for additional information.
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Visit Identifier
Visit 1
Visit 2
Notes
Visit Description 
Study Intervention 
Administration
Follow-Up After Study Intervention 
Administration
Visit Window (Days)
Day 1
28 to 42 Days After IP 
Administration
•
See Section 8.4.3 for follow-up AE and SAE assessments.
Perform urine pregnancy 
test for female participants 
of childbearing potential
X
•
See Section 8.3.6 for additional information.
Review inclusion and 
exclusion criteria
X
•
The investigator or designee will inform the participant of the need 
to use highly effective contraception consistently and correctly until 
28 days after the last dose of the study intervention and document 
the conversation and the participant’s affirmation in the 
participant’s chart.
Review continued 
eligibility 
X
Assign randomization 
number via the IRT
X
Specialty sites: Obtain 
blood sample for 
immunogenicity assessment 
 
~20 mL (for 
immunogenicity) 
 
~20 mL (for immunogenicity) 
•
Blood samples from participants enrolled at specialty sites 
(n=15/group).
•
 
Other sites: Obtain blood 
sample for immunogenicity 
assessment
~60 mL
~60 mL
•
Blood sample for Visit 1 will be collected prior to administration.
Administer study 
intervention
X
•
See Section 6.1 for additional information.
Observe and record acute 
reactions for 30 minutes 
after study intervention 
administration
X
Provide a participant 
contact card
X
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Visit Identifier
Visit 1
Visit 2
Notes
Visit Description 
Study Intervention 
Administration
Follow-Up After Study Intervention 
Administration
Visit Window (Days)
Day 1
28 to 42 Days After IP 
Administration
•
See Section 8.4.3 for follow-up AE and SAE assessments.
Provide participant with an 
e-diary (device or 
application), thermometer, 
and measuring device, and 
instruct to collect prompted 
local reactions and systemic 
events
X
•
Participants will record in an e-diary prompted local reactions and 
systemic events occurring within 7 days after administration. 
Instruct the participant to complete the e-diary from Day 1 through 
Day 7, with Day 1 being the day of study intervention 
administration. Participants will be instructed to contact the study 
staff or investigator if they experience redness or swelling 
measuring >20 measuring device units, severe pain at the injection 
site, or any Grade 4 prompted systemic event.
Review e-diary
X
•
Designated site staff will review e-diary data online at frequent 
intervals (daily is optimal) for the 7 days following administration 
to evaluate participant compliance and reported events as part of the 
ongoing safety review.
Collect e-diary or assist the 
participant to delete the 
application
X
•
Any e-diary devices given to participants are to be collected at 
Visit 2.
Record and report AEs and 
SAEs
X-------------------X
•
AEs include nonserious AEs and SAEs.
•
See Section 8.4 for additional information.
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2. INTRODUCTION
S pneumoniae causes invasive disease (eg, meningitis, sepsis, bacteremic pneumonia) and 
noninvasive disease (eg, OM, nonbacteremic pneumonia, sinusitis) associated with a 
significant healthcare burden, morbidity, and mortality.1 The 13-valent pneumococcal 
conjugate vaccine (Prevnar 13, 13vPnC) was licensed more than a decade ago by the FDA 
and in other countries for use in infants and young children for the prevention of 
pneumococcal disease. It was subsequently indicated for prevention of pneumonia in adults 
≥18 years of age. 13vPnC has been introduced into national immunization programs for 
pediatric and adult populations worldwide.
Despite significant reductions in pneumococcal disease following use of 13vPnC, a 
significant burden of pneumococcal disease remains. The pneumococcal 20-valent conjugate 
vaccine (20vPnC, Prevnar 20) was developed to expand protection against IPD and 
pneumonia and has been approved by the FDA and EMA for adults ≥18 years of age. It is 
also being developed for pediatric patients. 20vPnC contains the identical polysaccharide 
conjugates and excipients as 13vPnC, but with additional conjugate polysaccharides for 
7 additional serotypes.
 
 
 
 
 
2.1. Study Rationale
The purpose of the study is to evaluate the safety and immunogenicity of 
candidates 
 
 
The study is open-label, so as to allow maximum flexibility for testing and generating the 
. The risk of this approach is low as this is a 1-dose Phase 1 
exploratory study, there is no clinical endpoint in this study, and immunogenicity endpoints 
are not easily biased. The risk of bias in terms of safety assessments is also low as the 
participants and investigators will have little preconceived ideas about these candidates.
 
.
2.2. Background
Since the 
 
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Literature suggests that increased levels of vaccine-elicited antibodies may decrease nasal 
carriage.5,6
 
Potential mechanisms for enhancing the immunogenicity of
 
•
Increases in the polysaccharide dose level may increase the immune response. Early in 
the development of Prevnar (7vPnC), the impact of the polysaccharide dose level was 
assessed in an infant study using a 5-valent pneumococcal conjugate vaccine showing 
higher dose levels of some conjugates resulted in higher immunogenicity in infants for 
certain serotypes. Subsequently, in a mixing study with 2 and 4 times the standard dose 
of 7vPnC, higher immunogenicity was observed with 4 times the standard dose for
serotypes in older adults.7 In a study conducted by Jackson et al, older adults previously 
vaccinated with PPSV23 were given either a single dose of 13vPnC or 2 concurrent doses 
of 13vPnC. There were no safety issues identified in the study, and the response to a 
double dose of 13vPnC was higher than that of a single dose for a majority of the 13vPnC 
serotypes evaluated 
8 In contrast, in an infant 
study by Rupp et al evaluating an investigational 15-valent pneumococcal conjugate 
vaccine prepared with double the standard dose of polysaccharide and CRM197 conjugate, 
an increase in immunogenicity was not observed for most serotypes.9
 
 
 
 
 
•
 
 
 
 
 
 
•
 
 
 
 
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2.3. Benefit/Risk Assessment
The investigational 
candidates have not yet been evaluated in clinical studies; 
therefore, safety data are not available. 
 
. The most common 
AEs noted in adults after vaccination with 20vPnC are primarily related to local reactions 
(injection site pain, redness, and swelling) and systemic events (fever, headache, fatigue, 
joint pain, and muscle pain). Safety review of data from the 3 completed Phase 3 adult trials 
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has not revealed any unexpected safety concerns. See the 13vPnC and 20vPnC package 
inserts for additional details.
In a dose-ranging study to assess the safety and immunogenicity of 1-fold, 2-fold, and 4-fold 
higher doses of 7vPnC or 9vPnC compared to a standard dose of PPSV23 conducted in 
adults ≥70 years of age with no history of pneumococcal vaccination, local reactions 
occurred at higher frequencies for the 4-fold higher dose level than with any other dose of 
7vPnC, 9vPnC, or PPSV23.7 However, at the 2-fold higher dose, local reactions were not 
statistically significantly higher than the standard dose and there were no significant 
differences between groups for systemic events.7
 this study gives dose-ranging safety information for serotypes with CRM197. In a 
study by Jackson et al, older adults previously vaccinated with PPSV23 were given either a 
single dose of 13vPnC or 2 concurrent doses of 13vPnC. The response to a double dose of 
13vPnC in previously vaccinated adults was higher than that of a single dose for a majority 
of the 13vPnC serotypes that were evaluated, 
 
. While double dose of 13vPnC was associated with a higher frequency of solicited 
local and systemic AEs than the single dose among those previously vaccinated with 
PPSV23, the AEs tended to be mild or moderate and were self-limited.8
 
 
 
 
 
 
 
 
 
As with any vaccine, an allergic reaction can occur. The allergic reaction can vary from skin 
rash to swelling of the face or lips, wheezing, and/or shortness of breath. A severe allergic 
reaction (anaphylactic shock, collapse, or shock-like state [hypotonic-hyporesponsive 
episode]) may also occur. There may also be additional risks related to the vaccines 
administered in the study that are not known at this time.
Additional potential risks of clinical significance are presented in the table in Section 2.3.1.
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of the 
 candidates may be found in the IB, which is the SRSD, for this 
study. For 13vPnC and PCV15, the SRSD will be the individual USPI respectively.
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2.3.1. Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Intervention(s): Administration with
The safety profile of the
candidates
 
 is not yet fully 
characterized. Local and systemic reactions to the 
candidates may occur (injection site 
redness, injection site swelling, and injection site 
pain; fever, fatigue, headache, muscle pain, and 
joint pain) following study intervention.
•
Eligibility criteria have been selected to ensure 
that only appropriate participants are included 
in the study (see Section 5).
•
All study participants will be observed for 
30 minutes after study intervention 
administration.
•
E-diary and AE data will be monitored by the 
investigator (or designee) and sponsor.
Study Intervention: Administration with 
The relevant key risks associated with 
 
include: local reactions (injection site pain, redness, 
and swelling) and systemic events (fever, headache, 
fatigue, joint pain, and muscle pain). Uncommon 
events can include allergic reactions, which may be 
associated with skin rash, face or lip swelling, 
wheezing, shortness of breath, or rare severe 
allergic reactions (eg, anaphylactic shock).
The risks are derived from the related 13vPnC
clinical trials and postmarketing data and the 
13vPnC USPI.
•
Eligibility criteria have been selected to ensure 
that only appropriate participants are included 
in the study (see Section 5).
•
All study participants will be observed for 
30 minutes after study intervention 
administration.
•
E-diary and AE data will be monitored by the 
investigator (or designee) and sponsor.
Study Intervention: Vaccination with 13vPnC
The relevant key risks associated with 13vPnC 
include: local reactions (injection site pain, redness, 
and swelling) and systemic events (fever, headache, 
fatigue, joint pain, and muscle pain). Uncommon 
events can include allergic reactions, which may be 
associated with skin rash, face or lip swelling, 
wheezing, shortness of breath, or rare severe 
allergic reactions (eg, anaphylactic shock).
The risks are derived from the related 13vPnC 
clinical trials and postmarketing data and the 
clinical data described in the 13vPnC USPI.
•
Eligibility criteria have been selected to ensure 
that only appropriate participants are included 
in the study (see Section 5).
•
All study participants will be observed for 
30 minutes after vaccination.
•
E-diary and AE data will be monitored by the 
investigator (or designee) and sponsor.
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Study Intervention: Vaccination with PCV15
The relevant key risks associated with PCV15 
include: local reactions (injection site pain, redness, 
and swelling) and systemic events (fever, headache, 
fatigue, joint pain, and muscle pain).
The risks are derived from the USPI for 
Vaxneuvance under the Prescribing Information 
section.
•
Eligibility criteria have been selected to ensure 
that only appropriate participants are included 
in the study (see Section 5).
•
All study participants will be observed for 
30 minutes after vaccination.
•
E-diary and AE data will be monitored by the 
investigator (or designee) and sponsor.
Study Procedures: Venipuncture 
Venipuncture is required to collect immunogenicity 
data from participants.
There is the risk of fainting, and pain, swelling, 
bruising, and infection at the venipuncture site.
•
Only qualified nurses, physicians, nurse 
practitioners, physician assistants, 
phlebotomists, or medical assistants certified or 
otherwise authorized to draw blood per the 
standards and procedures of the investigative 
site, as allowed by institutional, local, and 
country guidance, will be allowed to draw 
blood, to minimize local complications.
Other 
Participants will be required to attend healthcare 
facilities during the global SARS-CoV-2 pandemic.
Without appropriate social distancing and PPE, 
there is a potential for increased exposure to 
SARS-CoV-2.
•
Pfizer will work with sites to ensure an 
appropriate COVID-19 prevention strategy.
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2.3.2. Benefit Assessment
Joining this study will be contributing to research to help others.
 
 
A safe and immunogenic pneumococcal conjugate vaccine 
with expanded pneumococcal serotype coverage would fulfill an unmet need for expanded 
protection against pneumococcal disease.
2.3.3. Overall Benefit/Risk Conclusion
Participants enrolled in this study are in an age group that is not currently covered by the 
indication for vaccines containing 
. These participants are relatively 
healthy and therefore are not recommended for pneumococcal conjugate vaccines. Receiving 
the 
 candidates or controls will not interfere with standard of care for these 
participants. For those with risk factors for pneumococcal vaccination, the investigator site 
and ICD will inform participants to seek advice from their healthcare provider regarding the 
need for immunization after the study.
The study will provide the immune impact of
 
 
that could potentially benefit adults and 
children.
Taking into account the measures to minimize risk to study participants, the potential risks 
identified in association with
 candidates are justified by the anticipated benefits that 
may be afforded to healthy participants and those at high risk of pneumococcal disease.
3. OBJECTIVES, ENDPOINTS, AND ESTIMANDS
Objectives
Endpoints
Estimands
Primary: 
Primary:
Primary: 
To describe the safety profile of 
candidates in adults 
18 through 49 years of age
•
Prompted local reactions 
(redness, swelling, and pain at 
the injection site)
•
Prompted systemic events 
(fever, headache, fatigue, 
muscle pain, and joint pain)
•
AEs
•
SAEs
In participants receiving the study 
intervention from each group, the 
percentage of participants 
reporting: 
•
Prompted local reactions 
within 7 days after
administration
•
Prompted systemic events 
within 7 days after
administration
•
AEs within 1 month after
administration
•
SAEs within 1 month after
administration
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Objectives
Endpoints
Estimands
Secondary: 
Secondary:
Secondary: 
To describe the immune responses
elicited by the 
candidates
•
OPA titers
In participants complying with the 
key protocol criteria (evaluable 
participants) from each group:
•
 OPA GMTs 
1 month after administration
 
 
 
 
 
 
 
 
 
 
 
 
4. STUDY DESIGN
4.1. Overall Design
This is a Phase 1, multicenter, randomized, open-label, active-control study designed to 
evaluate the safety and immunogenicity of different 
candidates
 This study
will be conducted at investigator sites in the US. Approximately 405 adults 18 through 
49 years of age with no history of pneumococcal vaccination will be enrolled. Participants 
will be enrolled and randomized equally to 1 of 9 groups (45 participants per group): 
6 groups will receive 1 of 6 different
candidates and 3 groups will receive 
, 
13vPnC, or PCV15 (see Table 1) by site-based randomization 
 
.
 
 
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The following preformulated products have been manufactured and will comprise the 
following 
candidates:
 
All formulations include AlPO4.
The key control group will receive polysaccharide conjugate for
 
 as contained in 13vPnC (Prevnar 13) and 20vPnC (Prevnar 20). In addition, PCV15 
(Vaxneuvance [Merck]), which is also licensed in the US for use in adults, and 13vPnC will 
be included as controls.
Table 1.
Study Intervention Groups
Group
Carrier 
Protein 
Chemistry
Polysaccharide 
Dose
Dose Volume
n
45
45
L
45
45
45
45
45
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Table 1.
Study Intervention Groups
Group
Carrier 
Protein 
Chemistry
Polysaccharide 
Dose
Dose Volume
n
PCV15 (control)
N/A
N/A
0.5 mL
45
13vPnC (control)
CRM197
RAC
0.5 mL
45
Abbreviations: N/A = not applicable; 
 
.
On Day 1 (Visit 1), participants will be assessed for eligibility, have blood drawn for 
immunogenicity assessments, receive 1 dose of 1 of the 
candidates or controls, be 
observed for 30 minutes after administration, and receive safety follow-up and e-diary 
instructions.
Local reactions (pain, redness, and swelling) occurring at the injection site and systemic 
events (fever, fatigue, headache, muscle pain, and joint pain) will be prompted for and 
collected daily in an e-diary from Day 1 through Day 7 after study intervention 
administration, where Day 1 is the day of administration. AEs (including nonserious AEs and 
SAEs) will be assessed for approximately 1 month after study intervention administration 
(through Visit 2).
At Visit 2 (28-42 days after Visit 1), participants will return for follow-up. Information will 
be collected from the participants on AEs and e-diary follow-up (as needed), and blood will 
be drawn for immunogenicity assessments.
 
 
 
.
The study duration is estimated to be approximately 2 months.
4.2. Scientific Rationale for Study Design
Pfizer is investigating
 
 
 
 Clinical dosage is 
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managed by volume administered (0.5 or 0.25 mL). 
 
 
 
The primary control study intervention for the study,
 
 
 
The inclusion of 13vPnC as a control will be informative about differences between the 
responses to the current formulation 
 
 
 
The inclusion of PCV15 will be informative about the response to the 
 in 
PCV15, as determined by the Pfizer assays. PCV15 contains capsular polysaccharides from 
pneumococcal serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, and 33F 
individually conjugated to CRM197. The vaccine formulation contains 2.0 μg of each 
saccharide, except for 4.0 μg of 6B, per 0.5-mL dose.
In adults, administration of a single dose of pneumococcal conjugate vaccine induces 
immune responses, so the candidates in this study will be evaluated after a single dose. 
 
 
 
 
 
4.2.1. Diversity of Study Population
This study will be conducted in the US and the diversity strategy will include high 
performing sites with the potential to support the recruitment of diverse populations. 
The diversity strategy for this study will include the following:
•
Selecting sites that have access to diverse participants within their locale.
•
Educating sites about the importance of increasing diversity on clinical trials and 
Pfizer commitment.
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•
Investigator site recruitment plans that are cocreated with and include diverse 
recruitment tools and information to support enrollment.
•
Real-world data is used to target outreach and potential referring physicians.
•
Continual monitoring of diverse enrollment to identify additional opportunities to
include diverse populations.
4.2.2. Choice of Contraception/Barrier Requirements
Human reproductive safety data are not available for the candidate formulations, but there is 
no suspicion of human teratogenicity based on the intended pharmacology of the compound.
Therefore, the use of a highly effective method of contraception is required (see Appendix 4).
4.3. Justification for Dose
 
 
 
 
 
 
The polysaccharide conjugates and CRM197 have 
been tested at up to 4 times the standard dose in adults and up to 2 times the standard dose in 
infants. In dose-ranging studies with investigational vaccines and with 13vPnC, immune 
responses were at times higher, but not consistently, leaving dose-response to remain in 
question. The safety profile was acceptable even at the highest doses in these studies.7,8,9
 
.
 
No significant adverse effects were seen with animal data in 
rats at the highest dose range.
4.4. End of Study Definition
The end of the study is defined as the date of the last visit of the last participant in the study.
A participant is considered to have completed the study if they have completed all periods of 
the study, including the last visit.
5. STUDY POPULATION
This study can fulfill its objectives only if appropriate participants are enrolled, including 
participants across diverse and representative racial and ethnic backgrounds. If a 
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prescreening tool is utilized for study recruitment purposes, it will include collection of 
information that reflects the enrollment of a diverse participant population including, where 
permitted under local regulations, age, sex, race, and ethnicity. The following eligibility 
criteria are designed to select participants for whom participation in the study is considered 
appropriate. All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular participant is suitable for this protocol.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age and Sex:
1. Male or female participants ≥18 and ≤49 years of age at the time of consent.
•
Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female
(Section 10.4.2) participants.
Disease Characteristics:
2. Participants who are willing and able to comply with all scheduled visits, the 
investigational plan, laboratory tests, lifestyle considerations, and other study procedures.
3. Adults determined by clinical assessment, including medical history and clinical 
judgment, to be eligible for the study, including adults with preexisting stable disease, 
defined as disease not requiring significant change in therapy or hospitalization for 
worsening disease, within 12 weeks before receipt of study intervention.
4. Participants who can be expected to be available for the duration of the study and can be 
contacted by telephone during study participation.
5. Female participants of childbearing potential or male participants who are able to father 
children and are willing to use acceptable methods of contraception for at least 28 days 
after the dose of study intervention; or female participants not of childbearing potential; 
or male participants not able to father children.
Note: Female participants of nonchildbearing potential must meet the criteria described in 
the WOCBP (Section 10.4.3) section of the protocol.
Other Inclusion Criteria:
6. Participants capable of giving signed informed consent, which includes compliance with 
the requirements and restrictions listed in the ICD and in this protocol.
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5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
1. History of severe adverse reaction associated with a vaccine and/or severe allergic 
reaction (eg, anaphylaxis) to any component in pneumococcal conjugate vaccines and 
any other diphtheria toxoid–containing vaccine.
2. Serious chronic disorder, including metastatic malignancy, severe COPD requiring 
supplemental oxygen, end-stage renal disease with or without dialysis, cirrhosis of the 
liver, clinically unstable cardiac disease, or any other disorder that in the 
investigator’s opinion would make the participant inappropriate for entry into the 
study.
3. Other medical or psychiatric condition including recent (within the past year) or 
active suicidal ideation/behavior or laboratory abnormality that may increase the risk 
of study participation or, in the investigator’s judgment, make the participant 
inappropriate for the study.
4. History of microbiologically proven invasive disease caused by S pneumoniae.
5. Known or suspected immunodeficiency or other conditions associated with 
immunosuppression, including, but not limited to, immunoglobulin class/subclass 
deficiencies, generalized malignancy, HIV infection, leukemia, lymphoma, or organ 
or bone marrow transplant.
6. Bleeding diathesis or condition associated with prolonged bleeding that would, in the 
opinion of the investigator, contraindicate intramuscular injection.
7. Congenital, functional, or surgical asplenia.
8. Current febrile illness (body temperature ≥100.4°F [≥38.0°C]) or other acute illness 
within 48 hours before study intervention administration.
9. Pregnant female participants or breastfeeding female participants (known or 
suspected).
Prior/Concomitant Therapy:
10. Previous vaccination with any licensed or investigational pneumococcal vaccine, or 
planned receipt of any licensed or investigational pneumococcal vaccine through 
study participation.
11. Currently receives treatment with immunosuppressive therapy, including cytotoxic 
agents or systemic corticosteroids, or planned receipt through the last blood draw 
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(Visit 2). Participants may not be enrolled if corticosteroids were administered within 
28 days of study intervention administration. Inhaled/nebulized, intra-articular, 
intrabursal, or topical (skin, eyes, or ears) corticosteroids are permitted.
12. Receipt of blood/plasma products or immunoglobulin within the 60 days before study 
intervention administration, or planned receipt during study participation.
13. Receipt of any inactivated or otherwise nonlive vaccine within 14 days or any live 
vaccine within 28 days before administration of study intervention.
Prior/Concurrent Clinical Study Experience:
14. Participation in other studies involving investigational drugs, investigational vaccines 
(except for investigational pandemic vaccines recommended and authorized in this 
population for emergency use), or investigational devices within 28 days prior to 
study entry and/or during study participation. Participation in purely observational 
studies is acceptable.
Diagnostic Assessments:
Not applicable.
Other Exclusion Criteria:
15. Investigator site staff directly involved in the conduct of the study and their family 
members, site staff otherwise supervised by the investigator, and sponsor and sponsor 
delegate employees directly involved in the conduct of the study and their family 
members.
5.3. Lifestyle Considerations
5.3.1. Contraception
The investigator or their designee, in consultation with the participant, will confirm that the 
participant is utilizing an appropriate method of contraception for the individual participant 
and their partner(s) from the permitted list of contraception methods (see Appendix 4,
Section 10.4.4) and will confirm that the participant has been instructed in its consistent and 
correct use. At time points indicated in the SoA, the investigator or designee will inform the 
participant of the need to use acceptable effective contraception consistently and correctly 
and document the conversation and the participant’s affirmation in the participant’s chart.
Participants need to affirm their consistent and correct use of at least 1 of the selected 
methods of contraception, considering that their risk for pregnancy may have changed since 
the last visit.
In addition, the investigator or designee will instruct the participant to call immediately if the 
selected contraception method is discontinued and document the requirement to use an 
alternate protocol-specified method, including if the participant will no longer use abstinence 
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as the selected contraception method, or if pregnancy is known or suspected in the participant 
or partner.
5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomly assigned to study intervention/enrolled in the study. A 
minimal set of screen failure information is required to ensure transparent reporting of screen 
failure participants to meet the CONSORT publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure 
details, and any SAE.
Individuals who do not meet the criteria for participation in this study (screen failure) may 
not be rescreened.
5.5. Criteria for Temporarily Delaying Enrollment/Randomization/Administration of 
Study Intervention 
Not applicable.
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY
Study interventions are all prespecified investigational and noninvestigational medicinal 
products, medical devices, and other interventions (eg, surgical and behavioral) intended to 
be administered to the study participants during the study conduct.
For the purposes of this protocol, study intervention refers to investigational products
and noninvestigational products (13vPnC and 
PCV15).
Study interventions will be provided as 4 preformulated products in vials and 2 products in 
PFSs, as outlined below:
•
 
 
•
 
 
•
 
 
•
 
•
13vPnC (Prevnar 13) (PFS)
•
PCV15 (Vaxneuvance) (PFS)
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The study interventions
 
will be prepared by adjusting the volume extracted from the preformulated 
products in vials to a dose of either 0.25 mL or 0.5 mL. The study intervention 
 
will be prepared by adjusting the volume extracted from the preformulated product in the vial 
to a dose of 0.5 mL. The PFSs will be administered as 0.5-mL doses for 13vPnC and PCV15.
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6.1. Study Intervention(s) Administered
Study Intervention(s)
Intervention 
name
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
13vPnC 
(Prevnar 13)
0.5-mL 
suspension for 
injection 
PCV15 
(Vaxneuvance)
(pneumococcal 
15-valent 
conjugate 
vaccine)
suspension for 
injection
Arm name
(group of 
participants 
receiving a 
specific 
intervention or 
no intervention)
 
group, n=45
 
group, n=45
 
group, n= 45
 group, 
n=45
 
group, n=45
 
group, n=45
 
monovalent 
control group, 
n=45
13vPnC control 
group, n=45
PCV15 control 
group, n=45
Dosage level(s)
 
 
 
 
 
 
 
 
 
 
 
2.2 μg for all 
serotypes except 
6B; 4.4 μg for 
serotype 6B per 
0.5-mL dose
2.0 μg for all 
serotypes except 
6B; 4.0 μg for 
serotype 6B per 
0.5-mL dose
Dose volume
0.5 mL
0.5 mL
Type
Biologic
Biologic 
Biologic
Biologic 
Biologic
Biologic 
Biologic
Biologic 
Biologic
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Study Intervention(s)
Dose formulation Suspension for 
injection in a 
single-use vial
Suspension for 
injection in a 
single-use vial
Suspension for 
injection in a 
single-use vial
Suspension for 
injection in a 
single-use vial
Suspension for 
injection in a 
single-use vial
Suspension for 
injection in a 
single-use vial
Suspension for 
injection in a 
single-use vial
Sterile liquid 
suspension 
formulation in a 
PFS containing 
saccharides from 
pneumococcal 
serotypes 1, 3, 4, 
5, 6A, 6B, 7F, 9V, 
14, 18C, 19A, 
19F, and 23F 
individually 
conjugated to 
CRM197
Sterile liquid 
suspension 
formulation in a 
PFS containing 
saccharides from 
pneumococcal 
serotypes 1, 3, 4, 
5, 6A, 6B, 7F, 
9V, 14, 18C, 
19A, 19F, 22F, 
23F, and 33F 
individually 
conjugated to 
CRM197
Route of 
administration
Intramuscular 
injection
Intramuscular 
injection
Intramuscular 
injection
Intramuscular 
injection
Intramuscular 
injection
Intramuscular 
injection
Intramuscular 
injection
Intramuscular 
injection
Intramuscular 
injection
Use
Experimental
Experimental 
Experimental 
Experimental
Experimental 
Experimental 
Control
Control
Control
IMP or 
NIMP/AxMP
IMP 
IMP 
IMP 
IMP 
IMP
IMP
IMP
NIMP
NIMP
Sourcing
Provided 
centrally by the 
sponsor 
Provided 
centrally by the 
sponsor
Provided 
centrally by the 
sponsor
Provided 
centrally by the 
sponsor
Provided 
centrally by the 
sponsor
Provided 
centrally by the 
sponsor
Provided 
centrally by the 
sponsor
Provided centrally 
by the sponsor
Provided 
centrally by the 
sponsor
Packaging and 
labeling
Study 
intervention will 
be provided in 
vials. Each vial 
will be labeled 
as required per 
country 
requirement.
Study 
intervention will 
be provided in 
vials. Each vial 
will be labeled 
as required per 
country 
requirement.
Study 
intervention 
will be 
provided in 
vials. Each vial 
will be labeled 
as required per 
country 
requirement.
Study 
intervention will 
be provided in 
vials. Each vial 
will be labeled 
as required per 
country 
requirement.
Study 
intervention will 
be provided in 
vials. Each vial 
will be labeled 
as required per 
country 
requirement.
Study 
intervention will 
be provided in 
vials. Each vial 
will be labeled 
as required per 
country 
requirement.
Study 
intervention will 
be provided in 
vials. Each vial 
will be labeled 
as required per 
country 
requirement.
Study intervention 
will be provided 
in a PFS. Each 
PFS will be 
labeled as 
required per 
country 
requirement.
Study 
intervention will 
be provided in a 
PFS. Each PFS 
will be labeled 
as required per 
country 
requirement.
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Study intervention will be supplied by Pfizer as PFSs or vials as open-label supply. Each vial 
will be packaged in a carton, with a label and tamper-evident seal, and will be labeled as 
required per country requirement. Each syringe will be packaged in a commercial carton and 
will be labeled as required per country requirement. Refer to the IPM for additional details.
6.1.1. Administration
All participants will be administered 1 of the
 candidates
 
or a control 
PCV15, or 13vPnC).
Study intervention will be provided by the sponsor to the study sites. A 0.25-mL or 0.5-mL
dose of 1 of the preformulated products or a 0.5-mL dose of 1 of the controls will be 
administered intramuscularly in the deltoid muscle of the nondominant arm by a site staff 
member or designee. The description of the
 candidates and controls can be found in
the IPM.
Standard vaccination practices must be observed and vaccine must not be injected into blood 
vessels. Appropriate medication and other supportive measures for management of an acute 
hypersensitivity reaction should be available in accordance with local guidelines for standard 
immunization practices.
Administration of study interventions should be performed by an appropriately qualified, 
GCP-trained, and vaccine-experienced member of the study staff (eg, physician, nurse, 
physician’s assistant, nurse practitioner, pharmacist, or medical assistant) as allowed by local, 
state, and institutional guidance.
Study intervention administration details will be recorded on the CRF.
6.1.2. Medical Devices
1. In this study, medical devices being deployed are the PFSs containing 13vPnC and 
PCV15.
2. Instructions for medical device use are provided in the IPM or in the package insert.
3. All medical device deficiencies (including malfunctions of the device, use error and 
inadequate labelling) must be detected, documented, and reported by the study 
personnel throughout the study. Please refer to Section 8.4.9 for details.
6.2. Preparation, Handling, Storage, and Accountability
The investigator or an approved representative, eg, pharmacist, will ensure that all study 
interventions are stored in a secured area with controlled access under required storage 
conditions and in accordance with applicable regulatory requirements.
Study interventions should be stored in their original containers and in accordance with the 
labels.
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1. The investigator or designee must confirm that appropriate conditions (eg, 
temperature) have been maintained during transit for all study interventions received 
and any discrepancies are reported and resolved before use of the study intervention.
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply, prepare, and/or administer study intervention.
3. All study interventions must be stored in a secure, environmentally controlled, and 
monitored (manual or automated recording) area in accordance with the labeled 
storage conditions with access limited to the investigator and authorized site staff. At 
a minimum, daily minimum and maximum temperatures for all site storage locations 
must be documented and available upon request. Data for nonworking days must 
indicate the minimum and maximum temperatures since previously documented upon 
return to business.
4. Any excursions from the study intervention label storage conditions should be 
reported to Pfizer upon discovery along with actions taken. The site should actively 
pursue options for returning the study intervention to labeled storage conditions, as 
soon as possible. Once an excursion is identified, the study intervention must be 
quarantined and not used until Pfizer provides permission to use the study 
intervention. Specific details regarding the excursion definition and information to
report for each excursion will be provided to the site in the IPM.
5. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the label.
6. Study interventions should be stored in their original containers.
7. The investigator, institution, head of the medical institution (where applicable), or 
authorized site staff is responsible for study intervention accountability, 
reconciliation, and record maintenance (ie, receipt, reconciliation, and final 
disposition records), such as the IPAL or sponsor-approved equivalent. All study 
interventions will be accounted for using a study intervention accountability 
form/record.
8. Further guidance and information for the final disposition of unused study 
interventions are provided in the IPM. All destruction must be adequately 
documented. If destruction is authorized to take place at the investigator site, the 
investigator must ensure that the materials are destroyed in compliance with 
applicable environmental regulations, institutional policy, and any special instructions 
provided by Pfizer.
Upon identification of a product complaint, notify the sponsor within 1 business day of 
discovery as described in the IPM.
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6.2.1. Preparation and Dispensing
See the IPM for instructions on how to prepare the study intervention for administration. 
Study intervention should be prepared and dispensed by an appropriately qualified and 
experienced member of the study staff (eg, physician, nurse, physician’s assistant, nurse 
practitioner, pharmacy assistant/technician, or pharmacist) as allowed by local, state, and 
institutional guidance. A second staff member will verify the preparation and dispensing.
The study intervention will be prepared by qualified site personnel according to the IPM.
6.3. Assignment to Study Intervention
Allocation (randomization) of participants to intervention groups will proceed through the 
use of an IRT system (IWR). The site personnel (study coordinator or specified designee) 
will be required to enter or select information including but not limited to the user’s ID and 
password, the protocol number, and the participant number.
The site personnel will then be provided with a randomization number corresponding to the 
assigned intervention group, and DU or container number(s) when study intervention and 
proper dose is being supplied via the IRT system. The IRT system will provide a 
confirmation report containing the participant number, randomization number, and DU or 
container number assigned. The confirmation report must be stored in the site’s files.
The site will record the study intervention assignment on the applicable CRF, if required.
Study intervention will be dispensed at the study visits summarized in the SoA.
The study-specific IRT reference manual and IPM will provide the contact information and 
further details on the use of the IRT system.
This is an open-label study. The investigator’s knowledge of the intervention assignment 
must not influence the decision to enroll a particular participant or affect the order in which 
participants are enrolled. Potential bias will be reduced by the following steps: central IRT 
system for randomization
6.4. Blinding
This is an open-label study.
6.4.1. Blinding of Participants
Participants will be unblinded to their assigned study intervention.
6.4.2. Blinding of Site Personnel
Investigators and other site staff will be unblinded to participants’ assigned study 
intervention.
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6.4.3. Blinding of the Sponsor
Sponsor staff will be unblinded to participants’ assigned study intervention. All laboratory 
testing personnel performing serology assays will remain blinded to study intervention 
assigned/received throughout the study.
6.5. Study Intervention Compliance
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision. The date and time of each dose 
administered in the clinic will be recorded in the source documents and recorded in the CRF. 
The dose of study intervention and study participant identification will be confirmed at the 
time of dosing by a member of the study site staff other than the person administering the 
study intervention.
The site will complete the required dosage preparation record located in the IPM. The use of 
the preparation record is required. The use of alternative preparation records must be 
approved by the Sponsor’s clinical research pharmacist prior to its use.
6.6. Dose Modification
Not applicable.
6.7. Continued Access to Study Intervention After the End of the Study
This exploratory study is describing the tolerability and immunogenicity of 6 
 
candidates. There will be no further intervention provided to participants at the end 
of their study participation. It is expected that participants will be treated as required with 
standard-of-care treatments, as advised by their usual care physician.
6.8. Treatment of Overdose
For this study, any dose of study intervention greater than 0.5 mL of study intervention
within a 24-hour time period will be considered an overdose. If the participant assigned to 
0.25 mL has inadvertently been administered a 0.5-mL dose, this will not be considered an 
overdose but will be a dosing error and a protocol deviation requiring communication to the 
sponsor (Section 8.4.10).
There is no specific treatment for an overdose.
In the event of an overdose, the investigator should:
1. Contact the study medical monitor within 24 hours.
2. Closely monitor the participant for any AEs/SAEs as medically appropriate and at 
least until the next scheduled follow-up.
3. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF.
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4. Overdose is reportable to Pfizer Safety only when associated with an SAE.
6.9. Prior and Concomitant Therapy
The name and date of administration for all nonstudy vaccinations received from the time of 
signing of the ICD to Visit 2 will be collected and recorded in the CRF.
Medications taken to treat SAEs from the time of signing of the ICD through Visit 2 will be 
recorded in the CRF.
6.9.1. Prohibited During the Study
•
Receipt of any investigational vaccines, drugs, or medical devices is prohibited 
during study participation.
•
Receipt of nonstudy pneumococcal vaccine is prohibited during study participation.
•
Receipt of any other licensed nonstudy vaccine is prohibited during study 
participation, except as noted in Section 6.9.2.
•
Receipt of blood/plasma products, immunoglobulins, and/or immunosuppressive 
therapy (including a ≥14-day course of systemic corticosteroids) is prohibited during 
study participation.
6.9.2. Permitted During the Study
•
Prescription and nonprescription medications, vitamins, minerals, and herbal 
remedies are permitted during participation in the study.
•
Inhaled/nebulized, topical (eg, skin, eyes, ears), or localized injections of 
corticosteroids (eg, intra-articular or intrabursal administration) are permitted during 
study participation.
•
Licensed inactivated influenza vaccine may be given >14 days after study 
intervention administration (Visit 1).
•
If medically necessary (eg, during a pandemic), a COVID-19 vaccine, or tetanus 
vaccine required following wound care, may be given during the study, with 
preference for >7 days after study intervention administration (Visit 1), if feasible.
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention
Since this is a single-dose study, this section is not applicable.
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7.2. Participant Discontinuation/Withdrawal From the Study
A participant may withdraw from the study at any time at their own request. Reasons for 
discontinuation from the study include the following:
•
Refused further study procedures; 
•
Lost to follow-up; 
•
Death; 
•
Study terminated by sponsor; 
•
AE; 
•
Physician decision; 
•
Pregnancy; 
•
Protocol deviation; 
•
Screen failure; 
•
Participant request; 
•
Vaccination error without associated AE; 
•
No longer meets eligibility criteria; 
•
Other.
If a participant withdraws from the study, they may request destruction of any remaining 
samples taken and not tested, and the investigator must document any such requests in the 
site study records and notify the sponsor accordingly.
If the participant withdraws from the study and also withdraws consent (see Section 7.2.1) 
for disclosure of future information, no further evaluations will be performed and no 
additional data will be collected. The sponsor may retain and continue to use any data 
collected before such withdrawal of consent.
7.2.1. Withdrawal of Consent
Participants who request to discontinue will remain in the study and must continue to be 
followed for protocol-specified follow-up procedures. The only exception to this is when a 
participant specifically withdraws consent for any further contact with them or persons 
previously authorized by the participant to provide this information. Participants should 
notify the investigator in writing of the decision to withdraw consent from future follow-up, 
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whenever possible. The withdrawal of consent should be explained in detail in the medical 
records by the investigator and entered on the appropriate CRF page. In the event that vital 
status (whether the participant is alive or dead) is being measured, publicly available 
information should be used to determine vital status only as appropriately directed in 
accordance with local law.
7.3. Lost to Follow-Up
A participant will be considered lost to follow-up if the participant repeatedly fails to return 
for scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to attend a required study visit:
•
The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible. Counsel the participant on the importance of maintaining the 
assigned visit schedule, and ascertain whether the participant wishes to and/or should 
continue in the study;
•
Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record;
•
Should the participant continue to be unreachable, the participant will be considered 
to have withdrawn from the study.
8. STUDY ASSESSMENTS AND PROCEDURES
8.1. Administrative Procedures
The investigator (or an appropriate delegate at the investigator site) must obtain a signed and 
dated ICD before performing any study-specific procedures.
The date of birth will be collected to critically evaluate the immune response and safety 
profile by age.
Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
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Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances outside the control of the investigator that make it unfeasible to perform the 
test. In these cases, the investigator must take all steps necessary to ensure the safety and 
well-being of the participant. When a protocol-required test cannot be performed, the 
investigator will document the reason for the missed test and any corrective and preventive 
actions that they have taken to ensure that required processes are adhered to as soon as 
possible. The study team must be informed of these incidents in a timely manner.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.
8.2. Efficacy and/or Immunogenicity Assessments
Blood will be collected before study intervention administration (Visit 1) and approximately 
1 month after administration (Visit 2) to assess immunogenicity.
Approximately 135 participants (approximately n=15/group) will be enrolled at specific 
investigator sites,
 
and approximately 20 mL of blood will be collected for sera 
measurements of immunogenicity (OPA titers and IgG concentrations) at each time point 
(Visit 1 and Visit 2). The remaining approximately 270 participants enrolled at other sites 
(approximately n=30/group) will have approximately 60 mL of blood collected for 
measurement of immunogenicity (OPA titers and IgG concentrations) at each time point 
(Visit 1 and Visit 2).
 
 
Immune Responses
OPA titers and IgG concentrations 
 will be measured in sera 
collected at Visits 1 and 2.
 
 
 
 
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8.2.1. Biological Samples 
Blood samples will be used only for scientific research. Each sample will be labeled with a 
code so that the laboratory analyst testing the samples will not know the participant’s 
identity, study visit, or study cohort associated with the sample. Samples that remain after 
performing assays outlined in the protocol may be stored by Pfizer. Unless a time limitation 
is required by local regulations or ethical requirements, the samples will be stored for up to 
15 years after the end of the study and then destroyed.
 
 
No testing of the participant’s genetic material will be performed,
 
 
The participant may request that their samples, if still identifiable, be destroyed at any time; 
however, any data already collected from those samples will still be used for this research. 
The biological samples may be shared with other researchers as long as confidentiality is 
maintained and no testing of the participant’s genetic material is performed, 
 
8.3. Safety Assessments
A clinical assessment, including medical history and measurement of oral temperature, will 
be performed on all participants prior to receipt of study intervention administration at Visit 1 
to determine participant eligibility and to establish a clinical baseline. Significant medical 
history and significant findings from any physical examination (if performed) will be 
recorded as medical history in the CRF. Temperature measurement prior to administration at 
Visit 1 will be documented and recorded in the CRF.
The participant will be observed for 30 minutes after study intervention administration, and 
any reactions occurring during that time will be recorded as AEs.
Prompted e-diary events, including local reactions (redness, swelling, and pain at the 
injection site) and systemic events (fever, headache, fatigue, muscle pain, and joint pain) that 
occur from Days 1 through 7, where Day 1 is the day of study intervention administration, 
are graded as noted in Table 2 and Table 3. AEs and SAEs will be collected from the signing 
of the ICD through Visit 2.
Planned time points for all safety assessments are provided in the SoA. Unscheduled safety 
measurements may be obtained at any time during the study to assess any perceived safety 
issues.
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8.3.1. Participant Electronic Diary
Participants will be asked to monitor and record local reactions and systemic events after 
vaccination (Day 1 through Day 7, where Day 1 is the day of study intervention 
administration) using an e-diary through an application installed on a provisioned device or 
on the participant’s own personal device. This allows recording of these assessments only 
within a fixed time window, thus providing the accurate representation of the participant’s 
experience. Data reported in the e-diary will be transferred electronically to the e-diary 
vendor, where they will be available for review by investigators, their appropriately qualified 
designees, and sponsor staff at all times via an internet-based portal. At intervals agreed to by 
the vendor and Pfizer, these data will be transferred electronically to Pfizer for analysis and 
reporting.
The daily e-diary data will not be captured in the CRF. However, if a participant is 
withdrawn because of prompted events reported in the e-diary, the event(s) should be 
recorded on the AE page of the CRF, regardless of whether the investigator considers the 
event(s) to be clinically significant.
The investigator or designee must obtain stop dates for any local reactions and specific 
systemic events that were ongoing on the last day that the e-diary was completed. The stop 
dates should be entered in the CRF.
Investigators (or an appropriately qualified designee) are required to review the e-diary data 
online at frequent intervals (daily is optimal) to evaluate participant compliance and reported 
events as part of the ongoing safety review.
8.3.2. Grading Scale for Prompted Events
The grading scales used in this study to assess prompted events as described below are based 
on concepts outlined in the FDA CBER guidelines on toxicity grading scales for healthy 
adult volunteers enrolled in preventive vaccine clinical trials.26
8.3.2.1. Local Reactions
From Day 1 through Day 7 following study intervention administration at Visit 1, where 
Day 1 is the day of study intervention administration, participants will be asked to assess 
redness, swelling, and pain at the injection site and to record the symptoms in the e-diary in 
the evening. Redness and swelling will be measured and recorded in measuring device 
(caliper) units (range: 1 to 21+) and then categorized during analysis as mild, moderate, or 
severe based on the grading scale in Table 2. Measuring device units can be converted to 
centimeters according to the following scale: 1 measuring device unit = 0.5 cm. Pain at the 
study intervention injection site will be assessed by the participant as mild, moderate, or 
severe according to the grading scale in Table 2. The participant will be prompted to contact 
the investigator if he/she experiences a severe (Grade 3 or above) local reaction to assess the 
reaction and perform an unscheduled assessment or visit as appropriate. Only an investigator 
is able to classify a participant’s local reaction as Grade 4, after physical examination of the 
participant or documentation from another medically qualified source (eg, emergency room 
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or hospital record). If a participant experiences a Grade 4 local reaction, the investigator must 
immediately notify the sponsor. Site staff will educate the participants regarding signs and 
symptoms that would prompt site contact. Grade 4 reactions will be collected as AEs on the 
CRF. The event will be graded using the AE intensity grading scale (Section 10.3.3).
The procedure for notification of the sponsor is provided in the investigator site file or 
equivalent.
Table 2.
Grading Scales for Local Reactions
Mild
Grade 1
Moderate
Grade 2
Severe
Grade 3a
Grade 4b
Redness
5 to 10 measuring 
device units
=
>2.0 to 5.0 cm
11 to 20 measuring
device units
=
>5.0 to 10.0 cm
>20 measuring 
device units
=
>10.0 cm
Necrosis or 
exfoliative 
dermatitis
Swelling
5 to 10 measuring 
device units
=
>2.0 to 5.0 cm
11 to 20 measuring 
device units
=
>5.0 to 10.0 cm
>20 measuring 
device units
=
>10.0 cm
Necrosis
Pain at injection site
Does not interfere 
with activity
Interferes with 
activity
Prevents daily 
activityc
Emergency room 
visit or 
hospitalization for 
severe injection site 
pain
Note: If the size of the redness and/or swelling falls between 2 measuring device units, the higher measuring 
device unit number will be recorded in the e-diary.
a.
Participants experiencing Grade 3 local reactions are required to contact the investigator site. In the event 
that the participant does not call, the investigator will call the participant.
b.
Grade 4 assessment should be made by the investigator; Grade 4 local reactions will not be collected in 
the e-diary but will be collected as AEs on the CRF. The intensity of the local reaction should be graded 
using the AE intensity grading scale in Section 10.3.3.
c.
Prevents daily activity, eg, results in missed days of school or work or is otherwise incapacitating.
8.3.2.2. Systemic Events
From Day 1 through Day 7 following study intervention administration at Visit 1, where 
Day 1 is the day of study intervention administration, participants will be asked to assess 
headache, fatigue, muscle pain, and joint pain and to record the symptoms in the e-diary in 
the evening. The symptoms will be assessed by the participant as mild, moderate, or severe 
according to the grading scale in Table 3 below. Participants will also be instructed to contact 
site staff or the investigator if they experience any severe (Grade 3 or above) prompted 
systemic event within 7 days after administration. Study staff may also contact the participant 
to obtain additional information on Grade 3 events entered into the e-diary.
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Only an investigator is able to classify a participant’s systemic event as Grade 4, after 
physical examination of the participant or documentation from another medically qualified 
source (eg, emergency room or hospital record) or telephone contact with the participant. If a 
participant experiences a Grade 4 systemic event, the investigator must immediately notify 
the sponsor. Grade 4 events will be collected as an AE on the CRF. The event will be graded 
using the AE intensity grading scale (See Section 10.3.3).
The procedure for notification of the sponsor is provided in the investigator site file or 
equivalent.
Table 3.
Grading Scales for Systemic Events
Mild
Grade 1
Moderate
Grade 2
Severe
Grade 3a
Grade 4b
Fatigue (tiredness)
Does not interfere 
with activity
Some interference 
with activity
Prevents daily 
routine activity
Emergency room 
visit or 
hospitalization for 
severe fatigue
Headache
Does not interfere 
with activity
Some interference 
with activity
Prevents daily 
routine activity
Emergency room 
visit or 
hospitalization for 
severe headache
Muscle pain
Does not interfere 
with activity
Some interference 
with activity
Prevents daily 
routine activity
Emergency room 
visit or 
hospitalization for 
severe muscle pain
Joint pain
Does not interfere 
with activity
Some interference 
with activity
Prevents daily 
routine activity
Emergency room 
visit or 
hospitalization for 
severe joint pain
a.
Prevents daily routine activity, eg, results in missed days of school or work or is otherwise incapacitating; 
includes use of narcotics for analgesia.
b.
Grade 4 assessment should be made by the investigator; Grade 4 systemic events will not be collected in 
the e-diary but will be collected as AEs on the CRF. The intensity of the systemic event should be graded 
using the AE intensity grading scale in Section 10.3.3.
8.3.2.2.1. Fever
In order to record information on fever, a digital thermometer will be given to the participant 
with instructions on how to measure oral temperature at home. Temperature will be collected 
in the evening daily for 7 days following each study intervention administration (Days 1 
through 7, where Day 1 is the day of study intervention administration) and at any time 
during the 7 days that fever is suspected. The highest temperature for each day will be 
recorded in the e-diary. In the event of a fever on Day 7, temperature will be collected daily 
until the fever has resolved (1 day of temperature <100.4°F [<38.0°C]) in order to collect a 
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stop date in the CRF. Participants reporting a fever >102.0°F (>38.9°C) will be prompted to 
contact the study site. Study staff may also contact the participant to obtain additional 
information if a temperature of >102.0°F (>38.9°C) is entered into an e-diary. Temperature 
will be measured and recorded to 1 decimal place.
Temperatures obtained in degrees Fahrenheit will be programmatically converted to degrees 
Celsius for reporting. Fever will be grouped into ranges for the analysis according to Table 4.
Table 4.
Ranges for Fever
≥38.0°C to 38.4°C
>38.4°C to 38.9°C
>38.9°C to 40.0°Ca
>40.0°Ca
Note: Fever is defined as a temperature of ≥38.0°C.
a.
Participants reporting a fever >102.0°F (>38.9°C) will be prompted to contact the study site.
8.3.3. Physical Examinations
Physical examination findings collected during the study will be considered source data and 
will not be required to be reported, unless otherwise noted. Any untoward physical 
examination findings that are identified during the active collection period and meet the 
definition of an AE or SAE (Appendix 3) must be reported according to the processes in 
Sections 8.4.1 to 8.4.3.
8.3.4. Vital Signs
The participant’s oral temperature will be measured prior to study intervention 
administration.
Any untoward vital sign findings that are identified during the active collection period and 
meet the definition of an AE or SAE (Appendix 3) must be reported according to the 
processes in Sections 8.4.1 to 8.4.3.
8.3.5. Clinical Safety Laboratory Assessments
Clinical safety laboratory assessments will not be collected in this study.
8.3.6. Pregnancy Testing
Following screening, pregnancy tests may be urine or serum tests, but must have a sensitivity 
of at least 25 mIU/mL. Pregnancy tests will be performed in WOCBP at the times listed in 
the SoA, immediately before the administration of each vaccine dose. A negative pregnancy 
test result will be required prior to the participant’s receiving the study intervention. 
Pregnancy tests may also be repeated if requested by IRBs/ECs or if required by local 
regulations. In the case of a positive confirmed pregnancy, the participant will be withdrawn 
from administration of study intervention and from the study.
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8.4. Adverse Events, Serious Adverse Events, and Other Safety Reporting
The definitions of an AE and an SAE can be found in Appendix 3.
The definitions of device-related safety events (ADEs and SADEs) ca.n be found in 
Appendix 8. Device deficiencies are covered in Section 8.4.9.
AEs may arise from symptoms or other complaints reported to the investigator by the 
participant (or, when appropriate, by a caregiver, surrogate, or the participant's legally 
authorized representative), or they may arise from clinical findings of the investigator or 
other healthcare providers (clinical signs, test results, etc).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether the 
event meets the criteria for classification as an SAE or caused the participant to discontinue 
the study (see Section 7.1).
During the active collection period as described in Section 8.4.1, each participant will be 
questioned about the occurrence of AEs in a nonleading manner.
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion.
8.4.1. Time Period and Frequency for Collecting AE and SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant provides informed consent, 
which is obtained before the participant’s participation in the study (ie, before undergoing 
any study-related procedure and/or receiving study intervention), through and including 
Visit 2.
Follow-up by the investigator continues throughout the active collection period and until the 
AE or SAE or its sequelae resolve or stabilize at a level acceptable to the investigator.
When a clinically important AE remains ongoing at the end of the active collection period, 
follow-up by the investigator continues until the AE or SAE or its sequelae resolve or 
stabilize at a level acceptable to the investigator and Pfizer concurs with that assessment.
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.
If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn.
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If a participant permanently discontinues or temporarily discontinues study because of an AE 
or SAE, the AE or SAE must be recorded on the CRF and the SAE reported using the 
Vaccine SAE Reporting Form.
Investigators are not obligated to actively seek information on AEs or SAEs after the 
participant has concluded study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has completed the study, and they consider 
the event to be reasonably related to the study intervention, the investigator must promptly 
report the SAE to Pfizer using the Vaccine SAE Reporting Form.
8.4.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period as described in
Section 8.4.1 are reported to Pfizer Safety on the Vaccine SAE Reporting Form immediately 
upon awareness and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 3. The investigator will submit any updated SAE data to the sponsor within 
24 hours of its being available.
8.4.1.2. Recording Nonserious AEs and SAEs on the CRF
All nonserious AEs and SAEs occurring in a participant during the active collection period, 
which begins after obtaining informed consent as described in Section 8.4.1, will be recorded 
on the AE section of the CRF.
The investigator is to record on the CRF all directly observed and all spontaneously reported 
AEs and SAEs reported by the participant.
As part of ongoing safety reviews conducted by the sponsor, any nonserious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE. To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.
8.4.2. Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3.
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.4.3. Follow-Up of AEs and SAEs
After the initial AE or SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. For each event, the investigator must pursue and 
obtain adequate information until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3).
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In general, follow-up information will include a description of the event in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality. Any information relevant to the event, such as concomitant medications 
and illnesses, must be provided. In the case of a participant death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer Safety.
Further information on follow-up procedures is provided in Appendix 3.
8.4.4. Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities toward the safety of participants and the safety of a 
study intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/ECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.
An investigator who receives SUSARs or other specific safety information (eg, summary or 
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the 
study and will notify the IRB/EC, if appropriate according to local requirements.
8.4.5. Environmental Exposure, Exposure During Pregnancy or Breastfeeding, and 
Occupational Exposure
Environmental exposure occurs when a person not enrolled in the study as a participant 
receives unplanned direct contact with or exposure to the study intervention. Such exposure 
may or may not lead to the occurrence of an AE or SAE. Persons at risk for environmental 
exposure include healthcare providers, family members, and others who may be exposed. An 
environmental exposure may include EDP, EDB, and occupational exposure.
Any such exposures to the study intervention under study are reportable to Pfizer Safety 
within 24 hours of investigator awareness.
8.4.5.1. Exposure During Pregnancy
An EDP occurs if:
•
A female participant is found to be pregnant while receiving or after discontinuing 
study intervention.
•
A male participant who is receiving or has discontinued study intervention 
inseminates a female partner.
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•
A female nonparticipant is found to be pregnant while being exposed or having been 
exposed to study intervention because of environmental exposure. Below are 
examples of environmental EDP:
•
A female family member or healthcare provider reports that she is pregnant after 
having been exposed to the study intervention by injection, inhalation, or skin 
contact.
•
A male family member or healthcare provider who has been exposed to the study 
intervention by injection, inhalation, or skin contact then inseminates his female 
partner prior to or around the time of conception.
The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The initial information submitted 
should include the anticipated date of delivery (see below for information related to 
termination of pregnancy).
•
If EDP occurs in a participant or participant’s partner, the investigator must report 
this information to Pfizer Safety on the Vaccine SAE Reporting Form and an EDP 
Supplemental Form, regardless of whether an SAE has occurred. Details of the 
pregnancy will be collected after the start of study intervention and until Visit 2.
•
If EDP occurs in the setting of environmental exposure, the investigator must report 
information to Pfizer Safety using the Vaccine SAE Reporting Form and EDP 
Supplemental Form. Since the exposure information does not pertain to the 
participant enrolled in the study, the information is not recorded on a CRF; however, 
a copy of the completed Vaccine SAE Reporting Form is maintained in the 
investigator site file.
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome. The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP Supplemental Form. In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth. In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
preprocedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
Abnormal pregnancy outcomes are considered SAEs. If the outcome of the pregnancy meets 
the criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal 
demise, neonatal death, or congenital anomaly in a live-born baby, a terminated fetus, an 
intrauterine fetal demise, or a neonatal death), the investigator should follow the procedures 
for reporting SAEs. Additional information about pregnancy outcomes that are reported to 
Pfizer Safety as SAEs follows: 
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•
Spontaneous abortion including miscarriage and missed abortion should be reported 
as an SAE;
•
Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs. In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the study intervention.
Additional information regarding the EDP may be requested by the sponsor. Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays). In the case of paternal exposure, the 
investigator will provide the participant with the Pregnant Partner Release of Information 
Form to deliver to his partner. The investigator must document in the source documents that 
the participant was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.4.5.2. Exposure During Breastfeeding
An EDB occurs if:
•
A female participant is found to be breastfeeding while receiving or after 
discontinuing study intervention.
•
A female nonparticipant is found to be breastfeeding while being exposed or having 
been exposed to study intervention (ie, environmental exposure). An example of 
environmental EDB is a female family member or healthcare provider who reports 
that she is breastfeeding after having been exposed to the study intervention by
injection, inhalation, or skin contact.
The investigator must report EDB to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The information must be reported 
using the Vaccine SAE Reporting Form. When EDB occurs in the setting of environmental 
exposure, the exposure information does not pertain to the participant enrolled in the study, 
so the information is not recorded on a CRF. However, a copy of the completed Vaccine SAE
Reporting Form is maintained in the investigator site file.
An EDB report is not created when a Pfizer drug specifically approved for use in 
breastfeeding women (eg, vitamins) is administered in accordance with authorized use. 
However, if the infant experiences an SAE associated with such a drug, the SAE is reported 
together with the EDB.
8.4.5.3. Occupational Exposure
The investigator must report any instance of occupational exposure to Pfizer Safety within 
24 hours of the investigator’s awareness using the Vaccine SAE Reporting Form, regardless 
of whether there is an associated SAE. Since the information about the occupational exposure
does not pertain to a participant enrolled in the study, the information is not recorded on a 
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CRF; however, a copy of the completed Vaccine SAE Reporting Form must be maintained in 
the investigator site file.
8.4.6. Cardiovascular and Death Events
Not applicable.
8.4.7. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs
Not applicable.
8.4.8. Adverse Events of Special Interest
Not applicable.
8.4.8.1. Lack of Efficacy
The investigator must report signs, symptoms, and/or clinical sequelae resulting from lack of 
efficacy. Lack of efficacy or failure of expected pharmacological action is reportable to Pfizer 
Safety only if associated with an SAE.
8.4.9. Medical Device Deficiencies
Medical devices being provided for use in this study are those listed in Section 6.1.2. In order 
to fulfill regulatory reporting obligations worldwide, the investigator is responsible for the 
detection and documentation of events meeting the definitions of device deficiency that occur 
during the study with such devices.
The definition of a medical device deficiency can be found in Appendix 8.
Note: AEs and/or SAEs that are associated with a medical device deficiency will follow the 
same processes as other AEs or SAEs, as outlined in Sections 8.4.1 through 8.4.4 and 
Appendix 3 of the protocol.
8.4.9.1. Time Period for Detecting Medical Device Deficiencies
Medical device deficiencies that result in an incident will be detected, documented, and 
reported during all periods of the study in which the medical device is used.
Importantly, reportable device deficiencies are not limited to problems with the device itself 
but also include incorrect or improper use of the device and even intentional misuse, etc.
If the investigator learns of any device deficiency at any time after a participant has been 
discharged from the study, and such deficiency is considered reasonably related to a medical 
device provided for the study, the investigator will promptly notify the sponsor.
The method of documenting medical device deficiencies is provided in Appendix 8.
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8.4.9.2. Follow-Up of Medical Device Deficiencies
Follow-up applies to all participants, including those who discontinue study intervention.
The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the deficiency.
New or updated information will be recorded on a follow-up form with all changes signed 
and dated by the investigator.
8.4.9.3. Prompt Reporting of Device Deficiencies to the Sponsor
When a device deficiency occurs: 
1. The investigator notifies the sponsor by telephone or email within 1 business day of 
determining that the incident meets the protocol definition of a medical device 
deficiency.
2. The device deficiency must be recorded on the Medical Device Complaint form.
3. If an AE (either serious or nonserious) associated with the device deficiency occurs, 
then the AE must be entered into the AE section of the CRF.
4. If an SAE associated with the device deficiency is brought to the attention of the 
investigator, the investigator must immediately notify Pfizer Safety of the SAE 
(see Section 8.4.1.1). All relevant details related to the role of the device in the event 
must be included in the Vaccine SAE Reporting Form as outlined in Sections 8.4.1.1
and 8.4.1.2.
The sponsor will be the contact for the receipt of device deficiency information.
8.4.9.4. Regulatory Reporting Requirements for Device Deficiencies
The investigator will promptly report all device deficiencies occurring with any medical 
device provided for use in the study in order for the sponsor to fulfill the legal responsibility 
to notify appropriate regulatory authorities and other entities about certain safety information 
relating to medical devices being used in clinical studies.
The investigator, or responsible person according to local requirements (eg, the head of the 
medical institution), will comply with the applicable local regulatory requirements relating to 
the reporting of device deficiencies to the IRB/EC.
8.4.10. Vaccination Errors
Vaccination errors may result from the administration or consumption of the study 
intervention by the wrong participant, or at the wrong time, or at the wrong dosage strength.
Vaccination errors are recorded and reported as follows:
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Recorded on the 
Vaccination Error Page 
of the CRF
Recorded on the 
Adverse Event Page 
of the CRF
Reported on the Vaccine 
SAE Reporting Form to 
Pfizer Safety Within 
24 Hours of Awareness
All (regardless of whether 
associated with an AE)
Any AE or SAE associated 
with the vaccination error
Only if associated with an 
SAE
Vaccination errors include:
•
Vaccination errors involving participant exposure to the study intervention;
•
Potential vaccination errors or uses outside of what is foreseen in the protocol that do 
or do not involve the study participant.
Other examples include, but are not limited to:
•
The administration of expired study intervention;
•
The administration of an incorrect study intervention;
•
The administration of an incorrect dosage;
•
The administration of study intervention that has undergone temperature excursion 
from the specified storage range, unless it is determined by the sponsor that the study 
intervention under question is acceptable for use.
Such vaccination errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
Whether or not the vaccination error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if
applicable, any associated AE(s), serious and nonserious, are recorded on the AE page of the 
CRF.
In the event of a vaccination dosing error, the sponsor should be notified within 24 hours.
Vaccination errors should be reported to Pfizer Safety within 24 hours on a Vaccine SAE
Reporting Form only when associated with an SAE.
8.5. Pharmacokinetics
Pharmacokinetic parameters are not evaluated in this study.
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8.6. Genetics
8.6.1. Specified Genetics
Specified genetic analyses are not evaluated in this study.
 
See Section 10.5 for information regarding genetic research. Details on processes for 
collection and shipment of these samples will be provided separately.
8.6.2. Retained Research Samples for Genetics
Not applicable.
8.7. Biomarkers
Biomarkers are not evaluated in this study.
8.8. Immunogenicity Assessments
Immunogenicity assessments are described in Section 8.2.
8.9. Health Economics
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study.
8.10. Study Procedures
Before enrollment and before any study-related procedures are performed, voluntary, written, 
study-specific informed consent will be obtained from the participant. Each signature on the 
ICD must be personally dated by the signatory. The investigator or his or her designee will 
also sign the ICD. A copy of the signed and dated ICD must be given to the participant. The 
source data must reflect that the informed consent was obtained before participation in the 
study.
The timing of visit procedures (ie, prior to randomization and after randomization) must be 
maintained; however, there is flexibility in the order in which the procedures can be 
conducted at each visit. The ICD must be signed prior to the start of any study procedure.
8.10.1. Visit 1 – Study Intervention Administration – Day 1
Prior to randomization:
•
Obtain a personally signed and dated ICD indicating that the participant has been 
informed of all pertinent aspects of the study before performing any study-specific 
procedures.
•
Assign a participant number via the IRT.
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•
Obtain and record the participant’s demographic information (including date of birth, sex, 
race, and ethnicity). The complete date of birth (ie, DD-MMM-YYYY) will be collected 
to critically evaluate the immune response and safety profile by age.
•
Perform a clinical assessment. If the clinical assessment indicates that a physical 
examination is necessary to comprehensively evaluate the participant, perform a physical 
examination and record any findings in the source documents and, if significant, record 
such findings on the medical history CRF.
•
Measure and record the participant’s oral temperature (°F/°C)
•
Record nonstudy vaccinations given up to 28 days prior to study intervention 
administration, in source documents, if applicable (see Section 6.9).
•
If applicable, instruct the participant to use appropriate contraceptives until 28 days after 
administration of the last dose of study intervention and document the conversation and 
the participant’s affirmation in the participant’s source document (see Section 10.4).
•
Perform urine pregnancy test for female participants of childbearing potential
(see Section 8.3.6).
•
Ensure and document that all of the inclusion criteria and none of the exclusion criteria 
are met.
•
Assign a randomization number and a study intervention container number via the IRT. 
This must be the last step before proceeding. A site staff member will prepare the study 
intervention according to the IPM.
After randomization:
 
 
•
Collect approximately 60 mL of blood prior to study intervention administration.
•
Administer a single 0.25-mL or 0.5-mL injection of the assigned study intervention into 
the deltoid muscle of the preferably nondominant arm (see Section 6.1).
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After study intervention administration:
•
Site staff will observe the participant for 30 minutes after administration of study 
intervention for any reactions. Record any acute reactions (including time of onset) in the 
participant’s source documents and on the AE page of the CRF, and on the Vaccine SAE 
Reporting Form, as applicable. Record concomitant medications used to treat SAEs.
•
Record concomitant medications used to treat SAEs, if applicable.
•
Record AEs and SAEs as described in Section 8.4.
•
Explain the e-diary technologies available for this study (Section 8.3.1) and assist the 
participant in downloading the study application onto the participant’s own device or 
issue a provisioned device, if required. Provide instructions on the e-diary’s use and 
completion and ask the participant to complete the e-diary from Day 1 through Day 7, 
with Day 1 being the day of study intervention administration.
•
Issue the participant a measuring device to measure injection site reactions and a digital 
thermometer and provide instructions on their use.
•
Ask the participant to contact the investigator site staff or investigator as soon as possible 
during the 7-day postadministration period if the participant has redness and/or swelling 
at the injection site measuring >20 measuring device units (>10 cm) or severe injection 
site pain (prevents daily activity) to determine if an unscheduled visit is required (refer to 
Section 8.10.3).
•
Ask the participant to contact the investigator site staff or investigator as soon as possible 
if he or she experiences a fever ≥104°F (≥40.0°C) or any severe systemic event from 
Day 1 through Day 7 after study intervention administration (where Day 1 is the day of
administration) to determine if an unscheduled visit is required (see Section 8.10.3).
•
Ask the participant to contact the site staff or investigator immediately if any significant 
illness or medical event (eg, emergency room visit or hospitalization) occurs.
•
Provide the participant with the participant contact card containing the study and 
investigator information (see Section 10.1.11).
•
Remind the participant to use appropriate contraceptives until 28 days after study 
intervention administration, if applicable.
•
Schedule an appointment for the participant to return for the next study visit.
•
Remind the participant to bring the e-diary to the next visit.
•
The investigator or an authorized designee completes the CRF and the source documents 
and updates the study intervention accountability records.
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•
The investigator or appropriately qualified designee reviews the e-diary data online at 
frequent intervals (daily is optimal) for the 7 days (Day 1 is the day of study intervention 
administration) following administration to evaluate participant compliance and as part of 
the ongoing safety review.
8.10.2. Visit 2 – Follow-Up After Study Intervention Administration – 28 to 42 Days 
After Study Intervention Administration
•
Ensure and document that the participant continues to be eligible for the study 
(see Section 7 for participant discontinuation/withdrawal).
•
Record nonstudy vaccinations, if applicable, as described in Section 6.9.
•
Discuss contraceptive use since Visit 1 (see Section 10.4), if applicable, and record any 
contraceptive use in the source documents.
•
Review the participant’s e-diary data. Collect stop dates of any e-diary events (local 
reactions or systemic events) ongoing on the last day that the e-diary was completed and 
record stop dates in the CRF.
•
Collect the participant’s e-diary or assist the participant in removing the study application 
from his or her own personal device.
•
Determine if any AEs (including nonserious AEs and SAEs) have occurred since the 
previous visit, follow up on any previously reported events to determine the outcome 
(ie, record stop dates or confirm if they are still continuing), record such AEs as 
described in Section 8.4, and record concomitant medications used to treat SAEs.
 
•
The investigator or an authorized designee completes the CRF and the source documents.
8.10.3. Unscheduled Visit for a Grade 3 Systemic Event or Suspected Grade 4 Reaction
If the participant reports redness or swelling at the injection site measuring >20 measuring 
device units (>10.0 cm) or severe injection site pain (Section 8.3.2.1), a temperature >40°C
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during the 7 days following study intervention administration at Visit 1, or a severe systemic 
event (Section 8.3.2.2) during the 7 days following study intervention administration at 
Visit 1, a telephone contact must occur as soon as possible between the investigator or 
medically qualified designee and the participant to assess if an unscheduled investigator site 
visit is required. A site visit should be scheduled as soon as possible to assess the extent of 
the injection site reaction unless any of the following is true:
•
The participant is unable to attend the unscheduled visit.
•
The reaction is no longer present at the time of the telephone contact.
•
The participant recorded an incorrect value in the e-diary (confirmation of an e-diary 
data entry error).
•
The PI or authorized designee determined it was not needed.
This telephone contact will be recorded in the participant’s source documentation and the 
CRF. If the participant is unable to attend the unscheduled visit, or the PI or authorized 
designee determined it was not needed, any ongoing reactions must be assessed at the next 
study visit. During the unscheduled visit, the reactions should be assessed by the investigator 
or a medically qualified member of the study staff, such as a study physician or a study 
nurse, as applicable to the investigator’s local practice, who will:
•
Measure oral temperature (°F/°C).
•
Measure minimum and maximum diameters of redness (if present).
•
Measure minimum and maximum diameters of swelling (if present).
•
Assess injection site pain (if present) in accordance with the grades provided in 
Section 8.3.2.1.
•
Assess systemic events (if present) in accordance with the grades provided in 
Section 8.3.2.2.
•
Assess for other findings associated with the reaction and record on the AE page of 
the CRF, if appropriate.
The investigator or an authorized designee will complete the unscheduled visit assessment 
page of the CRF.
9. STATISTICAL CONSIDERATIONS
Methodology for summary and statistical analyses of the data collected in this study is 
described here and further detailed in the SAP, which will be maintained by the sponsor. The 
SAP may modify what is outlined in the protocol where appropriate; however, any major 
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modifications of the primary endpoint definitions or their analyses will also be reflected in a 
protocol amendment.
9.1. Statistical Hypothesis
There is no formal statistical hypothesis testing planned for this study.
9.1.1. Estimands
The estimands corresponding to the primary and secondary objectives are described in the 
table in Section 3. The estimands to evaluate the immunogenicity objectives will be based on 
the evaluable immunogenicity population (see Section 9.2 for definition). The estimands 
estimate the study intervention effect in the hypothetical setting where participants follow the 
study schedules and protocol requirements as directed. Missing serology results will not be 
imputed. Immunogenicity results that are below the LLOQ will be set to 0.5 × LLOQ in the 
analysis.
In the primary safety objective evaluations, missing e-diary data will not be imputed. A 
partial AE start date (eg, missing day, missing both month and day) will be imputed by 
assigning the earliest possible start date using all available information (eg, stop date of AE, 
vaccination date from the same participant) following the Pfizer standards for handling 
incomplete AE start date. An AE with a completely missing start date is not allowed in the 
data collection. No other missing information will be imputed in the safety analysis..
9.2. Analysis Sets
For purposes of analysis, the following analysis sets are defined:
Participant Analysis Set
Description
Enrolled 
All participants who sign the ICD.
Randomized
All participants who are assigned a randomization number in 
the IRT system.
Evaluable immunogenicity
All eligible randomized participants who receive the study 
intervention to which they are randomly assigned, have at 
least 1 valid immunogenicity result from the blood sample 
collected within an appropriate window 1 month after 
administration, and have no other major protocol deviations 
as determined by the clinician.
 
 
Safety 
All participants who receive the study intervention.
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9.3. Statistical Analyses
The SAP will be developed and finalized before database lock for any of the planned 
analyses in Section 9.4. It will describe the analyses and procedures for accounting for 
missing, unused, and spurious data. This section is a summary of the planned statistical 
analyses of the primary, secondary 
9.3.1. General Considerations
In general, the study data will be summarized by study intervention groups. CIs for all 
endpoints in the statistical analysis will be presented as 2-sided at the 95% level.
 
 
Participants will be 
summarized according to the study intervention group to which they were randomized. 
Missing laboratory results will not be imputed.
The safety analyses are based on the safety population. Participants will be summarized 
according to the study interventions they received.
9.3.1.1. Analyses for Binary Data
Descriptive statistics for categorical variables (eg, proportions) are the percentage (%), the 
numerator (n) and denominator (N) used in the percentage calculation, and the 2-sided 95% 
CIs, where applicable.
The exact 95% CI for binary endpoints for each group will be computed using the 
F distribution (Clopper-Pearson).
9.3.1.2. Analyses for Continuous Data
Unless otherwise stated, descriptive statistics for continuous variables are n, mean, median, 
standard deviation, minimum, and maximum.
9.3.1.2.1. Geometric Means
The geometric mean for each group will be calculated as the mean of the logarithmically 
transformed assay results and then exponentiating the mean. The 2-sided 95% CI will be 
obtained by exponentiating the CI for the mean of the logarithmically transformed assay 
results based on Student’s t distribution.
 
 
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9.3.2. Primary Endpoint(s)/Estimand(s) Analysis
Endpoints and Estimands
Statistics
•
Percentage of participants with local reactions 
(redness, swelling, and pain at the injection 
site) within 7 days after study intervention 
administration in each group
•
Percentage of participants with systemic events 
(fever, fatigue, headache, muscle pain, and 
joint pain) within 7 days after study 
intervention administration in each group
•
Descriptive summary statistics for 
participants with each local 
reaction/systemic event within 
7 days after study intervention 
administration, by severity level
•
Percentage of participants with AEs from 
study intervention administration through
1 month after administration in each group
•
Descriptive summary statistics
•
Percentage of participants with SAEs from 
study intervention administration through
1 month after administration in each group
•
Descriptive summary statistics
9.3.3. Secondary Endpoint(s)/Estimand(s) Analysis
Endpoints and Estimands
Statistics
•
 OPA GMT 1 month after study 
intervention administration 
•
GMT and 2-sided 95% CI
 
 
 
 
 
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.
9.4. Interim Analyses
No interim analysis will be conducted for this study. As this is an open-label study, the 
sponsor may conduct unblinded reviews of the data during the course of the study for the 
purpose of safety assessment and/or for supporting clinical development.
9.4.1. Analysis Timing
Statistical analyses will be carried out as specified below:
•
An analysis will be conducted when safety data through approximately 1 month after 
study intervention administration are available.
•
Immunogenicity data of OPA and IgG results through Visit 2 (1 month after study 
intervention administration) may be analyzed, when available, for 1 or more 
immunogenicity endpoints
 
.
•
A final analysis of safety, including complete OPA and IgG results available after the 
completion of the study, will be performed.
 
This is an open-label Phase 1 exploratory study. Immunogenicity data reviews by the sponsor 
may be conducted at any time the data are available to aid in decision-making for the sponsor 
programs.
Certain analyses may be combined if the data become available around the same time. 
Additional analyses may be conducted or combined if required for regulatory purposes or for 
further clinical evaluation of the study intervention.
9.5. Sample Size Determination
The sample size of this study is not driven by any formal hypothesis test. It is determined 
primarily based on the consideration of providing pioneer information on the immune 
responses induced by the 
candidates and the corresponding safety profiles in order to 
support a decision for further clinical development.
The primary safety objective includes the endpoints for AEs, local reactions, and systemic 
events. Table 5 shows the binomial probability of detecting at least 1 AE. The number of 
participants in each study group is 45, which provides a >90% chance of observing at least 
1 event in a group, assuming a true event rate of at least 5%.
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Table 5.
Probability of Detecting at Least 1 Adverse Event in a Study Group
True Rate of AEs
Probability of Observing at Least 1 AE
2.0%
59.7%
3.0%
74.6%
4.0%
84.1%
5.0%
90.1%
6.0%
93.8%
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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1. Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:
•
Consensus ethical principles derived from international guidelines, including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines;
•
Applicable ICH GCP guidelines;
•
Applicable laws and regulations, including applicable privacy laws.
The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents 
(eg, advertisements) must be reviewed and approved by the sponsor, submitted to an IRB/EC 
by the investigator, and reviewed and approved by the IRB/EC before the study is initiated.
Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.
Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard to 
study participants.
The investigator will be responsible for the following:
•
Providing written summaries of the status of the study to the IRB/EC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC;
•
Notifying the IRB/EC of SAEs or other significant safety findings as required by 
IRB/EC procedures;
•
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH GCP guidelines, the IRB/EC, European regulation 
536/2014 for clinical studies, European Medical Device Regulation 2017/745 for 
clinical device research, and all other applicable local regulations.
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the study 
intervention, Pfizer should be informed immediately.
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In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study participants against any immediate hazard, and 
of any serious breaches of this protocol or of the ICH GCP guidelines that the investigator 
becomes aware of.
10.1.2. Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
10.1.3. Informed Consent Process
The investigator or the investigator’s representative will explain the nature of the study, 
including the risks and benefits, to the participant and answer all questions regarding the 
study. The participant should be given sufficient time and opportunity to ask questions and to 
decide whether or not to participate in the trial.
Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 50, 
local regulations, ICH guidelines, privacy and data protection requirements, where 
applicable, and the IRB/EC or study center.
The investigator must ensure that each participant is fully informed about the nature and 
objectives of the study, the sharing of data related to the study, and possible risks associated 
with participation, including the risks associated with the processing of the participant’s 
personal data.
The participant must be informed that their personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant
The participant must be informed that their medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/EC members, and by inspectors from regulatory authorities.
The investigator further must ensure that each study participant is fully informed about their
right to access and correct their personal data and to withdraw consent for the processing of 
their personal data.
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date on which the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICD.
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Participants must be reconsented to the most current version of the IRB/EC-approved ICD(s) 
during their participation in the study as required per local regulations.
A copy of the ICD(s) must be provided to the participant.
10.1.4. Data Protection
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data.
Participants’ personal data will be stored at the study site in encrypted electronic and/or paper
form and will be password protected or secured in a locked room 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 will be responsible for 
determining whether a personal data breach has in fact occurred and, if so, providing breach 
notifications as required by law.
To protect the rights and freedoms of participants with regard to the processing of personal 
data, participants will be assigned a single, participant-specific numerical code. Any 
participant records or data sets that are transferred to the sponsor will contain the numerical 
code; participant names will not be transferred. All other identifiable data transferred to the 
sponsor will be identified by this single, participant-specific code. The study site will 
maintain a confidential list of participants who participated in the study, linking each 
participant’s numerical code to their actual identity and medical record ID. In case of data 
transfer, the sponsor will protect the confidentiality of participants’ personal data consistent 
with the clinical study agreement and applicable privacy laws.
Information technology systems used to collect, process, and store study-related data are 
secured by technical and organizational security measures designed to protect such data 
against accidental or unlawful loss, alteration, or unauthorized disclosure or access.
The sponsor maintains SOPs on how to respond in the event of unauthorized access, use, or 
disclosure of sponsor information or systems.
10.1.5. Committees Structure
10.1.5.1. Data Monitoring Committee 
This study will not use an EDMC.
10.1.6. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the EudraCT/CTIS, and/or 
www.pfizer.com, and other public registries and websites in accordance with applicable local 
laws/regulations. In addition, Pfizer reports study results outside of the requirements of local 
laws/regulations pursuant to its SOPs.
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In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer-sponsored interventional 
studies (conducted in patients) that evaluate the safety and/or efficacy of a product, 
regardless of the geographical location in which the study is conducted. These results are 
submitted for posting in accordance with the format and timelines set forth by US law.
EudraCT/CTIS
Pfizer posts clinical trial results on EudraCT/CTIS for Pfizer-sponsored interventional studies 
in accordance with the format and timelines set forth by EU requirements.
www.pfizer.com
Pfizer posts CSR synopses and plain-language study results summaries on www.pfizer.com 
for Pfizer-sponsored interventional studies at the same time the corresponding study results 
are posted to www.clinicaltrials.gov. CSR synopses will have personally identifiable 
information anonymized.
Documents within marketing applications
Pfizer complies with applicable local laws/regulations to publish clinical documents included 
in marketing applications. Clinical documents include summary documents and CSRs 
including the protocol and protocol amendments, sample CRFs, and SAPs. Clinical 
documents will have personally identifiable information anonymized.
Data sharing
Pfizer provides researchers secure access to participant-level data or full CSRs for the 
purposes of “bona-fide scientific research” that contributes to the scientific understanding of 
the disease, target, or compound class. Pfizer will make data from these trials available 
24 months after study completion. Participant-level data will be anonymized in accordance 
with applicable privacy laws and regulations. CSRs will have personally identifiable 
information anonymized.
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses. Research teams must include a biostatistician. Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.
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10.1.7. Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.
Guidance on completion of CRFs will be provided in the CRF Completion Requirements 
document.
The investigator must ensure that the CRFs are securely stored at the study site in encrypted 
electronic and/or paper form and are password protected or secured in a locked room to 
prevent access by unauthorized third parties.
QTLs are predefined parameters that are monitored during the study. Important deviations 
from the QTLs and any remedial actions taken will be summarized in the CSR.
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source data documents. This 
verification may also occur after study completion. It is important that the investigator(s) and 
their relevant personnel are available during the monitoring visits and possible audits or 
inspections and that sufficient time is devoted to the process.
Monitoring details describing strategy, including definition of study-critical data items and 
processes (eg, risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
requirements, including handling of noncompliance issues and monitoring techniques 
(central, virtual, or on-site monitoring), are provided in the data management plan and 
monitoring plan maintained and utilized by the sponsor or designee.
The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data.
Records and documents, including signed ICDs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. The 
investigator must ensure that the records continue to be stored securely for as long as they are 
maintained.
When participant data are to be deleted, the investigator will ensure that all copies of such 
data are promptly and irrevocably deleted from all systems.
The investigator(s) will notify the sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study. Furthermore, the investigator will cooperate 
with the sponsor or its agents to prepare the investigator site for the inspection and will allow 
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the sponsor or its agent, whenever feasible, to be present during the inspection. The 
investigator site and investigator will promptly resolve any discrepancies that are identified 
between the study data and the participant’s medical records. The investigator will promptly 
provide copies of the inspection findings to the sponsor or its agent. Before response 
submission to the regulatory authorities, the investigator will provide the sponsor or its 
agents with an opportunity to review and comment on responses to any such findings.
10.1.8. Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator site.
Data reported on the CRF or entered in the eCRF that are from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
In this study, the CRF will serve as the source document. A document must be available at 
the investigative site that identifies those data that will be recorded on the CRF and for which 
the CRF will be the source document.
Definition of what constitutes source data and its origin can be found in the Source 
Document Locator, which is maintained by the sponsor.
Description of the use of the computerized system is documented in the data management 
plan, which is maintained by the sponsor
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The sponsor or designee will perform monitoring to confirm that data entered into the CRF 
by authorized site personnel are accurate, complete, and verifiable from source documents; 
that the safety and rights of participants are being protected; and that the study is being 
conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP guidelines, and all applicable regulatory requirements.
10.1.9. Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The first act of recruitment is the date of the first participant’s first visit and will be the study 
start date.
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor, including (but not limited to) 
regulatory authority decision, change in opinion of the IRB/EC, or change in benefit-risk 
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assessment. Study sites will be closed upon study completion. A study site is considered 
closed when all required documents and study supplies have been collected and a study-site 
closure visit has been performed.
The investigator may initiate study-site closure at any time upon notification to the sponsor 
or designee/CRO if requested to do so by the responsible IRB/EC or if such termination is 
required to protect the health of study participants.
Reasons for the early closure of a study site by the sponsor may include but are not limited 
to:
•
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the sponsor’s procedures, or the ICH GCP 
guidelines;
•
Inadequate recruitment of participants by the investigator;
•
Discontinuation of further study intervention development.
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
Study termination is also provided for in the clinical study agreement. If there is any conflict 
between the contract and this protocol, the contract will control as to termination rights.
10.1.10. Publication Policy
For multicenter trials, the primary publication will be a joint publication developed by the 
investigator and Pfizer reporting the primary endpoint(s) of the study covering all study sites. 
The investigator agrees to refer to the primary publication in any subsequent publications. 
Pfizer will not provide any financial compensation for the investigator’s participation in the 
preparation of the primary congress abstract, poster, presentation, or primary manuscript for 
the study.
Investigators are free to publish individual center results that they deem to be clinically 
meaningful after publication of the overall results of the study or 12 months after primary 
completion date or study completion at all sites, whichever occurs first, subject to the other 
requirements described in this section.
The investigator will provide Pfizer an opportunity to review any proposed publication or 
any other type of disclosure of the study results (collectively, “publication”) before it is 
submitted or otherwise disclosed and will submit all publications to Pfizer 30 days before 
submission. If any patent action is required to protect intellectual property rights, the 
investigator agrees to delay the disclosure for a period not to exceed an additional 60 days 
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upon request from Pfizer. This allows Pfizer to protect proprietary information and to provide 
comments, and the investigator will, on request, remove any previously undisclosed 
confidential information before disclosure, except for any study-intervention or Pfizer-related 
information necessary for the appropriate scientific presentation or understanding of the 
study results. For joint publications, should there be disagreement regarding interpretation 
and/or presentation of specific analysis results, resolution of, and responsibility for, such 
disagreements will be the collective responsibility of all authors of the publication.
For all publications relating to the study, the investigator and Pfizer will comply with 
recognized ethical standards concerning publications and authorship, including those 
established by the International Committee of Medical Journal Editors. The investigator will 
disclose any relationship with Pfizer and any relevant potential conflicts of interest, including 
any financial or personal relationship with Pfizer, in any publications. All authors will have 
access to the relevant statistical tables, figures, and reports (in their original format) required 
to develop the publication.
10.1.11. Sponsor’s Medically Qualified Individual 
The contact information for the sponsor’s MQI for the study is documented in the study 
contact list located in the supporting study documentation/study portal or other electronic 
system.
To facilitate access to their investigator and the sponsor’s MQI for study-related medical 
questions or problems from nonstudy healthcare professionals, participants are provided with 
an ECC at the time of informed consent. The ECC contains, at a minimum, (a) protocol and 
study intervention identifiers, (b) participant’s study identification number, (c) site 
emergency phone number active 24 hours/day, 7 days per week, and (d) Pfizer Call Center 
number.
The ECC is intended to augment, not replace, the established communication pathways 
between the participant and their investigator and site staff, and between the investigator and 
sponsor study team. The ECC is only to be used by healthcare professionals not involved in 
the research study, as a means of reaching the investigator or site staff related to the care of a 
participant. The Pfizer Call Center number is to be used when the investigator and site staff 
are unavailable. The Pfizer Call Center number is not for use by the participant directly; if a 
participant calls that number directly, they will be directed back to the investigator site.
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10.2. Appendix 2: Clinical Laboratory Tests
Unscheduled clinical laboratory measurements may be obtained at any time during the study 
to assess any perceived safety issues. The investigator must review the laboratory report, 
document this review, and record any clinically relevant changes occurring during the study 
in the AE section of the CRF.
Pregnancy test (β-hCG): Local urine testing will be standard for the protocol unless serum 
testing is required by local regulation or IRB/EC for participants who are WOCBP.
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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting
10.3.1. Definition of AE
AE Definition
•
An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered 
related to the study intervention.
•
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention.
Events Meeting the AE Definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital sign measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator. Any abnormal laboratory test 
results that meet any of the conditions below must be recorded as an AE:
•
Is associated with accompanying symptoms.
•
Requires additional diagnostic testing or medical/surgical intervention.
•
Leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy.
•
Exacerbation of a chronic or intermittent preexisting condition, including an 
increase in either frequency and/or intensity of the condition.
•
New condition detected or diagnosed after study intervention administration, even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE or SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae.
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Events NOT Meeting the AE Definition
•
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.
•
The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
10.3.2. Definition of an SAE
An SAE is defined as any untoward medical occurrence that, at any dose, meets one or 
more of the criteria listed below:
a. Results in death
b. Is life-threatening
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event that
hypothetically might have caused death if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been admitted (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the 
AE should be considered serious.
Hospitalization for elective treatment of a preexisting condition that did not worsen 
from baseline is not considered an AE.
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d. Results in persistent or significant disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
•
This definition is not intended to include experiences of relatively minor medical 
significance, such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle), that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Is a suspected transmission via a Pfizer product of an infectious agent, pathogenic 
or nonpathogenic
The event may be suspected from clinical symptoms or laboratory findings indicating an 
infection in a participant exposed to a Pfizer product. The terms “suspected 
transmission” and “transmission” are considered synonymous. These cases are 
considered unexpected and handled as serious expedited cases by pharmacovigilance 
personnel. Such cases are also considered for reporting as product defects, if 
appropriate.
g. Other situations:
•
Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations, such as significant medical 
events that may jeopardize the participant or may require medical or surgical 
intervention to prevent one of the other outcomes listed in the above definition.
These events should usually be considered serious.
•
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
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10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During the Active 
Collection Period 
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording AEs on the CRF and for 
reporting SAEs on the Vaccine SAE Reporting Form to Pfizer Safety throughout the active 
collection period. These requirements are delineated for 3 types of events: (1) SAEs; 
(2) nonserious AEs; and (3) exposure to the study intervention under study during 
pregnancy or breastfeeding, and occupational exposure.
It should be noted that the Vaccine SAE Reporting Form for reporting of SAE information 
is not the same as the AE page of the CRF. When the same data are collected, the forms 
must be completed in a consistent manner. AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the Vaccine SAE
Reporting Form for reporting of SAE information.
Safety Event
Recorded on the CRF
Reported on the Vaccine
SAE Reporting Form to 
Pfizer Safety Within 
24 Hours of Awareness
SAE
All
All
Nonserious AE
All
None
Exposure to the study 
intervention under study 
during pregnancy or 
breastfeeding 
All AEs or SAEs associated 
with EDP or EDB
Note: Instances of EDP or 
EDB not associated with an 
AE or SAE are not captured 
in the CRF
All instances of EDP are 
reported (whether or not 
there is an associated SAE)*
All instances of EDB are 
reported (whether or not 
there is an associated 
SAE)**
Environmental or 
occupational exposure to 
the product under study to 
a nonparticipant (not 
involving EDP or EDB)
None. Exposure to a study 
nonparticipant is not 
collected on the CRF
The exposure (whether or 
not there is an associated 
AE or SAE) must be 
reported***
*
EDP (with or without an associated AE or SAE): any pregnancy information is reported to Pfizer 
Safety using the Vaccine SAE Reporting Form and EDP Supplemental Form; if the EDP is associated 
with an SAE, then the SAE is reported to Pfizer Safety using the Vaccine SAE Reporting Form.
** EDB is reported to Pfizer Safety using the Vaccine SAE Reporting Form, which would also include 
details of any SAE that might be associated with the EDB.
*** Environmental or occupational exposure: AEs or SAEs associated with occupational exposure are 
reported to Pfizer Safety using the Vaccine SAE Reporting Form.
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•
When an AE or SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostic 
reports) related to the event.
•
The investigator will then record all relevant AE or SAE information in the CRF.
•
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of completion of the Vaccine SAE Reporting
Form/AE or SAE CRF page.
•
There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety. In this case, all participant identifiers, with the exception 
of the participant number, will be redacted on the copies of the medical records 
before submission to Pfizer Safety.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE or SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported during 
the study and assign it to 1 of the following categories:
•
Mild: A type of AE that is usually transient and may require only minimal treatment 
or therapeutic intervention. The event does not generally interfere with usual ADL.
•
Moderate: A type of AE that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual ADL, causing discomfort,
but poses no significant or permanent risk of harm to the research participant.
•
Severe: A type of AE that interrupts usual ADL, or significantly affects clinical 
status, or may require intensive therapeutic intervention.
GRADE 
If required on the AE page of the CRF, the investigator will use the adjectives 
MILD, MODERATE, SEVERE to describe the maximum intensity of the 
AE. For purposes of consistency, these intensity grades are defined as 
follows:
1
MILD
Does not interfere with participant’s usual 
function.
2
MODERATE
Interferes to some extent with participant’s usual 
function.
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3
SEVERE
Interferes significantly with participant’s usual 
function.
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality
•
The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE or SAE. The investigator will use clinical 
judgment to determine the relationship.
•
A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.
•
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration, will be considered and investigated.
•
The investigator will also consult the IB and/or product information, for marketed 
products, in their assessment.
•
For each AE or SAE, the investigator must document in the medical notes that they 
have reviewed the AE or SAE and have provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor. However, it is 
very important that the investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to the sponsor.
•
The investigator may change their opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.
•
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
•
If the investigator does not know whether or not the study intervention caused the 
event, then the event will be handled as “related to study intervention” for reporting 
purposes, as defined by the sponsor. In addition, if the investigator determines that 
an SAE is associated with study procedures, the investigator must record this 
causal relationship in the source documents and CRF, and report such an 
assessment in the dedicated section of the Vaccine SAE Reporting Form and in 
accordance with the SAE reporting requirements.
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Follow-Up of AEs and SAEs
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations, as medically indicated or as requested by the 
sponsor, to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other healthcare providers.
•
If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide Pfizer Safety with a copy of any 
postmortem findings, including histopathology.
•
New or updated information will be recorded in the originally submitted documents.
•
The investigator will submit any updated SAE data to the sponsor within 24 hours of 
receipt of the information.
10.3.4. Reporting of SAEs
SAE Reporting to Pfizer Safety via an Electronic DCT
•
The primary mechanism for reporting an SAE to Pfizer Safety will be the electronic 
DCT.
•
If the electronic system is unavailable, then the site will use the paper SAE DCT
(see next section) to report the event within 24 hours.
•
The site will enter the SAE data into the electronic DCT (eg, eSAE or PSSA) or 
paper form (as applicable) as soon as the data become available.
•
After the study is completed at a given site, the electronic DCT will be taken off-line 
to prevent the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic DCT has been taken off-line, 
then the site can report this information on a paper SAE form (see next section) or to 
Pfizer Safety by telephone.
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SAE Reporting to Pfizer Safety via the Vaccine SAE Reporting Form
•
Facsimile transmission of the Vaccine SAE Reporting Form is the preferred method 
to transmit this information to Pfizer Safety.
•
In circumstances when the facsimile is not working, an alternative method should be 
used, eg, secured (Transport Layer Security) or password-protected email. If none of 
these methods can be used, notification by telephone is acceptable with a copy of the 
Vaccine SAE Reporting Form sent by overnight mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the Vaccine SAE Reporting Form pages within the designated 
reporting time frames.
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10.4. Appendix 4: Contraceptive and Barrier Guidance 
10.4.1. Male Participant Reproductive Inclusion Criteria
Male participants are eligible to participate if they agree to the following requirements during 
the intervention period and for at least 28 days after the last dose of study intervention, which 
corresponds to the time needed to eliminate reproductive safety risk of the study 
intervention(s)
•
Refrain from donating sperm.
PLUS either:
•
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent.
OR
•
Must agree to use contraception/barrier as detailed below:
•
Agree to use a male condom when having sexual intercourse with a WOCBP who 
is not currently pregnant.
•
In addition to male condom use, a highly effective method of contraception may be 
considered in WOCBP partners of male participants (refer to the list of highly 
effective methods below in Section 10.4.4).
10.4.2. Female Participant Reproductive Inclusion Criteria
The criteria below are part of inclusion criterion 1 (Age and Sex; Section 5.1) and specify the 
reproductive requirements for including female participants. Refer to Section 10.4.4 for a 
complete list of contraceptive methods permitted in the study.
A female participant is eligible to participate if she is not pregnant or breastfeeding and at 
least 1 of the following conditions applies:
•
Is not a WOCBP (see definitions below in Section 10.4.3).
•
OR
•
Is a WOCBP and agrees to use an acceptable contraceptive method during the 
intervention period (for a minimum of 28 days after the last dose of study 
intervention). The investigator should evaluate the effectiveness of the contraceptive 
method in relationship to the first dose of study intervention.
The investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected 
pregnancy.
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10.4.3. Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
1. Premenarchal.
2. Premenopausal female with 1 of the following:
•
Documented hysterectomy;
•
Documented bilateral salpingectomy;
•
Documented bilateral oophorectomy.
For individuals with permanent infertility due to a medical cause other than the above
(eg, mullerian agenesis, androgen insensitivity), investigator discretion should be applied to 
determining study entry.
Note: Documentation for any of the above categories can come from the site personnel’s 
review of the participant’s medical records, medical examination, or medical history 
interview. The method of documentation should be recorded in the participant’s medical 
record for the study.
3. Postmenopausal female:
•
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. In addition:
•
A high FSH level in the postmenopausal range must be used to confirm a 
postmenopausal state in women under 60 years of age and not using hormonal 
contraception or HRT.
•
A female on HRT and whose menopausal status is in doubt will be required to use 
one of the highly effective nonestrogen hormonal contraception methods if she
wishes to continue her HRT during the study. Otherwise, she must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment.
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10.4.4. Contraception Methods
Contraceptive use by men or women should be consistent with local availability/regulations 
regarding the use of contraceptive methods for those participating in clinical trials.
The following contraceptive methods are appropriate for this study:
Highly Effective Methods That Have Low User Dependency
1. Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation.
2. Intrauterine device.
3. Intrauterine hormone-releasing system.
4. Bilateral tubal occlusion.
5. Vasectomized partner:
•
Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the WOCBP and the absence of sperm has 
been confirmed. If not, an additional highly effective method of contraception 
should be used. The spermatogenesis cycle is approximately 90 days.
Highly Effective Methods That Are User Dependent 
6. Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation:
•
Oral;
•
Intravaginal;
•
Transdermal.
7. Progestogen-only hormone contraception associated with inhibition of ovulation:
•
Oral;
•
Injectable.
Sexual Abstinence
8. Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention. The reliability of sexual abstinence needs to be evaluated 
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in relation to the duration of the study and the preferred and usual lifestyle of the 
participant.
Other Effective Methods
9. Progestogen-only oral hormonal contraception where inhibition of ovulation is not the 
primary mode of action.
10. Male or female condom, with or without spermicide.
11. Cervical cap, diaphragm, or sponge with spermicide.
12. A combination of male condom with either cervical cap, diaphragm, or sponge with 
spermicide (double-barrier methods).
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10.5. Appendix 5: Genetics
Use/Analysis of DNA
 
 
 
•
The results of genetic analyses may be reported in the CSR or in a separate study 
summary, or may be used for internal decision making without being included in a 
study report.
•
The sponsor will store the DNA and/or RNA samples in a secure storage space with 
adequate measures to protect confidentiality.
•
The samples will be retained as indicated:
•
Samples for specified genetic analysis (see Section 8.6.1) will be stored for up to 
15 years or other period as per local requirements.
•
Samples for genetic research will be labeled with a code. The key between the code 
and the participant’s personally identifying information (eg, name, address) will be 
held securely at the study site.
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10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments 
Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury but adapt 
are termed “adaptors.” In some participants, transaminase elevations are a harbinger of a 
more serious potential outcome. These participants fail to adapt and therefore are 
“susceptible” to progressive and serious liver injury, commonly referred to as DILI. 
Participants who experience a transaminase elevation above 3 × ULN should be monitored 
more frequently to determine if they are “adaptors” or are “susceptible.”
LFTs are not required as a routine safety monitoring procedure in this study. However, should 
an investigator deem it necessary to assess LFTs because a participant presents with clinical 
signs/symptoms, such LFT results should be managed and followed as described below.
In the majority of DILI cases, elevations in AST and/or ALT precede T bili elevations 
(>2 × ULN) by several days or weeks. The increase in T bili typically occurs while AST/ALT 
is/are still elevated above 3 × ULN (ie, AST/ALT and T bili values will be elevated within 
the same laboratory sample). In rare instances, by the time T bili elevations are detected, 
AST/ALT values might have decreased. This occurrence is still regarded as a potential DILI. 
Therefore, abnormal elevations in either AST OR ALT in addition to T bili that meet the 
criteria outlined below are considered potential DILI (assessed per Hy’s law criteria) cases
and should always be considered important medical events, even before all other possible 
causes of liver injury have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the 
participant’s individual baseline values and underlying conditions. Participants who present 
with the following laboratory abnormalities should be evaluated further as potential DILI 
(Hy’s law) cases to definitively determine the etiology of the abnormal laboratory values:
•
Participants with AST/ALT and T bili baseline values within the normal range who 
subsequently present with AST OR ALT values ≥3 × ULN AND a T bili value 
≥2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available.
•
For participants with baseline AST OR ALT OR T bili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:
•
Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values ≥2 times the baseline values AND ≥3 × ULN; or ≥8 × ULN (whichever is 
smaller).
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•
Preexisting values of T bili above the normal range: T bili level increased from 
baseline value by an amount of ≥1 × ULN or if the value reaches ≥3 × ULN 
(whichever is smaller).
Rises in AST/ALT and T bili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor.
The participant should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results. This evaluation should 
include laboratory tests, detailed history, and physical assessment.
In addition to repeating measurements of AST and ALT and T bili for suspected Hy’s law
cases, additional laboratory tests should include albumin, CK, direct and indirect bilirubin, 
GGT, PT/INR, total bile acids, and alkaline phosphatase. Consideration should also be given 
to drawing a separate tube of clotted blood and an anticoagulated tube of blood for further 
testing, as needed, for further contemporaneous analyses at the time of the recognized initial 
abnormalities to determine etiology. A detailed history, including relevant information, such 
as review of ethanol, acetaminophen/paracetamol (either by itself or as a coformulated 
product in prescription or over-the-counter medications), recreational drug, or supplement 
(herbal) use and consumption, family history, sexual history, travel history, history of contact 
with a jaundiced person, surgery, blood transfusion, history of liver or allergic disease, and 
potential occupational exposure to chemicals, should be collected. Further testing for acute 
hepatitis A, B, C, D, and E infection, liver imaging (eg, biliary tract), and collection of serum 
samples for acetaminophen/paracetamol drug and/or protein adduct levels may be warranted.
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
T bili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the LFT abnormalities has yet been found. Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.
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10.7. Appendix 7: Kidney Safety Monitoring Guidelines
10.7.1. Laboratory Assessment of Change in Kidney Function and Detection of Kidney 
Injury
Standard kidney safety monitoring requires assessment of baseline and postbaseline serum 
creatinine (Scr measurement to eGFR [Scr-based eGFR] or [eCrCl]). Baseline and 
postbaseline Scys makes it feasible to distinguish AKI from other causes of Scr increase. If 
Scr increase is confirmed after baseline, then reflex measurement of Scys is indicated to 
estimate the combined Scr-Scys eGFR calculation (for adults only).
Regardless of whether kidney function monitoring tests are required as a routine safety 
monitoring procedure in the study, if the investigator or sponsor deems it necessary to further 
assess kidney safety and quantify kidney function, then these test results should be managed 
and followed per standard of care.
10.7.2. Age-Specific Kidney Function Calculation Recommendations
10.7.2.1. Adults (18 Years and Above)—2021 CKD-EPI Equations
2021 CKD-EPI
Scr Only
Scr
(mg/dL)
Scys
(mg/L)
Recommended eGFR Equation
Female
if ≤0.7
N/A
eGFR = 143 × (Scr/0.7)-0.241  ×  (0.9938)Age
Female
if >0.7
N/A
eGFR = 143 × (Scr/0.7)-1.200  ×  (0.9938)Age
Male
if ≤0.9
N/A
eGFR = 142 × (Scr/0.9)-0.302  ×  (0.9938)Age
Male
if >0.9
N/A
eGFR = 142 × (Scr/0.9)-1.200  ×  (0.9938)Age
2021 CKD-EPI 
Scr-Scys 
Combined
Scr
(mg/dL)
Scys
(mg/L)
Recommended eGFR Equation
Female
if ≤0.7
if ≤0.8
eGFR = 130 × (Scr/0.7)-0.219  ʹ (Scys/0.8)-0.323  ʹ (0.9961)Age
Female
if ≤0.7
if >0.8
eGFR = 130 × (Scr/0.7)-0.219  ʹ (Scys/0.8)-0.778  ʹ (0.9961)Age
Female
if >0.7
if ≤0.8
eGFR = 130 × (Scr/0.7)-0.544  ʹ (Scys/0.8)-0.323  ʹ (0.9961)Age
Female
if >0.7
if >0.8
eGFR = 130 × (Scr/0.7)-0.544  ʹ (Scys/0.8)-0.778  ʹ (0.9961)Age
Male
if ≤0.9
if ≤0.8
eGFR = 135 × (Scr/0.9)-0.144  ʹ (Scys/0.8)-0.323  ʹ (0.9961)Age
Male
if ≤0.9
if >0.8
eGFR = 135 × (Scr/0.9)-0.144  ʹ (Scys/0.8)-0.778  ʹ (0.9961)Age
Male
if >0.9
if ≤0.8
eGFR = 135 × (Scr/0.9)-0.544  ʹ (Scys/0.8)-0.323  ʹ (0.9961)Age
Male
if >0.9
if >0.8
eGFR = 135 × (Scr/0.9)-0.544  ʹ (Scys/0.8)-0.778  ʹ (0.9961)Age
Note: The table source is Inker LA, et al. N Engl J Med. 2021;385(18):1737-49.
10.7.3. Adverse Event Grading for Kidney Safety Laboratory Abnormalities
AE grading for decline in kidney function (ie, eGFR or eCrCl) will be according to KDIGO
criteria.
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10.8. Appendix 8: AEs, ADEs, SAEs, SADEs, USADEs, and Device Deficiencies:
Definitions and Procedures for Recording, Evaluating, Follow-Up, and Reporting in 
Medical Device Studies
Definitions of a Medical Device Deficiency
The definitions and procedures detailed in this appendix are in accordance with ISO 14155
and the European MDR 2017/745 for clinical device research (if applicable).
Both the investigator and the sponsor will comply with all local reporting requirements for 
medical devices.
The detection and documentation procedures described in this protocol apply to all sponsor 
medical devices provided for use in the study (see Section 6.1.2 for the list of sponsor 
medical devices).
10.8.1. Definition of AE and ADE
AE and ADE Definition
•
An AE is defined in Appendix 3 (Section 10.3.1).
•
An ADE is defined as an AE related to the use of an investigational medical device. 
This definition includes any AEs resulting from insufficient or inadequate 
instructions for use, deployment, implantation, installation, or operation, or any 
malfunction of the investigational medical device as well as any event resulting 
from use error or from intentional misuse of the investigational medical device.
10.8.2. Definition of SAE, SADE, and USADE
SAE Definition
•
An SAE is defined in Appendix 3 (Section 10.3.2).
SADE Definition
•
An SADE is defined as an ADE that has resulted in any of the consequences 
characteristic of an SAE.
•
Any device deficiency that might have led to an SAE if appropriate action had not 
been taken, intervention had not occurred, or circumstances had been less fortunate.
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USADE Definition
•
A USADE (also identified as UADE in US Regulations 21 CFR 813.3) is a SADE
that by its nature, incidence, severity, or outcome has not been identified in the 
current version of the risk analysis management file.
10.8.3. Definition of Device Deficiency
Device Deficiency Definition
•
A device deficiency is an inadequacy of a medical device with respect to its identity, 
quality, durability, reliability, safety, or performance. Device deficiencies include 
malfunctions, use errors, and inadequate information supplied by the manufacturer.
10.8.4. Recording/Reporting and Follow-Up of Medical Device Deficiencies
Device Deficiency Recording
•
When a device deficiency occurs, it is the responsibility of the investigator to review 
all documentation (eg, hospital progress notes, laboratory reports, and diagnostic 
reports) related to the event.
•
The investigator will then record all relevant device deficiency information in the 
participant’s medical records, in accordance with the investigator’s normal clinical 
practice, and will also capture the required information on the Medical Device 
Complaint form.
•
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of following the reporting process described 
in the Medical Device Complaint form.
•
There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety. In this case, all participant identifiers, with the exception 
of the participant number, will be redacted on the copies of the medical records 
before submission to Pfizer Safety.
•
If the investigator determines that the medical device deficiency may have injured 
the participant (ie, the medical device deficiency is associated with an AE or SAE), 
then the investigator will attempt to establish a diagnosis of the event based on 
signs, symptoms, and/or other clinical information. Whenever possible, the 
diagnosis will be documented in the participant’s medical record and recorded as the 
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AE or SAE rather than the individual signs/symptoms. Requirements for recording 
and reporting an AE or SAE are provided in Appendix 3 (Section 10.3.3).
•
For device deficiencies, it is very important that the investigator describes any 
corrective or remedial actions taken to prevent recurrence of the incident.
•
A remedial action is any action other than routine maintenance or servicing of a 
medical device where such action is necessary to prevent recurrence of a device 
deficiency. This includes any amendment to the device design to prevent 
recurrence.
Assessment of Causality Occurring in Conjunction With a Medical Device Deficiency
•
If an AE or SAE has occurred in conjunction with a medical device deficiency, the 
investigator must assess the relationship between each occurrence of the AE or SAE 
and the medical device deficiency. The investigator will use clinical judgment to 
determine the relationship.
•
A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.
•
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.
•
The investigator will also consult the IB in their assessment.
•
For each device deficiency, the investigator must document in the medical notes 
that they have reviewed the device deficiency and have provided an assessment of 
causality.
•
There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor. However, it is 
very important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to the sponsor.
•
The investigator may change their opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.
•
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
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Follow-Up of Medical Device Deficiency
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations, as medically indicated or as requested by the 
sponsor to elucidate the nature and/or causality of the device deficiency as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other healthcare providers.
•
New or updated information regarding the nature of the device deficiency will be 
recorded in the originally completed Medical Device Complaint form.
•
New or updated information regarding any SAE that was potentially associated with 
the medical device deficiency will be submitted to Pfizer Safety on the Vaccine SAE 
Reporting Form within 24 hours of receipt of the information, according to the 
requirements provided in Appendix 3.
10.8.5. Reporting of SAEs
Reporting of an SAE to Pfizer Safety must be performed according to the processes 
described in Appendix 3 (Section 10.3.4).
10.8.6. Reporting of SADEs
SADE Reporting to Pfizer Safety
Note: There are additional reporting obligations for medical device deficiencies that are 
potentially related to SAEs (ie, an SADE) that must fulfill the legal responsibility to notify 
appropriate regulatory authorities and other entities about certain safety information relating 
to medical devices being used in clinical studies.
•
Any device deficiency that is associated with an SAE must be reported to the 
sponsor within 24 hours after the investigator determines that the event meets the 
definition of a device deficiency.
•
The sponsor shall review all device deficiencies and determine and document in 
writing whether they could have led to an SAE. These shall be reported to the 
regulatory authorities and IRBs/ECs as required by national regulations.
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10.9. Appendix 9: Abbreviations
The following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
7vPnC
7-valent pneumococcal conjugate vaccine
9vPnC
9-valent pneumococcal conjugate vaccine
13vPnC
13-valent pneumococcal conjugate vaccine
20vPnC
20-valent pneumococcal conjugate vaccine
ADE
adverse device effect
ADL
activity/activities of daily living
AE
adverse event
AKI
acute kidney injury
AlPO4
aluminum phosphate
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AxMP
auxiliary medicinal product
BCR
B-cell receptor
b-hCG
b-human chorionic gonadotropin
CBER
Center for Biologics Evaluation and Research
CFR
Code of Federal Regulations
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CONSORT
Consolidated Standards of Reporting Trials
COPD
chronic obstructive pulmonary disease
COVID-19
coronavirus disease 2019
CRF
case report form
CRO
contract research organization
CSR
clinical study report
CTIS
Clinical Trial Information System
DCT
data collection tool
DILI
drug-induced liver injury
DNA
deoxyribonucleic acid
DU
dispensable unit
EC
ethics committee
ECC
emergency contact card
ECG
electrocardiogram
eCrCl
estimated creatinine clearance
eCRF
electronic case report form
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Abbreviation
Term
EDB
exposure during breastfeeding
e-diary
electronic diary
EDMC
External Data Monitoring Committee
EDP
exposure during pregnancy
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
eSAE
electronic serious adverse event
EU
European Union
EudraCT
European Union Drug Regulating Authorities Clinical Trials 
(European Clinical Trials Database)
FDA
(United States) Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GMC
geometric mean concentration
GMFR
geometric mean fold rise
GMT
geometric mean titer
HIV
human immunodeficiency virus
HRT
hormone replacement therapy
IB
investigator’s brochure
ICD
informed consent document
ICH
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use
ID
identification
IgG
immunoglobulin G
IMP
investigational medicinal product
IND
investigational new drug
INR
international normalized ratio
IPAL
Investigational Product Accountability Log
IPD
invasive pneumococcal disease
IPM
investigational product manual
IRB
institutional review board
IRT
interactive response technology
ISO
International Organization for Standardization
IWR
interactive Web-based response
KDIGO
Kidney Disease: Improving Global Outcomes
LFT
liver function test
LLOQ
lower limit of quantitation
MDR
medical device regulation
MHCII
major histocompatibility complex class II
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Abbreviation
Term
MQI
medically qualified individual
N/A
not applicable
NIMP
noninvestigational medicinal product
NIP
national immunization program
OM
otitis media
OPA
opsonophagocytic activity
PCV15
15-valent pneumococcal conjugate vaccine
PFS
prefilled syringe
PI
principal investigator
PPE
personal protective equipment
PPSV23
23-valent pneumococcal polysaccharide vaccine
PSSA
Pfizer's Serious Adverse Event Submission Assistant
PT
prothrombin time
QTL
quality tolerance limit
RAC
reductive amination chemistry
RNA
ribonucleic acid
SADE
serious adverse device effect
SAE
serious adverse event
SAP
statistical analysis plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
Scr
serum creatinine
Scys
serum cystatin C
SoA
schedule of activities
SOP
standard operating procedure
SRSD
single reference safety document
SUSAR
suspected unexpected serious adverse reaction
TBD
to be determined
T bili
total bilirubin
TCR
T-cell receptor
UADE
unanticipated adverse device effect
ULN
upper limit of normal
US
United States
USADE
unanticipated serious adverse device effect
USPI
United States prescribing information
VE
vaccine efficacy
WOCBP
woman/women of childbearing potential
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11. REFERENCES
1
Theilacker C, Fletcher MA, Jodar L, et al. PCV13 vaccination of adults against 
pneumococcal disease: what we have learned from the Community-Acquired 
Pneumonia Immunization Trial in Adults (CAPiTA). Microorganisms. 2022;10(1):127.
 
 
 
 
 
 
 
 
 
 
7
Lode H, Schmoele-Thoma B, Gruber W, et al. Dose-ranging study of a single injection 
of pneumococcal conjugate vaccine (1 ×, 2 ×, or 4 ×) in healthy subjects aged 70 years 
or older. Vaccine. 2011;29(31):4940-6.
 
9
Rupp R, Hurley D, Grayson S, et al. A dose ranging study of 2 different formulations of 
15-valent pneumococcal conjugate vaccine (PCV15) in healthy infants. Hum Vaccin 
Immunother. 2019;15(3):549-59. 
10
Wantuch PL, Sun L, LoPilato RK, et al. Isolation and characterization of new human 
carrier peptides from two important vaccine immunogens. Vaccine. 2020;38(10):2315-
25.
                                                
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11
Savulescu C, Krizova P, Slotved HC, et al. Effectiveness of 13-valent pneumococcal 
conjugate vaccine on invasive pneumococcal disease in the European Union: results of 
SpIDnet multicentre study. Poster presented at ESPID 36th Annual Meeting; 28 May–02 
June 2018; Malmö, Sweden.
12
Andrews N, Kent A, Amin-Chowdhury Z, et al. Effectiveness of the seven-valent and 
thirteen-valent pneumococcal conjugate vaccines in England: the indirect cohort design, 
2006-2018. Vaccine. 2019;37(32):4491-8. 
13
Dagan R, Van Der Beek BA, Ben-Shimol S, et al. Effectiveness of the 7- and 13-valent 
pneumococcal conjugate vaccines against vaccine-serotype otitis media. Clin Infect Dis. 
2021;73(4):650-8. 
14
Gessner BD, Jiang Q, Van Werkhoven CH, et al. A post-hoc analysis of serotype-
specific vaccine efficacy of 13-valent pneumococcal conjugate vaccine against clinical 
community acquired pneumonia from a randomized clinical trial in the Netherlands. 
Vaccine. 2019;37(30):4147-54. 
15
Warren JL, Weinberger DM. Estimating serotype-specific efficacy of pneumococcal 
conjugate vaccines using hierarchical models. Epidemiology. 2020;31(2):259-62. 
16
Ladhani SN, Collins S, Djennad A, et al. Rapid increase in non-vaccine serotypes 
causing invasive pneumococcal disease in England and Wales, 2000-17: a prospective 
national observational cohort study. Lancet Infect Dis. 2018;18(4):441-51. 
17
van der Linden M, Imöhl M, Perniciaro S. Limited indirect effects of an infant 
pneumococcal vaccination program in an aging population. PLoS One. 
2019;14(8):e0220453. 
18
Grant LR, Slack MPE, Theilacker C, et al. Invasive pneumococcal disease due to 
serotypes in pneumococcal vaccines in older adults of high-income countries. Poster 
presentation at the 12th International Symposium on Pneumococci and Pneumococcal 
Diseases (ISPPD-12); 19-23 June 2022; Toronto, Canada. Available upon request.
 
 
 
 
 
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24
Kolb HC, Finn MG, Sharpless KB. Click chemistry: diverse chemical function from a 
few good reactions. Angew Chem Int Ed Engl. 2001;40(11):2004-21. 
25
Takayama Y, Kusamori K, Nishikawa M. Click chemistry as a tool for cell engineering 
and drug delivery. Molecules. 2019;24(1):172. 
26
US Food and Drug Administration. Guidance for industry: toxicity grading scale for 
healthy adult and adolescent volunteers enrolled in preventive vaccine clinical trials. 
Rockville, MD: Center for Biologics Evaluation and Research; September 2007.
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