A PHASE 3, RANDOMIZED, DOUBLE-BLIND, THIRD PARTY UNBLIND TRIAL TO EVALUATE THE SAFETY AND IMMUNOGENICITY OF A 20-VALENT PNEUMOCOCCAL CONJUGATE VACCINE IN HEALTHY JAPANESE INFANTS
Phase: PHASE3
Conditions: Pneumococcal Disease
Sponsor: Pfizer

20-valent Pneumococcal Conjugate Vaccine (20vPnC)
Protocol B7471016
Final Protocol 09 June 2020
PFIZER CONFIDENTIAL
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A PHASE 3, RANDOMIZED, DOUBLE-BLIND, THIRD PARTY UNBLIND TRIAL 
TO EVALUATE THE SAFETY AND IMMUNOGENICITY OF A 20-VALENT 
PNEUMOCOCCAL CONJUGATE VACCINE IN HEALTHY JAPANESE INFANTS
Study Intervention Number:
PF-06482077
Study Intervention Name:
20-valent Pneumococcal Conjugate Vaccine
(20vPnC)
US IND Number:
N/A
EudraCT Number:
N/A
Protocol Number:
B7471016
Phase:
3
Short Title: 20-valent Pneumococcal Conjugate Vaccine Safety and Immunogenicity
Study in Healthy Japanese Infants
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Protocol Amendment Summary of Changes Table
Document History
Document
Version Date
Summary and Rationale for Changes
Original protocol
09-June-2020
N/A
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Final Protocol 09 June 2020
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................8
1. PROTOCOL SUMMARY.....................................................................................................9
1.1. Synopsis ....................................................................................................................9
1.2. Schema ....................................................................................................................14
1.3. Schedule of Activities .............................................................................................15
2. INTRODUCTION ...............................................................................................................17
2.1. Study Rationale .......................................................................................................20
2.2. Background .............................................................................................................21
2.2.1. Clinical Overview.......................................................................................21
2.3. Benefit/Risk Assessment.........................................................................................22
2.3.1. Risk Assessment.........................................................................................23
2.3.2. Benefit Assessment.....................................................................................25
2.3.3. Overall Benefit/Risk Conclusion................................................................25
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS ...........................................................25
4. STUDY DESIGN.................................................................................................................29
4.1. Overall Design.........................................................................................................29
4.1.1. Approximate Duration of Participation for Each Participant .....................31
4.1.2. Approximate Number of Participants.........................................................31
4.2. Scientific Rationale for Study Design.....................................................................31
4.3. Justification for Dose ..............................................................................................31
4.4. End of Study Definition ..........................................................................................31
5. STUDY POPULATION......................................................................................................32
5.1. Inclusion Criteria.....................................................................................................32
5.2. Exclusion Criteria....................................................................................................32
5.3. Lifestyle Considerations..........................................................................................34
5.4. Screen Failures ........................................................................................................34
5.5. Temporary Delay Criteria .......................................................................................34
6. STUDY INTERVENTION..................................................................................................35
6.1. Study Intervention(s) Administered........................................................................35
6.1.1. Administration............................................................................................36
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6.1.2. Medical Devices .........................................................................................37
6.2. Preparation/Handling/Storage/Accountability ........................................................37
6.2.1. Preparation and Dispensing........................................................................38
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................39
6.3.1. Allocation to Study Intervention ................................................................39
6.3.2. Blinding of Site Personnel..........................................................................39
6.3.3. Blinding of the Sponsor..............................................................................40
6.3.4. Breaking the Blind......................................................................................40
6.4. Study Intervention Compliance...............................................................................40
6.5. Concomitant Therapy..............................................................................................40
6.5.1. Prohibited Concomitant Vaccines and Treatments.....................................40
6.5.2. Permitted Concomitant Vaccines and Treatments......................................40
6.5.3. Recording Prior and Concomitant Vaccines and Treatments.....................42
6.6. Dose Modification...................................................................................................42
6.7. Intervention After the End of the Study..................................................................42
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................42
7.1. Discontinuation of Study Intervention ....................................................................42
7.2. Participant Discontinuation/Withdrawal From the Study.......................................43
7.2.1. Withdrawal of Consent...............................................................................44
7.3. Lost to Follow-up....................................................................................................44
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................45
8.1. Immunogenicity Assessments.................................................................................46
8.1.1. Immunogenicity Assessments ....................................................................46
8.1.1.1. Pneumococcal Responses..........................................................46
8.2. Safety Assessments .................................................................................................47
8.2.1. Participant Electronic Diary .......................................................................47
8.2.2. Grading Scale for Prompted Events ...........................................................48
8.2.2.1. Local Reactions.........................................................................48
8.2.2.2. Systemic Events (Systemic Symptoms and Fever)...................49
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8.2.2.3. Use of Antipyretic/Pain Medication..........................................51
8.2.3. Clinical Safety Laboratory Assessments ....................................................51
8.2.4. Procedures to Monitor Safety.....................................................................51
8.3. Adverse Events and Serious Adverse Events..........................................................51
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......52
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................53
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................53
8.3.2. Method of Detecting AEs and SAEs ..........................................................53
8.3.3. Follow-up of AEs and SAEs.......................................................................53
8.3.4. Regulatory Reporting Requirements for SAEs...........................................54
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational 
Exposure ..........................................................................................................54
8.3.5.1. Exposure During Pregnancy......................................................54
8.3.5.2. Exposure During Breastfeeding ................................................55
8.3.5.3. Occupational Exposure .............................................................56
8.3.6. Cardiovascular and Death Events...............................................................56
8.3.7. Disease Related Events and/or Disease Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................56
8.3.8. Adverse Events of Special Interest.............................................................56
8.3.8.1. Lack of Efficacy........................................................................56
8.3.9. Medical Device Deficiencies......................................................................56
8.3.9.1. Time Period for Detecting Medical Device Deficiencies .........57
8.3.9.2. Follow-up of Medical Device Deficiencies...............................57
8.3.9.3. Prompt Reporting of Device Deficiencies to Sponsor ..............57
8.3.9.4. Regulatory Reporting Requirements for Device 
Deficiencies .......................................................................................57
8.3.10. Medication Errors.....................................................................................58
8.4. Treatment of Overdose............................................................................................59
8.5. Pharmacokinetics ....................................................................................................59
8.6. Pharmacodynamics..................................................................................................59
8.7. Genetics...................................................................................................................59
8.8. Biomarkers ..............................................................................................................59
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8.9. Immunogenicity Assessments.................................................................................59
8.10. Health Economics .................................................................................................59
8.11. Study Procedures...................................................................................................60
8.11.1. Visit 1 (Dose 1 Visit, Day 1) ....................................................................60
8.11.2. Visit 2 (Dose 2 Visit, 4 to 8 Weeks After Visit 1 [Dose 1]).....................61
8.11.3. Visit 3 (Dose 3 Visit, 4 to 8 Weeks After Visit 2[Dose 2])......................63
8.11.4. Visit 4 (Dose 3 Follow-up Visit, 28 to 42 Days After Visit 3 [Dose 
3]).....................................................................................................................64
8.11.5. Visit 5 (Dose 4 Visit, 12 to 15 Months of Age)........................................65
8.11.6. Visit 6 (Dose 4 Follow-up Visit, 28 to 42 Days After Visit 5 [Dose 
4]).....................................................................................................................66
8.11.7. Unscheduled Visits...................................................................................67
9. STATISTICAL CONSIDERATIONS ................................................................................68
9.1. Estimands and Statistical Hypotheses.....................................................................68
9.1.1. Estimands....................................................................................................68
9.1.2. Statistical Hypotheses.................................................................................69
9.1.2.1. Noninferiority Comparing Percentage of Participants with 
Predefined Pneumococcal Serotype-Specific IgG 
Concentrations 1 Month after Dose 3 (Primary Endpoint) ...............69
9.1.2.2. Noninferiority Comparing Pneumococcal Serotype-
Specific IgG Concentrations 1 Month after Dose 3 (Secondary 
Endpoint)...........................................................................................70
9.1.3. Multiplicity Considerations ........................................................................71
9.2. Sample Size Determination.....................................................................................71
9.2.1. Sample size Considerations for 20vPnC SC Group and 13vPnC SC 
Group ...............................................................................................................71
9.2.2. Sample Size Considerations for 20vPnC IM Group...................................73
9.2.3. Sample Size Considerations for Safety Endpoints .....................................73
9.3. Analysis Sets ...........................................................................................................74
9.4. Statistical Analyses .................................................................................................75
9.4.1. Immunogenicity Analyses ..........................................................................75
9.4.2. Safety Analyses ..........................................................................................79
9.5. Interim Analyses .....................................................................................................80
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10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................81
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............81
10.1.1. Regulatory and Ethical Considerations ....................................................81
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................81
10.1.2. Financial Disclosure .................................................................................82
10.1.3. Informed Consent Process ........................................................................82
10.1.4. Data Protection .........................................................................................83
10.1.5. Dissemination of Clinical Study Data ......................................................83
10.1.6. Data Quality Assurance ............................................................................84
10.1.7. Source Documents....................................................................................86
10.1.8. Study and Site Start and Closure ..............................................................86
10.1.9. Publication Policy.....................................................................................87
10.1.10. Sponsor’s Qualified Medical Personnel .................................................87
10.2. Appendix 2: Clinical Laboratory Tests .................................................................88
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ......................................................................89
10.3.1. Definition of AE .......................................................................................89
10.3.2. Definition of SAE.....................................................................................90
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs.......................92
10.3.4. Reporting of SAEs....................................................................................95
10.3.5. Definition of NDCMC..............................................................................96
10.5. Appendix 5: Genetics............................................................................................96
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments ........97
10.7. Appendix 7: ECG Findings of Potential Clinical Concern ...................................98
10.8. Appendix 8: Medical Device Adverse Events, Adverse Device Effects, 
Serious Adverse Events, and Device Deficiencies: Definition and Procedures 
for Recording, Evaluating, Follow-up, and Reporting..............................................99
10.8.1. Definition of AE and ADE .......................................................................99
10.8.2. Definition of SAE, SADE, and Unanticipated Serious Adverse 
Device Effect ...................................................................................................99
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10.8.3. Definition of Device Deficiency.............................................................100
10.8.4. Recording/Reporting and Follow-up of AEs and/or SAEs and 
Device Deficiencies .......................................................................................101
10.8.5. Reporting of SAEs..................................................................................103
10.8.6. Reporting of SADEs...............................................................................104
10.9. Appendix 9: Country-Specific Requirements .....................................................104
10.10. Appendix 10: Abbreviations .............................................................................105
11. REFERENCES ................................................................................................................108
LIST OF TABLES
Table 1.
Vaccination Schedule for Investigational Product and Specified 
Concomitant Vaccines..............................................................................41
Table 2.
Grading Scales for Local Reactions .........................................................49
Table 3.
Grading Scales for Systemic Event Symptoms ........................................50
Table 4.
Ranges for Fever for the E-diary ..............................................................51
Table 6.
Sample Size and Power to Demonstrate Noninferiority Comparing 
Serotype-Specific IgG Concentrations From 20vPnC SC Group to 
13vPnC SC Group with the Specified Criteria.........................................72
Table 7.
Probability of Observing at Least 1 Event by Assumed True 
Incidence Rates.........................................................................................73
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1. PROTOCOL SUMMARY 
1.1. Synopsis
Short Title: 20-valent Pneumococcal Conjugate Vaccine Safety and Immunogenicity Study
in Healthy Japanese Infants.
Rationale
Pfizer is developing a new 20-valent pneumococcal conjugate vaccine (20vPnC) candidate to 
expand protection against pneumococcal disease beyond what is covered by current 
pneumococcal vaccines in children.  20vPnC has the same composition as 13-valent 
pneumococcal conjugate vaccine (13vPnC; Prevenar 13®), and contains an additional 
7 polysaccharide conjugates targeting serotypes responsible for a substantial burden of 
remaining pneumococcal disease. 20vPnC uses the same platform and contains the same 
excipients as 13vPnC.  A Phase 1 study (B7471005) in Japanese healthy adults conducted in 
the United States has shown that 20vPnC was safe and immunogenic when the vaccine was 
given intramuscularly in Japanese people.  Phase 2 (B7471003) safety and immunogenicity 
data from 20vPnC (given by the intramuscular route) in infants from the United States 
support further development of 20vPnC in the pediatric population.
Objectives, Estimands, and Endpoints
Primary Safety Objective
Estimands
Primary Safety Endpoints
•
To describe the safety profile 
of 20vPnC by both SC 
injection and IM injection 
In participants receiving at least 
1 dose of investigational product 
and having safety data reported 
after any vaccination:
•
The percentage of 
participants reporting 
prompted local reactions at 
injection site of 
investigational product within 
7 days after each vaccination 
in each group
•
The percentage of 
participants reporting 
prompted systemic events 
within 7 days after each 
vaccination in each group
•
The percentage of 
participants reporting AEs 
from Dose 1 to 1 month after 
Dose 3 in each group
•
The percentage of 
participants reporting AEs 
from Dose 4 to 1 month after 
Dose 4 in each group
•
The percentage of 
participants reporting SAEs 
•
Prompted local reactions 
(redness, swelling, and pain 
at the injection site)
•
Prompted systemic events 
(fever, decreased appetite, 
drowsiness/increased sleep, 
and irritability)
•
AEs
•
SAEs
•
NDCMCs
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up to 1 month after Dose 4 in 
each group
•
The percentage of 
participants reporting an 
NDCMC up to 1 month after 
Dose 4 in each group
Primary Immunogenicity 
Objectives
Estimands
Primary Immunogenicity 
Endpoints
For 20vPnC SC group:
•
To demonstrate that the 
percentage of participants 
with predefined serotype-
specific IgG concentrations 
for the 13 serotypes in the 
20vPnC SC group are 
noninferior to the percentage 
of the corresponding 
serotypes in the 13vPnC SC 
group at 1 month after Dose 3
In participants in compliance with 
the key protocol criteria 
(evaluable participants) at 
1 month after Dose 3:
•
For each of the 13 matched 
serotypes: difference in the 
percentage of participants 
with predefined serotype-
specific IgG concentrations 
between the 20vPnC SC 
group and the 13vPnC SC 
group
•
Pneumococcal serotype-
specific IgG concentration
•
To demonstrate that the 
percentage of participants 
with predefined serotype-
specific IgG concentrations 
for the 7 additional serotypes 
in the 20vPnC SC group are 
noninferior to the lowest 
percentage among the 13 
serotypes in the 13vPnC SC 
group at 1 month after Dose 3
In evaluable participants at 
1 month after Dose 3:
•
For each of the 7 additional 
serotypes in 20vPnC: 
difference in the percentage 
of participants with 
predefined serotype-specific 
IgG concentrations, between 
the 20vPnC SC group and the 
lowest percentage of 
participants with predefined 
serotype-specific IgG 
concentrations among the 
13 serotypes from the 
13vPnC SC group
•
Pneumococcal serotype-
specific IgG concentration
For 20vPnC IM group:
•
To describe the immune 
response to 20 serotypes 
induced by 20vPnC given by 
IM injection at 1 month after 
Dose 3
In evaluable participants at 
1 month after Dose 3:
•
For each of the serotypes in 
20vPnC: difference in the 
percentage of participants 
with predefined serotype-
specific IgG concentrations 
between the 20vPnC IM 
group and the 20vPnC SC 
group
•
Pneumococcal serotype-
specific IgG concentration
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Secondary Immunogenicity 
Objectives
Estimands
Secondary Immunogenicity 
Endpoints
•
To demonstrate that the 
serotype-specific IgG GMCs 
for the 13 serotypes in the 
20vPnC SC group are 
noninferior to the GMCs for 
the corresponding serotypes 
in the 13vPnC SC group at 1 
month after Dose 3
In evaluable participants at 1 month 
after Dose 3:
•
For each of the 13 matched 
serotypes: GMR of the 
serotype-specific IgG 
concentrations from the 
20vPnC group to the 13vPnC 
group
•
Pneumococcal 
serotype-specific IgG 
concentration
•
To demonstrate that the 
serotype-specific IgG GMCs 
for the 7 additional serotypes 
in the 20vPnC SC group are 
noninferior to the lowest IgG 
GMC among the 13 serotypes 
induced by the 13vPnC SC 
group at 1 month after Dose 3
In evaluable participants at 1 month 
after Dose 3:
•
For each of the 7 additional 
serotypes in 20vPnC: GMR of 
the serotype-specific IgG
concentration from the 20vPnC 
group to the serotype with the 
lowest IgG GMC among the 
13 serotypes from the 13vPnC 
group
•
Pneumococcal 
serotype-specific IgG 
concentration
•
To further describe the 
immunogenicity of 20vPnC 
by both SC and IM injection 
In evaluable participants at 
1 month after Dose 3:
•
For each of the serotypes in 
20vPnC: GMR of serotype-
specific IgG concentration 
from the 20vPnC IM group to 
the 20vPnC SC group
•
Pneumococcal 
serotype-specific IgG 
concentrations
In evaluable participants at 
1 month after Dose 4:
•
For each of the serotypes in 
20vPnC: Serotype-specific 
IgG GMCs at 1 month after 
Dose 4 in each group
•
Pneumococcal 
serotype-specific IgG 
concentrations
In evaluable participants at 
1 month after Dose 3 and 1 month 
after Dose 4:
•
Serotype-specific OPA 
GMTs at 1 month after Dose 
3, prior to Dose 4, and 1 
month after Dose 4 in each 
group
•
Pneumococcal 
serotype-specific OPA titers
In evaluable participants at 
1 month after Dose 4:
•
For each of the serotypes in 
20vPnC: percentage of 
participants with the 
predefined serotype-specific 
IgG concentration in each 
group
•
Pneumococcal 
serotype-specific IgG 
concentrations
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In evaluable participants:
•
GMFRs in serotype-specific 
IgG concentrations from 
1 month after Dose 3 to 
before Dose 4, from before 
Dose 4 to 1 month after Dose 
4, and from 1 month after 
Dose 3 to 1 month after Dose 
4 in each group
•
Pneumococcal 
serotype-specific IgG 
concentrations
Overall Design
This Phase 3, multicenter, randomized, double-blinded, third party unblind study will be 
conducted at investigator sites in Japan. 
 
  The 
purpose of this study is to describe safety and conduct the pivotal immunogenicity 
comparison of 20vPnC administered by SC injection to the licensed pneumococcal conjugate 
vaccine, 13vPnC, administered by the currently indicated SC injection in infants 
 
  Data will also be generated from 20vPnC administered by IM injection, 
with the 20vPnC administered by SC as a control.
Approximately 666 infants between 2 through 6 months of age at the time of consent, by 
their parent(s)/legal guardian(s), will be enrolled into the study.  Participants will be 
randomized equally to 1 of the following vaccine groups: (1) 20vPnC SC group, (2) 13vPnC 
SC group (control vaccine), or (3) 20vPnC IM group.  Participants will receive the same 
vaccine (20vPnC or 13vPnC) by the same injection method (SC or IM injection) for all 4 
doses at Visits 1, 2, 3, and 5 (refer to the SoA table for the timing of the visits).  All vaccine 
groups will be blinded to all members of the site involved in the study except unblinded staff 
who will administer 20vPnC or 13vPnC.
Specific vaccines containing Haemophilus influenza type b (Hib), hepatitis B (Hep B), 
rotavirus, diphtheria, tetanus, acellular pertussis, and poliovirus antigens will also be 
administered concomitantly with Doses 1 to 3 (Visit 1, Visit 2, and Visit 3) in the upper arm 
or orally (in the case of rotavirus vaccine) consistent with the vaccination schedule 
recommended by the Japan Pediatric Society.1  Specific vaccines containing Hib, diphtheria, 
tetanus, acellular pertussis, poliovirus, measles, rubella, and varicella antigens will be 
administered concomitantly with Dose 4 (Visit 5) in the upper arm(s) consistent with the 
vaccination schedule recommended by the Japan Pediatric Society.
Local reactions (redness, swelling, and pain at the injection site), systemic events (fever, 
decreased appetite, drowsiness/increased sleep, and irritability), and use of antipyretic/pain 
medication will be prompted for and collected by the participant’s parent(s)/legal guardian(s) 
in an e-diary, device or application, from Day 1 through Day 7 after each vaccination (where 
Day 1 is the day of vaccination).
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AEs will be collected from the time the participant’s parent(s)/legal guardian(s) provides 
informed consent through 1 month after Dose 3 (Visit 4) and from Dose 4 (Visit 5) through 
1 month after Dose 4 (Visit 6).  SAEs and NDCMCs will be collected from informed consent 
through 1 month after Dose 4 (Visit 6).
Blood will be collected 1 month after Dose 3 (Visit 4), immediately prior to Dose 4 (Visit 5), 
and 1 month after Dose 4 (Visit 6) to assess immunogenicity.
Number of Participants
Approximately 666 participants will be enrolled to achieve a target of 600 evaluable 
participants (200 in each vaccine group) at the follow-up time point 1 month after Dose 3.
Note: "Enrolled" means a participant's, parent(s)/legal guardian(s) agreement to participate in 
a clinical study following completion of the informed consent process. Potential participants 
who are screened for the purpose of determining eligibility for the study, but are not 
randomized in the study, are not considered enrolled, unless otherwise specified by the 
protocol.
Intervention Groups and Duration
Each participant will participate in the study approximately 7 to 14 months depending on the 
age of commencing in the study.
Participants will receive 1 dose of 20vPnC or 13vPnC at each vaccination visit (Visits 1, 2, 3, 
and 5 with Doses 1, 2, 3, and 4, respectively) in accordance with the study’s SoA.
In the 20vPnC SC and 13vPnC SC groups, 20vPnC or 13vPnC should be administered 
subcutaneously by injecting 0.5 mL into the anterolateral thigh (preferably into the left 
anterolateral thigh) at the vaccination visits.  In the 20vPnC IM group, 20vPnC should be 
administered intramuscularly by injecting 0.5 mL into the anterolateral thigh muscle of the 
leg (preferably of the left leg) at the vaccination visits.
 
  
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Statistical Methods
The primary safety objective will be evaluated by descriptive summary statistics for local 
reactions, systemic events, and AEs, including SAEs and NDCMCs, for each vaccine group.  
A 3-tier approach will be used to summarize AEs.
The primary pneumococcal immunogenicity objectives for the 20vPnC SC group will be 
evaluated by formal hypothesis test for noninferiority of 20vPnC to 13vPnC based on 
serotype-specific IgG results.  At 1 month after Dose 3, noninferiority for a serotype will be 
declared if the lower bound of the 2-sided 95% CI for the between-group difference in 
percentage of participants with a predefined serotype-specific IgG concentration level 
(20vPnC SC – 13vPnC SC) is greater than –10% (10% noninferiority margin).  The primary 
pneumococcal immunogenicity objectives for the 20vPnC SC group of the study for 
pneumococcal immunogenicity assessment at 1 month after Dose 3 will be achieved, in 
principle, if noninferiority of the pneumococcal immune response to 20vPnC SC compared 
to 13vPnC SC is met for all 20 serotypes; each of the 13 matched serotypes in the 20vPnC 
SC group relative to each serotype in the 13vPnC SC group, and each of the 7 additional 
serotypes in 20vPnC group relative to the lowest value in the 13vPnC SC group.
The primary pneumococcal immunogenicity objective for 20vPnC IM group will be 
evaluated by descriptive assessments for difference in the percentage of participants with a 
predefined serotype-specific IgG concentration level (20vPnC IM – 20vPnC SC) at 1 month 
after Dose 3.
 
 
 
1.2. Schema
Not applicable.
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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 Number
1
2
3
4
5
6
Visit Description
Dose 1 Visit
Dose 2 Visit
Dose 3 Visit
Dose 3 
Follow-up Visit
Dose 4 Visit
Dose 4 
Follow-up Visit
Visit Windows (Days)
Day 1
(2 through 6 
Months of Age)
4 to 8 Weeks 
After Visit 1
4 to 8 Weeks 
After Visit 2
(Completed by 
12 Month of Age)
28 to 42 Days 
After Visit 3
12 to 15 
Months of Age
(≥60 Days After 
Dose 3)
28 to 42 Days 
After Visit 5
Obtain informed consent
X
Assign participant number via the IRT
X
Record demography
X
Perform clinical assessment, including 
medical history
X
Record vaccine history
X
Record nonstudy vaccinations
X
X
X
X
X
X
Record concomitant medicationsa
X
X
X
X
X
X
Obtain prevaccination axillary temperature
X
X
X
X
Review inclusion and exclusion criteria
X
Review temporary delay criteria
X
X
X
X
X
X
Review continued eligibility
X
X
X
X
X
Assign randomization number
X
Obtain ~5-mL blood sample
X
Xb
X
Administer investigational product 
(20vPnC or 13vPnC)c
X
X
X
X
Administer specific concomitant vaccines 
as applicable for the visitd
X
X
X
X
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Visit Number
1
2
3
4
5
6
Visit Description
Dose 1 Visit
Dose 2 Visit
Dose 3 Visit
Dose 3 
Follow-up Visit
Dose 4 Visit
Dose 4 
Follow-up Visit
Visit Windows (Days)
Day 1
(2 through 6 
Months of Age)
4 to 8 Weeks 
After Visit 1
4 to 8 Weeks 
After Visit 2
(Completed by 
12 Month of Age)
28 to 42 Days 
After Visit 3
12 to 15 
Months of Age
(≥60 Days After 
Dose 3)
28 to 42 Days 
After Visit 5
Observe and record acute reactions for 
30 minutes after investigational product 
administration
X
X
X
X
Provide a participant contact card
X
Provide parent(s)/legal guardian(s) with an 
e-diary, thermometer, and measuring 
device and instruct to collect prompted 
local reactions and systemic events until 
7 days after vaccinatione
X
X
X
X
Review and/or collect e-diary (if 
applicable)f
X
X
X
X
Record and report adverse events
X----------------------------------------------------------------- X
X ------------------- X
Record and report SAEs and NDCMCsg
X --------------------------------------------------------------------------------------------------------------X
Abbreviations: IRT = interactive response technology; NDCMC = newly diagnosed chronic medical condition.
a.
Record only concomitant medications used to treat SAEs and NDCMCs.
b.
Blood sample will be collected prior to vaccination.
c.
Remind the participant’s parent(s)/legal guardian(s) that the use of prophylactic antipyretic/pain medication, while permitted, is not recommended on the 
day of investigational product administration (before or after vaccination).
d.
Specific concomitant vaccines containing Hib, Hep B, rotavirus, diphtheria, tetanus, acellular pertussis, poliovirus, measles, rubella, and varicella antigens 
will be administered with Doses 1 through 4 into the upper arm(s) or orally (in the case of rotavirus vaccine).
e.
The participant’s parent(s)/legal guardian(s) will record prompted local reactions and systemic events in an e-diary for the 7 days following each dose of 
20vPnC or 13vPnC.  Use of antipyretic/pain medications will also be prompted for and collected daily in an e-diary for 7 days after vaccination.  The 
participant’s parent(s)/legal guardian(s) will be instructed to contact the study staff if the participant experiences redness or swelling >14 caliper units, 
severe pain at the 20vPnC or 13vPnC injection site, or a fever >40.0°C, or has an emergency room visit or hospitalization.
f.
Designated site staff will review e-diary data online at frequent intervals (daily is optimal) for the 7 days following each dose of 20vPnC or 13vPnC to 
evaluate participant compliance and as part of the ongoing safety review.
g.
An NDCMC is defined as a disease or medical condition, not previously identified, that is expected to be persistent or otherwise long-lasting in its effects.
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2. INTRODUCTION
Pneumococcal Disease
Streptococcus pneumoniae are gram-positive encapsulated cocci that are a leading cause of 
bacteremia, bacterial meningitis, pneumonia, and AOM and continue to be a major global 
public health concern.2,3,4  Serious pneumococcal disease may occur at any age; however, 
children <5 years and adults ≥65 years of age are at particularly increased risk.5  Individuals 
with certain comorbidities and immunocompromising conditions are also at risk, especially 
persons with chronic heart, lung, liver, and renal disease, as well as those who are 
functionally asplenic.  The global burden of pneumococcal disease has been substantially 
impacted by pneumococcal conjugate vaccines.  S pneumoniae caused an estimated 
14.5 million cases of serious disease and 826,000 deaths annually in children <5 years of age 
prior to introduction of pneumococcal conjugate vaccines.3  It has been estimated that in 
2015, several years following introduction of pneumococcal conjugate vaccines into the 
national infant immunization programs of more than 100 countries, the global disease burden 
had declined, but S pneumoniae still accounted for 2.6 million cases of severe pneumococcal 
disease, 332,000 deaths in children <5 years of age, and 11% of deaths in children between 
the ages of 1 and 5 years.6
The overall IPD burden was estimated in 2013 to have decreased approximately 90% in the 
population <5 years of age in the United States since the introduction of pneumococcal 
conjugate vaccines; however, there was a slight increase in the proportions of IPD cases 
associated with hospitalization (63% to 71%), and the IPD case fatality rate was also slightly 
but statistically significantly increased (2% to 3%) in that age group.7  This is due to the 
decrease in disease due to the serotypes in 7-valent pneumococcal conjugate vaccine (7vPnC; 
Prevnar®) and 13vPnC.  However, disease due to serotypes not covered by those vaccines 
remains, and causes significant morbidity and mortality. National IPD surveillance data in 
England and Wales for the epidemiological year 2016-2017, approximately 10 years after the 
introduction of 7vPnC in the national infant immunization program and 6 years after the 
introduction of 13vPnC, showed the overall incidence of IPD was 9.87 per 100,000 
population, with an incidence of 13.90 per 100,000 population <2 years of age.8  The data for 
England and Wales are consistent with the patterns observed in data from the EU for 2017, 
which showed an overall IPD incidence of 6.2 cases per 100,000 population, with an 
incidence of 14.5 per 100,000 infants under 1 year of age.9  Pediatric surveillance studies 
conducted between 2007 and 2013 in 8 US children’s hospitals, and between 1997 and 2010 
in a referral center in Utah, found case fatality rates of 10% and 13% with pneumococcal 
meningitis, respectively.  These studies also found that between 52% and 63% of children 
surviving pneumococcal meningitis experience neurologic sequelae.10,11  More recent 
pediatric surveillance conducted between 2014 and 2017 in 8 US children’s hospitals 
following 13vPnC introduction in 2010 showed that 76.1% of residual IPD was caused by 
non-13vPnC serotype isolates.12  Serotypes 10A, 12F, 15B/15C, 22F, and 33F accounted for 
36% of isolates causing IPD.  The most common clinical presentations of IPD due to 
non-13vPnC serotypes included bacteremia (49.6%), meningitis (19.1%), and pneumonia 
(18.8%). These data demonstrate the continued need for expanded serotype coverage.
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Surveillance studies conducted in 2010-2012 by the CDC found that S pneumoniae remains 
among the most common pathogens identified in CAP requiring hospitalization in the United 
States in both children and adults.13,14  It was the most common bacterial cause in children 
<2 years of age, even in the setting of a 43% reduction in CAP hospitalizations over the 
previous decade between 1997-1999 and 2007-2009, due to the introduction to 7vPnC.13,15  
Surveillance reported in 2017 by the ECDC showed that among cases of IPD for which the 
clinical presentation was known across all age groups, bacteremic pneumonia was reported in 
42% of cases.  The most common clinical presentations in children <5 years of age were 
septicemia and bacteremic pneumonia (1-4 year olds), and meningitis (<1 year olds).9  These 
data suggest that S pneumoniae remains an important cause of serious disease in the United 
States and worldwide.
AOM is a common childhood illness, with 2011 visit rates of 0.82 and 0.81 visits per 
AOM/child-year in children <2 years of age and 2 to 6 years of age, respectively, and
represents a significant medical burden.16  S pneumoniae is one of the common bacterial 
causes of AOM, and accounted for an estimated 850,000 outpatient and 125,000 emergency 
room visits in the United States in 2004 in children <5 years of age, representing a significant 
burden on the healthcare system.4  While AOM is generally not considered a serious disease, 
it does carry the risk of more serious complications.  These complications can range from the 
development of chronic or recurrent otitis media necessitating surgical intervention 
(tympanostomy tube placement), and accompanied by hearing losses with potential 
developmental and language delays, to invasive extension leading to mastoiditis and 
meningitis.
In Japan, 7-valent pneumococcal conjugate vaccine (7vPnC; Prevenar®) was licensed in 
February 2010 to prevent IPD in children and was incorporated into the NIP in April 2013.  
Subsequently 7vPnC was replaced by 13vPnC, in the NIP in November 2013.  Since 2008 
active surveillance for IPD in children <15 years of age has been conducted in 
10 prefectures.17  The incidence rate of IPD caused by serotypes covered by 7vPnC in 
children <5 years of age decreased by 98% compared to before 7vPnC launch (2008 to 
2010).  After introduction of 13vPnC in the NIP in November 2013, the incidence rate of IPD 
caused by 13vPnC serotypes decreased by 97% compared to before the launch of 7vPnC. 
The overall IPD incidence rate was reduced by 50% compared to before the 7vPnC launch 
although the incidence of disease due to serotypes not in 13vPnC (NVT) increased. In 2017 
96% of isolates causing IPD were NVT.  In the surveillance by Ubukata et al,18 serotype 
distribution of clinical isolates from IPD patients collected from April 2010 to March 2017 
was investigated. Considering the isolates from children, serotypes contained in 7vPnC 
accounted for 73.3% of the isolates in 2010 (during the pre-7vPnC period) which decreased 
to 7.4% in 2013 after 7vPnC introduction. IPD caused by the 6 additional serotypes 
contained in 13vPnC decreased from 25.9% in 2013 to 11.1% in 2016. The proportion of IPD 
in 2016 due to all serotypes contained in 20vPnC was estimated at 50.7% (17.2% for the 
13 serotypes in 13vPnC, and 33.5% for 7 additional serotypes [estimated by Pfizer based on 
the serotype distribution]).
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Although the introduction of pneumococcal conjugate vaccines into the NIP in Japan and 
other national infant immunization programs has brought about substantial reductions in the 
various manifestations of pneumococcal disease in pediatric (infants and children) 
populations, a substantial burden of pneumococcal disease remains.  Serotypes not included 
in existing vaccines continue to contribute significantly to morbidity and mortality.  
 
Vaccines to Prevent Pneumococcal Disease
Pneumococcal Polysaccharide Vaccines
The polysaccharide capsule has been identified as an important virulence factor for this 
pathogen. While more than 95 pneumococcal serotypes, differentiated by their capsular 
polysaccharide composition, have been identified, serious disease is generally caused by a 
smaller subset of serotypes.19,20  Anticapsular antibodies directed against the specific 
serotype bind to the capsule and promote complement-mediated opsonophagocytic killing 
and clearance of the organism.21  Pneumococcal disease can be prevented with 
polysaccharide-based vaccines that induce antibody responses with functional OPA activity 
and target the capsular serotypes responsible for disease.22
Vaccines containing free polysaccharides have been licensed since the 1970s.  One such 
vaccine, the 23-valent pneumococcal polysaccharide vaccine (PPSV23), has been licensed in 
the United States since 1983.23,24  PPSV23 contains capsular polysaccharides for 
23 serotypes (1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19F, 19A, 
20, 22F, 23F, and 33F).  Pneumococcal vaccines containing free polysaccharides such as 
PPSV23 elicit a T-cell–independent immune response.  Unconjugated polysaccharide 
vaccines do not induce robust responses in certain populations (eg, immunocompromised 
persons, and children <2 years of age), nor do they generate immunologic memory, so that 
their protective effect wanes over 2 to 5 years.5,24,25,26  Moreover, their ability to prevent 
nonbacteremic pneumonia, CAP, and AOM is limited or lacking.22,26,27,28,29  In addition, 
polysaccharide vaccines do not reduce VT nasopharyngeal carriage, which is important for 
herd immunity.29  PPSV23 is not recommended for children <2 years of age and only 
recommended in children >2 years of age who are at high risk for IPD to provide some 
degree of protection from disease caused by serotypes not covered by existing pneumococcal 
conjugate vaccines.22
Pneumococcal Polysaccharide Conjugate Vaccines
Pneumococcal conjugate vaccines contain polysaccharides that are covalently linked 
(conjugated) to an immunogenic protein.  This modification results in T-cell–dependent 
immune responses, which have been shown to be protective in young children, older adults, 
and populations with high-risk conditions.25,30  7vPnC was the first pneumococcal conjugate 
vaccine to be licensed (2000) and was indicated for prevention of pneumococcal disease in 
infants and young children on the basis of efficacy studies.  7vPnC contained capsular 
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polysaccharide conjugates for 7 pneumococcal serotypes (4, 6B, 9V, 14, 18C, 19F, and 23F), 
each covalently linked to CRM197, a nontoxic variant of diphtheria toxin.  These 7 serotypes 
were responsible for approximately 80% to 90% of IPD in children <5 years of age in the 
United States and approximately 60% to 80% of IPD in the same age group in Europe at that 
time (1998-2000).31,32,33,34,35  These serotypes also accounted for a high proportion of 
antibiotic-resistant strains.36  7vPnC demonstrated efficacy against VT IPD, pneumonia, and 
AOM in large randomized, controlled efficacy studies in infants.37,38  The 7vPnC components 
contained in a related pneumococcal conjugate vaccine also were demonstrated to be 
efficacious against clinically/radiographically defined pneumonia.39,40,41,42  Following 
introduction of 7vPnC, reduction of nasopharyngeal carriage and transmission has resulted in 
indirect herd effects, with a 92% reduction of 7vPnC VT IPD in older adults ≥65 years of 
age.43
13vPnC was developed to expand serotype coverage and was licensed in the United States in 
2010.  13vPnC includes the same S pneumoniae serotypes as 7vPnC and an additional 
6 polysaccharide conjugates for serotypes 1, 3, 5, 6A, 7F, and 19A.30,34,44  The vaccine was 
licensed for use in infants and young children based on comparisons of serotype-specific 
serum IgG antibody concentrations to 7vPnC, with supportive data to demonstrate the 
functional activity of the immune responses.  13vPnC has also been licensed in adults based 
on demonstration of efficacy against CAP due to serotypes contained in 13vPnC in adults 
65 years of age and older.45  13vPnC has replaced 7vPnC and is licensed in the United States 
and many other countries including Japan, with national recommendations for use in children 
and older adults.46,47,48,49,50  It has also been prequalified by the WHO for use in national 
infant immunization programs in lower- and middle-income countries.51,52  Surveillance data 
from several countries following introduction of 13vPnC into the routine infant 
immunization program have demonstrated vaccine effectiveness against 13vPnC VT IPD in 
the vaccinated population.53,54,55
Development of 20vPnC
The 20vPnC candidate is modeled after 7vPnC and 13vPnC, and contains polysaccharides of 
capsular serotypes of S pneumoniae, each covalently linked to CRM197.  The amount of 
polysaccharide (2.2 μg/dose) selected for each new serotype (8, 10A, 11A, 12F, 15B, 22F, 
and 33F) contained in the 20vPnC candidate mirrors the approach taken for the addition of 
the 6 new serotypes when developing 13vPnC.  The 20vPnC candidate contains the same 
components as 13vPnC, including the 13 polysaccharide conjugates, excipients (polysorbate 
80, succinate buffer, sodium chloride), and aluminum phosphate, in addition to the 7 new 
polysaccharide conjugates.  Additional epidemiology data of the 7 serotypes and the 
preclinical program are described in the 20vPnC IB.  The vaccine is being developed for use 
in pediatric and adult populations.
2.1. Study Rationale
 
  In Japan, 7vPnC and 13vPnC have been administered to 
infants by SC injection on a 4-dose vaccination schedule (3 doses for infant series and 1 dose 
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for toddler dose). 
 
 
 
 The targeted age of the 
population for this study, infants ≥2 to ≤6 months of age, has been selected as the routinely 
recommended vaccination schedule for pneumococcal conjugate vaccines and other vaccines 
in infants starts at approximately 2 months of age.  The participants will be administered 
either 20vPnC (SC or IM injection) or 13vPnC SC by the same injection route for all 4 doses 
starting from 2 months of age.
2.2. Background
20vPnC is being developed to further expand protection against the global burden of vaccine-
preventable pneumococcal disease in children and adults over that of 13vPnC.  20vPnC 
contains the serotypes present in 13vPnC, and 7 new serotypes (8, 10A, 11A, 12F, 15B, 22F, 
and 33F) individually conjugated to CRM197.  As noted above, 20vPnC uses the same 
platform and contains the same excipients as 13vPnC.  These 7 additional serotypes were 
selected based on their relative prevalence as a cause of IPD, their generalized geographic 
distribution, and other factors that would support inclusion, such as the presence of antibiotic 
resistance (11A,15B), association with outbreaks (8, 12F), and greater disease severity (eg, 
meningitis, mortality) (10A, 11A, 22F).56,57,58,59,60,61,62,63,64,65,66,67  These 7 serotypes have a 
long-standing association with serious pneumococcal disease and are responsible for a 
substantial burden of remaining pneumococcal disease.  The incidence of IPD due to these 
7 serotypes in children <5 years of age has remained relatively stable or slightly increased 
over the past several years, and these serotypes cause a significant amount of IPD in 
children.68,69,70,71,72,73,74  These 7 serotypes contribute to the burden of IPD in the United 
States and elsewhere.  It is estimated that between 2015 and 2016, these 7 serotypes 
accounted for 34% to 39% of IPD in children in the United States.75  In the EU, according to 
the ECDC annual IPD epidemiological report, in 2017, approximately 75% of cases of IPD 
in children <5 years of age were caused by a serotype not in 13vPnC, increased from 63% in 
2013.  Five of the 10 most common serotypes included serotypes 8, 10A, 11A, 12F, and 22F, 
with serotypes 8, 10A, 12F, and 24F being among the most common in children in this age 
group.9
A meta-analysis of serotypes causing IPD in children <5 years of age in regions of the world 
(including Japan) that have introduced higher-valent pneumococcal conjugate vaccines (such 
as 13vPnC) showed that, overall, these 7 new serotypes accounted for approximately 70% of 
disease not due to the 13vPnC vaccine types.70
2.2.1. Clinical Overview
Safety and immunogenicity data from a 20vPnC Phase 1 study (B7471001) conducted in 
healthy adults 18 through 49 years of age demonstrated that the vaccine induced immune 
responses to the 20 vaccine serotypes and had a safety profile consistent with other 
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pneumococcal conjugate vaccines.  These data supported clinical development in other 
populations, including pediatric populations.
A Phase 1 study (B7471005) of 20vPnC in healthy Japanese adults 18 through 49 years of 
age was conducted in the United States.  The administration of 20vPnC by IM injection was 
well tolerated and induced immune responses to the 20 vaccine serotypes.  These data 
support continued development of 20vPnC in Japan.
A Phase 2 study (B7471003) of 20vPnC in healthy infants ≥42 to ≤98 days of age has been 
conducted. The study randomized 460 US participants to receive either blinded 20vPnC or 
13vPnC by IM injection.  Safety and immunogenicity data are available from this study.
20vPnC was well tolerated in the infants and the safety profile was similar to that of the 
13vPnC group in the study and consistent with other pneumococcal conjugate vaccines.  
Immune responses (either IgG GMCs or percentages of participants meeting a predefined
IgG concentration) after 3 doses of 20vPnC were similar to those in the 13vPnC group.  
These data support continued development of 20vPnC in a pediatric population.
2.3. Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of 20vPnC may be found in the IB, which is the SRSD for this study.  
The SRSD for the 13vPnC agent is the Japan package insert.
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2.3.1. Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
20vPnC and 13vPnC
13vPnC is a licensed vaccine and the most 
common AEs noted in children <5 years of age 
after vaccination are primarily related to local 
reactions (injection site pain or tenderness, 
redness, and swelling) and systemic events (fever, 
irritability, decreased appetite, and increased 
sleep).
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.
The 20vPnC investigational product contains the 
same components and excipients as 13vPnC, and 
also contains the polysaccharide conjugates for the 
7 additional pneumococcal serotypes.  Thus, the 
AE profile of 20vPnC is expected to be similar to 
13vPnC, but AEs may be different with the 
investigational 20vPnC.
In a randomized, active-controlled, double-blind 
study with a 2-arm parallel design (B7471003), 
20vPnC was administered intramuscularly to 
460 infants ≥42 to ≤98 days of age naive to 
pneumococcal vaccine.  The vaccine was well 
tolerated and the AE profile was consistent with 
events commonly seen in this age group.  The 
most common AEs after 20vPnC administration 
were local reactions (pain, redness, and swelling at 
the injection site) and systemic events (irritability, 
drowsiness/increased sleep, and decreased 
appetite).
Safety assessments (ie, local reactions, systemic 
events, AEs [including observation for 30 minutes 
after vaccination], SAEs, and NDCMCs) described 
in the protocol and ongoing review of safety data 
by the investigator and sponsor study team will 
serve to monitor and mitigate these risks.  
 
 
This study is the first study that 20vPnC will be 
administered subcutaneously and the study 
participants are infants.
The 20vPnC investigational product contains the 
same components and excipients as 13vPnC, and 
also contains the polysaccharide conjugates for the 
7 additional pneumococcal serotypes.  Thus, the 
AE profile of 20vPnC is expected to be similar to 
13vPnC, but AEs may be different with the 
investigational 20vPnC.
In a clinical study of 13vPnC administered by SC 
injection in Japan, local reactions at the 13vPnC 
injection site (SC injection), particularly redness 
Daily enrollment will be limited initially with 
enhanced monitoring of the safety and tolerability 
of the study vaccine after Dose 1.  If there are no 
unexpected safety concerns after Dose 1 in the first 
45 participants, the daily enrollment limit will be 
removed.  Ongoing regular monitoring and review 
of safety and tolerability of the blinded study data 
by the study team.
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
20vPnC and 13vPnC
and swelling, occurred at somewhat higher rates 
compared with studies that administered 13vPnC 
by IM injection.  However local reactions in the 
study were generally mild or moderate, consistent 
with other published studies of 13vPnC.76
In another clinical study of 13vPnC administered 
by SC injection in Japan, local reactions, 
particularly redness and swelling, occurred at 
higher rates at the 13vPnC injection site were 
comparable with those of 7vPnC administered by 
SC injection.77
Study Procedures
Risks that may be associated with study 
procedures include risks from blood sample 
collection, including pain, swelling, bruising, and 
infection where blood is taken.
Risks and possible discomforts from the study 
procedures such as pain, swelling, bruising, 
infection around the vein where the child’s blood 
is collected may also occur, although this is very 
uncommon.
The volume and frequency of blood sample 
collection required during the study has been 
minimized as far as possible.
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2.3.2. Benefit Assessment
13vPnC is approved in Japan (and in many other countries worldwide) for the prevention of 
IPD due to the serotypes in the vaccine, and should provide a clinical benefit to those 
receiving the vaccine.  In the B7471003 study, 20vPnC induced immune responses to the 
pneumococcal serotypes in the vaccine.  This suggests that protection against pneumococcal 
disease will be similar to 13vPnC.  If 20vPnC is successful in Phase 3 studies, and approved, 
it is anticipated to provide a public health benefit by reducing the burden of IPD due to 
pneumococcal serotypes contained in the vaccine.
2.3.3. Overall Benefit/Risk Conclusion
Pfizer considers that the available information from Study B7471003 with 20vPnC, the 
available safety profile of similar pneumococcal conjugate vaccines (ie, Prevenar and 
Prevenar 13), and the limited risks from study procedures support a favorable benefit-risk 
profile for 20vPnC and this study.
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS
Primary Safety Objective
Estimands
Primary Safety Endpoints
y
To describe the safety profile 
of 20vPnC by both SC 
injection and IM injection 
In participants receiving at least 
1 dose of investigational product 
and having safety data reported 
after any vaccination:
y The percentage of participants 
reporting prompted local 
reactions at injection site of 
investigational product within 
7 days after each vaccination in 
each group
y The percentage of participants 
reporting prompted systemic 
events within 7 days after each 
vaccination in each group
y The percentage of participants 
reporting AEs from Dose 1 to 
1 month after Dose 3 in each 
group
y The percentage of participants 
reporting AEs from Dose 4 to 
1 month after Dose 4 in each 
group
y The percentage of participants 
reporting SAEs up to 1 month 
after Dose 4 in each group
y The percentage of participants 
reporting NDCMCs up to 
1 month after Dose 4 in each 
group
y
Prompted local reactions 
(redness, swelling, and pain at 
the injection site)
y
Prompted systemic events 
(fever, decreased appetite, 
drowsiness/increased sleep, 
and irritability)
y
AEs
y
SAEs
y
NDCMCs
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Primary Immunogenicity 
Objectives
Estimands
Primary Immunogenicity 
Endpoints
For 20vPnC SC group:
y
To demonstrate the percentage 
of participants with predefined 
serotype-specific IgG 
concentrations for the 
13 serotypes in the 20vPnC SC 
group are noninferior to the 
percentage of the 
corresponding serotypes in the 
13vPnC SC group at 1 month 
after Dose 3
In participants in compliance with 
the key protocol criteria 
(evaluable participants) at 
1 month after Dose 3:
y For each of the 13 matched 
serotypes: difference in the 
percentage of participants with 
predefined serotype-specific 
IgG concentrations between the 
20vPnC SC group and the 
13vPnC SC group
y Pneumococcal serotype-specific 
IgG concentration
y
To demonstrate the percentage 
of participants with predefined 
serotype-specific IgG 
concentrations for the 7 
additional serotypes in the 
20vPnC SC group are 
noninferior to the lowest 
percentage among the 13 
serotypes in the 13vPnC SC 
group at 1 month after Dose 3
In evaluable participants at 
1 month after Dose 3:
y For each of the 7 additional 
serotypes in 20vPnC: 
difference in the percentage of 
participants with predefined 
serotype-specific IgG 
concentrations, between the 
20vPnC SC group and the 
lowest percentage of 
participants with predefined 
serotype-specific IgG 
concentrations among the 
13 serotypes from the 13vPnC 
SC group
y Pneumococcal serotype-specific 
IgG concentration
For 20vPnC IM group:
y
To describe the immune 
responses to 20 serotypes 
induced by 20vPnC given by 
IM injection at 1 month after 
Dose 3
In evaluable participants at 
1 month after Dose 3:
y For each of the serotypes in 
20vPnC: difference in the 
percentage of participants with 
predefined serotype-specific 
IgG concentrations between the 
20vPnC IM group and the 
20vPnC SC group
y Pneumococcal serotype-specific 
IgG concentration
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Secondary Immunogenicity 
Objectives
Estimands
Secondary Immunogenicity 
Endpoints
y
To demonstrate the serotype-
specific IgG GMCs for the 13 
serotypes in the 20vPnC SC
group are noninferior to the 
GMCs for the corresponding 
serotypes in the 13vPnC SC 
group at 1 month after Dose 3
In evaluable participants at 
1 month after Dose 3:
y For each of the 13 matched 
serotypes: GMR of serotype-
specific IgG concentrations 
from the 20vPnC SC group to 
the 13vPnC SC group
y Pneumococcal serotype-specific 
IgG concentrations
• To demonstrate the serotype-
specific IgG GMCs for the 7 
additional serotypes in the 
20vPnC SC group are 
noninferior to the lowest IgG 
GMC among the 13 serotypes 
induced by the 13vPnC SC 
group at 1 month after Dose 3
In evaluable participants at 
1 month after Dose 3:
y For each of the 7 additional 
serotypes in 20vPnC: GMR of 
serotype-specific IgG 
concentration from the 20vPnC 
SC group to the serotype with 
the lowest IgG GMC among the 
13 serotypes from the 13vPnC 
SC group
y Pneumococcal serotype-specific 
IgG concentrations
y To further describe the 
immunogenicity of 20vPnC by 
both SC and IM injection
In evaluable participants at 
1 month after Dose 3:
y For each of the serotypes in 
20vPnC: GMR of serotype-
specific IgG concentrations 
from the 20vPnC IM group to 
the 20vPnC SC group
y Pneumococcal serotype-specific 
IgG concentrations
In evaluable participants at 
1 month after Dose 4:
y For each of the serotypes in 
20vPnC: Serotype-specific IgG 
GMCs at 1 month after Dose 4 
in each group
y Pneumococcal serotype-specific 
IgG concentrations
In evaluable participants at 
1 month after Dose 3 and 1 month 
after Dose 4:
y Serotype-specific OPA GMTs 
at 1 month after Dose 3, prior to 
Dose 4, and 1 month after Dose 
4 in each group
y Pneumococcal serotype-specific 
OPA titers
In evaluable participants at 
1 month after Dose 4:
y For each of the serotypes in 
20vPnC: percentage of 
participants with the predefined 
serotype-specific IgG 
concentration in each group
y Pneumococcal serotype-specific 
IgG concentrations
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In evaluable participants:
y GMFRs in serotype-specific 
IgG concentrations from 
1 month after Dose 3 to before 
Dose 4, from before Dose 4 to 
1 month after Dose 4, and from 
1 month after Dose 3 to 
1 month after Dose 4 in each 
group
y Pneumococcal serotype-specific 
IgG concentrations
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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4. STUDY DESIGN
4.1. Overall Design
This Phase 3, multicenter, randomized, double-blind, third party unblind study will be 
conducted at investigator sites in Japan. 
 
  The 
purpose of this study is to describe safety and conduct the pivotal immunogenicity
comparison of 20vPnC administered by SC injection to the licensed pneumococcal conjugate 
vaccine, 13vPnC, administered by the currently indicated SC injection
 
  Data will also be generated on 20vPnC administered by IM injection, 
with the 20vPnC administered by SC as a control.
Approximately 666 infants between 2 through 6 months of age at the time of consent, by 
their parent(s)/legal guardian(s), will be enrolled into the study.  Participants will be 
randomized equally to one of the following vaccine groups: (1) 20vPnC SC group, (2) 
13vPnC SC group (control vaccine), or (3) 20vPnC IM group.  Participants will receive the 
same vaccine (20vPnC or 13vPnC) by the same injection method (SC or IM injection) for all 
4 doses at Visits 1, 2, 3, and 5 (refer to the SoA table for the timing of the visits).  All vaccine 
groups will be blinded to all members of the site involved in the study except unblinded site 
staff who will administer 20vPnC or 13vPnC.
On Day 1 (Visit 1, Dose 1 vaccination) of the study, participants will be assessed for 
eligibility and information collected, including medical history and vaccine history.
At Visit 1, participants will be randomized.  In the 20vPnC SC and 13vPnC SC groups, 
20vPnC or 13vPnC will be administered subcutaneously into the anterolateral thigh 
(preferably into the left anterolateral thigh).  In the 20vPnC IM group, 20vPnC will be 
administered intramuscularly into the anterolateral thigh muscle of the leg (preferably into 
the left anterolateral thigh).  The inner syringe label will be open labeled.  Except for the 
inner syringe label, 20vPnC and 13vPnC will be identical in appearance including outer 
carton and will be administered by a qualified and unblinded site staff member.  Specific 
vaccines containing Hib, Hep B, and rotavirus antigens will also be administered 
concomitantly with Dose 1 in the upper arm(s) or orally (in the case of rotavirus vaccine) 
consistent with the vaccination schedule recommended by the Japan Pediatric Society”.1  
Participants will be observed for 30 minutes after vaccination and any reactions occurring 
during that time will be recorded as AEs.  The parent(s)/legal guardian(s) will be provided 
with an e-diary (or e-diary application), thermometer, and measuring device and instructed to 
collect prompted local reactions at the pneumococcal vaccine injection site (redness, 
swelling, and pain at the injection site), systemic events (fever, decreased appetite, 
drowsiness/increased sleep, and irritability) occurring within 7 days after each vaccination.  
Use of antipyretic/pain medication will also be prompted for and collected by the 
participant’s parent(s)/legal guardian(s) in an e-diary, device or application, from Day 1 
through Day 7 after each vaccination (where Day 1 is the day of vaccination).  
The participant’s parent(s)/legal guardian(s) will be instructed to contact the study staff if the 
participant experiences redness or swelling >14 caliper units, severe pain at the injection site, 
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or fever >40.0°C (axillary) in the 7 days after vaccination or has an emergency room visit or 
hospitalization.
As this study is the first study where 20vPnC is administered subcutaneously and the study 
participants are infants, a daily enrollment limit of ≤5 participants will be in place from study 
start until the study has accumulated safety data from 45 participants through 7 days of 
follow up after Dose 1. These data will be carefully monitored and reviewed by the study 
team.  If there are no safety signals in the first 45 participants after Dose 1, the daily 
enrollment limit will be removed (see Section 8.2.4).
Participants will return to the site for Visit 2 (4 to 8 weeks after Visit 1) and Visit 3 (4 to 
8 weeks after Visit 2); they will be assessed for continued eligibility and information will be 
collected from the participants’ parent(s)/legal guardian(s) on AEs, including nonserious 
AEs, SAEs, NDCMCs, and e-diary follow-up (as needed).  Concomitant medications used to 
treat SAEs or NDCMCs will be recorded.
Information on vaccines administered since the last visit will also be recorded.  Participants 
with continued eligibility will be administered Dose 2 (Visit 2) and Dose 3 (Visit 3).  
Consistent with the vaccination schedule recommended by the Japan Pediatric Society”,1
specific vaccines containing Hib, Hep B, rotavirus, diphtheria, tetanus, acellular pertussis, 
and poliovirus antigens will also be administered concomitantly with Doses 2 and 3 (apart 
from HepB vaccine which is not given with Dose 3) in the upper arm(s) or orally (in the case 
of rotavirus vaccine).  Participants will be observed for 30 minutes after vaccination.  
Participant’s parent(s)/legal guardian(s) will be instructed as in Visit 1.
Participants will return to the site for Visit 4, approximately 1 month (28 to 42 days) after 
Visit 3.  Information will be collected from the participants’ parent(s)/legal guardian(s) on 
AEs, SAEs, NDCMCs, and e-diary follow-up (as needed).  Concomitant medications used to 
treat SAEs or NDCMCs will be recorded.  Information on vaccines administered since the 
last visit will also be recorded.  A blood sample will be collected for immunogenicity 
assessment.
Participants will return to the site for Visit 5 (12 to 15 months of age with ≥60 days after 
Dose 3) and be assessed for continued eligibility.  Information will be collected from the 
participants’ parent(s)/legal guardian(s) on SAEs, NDCMCs, and e-diary follow-up (as 
needed).  Concomitant medications used to treat SAEs or NDCMCs will be recorded.  
Information on vaccines given since the last visit will also be recorded.  A blood sample will 
be taken for immunogenicity assessment prior to vaccination.  Dose 4 (of 20vPnC or 
13vPnC) will be administered at this visit.  Consistent with the vaccination schedule 
recommended by the Japan Pediatric Society,1 specific concomitant vaccines containing Hib, 
diphtheria, tetanus, acellular pertussis, poliovirus, measles, rubella, and varicella antigens 
will be administered subcutaneously into the upper arm(s) at this visit.  Participants will be 
observed for 30 minutes after vaccination and any reactions occurring during that time will 
be recorded as AEs.  Participant’s parent(s)/legal guardian(s) will be instructed as in Visit 1.
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Participants will return for Visit 6, approximately 1 month (28 to 42 days) after Visit 5.  
Information will be collected from the participants’ parent(s)/legal guardian(s) on AEs, 
SAEs, NDCMCs, and e-diary follow-up (as needed).  Concomitant medications used to treat 
SAEs or NDCMCs will be recorded.  Information on vaccines given since the last visit will 
also be recorded.  A blood sample will be taken for immunogenicity assessment.
4.1.1. Approximate Duration of Participation for Each Participant
Each participant will participate in the study approximately between 7 to 14 months 
depending on the age of commencing in the study.
4.1.2. Approximate Number of Participants
Approximately 666 participants will be enrolled to achieve a target of 600 evaluable 
participants (200 in each vaccine group) at the follow-up time point 1 month after Dose 3.
4.2. Scientific Rationale for Study Design
 
 
Infants 2 through 6 months of age will be 
eligible if they are naive to pneumococcal vaccination and the specified concomitant 
vaccines.  This study population has been selected as this is the historical population studied 
for licensure of 13vPnC in infants.  The participants will be administered either 20vPnC or 
13vPnC for all 4 doses by the same injection route (SC or IM) at Visits 1, 2, 3, and 5.  This is 
consistent with the current vaccination schedule recommended by the Japan Pediatric Society 
for infants in Japan.1  13vPnC will serve as the comparator to 20vPnC for assessment of 
safety and immunogenicity when 20vPnC or 13vPnC will be administered by SC injection.
The safety and immunogenicity of 20vPnC administered by IM injection will also be 
assessed.
4.3. Justification for Dose
The 20vPnC candidate is modeled after 7vPnC and 13vPnC, and contains capsular 
polysaccharides from pneumococcal serotypes 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 
14, 15B, 18C, 19A, 19F, 22F, 23F, and 33F individually conjugated to CRM197.  The vaccine 
is formulated to contain 2.2 μg of each saccharide, except for 4.4 μg of 6B, per 0.5-mL dose.  
In infants, administration of all 4 doses of pneumococcal conjugate vaccine given at the 
defined schedule shown in the SoA induce protective immune responses.
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.
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5. STUDY POPULATION
This study can fulfill its objectives only if appropriate participants are enrolled.  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. Japanese male or female infants ≥2 months to ≤6 months (defined as the first day the 
participant is 2 months of age to the last day the participant is 6 months of age) at the 
time of consent.
Type of Participant and Disease Characteristics:
2. Participants whose parent(s)/legal guardian(s) is willing and able to comply with all 
scheduled visits, treatment plan, and other study procedures.
3. Healthy infants determined by clinical assessment, including medical history and clinical 
judgment, to be eligible for the study.
4. Expected to be available for the duration of the study and whose parent(s)/legal 
guardian(s) can be contacted by telephone during study participation.
Informed Consent:
5. Participants whose parent(s)/legal guardian(s) is capable of giving signed informed 
consent as described in Appendix 1, which includes compliance with the requirements 
and restrictions listed in the ICD and in this protocol.
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 of investigational product, the specified 
concomitant vaccines containing Hib, HepB, rotavirus, diphtheria, tetanus, acellular 
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pertussis, poliovirus, measles, rubella, and/or varicella antigens, or any diphtheria toxoid-
containing vaccine.
2. Contraindication to vaccination with pneumococcal conjugate vaccine, or the specified 
concomitant vaccines containing Hib, Hep B, rotavirus, diphtheria, tetanus, acellular 
pertussis, poliovirus, measles, rubella, and/or varicella antigens.
3. Significant neurological disorder or history of seizure including febrile seizure or 
significant stable or evolving disorders such as cerebral palsy, encephalopathy, 
hydrocephalus, or other significant disorders. Does not include resolving syndromes due 
to birth trauma, such as Erb's palsy and/or hypotonic-hyporesponsive episodes.
4. Major known congenital malformation or serious chronic disorder.
5. History of microbiologically proven invasive disease caused by S pneumoniae.
6. Known or suspected immunodeficiency or other conditions associated with 
immunosuppression, including, but not limited to, immunoglobulin class/subclass 
deficiencies, DiGeorge syndrome, generalized malignancy, HIV infection, leukemia, 
lymphoma, or organ or bone marrow transplant.
7. Bleeding diathesis or condition associated with prolonged bleeding that would, in the 
opinion of the investigator, contraindicate intramuscular or subcutaneous injection.
8. Congenital, functional, or surgical asplenia.
9. Other acute or chronic medical or psychiatric condition or laboratory abnormality that 
may increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the participant inappropriate for entry into this 
study.
Prior/Concomitant Therapy:
10. Previous vaccination with any licensed or investigational pneumococcal vaccine, or 
planned receipt through study participation.
11. Prior receipt of Hib, Hep B, rotavirus, diphtheria, tetanus, acellular pertussis, and/or 
poliovirus vaccines.
12. Currently receives treatment with immunosuppressive therapy, including cytotoxic agents 
or systemic corticosteroids, or planned receipt through the last blood sample collection
(Visit 6).  If systemic corticosteroids have been administered short term (<14 days) for 
treatment of an acute illness, participants should not be enrolled into the study until 
corticosteroid therapy has been discontinued for at least 28 days before investigational 
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product administration. Inhaled/nebulized, intra-articular, intrabursal, or topical (skin, 
eyes, or ears) corticosteroids are permitted.
13. Receipt of blood/plasma products or immunoglobulins (including hepatitis B 
immunoglobulin and monoclonal antibodies) since birth or planned receipt through the 
last planned blood sample collection in the study (through Visit 6).
Prior/Concurrent Clinical Study Experience:
14. Participation in other studies involving investigational drug(s), investigational vaccines, 
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 Exclusions:
15. Children or grandchildren who are direct descendants of investigator site staff or Pfizer 
employees who are directly involved in the conduct of the study, or children or 
grandchildren of site staff otherwise supervised by the investigator, and their respective 
family members.
5.3. Lifestyle Considerations
No restrictions are required.
5.4. Screen Failures
Screen failures are defined as participants whose parent(s)/legal guardian(s) have consented 
for them to participate in the clinical study but are not subsequently randomly assigned to 
investigational product/entered in the study.  A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any AEs and SAEs.
Individuals who do not meet the criteria for participation in this study (screen failures) may 
not be rescreened.
5.5. Temporary Delay Criteria
The following conditions are temporary or self-limiting and a participant may be vaccinated 
and/or have blood sample collection in the study once the condition(s) has/have resolved and 
no other exclusion criteria are met.
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The blood sample collection prior to vaccination (Dose 4 at Visit 5) should take place on the 
same day as the vaccination.
Criteria for Temporarily Delaying Vaccine Administration
•
Current febrile illness (eg, axillary temperature ≥37.5°C) or other acute illness within 
48 hours before investigational product administration.
•
Receipt of any inactivated or otherwise nonlive vaccine within 14 days or any live 
vaccine within 28 days before investigational product administration (with the exception 
of the influenza vaccine, which may be given at any time during the influenza season).  
Receipt of permitted concomitant vaccines on the same day as Dose 1, 2, 3, or 4 does not 
require temporary delay of investigational product administration.
•
Receipt of short-term (<14 days) systemic corticosteroids.  Investigational product 
administration should be delayed until systemic corticosteroid use has been discontinued 
for at least 28 days.  Inhaled/nebulized, intra-articular, intrabursal, or topical (skin, eyes, 
or ears) corticosteroids are permitted.
Criteria for Temporarily Delaying Immunogenicity Blood Sample Collection
•
Receipt of antibiotic therapy within 72 hours before blood sample collection.  Topical 
antibiotics are permitted.
6. STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
For the purposes of this protocol, study intervention refers to investigational product.
Administration and vaccination schedule of the specified concomitant vaccines containing 
Hib, Hep B, rotavirus, diphtheria tetanus, acellular pertussis, polio virus, measles, rubella, 
and varicella antigens will be described in Section 6.5.2.
6.1. Study Intervention(s) Administered
20vPnC is a sterile liquid suspension formulation containing saccharides from pneumococcal 
serotypes 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15B, 18C, 19A, 19F, 22F, 23F, 
and 33F individually conjugated to CRM197. 
 
13vPnC is a sterile liquid suspension formulation containing saccharides from pneumococcal 
serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14,18C, 19A, 19F, and 23F individually conjugated to 
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CRM197. 
 
 
 
The inner syringe label will be open labeled.  Except for the inner syringe label, 20vPnC and 
13vPnC are both white suspensions and are identical in appearance including outer carton, 
and will be supplied as prefilled syringes.
All vaccines listed in this section will be provided by Pfizer as prefilled syringes.  Each 
syringe will be packaged in a carton with a label and a tamper-evident seal, and will be 
labeled as required per country requirement (refer to the investigational product manual).
6.1.1. Administration
Participants will receive 1 dose of 20vPnC or 13vPnC at each vaccination visit (Visits 1, 2, 3, 
and 5 with Doses 1, 2, 3, and 4, respectively) in accordance with the study’s SoA.  Doses 1 to 
3 will be preferred to be administered at 2, 3, and 4 months of age consistent with the 
vaccination schedule recommended by the Japan Pediatric Society.1  In addition, Dose 3 will 
be completed by 12 months of age and Dose 4 will be administered ≥60 days after Dose 3.
In the 20vPnC SC and 13vPnC SC groups, 20vPnC or 13vPnC should be administered 
subcutaneously by injecting 0.5 mL into the anterolateral thigh (preferably into the left 
anterolateral thigh) at the vaccination visits.  In the 20vPnC IM group, 20vPnC should be
administered intramuscularly by injecting 0.5 mL into the anterolateral thigh muscle of the 
leg (preferably of the left leg) at the vaccination visits.
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, vaccine-experienced, and unblinded 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. (NOTE: A blinded site staff should not open a 
carton of the investigational product in order to maintain the blind).
Study intervention administration details will be recorded on the CRF.
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6.1.2. Medical Devices
1. In this study, medical devices being deployed are the 20vPnC and 13vPnC prefilled 
syringes.
2. Instructions for medical device use are provided in the IP manual.
3. All medical device deficiencies (including malfunctions, use error, and inadequate 
labeling) shall be documented and reported by the investigator throughout the clinical 
investigation (see Section 8.3.9) and appropriately managed by the sponsor.
6.2. Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study interventions received and any discrepancies are 
reported and resolved before use of the study intervention, as applicable for 
temperature-monitored shipments.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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6.2.1. Preparation and Dispensing
See the IP manual or applicable SRSD for instructions on how to prepare the investigational 
product for administration.  Investigational product 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.
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6.3. Measures to Minimize Bias: Randomization and Blinding
6.3.1. Allocation to Study Intervention
Participants will be randomized equally to one of the following vaccine groups: 
(1) 20vPnC SC group, (2) 13vPnC SC group (control vaccine), or (3) 20vPnC IM group.
Allocation of participants to vaccine groups will proceed through the use of an IRT system 
(IWR).  The site personnel (study coordinator or specified designee; either blinded or 
unblinded) 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 vaccine assignment, randomization number, and DU or 
container number when study intervention 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 files.
Study intervention will be dispensed at the study visits summarized in the SoA. 
Returned study intervention must not be redispensed to the participants.
An otherwise uninvolved third party (unblinded site staff) will be responsible for 
administration of the study intervention.  This includes ensuring that there are no differences 
in time or effort taken to administer the study intervention and no blinded site staff or 
participant’s parent(s)/legal guardian(s) are able to view the administration (refer to SRM for 
details).
The study-specific IRT reference manual and IP manual will provide the contact information 
and further details on the use of the IRT system.
6.3.2. Blinding of Site Personnel
In this observer-blinded study, the study staff administering the vaccine and confirming the 
administration route of study intervention will be unblinded, but all other site study 
personnel, including the principal investigator and the parent(s)/guardian(s) of the 
participant, will be blinded.
The principal investigator will assign the responsibility of the unblinded administrator who 
will not participate in the evaluation of any study subject.  At least 1 unblinded administrator 
will be assigned per site.  A member of the study site staff should fulfill this role.  
The investigator, study coordinator, and any site staff other than the unblinded administrator 
must not be allowed to know the investigational product assigned (including the route of 
administration) to any study participant and must not be allowed to see the investigational 
product container contents.
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6.3.3. Blinding of the Sponsor
Those study team members who are involved in ensuring that protocol requirements for 
study intervention handling, allocation, and administration are fulfilled at the site (eg, study 
manager; CRAs and unblinded medical monitor) will be unblinded for the duration of the 
study.  All other study team members and all laboratory personnel performing the serology 
assays will remain blinded to vaccine assigned/received throughout the study.
6.3.4. Breaking the Blind
The study will be participant-, participant's parent(s)/legal guardian(s)-, and 
investigator-blinded.
The IRT will be programmed with blind-breaking instructions.  In case of an emergency, the 
investigator has the sole responsibility for determining if unblinding of a participant’s 
treatment assignment is warranted.  Participant safety must always be the first consideration 
in making such a determination.  If the investigator decides that unblinding is warranted, the 
investigator should make every effort to contact the sponsor prior to unblinding a 
participant’s treatment assignment unless this could delay further management of the 
participant.  If a participant’s treatment assignment is unblinded, the sponsor must be notified 
within 24 hours after breaking the blind.  The date and reason that the blind was broken must 
be recorded in the source documentation and the CRF.
6.4. Study Intervention Compliance
All doses of investigational product will be administered by the appropriately designated 
unblinded study staff at the investigator site.  The date and time of each dose administered in 
the study site will be recorded in the source documents and recorded in the CRF.  The 
administration route (SC or IM) of study intervention and study participant identification will 
be confirmed at the time of dosing by an unblinded member of the study site staff.
6.5. Concomitant Therapy
6.5.1. Prohibited Concomitant Vaccines and Treatments
•
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 blood/plasma products, immunoglobulins, and/or immunosuppressive therapy 
(including a ≥14-day course of systemic corticosteroids) is prohibited through Visit 6.
6.5.2. Permitted Concomitant Vaccines and Treatments
Specified concomitant vaccines
Consistent with the vaccination schedule recommended by the Japan Pediatric Society”,1
specified concomitant vaccines containing Hib, HepB, rotavirus, diphtheria, tetanus, acellular 
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pertussis, polio virus, measles, rubella, and varicella antigens will be administered 
concomitantly with the relevant dose of investigational product.  The vaccination schedule of 
the specified concomitant vaccines are shown in Table 1.
Table 1.
Vaccination Schedule for Investigational Product and Specified 
Concomitant Vaccines
Visit Number
Visit 1
Visit 2
Visit 3
Visit 5
IP Vaccinationa
Dose 1
Dose 2
Dose 3
Dose 4
Visit Window
2 through 6
Months of Age
4 to 8 Weeks
After Visit 1
4 to 8 Weeks
After Visit 2
(Completed by 12 
Month of Age)
12 to 15
Months of Age
(≥60 Days After 
Dose 3)
Investigational Product
(20vPnC or 13vPnC)
X
X
X
X
Specified concomitant vaccines
Hib vaccine
X
(Vax 1)
X
(Vax 2)
X
(Vax 3)
X
(Vax 4)
Hep B vaccineb
X
(Vax 1)
X
(Vax 2)
Rotavirus vaccine
X
(Vax 1)
X
(Vax 2)
Xc
(Vax 3)
DTaP-IPVb
X
(Vax 1)
X
(Vax 2)
X
(Vax 4)
MR combination vaccined
X
(Vax 1)
Varicella vaccined
X
(Vax 1)
Abbreviation: DTaP-IPV = diphtheria, tetanus, acellular pertussis, inactivated polio combination vaccine, 
Hep B = hepatitis B, Hib = Haemophilus influenzae type b, MR = measles and rubella, Vax = vaccination
a.
Doses of vaccines to be administrated at visits 1 to 3 will be preferred to be administered at 2, 3, and 4 
months of age consistent with the recommended vaccination schedule..
b.
Dose 3 of DTaP-IPV and Hep B vaccine will be administered according to the vaccination schedule 
defined in the labeling.  These vaccines will be administered between the blood sample collection 1 
month after Dose 3 (Visit 4) and 14 days before Dose 4 (Visit 5).
c.
Dose 3 for penta-valent rotavirus vaccine only.
d.
Dose 2 of MR combination vaccine and varicella vaccine will be administered according to the 
vaccination schedule defined in the labeling.
Other Concomitant Vaccines and Treatments
•
Influenza vaccine is permitted at any time during influenza season in this study.
•
Other nonprohibited licensed age appropriate vaccines may be given between the blood 
sample collection 1 month after Dose 3 (Visit 4) and 14 days before Dose 4 (Visit 5) for 
inactivated vaccines or 28 days before Dose 4 (Visit 5) for live vaccines, according to 
vaccination schedule recommended by the Japan Pediatric Society”.1  Following the 
blood sample collection performed 1 month after Dose 4 (Visit 6), all licensed vaccines 
are permitted.
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•
Use of topical anesthetic is permitted.
•
The use of prophylactic antipyretic/pain medication, while permitted, is not 
recommended on the day prior to vaccination or the day of investigational product 
administration.
•
Inhaled/nebulized, topical (skin, eyes, or ears), or localized injections of corticosteroids 
(eg, intra-articular or intrabursal administration) are permitted during participant 
participation in the study.
•
Prescription and nonprescription medications, vitamins, minerals, and herbal remedies 
are permitted during the study.
6.5.3. Recording Prior and Concomitant Vaccines and Treatments
The name and date of administration for all vaccinations should be collected from the time of 
signing of the ICD to Visit 6 and will be recorded in the CRF.  At Visit 1, information on 
prior vaccinations will also be recorded in the CRF.  Vaccines required by the protocol, as 
well as those not stipulated, will be recorded throughout study participation.
Medications taken to treat SAEs or NDCMCs from the signing of informed consent to the 
final visit will be recorded in the CRF.
6.6. Dose Modification
Not applicable.
6.7. Intervention After the End of the Study
No intervention will be provided to study participants after the end of the study.
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention
Participant eligibility must be confirmed at each visit (for the vaccination visit, prior to each 
vaccination) in order to continue in the study.
If a participant no longer meets the eligibility criteria during the vaccination period of the 
study, further vaccinations should be discontinued, but the participant may remain in the 
study.  If a participant is discontinued from vaccination and the participant’s parent(s)/legal 
guardian(s) consents, safety follow-up will be conducted as per Section 8.3 (AEs and SAEs 
will be collected for 1 month after the last study vaccination).
See the SoA for data to be collected at the time of intervention discontinuation and follow-up 
and for any further evaluations that need to be completed.
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7.2. Participant Discontinuation/Withdrawal From the Study
A participant may be withdrawn from the study at any time at the request of his/her 
parent(s)/legal guardian(s) or may be withdrawn at any time at the discretion of the 
investigator for safety, behavioral, compliance, or administrative reasons.  Reasons for 
discontinuation from the study include the following:
•
Adverse event;
•
Death;
•
No longer meets eliginility criteria;
•
Protocol deviation;
•
Physician decision;
•
Study terminated by sponsor;
•
Medication error without associated adverse event;
•
Withdrawal by participant’s parent(s)/legal guardian(s);
•
Lost to follow-up;
•
Other.
If a participant does not return for a scheduled visit, every effort should be made to contact 
the participant’s parent(s)/legal guardian(s).  All attempts to contact the participant’s 
parent(s)/legal guardian(s) and information received during contact attempts must be 
documented in the participant’s source document.  In any circumstance, every effort should 
be made to document participant outcome, if possible.
At the time of discontinuing please refer to the ISF and SoA for assessments to be collected 
at the time of study discontinuation and follow-up and for any further evaluations that need 
to be completed.
The participant’s parent(s)/legal guardian(s) should ideally notify the investigator in writing 
of the decision to withdraw consent from future follow-up, whenever possible.  The 
participant’s parent(s)/legal guardian(s) should be questioned regarding their reason for 
withdrawal. The investigator or his or her designee should capture the reason for withdrawal 
in the CRF for all participants.
The participant should be requested to return for a final visit, if applicable, and the 
investigator will perform the procedures indicated for the next visit.  Any AEs or SAEs that 
are continuing at the time of withdrawal from the study should be followed until resolution 
or, in case of permanent impairment, until the condition stabilizes.
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If a participant is withdrawn from the study, his/her parent(s)/legal guardian(s) may request 
destruction of any remaining samples, but data already generated from the samples will 
continue to be available, and may be used to protect the integrity of existing analyses.  The 
investigator must document any such requests in the site study records and notify the sponsor 
accordingly.
If the participant is withdrawn from the study and his/her parent(s)/legal guardian(s) also 
withdraws consent (see Section 7.2.1) for disclosure of future information), no further 
evaluations should be performed and no additional data should be collected.  The sponsor 
may retain and continue to use any data collected before such withdrawal of consent.
When a participant is withdrawn from the study because of an SAE, the SAE must be 
recorded on the CRF and reported on the Vaccine SAE Reporting form.
Lack of completion of all or any of the withdrawal/early termination procedures will not be 
viewed as protocol deviations so long as the participant’s safety was preserved.
7.2.1. Withdrawal of Consent 
Participant’s parent(s)/legal guardian(s) who request to discontinue receipt of study 
intervention 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’s parent(s)/legal 
guardian(s) specifically withdraws consent for any further contact with him or her or persons 
previously authorized by the participant to provide this information.  Participant’s 
parent(s)/legal guardian(s) should notify the investigator in writing of the decision to 
withdraw consent from future follow-up, whenever possible.  The withdrawal of consent 
should be explained in detail in the medical records by the investigator, as to whether the 
withdrawal is only from further receipt of study intervention or also from study procedures 
and/or posttreatment study follow-up, 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 he or she repeatedly fails to return for 
scheduled visits and the participant’s parent(s)/legal guardian(s) is unable to be contacted by 
the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:
•
The site must attempt to contact the participant’s parent(s)/legal guardian(s) and 
reschedule the missed visit as soon as possible and counsel the participant’s 
parent(s)/legal guardian(s) on the importance of maintaining the assigned visit schedule 
and ascertain whether or not the participant’s parent(s)/legal guardian(s) wishes the 
participant to, and/or should, continue in the study;
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•
Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant’s parent(s)/legal guardian(s) (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’s parent(s)/legal guardian(s) continue to be unreachable, the 
participant will be considered to have been withdrawn from the study.
Discontinuation of specific sites or of the study as a whole is handled as part of Section 10.1
(Appendix 1).
8. STUDY ASSESSMENTS AND 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.
Safety issues should be discussed with the sponsor immediately upon occurrence or 
awareness to determine if the participant should continue or discontinue study intervention.
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.
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 may 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 he or she has 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.
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The total blood sampling volume for individual participants in this study is approximately 
15 mL.
8.1. Immunogenicity Assessments
8.1.1. Immunogenicity Assessments
Blood samples (approximately 5 mL per sample) will be collected from all participants at 
Visit 4 (1 month after Dose 3), Visit 5 (prior to administration of Dose 4), and Visit 6 
(1 month after Dose 4).  These are the immunogenicity time points.
8.1.1.1. Pneumococcal Responses
IgG Responses to the 20 Serotypes Contained in 20vPnC
IgG antibody concentrations for serotypes present in 20vPnC (1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 
10A, 11A, 12F, 14, 15B, 18C, 19A, 19F, 22F, 23F, and 33F) will be determined on all sera 
collected at the 3 immunogenicity time points (Visits 4, 5, and 6).  The serotype-specific IgG 
concentrations will be measured by Pfizer’s multiplex Luminex immunoassay.
OPA Responses to the 20 Serotypes Contained in 20vPnC
OPA titers for serotypes present in 20vPnC (1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 
15B, 18C, 19A, 19F, 22F, 23F, and 33F) will be determined in selected subsets of sera for 
the immunogenicity time points (Visits 4, 5, and 6). These subsets will be randomly selected, 
by an unblinded third party, to assure that each subset has equal representation of all vaccine 
groups. Further details will be described in the CSAP.
 
 
 
 
 
  
 
 
 
 
 
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8.2. Safety Assessments
A clinical assessment, including medical history and measurement of axillary temperature, 
will be performed on all participants prior to vaccination 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 vaccination will be documented and recorded in the CRF.
The participant will be observed for 30 minutes after each study vaccination 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, decreased appetite, drowsiness/increased sleep, and 
irritability) that occur 7 days after investigational product administration (Days 1 through 7, 
where Day 1 is the day of vaccination), are graded as described in Section 8.2.2.1 and 
Section 8.2.2.2.  Furthermore, AEs, SAEs, and NDCMCs will be collected as defined in 
Section 10.3.
Planned time points for all safety assessments are provided in the SoA.  Unscheduled clinical 
laboratory measurements may be obtained at any time during the study to assess any 
perceived safety concerns.
8.2.1. Participant Electronic Diary
The participant’s parent(s)/legal guardian(s) will be asked to monitor and record local 
reactions, specific systemic events, and antipyretic/pain medication taken for 7 days, each 
evening, following each administration of investigational product (20vPnC or 13vPnC) using 
an e-diary (in a provisioned device or application on a 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 on local reactions, specific systemic 
events, and antipyretic/pain medication reported in the e-diary will be transferred 
electronically to the e-diary vendor, where they will be available for review by investigators, 
their 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.
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The investigator or designee must obtain stop dates for any local reactions or specific 
systemic events 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.
8.2.2. 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 adults and 
adolescent volunteers enrolled in preventive vaccine clinical trials, but have been adapted for 
applicability to healthy infants.78
8.2.2.1. Local Reactions
For the first 7 days following each study vaccination (Days 1 through 7, where Day 1 is the 
day of vaccination), the participant’s parent(s)/legal guardian(s) will be asked to assess 
redness, swelling, and pain at the 20vPnC or 13vPnC injection site (anterolateral thigh) 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 >14; an entry in the e-diary of 
15 will denote >14), 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 vaccine 
injection site will be assessed by the participant’s parent(s)/legal guardian(s) as mild, 
moderate, or severe according to the grading scale in Table 2.  The participant’s 
parent(s)/legal guardian(s) will be prompted to contact the investigator if the participant 
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 or hospital record).  If a participant experiences a Grade 4 local reaction, 
the investigator must immediately notify the sponsor.  Site staff will educate the participant’s 
parent(s)/legal guardian(s) regarding signs and symptoms that would prompt site contact.
The procedure for notification of the sponsor is provided in the ISF or equivalent.
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Table 2.
Grading Scales for Local Reactions
Local 
Reaction
Grade 1
(Mild)
Grade 2
(Moderate)
Grade 3a
(Severe)
Grade 4b
Redness
1 to 4 caliper units
(or measuring 
device units)
=
>0 to 2.0 cm
5 to 14 caliper units
(or measuring 
device units)
=
>2.0 to 7.0 cm
>14 caliper units
(or measuring 
device units)
=
>7 cm
Necrosis or exfoliative 
dermatitis
Swelling
1 to 4 caliper units
(or measuring 
device units)
=
>0 to 2.0 cm
5 to 14 caliper units
(or measuring 
device units)
=
>2.0 to 7.0 cm
>14 caliper units
(or measuring 
device units)
=
>7 cm
Necrosis
Pain at 
injection site
(tenderness)
Hurts if gently 
touched
(eg, whimpers, 
winces, protests, or 
withdraws)
Hurts if gently 
touched with crying
Causes limitation 
of limb movement
Emergency room visit or 
hospitalization for severe 
pain (tenderness) at 
injection site
Abbreviation: CRF = case report form.
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.
Parents/legal guardians of the participants experiencing local reactions >14 caliper units (>7.0 cm) are to 
be contacted by the study site. An unscheduled visit may be required.
b.
Grade 4 assessment should be made by the investigator.  Grade 4 will not be collected in the e-diary but 
will be collected as an AE on the CRF.  The severity of the local reaction should be graded using the AE 
grading scale.
8.2.2.2. Systemic Events (Systemic Symptoms and Fever)
For the first 7 days following each study vaccination (Days 1 through 7, where Day 1 is the 
day of vaccination), the participant’s parent(s)/legal guardian(s) will be asked to assess 
decreased appetite, drowsiness/increased sleep, and irritability and to record the symptoms in 
the e-diary (in a provisioned device or application on a personal device) in the evening.  The 
symptoms will be assessed by the participant’s parent(s)/legal guardian(s) as mild, moderate, 
or severe according to the grading scale in Table 3.  The participant’s parent(s)/legal 
guardian(s) will also be instructed to contact site staff if the participant experiences any 
possible Grade 4 prompted systemic event (ie, emergency room visit or hospitalization for 
severe decreased appetite, severe drowsiness/increased sleep, or severe irritability) within 
7 days after vaccination.  Study staff may also contact the participant’s parent(s)/legal 
guardian(s) to obtain additional information on Grade 3 events entered into the e-diary.
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’s 
parent(s)/legal guardian(s).  If a participant experiences a Grade 4 systemic event, the 
investigator must immediately notify the sponsor.
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The procedure for notification of the sponsor is provided in the ISF or equivalent.
Table 3.
Grading Scales for Systemic Event Symptoms
Systemic Event
Grade 1
(Mild)
Grade 2
(Moderate)
Grade 3
(Severe)
Grade 4a
Decreased 
appetite (loss of 
appetite)
Decreased interest 
in eating
Decreased oral 
intake
Refusal to feed
Emergency room 
visit or 
hospitalization for 
severe decreased 
appetite (loss of 
appetite)
Drowsiness 
(increased sleep)
Increased or 
prolonged sleeping 
bouts
Slightly subdued 
interfering with 
daily activity
Disabling not 
interested in usual 
daily activity
Emergency room 
visit or 
hospitalization for 
severe drowsiness 
(increased sleep)
Irritability 
(fussiness)
(synonymous with 
restless sleep; 
decreased sleep)
Easily consolable
Requiring 
Increased attention
Inconsolable; 
crying cannot be 
comforted
Emergency room 
visit or 
hospitalization for 
severe irritability 
(fussiness)
Abbreviations: CRF = case report form.
a.
Grade 4 assessment should be made by the investigator. Grade 4 will not be collected in the e-diary but 
will be collected as an AE on the CRF. The severity of the systemic event should be graded using the 
AE severity grading scale.
8.2.2.2.1. Fever
In order to record information on fever, a digital thermometer will be given to the 
participant’s parent(s)/legal guardian(s) with instructions on how to measure axillary 
temperature at home.  Temperature will be collected in the evening, daily, for 7 days 
following each study vaccination (Days 1 through 7, where Day 1 is the day of vaccination) 
and at any time during the 7 days that fever is suspected.  Fever is defined as an axillary 
temperature of ≥37.5°C.  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 fever has 
resolved (1 day of temperature <37.5°C) in order to collect a stop date in the CRF.  A 
participant’s parent(s)/legal guardian(s) will be prompted to contact the investigator if the  
participant experiences a fever >40.0°C within the 7 days following vaccination to assess the 
fever and perform an unscheduled assessment, as applicable (see Section 8.11.7).  Study staff 
may also contact the participant’s parent(s)/legal guardian(s) to obtain additional information 
if a temperature of >38.9°C is entered into an e-diary.  Temperature will be measured and 
recorded to 1 decimal place and then grouped into ranges for the analysis; see Table 4.
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Table 4.
Ranges for Fever for the E-diary
≥37.5°C to 38.4°C
>38.4°C to 38.9°C
>38.9°C to 40.0°C
>40.0°C
Note: Fever is defined as axillary temperature ≥37.5°C.
8.2.2.3. Use of Antipyretic/Pain Medication
The participant’s parent(s)/legal guardian(s) will be asked to record the use of 
antipyretic/pain medication (yes/no) in the e-diary (in a provisioned device or application on 
a personal device) in the evening, daily, for 7 days after each dose of investigational product.
8.2.3. Clinical Safety Laboratory Assessments
Clinical safety laboratory tests are not required by this protocol.
If laboratory values from non–protocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in participant management or are considered 
clinically significant by the investigator (eg, SAE or AE or dose modification), then the 
results must be recorded in the CRF.
8.2.4. Procedures to Monitor Safety
As this study is the first study where 20vPnC is administered subcutaneously and the study 
participants are infants, a daily enrollment limit of 5 participants will be in place from study 
start until the study has accumulated safety data for 45 participants through 7 days of follow-
up after Dose 1 and these blinded data have been carefully monitored and reviewed by the 
study team.  If there is no safety signal in the first 45 participants after Dose 1, the daily 
enrollment limit will be removed.
If any safety signal in the first 45 participants after Dose 1 is identified by the study team, 
these safety data will be reviewed by senior Pfizer personnel not directly involved with the 
study conduct.  The daily limit will continue until the senior Pfizer personnel reviews the 
safety data and makes recommendations.
8.3. Adverse Events and Serious Adverse Events
The definitions of an AE and an SAE can be found in Appendix 3.
The definitions of device-related safety events (ADEs and SADEs) can be found in 
Appendix 8.  Device deficiencies are covered in Section 8.3.9.
AEs will be reported by the participant’s parent(s)/legal guardian(s).  Events that, in the 
clinical judgment of the investigator, are 1) consistent with normal growth and development 
and 2) do not differ significantly in frequency or severity from expected, are not generally to 
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be considered AEs.  Examples may include, but are not limited to, teething, contact diaper 
rash, spitting up, colic, or typical fussiness/crying in infants and children.
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 
from the study (see Section 7).
Each participant’s parent(s)/legal guardian(s) 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.
8.3.1. 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’s parent(s)/legal guardian(s) 
provides informed consent, which is obtained before the participant’s participation in the 
study (ie, before undergoing any study-related procedure and/or receiving investigational 
product), through and including Visit 4, and from Visit 5 to Visit 6.  Between Visit 4 and 
Visit 5, only SAEs and NDCMCs will be reported. 
Follow-up by the investigator continues throughout and after the active collection period and 
until the event 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.
If a participant definitively discontinues or temporarily discontinues study intervention 
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 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 or withdrawn early from the study, and 
he/she considers 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.
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8.3.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period as described in 
Section 8.3.1 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 it being available.
SAEs occurring in a participant after the active collection period has ended are reported to 
Pfizer Safety if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to investigational 
product must be reported to Pfizer Safety.
8.3.1.2. 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 8.3.1, 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’s parent(s)/legal guardian(s).
8.3.2. 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’s parent(s)/legal guardian(s) is the preferred 
method to inquire about AE occurrences.
8.3.3. Follow-up of AEs and SAEs
After the initial AE/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).
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 given in Appendix 3.
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8.3.4. 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 towards 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 IB and will 
notify the IRB/EC, if appropriate according to local requirements.
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational Exposure
Exposure to the investigational product under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness.
8.3.5.1. Exposure During Pregnancy
An EDP occurs if:
•
A female is found to be pregnant while being exposed or having been exposed to study 
intervention due to environmental exposure.  Below are examples of environmental 
exposure during pregnancy:  
•
A female family member or healthcare provider reports that she is pregnant after 
having been exposed to the study intervention by inhalation or skin contact.
•
A male family member or healthcare provider who has been exposed to the study 
intervention by inhalation or skin contact then exposes 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 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 
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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: 
•
Spontaneous abortion including miscarriage and missed abortion;
•
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.
8.3.5.2. Exposure During Breastfeeding
An exposure during breastfeeding occurs if:
•
A female is found to be breastfeeding while being exposed or having been exposed to 
study intervention (ie, environmental exposure).  An example of environmental exposure 
during breastfeeding is a female family member or healthcare provider who reports that 
she is breastfeeding after having been exposed to the study intervention by inhalation or 
skin contact.  
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The investigator must report exposure during breastfeeding 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 exposure 
during breastfeeding 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.
8.3.5.3. Occupational Exposure
An occupational exposure occurs when a person receives unplanned direct contact with the 
study intervention, which may or may not lead to the occurrence of an AE.  Such persons 
may include healthcare providers, family members, and other roles that are involved in the 
trial participant’s care.
The investigator must report occupational exposure to Pfizer Safety within 24 hours of the 
investigator’s awareness, regardless of whether there is an associated SAE.  The information 
must be reported using the Vaccine SAE Reporting Form.  Since the information does not 
pertain to a 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.
8.3.6. Cardiovascular and Death Events
Not applicable.
8.3.7. Disease Related Events and/or Disease Related Outcomes Not Qualifying as AEs 
or SAEs
Not applicable.
8.3.8. Adverse Events of Special Interest
Not applicable.
8.3.8.1. Lack of Efficacy
Not applicable.
8.3.9. Medical Device Deficiencies
Medical devices are being provided for use in this study for the purposes of administering the 
investigational product.  In order to fulfill regulatory reporting obligations worldwide, the 
unblinded site staff is responsible for the detection and documentation of events meeting the 
definitions of device deficiency that occur during the study with such devices.  Refer to the 
SRM for details.
The definition of a medical device deficiency can be found in Appendix 8.
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NOTE: Deficiencies fulfilling the definition of an AE/SAE will also follow the processes 
outlined in Section 8.3.1 through 8.3.4 and Appendix 3 of the protocol.
8.3.9.1. Time Period for Detecting Medical Device Deficiencies
Medical device deficiencies or malfunctions of the device will be detected, documented, and 
reported during all periods of the study in which the medical device is used.
If the investigator learns of any device deficiency at any time after a participant has been 
discharged from the study, and such incident 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.
8.3.9.2. Follow-up of Medical Device Deficiencies
Follow-up applies to all participants, including those who discontinue study intervention.
The unblinded site staff 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 unblinded site staff.
8.3.9.3. Prompt Reporting of Device Deficiencies to Sponsor
Device deficiencies will be reported to the sponsor within 1 day after the unblinded site staff
determines that the event meets the protocol definition of a medical device deficiency.  
Information will be provided to the sponsor as described in the IP Manual.  The Medication 
Error CRF will also be completed.
Any device deficiency that is associated with an SAE must be reported to Pfizer Safety 
within 24 hours upon the unblinded site staff’s awareness as outlined in Sections 8.3.1.1 and 
8.3.1.2.
The sponsor will be the contact for the receipt of device deficiency information.
8.3.9.4. Regulatory Reporting Requirements for Device Deficiencies
The unblinded site staff 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 unblinded site staff, 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.
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8.3.10. Medication Errors
Medication errors may result from the administration or consumption of the investigational 
product by the wrong participant, or at the wrong time, or at the wrong dosage strength.
Exposures to the study intervention under study may occur in clinical trial settings, such as 
medication errors.
Safety Event
Recorded on the CRF
Reported on the Vaccine SAE 
Reporting Form to Pfizer Safety 
Within 24 Hours of Awareness
Medication errors 
All (regardless of whether 
associated with an AE)
Only if associated with an SAE
Medication errors include:
•
Medication errors involving participant exposure to the study intervention;
•
Potential medication errors or uses outside of what is foreseen in the protocol that do or 
do not involve the study participant.
Such medication 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.
In the event of a medication dosing error, the sponsor should be notified within 24 hours.
Whether or not the medication 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.
Medication errors should be reported to Pfizer Safety within 24 hours on a Vaccine SAE 
Reporting Form only when associated with an SAE.
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;
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•
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.
8.4. Treatment of Overdose
For this study, any dose of investigational product greater than 1 dose of investigational 
product within a 24-hour time period will be considered an overdose.
Pfizer does not recommend specific treatment for an overdose.
In the event of an overdose, the investigator/treating physician should:
1. Contact the medical monitor within 24 hours.
2. Closely monitor the participant for any AEs/SAEs.
3. Document the quantity of the excess dose as well as the duration of the overdose in the 
CRF.
4. Overdose is reportable to Safety only when associated with an SAE.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the medical monitor based on the clinical evaluation of the participant.
8.5. Pharmacokinetics 
Pharmacokinetic parameters are not evaluated in this study. 
8.6. Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
8.7. Genetics
Genetics (specified analyses) are not evaluated in this study.
8.8. Biomarkers
Biomarkers are not evaluated in this study.
8.9. Immunogenicity Assessments
Immunogenicity assessments are described in Section 8.1.
8.10. Health Economics
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study.
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8.11. Study Procedures
The study procedures are summarized in the SoA (Section 1.3).  The day of Dose 1 is 
considered to be Day 1.
Unless specified in the sections below, the order of key procedures within a given visit may 
have some flexibility.
8.11.1. Visit 1 (Dose 1 Visit, Day 1)
Prior to vaccination:
•
Obtain a personally signed and dated ICD indicating that the participant’s parent(s)/legal 
guardian(s) has been informed of all pertinent aspects of the study before performing any 
study-specific procedures.
•
Assign a participant number via the IRT.
•
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 including medical history (including significant birth 
history); record any findings on the medical history CRF.
•
Record vaccine history.
•
Measure and record the participant’s axillary temperature (°C).
•
Ensure that all inclusion criteria, none of the exclusion criteria, and none of the temporary 
delay criteria are met.
•
Assign a randomization number and an investigational product container number via the 
IRT.  This must be the last step before proceeding.  A site staff member will prepare the 
investigational product according to the IP manual (NOTE: A blinded site staff should 
not open a carton of the investigational product in order to maintain the blind).
After randomization:
•
Unblinded site staff will administer a single 0.5-mL injection of 20vPnC or 13vPnC into 
the anterolateral thigh (preferably into the left anterolateral thigh).
•
The site staff (either blinded or unblinded) will administer concomitant vaccines 
containing hepatitis B, Hib, and rotavirus antigens and other permitted vaccines into the
upper arm(s) or orally (in the case of rotavirus vaccine) (Section 6.5.2).  A blinded site 
staff member will record the site of administration on the CRF.
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•
Blinded site staff will observe the participant for 30 minutes after vaccination for any 
reactions.
•
Record any AEs on the CRF and on an SAE form as applicable.  Record concomitant 
medications used to treat SAEs and NDCMCs.
•
Issue the participant’s parent(s)/legal guardian(s) a measuring device to measure 20vPnC 
or 13vPnC injection site reactions and a digital thermometer and provide instructions on 
their use.
•
Issue the participant’s parent(s)/legal guardian(s) an e-diary (device or application).
•
Provide instructions on use and completion of the e-diary.  Ask the participant’s 
parent(s)/legal guardian(s) to complete the e-diary from Day 1 to Day 7, with Day 1 
being the day of vaccination.
•
Ask the participant’s parent(s)/legal guardian(s) to contact the investigator site staff or 
investigator as soon as possible during the 7-day postvaccination period if the participant 
has a fever >40.0°C, redness and/or swelling at the 20vPnC or 13vPnC injection site 
measuring >14 measuring device units (>7 cm), or severe 20vPnC or 13vPnC injection 
site pain (causes limitation of limb movement) to determine if the event requires further 
assessment by the investigator.
•
Ask the participant’s parent(s)/legal guardian(s) to contact the investigator or investigator 
site staff as soon as possible if any significant illness or medical event (eg, emergency 
room visit or hospitalization) occurs.
•
Provide the participant’s parent(s)/legal guardian(s) with the participant contact card 
containing the study and investigator information (see Section 10.1.10).
•
Inform the participant’s parent(s)/legal guardian(s) that the use of prophylactic 
antipyretic/pain medication, while permitted, is not recommended on the day of 
investigational product administration (before or after vaccination).
•
The investigator or an authorized designee completes the CRF and the source documents 
and the site staff will update the investigational product accountability records.
•
The investigator or appropriately qualified designee reviews the e-diary data online at 
frequent intervals for the 7 days following vaccination to evaluate participant compliance 
and as part of the ongoing safety review.
8.11.2. Visit 2 (Dose 2 Visit, 4 to 8 Weeks After Visit 1 [Dose 1])
•
Ensure and document that the participant continues to be eligible for the study (see 
Section 7.2 for participant discontinuation/withdrawal) and none of the temporary delay 
criteria are met (Section 5.5).
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•
Record nonstudy vaccinations administered since Visit 1, as described in Section 6.5.
•
Review the participant’s e-diary data with the participant’s parent(s)/legal guardian(s); 
collect stop dates of any e-diary events ongoing on the last day that the e-diary was 
completed and record stop dates in the CRF.
•
Determine whether any AEs (includes nonserious AEs, SAEs, and NDCMCs) have 
occurred since the previous visit and follow up on any previously reported events to 
determine the outcome (ie, record stop dates or confirm if they are still continuing) and 
record as described in Section 10.3, and record concomitant medications used to treat 
NDCMCs and SAEs.
•
Measure and record the participant’s axillary temperature (°C).
•
Unblinded site staff will administer a single 0.5-mL injection of 20vPnC or 13vPnC into 
the anterolateral thigh (preferably into the left anterolateral thigh). (NOTE: A blinded
site staff should not open a carton of the investigational product in order to maintain the 
blind).
•
The site staff (either blinded or unblinded) will administer concomitant vaccines 
containing hepatitis B. Hib, rotavirus, diphtheria, tetanus, acellular pertussis, and 
poliovirus antigens and other permitted vaccines into the upper arm(s) or orally (in the 
case of rotavirus vaccine) (Section 6.5.2).  A blinded staff member will record the site of 
administration on the CRF.
After vaccination:
•
Blinded site staff will observe the participant for 30 minutes after vaccination for any 
reactions.  Record any AEs on the CRF and on an SAE form as applicable.  
Record concomitant medications used to treat SAEs and NDCMCs.
•
Confirm that the e-diary is working and review instructions if necessary.  Remind the 
participant’s parent(s)/legal guardian(s) to complete the e-diary from Day 1 to Day 7, 
with Day 1 being the day of vaccination.  Provide a thermometer or measuring device if 
needed.
•
Ask the participant’s parent(s)/legal guardian(s) to contact the investigator site staff or 
investigator as soon as possible during the 7-day postvaccination period if the participant 
has a fever >40.0°C, redness and/or swelling at the 20vPnC or 13vPnC injection site 
measuring >14 measuring device units (>7 cm), or severe 20vPnC or 13vPnC injection 
site pain (causes limitation of limb movement), to determine if the event requires further 
assessment by the investigator.
•
Remind the participant’s parent(s)/legal guardian(s) to contact the investigator or 
investigator site staff as soon as possible if any significant illness or medical event 
(eg, emergency room visit or hospitalization) occurs during the study period.
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•
Confirm whether the participant’s parent(s)/legal guardian(s) still possesses the 
participant contact card.  Provide a participant contact card if needed.
•
Remind the participant’s parent(s)/legal guardian(s) that the use of prophylactic 
antipyretic/pain medication, while permitted, is not recommended on the day of 
investigational product administration (before or after vaccination).
•
The investigator or an authorized designees completes the CRF and the source documents 
and the site staff will update the investigational product accountability records.
•
The investigator or appropriately qualified designee reviews the e-diary data online at 
frequent intervals for the 7 days following vaccination to evaluate participant compliance 
and as part of the ongoing safety review.
8.11.3. Visit 3 (Dose 3 Visit, 4 to 8 Weeks After Visit 2[Dose 2])
•
Ensure and document that the participant continues to be eligible for the study (see 
Section 7.2 for participant discontinuation/withdrawal) and none of the temporary delay 
criteria are met (Section 5.5).
•
Record nonstudy vaccinations administered since Visit 2, as described in Section 6.5.
•
Review the participant’s e-diary data with the participant’s parent(s)/legal guardian(s); 
collect stop dates of any e-diary events ongoing on the last day that the e-diary was 
completed and record stop dates in the CRF.
•
Determine whether any AEs (includes nonserious AEs, SAEs, and NDCMCs) have 
occurred since the previous visit and follow up on any previously reported events to 
determine the outcome (ie, record stop dates or confirm if they are still continuing) and 
record as described in Section 10.3, and record concomitant medications used to treat 
NDCMCs and SAEs.
•
Measure and record the participant’s axillary temperature (°C).
•
Unblinded site staff will administer a single 0.5-mL injection of 20vPnC or 13vPnC into 
the anterolateral thigh (preferably into the left anterolateral thigh). (NOTE: A blinded
site staff should not open a carton of the investigational product in order to maintain the 
blind).
•
The site staff (either blinded or unblinded) will administer concomitant vaccines 
containing diphtheria, tetanus, acellular pertussis, poliovirus, and Hib and rotavirus 
antigens and other permitted vaccines into the upper arm(s) or orally (in the case of 
rotavirus vaccine).  A blinded staff member will record the site of administration on the 
CRF.
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After vaccination:
•
Blinded site staff will observe the participant for 30 minutes after vaccination for any 
reactions.
•
Record any AEs on the CRF and on an SAE form as applicable. Record concomitant 
medications used to treat SAEs and NDCMCs.
•
Confirm that the e-diary is working and review instructions if necessary. Remind the 
participant’s parent(s)/legal guardian(s) to complete the e-diary from Day 1 to Day 7, 
with Day 1 being the day of vaccination. Provide a thermometer or measuring device if 
needed.
•
Ask the participant’s parent(s)/legal guardian(s) to contact the investigator site staff or 
investigator as soon as possible during the 7-day postvaccination period if the participant 
has a fever >40.0°C, redness and/or swelling at the 20vPnC or 13vPnC injection site 
measuring >14 measuring device units (>7 cm), or severe 20vPnC or 13vPnC injection 
site pain (causes limitation of limb movement), to determine if the event requires further 
assessment by the investigator.
•
Remind the participant’s parent(s)/legal guardian(s) to contact the investigator or 
investigator site staff as soon as possible if any significant illness or medical event 
(eg, emergency room visit or hospitalization) occurs during the study period.
•
Confirm whether the participant’s parent(s)/legal guardian(s) still possesses the 
participant contact card. Provide a participant contact card if needed.
•
Remind the participant’s parent(s)/legal guardian(s) that the use of prophylactic 
antipyretic/pain medication, while permitted, is not recommended on the day of 
investigational product administration (before or after vaccination).
•
The investigator or an authorized designee completes the CRF and the source documents 
and updates the investigational product accountability records.
•
The investigator or appropriately qualified designee reviews the e-diary data online at 
frequent intervals for the 7 days following vaccination to evaluate participant compliance 
and as part of the ongoing safety review.
8.11.4. Visit 4 (Dose 3 Follow-up Visit, 28 to 42 Days After Visit 3 [Dose 3])
•
Ensure and document that the participant continues to be eligible for the study (see 
Section 7.2 for participant discontinuation/withdrawal) and none of the temporary delay 
criteria are met (Section 5.5).
•
Record nonstudy vaccinations administered since Visit 3, as described in Section 6.5.
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•
Review the participant’s e-diary data with the participant’s parent(s)/legal guardian(s); 
collect stop dates of any e-diary events ongoing on the last day that the e-diary was 
completed and record stop dates in the CRF.
•
Collect the e-diary (if applicable).
•
Determine whether any AEs (includes nonserious AEs, SAEs, and NDCMCs) have 
occurred since the previous visit and follow up on any previously reported events to 
determine the outcome (ie, record stop dates or confirm if they are still continuing) and 
record as described in Section 10.3, and record concomitant medications used to treat 
NDCMCs and SAEs.
•
Collect a blood sample of approximately 5 mL for immunogenicity (a topical anesthetic 
is permitted).
•
The investigator or an authorized designee completes the CRF and the source documents.
8.11.5. Visit 5 (Dose 4 Visit, 12 to 15 Months of Age)
•
Ensure and document that the participant continues to be eligible for the study (see 
Section 7.2 for participant discontinuation/withdrawal) and none of the temporary delay 
criteria are met (Section 5.5).
•
Record nonstudy vaccinations administered since Visit 4, as described in Section 6.5.
•
Determine whether any SAEs or NDCMCs have occurred since the previous visit and 
follow up on any previously reported events to determine the outcome (ie, record stop 
dates or confirm if they are still continuing) and record as described in Section 10.3, and 
record concomitant medications used to treat NDCMCs and SAEs.
•
Measure and record the participant’s axillary temperature (°C).
•
Prior to vaccination, collect a blood sample of approximately 5 mL for immunogenicity 
(a topical anesthetic is permitted).
•
Unblinded site staff will administer a single 0.5-mL injection of 20vPnC or 13vPnC into 
the anterolateral thigh (preferably into the left anterolateral thigh). (NOTE: A blinded
site staff should not open a carton of the investigational product in order to maintain the 
blind).
•
The site staff (either blinded or unblinded) will administer concomitant vaccines 
containing Hib, diphtheria, tetanus, acellular pertussis, poliovirus, measles, rubella, and 
varicella antigens and other permitted vaccines into the upper arm(s).  A blinded staff 
member will record the site of administration on the CRF.
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After vaccination:
•
Blinded site staff will observe the participant for 30 minutes after vaccination for any 
reactions.  Record any AEs on the CRF and on an SAE form as applicable. Record 
concomitant medications used to treat SAEs and NDCMCs.
•
Issue the participant’s parent(s)/legal guardian(s) an e-diary (device or application).  
Provide instructions on use and completion of the e-diary. Ask the participant’s 
parent(s)/legal guardian(s) to complete the e-diary from Day 1 to Day 7, with Day 1 
being the day of vaccination.
•
Ask the participant’s parent(s)/legal guardian(s) to contact the investigator site staff or 
investigator as soon as possible during the 7-day postvaccination period if the participant 
has a fever >40.0°C, redness and/or swelling at the 20vPnC or 13vPnC injection site 
measuring >14 measuring device units (>7 cm), or severe 20vPnC or 13vPnC injection 
site pain (causes limitation of limb movement), to determine if the event requires further 
assessment by the investigator.
•
Remind the participant’s parent(s)/legal guardian(s) to contact the investigator or 
investigator site staff as soon as possible if any significant illness or medical event 
(eg, emergency room visit or hospitalization) occurs during the study period.
•
Confirm whether the participant’s parent(s)/legal guardian(s) still possesses the 
participant contact card. Provide a participant contact card if needed.
•
Remind the participant’s parent(s)/legal guardian(s) that the use of prophylactic 
antipyretic/pain medication, while permitted, is not recommended on the day of 
investigational product administration (before or after vaccination).
•
The investigator or an authorized designees completes the CRF and the source documents 
and updates the investigational product accountability records.
•
The investigator or appropriately qualified designee reviews the e-diary data online at 
frequent intervals for the 7 days following vaccination to evaluate participant compliance 
and as part of the ongoing safety review.
8.11.6. Visit 6 (Dose 4 Follow-up Visit, 28 to 42 Days After Visit 5 [Dose 4])
•
Ensure and document that the participant continues to be eligible for the study (see 
Section 7.2 for participant discontinuation/withdrawal) and none of the temporary delay 
criteria are met (Section 5.5).
•
Record nonstudy vaccinations administered since Visit 5, as described in Section 6.5.
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•
Review the participant’s e-diary data with the participant’s parent(s)/legal guardian(s); 
collect stop dates of any e-diary events ongoing on the last day that the e-diary was 
completed and record stop dates in the CRF.
•
Collect the e-diary (if device provided).
•
Determine whether any AEs (includes nonserious AEs, SAEs, and NDCMCs) have 
occurred since the previous visit and follow up on any previously reported events to 
determine the outcome (ie, record stop dates or confirm if they are still continuing) and 
record as described in Section 10.3, and record concomitant medications used to treat 
NDCMCs and SAEs.
•
Collect a blood sample of approximately 5 mL for immunogenicity (a topical anesthetic 
is permitted).
•
The investigator or an authorized designee completes the CRF and the source documents.
8.11.7. Unscheduled Visits
If the participant’s parent(s)/legal guardian(s) reports redness or swelling at the injection site 
measuring >14 measuring device units (>7 cm), severe injection site pain, or a fever >40.0°C 
during the 7-day postvaccination period, a telephone contact must occur as soon as possible 
between the investigator or medically qualified designee and the participant’s parent(s)/legal 
guardian(s) to assess if an unscheduled investigator site visit is required.  Note that for a 
fever >40.0°C, the participant’s parent(s)/legal guardian(s) should be instructed not to delay 
seeking medical care, as appropriate, while arranging for an unscheduled visit if applicable.  
A 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’s parent(s)/legal guardian(s) is unable to bring the participant to the 
unscheduled visit.
•
The reaction is no longer present at the time of the telephone contact.
•
The participant’s parent(s)/legal guardian(s) recorded an incorrect value in the e-diary 
(confirmation of an e-diary data entry error).
•
The principal investigator (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’s parent(s)/legal guardian(s) is unable to bring the participant to an 
unscheduled visit, or the PI or authorized designee determined it was not needed, any 
ongoing reactions must be assessed at the next study visit.
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During the investigator site 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 axillary temperature (°C).
•
Measure minimum and maximum diameters of redness (if present).
•
Measure minimum and maximum diameters of swelling (if present).
•
Assess injection site pain in accordance with the grades provided in Section 8.2.2
(if present).
•
Assess 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.
The participant’s parent(s)/legal guardian(s) will also be instructed to contact investigator site 
staff if the participant experiences any emergency room visit or hospitalization for decreased 
appetite, drowsiness/increased sleep, irritability, or local reaction within 7 days of 
vaccination.
The participant’s parent(s)/legal guardian(s) will also be instructed to contact the investigator 
site to report any significant illness, medical event, or hospitalization that occurs during the 
study period.  The investigator site should determine if an unscheduled visit to further 
evaluate the event is warranted in all such cases.
Additionally, study staff may contact the participant’s parent(s)/legal guardian(s) to obtain 
additional information on Grade 3 events entered into the e-diary.
9. STATISTICAL CONSIDERATIONS
Methodology for summary and statistical analyses of the data collected in this study is 
described here and further detailed in a SAP, which will be maintained by the sponsor.  The 
SAP may modify what is outlined in the protocol where appropriate; however, any major 
modifications of the primary endpoint definitions or their analyses will also be reflected in a 
protocol amendment.
9.1. Estimands and Statistical Hypotheses
9.1.1. Estimands
The estimands corresponding to each of the primary, secondary 
 objectives is 
described in the table in Section 3.  The estimands to evaluate the immunogenicity objectives 
for noninferiority are based on evaluable populations (Section 9.3). These estimands 
estimate the vaccine effect in the hypothetical setting where participants follow the study 
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schedules and protocol requirements as directed.  The estimand addresses the objective of 
estimating the maximum potential difference between the 2 compared groups, since the 
impact of noncompliance is likely to diminish the observed difference between the 2 groups.  
Missing serology results will not be imputed.  Immunogenicity results that are below the 
LLOQ will be set to 0.5 x LLOQ in the analysis.
In the primary safety objective evaluations, missing e-diary data will not be imputed.
Missing AE dates will be imputed according to Pfizer safety rules.  No other missing 
information will be imputed in the safety analysis.
9.1.2. Statistical Hypotheses
Noninferiority of the immune response at 1 month after Dose 3 for each serotype in 20vPnC 
is evaluated by the percentage of participants with predefined pneumococcal 
serotype-specific IgG concentrations based on results from the 20vPnC SC group and the 
13vPnC SC group as below.  The noninferiority for the immune response at 1 month after 
Dose 3 for a serotype will be declared if the null hypotheses (H0) is rejected at the 0.05 level.
9.1.2.1. Noninferiority Comparing Percentage of Participants with Predefined 
Pneumococcal Serotype-Specific IgG Concentrations 1 Month after Dose 3 (Primary 
Endpoint)
Hypothesis testing will be used to assess noninferiority of 20vPnC SC to 13vPnC SC by the 
percentage of participants with predefined pneumococcal serotype-specific IgG 
concentrations 1 month after Dose 3.  The null hypothesis (H0A) for each serotype is
H0A: π20vPnC SC – π13vPnC SC ≤-10%,
with a 10% margin for noninferiority, where
•
π20vPnC SC is the percentage of participants achieving an IgG antibody concentration of a 
predetermined level in the 20vPnC SC group from the serotype 1 month after Dose 3;
•
If the serotype is from the 13 matched serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 
19F, 23F), π13vPnC SC is the percentage of participants achieving a predefined IgG 
concentration level for the serotype from the 13vPnC SC group 1 month after Dose 3;
•
If the serotype is from the 7 additional serotypes (8, 10A, 11A, 12F, 15B, 22F, 33F) in 
20vPnC, π13vPnC SC is the percentage of participants achieving a predefined IgG 
concentration level from the serotype with the lowest percentage 1 month after Dose 3 
among the 13 serotypes from the 13vPnC SC group, provided that the lowest percentage is 
not from serotype 3.  If the lowest percentage in the 13vPnC SC group is from serotype 3, 
the next lowest percentage in the 13vPnC SC group will be used in the comparison. 
Historical data suggest that serotype 3 behaves somewhat differently from the other 
serotypes in 13vPnC; therefore, IgG results from serotype 3 will not be used in the 
comparison to assess the noninferiority of the 7 additional serotypes.
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•
The predefined levels for serotype-specific IgG concentrations are 0.35 μg/mL for all 
serotypes in 20vPnC except that the predefined levels are 0.23 μg/mL, 0.10 μg/mL, and 
0.12 μg/mL for serotypes 5, 6B, and 19A, respectively.
The null hypothesis H0A will be rejected and noninferiority of 20vPnC SC to 13vPnC SC for 
the percentage of participants with predefined IgG concentration level will be declared for a 
serotype if the lower bound of the 2-sided 95% CI for the difference (20vPnC SC group –
13vPnC SC group) in percentages, computed using the Miettinen and Nurminen method, is 
greater than –10% (10% noninferiority margin).
9.1.2.2. Noninferiority Comparing Pneumococcal Serotype-Specific IgG Concentrations
1 Month after Dose 3 (Secondary Endpoint)
Hypothesis testing will be used to assess noninferiority of 20vPnC SC to 13vPnC SC for
pneumococcal serotype-specific IgG GMCs 1 month after Dose 3. The null hypothesis (H0B) 
for each serotype is
H0B: ln(μ20vPnC SC) – ln(μ13vPnC SC) ≤ln(0.5)
where ln(0.5) corresponds to a 2-fold margin for noninferiority and
•
ln(μ20vPnC SC) is the natural log of the IgG GMC in the 20vPnC SC group for that serotype
1 month after Dose 3;
•
If the serotype is from the 13 matched serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 
19F, 23F), ln(μ13vPnC SC) is the natural log of the IgG GMC in the 13vPnC SC group 1 
month after Dose 3;
•
If the serotype is from the 7 additional serotypes (8, 10A, 11A, 12F, 15B, 22F, 33F) in 
20vPnC, ln(μ13vPnC SC) is the natural log of the IgG GMC for the serotype with the lowest 
IgG GMC 1 month after Dose 3 among the 13 serotypes from the 13vPnC SC group, 
provided that the lowest GMC is not from serotype 3. If the lowest GMC in the 13vPnC 
SC group is from serotype 3, the next lowest GMC in the 13vPnC SC group will be used 
in the comparison. As stated in Section 9.1.2.1, historical data suggest that serotype 3 
behaves somewhat differently from the other serotypes in 13vPnC; therefore, IgG results 
from serotype 3 will not be used in the comparison to assess the noninferiority of the 7 
additional serotypes.
The null hypothesis H0B will be rejected and noninferiority of 20vPnC SC to 13vPnC SC for 
the serotype-specific IgG GMC will be declared for a serotype if the lower bound of the 
2-sided 95% CI for GMR of serotype-specific IgG GMCs (20vPnC SC group over 13vPnC 
SC group) is greater than 0.5 (2-fold margin).
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9.1.3. Multiplicity Considerations
For the primary immunogenicity objectives comparing serotype-specific IgG concentrations 
from 20vPnC SC group to the13vPnC SC group, noninferiority of the immune response for 
each serotype is assessed by the hypothesis tests as described in Section 9.1.2.1. 
The hypothesis is tested at an alpha level of 0.05 for the comparison of percentage of 
participants with the predefined threshold. The primary pneumococcal immunogenicity 
objective will be achieved if the noninferiority of the immune response induced by 20vPnC 
SC group compared to 13vPnC SC group at 1 month after Dose 3 is established for all 
20 serotypes. Therefore, the overall type I error rate for the primary immunogenicity 
assessment of the pneumococcal immune response is well controlled at the 0.05 level.
9.2. Sample Size Determination
9.2.1. Sample size Considerations for 20vPnC SC Group and 13vPnC SC Group
Sample size and power for the primary immunogenicity objective are based on simulations of 
multivariate log-normal distributed random numbers with assumptions supported by IgG 
results from historical 13vPnC infant
 
 
 
 
 With 200 evaluable participants in each group (Table 6), the power to
demonstrate noninferiority of 20vPnC to 13vPnC for all 20 serotypes comparing IgG results 
at 1 month after Dose 3 is approximately 92%, with NI for each serotype defined by the 
lower limit of the 2-sided 95% confidence interval for difference (20vPnC SC – 13vPnC SC) 
in percentages above -10%. To ensure 200 evaluable participants 1 month after Dose 3, 
222 participants will be randomized by assuming a dropout rate of about 10%.
 
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Table 6.
Sample Size and Power to Demonstrate Noninferiority Comparing 
Serotype-Specific IgG Concentrations From 20vPnC SC Group to 13vPnC 
SC Group with the Specified Criteria
Evaluable Sample Size per 
Group
Power (%) to Demonstrate Noninferiority of Serotype-Specific IgG 
Concentrations for all 20 Serotypesa
150
82
180
89
200
92
Note: Power is estimated by 5,000 simulations.
a.
Noninferiority for each serotype is defined by the lower bound of the 2-sided 95% CI for difference 
(20vPnC SC – 13vPnC SC) in percentage of participants with specified threshold above -10%, 
calculated with Miettinen and Nurminen method. 
 
 
 
 
 
 
 
 
 
 
 
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9.2.2. Sample Size Considerations for 20vPnC IM Group
The study size in the 20vPnC IM group is not based on any formal hypothesis test for any 
immunogenicity endpoint. All statistical analyses of immunogenicity results from 20vPnC 
IM group will be descriptive.
 
 
 
  
 
 
9.2.3. Sample Size Considerations for Safety Endpoints
From safety endpoints, the probabilities of observing at least 1 occurrence of any AE with a 
true incidence rate are displayed in Table 7.
Table 7.
Probability of Observing at Least 1 Event by Assumed True Incidence
Rates
Assumed True Incidence Rate
N=222
0.5%
67%
1.0%
89%
1.5%
97%
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9.3. Analysis Sets
For purposes of analysis, the following analysis sets are defined:
Population
Description
Enrolled 
All participants who have a signed ICD.
Randomized
All participants who are assigned a randomization number in the 
IWR system. 
Dose 3 evaluable 
immunogenicity
All eligible randomized participants who are ≥2 to ≤6 months of 
age at the first vaccination, receive the vaccines to which they are 
randomly assigned at the first 3 doses, have at least 1 valid and 
determinate immunogenicity results from 1 month after Dose 3 
visit (Visit 4), with blood sample collection within an appropriate 
window after Dose 3, have no other major protocol deviations as 
determined by the clinician. 
The Dose 3 evaluable immunogenicity population will be the 
primary population for the immunogenicity analyses.
Dose 4 evaluable 
immunogenicity
All eligible randomized participants who are ≥2 to ≤6 months of 
age at the first vaccination, receive all 4 randomized vaccines with 
Dose 4 received within the defined window (12 to 15 months of 
age [also at least 60 days after Dose 3]), have at least 1 valid and 
determinate immunogenicity results after Dose 4, have blood 
sample collection within an appropriate window after Dose 4, and 
have no other major protocol deviations as determined by the 
clinician.
 
 
 
 
Safety
All participants who receive at least 1 dose of the investigational 
product and have safety data after any vaccination.
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9.4. Statistical Analyses
The SAP will be developed and finalized before database lock for any of the planned analysis 
in Section 9.5.  The SAP will describe the participant populations to be included in 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, 
 
endpoints.
All CIs in the statistical analysis will be calculated as two-sided at 95% level.
9.4.1. Immunogenicity Analyses
The statistical analysis of immunogenicity results will be primarily based on the evaluable 
immunogenicity populations (primary immunogenicity population) as defined in Section 9.3.
 
Participants will be summarized according to the vaccine group to which they are 
randomized.  Missing serology data will not be imputed.
Endpoint
Statistical Analysis Methods
Primary 
immunogenicity
•
The difference of the percentage of participants with 
predefined pneumococcal serotype-specific IgG 
concentrations 1 month after Dose 3
For each of the 20 serotypes for 20vPnC SC and 13vPnC SC 
groups, between-group difference (20vPnC SC - 13vPnC SC) 
and the 2-sided 95% CI for the percentage of participants with 
predefined serotype-specific IgG concentrations 1 month after 
Dose 3 will be provided.  If a serotype is from the 13 matched 
serotypes, the percentage of participants with the predefined IgG 
level for the serotype in the 20vPnC SC group will be compared 
with the percentage for that serotype in the 13vPnC SC group. If 
a serotype is from the 7 additional serotypes, the percentage of 
participants with the predefined IgG level in the 20vPnC SC 
group will be compared with the lowest percentage among the 
13 serotypes from the 13vPnC SC group, provided that the 
lowest percentage is not from serotype 3. If the lowest 
percentage in the 13vPnC SC group is from serotype 3, the next 
lowest percentage in the 13vPnC group will be used in the 
comparison. 
The lower limit of the CI will be used in the hypothesis test for 
NI of 20vPnC to 13vPnC as detailed in Section 9.1.2.1.
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Endpoint
Statistical Analysis Methods
For each of the 20 serotypes for 20vPnC IM and 20vPnC SC 
groups, difference (20vPnC IM - 20vPnC SC) and the 2-sided 
95% CI for the percentage of participants with predefined 
serotype-specific IgG concentrations 1 month after Dose 3 will 
be provided. 
The Miettinen and Nurminen method will be used to derive the 
CI for the difference in percentages between vaccine groups. 
The analysis will be based on the Dose 3 evaluable 
immunogenicity population.  An additional analysis will be 
performed based on the Dose 3 all-available immunogenicity 
population if there is a large enough difference in sample size 
between the all-available immunogenicity population and the 
evaluable immunogenicity population.  Participants will be 
summarized according to the vaccine group to which they were 
randomized.  Missing serology data will not be imputed.
Secondary 
immunogenicity
•
GMRs of pneumococcal serotype-specific IgG 
concentrations 1 month after Dose 3
For each of the 20 serotypes, the GMR of 20vPnC SC to 
13vPnC SC at 1 month after Dose 3 will be provided. GMRs 
and their 2-sided 95% CIs will be derived by calculating 
differences in means and CIs on the natural log scale based on 
the Student’s t-distribution, then exponentiating the results. The 
difference in means, on the natural log scale, will be 20vPnC SC 
-13vPnC SC.
Hypothesis testing for noninferiority of 20vPnC SC to 13vPnC
SC will be performed as described in Section 9.1.2.2.
For each of the 20 serotypes, the GMR of 20vPnC IM to 
20vPnC SC at 1 month after Dose 3 will be provided.
•
GMCs of pneumococcal serotype-specific IgG 
concentrations 1 month after Dose 4
For each of the 20 serotypes, GMCs and 2-sided 95% CIs for 
pneumococcal serotype-specific IgG concentrations at 1 month 
after Dose 4 will be provided for each group. Geometric means 
and the associated 2-sided 95% CIs will be derived by 
calculating means and CIs on the natural log scale based on the 
Student’s t-distribution, and then exponentiating the results.
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Endpoint
Statistical Analysis Methods
•
Pneumococcal serotype-specific OPA GMTs
For each of the 20 serotypes, GMTs and 2-sided 95% CIs for 
pneumococcal serotype-specific OPA titers at 1 month after 
Dose 3, prior to Dose 4 and 1 month after Dose 4 in each group 
will be provided. Geometric means and the associated 2-sided 
CIs will be derived by calculating means and CIs on the natural 
log scale based on the Student’s t-distribution, then 
exponentiating the results.
•
Percentages of participants with predefined pneumococcal 
serotype-specific IgG concentrations 1 month after Dose 4
For each of the 20 serotypes, the percentage (and 2-sided 95% 
CI) of participants with the predefined serotype-specific IgG 
concentration level 1 month after Dose 4 will be provided for 
each vaccine group. The Clopper-Pearson method will be used 
to calculate the CIs.
•
GMFRs of pneumococcal serotype-specific IgG 
concentrations
For each of the 20 serotypes, GMFRs and 2-sided 95% CIs in 
serotype-specific IgG concentrations from 1 month after Dose 3 
to before Dose 4, from before Dose 4 to 1 month after Dose 4, 
and from 1 month after Dose 3 to 1 month after Dose 4 will be 
provided for each vaccine group. GMFRs will be limited to 
participants with nonmissing values at both time points. The 
GMFR will be calculated as the mean of the difference of 
logarithmically transformed assay results (later time point –
earlier time point) and transformed back to the original scale.
Two-sided 95% CIs will be obtained by calculating CIs using 
Student’s t-distribution for the mean difference of the 
logarithmically transformed assay results and transforming the 
limits back to the original scale.
 
 
 
 
 
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Endpoint
Statistical Analysis Methods
 
 
 
 
 
 
 
 
•
 
 
 
 
 
 
 
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9.4.2. Safety Analyses
Endpoint
Statistical Analysis Methods
Primary 
•
Descriptive statistics will be provided for each reactogenicity 
endpoint for each dose and vaccine group. Local reactions and 
systemic events from Day 1 through Day 7 after each 
vaccination will be presented by severity cumulatively across 
severity levels. Descriptive summary statistics will include 
counts and percentages of participants with the indicated 
endpoint and the associated Clopper-Pearson 95% CIs. 
Between-group differences (20vPnC SC – 13vPnC SC and 
20vPnC IM – 20vPnC SC) in percentage and 2-sided 95% CIs 
will be provided.  The Miettinen and Nurminen method will be 
used to derive the 95% CI for the difference in percentages 
between vaccine groups.
•
AEs will be categorized according to Medical Dictionary for 
Regulatory Activities (MedDRA) terms. A 3-tier approach will 
be used to summarize AEs. Under this approach AEs are 
classified into 1 of 3 tiers: (1) Tier 1 events are prespecified 
events of clinical importance and are identified in a list in the 
product’s safety review plan; (2) Tier 2 events are those that are 
not Tier 1 but are considered “relatively common”; a MedDRA 
preferred term is defined as a Tier 2 event if there are at least 4 
of participants in at least 1 vaccine group reporting the event; 
and (3) Tier 3 events are those that are neither Tier 1 nor Tier 2 
events. For both Tier 1 and Tier 2 events, the 95% CIs for the 
difference in percentage of participants reporting the events 
between 20vPnC SC and 13vPnC SC groups, or 20vPnC IM and 
20vPnC SC groups will be calculated using the Miettinen and 
Nurminen’s method. In addition, for Tier 1 events, the 
asymptotic p-values will also be presented for the difference in 
percentage of participants reporting the events, based on the 
same test statistic and under the assumption that the test statistic 
is asymptotically normally distributed. There is no Tier 1 event 
identified for 20vPnC at this stage. Descriptive summary 
statistics (counts and percentages and associated Clopper-
Pearson 95% CIs) will be provided for Tier 3 events for each 
vaccine group.
•
SAEs and NDCMCs will be categorized according to MedDRA 
terms. Counts, percentages and the associated Clopper-Pearson 
95% CIs of SAEs and NDCMCs from Dose 1 to 1 month after 
Dose 4 will be provided for each vaccine group.
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Endpoint
Statistical Analysis Methods
•
The safety analyses are based on the safety population. 
Participant data will be summarized by vaccine group according 
to the investigational products they actually received. Missing e-
diary data will not be imputed; missing AE dates will be 
handled according to the Pfizer safety rules.
Secondary
•
Not applicable (N/A)
9.5. Interim Analyses
No interim analysis is planned in this study.  Statistical analyses will be carried out when the 
final data for the specified analyses are available.
 
 
 
  
 
 
 
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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 and 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.
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 guidelines, the IRB/EC, European regulation 536/2014 for clinical 
studies (if applicable), 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. 
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 ICH GCP that the investigator becomes aware 
of.
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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 his/her representative will explain the nature of the study to the 
participant’s parent(s)/legal guardian(s) and answer all questions regarding the study.  The 
participant’s parent(s)/legal guardian(s) should be given sufficient time and opportunity to 
ask questions and to decide whether or not to participate in the trial.
The participant’s parent(s)/legal guardian(s) must be informed that their participation is 
voluntary.  The participant’s parent(s)/legal guardian(s) will be required to sign a statement 
of informed consent that meets the requirements of 21 CFR 50, local regulations, ICH 
guidelines, Health Insurance Portability and Accountability Act (HIPAA) requirements, 
where applicable, and the IRB/EC or study center.
The investigator must ensure that each study participant’s parent(s)/legal guardian(s) 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’s parent(s)/legal guardian(s) must be informed that the participant’s 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’s parent(s)/legal guardian(s).
The participant’s parent(s)/legal guardian(s) must be informed that the participant’s 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’s parent(s)/legal guardian(s) 
is fully informed about his or her right to access and correct the participant’s personal data 
and to withdraw consent for the processing of the participant’s 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 the written consent was obtained.  
The authorized person obtaining the informed consent must also sign the ICD.
The participant’s parent(s)/legal guardian(s) must be reconsented to the most current version 
of the ICD(s) during the participant’s participation in the study.
A copy of the ICD(s) must be provided to the participant’s parent(s)/legal guardian(s).
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Unless prohibited by local requirements or IRB/EC decision, the ICD will contain a separate 
section that addresses the use of samples for optional additional research.  The optional 
additional research does not require the collection of any further samples.  The investigator 
or authorized designee will explain to the participant’s parent(s)/legal guardian(s) the 
objectives of the additional research.  The participants parent(s)/legal guardian(s) will be told 
that they are free to refuse to participate and may withdraw their consent at any time and for 
any reason during the storage period.
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 shall 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 natural persons 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 his or her actual identity and medical record.  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.
10.1.5. 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), EudraCT, and/or 
www.pfizer.com, and other public registries 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.
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, 
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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
Pfizer posts clinical trial results on EudraCT for Pfizer-sponsored interventional studies in 
accordance with the format and timelines set forth by EU requirements.
www.pfizer.com
Pfizer posts public disclosure synopses (CSR synopses in which any data that could be used 
to identify individual participants have been removed) on www.pfizer.com for Pfizer-
sponsored interventional studies at the same time the corresponding study results are posted 
to www.clinicaltrials.gov.
Documents within marketing authorization packages/submissions
Pfizer complies with the European Union Policy 0070, the proactive publication of clinical 
data to the EMA website.  Clinical data, under Phase 1 of this policy, includes clinical 
overviews, clinical summaries, CSRs, and appendices containing the protocol and protocol 
amendments, sample CRFs, and statistical methods.  Clinical data, under Phase 2 of this 
policy, includes the publishing of individual participant data.  Policy 0070 applies to new 
marketing authorization applications submitted via the centralized procedure since 
01 January 2015 and applications for line extensions and for new indications submitted via 
the centralized procedure since 01 July 2015.
Data Sharing
Pfizer provides researchers secure access to patient-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 available data from these trials 
24 months after study completion.  Patient-level data will be anonymized in accordance with 
applicable privacy laws and regulations.  CSRs will have personally identifiable information 
redacted.
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.
10.1.6. 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.
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The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
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.
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 (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, remote, or on-site monitoring), are provided in the 
monitoring plan.
The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data.
Study monitors will perform ongoing source data verification 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, and all applicable regulatory requirements.
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 
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 
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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.
10.1.7. 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 transcribed 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.
Definition of what constitutes source data can be found in the ISF.
Description of the use of computerized system is documented in the Data Management Plan.
10.1.8. 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.  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 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 
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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.
10.1.9. Publication Policy
The results of this study may be published or presented at scientific meetings by the 
investigator after publication of the overall study results or 1 year after the end of the study 
(or study termination), whichever comes first. 
The investigator agrees to refer to the primary publication in any subsequent publications 
such as secondary manuscripts, and submits all manuscripts or abstracts to the sponsor 
30 days before submission.  This allows the sponsor 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- or Pfizer 
intervention-related information necessary for the appropriate scientific presentation or 
understanding of the study results.
For all publications relating to the study, the investigator will comply with recognized ethical 
standards concerning publications and authorship, including those established by the 
International Committee of Medical Journal Editors.
The sponsor will comply with the requirements for publication of the overall study results 
covering all investigator sites.  In accordance with standard editorial and ethical practice, the 
sponsor will support publication of multicenter studies only in their entirety and not as 
individual site data.  In this case, a coordinating investigator will be designated by mutual 
agreement.
Authorship of publications for the overall study results will be determined by mutual 
agreement and in line with International Committee of Medical Journal Editors authorship 
requirements. 
If publication is addressed in the clinical study agreement, the publication policy set out in 
this section will not apply.
10.1.10. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the ISF.  
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, the participant’s parent(s)/legal guardian(s) are provided with a 
contact card at the time of informed consent.  The contact card contains, at a minimum, 
protocol and study intervention identifiers, participant numbers, contact information for the 
investigator site, and contact details for a contact center in the event that the investigator site 
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staff cannot be reached to provide advice on a medical question or problem originating from 
another healthcare professional not involved in the participant’s participation in the study.  
The contact number can also be used by investigator staff if they are seeking advice on 
medical questions or problems; however, it should be used only in the event that the 
established communication pathways between the investigator site and the study team are not 
available.  It is therefore intended to augment, but not replace, the established communication 
pathways between the investigator site and the study team for advice on medical questions or 
problems that may arise during the study.  The contact number is not intended for use by the 
participant’s parent(s)/legal guardian(s) directly, and if a participant’s parent(s)/legal 
guardian(s) calls that number, he or she will be directed back to the investigator site.
10.2. Appendix 2: Clinical Laboratory Tests
Not applicable.
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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 either an 
increase in frequency and/or intensity of the condition.
•
New conditions 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/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
•
Events that, in the clinical judgement of the investigator, are 1) consistent with normal 
growth and development and 2) do not differ significantly in frequency or severity 
from expected, are not generally to be considered adverse events. Examples may 
include, but are not limited to, teething, contact diaper rash, spitting up, colic, or 
typical fussiness/crying in infants and children.
•
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which 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 SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, death 
due to progression of disease).
An SAE is defined as any untoward medical occurrence that, at any dose:
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 detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
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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.
d. Results in persistent 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) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:
•
Medical or scientific judgment should be exercised in deciding whether SAE reporting 
is appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but 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.
•
Suspected transmission via a Pfizer product of an infectious agent, pathogenic or non-
pathogenic, is considered serious.  The event may be suspected from clinical symptoms 
or laboratory findings indicating an infection in a patient 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.
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10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording adverse events on the CRF
and for reporting serious adverse events on the Vaccine SAE Reporting Form to Pfizer 
Safety.  These requirements are delineated for 3 types of events: (1) SAEs; (2) nonserious 
adverse events (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, and 
occupational exposure
All AEs/SAEs associated 
with exposure during 
pregnancy or breastfeeding
Occupational exposure is 
not recorded.
All (and EDP supplemental 
form for EDP)  
Note:  Include all SAEs 
associated with exposure 
during pregnancy or 
breastfeeding. Include all 
AEs/SAEs associated with 
occupational exposure.
•
When an AE/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/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/SAE CRF page.
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•
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/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: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities.
•
Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.
•
Severe: An event that prevents normal everyday activities.  An AE that is assessed
as severe should not be confused with an SAE.  Severe is a category utilized for 
rating the intensity of an event; and both AEs and SAEs can be assessed as severe.
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.
GRADE If required on the AE page of the CRF, the investigator will use the 
adjectives MILD, MODERATE, or 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.
3
SEVERE
Interferes significantly with participant's usual 
function.
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Assessment of Causality
•
The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE.
•
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.
•
The investigator will use clinical judgment to determine the relationship.
•
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 his/her assessment.
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has 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 his/her 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 completed CRF.
•
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 Data Collection Tool
•
The primary mechanism for reporting an SAE to Pfizer Safety will be the electronic 
data collection tool.
•
If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.
•
The site will enter the SAE data into the electronic system as soon as the data become 
available.
•
After the study is completed at a given site, the electronic data collection tool 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 data collection tool 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 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, 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.
10.3.5. Definition of NDCMC
A NDCMC is defined as a significant disease or medical condition, not previously identified, 
that is expected to be persistent or is otherwise long-lasting in its effects.
10.5. Appendix 5: Genetics
Not applicable.
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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 an “adaptor” 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 TBili elevations 
(>2 × ULN) by several days or weeks.  The increase in TBili typically occurs while 
AST/ALT is/are still elevated above 3 × ULN (ie, AST/ALT and TBili values will be 
elevated within the same laboratory sample).  In rare instances, by the time TBili 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 TBili 
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 TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili 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 TBili 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 TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches >3 × ULN 
(whichever is smaller).
Rises in AST/ALT and TBili 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 TBili for suspected cases of 
Hy’s law, 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, 
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 and 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 
TBili 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.
10.7. Appendix 7: ECG Findings of Potential Clinical Concern
Not applicable.
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10.8. Appendix 8: Medical Device Adverse Events, Adverse Device Effects, Serious 
Adverse Events, and Device Deficiencies: Definition and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
Definitions of a Medical Device Incident
The definitions and procedures detailed in this appendix are in accordance with ISO 14155. 
Both the investigator and the sponsor will comply with all local medical device reporting 
requirements.
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 as any untoward medical occurrence, unintended disease or 
injury, or untoward clinical signs (including abnormal laboratory finding) in study 
participants, users, or other persons, whether or not related to the investigational 
medical device.  This definition includes events related to the investigational 
medical device or comparator for study participants, users, and other persons.  This 
definition also includes events considered related to the procedures for study 
participants only.
•
An ADE is defined as an adverse event related to the use of an investigational 
medical device.  This definition includes any adverse events 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 Unanticipated Serious Adverse Device Effect
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, death 
due to progression of disease).
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An SAE is an AE that:
a.
Led to death. 
b. Led to serious deterioration in the health of the participant, that either resulted in:
•
A life-threatening illness or injury.  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.
•
A permanent impairment of a body structure or a body function.
•
Inpatient or prolonged hospitalization.  Planned hospitalization for a preexisting 
condition, or a procedure required by the protocol, without serious deterioration in 
health, is not considered an SAE.
•
Medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function.
c.
Led to fetal distress, fetal death, or a congenital abnormality or birth defect.
SADE Definition
•
An SADE is defined as an adverse device effect that has resulted in any of the 
consequences characteristic of a serious adverse event.
USADE Definition
•
A USADE is a serious adverse device effect which 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 labeling.
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10.8.4. Recording/Reporting and Follow-up of AEs and/or SAEs and Device 
Deficiencies
AE, SAE, and Device Deficiency Recording
•
When an AE/SAE/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 AE/SAE/device deficiency 
information in the participant’s medical records, in accordance with the 
investigator’s normal clinical practice and on the appropriate form of the CRF.
•
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 IP Manual and completing the Medical Device Complaint CRF.
•
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/SAE.
•
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 Intensity
The investigator will make an assessment of intensity for each AE/SAE/device deficiency 
reported during the study and assign it to 1 of the following categories: 
•
Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities.
•
Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.
•
Severe: An event that prevents normal everyday activities.  An AE that is assessed 
as severe should not be confused with an SAE.  Severe is a category utilized for 
rating the intensity of an event; and both AEs and SAEs can be assessed as severe.
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•
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/SAE/device deficiency.
•
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.
•
The investigator will use clinical judgment to determine the relationship.
•
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 his/her assessment.
•
For each AE/SAE/device deficiency, the investigator must document in the 
medical notes that he/she has reviewed the AE/SAE/device deficiency and has 
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 his/her 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.
Follow-up of AE/SAE/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 AE/SAE/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 will be recorded in the originally completed CRF.
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•
The investigator will submit any updated SAE data to the sponsor within 24 hours 
of receipt of the information.
10.8.5. Reporting of SAEs
SAE Reporting to Pfizer Safety via an Electronic Data Collection Tool
•
The primary mechanism for reporting an SAE to Pfizer Safety will be the 
electronic data collection tool.
•
If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.
•
The site will enter the SAE data into the electronic system as soon as the data 
become available.
•
After the study is completed at a given site, the electronic data collection tool 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 data collection tool 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.
SAE Reporting to Pfizer Safety via 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, 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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10.8.6. Reporting of SADEs
SADE Reporting to Pfizer Safety
NOTE: There are additional reporting obligations for medical device incidents that are 
potentially related to SAEs 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.
10.9. Appendix 9: Country-Specific Requirements
Not applicable.
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10.10. Appendix 10: Abbreviations
The following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
7vPnC
7-valent pneumococcal conjugate vaccine
13vPnC
13-valent pneumococcal conjugate vaccine
20vPnC
20-valent pneumococcal conjugate vaccine
ADE
adverse device effect
AE
adverse event
ALT
alanine aminotransferase
AOM
acute otitis media
AST
aspartate aminotransferase
CAP
community-acquired pneumonia
CBER
Center for Biologics Evaluation and Research
CDC
Centers for Disease Control and Prevention
CFR
Code of Federal Regulations
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
CONSORT
Consolidated Standards of Reporting Trials
CRA
clinical research association
CRF
case report form
CRM197
cross-reactive material 197
CRO
contract research organization
CSAP
clinical specimen analysis plan
CSR
clinical study report
CT
clinical trial
DILI
drug-induced liver injury
DTaP
diphtheria, tetanus, and acellular pertussis
DU
dispensable unit
EC
ethics committee
ECDC
European Centre for Disease Prevention and Control
ECG
electrocardiogram
eCRF
electronic case report form
e-diary
electronic diary
 
EDP
exposure during pregnancy
EMA
European Medicines Agency
EU
European Union
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
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Abbreviation
Term
GMC
geometric mean concentration
GMFR
geometric mean fold rise
GMR
geometric mean ratio
GMT
geometric mean titer
Hib
Haemophilus influenzae type b
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
IB
investigator’s brochure
ICD
informed consent document
ICH
International Council for Harmonisation
ID
identification
IgG
immunoglobulin G
IM
intramuscular
IND
investigational new drug application
INR
international normalized ratio
IPAL
investigational product accountability log
IP manual
investigational product manual
IPD
invasive pneumococcal disease
IRB
institutional review board
IRT
interactive response technology
ISF
investigator site file
ISO
International Organization for Standardization
IU
international units
IWR
interactive Web-based response
LFT
liver function test
LLOQ
lower limit of quantitation
MedDRA
Medical Dictionary for Regulatory Activities
MR
measles and rubella vaccine
N/A
not applicable
NDCMC
newly diagnosed chronic medical condition
NI
noninferiority
NIP
national immunization program
NVT
non-vaccine serotypes
OPA
opsonophagocytic activity
PI
principal investigator
PPSV23
23-valent pneumococcal polysaccharide vaccine
SADE
serious adverse device effect
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
SoA
schedule of activities
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Abbreviation
Term
SOP
standard operating procedure
SRSD
single reference safety document
SUSAR
suspected unexpected serious adverse reaction
TBili
total bilirubin
ULN
upper limit of normal
US
United States
USADE
unanticipated serious adverse device effect
VT
vaccine-type
WHO
World Health Organization
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23
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Torres A, Bonanni P, Hryniewicz W, et al. Pneumococcal vaccination: what have we 
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Robinson KA, Baughman W, Rothrock G, et al. Epidemiology of invasive 
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