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

20-valent Pneumococcal Conjugate Vaccine (20vPnC)
Protocol B7471011
Final Protocol Amendment 2, 01 April 2022
PFIZER CONFIDENTIAL
Page 1
A PHASE 3, RANDOMIZED, DOUBLE-BLIND TRIAL TO EVALUATE THE 
SAFETY AND IMMUNOGENICITY OF A 20-VALENT PNEUMOCOCCAL 
CONJUGATE VACCINE IN HEALTHY INFANTS
Investigational Product Number:
PF-06482077
Investigational Product Name:
20-valent pneumococcal conjugate vaccine 
(20vPnC)
United States (US) Investigational New 
Drug (IND) Number:
European Clinical Trials Database 
(EudraCT) Number:
Protocol Number:
B7471011
Phase:
3
Short Title: 20-valent Pneumococcal Conjugate Vaccine Safety and Immunogenicity Study 
in Healthy Infants
 
 
 
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20-valent Pneumococcal Conjugate Vaccine (20vPnC)
Protocol B7471011
Final Protocol Amendment 2, 01 April 2022
PFIZER CONFIDENTIAL
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Protocol Amendment Summary of Changes Table
Document History
Document
Version Date
Summary of Changes and Rationale
Amendment 2
01 April 2022
Section 1.3: Addition of text clarifying changes to Visits 5, 6,
and 7, including relevant calendar dates.
Section 2.1: Addition of text describing the rationale for changes 
to the protocol.
Section 4.1: Addition of text describing changes to the overall 
design.
Section 6.3.2: Changed the timing for unblinding of sponsor 
personnel from 1 month after Dose 3 to 1 month after Dose 4.
Section 7.2: Addition of text describing follow-up for 
participants discontinued prior to completing all 4 doses of study 
intervention.
Section 8.10.5: Addition of text specifying the end date for 
Visit 5. Addition of guidance for discontinuation of participants 
after that date.
Section 8.10.6: Addition of text specifying the latest date for 
Visit 6 blood collection. Added a contingency to conduct this 
visit by phone after the cutoff date.
Section 8.10.7: Addition of text specifying the latest date for 
Visit 7, and modifying study visit windows based on the 
calendar date of the last vaccine dose.
Section 9.5.1: Detailed changes to the analysis timing, as the 
analyses of Doses 3 and 4 are now being done together.
Amendment 1
23 April 2020
Section 1: Update of wording to the Objectives, Estimands, and 
Endpoints and Statistical Methods.  The primary objective to 
compare IgG GMCs at the time point 1 month after the third
dose has been changed to a key secondary endpoint.  Added 
additional wording to the objectives for clarification.
Section 3: Update of wording to the Objectives, Estimands, and 
Endpoints.  The primary objectives to compare IgG GMCs at the 
time point 1 month after the third dose have been changed to key 
secondary endpoints.  Added additional wording to the 
objectives for clarification.
Section 9: Update of wording throughout the section  
(in particular Sections 9.1.2.1, 9.1.3, 9.2.1, and 9.4.1) to reflect
that the primary objective to compare IgG GMCs at the time 
point 1 month after the third dose has been changed to a key 
secondary endpoint.

20-valent Pneumococcal Conjugate Vaccine (20vPnC)
Protocol B7471011
Final Protocol Amendment 2, 01 April 2022
PFIZER CONFIDENTIAL
Page 3
Document History
Document
Version Date
Summary of Changes and Rationale
Section 6.1.2, Section 8.3.6, Section 10.1.5, and Section 10.8: 
Mandatory protocol template text updates.
Original protocol
19 February 2020
Not applicable (N/A)
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and IRBs/ECs.

20-valent Pneumococcal Conjugate Vaccine (20vPnC)
Protocol B7471011
Final Protocol Amendment 2, 01 April 2022
PFIZER CONFIDENTIAL
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................8
1. PROTOCOL SUMMARY...................................................................................................10
1.1. Synopsis ..................................................................................................................10
1.2. Schema ....................................................................................................................16
1.3. Schedule of Activities (SoA)...................................................................................17
2. INTRODUCTION ...............................................................................................................20
2.1. Study Rationale .......................................................................................................24
2.2. Background .............................................................................................................24
2.2.1. Clinical Overview.......................................................................................25
2.3. Benefit/Risk Assessment.........................................................................................25
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS ...........................................................27
4. STUDY DESIGN.................................................................................................................32
4.1. Overall Design.........................................................................................................32
4.1.1. Approximate Duration of Participation for Each Participant .....................34
4.1.2. Approximate Number of Participants.........................................................34
4.2. Scientific Rationale for Study Design.....................................................................34
4.3. Justification for Dose ..............................................................................................34
4.4. End of Study Definition ..........................................................................................35
5. STUDY POPULATION......................................................................................................35
5.1. Inclusion Criteria.....................................................................................................35
5.2. Exclusion Criteria....................................................................................................36
5.3. Lifestyle Considerations..........................................................................................37
5.4. Screen Failures ........................................................................................................37
5.5. Temporary Delay Criteria .......................................................................................38
5.5.1. Criteria for Temporarily Delaying Vaccine Administration ......................38
5.5.2. Criteria for Temporarily Delaying Immunogenicity Blood Draw..............38
6. STUDY INTERVENTION..................................................................................................38
6.1. Study Intervention(s) Administered........................................................................38
6.1.1. Administration............................................................................................39
6.1.2. Medical Devices .........................................................................................40

20-valent Pneumococcal Conjugate Vaccine (20vPnC)
Protocol B7471011
Final Protocol Amendment 2, 01 April 2022
PFIZER CONFIDENTIAL
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6.2. Preparation/Handling/Storage/Accountability ........................................................40
6.2.1. Preparation and Dispensing........................................................................42
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................42
6.3.1. Allocation to Investigational Product .........................................................42
6.3.2. Blinding of the Sponsor..............................................................................42
6.3.3. Breaking the Blind......................................................................................42
6.4. Study Intervention Compliance...............................................................................43
6.5. Concomitant Therapy..............................................................................................43
6.5.1. Prohibited Concomitant Vaccines and Treatments.....................................43
6.5.2. Permitted Concomitant Vaccines and Treatments......................................43
6.5.3. Recording Prior and Concomitant Vaccines and Treatments.....................44
6.6. Dose Modification...................................................................................................44
6.7. Intervention After the End of the Study..................................................................44
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................44
7.1. Discontinuation of Study Intervention ....................................................................44
7.2. Participant Discontinuation/Withdrawal From the Study.......................................44
7.3. Lost to Follow-up....................................................................................................46
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................46
8.1. Efficacy Assessments..............................................................................................47
8.1.1. Immunogenicity Assessments ....................................................................47
8.1.2. Biological Samples.....................................................................................49
8.2. Safety Assessments .................................................................................................49
8.2.1. Participant Electronic Diary .......................................................................50
8.2.2. Grading Scale for Prompted Events ...........................................................51
8.2.2.1. Local Reactions.........................................................................51
8.2.2.2. Systemic Events (Systemic Symptoms and Fever)...................52
8.2.2.3. Use of Antipyretic/Pain Medication..........................................54
8.2.3. Clinical Safety Laboratory Assessments ....................................................54
8.3. Adverse Events and Serious Adverse Events..........................................................54
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......54
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................55

20-valent Pneumococcal Conjugate Vaccine (20vPnC)
Protocol B7471011
Final Protocol Amendment 2, 01 April 2022
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8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................55
8.3.2. Method of Detecting AEs and SAEs ..........................................................55
8.3.3. Follow-up of AEs and SAEs.......................................................................55
8.3.4. Regulatory Reporting Requirements for SAEs...........................................56
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational 
Exposure ..........................................................................................................56
8.3.5.1. Exposure During Pregnancy......................................................56
8.3.5.2. Exposure During Breastfeeding ................................................57
8.3.5.3. Occupational Exposure .............................................................57
8.3.6. Medical Device Deficiencies......................................................................57
8.3.6.1. Time Period for Detecting Medical Device Deficiencies .........57
8.3.6.2. Follow-up of Medical Device Deficiencies...............................58
8.3.6.3. Prompt Reporting of Device Deficiencies to Sponsor ..............58
8.3.6.4. Regulatory Reporting Requirements for Medical Device 
Deficiencies .......................................................................................58
8.3.7. Medication Errors .......................................................................................58
8.4. Treatment of Overdose............................................................................................59
8.5. Pharmacokinetics ....................................................................................................60
8.6. Pharmacodynamics..................................................................................................60
8.7. Genetics...................................................................................................................60
8.8. Biomarkers ..............................................................................................................60
8.9. Health Economics ...................................................................................................60
8.10. Study Procedures...................................................................................................60
8.10.1. Visit 1 (Dose 1 Visit, Day 1) ....................................................................60
8.10.2. Visit 2 (Dose 2 Visit, 42 to 63 Days After Dose 1, ie, Study Day 43 
Through Study Day 64) ...................................................................................62
8.10.3. Visit 3 (Dose 3 Visit, 42 to 63 Days After Dose 2)..................................63
8.10.4. Visit 4 (Dose 3 Follow-up Visit, 28 to 42 Days After Dose 3) ................65
8.10.5. Visit 5 (Dose 4 Visit, 365 to 455 Days of Age)........................................65
8.10.6. Visit 6 (Dose 4 Follow-up Visit, 28 to 42 Days After Dose 4) ................67
8.10.7. Visit 7 (Dose 4 6-Month Visit, 168 to 196 Days After Dose 4)...............68
8.10.8. Unscheduled Visits...................................................................................68

20-valent Pneumococcal Conjugate Vaccine (20vPnC)
Protocol B7471011
Final Protocol Amendment 2, 01 April 2022
PFIZER CONFIDENTIAL
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9. STATISTICAL CONSIDERATIONS ................................................................................70
9.1. Estimands and Statistical Hypotheses.....................................................................70
9.1.1. Estimands....................................................................................................70
9.1.2. Statistical Hypotheses.................................................................................70
9.1.2.1. Pneumococcal Immunogenicity Hypotheses.............................70
9.1.2.2. Concomitant Immunogenicity Hypotheses ...............................72
9.1.3. Multiplicity Considerations ........................................................................73
9.2. Sample Size Determination.....................................................................................74
9.2.1. Sample Size Consideration for Primary Pneumococcal 
Immunogenicity Objectives.............................................................................74
9.2.2. Sample Size Consideration for Concomitant Immunogenicity 
Objectives ........................................................................................................76
9.3. Populations for Analysis .........................................................................................78
9.4. Statistical Analyses .................................................................................................78
9.4.1. Immunogenicity Analyses ..........................................................................78
9.4.2. Safety Analyses ..........................................................................................84
9.4.3. Other Analyses............................................................................................85
9.5. Interim Analyses .....................................................................................................85
9.5.1. Analysis Timing..........................................................................................86
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................87
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............87
10.1.1. Regulatory and Ethical Considerations ....................................................87
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................87
10.1.2. Financial Disclosure .................................................................................88
10.1.3. Informed Consent Process ........................................................................88
10.1.4. Data Protection .........................................................................................89
10.1.5. Dissemination of Clinical Study Data ......................................................89
10.1.6. Data Quality Assurance ............................................................................91
10.1.7. Source Documents....................................................................................92
10.1.8. Study and Site Closure..............................................................................92
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20-valent Pneumococcal Conjugate Vaccine (20vPnC)
Protocol B7471011
Final Protocol Amendment 2, 01 April 2022
PFIZER CONFIDENTIAL
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10.1.9. Publication Policy.....................................................................................93
10.1.10. Sponsor’s Qualified Medical Personnel .................................................93
10.2. Appendix 2: Clinical Laboratory Tests .................................................................94
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ......................................................................95
10.3.1. Definition of AE .......................................................................................95
10.3.2. Definition of an NDCMC.........................................................................96
10.3.3. Definition of SAE.....................................................................................96
10.3.4. Recording/Reporting and Follow-up of AEs and/or SAEs.......................98
10.3.5. Reporting of SAEs..................................................................................101
10.5. Appendix 5: Genetics..........................................................................................104
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments ......105
10.7. Appendix 7: ECG Findings of Potential Clinical Concern .................................106
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............................................107
10.8.1. Definition of AE and ADE .....................................................................107
10.8.2. Definition of SAE, SADE, and Unanticipated Serious Adverse 
Device Effect .................................................................................................107
10.8.3. Definition of Device Deficiency.............................................................108
10.8.4. Recording/Reporting and Follow-up of AEs and/or SAEs and 
Device Deficiencies .......................................................................................109
10.8.5. Reporting of SAEs..................................................................................111
10.8.6. Reporting of SADEs...............................................................................112
10.9. Appendix 9: Country-Specific Requirements .....................................................112
10.10. Appendix 10: Abbreviations .............................................................................113
11. REFERENCES ................................................................................................................116
LIST OF TABLES
Table 1.
Grading Scales for Local Reactions .........................................................51
Table 2.
Grading Scales for Systemic Event Symptoms ........................................53
Table 3.
Ranges for Fever.......................................................................................54
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20-valent Pneumococcal Conjugate Vaccine (20vPnC)
Protocol B7471011
Final Protocol Amendment 2, 01 April 2022
PFIZER CONFIDENTIAL
CT02-GSOP-RF04 6.0 Clinical Protocol Template Phase 1 2 3 4 (04 September 2018)
Page 9
 
Table 5.
Sample Size Required With Specified Power to Demonstrate NI 
Comparing the 20vPnC Group to the 13vPnC Group Based on 
Percentage of Participants With Prespecified Antibody Levels 1 
Month After Dose 3 for Concomitant Antigens, With an NI Margin 
of 10%.......................................................................................................76
Table 6.
Sample Size Required With Specified Power to Demonstrate NI 
Based on Ratio of GMCs 1 Month After Dose 4 for Concomitant 
Antigens, With a 2-Fold NI Margin .........................................................77
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20-valent Pneumococcal Conjugate Vaccine (20vPnC)
Protocol B7471011
Final Protocol Amendment 2, 01 April 2022
PFIZER CONFIDENTIAL
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1. PROTOCOL SUMMARY
1.1. Synopsis
Pfizer is developing a new 20-valent pneumococcal conjugate vaccine (20vPnC) candidate to 
expand protection against pneumococcal disease beyond that covered by current 
pneumococcal vaccines in children. 20vPnC has the same composition as 13-valent 
pneumococcal conjugate vaccine (13vPnC; Prevnar 13®/Prevenar 13®), but 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. Phase 2 safety and immunogenicity data in infants support 
further development of 20vPnC in the pediatric population.
This Phase 3, multicenter, randomized, double-blind study will be conducted at investigator 
sites in the United States and potentially other countries to be determined. 
 
 The purpose of this study is to describe safety and conduct the pivotal 
immunogenicity comparison of 20vPnC to the licensed pneumococcal conjugate vaccine, 
13vPnC, in infants to support licensure.
Approximately 2000 infants ≥42 to ≤98 days of age at the time of consent, by their 
parent(s)/legal guardian(s), will be enrolled into the study.  Participants will be randomized 
in a 1:1 ratio to receive either 20vPnC or 13vPnC (control vaccine) at 2, 4, 6, and 12 to 
15 months of age (Doses 1 [Visit 1], 2 [Visit 2], 3 [Visit 3], and 4 [Visit 5], respectively).  
Participants will receive the same vaccine (either 20vPnC or 13vPnC) for all 4 doses.
Specific vaccines containing diphtheria, tetanus, acellular pertussis, hepatitis B, poliovirus, 
and Haemophilus influenzae type b (Hib) vaccine antigens will be administered
concomitantly with Doses 1 to 3 (Visit 1, Visit 2, and Visit 3) into a limb other than the site 
of 20vPnC or 13vPnC injection. Specific vaccines containing measles, mumps, rubella, and 
varicella antigens will be administered concomitantly with Dose 4 (Visit 5) into a limb other 
than the site of 20vPnC or 13vPnC injection.
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 electronic diary (e-diary), device or application, from Day 1 through Day 7 after each 
vaccination (where Day 1 is the day of vaccination).
Adverse events (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). Serious adverse events (SAEs) and newly 
diagnosed chronic medical conditions (NDCMCs) will be collected from informed consent 
through 6 months after Dose 4 (Visit 7).
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.
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20-valent Pneumococcal Conjugate Vaccine (20vPnC)
Protocol B7471011
Final Protocol Amendment 2, 01 April 2022
PFIZER CONFIDENTIAL
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Objectives, Estimands, and Endpoints
Primary Safety Objective
Estimands
Primary Safety Endpoints

To describe the safety 
profile of 20vPnC
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 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 percentages of participants 
reporting SAEs up to 6 months 
after Dose 4 in each group

The percentages of participants 
reporting NDCMCs up to 6 
months after Dose 4 in each 
group

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
Primary Pneumococcal 
Immunogenicity Objectives
Estimands
Primary Pneumococcal 
Immunogenicity Endpoints

To demonstrate that the 
percentages of participants 
with predefined serotype-
specific immunoglobulin G 
(IgG) concentrations for the 
13  serotypes in the 20vPnC 
group are noninferior to the
percentages for the 
corresponding serotypes in 
the 13vPnC 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 
percentages of participants with 
predefined serotype-specific IgG 
concentrations between the 20vPnC 
group and the 13vPnC group

Pneumococcal 
serotype-specific IgG 
concentration

20-valent Pneumococcal Conjugate Vaccine (20vPnC)
Protocol B7471011
Final Protocol Amendment 2, 01 April 2022
PFIZER CONFIDENTIAL
Page 12

To demonstrate that the 
percentages of participants 
with predefined serotype-
specific IgG concentrations
for the 7 additional 
serotypes in the 20vPnC 
group are noninferior to the 
lowest percentage among 
the 13 serotypes in the
13vPnC 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 percentages of participants with 
predefined serotype-specific IgG 
concentrations, between the 20vPnC 
group and the lowest percentage of 
participants with predefined 
serotype-specific IgG concentrations 
among the 13 serotypes from the 
13vPnC group

Pneumococcal 
serotype-specific IgG 
concentration

To demonstrate that the 
serotype-specific IgG 
geometric mean 
concentrations (GMCs) for
the 13 serotypes in the 
20vPnC group are 
noninferior to the GMCs for 
the corresponding serotypes 
in the 13vPnC group at 
1 month after Dose 4
In evaluable participants at 1 month after 
Dose 4:

For each of the 13 matched 
serotypes: geometric mean ratio 
(GMR) of 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 
group are noninferior to the 
lowest IgG GMC among the 
13 serotypes in the 13vPnC 
group at 1 month after 
Dose 4
In evaluable participants at 1 month after 
Dose 4:

For each of the 7 additional 
serotypes in 20vPnC: GMR of 
serotype-specific IgG concentration 
from the 20vPnC group to that from 
the serotype with the lowest IgG 
GMC among the 13 serotypes from 
the 13vPnC group

Pneumococcal 
serotype-specific IgG 
concentration
Primary Concomitant 
Immunogenicity Objective
Estimand
Primary Concomitant 
Immunogenicity Endpoints

To demonstrate that the 
percentages of participants 
with prespecified antibody 
levels to specific 
concomitant vaccine 
antigens when given with 
20vPnC are noninferior to 
the corresponding 
percentages when the 
antigens are given with 
13vPnC at 1 month after 
Dose 3
In evaluable participants who receive the 
appropriate concomitant vaccines:

Differences in percentages of 
participants with prespecified 
antibody levels to diphtheria toxoid, 
tetanus toxoid, pertussis antigens 
(pertussis toxin [PT], filamentous 
hemagglutinin [FHA], pertactin 
[PRN]), hepatitis B surface antigen
(HBsAg), poliovirus strains, and 
Hib between the 20vPnC group and 
the 13vPnC group at 1 month after 
Dose 3

Antibody levels to 
diphtheria toxoid, tetanus 
toxoid, and pertussis 
antigens (PT, FHA, PRN) 

Antibody levels to 
HBsAg

Antibody levels to 
poliovirus strains 
(types 1, 2, and 3)

Antibody levels to Hib

20-valent Pneumococcal Conjugate Vaccine (20vPnC)
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PFIZER CONFIDENTIAL
Page 13
Key Secondary Pneumococcal 
Immunogenicity Objectives
Estimands
Key Secondary 
Pneumococcal 
Immunogenicity Endpoints

To demonstrate that the 
serotype-specific IgG 
GMCs for the 13 serotypes 
in the 20vPnC group are 
noninferior to the GMCs for 
the corresponding serotypes 
in the 13vPnC 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: 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 
group are noninferior to the 
lowest IgG GMC among the 
13 serotypes induced by the 
13vPnC 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 that from 
the serotype with the lowest IgG 
GMC among the 13 serotypes from 
the 13vPnC group

Pneumococcal 
serotype-specific IgG 
concentration
Secondary Pneumococcal 
Immunogenicity Objective 
Estimands
Secondary Pneumococcal 
Immunogenicity Endpoints

To further describe the 
immunogenicity of 20vPnC
In evaluable participants at 1 month after 
Dose 3 and 1 month after Dose 4:

Serotype-specific opsonophagocytic 
activity (OPA) geometric mean titers 
(GMTs) at 1 month after Dose 3, 
prior to Dose 4, and 1 month after 
Dose 4 in each group
In evaluable participants at 1 month after 
Dose 4:

For each of the serotypes in 20vPnC: 
percentages of participants with the 
predefined serotype-specific IgG 
concentration in each group
In evaluable participants:

Geometric mean fold rises 
(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 OPA 
titers

Pneumococcal 
serotype-specific IgG 
concentrations

20-valent Pneumococcal Conjugate Vaccine (20vPnC)
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PFIZER CONFIDENTIAL
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Secondary Concomitant 
Immunogenicity Objectives
Estimands
Secondary Concomitant 
Immunogenicity Endpoints

To further describe the 
immune responses induced 
by specific concomitant 
vaccine antigens given with 
20vPnC or 13vPnC
In evaluable participants who receive the 
appropriate concomitant vaccines:

Differences in percentages of 
participants with alternative 
prespecified antibody levels to Hib
between the 20vPnC group and the 
13vPnC group at 1 month after 
Dose 3

Antibody levels to Hib

To demonstrate that GMCs 
to specific concomitant 
vaccine antigens when
given with 20vPnC are 
noninferior to the 
corresponding GMCs when 
the antigens are given with 
13vPnC at 1 month after 
Dose 4

GMRs of antibody levels to measles, 
mumps, rubella, and varicella 
viruses from the 20vPnC group to 
the 13vPnC group at 1 month after 
Dose 4

Antibody levels to 
measles, mumps, rubella,
and varicella viruses
Number of Participants
Approximately 2000 participants will be enrolled to achieve a target of 1600 evaluable 
participants (800 in each vaccine group) at the time point 1 month after Dose 3 (Visit 4).
Duration of Participation for Each Participant
Each participant will participate in the study for approximately 16 to 19 months.
 
 
  
Statistical Methods
Safety Objectives
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.
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Pneumococcal Immunogenicity Objectives
The primary pneumococcal immunogenicity objectives will be evaluated by formal 
hypothesis tests 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% confidence interval (CI) for the between-group difference in 
percentage of participants with a predefined serotype-specific IgG concentration level
(20vPnC – 13vPnC) is greater than –10% (10% noninferiority margin).
 
 
For the other primary pneumococcal immunogenicity objectives to evaluate the
pneumococcal immune response at 1 month after Dose 4, noninferiority for a serotype at 
1 month after Dose 4 will be declared if the lower bound of the 2-sided 95% CI for the IgG 
GMR of the 20vPnC group relative to the 13vPnC group is greater than 0.5 (2-fold 
noninferiority margin).
 
 
 
 
 
 
 
Additionally, serotype-specific IgG GMCs, OPA GMTs, IgG 
 GMFRs, 
 
 
, will be provided for the specified time points for each vaccine group to provide further 
characterization of the immune response.
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Concomitant Immunogenicity Objectives
The primary concomitant immunogenicity objective will also be evaluated by formal
hypothesis tests for noninferiority of the 20vPnC group to the 13vPnC group. At the visit 
1 month after Dose 3 (Visit 4), noninferiority for each antigen will be declared if the lower 
bound of the 2-sided 95% CI for the difference in percentages (20vPnC – 13vPnC) of 
participants with prespecified antibody levels to diphtheria toxoid, tetanus toxoid, pertussis 
antigens (PT, FHA, PRN), HBsAg, poliovirus strains, and Hib is greater than –10%
(10% noninferiority margin). 
 
1.2. Schema
Not applicable.
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1.3. Schedule of Activities (SoA)
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
7
Visit Description
Dose 1 Visit
Dose 2 Visit
Dose 3 Visit
Dose 3 
Follow-up Visit
Dose 4
Visit
Dose 4
Follow-up Visit
Dose 4
6-Month Visit
Visit Window (Days)
Day 1
42 to 63 Days
After Visit 1
42 to 63 Days 
After Visit 2
28 to 42 Days 
After Visit 3
365 to 455
Days of Agea  
28 to 42 Days 
After Visit 5b
168 to 196 Days 
After Visit 5c
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 vaccines received during 
pregnancy and intrapartum antibiotics
(if available)
X
Record nonstudy vaccinations
X
X
X
X
X
X
Record concomitant medicationsd
X
X
X
X
X
X
X
Obtain prevaccination rectal 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
Xe
X
Administer investigational product
(20vPnC or 13vPnC)f
X
X
X
X
Administer specific concomitant vaccines 
as applicable for the visit
Xg
Xg
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Visit Number
1
2
3
4
5
6
7
Visit Description
Dose 1 Visit
Dose 2 Visit
Dose 3 Visit
Dose 3 
Follow-up Visit
Dose 4
Visit
Dose 4
Follow-up Visit
Dose 4
6-Month Visit
Visit Window (Days)
Day 1
42 to 63 Days
After Visit 1
42 to 63 Days 
After Visit 2
28 to 42 Days 
After Visit 3
365 to 455
Days of Agea  
28 to 42 Days 
After Visit 5b
168 to 196 Days 
After Visit 5c
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 vaccinationi
X
X
X
X
Review and/or collect e-diary 
(if applicable)j
X
X
X
X
Record and report adverse events
X------------------------------------------------------------X
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Visit Number
1
2
3
4
5
6
7
Visit Description
Dose 1 Visit
Dose 2 Visit
Dose 3 Visit
Dose 3 
Follow-up Visit
Dose 4
Visit
Dose 4
Follow-up Visit
Dose 4
6-Month Visit
Visit Window (Days)
Day 1
42 to 63 Days
After Visit 1
42 to 63 Days 
After Visit 2
28 to 42 Days 
After Visit 3
365 to 455
Days of Agea  
28 to 42 Days 
After Visit 5b
168 to 196 Days 
After Visit 5c
Record and report SAEs and NDCMCsk,l
X---------------------------------------------------------------------------------------------------------------------------X
Abbreviations: e-diary = electronic diary; IRT = interactive response technology; NDCMC = newly diagnosed chronic medical condition.
a.
Per Amendment 2: The last day to be eligible for Dose 4 (Visit 5) is 20 Apr 2022.  Participants who have not received Dose 4 by this date are ineligible 
and will be discontinued (Section 7).
b.
Per Amendment 2: The window for Visit 6 relative to Visit 5 does not change, but blood samples will be collected for Visit 6 only up through 
06 May 2022. After 06 May 2022, blood is not to be drawn and the investigator site has the option to collect information for Visit 6 by telephone.
c.
Per Amendment 2: The window for Visit 7 is modified for participants who have Visit 5 (receive Dose 4) after 18 Feb 2022: 

Visit 5 performed after 18 Feb 2022 through 14 Mar 2022: the window is 168 to 196 days after Visit 5, or until 02 Sep 2022, whichever is earlier.

Visit 5 performed on 15 Mar 2022 through 01 Apr 2022: the window is 145 to 168 days after Visit 5, or until 02 Sep 2022, whichever is earlier.

Visit 5 performed on 02 Apr 2022 through 20 Apr 2022: the window is 126 to 145 days after Visit 5, or until 02 Sep 2022, whichever is earlier.
d.
Record only concomitant medications used to treat SAEs and NDCMCs.
e.
Blood sample will be collected prior to vaccination.
f.
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).
g.
Specific concomitant vaccines containing diphtheria, tetanus, acellular pertussis, hepatitis B, poliovirus, and Haemophilus influenzae type b vaccine 
antigens will be administered with Doses 1 through 3 into a limb other than the site of 20vPnC or 13vPnC injection.  Rotavirus and influenza vaccines
may also be administered with the specific concomitant vaccines during the appropriate study visits (if applicable).  See Section 6.5 for details on 
prohibited and permitted concomitant vaccines.
h.
Specific concomitant vaccines containing measles, mumps, rubella, and varicella antigens will be administered with Dose 4 into a limb other than the site 
of 20vPnC or 13vPnC injection. Influenza vaccine may also be administered with the specific concomitant vaccines during the study visit.  
See Section 6.5 for details on prohibited and permitted concomitant vaccines.
i.
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 >104.0°F (>40.0°C) or has an emergency room visit or hospitalization
j.
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.
k.
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.
l.
If the parent(s)/legal guardian(s) consents, participants withdrawn from the study will receive a 6-month telephone safety follow-up after their last dose of 
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Amendment 2: Summary of the Modifications to the SoA Table
Visit 5: The upper limit for the Visit 5 window is no longer based on age.  Instead, eligibility 
for Visit 5 ends after 20 Apr 2022.
Visit 6: The blood draw at this visit will be performed through 06 May 2022; after that date, 
blood will not be collected at Visit 6, and investigator sites have the option of collecting the 
information for Visit 6 by telephone (the window between Visit 5 and Visit 6 remains the 
same, 28 to 42 days after Visit 5).
Visit 7: The last day to complete this visit is 02 Sep 2022.  The windows for Visit 7 are 
modified for participants who have Visit 5 (receive Dose 4) after 18 Feb 2022:

For a participant with Visit 5 performed after 18 Feb 2022 through 14 Mar 2022, the 
window is 168 to 196 days after Visit 5, or until 02 Sep 2022, whichever is earlier.

For a participant with Visit 5 performed on 15 Mar 2022 through 01 Apr 2022, the 
window is 145 to 168 days after Visit 5, or until 02 Sep 2022, whichever is earlier.

For a participant with Visit 5 performed on 02 Apr 2022 through 20 Apr 2022, the 
window is 126 to 145 days after Visit 5, or until 02 Sep 2022, whichever is earlier.
2. INTRODUCTION
Pneumococcal Disease
Streptococcus pneumoniae are gram-positive encapsulated cocci that are a leading cause of 
bacteremia, bacterial meningitis, pneumonia, and acute otitis media (AOM) and continue to 
be a major global public health concern.1,2,3 Serious pneumococcal disease may occur at any 
age; however, children <5 years and adults ≥65 years of age are at particularly increased 
risk.4  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.2  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.5
The overall invasive pneumococcal disease (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 

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fatality rate was also slightly but statistically significantly increased (2% to 3%) in that age 
group.6 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.7  The data for England and Wales are consistent with the patterns observed in data 
from the European Union (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.8  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.9,10  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.11  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.
Surveillance studies conducted in 2010-2012 by the Centers for Disease Control and 
Prevention (CDC) found that S pneumoniae remains among the most common pathogens
identified in community-acquired pneumonia (CAP) requiring hospitalization in the United 
States in both children and adults.12,13 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.12,14
Surveillance reported in 2017 by the European Centre for Disease Prevention and Control 
(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).8  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.15  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.3 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 

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(tympanostomy tube placement), and accompanied by hearing losses with potential 
developmental and language delays, to invasive extension leading to mastoiditis and 
meningitis.
Although the introduction of pneumococcal conjugate vaccines into the United States 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.16,17  Anticapsular antibodies directed against the specific 
serotype bind to the capsule and promote complement-mediated opsonophagocytic killing 
and clearance of the organism.18  Pneumococcal disease can be prevented with 
polysaccharide-based vaccines that induce antibody responses with functional 
(opsonophagocytic) activity and target the capsular serotypes responsible for disease.19
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 1983.20,21  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.4,21,22,23  Moreover, their ability to prevent 
nonbacteremic pneumonia, CAP, and AOM is limited or lacking.19,23,24,25,26  In addition, 
polysaccharide vaccines do not reduce vaccine-type (VT) nasopharyngeal carriage, which is 
important for herd immunity.26  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.19
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.22,27  7vPnC was the first pneumococcal conjugate 
vaccine to be licensed (2000) and was indicated for prevention of pneumococcal disease in 

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infants and young children on the basis of efficacy studies.  7vPnC contained capsular 
polysaccharide conjugates for 7 pneumococcal serotypes (4, 6B, 9V, 14, 18C, 19F, and 23F), 
each covalently linked to cross-reactive material 197 (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).28,29,30,31,32  These serotypes also 
accounted for a high proportion of antibiotic-resistant strains.33  7vPnC demonstrated 
efficacy against VT IPD, pneumonia, and AOM in large randomized, controlled efficacy 
studies in infants.34,35  The 7vPnC components contained in a related pneumococcal 
conjugate vaccine also were demonstrated to be efficacious against 
clinically/radiographically defined pneumonia.36,37,38,39  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.40
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.27,31,41  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.42  13vPnC has replaced 7vPnC and is licensed in the United States 
and many other countries, with national recommendations for use in children and older 
adults.43,44,45,46  It has also been prequalified by the World Health Organization (WHO) for 
use in national infant immunization programs in lower- and middle-income countries.47,48  
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.49,50,51
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 investigator’s brochure (IB).  The 
vaccine is being developed for use in pediatric and adult populations.

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2.1. Study Rationale
 
 
  The 
targeted age of the population for this study, infants ≥42 to ≤98 days of age, has been 
selected as the routinely recommended vaccination schedule for pneumococcal conjugate 
vaccines and other vaccines in infants, starting at approximately 2 months of age.  The 
participants will be administered either 20vPnC or 13vPnC at 2, 4, 6, and 12 to 15 months of 
age.  Data will also be generated on key routine pediatric vaccines given concomitantly with 
20vPnC or 13vPnC.
Amendment 2 is being implemented to complete the vaccination schedule in a timely manner 
as all participants are age-eligible for their final dose (Dose 4) as of the amendment date. 
There is no benefit to the participant to delay completion of the series. Delaying vaccination 
and in-person study visits later in the trial also carries a risk of additional delays in 
vaccination and exposure risks that may occur with a potential resurgence of coronavirus
disease in the near future. 
 
 
 
 
 
The modifications in this amendment impact only a very small overall 
proportion of participants who have not yet received Dose 4, and do not adversely affect the
safety, scientific integrity, or management of the study.
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).52,53,54,55,56,57,58,59,60,61,62,63  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.64,65,66,67,68,69,70  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.71 In the EU, according to 
the ECDC annual IPD epidemiological report, in 2017, approximately 75% of cases of IPD 
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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.8
A meta-analysis of serotypes causing IPD in children <5 years of age in regions of the world 
that have introduced higher-valent pneumococcal conjugate vaccines (such as 13vPnC) 
showed that, overall, these 7 serotypes accounted for approximately 70% of disease not due 
to the 13vPnC vaccine types.66
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 induces immune 
responses to the 20 vaccine serotypes and has a safety profile consistent with other 
pneumococcal conjugate vaccines.  These data supported clinical development in other 
populations, including pediatrics.
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. Safety and immunogenicity data are available from the 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
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).
The 20vPnC investigational product contains the same components and excipients as 
13vPnC, but 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 to 460 infants ≥42 to ≤98 days of age naïve 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).
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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.
Diphtheria, tetanus, and acellular pertussis (DTaP) combination vaccine is a licensed vaccine 
and the most common AEs seen after vaccination include local reactions (injection site pain, 
redness, and swelling) and systemic events (fever, drowsiness/increased sleep, 
irritability/fussiness, and loss of appetite).
Hib vaccine is a licensed vaccine and the most common AEs seen after vaccination include 
local reactions (injection site pain/tenderness, redness, and swelling) and systemic events 
(irritability, drowsiness/decreased activity, fever, and decreased appetite).
Measles, mumps, and rubella vaccine (MMR) is a licensed vaccine and the most common 
AEs after vaccination include local reactions (injection site tenderness, pain, redness, and 
swelling) and systemic events (fever and irritability).
Varicella vaccine is a licensed vaccine and the most common AEs include local reactions 
(injection site pain, swelling, redness, and rash) and fever.
Risks that may be associated with study procedures include risks from blood draws, 
including pain, swelling, bruising, and infection where blood is taken.
Safety assessments 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. 
 
 
13vPnC is approved for the prevention of pneumococcal disease due to the serotypes in the 
vaccine, and may provide a clinical benefit to those receiving it.
DTaP combination vaccine is approved for the prevention of diphtheria, tetanus, pertussis, 
diseases due to subtypes of hepatitis B virus, and poliomyelitis, and may provide a clinical 
benefit to those receiving it.
Hib vaccine is approved for the prevention of invasive disease caused by Hib and may 
provide a clinical benefit to those receiving it.
MMR is approved for the prevention of measles, mumps, and rubella and may provide a 
clinical benefit to those receiving it.
Varicella vaccine is approved for the prevention of varicella and may provide a clinical 
benefit to those receiving it.
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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 pneumococcal disease (invasive 
and noninvasive) due to vaccine serotypes.
Pfizer considers that the available information from Study B7471003 with 20vPnC, the 
available safety profile of similar pneumococcal conjugate vaccines (ie, Prevnar and 
Prevnar 13), and the limited risks from study procedures support a favorable benefit-risk 
profile for 20vPnC and this study.
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 single reference safety 
document (SRSD) for this study. The SRSD for the 13vPnC control vaccine is the US 
package insert. The SRSDs for the specified concomitant vaccines are the US package 
inserts.
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS
Primary Safety Objective
Estimands
Primary Safety Endpoints

To describe the safety 
profile of 20vPnC
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 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 percentages of participants 
reporting SAEs up to 6 months 
after Dose 4 in each group

The percentages of participants 
reporting NDCMCs up to 6 
months after Dose 4 in each 
group

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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Primary Pneumococcal 
Immunogenicity Objectives
Estimands
Primary Pneumococcal 
Immunogenicity Endpoints

To demonstrate that the 
percentages of participants 
with predefined serotype-
specific IgG concentrations
for the 13 serotypes in the 
20vPnC group are 
noninferior to the 
percentages for the 
corresponding serotypes in 
the 13vPnC 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 
percentages of participants with 
predefined serotype-specific IgG 
concentrations between the 20vPnC 
group and the 13vPnC group

Pneumococcal 
serotype-specific IgG 
concentration

To demonstrate that the 
percentages of participants 
with predefined serotype-
specific IgG concentrations
for the 7 additional 
serotypes in the 20vPnC
group are noninferior to the 
lowest percentage among
the 13 serotypes in the 
13vPnC 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 percentages of participants with 
predefined serotype-specific IgG 
concentrations, between the 20vPnC 
group and the lowest percentage of 
participants with predefined 
serotype-specific IgG concentrations 
among the 13 serotypes from the 
13vPnC group

Pneumococcal 
serotype-specific IgG 
concentration

To demonstrate that the 
serotype-specific IgG 
GMCs for the 13 serotypes 
in the 20vPnC group are 
noninferior to the GMCs for 
the corresponding serotypes 
in the 13vPnC group at 1 
month after Dose 4
In evaluable participants at 1 month after 
Dose 4:

For each of the 13 matched 
serotypes: GMR of 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
group are noninferior to the 
lowest IgG GMC among the 
13 serotypes in the 13vPnC 
group at 1 month after 
Dose 4
In evaluable participants at 1 month after 
Dose 4:

For each of the 7 additional 
serotypes in 20vPnC: GMR of 
serotype-specific IgG concentration 
from the 20vPnC group to that from 
the serotype with the lowest IgG 
GMC among the 13 serotypes from 
the 13vPnC group

Pneumococcal 
serotype-specific IgG 
concentration
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Primary Concomitant 
Immunogenicity Objective
Estimand
Primary Concomitant 
Immunogenicity Endpoints

To demonstrate that 
percentages of participants 
with prespecified antibody 
levels to specific 
concomitant vaccine 
antigens when given with 
20vPnC are noninferior to 
the corresponding 
percentages when the 
antigens are given with 
13vPnC at 1 month after 
Dose 3
In evaluable participants who receive the 
appropriate concomitant vaccines:

Differences in percentages of 
participants with prespecified 
antibody levels to diphtheria toxoid, 
tetanus toxoid, pertussis antigens 
(PT, FHA, PRN), HBsAg, 
poliovirus strains, and Hib between 
the 20vPnC group and the 13vPnC 
group at 1 month after Dose 3

Antibody levels to 
diphtheria toxoid, tetanus 
toxoid, and pertussis 
antigens (PT, FHA, PRN) 

Antibody levels to 
HBsAg

Antibody levels to 
poliovirus strains 
(types 1, 2, and 3)

Antibody levels to Hib
Key Secondary Pneumococcal 
Immunogenicity Objectives
Estimands
Key Secondary 
Pneumococcal 
Immunogenicity Endpoints

To demonstrate that the 
serotype-specific IgG 
GMCs for the 13 serotypes 
in the 20vPnC group are 
noninferior to the GMCs for 
the corresponding serotypes 
in the 13vPnC 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: GMR of serotype-specific 
IgG concentrations from the 20vPnC 
group to the 13vPnC group

Pneumococcal 
serotype-specific IgG 
concentration

To demonstrate that the 
serotype-specific IgG GMC
for the 7 additional 
serotypes in the 20vPnC 
group are noninferior to the 
lowest IgG GMC among the 
13 serotypes in the 13vPnC 
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 
serotype-specific IgG concentration 
from the 20vPnC group to that from 
the serotype with the lowest IgG 
GMC among the 13 serotypes from 
the 13vPnC group

Pneumococcal 
serotype-specific IgG 
concentration
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Secondary Pneumococcal 
Immunogenicity Objective 
Estimands
Secondary Pneumococcal 
Immunogenicity Endpoints

To further describe the 
immunogenicity of 20vPnC
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
In evaluable participants at 1 month after 
Dose 4:

For each of the serotypes in 20vPnC: 
percentages of participants with the 
predefined serotype-specific IgG 
concentration in each group
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 OPA 
titers

Pneumococcal 
serotype-specific IgG 
concentrations 
Secondary Concomitant 
Immunogenicity Objectives
Estimands
Secondary Concomitant 
Immunogenicity Endpoints

To further describe the 
immune responses induced 
by specific concomitant 
vaccine antigens given with 
20vPnC or 13vPnC
In evaluable participants who receive the 
appropriate concomitant vaccines:

Differences in percentages of 
participants with alternative 
prespecified antibody levels to Hib
between the 20vPnC group and the 
13vPnC group at 1 month after 
Dose 3

Antibody levels to Hib

To demonstrate that GMCs 
to specific concomitant 
vaccine antigens when 
given with 20vPnC are 
noninferior to the 
corresponding GMCs when 
the antigens are given with 
13vPnC at 1 month after 
Dose 4

GMRs of antibody levels to measles, 
mumps, rubella, and varicella 
viruses from the 20vPnC group to 
the 13vPnC group at 1 month after 
Dose 4

Antibody levels to 
measles, mumps, rubella,
and varicella viruses
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rs
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4. STUDY DESIGN
4.1. Overall Design
This Phase 3, multicenter, randomized, double-blind study will be conducted at investigator 
sites in the United States and potentially other countries to be determined. 
 
 
 The purpose of this study is to describe safety and conduct the pivotal 
immunogenicity comparison of 20vPnC to the licensed pneumococcal conjugate vaccine, 
13vPnC, in infants 
.  Data will also be generated on key routine pediatric 
vaccines given concomitantly with 20vPnC. 13vPnC will serve as an active comparator.
Approximately 2000 infants ≥42 to ≤98 days of age at the time of consent, by their 
parent(s)/legal guardian(s), will be enrolled.  Participants will be randomized in a 1:1 ratio to 
receive either 20vPnC or 13vPnC (control vaccine) at 2, 4, 6, and 12 to 15 months of age 
(Doses 1, 2, 3, and 4, respectively) by site-based randomization.  Participants will receive the 
same vaccine (20vPnC or 13vPnC) for all 4 doses.
On Day 1 (Visit 1, Dose 1 vaccination) of the study, participants will be assessed for 
eligibility and information collected, including medical history, vaccine history, and maternal 
immunization (vaccines administered during pregnancy) history (if available).
At Visit 1, participants will be randomized and receive Dose 1 of 20vPnC or 13vPnC. 
20vPnC and 13vPnC will be identical in appearance and will be prepared and administered 
by a qualified site staff member or designee. Specific concomitant vaccines containing 
diphtheria, tetanus, acellular pertussis, hepatitis B virus, poliovirus, and Hib antigens will 
also be administered at this visit and at Visits 2 and 3. Participants will be observed for 
30 minutes after vaccination and any reactions occurring during that time will be recorded as 
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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 (redness, swelling, and pain at the injection site) and systemic events (fever, 
decreased appetite, drowsiness/increased sleep, and irritability) occurring within 7 days after 
each vaccination. Use of antipyretic/pain medications will also be prompted for and 
collected daily in the 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 injection site, or fever >40.0°C (>104.0°F) in 
the 7 days after vaccination or has an emergency room visit or hospitalization.
Participants will return for Visit 2 (42 to 63 days after Visit 1, study Day 43 to 64) and Visit 
3 (42 to 63 days 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), 
observed for 30 minutes, and given the same instructions as in Visit 1.
Participants will return 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.  Blood will be collected for immunogenicity assessment.
Participants will return for Visit 5 (365 to 455 days of age) 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.  Blood will be taken for immunogenicity assessment prior to vaccination.  
Dose 4 (of 20vPnC or 13vPnC) will be administered at this visit.  Specific concomitant 
vaccines containing measles, mumps, rubella, and varicella antigens will be administered at 
this visit. Participants will be observed for 30 minutes after vaccination and any reactions 
occurring during that time will be recorded as AEs. Parents/legal guardians will be given an 
e-diary and instructed as in Visit 1.
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.  Blood will be taken for immunogenicity assessment.
Participants will have Visit 7, approximately 6 months (168 to 196 days) after Visit 5. The 
sites will contact the participants’ parent(s)/legal guardian(s) via telephone to inquire about 

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SAEs, NDCMCs, and concomitant medications used to treat SAEs or NDCMCs since the 
last visit.
Amendment 2 applies to a small number of participants, and with that the following 
modifications are being introduced into the study design: 1) the window for Visit 5 (time-
based rather than age-based, as all participants are now age-eligible), 2) collection of Visit 6 
immunogenicity blood samples will also be time-based, after which there is an option of 
conducting Visit 6 by telephone, and 3) Visit 7 windows will be modified slightly and/or be 
time-based (see Section 1.3, Schedule of Activities; Section 8.10.5, Visit 5 [Dose 4 Visit, 
365 to 455 Days of Age]; Section 8.10.6, Visit 6 [Dose 4 Follow-up Visit, 28 to 42 Days 
After Dose 4]; and Section 8.10.7, Visit 7 [Dose 4 6-Month Visit, 168 to 196 Days After 
Dose 4]).  These modified follow-up windows are consistent with the original protocol as
they will still allow for approximately 6 months of follow-up after the final vaccination in the 
series.
4.1.1. Approximate Duration of Participation for Each Participant
Each participant will participate in the study for approximately 16 to 19 months.
4.1.2. Approximate Number of Participants
Approximately 2000 participants will be enrolled to achieve a target of 1600 evaluable 
participants (800 in each vaccine group) at the follow-up time point 1 month after Dose 3.
4.2. Scientific Rationale for Study Design
 
 
Infants ≥42 to ≤98 days of age will be eligible if they 
are naïve to pneumococcal vaccination. 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 at 2, 4, 6, and 12 to 15 months of age. This is 
consistent with the current pneumococcal vaccine recommendations for infants in the United 
States.31 13vPnC will serve as the comparator to 20vPnC for assessment of safety and 
immunogenicity.
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 3 doses of pneumococcal conjugate vaccine given in infancy at 
2, 4, and 6 months of age, and 1 dose given at 12 to 15 months of age, induces protective 
immune responses.
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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.
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. Male or female infants born at >36 weeks of gestation and 2 months of age 
(≥42 to ≤98 days) at the time of consent (the day of birth is considered day of life 1).
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 informed consent document (ICD) and in this protocol.

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5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
1. History of severe adverse reaction associated with a vaccine and/or severe allergic 
reaction (eg, anaphylaxis) to any component of investigational product or any diphtheria 
toxoid–containing vaccine.
2. 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.
3. Major known congenital malformation or serious chronic disorder.
4. History of microbiologically proven invasive disease caused by S pneumoniae.
5. Known or suspected immunodeficiency or other conditions associated with 
immunosuppression, including, but not limited to, immunoglobulin class/subclass
deficiencies, DiGeorge syndrome, generalized malignancy, human immunodeficiency 
virus (HIV) infection, leukemia, lymphoma, or organ or bone marrow transplant.
6. Bleeding diathesis or condition associated with prolonged bleeding that would, in the 
opinion of the investigator, contraindicate intramuscular injection.
7. Congenital, functional, or surgical asplenia.
8. 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:
9. Previous vaccination with any licensed or investigational pneumococcal vaccine, or 
planned receipt through study participation.
10. Prior receipt of diphtheria, tetanus, pertussis, poliomyelitis, and/or Hib vaccine.
11. Previous receipt of >1 dose of hepatitis B vaccine; or receipt of a single hepatitis B 
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12. Currently receives treatment with immunosuppressive therapy, including cytotoxic agents 
or systemic corticosteroids, or planned receipt through the last blood draw (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 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) since birth or planned receipt through the last planned blood draw 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 or intrauterine exposure to investigational vaccines.  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 members 
or Pfizer employees who are directly involved in the conduct of the study.
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 
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5.5. Temporary Delay Criteria
The following conditions are temporary or self-limiting and a participant may be vaccinated 
and/or have blood drawn in the study once the condition(s) has/have resolved and no other 
exclusion criteria are met.
The blood draws prior to vaccination should take place on the same day as the vaccination.
5.5.1. Criteria for Temporarily Delaying Vaccine Administration

Current febrile illness (eg, rectal temperature ≥38.0°C [≥100.4°F]) 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 exceptions 
of: 1) influenza vaccine, which may be given at any time during the influenza season if 
the participant is of the appropriate age to receive it; and 2) permitted concomitant 
vaccines on the same day as Dose 1, 2, 3, or 4 (see Section 6.5.2).

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.
5.5.2. Criteria for Temporarily Delaying Immunogenicity Blood Draw

Receipt of antibiotic therapy within 72 hours before blood draw. 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, the term investigational product may be used 
synonymously with study intervention.
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. The vaccine is formulated to contain 2.2 µg of 
each saccharide, except for 4.4 µg of 6B, per 0.5-mL dose. The vaccine contains 5 mM 
succinate buffer, 150 mM sodium chloride, 0.02% polysorbate 80, and 125 µg aluminum as 
aluminum phosphate, per 0.5-mL dose.
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 vaccine is formulated to contain 2.2 µg of each saccharide, except for 4.4 µg 
of 6B, per 0.5-mL dose. The vaccine contains 295 μg succinate buffer, 0.85% sodium 
chloride, 100 μg polysorbate 80, and 125 µg aluminum as aluminum phosphate, per 0.5-mL 
dose.
 
 
20vPnC and 13vPnC are both white suspensions and have a matching appearance, and will 
be supplied as prefilled syringes.
DTaP combination vaccine is a vaccine indicated for active immunization against diphtheria, 
tetanus, pertussis, infection caused by all known subtypes of hepatitis B virus, and 
poliomyelitis. See the investigational product manual (IP manual) and applicable SRSD. 
The vaccine will be supplied as a prefilled syringe.
Hib vaccine is a vaccine indicated for the prevention of invasive disease caused by Hib. The 
vaccine will be supplied in vials.
MMR is a live virus vaccine for vaccination against measles (rubeola), mumps, and rubella 
(German measles).  See the IP manual and applicable SRSD provided. The vaccine will be 
supplied in vials.
Varicella vaccine is a live virus vaccine for vaccination against varicella. See the IP manual 
and applicable SRSD. The vaccine will be supplied in vials.
All vaccines listed in this section will be provided by Pfizer as prefilled syringes or vials. 
Each syringe/vial 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 IP 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.
They will also receive 1 dose of a DTaP-containing vaccine in combination with other 
antigens (including poliovirus and hepatitis B) and 1 dose of a Hib vaccine at Visits 1, 2, and 
3. MMR and varicella vaccines will be administered concomitantly with 20vPnC or 13vPnC 
at Visit 5 with Dose 4 in accordance with the study’s SoA.
20vPnC and 13vPnC should be administered intramuscularly by injecting 0.5 mL into the 
anterolateral thigh muscle of the left leg at the vaccination visits.
The DTaP-containing vaccine, Hib vaccine, MMR, and varicella vaccine will be 
administered concomitantly with 20vPnC or 13vPnC as noted above, but must be given in a 
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limb other than the left leg, as appropriate for the age of the child and the route of 
administration (ie, intramuscular or subcutaneous).
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 investigational products should be performed by an appropriately 
qualified, Good Clinical Practice (GCP)-trained, and vaccine-experienced member of the 
study staff (eg, physician, nurse, physician’s assistant, nurse practitioner, pharmacist, or 
medical assistant) as allowed by local, state, and institutional guidance.
Investigational product administration details will be recorded on the case report form (CRF).
6.1.2. Medical Devices
In this study, medical devices being deployed are the 20vPnC, 13vPnC, and DTaP
combination vaccine prefilled syringes.
Instructions for medical device use are provided in the IP manual or in the package insert.
Medical device deficiencies, including those resulting from malfunctions of the device, must 
be detected, documented, and reported by the study personnel throughout the study.  Please 
refer to Section 8.3.6 for details.
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.
6.3. Measures to Minimize Bias: Randomization and Blinding
6.3.1. Allocation to Investigational Product
All eligible participants will be randomized in a 1:1 ratio to receive either 20vPnC or 13vPnC 
(control vaccine).
Allocation of participants to vaccine groups will proceed through the use of an interactive 
response technology (IRT) system (interactive Web-based response [IWR]).  The site 
personnel (study coordinator or specified designee) will be required to enter or select 
information including but not limited to the user’s identification (ID) and password, the 
protocol number, and the participant number.  The site personnel will then be provided with a 
vaccine assignment, randomization number, and dispensable unit (DU) or container number 
when investigational product is being supplied via the IRT system.  The IRT system will 
provide a confirmation report containing the participant number, randomization number, and 
DU or container number assigned.  The confirmation report must be stored in the site’s files.
The 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 the Sponsor
Sponsor personnel directly involved in evaluating participant data will be blinded to vaccine 
assignment until the analysis of available data through 1 month after Dose 4, following the 
principles outlined in International Council for Harmonisation (ICH) E9 guideline on 
Statistical Principles for Clinical Trials.72 A data blinding plan will be created to describe the 
blinding requirements and unblinding events. Laboratory personnel performing the 
immunologic assays will be blinded until all assays have been completed and assay results 
finalized.
6.3.3. Breaking the Blind
The study will be participant- and investigator-blinded.
At the initiation of the study, the investigator site will be instructed on the method for 
breaking the blind for an individual participant.  The method will be an electronic process.  
Blinding codes should be broken only in exceptional circumstances when knowledge of the 
actual treatment code is absolutely essential for further management of the participant.  
Investigators are encouraged to discuss with a member of the study team if they believe that 
unblinding is necessary.  When the blinding code is broken, the reason must be recorded in 
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6.4. Study Intervention Compliance
All doses of investigational product will be administered by the appropriately designated 
study staff at the investigator site.
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

Influenza vaccine is permitted at any time during influenza season in this study, if the 
participant is eligible to receive influenza vaccine.

Rotavirus vaccine may be given at any time during the study, and according to local or 
national recommendations.

Receipt of quadrivalent meningococcal conjugate vaccine is permitted during the study 
only after blood is collected at the visit occurring 1 month after Dose 4.

Other nonprohibited licensed vaccines may be given between the blood draw 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 local or national 
recommendations.  Following the blood draw performed 1 month after Dose 4 (Visit 6), 
all licensed vaccines are permitted.

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 
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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.  Information on 
vaccines given to the participant’s mother during pregnancy and any intrapartum antibiotic 
use will also be collected (at Visit 1 only), if available.
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 at 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 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 will be 
collected for 1 month after the last study vaccination and SAEs will be collected for 6 months 
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.
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.
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 
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At the time of discontinuing please refer to the investigator site file (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.
For participants who are discontinued prior to completing all 4 doses of study intervention, 
the parents/guardians should be encouraged to follow up with their primary care physician to 
have the participant complete the pneumococcal conjugate vaccine series with commercial
Prevnar 13 as part of their recommended standard of care.
A final telephone contact 6 months after the last vaccination (similar to that described in 
Section 8.10.7) for the collection of safety information should be completed for all 
participants who have been withdrawn after administration of investigational product, unless 
consent for further contact has been withdrawn, or the participant is lost to follow-up.
Participant withdrawal should be explained in the source documents and should include 
whether the withdrawal is only from further receipt of investigational product or also from 
study procedures and/or posttreatment study follow-up.
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.
If the participant is withdrawn from the study and his/her parent(s)/legal guardian(s) also 
withdraws consent (see below) 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 
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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 or fails to respond to the 6-month safety follow-up telephone call:

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;

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 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.
Study procedures and their timing are summarized in the SoA.  Protocol waivers or 
exemptions are not allowed.
Immediate safety concerns 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 
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Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances outside the control of the investigator that 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.
The total blood sampling volume for individual participants in this study is approximately 
15 mL.
8.1. Efficacy Assessments
8.1.1. Immunogenicity Assessments
Blood samples (approximately 5mL 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.
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 randomly 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 
both vaccine groups. Further details will be described in the clinical specimen assessment 
plan (CSAP).
 
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Concomitant Vaccine Antigens
Responses to the following concomitant vaccine antigens will be assessed.  The randomly 
selected serum subsets to be assayed will be based on minimum sample sizes needed to 
demonstrate the objectives of the study balanced with the serum volume required and 
available for testing.
Diphtheria toxoid: Concentration of antibody (in international units [IU]) to diphtheria toxoid 
(predefined level ≥0.1 IU/mL) will be determined on subsets of sera collected at the 
immunogenicity time point 1 month after Dose 3. 
 
Tetanus toxoid: Concentration of antibody (in IU) to tetanus toxoid (predefined level 
≥0.1 IU/mL) will be determined on subsets of sera collected at the immunogenicity time 
point 1 month after Dose 3.  
 
Acellular pertussis: Concentration of IgG antibodies to pertussis antigens PT, FHA, and PRN
(predefined level ≥ the observed antipertussis antibody concentration achieved by 95% of 
13vPnC recipients) will be determined on subsets of sera collected at the immunogenicity 
time point 1 month after Dose 3.
 
Hepatitis B: Concentration of hepatitis B antibody (in milli-international units per mL 
[mIU/mL]) (predefined level ≥10 mIU/mL) will be determined on subsets of sera collected at 
the immunogenicity time point 1 month after Dose 3 (Visit 4). 
 
Poliomyelitis: Neutralizing antibody (NA) titers to poliovirus types 1, 2, and 3 (predefined 
level NA titer ≥1:8) will be determined on subsets of sera collected at the immunogenicity 
time point 1 month after Dose 3.
 
Hib: Concentration of antibody to Hib (polyribosylribitol phosphate [PRP]) in µg/mL 
(primary predefined level ≥0.15 µg/mL anti-PRP; alternative predefined level ≥1.0 µg/mL 
anti-PRP) will be determined on subsets of sera collected at the immunogenicity time point 
1 month after Dose 3. 
 
Measles: Concentration of antimeasles antibody will be determined on subsets of sera 
collected at 1 immunogenicity time point (1 month after Dose 4 [Visit 6]). 
 
Mumps: Concentration of antimumps antibody will be determined on subsets of sera 
collected at 1 immunogenicity time point (1 month after Dose 4 [Visit 6]). 
 
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Rubella: Concentration of antirubella antibody will be determined on subsets of sera 
collected at 1 immunogenicity time point (1 month after Dose 4 [Visit 6]). 
 
Varicella: Concentration of antivaricella antibody will be determined on subsets of sera 
collected at 1 immunogenicity time point (1 month after Dose 4 [Visit 6]). 
 
 
8.1.2. Biological Samples
Blood samples will be used only for scientific research.  Each sample will be labeled with a 
code so that the laboratory personnel testing the samples will not know the participant’s 
identity.  Samples that remain after performing assays outlined in the protocol may be stored 
by Pfizer.  Unless a time limitation is required by local regulations or ethical requirements, 
the samples will be stored for up to 15 years after the end of the study and then destroyed.   
 
 No testing of the participant’s genetic material will be performed.
The participant’s parent(s)/legal guardian(s) may request that the participant’s samples, if 
still identifiable, be destroyed at any time; however, any data already collected from those 
samples will still be used for this research.  The biological samples may be shared with other 
researchers as long as confidentiality is maintained and no testing of the participant’s genetic 
material is performed.
8.2. Safety Assessments
A clinical assessment, including medical history and measurement of rectal 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, 
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where Day 1 is the day of vaccination), are graded as described in Section 8.2.2.  
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 study vaccination 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.
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.

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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 Center for Biologics Evaluation and Research (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.73
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 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 1.  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 1.  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.
Table 1.
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 
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Table 1.
Grading Scales for Local Reactions
Local Reaction
GRADE 1
mild
GRADE 2 
moderate
GRADE 3a
severe
GRADE 4b
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
Abbreviations: CRF = case report form; e-diary = electronic 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 in Section 10.3.4.
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.
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 2.  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 2.
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; e-diary = electronic diary.
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 in Section 10.3.4.
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 rectal 
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 a rectal 
temperature of ≥38.0°C (≥100.4°F).  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 less than 38.0°C [100.4°F]) 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 (>104.0°F) within the 7 days 
following vaccination to assess the fever and perform an unscheduled assessment, as 
applicable (see Section 8.10.8).  Study staff may also contact the participant’s parent(s)/legal 
guardian(s) to obtain additional information if a temperature of >38.9°C (>102.0°F) 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 3.

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Table 3.
Ranges for Fever
≥38.0°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 temperature ≥38.0°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.
8.3. Adverse Events and Serious Adverse Events
The definitions of an AE and an SAE can be found in Appendix 3.
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 
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 it 
meets the criteria for classification as an SAE or caused the participant to discontinue from
the study (see Section 7).
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 

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study (ie, before undergoing any study-related procedure and/or receiving investigational 
product), through and including Visit 4 and from Visit 5 through Visit 6.  Between Visit 4 
and Visit 5, only SAEs and NDCMCs will be reported.  At Visit 7 (final telephone contact), 
the participant’s parent(s)/legal guardian(s) will be contacted by telephone to inquire about 
SAEs, including hospitalizations and NDCMCs, since Visit 6.
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.
Investigators are not obligated to actively seek AEs or SAEs after conclusion of the 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 or study participation, the investigator 
must promptly notify the sponsor.
8.3.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period 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
During the active collection period, both nonserious AEs and SAEs are recorded on the CRF.
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).

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In general, follow-up information will include a description of the event in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Any information relevant to the event, such as concomitant medications 
and illnesses, must be provided.  In the case of a participant death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer Safety.
Further information on follow-up procedures is given in Appendix 3 (Section 10.3).
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, institutional review boards (IRBs)/ethics committees 
(ECs), and investigators.
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE 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
Details of all pregnancies in females (via occupational exposure) will be collected after the
start of study intervention and until delivery.
 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.
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8.3.5.2. Exposure During Breastfeeding
Scenarios of exposure during breastfeeding (via occupational exposure) must be reported, 
irrespective of the presence of an associated SAE, to Pfizer Safety within 24 hours of the 
investigator’s awareness, using the Vaccine SAE Reporting Form.  An exposure during 
breastfeeding report is not created when a Pfizer drug specifically approved for use in 
breastfeeding women (eg, vitamins) is administered in accord with authorized use.  However, 
if the infant experiences an SAE associated with such a drug’s administration, the SAE is 
reported together with the exposure during breastfeeding.
8.3.5.3. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to Pfizer Safety within 24 hours of the investigator’s 
awareness, using the Vaccine SAE Reporting Form, regardless of whether there is an 
associated SAE.  Since the information 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 ISF.
8.3.6. 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 
investigator is responsible for the detection and documentation of events meeting the 
definitions of deficiencies that occur during the study with such devices.
The definition of a medical device deficiency can be found in Appendix 8.
NOTE: Deficiencies fulfilling the definition of an AE/SAE will also follow the processes 
outlined in Section 8.3.3 and Appendix 3 (Section 10.3) of the protocol.
8.3.6.1. 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
(Section 10.8).

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8.3.6.2. Follow-up of Medical Device Deficiencies
All medical device deficiencies involving an AE will be followed and reported in the same 
manner as other AEs (see Section 8.3.3).  This applies to all participants, including those who 
discontinue study intervention.
The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the deficiency.
New or updated information will be recorded on a follow-up form with all changes signed 
and dated by the investigator.
8.3.6.3. Prompt Reporting of Device Deficiencies to Sponsor
Device deficiencies will be reported to the sponsor within 1 day after the investigator 
determines that the event meets the protocol definition of a medical device deficiency.
Any device deficiency that is associated with an SAE must be reported to Pfizer Safety 
within 24 hours upon the investigator’s awareness as outlined in Section 8.3.1.1 and 
Section 8.3.1.2.
The sponsor will be the contact for the receipt of device deficiency information.
Information will be provided to the sponsor as described in the IP manual.
8.3.6.4. Regulatory Reporting Requirements for Medical Device Deficiencies
The investigator will promptly report all device deficiencies occurring with any medical 
device provided for use in the study in order for the sponsor to fulfill the legal responsibility 
to notify appropriate regulatory authorities and other entities about certain safety information 
relating to medical devices being used in clinical studies.
The investigator, or responsible person according to local requirements (eg, the head of the 
medical institution), will comply with the applicable local regulatory requirements relating to 
the reporting of device deficiencies to the IRB/EC.
8.3.7. 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 investigational product 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

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Medication errors include:

Medication errors involving participant exposure to the investigational product;

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 immediately.
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 an 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 investigational product;

The administration of an incorrect investigational product;

The administration of an incorrect dosage;

The administration of investigational product that has undergone temperature excursion 
from the specified storage range, unless it is determined by the sponsor that the 
investigational product 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 should:
1. Contact the medical monitor immediately.
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.

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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. Health Economics
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study.
8.10. 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.
8.10.1. 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.

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
Record vaccine history.

Record vaccines received during pregnancy and intrapartum antibiotics (if available).

Measure and record the participant’s rectal temperature (°C/°F).

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.
After randomization:

Administer a single 0.5-mL injection of 20vPnC or 13vPnC into the left anterolateral 
thigh.

Administer concomitant vaccines containing diphtheria, tetanus, acellular pertussis, 
hepatitis B, poliovirus, and Hib antigens and other permitted vaccines into a limb other 
than the site of 20vPnC or 13vPnC injection, as appropriate for the age of the child and 
the route of vaccine administration (ie, intramuscular, subcutaneous, or oral), and record 
the site of administration on the CRF.

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 (>104.0°F), 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.

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
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 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 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.
8.10.2. Visit 2 (Dose 2 Visit, 42 to 63 Days After Dose 1, ie, Study Day 43 Through Study 
Day 64)

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 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 rectal temperature (°C/°F).

Administer a single 0.5-mL injection of 20vPnC or 13vPnC into the left anterolateral 
thigh.

Administer concomitant vaccines containing diphtheria, tetanus, acellular pertussis, 
hepatitis B, poliovirus, and Hib antigens and other permitted vaccines into a limb other 
than the site of 20vPnC or 13vPnC injection, as appropriate for the age of the child and 

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the route of vaccine administration (ie, intramuscular, subcutaneous, or oral), and record 
the site of administration on the CRF.
After vaccination:

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 (>104.0°F), 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 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.
8.10.3. Visit 3 (Dose 3 Visit, 42 to 63 Days After 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.

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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.

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 rectal temperature (°C/°F).

Administer a single 0.5-mL injection of 20vPnC or 13vPnC into the left anterolateral 
thigh.

Administer concomitant vaccines containing diphtheria, tetanus, acellular pertussis, 
hepatitis B, poliovirus, and Hib antigens and other permitted vaccines into a limb other 
than the site of 20vPnC or 13vPnC injection, as appropriate for the age of the child and 
the route of vaccine administration (ie, intramuscular, subcutaneous, or oral), and record
the site of administration on the CRF.
After vaccination:

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 (>104.0°F), 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 parent(s)/legal guardian(s) still possesses the participant contact 
card. Provide a participant contact card if needed.

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
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.
8.10.4. Visit 4 (Dose 3 Follow-up Visit, 28 to 42 Days After 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.

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.
8.10.5. Visit 5 (Dose 4 Visit, 365 to 455 Days of Age)
NOTE: If participants do not receive Dose 4 by 20 April 2022, they will be ineligible for 
Dose 4 and discontinued as per Section 7. As with all participants who are discontinued 
prior to Dose 4, the parents/guardians should be encouraged to follow up with their primary 
care physician to have the participant complete the pneumococcal conjugate vaccine series 
with commercial Prevnar 13 as part of standard of care.

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.

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
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 rectal temperature (°C/°F).

Prior to vaccination, collect a blood sample of approximately 5 mL for immunogenicity 
(a topical anesthetic is permitted).

Administer a single 0.5-mL injection of 20vPnC or 13vPnC into the left anterolateral 
thigh.

Administer concomitant vaccines containing measles, mumps, rubella, and varicella
antigens and other permitted vaccines into a limb other than the site of 20vPnC or 
13vPnC injection, as appropriate for the age of the child and the route of vaccine 
administration (ie, intramuscular, subcutaneous, or oral), and record the site of 
administration on the CRF.
After vaccination:

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 (>104.0°F), 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 parent(s)/legal guardian(s) still possesses the participant contact 
card. Provide a participant contact card if needed.
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
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.
8.10.6. Visit 6 (Dose 4 Follow-up Visit, 28 to 42 Days After Dose 4)
NOTE:  Blood samples will be collected at this visit through 06 May 2022. After 
06 May 2022, blood samples will not be collected and the visit may be conducted by 
telephone.

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.

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.

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8.10.7. Visit 7 (Dose 4 6-Month Visit, 168 to 196 Days After Dose 4)
NOTE:

For a participant with Visit 5 performed after 18 Feb 2022 through 14 Mar 2022, the 
window is 168 to 196 days after Visit 5, or until 02 Sep 2022, whichever is earlier.

For a participant with Visit 5 performed on 15 Mar 2022 through 01 Apr 2022, the 
window for Visit 7 is 145 to 168 days after Visit 5, or until 02 Sep 2022, whichever is 
earlier.

For a participant with Visit 5 performed on 02 Apr 2022 through 20 Apr 2022, the 
window for Visit 7 is 126 to 145 days after Visit 5, or until 02 Sep 2022, whichever is 
earlier.

Contact the participant’s parent(s)/legal guardian(s) by telephone approximately 
6 months after the last study vaccination; this contact should be attempted for all 
participants who have received at least 1 study vaccination, unless the participant’s
parent(s)/legal guardian(s) has withdrawn consent.

Determine whether any 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.

The investigator or an authorized designee completes the CRF and the source documents.
8.10.8. 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 
(>104.0°F) 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 (>104.0°F), 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).

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
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.
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 rectal temperature (°C/°F).

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 for other findings associated with the reaction and record on the AE page of the 
CRF, if appropriate.
The investigator or an authorized designee will complete the unscheduled visit assessment 
page of the CRF.
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.

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9. STATISTICAL CONSIDERATIONS
Methodology for summary and statistical analyses of the data collected in this study is 
described here and further detailed in a statistical analysis plan (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 estimand corresponding to each primary, secondary,
 objective 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 
schedules and protocol requirements as directed. The estimand addresses the objective of 
estimating the maximum potential difference between 2 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 × 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
9.1.2.1. Pneumococcal Immunogenicity Hypotheses
9.1.2.1.1. Percentage of Participants With Predefined Pneumococcal Serotype-Specific 
IgG Concentration 1 Month After Dose 3 (Primary Pneumococcal Immunogenicity 
Objectives)
Hypothesis testing will be used to assess the noninferiority of 20vPnC to 13vPnC for
percentages of participants with predefined pneumococcal serotype-specific IgG 
concentrations 1 month after Dose 3. The null hypothesis (H0A) for a serotype is
H0A: π20vPnC – π13vPnC ≤–10%,
with a 10% margin for noninferiority, where

π20vPnC is the percentage of participants achieving an IgG antibody concentration of 
predefined level in the 20vPnC group for 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) in 13vPnC, π13vPnC is the percentage of participants achieving a
predefined IgG concentration level for the serotype from the 13vPnC group 1 month after 
Dose 3;
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
If the serotype is from the 7 additional serotypes (8, 10A, 11A, 12F, 15B, 22F, 33F) in 
20vPnC, π13vPnC 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 group, provided that the lowest percentage is 
not from serotype 3. If the lowest percentage in the 13vPnC group is from serotype 3, the 
next lowest percentage in the 13vPnC 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.

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 to 13vPnC 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 – 13vPnC) in 
percentages, based on the Miettinen and Nurminen method, is greater than –10% (10% 
noninferiority margin).
9.1.2.1.2. Pneumococcal Serotype-Specific IgG GMCs 1 Month After Dose 4 (Primary 
Pneumococcal Immunogenicity Objectives)
Hypothesis testing will be used to assess noninferiority of 20vPnC to 13vPnC for
pneumococcal serotype-specific IgG GMCs 1 month after Dose 4. The null hypothesis (H0B)
for a serotype is
H0B: ln(µ20vPnC) – ln(µ13vPnC) ≤ln(0.5)
where ln(0.5) corresponds to a 2-fold margin for noninferiority and

ln(μ20vPnC) is the natural log of the geometric mean IgG concentration in the 20vPnC 
group for that serotype 1 month after Dose 4;

If the serotype is from the 13 matched serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 
19A, 19F, 23F), ln(μ13vPnC) is the natural log of the geometric mean IgG concentration in 
the 13vPnC group 1 month after Dose 4;

If the serotype is from the 7 additional serotypes (8, 10A, 11A, 12F, 15B, 22F, 33F) in 
20vPnC, ln(μ13vPnC) is the natural log of the geometric mean IgG concentration for the 
serotype with the lowest IgG GMC 1 month after Dose 4 among the 13 serotypes from 
the 13vPnC group, provided that the lowest GMC is not from serotype 3. If the lowest 
GMC in the 13vPnC group is from serotype 3, the next lowest GMC in the 13vPnC group
will be used in the comparison. As stated in Section 9.1.2.1.1, historical data suggest that 
serotype 3 behaves somewhat differently from the other serotypes in 13vPnC; therefore,

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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 to 13vPnC for the
pneumococcal serotype-specific IgG GMC will be declared for a serotype if the lower bound 
of the 2-sided 95% CI for the IgG GMR of 20vPnC to 13vPnC is greater than 0.5 (2-fold 
noninferiority margin).
9.1.2.1.3. Pneumococcal Serotype-Specific IgG GMCs 1 Month After Dose 3 (Key 
Secondary Pneumococcal Immunogenicity Objectives)
Hypothesis testing to assess noninferiority of 20vPnC to 13vPnC for pneumococcal
serotype-specific IgG GMCs 1 month after Dose 3 will be performed similarly to that for IgG 
GMCs 1 month after Dose 4, as described in Section 9.1.2.1.2, with ln(μ20vPnC) and ln(μ13vPnC) 
being the natural log of the geometric mean IgG concentrations 1 month after Dose 3 from the 
20vPnC and 13vPnC groups, respectively. If the serotype is from the 7 additional serotypes 
(8, 10A, 11A, 12F, 15B, 22F, 33F) in 20vPnC, ln(μ13vPnC) is the natural log of the geometric 
mean IgG concentration for the serotype with the lowest IgG GMC among the 13 serotypes 
from the 13vPnC group, provided that the lowest GMC is not from serotype 3. If the lowest 
GMC in the 13vPnC group is from serotype 3, the next lowest GMC in the 13vPnC group will 
be used in the hypothesis testing.
The null hypothesis H0B will be rejected and noninferiority of 20vPnC to 13vPnC for the
pneumococcal serotype-specific IgG GMC will be declared for a serotype if the lower bound 
of the 2-sided 95% CI for the IgG GMR of 20vPnC to 13vPnC for the serotype is greater 
than 0.5 (2-fold noninferiority margin).
9.1.2.2. Concomitant Immunogenicity Hypotheses
9.1.2.2.1. Noninferiority for Percentage of Participants With Prespecified Antibody 
Level to Each Concomitant Vaccine Antigen at 1 Month After Dose 3 (Primary 
Concomitant Immunogenicity Objectives)
Hypothesis testing to assess noninferiority of the 20vPnC group to the 13vPnC group for
percentage of participants with prespecified antibody level to each concomitant vaccine 
antigen will be performed similarly to that for the percentage of participants with predefined 
serotype-specific IgG concentrations, as described in Section 9.1.2.1.1, with π20vPnC and 
π13vPnC being the percentages of participants with prespecified antibody levels to diphtheria
toxoid, tetanus toxoid, pertussis antigens (PT, FHA, PRN), HBsAg, poliovirus strains, or Hib 
at 1 month after Dose 3 from the 20vPnC and 13vPnC groups, respectively.  The following 
are the prespecified antibody thresholds for the concomitant vaccine antigens:
Antigen
Prespecified Level
Diphtheria
≥0.1 IU/mL
Tetanus
≥0.1 IU/mL
Acellular pertussis (PT, FHA, PRN)
≥ the observed antipertussis antibody concentration 
achieved by 95% of 13vPnC recipients

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Antigen
Prespecified Level
Hepatitis B
≥10 mIU/mL
Poliomyelitis (types 1, 2, and 3)
≥1:8
Hib
≥0.15 µg/mL anti-PRP 
Alternative: ≥1.0 µg/mL anti-PRP
The null hypothesis will be rejected and noninferiority will be declared for a concomitant 
vaccine antigen if the lower bound of the 2-sided 95% CI for the difference 
(20vPnC – 13vPnC) in percentages is greater than –10% (10% noninferiority margin) for that 
concomitant vaccine antigen.
9.1.2.2.2. Noninferiority for GMCs of Antibody Levels to Concomitant Vaccine Antigen 
at 1 Month After Dose 4 (Secondary Concomitant Immunogenicity Objectives)
Hypothesis testing to assess noninferiority of the 20vPnC group to the 13vPnC group for
GMCs of antibody levels to each concomitant vaccine antigen 1 month after Dose 4 will be 
performed similarly to that for the pneumococcal serotype-specific IgG concentration, as 
described in Section 9.1.2.1.2, with ln(µ20vPnC) and ln(µ13vPnC) being the natural log of the
GMCs for antibody levels to measles, mumps, rubella, and varicella viruses at 1 month after 
Dose 4 from the 20vPnC and 13vPnC groups, respectively.
The null hypothesis will be rejected and noninferiority will be declared for a concomitant 
vaccine antigen if the lower bound of the 2-sided 95% CI for GMR of the 20vPnC group to 
the 13vPnC group is greater than 0.5 (2-fold noninferiority margin) for that concomitant 
vaccine antigen.
9.1.3. Multiplicity Considerations
Pneumococcal Immunogenicity Evaluation
For the primary pneumococcal immunogenicity objectives comparing percentages of 
participants with predefined serotype-specific IgG concentration levels 1 month after Dose 3, 
noninferiority will be assessed by the hypothesis test as described in Section 9.1.2.1.1 at an 
alpha level of 0.05 for each serotype. The primary pneumococcal immunogenicity objectives
will be achieved if the noninferiority of 20vPnC to 13vPnC for the percentage of participants 
with the predefined IgG concentration level at 1 month after Dose 3 is established for all 
20 serotypes.
For the primary pneumococcal immunogenicity objectives comparing serotype-specific IgG
GMCs 1 month after Dose 4, noninferiority will be assessed by the hypothesis test as
described in Section 9.1.2.1.2 at an alpha level of 0.05 for each serotype. The primary 
pneumococcal immunogenicity objectives will be achieved if the noninferiority of the IgG 
GMCs from the 20vPnC group compared to the 13vPnC group at 1 month after Dose 4 is 
established for all 20 serotypes.

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The overall primary pneumococcal immunogenicity objectives will be achieved if 
noninferiority of 20vPnC comparing to 13vPnC based on both the percentage of participants
with predefined serotype-specific IgG concentration levels at 1 month after Dose 3 and the 
serotype-specific IgG GMC at 1 month after Dose 4 is demonstrated for all 20 serotypes.
Therefore, the overall type I error rate for the primary immunogenicity assessment of the 
pneumococcal immune response of 20vPnC is well controlled at the 0.05 level.
Concomitant Immunogenicity Evaluation
For the primary concomitant immunogenicity objective comparing immune responses 
induced by concomitant vaccine antigens at 1 month after Dose 3 from the 20vPnC group to 
that from the 13vPnC group, noninferiority is assessed by a hypothesis test 
(Section 9.1.2.2.1) at an alpha level of 0.05 for each concomitant vaccine antigen. The 
primary concomitant immunogenicity objective will be met if noninferiority is achieved for 
all concomitant vaccine antigens, diphtheria toxoid, tetanus toxoid, pertussis antigens (PT, 
FHA, PRN), HBsAg, poliovirus strains, and Hib. Therefore, the type I error rate for the 
concomitant immunogenicity assessment is well controlled at the 0.05 level.
Note that the noninferiority evaluations of concomitant immunogenicity results comparing 
the 20vPnC group to the 13vPnC group are meaningful only if the criteria for achieving the 
pneumococcal immunogenicity objectives are met. Consequently, there is no inflation in the 
type I error rate for the study, and no type I error adjustments are needed for the concomitant 
immunogenicity assessments.
9.2. Sample Size Determination
9.2.1. Sample Size Consideration for Primary Pneumococcal Immunogenicity 
Objectives
A total of approximately 2000 enrolled participants will yield approximately 1600 evaluable 
participants assuming a 20% nonevaluable rate for the study, resulting in approximately 
800 evaluable participants for each vaccine group with a 1:1 randomization ratio between the 
20vPnC and 13vPnC groups.  Sample size and power for the primary pneumococcal 
immunogenicity objectives associated with IgG concentration results at 1 month after Dose 3
and 1 month after Dose 4 are assessed based on simulations with assumptions supported by 
IgG results from an internal Pfizer Phase 2 infant study of 20vPnC (B7471003) following 
multivariate log-normal distributions 
Assuming the true GMCs and variance-covariance matrices for the 20 serotype-specific IgG 
concentrations from both 20vPnC and 13vPnC groups are the same as those observed from 
Study B7471003, with 800 evaluable participants from each vaccine group, the study has 
approximately 93% probability to show at least 37 (out of 40 total) positive noninferiority 
assessments comparing IgG results between the 20vPnC and 13vPnC groups, based on 
percentages of participants with predefined serotype specific IgG concentration levels at 
1 month after Dose 3 and serotype-specific IgG GMCs 1 month after Dose 4 for the 20 
serotypes.
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9.2.2. Sample Size Consideration for Concomitant Immunogenicity Objectives
For the primary concomitant immunogenicity objectives, Table 5 presents the minimum 
evaluable sample size required to demonstrate noninferiority based on the percentage of 
participants with prespecified antibody levels 1 month after Dose 3 with 10% noninferiority
margin for each concomitant vaccine antigen.  Evaluable sample sizes needed to achieve 
99% power to detect noninferiority for each antigen range from ~36 to ~367 per vaccine 
group.
Table 5.
Sample Size Required With Specified Power to Demonstrate NI 
Comparing the 20vPnC Group to the 13vPnC Group Based on Percentage
of Participants With Prespecified Antibody Levels 1 Month After Dose 3 
for Concomitant Antigens, With an NI Margin of 10%
Antigen
Antibody Level Threshold
Assumed Percentagea of 
Participants With 
Prespecified Threshold 
Reached
Sample Size per
Group With
20vPnC
13vPnC
At Least 
95% 
Power
At Least 
99% 
Power
Diphtheria
≥0.1 IU/mL
95
96
177
240
Tetanus
≥0.1 IU/mL
98
98
95
123
PT
≥ Concentration achieved by 
95% of 13vPnC group 
94
95
201
276
FHA
≥ Concentration achieved by 
95% of 13vPnC group 
95
95
155
212
PRN
≥ Concentration achieved by 
95% of 13vPnC group 
93
95
266
367
Hepatitis B
≥10 mIU/mL
100
100
36
36
Polio 1
≥1:8
100
100
36
36
Polio 2
≥1:8
98
99
101
128
Polio 3
≥1:8
100
100
36
36
Hib (PRP)
≥0.15 µg/mL
98
98
95
123
Abbreviations: FHA = filamentous hemagglutinin; Hib = Haemophilus influenzae type b;
NI = noninferiority; PRN = pertactin; PRP = polyribosylribitol phosphate; PT = pertussis toxin.
Note: NI criterion for each concomitant antigen: The lower bound of the 2-sided 95% CI for the difference 
between groups (20vPnC – 13vPnC) in the percentage of participants with specified threshold is 
above –10%, calculated using the Miettinen and Nurminen method.
a.
Differences between 20vPnC and 13vPnC are assumed to be similar to those observed between 13vPnC 
and Prevnar in Phase 3 Prevnar 13 Studies 6096A1-004 and 6096A1-3005.  Percentages of participants 
with specified thresholds for 13vPnC are assumed to be the same as observed in the 13vPnC groups in
Phase 3 Prevnar 13 Studies 6096A1-004 and 6096A1-3005.
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For the secondary concomitant immunogenicity objectives, Table 6 presents the minimum 
evaluable sample size required to demonstrate noninferiority based on the ratio of GMCs 
(GMRs) 1 month after Dose 4 with a 2-fold margin for each concomitant vaccine antigen.  
Evaluable sample sizes needed to achieve 99% power to detect noninferiority for each 
antigen range from ~20 to ~240 per vaccine group.
Table 6.
Sample Size Required With Specified Power to Demonstrate NI Based on 
Ratio of GMCs 1 Month After Dose 4 for Concomitant Antigens, With a
2-Fold NI Margin
Antigen
Assumed GMR for 
20vPnC vs 13vPnCa
Assumed Standard 
Deviation of GMRa (on 
the Natural Log Scale)
Sample Size per 
Group With
At Least
95% Power
At Least
99% Power
Measles
0.98
0.654
26
36
Mumps
1.00
0.743
31
44
Rubella
0.83
1.294
171
240
Varicella
1.00
0.497
15
20
Abbreviations: GMC = geometric mean concentration; GMR = geometric mean ratio; 
NI = noninferiority.
Note: NI criterion for each antigen: The lower bound of the 2-sided 95% CI for the GMR (20vPnC to 13vPnC) 
is greater than 0.5, calculated using a t-distribution.
a.
GMRs and standard deviations are obtained from an internal study (6096A1-004) for all antigens.
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9.3. Populations for Analysis
For purposes of analysis, the following populations 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 42 to 98 days of age 
(inclusive) on the day of first vaccination, receive the vaccines to 
which they are randomly assigned at the first 3 doses, have at least 1 
valid and determinate immunogenicity result from 1 month after 
Dose 3 visit (Visit 4), have blood collection within an appropriate 
window after Dose 3, and have no other major protocol deviations 
as determined by the clinician.
Dose 4 evaluable 
immunogenicity
All eligible randomized participants who are 42 to 98 days of age 
(inclusive) on the day of first vaccination, receive all 4 randomized 
vaccinations, with Dose 4 received within the defined window 
(365-455 days of age), have at least 1 valid and determinate 
immunogenicity result after Dose 4, have blood collection within an 
appropriate window after Dose 4, and have no other major protocol 
deviations as determined by the clinician.
 
 
 
Safety
All randomized participants who receive at least 1 dose of the 
investigational product and have safety data assessed after any dose.
9.4. Statistical Analyses
The SAP will be developed and finalized before database lock for any of the planned 
analyses in Section 9.5.1.  It will describe the participant populations to be included in the 
analyses and the procedures for accounting for missing, unused, and spurious data.  This 
section provides a summary of the planned statistical analyses of the primary, secondary,
 
 endpoints.
9.4.1. Immunogenicity Analyses
The statistical analysis of pneumococcal immunogenicity results will be primarily based on 
the evaluable immunogenicity populations as defined in Section 9.3.  The statistical analysis 
of concomitant immunogenicity results will be primarily based on the evaluable 
immunogenicity populations among those who receive the appropriate concomitant vaccines.
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Participants will be summarized according to the vaccine group to which they were 
randomized.
Endpoint
Statistical Analysis Methods
Primary 
pneumococcal 
immunogenicity

Percentages of participants with predefined pneumococcal 
serotype-specific IgG concentrations 1 month after Dose 3
For each of the 20 serotypes, the difference between groups
(20vPnC – 13vPnC) and its 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 group will be 
compared with the percentage for that serotype in the 13vPnC 
group. If a serotype is from the 7 additional serotypes, the 
percentage of participants with the predefined IgG level in the 
20vPnC group will be compared with the lowest percentage 
among the 13 serotypes from the 13vPnC group, provided that the 
lowest percentage is not from serotype 3.  If the lowest percentage 
in the 13vPnC group is from serotype 3, the next lowest 
percentage in the 13vPnC group will be used in the comparison.
The Miettinen and Nurminen method will be used to derive the CI 
for the difference in percentages between vaccine groups. The 
lower limit of the CI will be used in the hypothesis test for 
noninferiority of 20vPnC to 13vPnC as detailed in 
Section 9.1.2.1.1.
The analysis will be based on the Dose 3 evaluable 
immunogenicity population. 
 
 
 
Participants will be 
summarized according to the vaccine group to which they were 
randomized. Missing serology data will not be imputed.

GMRs of pneumococcal serotype-specific IgG concentrations 
from the 20vPnC group to the 13vPnC group 1 month after 
Dose 4
For each of the 20 serotypes, the GMR of 20vPnC to 13vPnC at 
1 month after Dose 4 will be provided. If a serotype is from the 13 
matched serotypes, the IgG GMC for the serotype in the 20vPnC 
group will be compared with the IgG GMC for that serotype in the 
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Endpoint
Statistical Analysis Methods
13vPnC group. If the serotype is from the 7 additional serotypes, 
the IgG GMC in the 20vPnC group will be compared with the 
lowest IgG GMC among the 13 serotypes from the 13vPnC group, 
provided that the lowest GMC is not from serotype 3.  If the 
lowest GMC in the 13vPnC group is from serotype 3, the next 
lowest GMC in the 13vPnC group will be used in the comparison. 
GMRs and their 2-sided 95% CIs will be derived by calculating 
differences in means and CIs on the natural log scale of the 
concentration based on the t-distribution, and then exponentiating 
the results. The difference in means, on the natural log scale, will 
be 20vPnC minus 13vPnC. The lower limit of the CI will be used 
in the hypothesis test for noninferiority of 20vPnC to 13vPnC as 
detailed in Section 9.1.2.1.2.
The analysis will be based on the Dose 4 evaluable 
immunogenicity population.  
 
 
 
Participants will be summarized according to the vaccine group to 
which they were randomized.  Missing serology data will not be 
imputed.
Primary 
concomitant 
immunogenicity

Percentages of participants with prespecified antibody levels to 
concomitant vaccine antigen 1 month after Dose 3
For each concomitant vaccine antigen,
a.
Antibody levels to diphtheria toxoid, tetanus toxoid, and 
pertussis antigens (PT, FHA, PRN),
b. Antibody levels to HBsAg,
c.
Antibody levels to poliovirus strains (types 1, 2, and 3),
d. Antibody levels to Hib,
The difference between groups (20vPnC – 13vPnC) and its 2-sided 
95% CI for the percentage of participants with prespecified 
antibody levels 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 lower 
limit of the CI will be used in the hypothesis test for assessing the 
noninferiority of the 20vPnC group to the 13vPnC group as 
detailed in Section 9.1.2.2.1.
The analysis will be based on the Dose 3 evaluable 
immunogenicity population, restricted to those who also receive 
the corresponding concomitant vaccines. 
 
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Endpoint
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Participants will be summarized 
according to the vaccine group to which they were randomized. 
Missing serology data will not be imputed.
Key secondary 
pneumococcal 
immunogenicity

GMRs of pneumococcal serotype-specific IgG concentrations 
from the 20vPnC group to the 13vPnC group 1 month after 
Dose 3
Serotype-specific IgG concentrations 1 month after Dose 3 will be 
analyzed similarly to the serotype-specific IgG concentrations 
1 month after Dose 4.  Hypothesis testing for noninferiority of 
20vPnC to 13vPnC will be performed as described in 
Section 9.1.2.1.3.
The analysis will be based on the Dose 3 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 
pneumococcal 
immunogenicity

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 will be provided for 
each group. Geometric means and the associated 2-sided CIs will 
be derived by calculating means and CIs on the natural log scale 
based on the t-distribution, and 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.
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Endpoint
Statistical Analysis Methods

GMFRs of pneumococcal serotype-specific IgG concentrations
GMFRs and 2-sided 95% CIs for 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.
Secondary
concomitant 
immunogenicity

Percentages of participants with alternative antibody levels to 
concomitant vaccine antigen at 1 month after Dose 3
Percentages (and Clopper-Pearson 2-sided 95% CIs) of 
participants with alternative prespecified antibody levels to Hib at 
1 month after Dose 3 will be provided for each vaccine group. 
Differences between groups (20vPnC – 13vPnC) in these 
percentages and the associated Miettinen and Nurminen CIs will 
be calculated.

GMRs of antibody levels to measles, mumps, rubella, and 
varicella viruses from the 20vPnC group to the 13vPnC group 
1 month after Dose 4
For each antibody level to measles, mumps, rubella, and varicella 
viruses, the GMR of the 20vPnC group to the 13vPnC group at 
1 month after Dose 4 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 t-distribution, and then 
exponentiating the results. The difference in means, on the natural 
log scale, will be 20vPnC minus 13vPnC. The lower limit of the 
CI will be used in the hypothesis test for noninferiority of the 
20vPnC group to the 13vPnC group as detailed in 
Section 9.1.2.2.2.

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
 
 
 
 

 
 
 
 

 
 
 
 

 
 
 
 

 
 
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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 – 13vPnC) in these percentages and 
their 2-sided 95% CIs will also be provided.  The Miettinen and 
Nurminen method will be used to derive the 95% CI for the difference in 
percentages between vaccine groups.
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Endpoint
Statistical Analysis Methods

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 
1% 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 the 20vPnC and 13vPnC groups 
will be calculated using the Miettinen and Nurminen 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,
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 for
SAEs and NDCMCs from Dose 1 to 6 months after Dose 4 will be 
provided for each vaccine group.
The safety analyses are based on the safety population. Participants 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)
9.4.3. Other Analyses 
None.
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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9.5.1. Analysis Timing
Statistical analyses will be carried out with all available data when:

Primary analysis: complete safety and immunogenicity data are available through 
1 month after Dose 4;

Final analysis: complete safety data are available through the visit occurring 6 months 
after Dose 4.
The study team will remain blinded up to the primary analysis. The investigator site staff 
will remain blinded to participant vaccine group until the last participant completes the final 
visit telephone call. Laboratory personnel performing the assays will remain blinded until all 
assays are completed.
 
 
 
 
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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 Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines;

Applicable ICH GCP guidelines;

Applicable laws and regulations, including applicable privacy laws.
The protocol, protocol amendments, ICD, IB, 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 Code of Federal Regulations (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 investigational 
product, 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 

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of any serious breaches of this protocol or of ICH GCP that the investigator becomes aware 
of.
10.1.2. Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities.  Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
10.1.3. Informed Consent Process
The investigator or 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) 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.

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A copy of the ICD(s) must be provided to the participant’s parent(s)/legal guardian(s).
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.  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), the European Clinical Trials 
Database (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 standard operating procedures (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, 
regardless of the geographical location in which the study is conducted.  The results are 
generally submitted for posting in accordance with the format and timelines set forth by US 
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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 (clinical study report [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 European Medicines Agency (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 contribute 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.

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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.
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.

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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 
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 electronic CRF (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.
10.1.8. Study and Site Closure
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 contract 
research organization (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.
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.

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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 18 months after 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.  The contact card contains, at a minimum, protocol and investigational product 
identifiers, participant numbers, contact information for the investigator site, and contact 
details for a contact center in the event that the investigator site 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 

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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, electrocardiogram [ECG], radiological scans, vital sign 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (ie, not related to 
progression of underlying disease).

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.

The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as an AE or SAE if they fulfill the definition of an AE or SAE.  Also, “lack of 
efficacy” or “failure of expected pharmacological action” constitutes an AE or SAE.

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Events NOT Meeting the AE Definition

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 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.

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 an NDCMC
An 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.
10.3.3. 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.

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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 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.

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10.3.4. 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 AEs; and 
(3) exposure to the investigational product 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 
investigational product 
under study during 
pregnancy or 
breastfeeding, and 
occupational exposure
None
All (and exposure during 
pregnancy [EDP] 
supplemental form for 
EDP)

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.
GRAD
E 
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 investigational product caused the 
event, then the event will be handled as “related to investigational product” 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 professionals.

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.
10.3.5. 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.
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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.

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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 drug-induced 
liver injury (DILI).  Participants who experience a transaminase elevation above 3 times the 
upper limit of normal (× ULN) should be monitored more frequently to determine if they are 
an “adaptor” or are “susceptible.”
Liver function tests (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 aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) precede total bilirubin (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, creatine kinase (CK), direct and 
indirect bilirubin, gamma-glutamyl transferase (GGT), prothrombin time/international 
normalized ratio (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 (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 sample for acetaminophen 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 and events related to the procedures involved except 
for events in users or other persons, which only include events related to 
investigational devices.

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.

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 and/or product information, for marketed 
products, 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.

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
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.
10.8.5. 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
CLIA
chemiluminescent immunoassay
CRF
case report form
CRM197
cross-reactive material 197
CRO
contract research organization
CSAP
clinical specimen assessment 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
ELISA
enzyme-linked immunosorbent assay
EMA
European Medicines Agency
EU
European Union
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration
FHA
filamentous hemagglutinin
CCI

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Abbreviation
Term
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GMC
geometric mean concentration
GMFR
geometric mean fold rise
GMR
geometric mean ratio
GMT
geometric mean titer
HBsAg
hepatitis B surface antigen
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
IND
investigational new drug
INR
international normalized ratio
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
MMR
measles, mumps, and rubella vaccine
N/A
not applicable
NA
neutralizing antibody
NDCMC
newly diagnosed chronic medical condition
NI
noninferiority
OPA
opsonophagocytic activity
PCD
primary completion date
PI
principal investigator
PPSV23
23-valent pneumococcal polysaccharide vaccine
PRN
pertactin
PRP
polyribosylribitol phosphate
PT
pertussis toxin
SADE
serious adverse device effect
CCI

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Abbreviation
Term
SAE
serious adverse event
SAP
statistical analysis plan
SoA
schedule of activities
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 effect
VT
vaccine-type
WHO
World Health Organization

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"' " .&-) *$  $ '), $ + )
Signed By:
Date(GMT)
Signing Capacity
	((	 12321
+4 5
	((	 9229
+4 5
PPD
PPD