A PHASE 3, SINGLE-ARM, OPEN-LABEL STUDY TO EVALUATE THE IMMUNOGENICITY, SAFETY, AND TOLERABILITY OF A TICK-BORNE ENCEPHALITIS VACCINE IN HEALTHY JAPANESE PARTICIPANTS 1 YEAR OF AGE AND OLDER
Phase: PHASE3
Conditions: Tick-Borne Encephalitis
Sponsor: Pfizer

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PFIZER CONFIDENTIAL
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A PHASE 3, SINGLE-ARM, OPEN-LABEL STUDY TO EVALUATE THE 
IMMUNOGENICITY, SAFETY, AND TOLERABILITY OF A TICK-BORNE 
ENCEPHALITIS VACCINE IN HEALTHY JAPANESE PARTICIPANTS 1 YEAR
OF AGE AND OLDER
Study Intervention Number:
PF-06830414
Study Intervention Name:
TBE vaccine
US IND Number:
N/A
EudraCT Number:
N/A
Protocol Number:
B9371039
Phase:
3
Short Title: A Phase 3, Single-Arm, Open-Label Study to Evaluate the Immunogenicity, 
Safety, and Tolerability of a TBE Vaccine in Healthy Japanese Participants 1 Year of Age 
and Older
This document and accompanying materials contain confidential information belonging to Pfizer.  Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this information 
in confidence and not copy or disclose it to others (except where required by applicable law) or use it for 
unauthorized purposes.  In the event of any actual or suspected breach of this obligation, Pfizer must be 
promptly notified.

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Protocol Amendment Summary of Changes Table
Document History
Document
Version Date
Summary and Rationale for Changes
Amendment 1
10 Nov 2020

Added fever to prespecified systemic 
events in primary safety endpoints for 
participants 1 to ≤2 years of age.

Prophylactic antipyretic/pain medication 
was removed from prohibited 
concomitant vaccines and treatments
during the study in Section 6.5.2 and 
added to permitted concomitant 
vaccines and treatments during the study 
in Section 6.5.3, with clarification that
use is not recommended on the day of 
vaccination. 

Clarified that pandemic vaccines may be 
given at any time; however, an interval 
of >14 days prior to or 14 days after 
investigational product administration is 
preferred.

In Section 7.2, added 3 reasons for 
participant discontinuation/withdrawal 
from the study.
Original protocol
22 Jul 2020
N/A

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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................8
1. PROTOCOL SUMMARY.....................................................................................................9
1.1. Synopsis ....................................................................................................................9
1.2. Schema ....................................................................................................................13
1.3. Schedule of Activities .............................................................................................14
2. INTRODUCTION ...............................................................................................................16
2.1. Study Rationale .......................................................................................................16
2.2. Background .............................................................................................................16
2.2.1. Tick-Borne Encephalitis.............................................................................16
2.2.2. TBE Vaccine...............................................................................................17
2.2.3. Status of TBE in Japan and the Development Request for TBE 
Vaccine ............................................................................................................17
2.2.4. Clinical Overview.......................................................................................17
2.3. Benefit/Risk Assessment.........................................................................................18
2.3.1. Risk Assessment.........................................................................................19
2.3.2. Benefit Assessment.....................................................................................20
2.3.3. Overall Benefit/Risk Conclusion................................................................20
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS ...........................................................20
4. STUDY DESIGN.................................................................................................................23
4.1. Overall Design.........................................................................................................23
4.2. Scientific Rationale for Study Design.....................................................................23
4.3. Justification for Dose ..............................................................................................23
4.4. End of Study Definition ..........................................................................................23
5. STUDY POPULATION......................................................................................................24
5.1. Inclusion Criteria.....................................................................................................24
5.2. Exclusion Criteria....................................................................................................25
5.3. Lifestyle Considerations..........................................................................................27
5.3.1. Contraception..............................................................................................27
5.4. Screen Failures ........................................................................................................27
5.5. Criteria for Temporarily Delaying Enrollment/Randomization/Study 
Intervention Administration ......................................................................................28

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6. STUDY INTERVENTION..................................................................................................28
6.1. Study Intervention(s) Administered........................................................................29
6.1.1. Administration............................................................................................29
6.1.2. Medical Devices .........................................................................................30
6.2. Preparation/Handling/Storage/Accountability ........................................................30
6.2.1. Preparation and Dispensing........................................................................31
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................31
6.3.1. Allocation to Study Intervention ................................................................31
6.4. Study Intervention Compliance...............................................................................32
6.5. Concomitant Therapy..............................................................................................32
6.5.1. Prohibited Concomitant Vaccines and Treatments Prior to the Study .......32
6.5.2. Prohibited Concomitant Vaccines and Treatments During the Study........32
6.5.3. Permitted Concomitant Vaccines and Treatments During the Study.........33
6.5.4. Recording Prior and Concomitant Vaccines and Treatments.....................33
6.6. Dose Modification...................................................................................................33
6.7. Intervention After the End of the Study..................................................................33
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................34
7.1. Discontinuation of Study Intervention ....................................................................34
7.2. Participant Discontinuation/Withdrawal From the Study.......................................34
7.2.1. Withdrawal of Consent...............................................................................35
7.3. Lost to Follow-up....................................................................................................36
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................36
8.1. Efficacy and/or Immunogenicity Assessments .......................................................37
8.1.1. Immunogenicity Assessments ....................................................................37
8.1.1.1. TBEV Antibody Testing ...........................................................38
8.1.2. Biological Samples.....................................................................................38
8.2. Safety Assessments .................................................................................................39
8.2.1. Participant Electronic Diary .......................................................................39
8.2.2. Grading Scale for Prompted Events ...........................................................39
8.2.2.1. Local Reactions.........................................................................39
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8.2.2.2. Systemic Events ........................................................................42
8.2.3. Physical Examinations................................................................................46
8.2.4. Vital Signs ..................................................................................................46
8.2.5. Clinical Safety Laboratory Assessments ....................................................46
8.2.6. Pregnancy Testing ......................................................................................47
8.3. Adverse Events and Serious Adverse Events..........................................................47
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......47
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................48
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................48
8.3.2. Method of Detecting AEs and SAEs ..........................................................48
8.3.3. Follow-up of AEs and SAEs.......................................................................48
8.3.4. Regulatory Reporting Requirements for SAEs...........................................49
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational 
Exposure ..........................................................................................................49
8.3.5.1. Exposure During Pregnancy......................................................49
8.3.5.2. Exposure During Breastfeeding ................................................51
8.3.5.3. Occupational Exposure .............................................................51
8.3.6. Cardiovascular and Death Events...............................................................52
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................52
8.3.8. Adverse Events of Special Interest.............................................................52
8.3.8.1. Lack of Efficacy........................................................................52
8.3.9. Medical Device Deficiencies......................................................................52
8.3.9.1. Time Period for Detecting Medical Device Deficiencies .........52
8.3.9.2. Follow-up of Medical Device Deficiencies...............................52
8.3.9.3. Prompt Reporting of Device Deficiencies to Sponsor ..............53
8.3.9.4. Regulatory Reporting Requirements for Device 
Deficiencies .......................................................................................53
8.3.10. Medication Errors.....................................................................................53
8.4. Treatment of Overdose............................................................................................54
8.5. Pharmacokinetics ....................................................................................................54
8.6. Pharmacodynamics..................................................................................................54

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8.9. Immunogenicity Assessments.................................................................................55
8.10. Health Economics .................................................................................................55
8.11. Study Procedures...................................................................................................55
8.11.1. Visit 1 (Dose 1 Visit, Day 1) ....................................................................55
8.11.2. Visit 2 (Dose 2 Visit, 21-35 Days After Visit 1 [Dose 1]) .......................57
8.11.3. Visit 3 (Blood Draw Visit, 21-35 Days After Visit 2 [Dose 2])...............59
8.11.4. Visit 4 (Dose 3 Visit, 150-365 Days After Dose 2)..................................59
8.11.5. Visit 5 (Dose 3 Follow-up Visit, 21-35 Days After Visit 4 [Dose 3])......61
8.11.6. Unscheduled Visits...................................................................................62
9. STATISTICAL CONSIDERATIONS ................................................................................63
9.1. Estimands and Statistical Hypotheses.....................................................................63
9.1.1. Estimands....................................................................................................63
9.1.1.1. Immunogenicity ........................................................................63
9.1.1.2. Safety.........................................................................................64
9.2. Sample Size Determination.....................................................................................64
9.3. Analysis Sets ...........................................................................................................65
9.4. Statistical Analyses .................................................................................................66
9.4.1. Immunogenicity Analyses ..........................................................................66
9.4.2. Safety Analyses ..........................................................................................67
9.5. Interim Analyses .....................................................................................................68
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................69
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............69
10.1.1. Regulatory and Ethical Considerations ....................................................69
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................69
10.1.2. Financial Disclosure .................................................................................70
10.1.3. Informed Consent Process ........................................................................70
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10.1.4. Data Protection .........................................................................................71
10.1.5. Dissemination of Clinical Study Data ......................................................71
10.1.6. Data Quality Assurance ............................................................................72
10.1.7. Source Documents....................................................................................74
10.1.8. Study and Site Start and Closure ..............................................................74
10.1.9. Publication Policy.....................................................................................75
10.1.10. Sponsor’s Qualified Medical Personnel .................................................75
10.2. Appendix 2: Clinical Laboratory Tests .................................................................76
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ......................................................................77
10.3.1. Definition of AE .......................................................................................77
10.3.2. Definition of SAE.....................................................................................78
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs.......................80
10.3.4. Reporting of SAEs....................................................................................83
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments ........89
10.7. Appendix 7: ECG Findings of Potential Clinical Concern ...................................90
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..............................................91
10.8.1. Definition of AE and ADE .......................................................................91
10.8.2. Definition of SAE, SADE, and Unanticipated Serious Adverse 
Device Effect ...................................................................................................91
10.8.3. Definition of Device Deficiency...............................................................92
10.8.4. Recording/Reporting and Follow-up of AEs and/or SAEs and 
Device Deficiencies .........................................................................................93
10.8.5. Reporting of SAEs....................................................................................95
10.8.6. Reporting of SADEs.................................................................................96
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10.9. Appendix 9: Country-Specific Requirements .......................................................97
10.9.1. Japan-Specific Regulatory Requirements.................................................97
10.9.1.1. Definitions of Serious Adverse Event, Serious Adverse 
Event Caused by Medical Device, and Unanticipated Serious 
Adverse Event Caused by Medical Device .......................................97
10.10. Appendix 10: Abbreviations ...............................................................................98
11. REFERENCES ................................................................................................................101
LIST OF TABLES
Table 1.
Grading Scale for Local Reactions (Participants ≥16 Years of Age).......40
Table 2.
Grading Scale for Local Reactions (Participants 1 to ≤2 Years of 
Age) ..........................................................................................................41
Table 3.
Grading Scale for Local Reactions (Participants >2 to <12 Years of 
Age) ..........................................................................................................41
Table 4.
Grading Scale for Local Reactions (Participants ≥12 to 16 Years 
of Age)......................................................................................................42
Table 5.
Grading Scale for Systemic Events (Participants ≥16 Years of Age) ......43
Table 6.
Grading Scale for Systemic Events (Participants 1 to ≤2 Years of 
Age) ..........................................................................................................44
Table 7.
Grading Scale for Systemic Events (Participants >2 to <12 Years of 
Age) ..........................................................................................................44
Table 8.
Grading Scale for Systemic Events (Participants ≥12 to <16 Years 
of Age)......................................................................................................45
Table 9.
Ranges for Fever.......................................................................................46

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1. PROTOCOL SUMMARY
1.1. Synopsis
Short Title
A Phase 3, Single-Arm, Open-Label Study to Evaluate the Immunogenicity, Safety, and 
Tolerability of a TBE Vaccine in Healthy Japanese Participants 1 Year of Age and Older.
Rationale
The Japanese Society of Travel and Health has submitted to the MHLW a recommendation 
to submit a development request for TBE vaccine in Japan, 
 
The purpose of this study is to provide key safety and immunogenicity data in Japanese 
participants.  Participants ≥16 years of age will receive the TBE vaccine 0.5 mL and 
participants ≥1 to <16 years of age will receive the TBE vaccine 0.25 mL.
Objectives, Estimands, and Endpoints
Primary Immunogenicity 
Objectives
Estimands
Primary Immunogenicity 
Endpoints
•
To evaluate the 
immunogenicity of TBE 
vaccine 0.5 mL by NT.
•
To evaluate the 
immunogenicity of TBE 
vaccine 0.25 mL by NT.
•
In healthy Japanese adult 
participants 16 years of age and 
older who received 3-dose TBE 
vaccine 0.5 mL in compliance 
with the key protocol criteria 
(evaluable participants): The 
proportion who are seropositive
(achieving NT titer ≥1:10) 
4 weeks after the third dose.
•
In healthy Japanese pediatric 
participants ≥1 to <16 years of 
age who received 3-dose TBE 
vaccine 0.25 mL in compliance 
with the key protocol criteria 
(evaluable participants): The 
proportion who are seropositive 
(achieving NT titer ≥1:10) 
4 weeks after the third dose.
TBEV-neutralizing antibody 
titers.
Primary Safety Objectives
Estimands
Primary Safety Endpoints
•
To evaluate the safety profile 
of TBE vaccine 0.5 mL.
•
To evaluate the safety profile 
of TBE vaccine 0.25 mL.
In healthy Japanese participants 
from each age group receiving at 
least 1 dose of investigational 
product:
•
The percentage of participants 
reporting local reactions within 
7 days after each vaccination.
•
Prespecified local reactions 
(redness, swelling, and pain at 
the injection site).
•
Prespecified systemic events 
(fever, decreased appetite, 
drowsiness, and irritability for 
participants 1 to ≤2 years of 
age; fever, fatigue, headache, 
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
The percentage of participants 
reporting systemic events 
within 7 days after each 
vaccination.

The percentage of participants 
reporting AEs within 1 month
after each dose.

The percentage of participants 
reporting SAEs during the study 
period.
vomiting, diarrhea, muscle 
pain, and joint pain for 
participants >2 years of age).

AEs within 1 month after 
vaccination.

SAEs throughout the study.
Secondary Immunogenicity 
Objectives
Estimands
Secondary Immunogenicity 
Endpoints

To describe the 
immunogenicity of TBE 
vaccine 0.5 mL by NT.

To describe the 
immunogenicity of TBE 
vaccine 0.25 mL by NT.
In healthy Japanese adult 
participants 16 years of age and 
older who received 3-dose TBE 
vaccine 0.5 mL in compliance with 
the key protocol criteria (evaluable 
participants):

The proportion who are 
seropositive (achieving NT titer 
≥1:10) 4 weeks after the second 
dose.

NT GMTs 4 weeks after the 
second and 4 weeks after the 
third dose.

NT GMFRs 4 weeks after the 
second and 4 weeks after the 
third dose as compared to 
baseline.

NT GMFR 4 weeks after the 
third dose as compared to 
4 weeks after the second dose.
In healthy Japanese pediatric 
participants 1 through 15 years of 
age who received 3-dose TBE 
vaccine 0.25 mL in compliance 
with the key protocol criteria 
(evaluable participants):

The proportion who are 
seropositive (achieving NT titer 
≥1:10) 4 weeks after the second 
dose.

NT GMTs 4 weeks after the 
second and 4 weeks after the 
third dose.

NT GMFRs 4 weeks after the 
second and 4 weeks after the 
third dose as compared to 
baseline.
TBEV-neutralizing antibody 
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•
NT GMFR 4 weeks after the 
third dose as compared to 
4 weeks after the second dose.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Overall Design
This Phase 3, multicenter, single-arm, open-label study will be conducted at investigator sites 
in Japan.  This study is part of the Phase 3 clinical development plan to support use of TBE 
vaccine 0.5 mL and 0.25 mL in healthy Japanese adults (≥16 years of age) and pediatric 
population (≥1 to 16 years of age).  The purpose of this study is to provide key safety and 
immunogenicity data in Japanese participants.
Number of Participants
Approximately 100 adults (≥16 years of age at the time of consent) and 65 children (≥1 to 
16 years of age at the time of consent) will be enrolled to receive study intervention such 
that approximately 150 evaluable participants complete the study.
Note: "Enrolled" means that a participant, or his or her legally authorized representative, has 
agreed to participate in a clinical study following completion of the informed consent process 
and is deemed eligible to participate.  Potential participants who are screened for the purpose 
of determining eligibility for the study, but do not participate in the study, are not considered 
enrolled, unless otherwise specified by the protocol.
Intervention Groups and Duration
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, medical device(s), or study procedure(s) intended to be administered to a study 
participant according to the study protocol.
For this study, the investigational product is TBE vaccine 0.5 mL and 0.25 mL.
Inactivated TBE Vaccine
TBE Vaccine 0.5 mL
TBE vaccine 0.5 mL contains formaldehyde-inactivated TBEV. The vaccine is formulated to 
contain 2 to 2.75 µg of inactivated TBEV (target: 2.4 µg) in 0.5 mL.
The dose will be administered intramuscularly into the deltoid muscle of the right or left 
upper arm (preferably in the nondominant arm) at Visits 1, 2, and 4 by an appropriately 
qualified site staff member or designee.
TBE Vaccine 0.25 mL
TBE vaccine 0.25 mL contains formaldehyde-inactivated TBEV. The vaccine is formulated 
to contain 1 to 1.38 µg of inactivated TBEV (target: 1.2 µg) in 0.25 mL.
The dose will be administered intramuscularly into the deltoid muscle of the right or left 
upper arm (preferably in the nondominant arm) at Visits 1, 2, and 4 by an appropriately 
qualified site staff member or designee.  However, in children up to 18 months of age or 

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dependent on a child’s development and nutrition status, TBE vaccine should be 
administered intramuscularly by injecting 0.25 mL into the anterolateral thigh muscle (refer 
to Section 6.1.1).
Vaccinations to Be Given at Visits 1, 2, and 4
Formulation/Schedule
Number of Participants (As Enrolled)
TBE vaccine 0.5 mL / Visits 1, 2, and 4
100
TBE vaccine 0.25 mL / Visits 1, 2, and 4
65
Statistical Methods
The primary hypothesis to be tested is that the seropositivity rate based on the TBEV 
neutralization antibody level 4 weeks after the third dose is more than 90% in each age 
population.  The primary endpoint will be tested by the exact method, which corresponds to 
evaluating 95% CI based on the Clopper-Pearson method comparing its lower limit to 90%.  
Assuming the expected seropositivity rate among 90 evaluable adults to be 99.4% and among 
60 evaluable children to be 99.6%, the statistical power to reject each null hypothesis 
(equivalently to demonstrate that the lower limit of the 95% CI of the estimate will exceed 
90%) is computed to be >99% and 97.3%, respectively.  Considering 10% dropout, 100 adult 
participants and 65 pediatric participants are intended to be enrolled.
1.2. Schema
Not applicable.
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1.3. Schedule of Activities
The SoA table provides an overview of the protocol visits and procedures.  Refer to the Study Assessments and Procedures section of 
the protocol for detailed information on each procedure and assessment required for compliance with the protocol.
The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA table, in order to conduct evaluations or 
assessments required to protect the well-being of the participant.
Visit Number
1
2
3
4
5
Visit ID
1st Vaccination
2nd Vaccination
Blood Draw
3rd Vaccination
Blood Draw
Visit Window
Day 1
21-35 Days
After 1st 
Vaccination
21-35 Days
After 2nd 
Vaccination
150-365 Days
After 2nd 
Vaccination
21 -35 Days
After 3rd 
Vaccination
Informed consent/assent
X
Provide participant contact card
X
Demographics
X
Medical history 
X
Concomitant vaccination and/or 
medicationa
X
X
X
X
X
Physical examinationb
X
X
X
Prevaccination axillary temperature
X
X
X
Urine pregnancy test (females of 
childbearing potential)c
X
X
X
Discuss contraceptive usec
X
X
X
Inclusion and exclusion criteriac
X
Temporary vaccination delay 
criteriab
X
X
X
Confirm continuing eligibilityc
X
X
X
X
Immunogenicity blood sampling
(TBEV NT 
)c
X
X
X
X
 
Investigational product 
administration
X
X
X
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Visit Number
1
2
3
4
5
Visit ID
1st Vaccination
2nd Vaccination
Blood Draw
3rd Vaccination
Blood Draw
Visit Window
Day 1
21-35 Days
After 1st 
Vaccination
21-35 Days
After 2nd 
Vaccination
150-365 Days
After 2nd 
Vaccination
21 -35 Days
After 3rd 
Vaccination
30-Minute postvaccination 
observation and assessment of acute 
reactions 
X
X
X
Dispense e-diary, digital 
thermometer, and caliper
X
Participants to record local reactions 
and systemic events in e-diaryd
Days 1 to 7
From 2nd vaccination 
to 6 days after
From 3rd vaccination 
to 6 days after
Review e-diary data
X--------
X--------
X--------
Collect e-diary
X
AE/SAE assessmente
X
X
X
X
X
Abbreviations: 
 HI = hemagglutination inhibition; 
 NT = neutralization test; 
TBEV = tick-borne encephalitis virus. 
a.
Record only concomitant medications used to treat SAEs; the use of prophylactic antipyretic/pain medication, while permitted, is not recommended on the 
day of vaccination. Administration of JEV vaccine is prohibited during a participant’s participation in this study.
b.
Prior to vaccination at Visit 1, a complete physical examination should be performed.  Prior to vaccination at Visits 2 and 4, a physical examination should 
be performed if the clinical assessment indicates that a physical examination is necessary to comprehensively evaluate the participant.  See Section 8.2.3.
c.
Prior to vaccination, if at a vaccination visit.
d.
The participant’s legally acceptable representative/parents/legal guardian is to record local reactions and systemic events for participants 1 through 15 years 
of age.  The participant’s legally acceptable representative/patient/legal guardian should monitor the participant’s compliance of data entry for participants 
16 through 19 years of age.
e.
The active collection period of AEs and SAEs for each participant begins from the time the participant/parent(s)/legal guardian/legally authorized 
representative provides informed consent through and including Visit 3, and from Visit 4 to Visit 5.  Between Visit 3 and Visit 4, only SAEs will be 
reported.  The detailed information is shown in Section 8.3.1.
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2. INTRODUCTION
TBE vaccine 0.5 mL and 0.25 mL are inactivated vaccines that are approved for prevention 
of TBE in European and other countries 
 
2.1. Study Rationale
The purpose of the study is to evaluate the immunogenicity, safety, and tolerability of TBE 
vaccine in healthy Japanese participants 1 year of age and older.  Many clinical studies in 
adults and children have been conducted overseas, which have confirmed the safety and 
immunogenicity of this vaccine in both adults and pediatric non-Japanese populations.  The 
field effectiveness of this vaccine has also been demonstrated in endemic countries where the 
vaccine has been approved.
2.2. Background
2.2.1. Tick-Borne Encephalitis
TBE is a disease caused by infection with the TBEV, which belongs to the genus Flavivirus 
in the family Flaviviridae, and can be categorized into Far Eastern, Siberian, and European 
subtypes.  The Siberian subtype is distributed mostly in Siberia, the Baltic states, and others; 
the Far Eastern subtype is distributed in China, Far Eastern Russia, Siberia, and Japan.  The 
European subtype is distributed throughout Europe and South Korea.  Recently the Baikalian 
subtype (Republic of Buryatia, Irkutsk, and Chita) and some other putatively new subtypes 
have been described.1,2,3  TBEV infection is asymptomatic in most cases.  In patients 
developing symptoms after infection, the incubation period is most commonly 7 to 14 days.  
Symptomatic infection due to the European subtype is characterized by a 2-phase illness.  
First symptoms include virus reproduction in the regional lymph nodes, as well as viremia 
and pyrexia, and then, after about a 1-week asymptomatic period, patients develop 
meningitis, encephalitis, myelitis, and combinations thereof.  One year after the acute phase 
of viral infection, chronic impairment of the central nervous system occurs in approximately 
30% of patients, and severe functional impairment requiring assistance for day-to-day 
activities occurs in 8.5% of patients.4  The mortality among infected patients is said to be 1% 
to 2%, and it is up to 20% among patients infected with the Siberian subtype virus.  The 
incubation period in patients infected with the Far Eastern subtype virus is 7 to 14 days.  
Disease due to infection with this subtype often does not have 2 phases as the disease caused 
by the European subtype does in many cases.  After the incubation period, headache, pyrexia, 
nausea, and vomiting occur, and at the peak of disease, mental confusion, lethargy, 
convulsion, paralysis, and other symptoms of encephalitis may occur.  The mortality can be 
≥20%, and 30% to 40% of survivors continue to have neurological sequelae.5
There is no specific therapy for TBE.  The WHO recommends vaccination as an effective 
means of prophylaxis for residents and people traveling to endemic areas.6
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2.2.2. TBE Vaccine
These are vaccines that consist of a glass prefilled syringe with a 0.5-mL solution (brand 
name overseas: FSME-IMMUN/TicoVac) containing 2.4 μg of TBEV inactivated with 
formaldehyde, or a 0.25-mL solution (brand name overseas: FSME-IMMUN Junior/TicoVac 
Junior) containing 1.2 μg of TBEV inactivated with formaldehyde. These vaccines also 
contain human serum albumin as a stabilizer and aluminum hydroxide as an adjuvant.
These vaccines, 0.5 mL and 0.25 mL (hereafter referred to as “investigational product” or 
“study intervention”), were first commercially available in Austria in 1976 and have since 
been marketed in the UK, France, Germany, and other European countries, as well as Russia.  
About 140 million doses of the vaccine have been supplied, including ≥75 million doses of 
the current formulation, which has been available since 2001.  Many clinical studies in adults 
and children have been conducted overseas, which have demonstrated the safety and 
immunogenicity of investigational product in both adults and children.  The field 
effectiveness of investigational product has also been demonstrated in Austria, where high 
vaccine coverage led to a decline in TBE incidence.7,8,9
2.2.3. Status of TBE in Japan and the Development Request for TBE Vaccine
The first TBE case in Japan was reported in Hokkaido in 1993.  As of the end of February 
2019, 4 additional cases have been reported in Hokkaido.10  However, as no commercially 
available diagnostic ELISA kit for TBE is available in Japan to date, and since patients with 
CNS symptoms in Japan are not systematically tested for TBE infection, underdiagnosis is a 
possibility.  At the same time, it has been reported in epizootiological surveys that the virus is 
circulating in nature in Japan.11
As described above, there have recently been cases of TBE reported in Japan.  Further, as 
described in Section 2.2.1, there is a medical need for immunization based on the WHO 
recommendation that travelers visiting various endemic areas be immunized if their visits 
will include extensive outdoor activities.  However, there is no TBE vaccine currently 
approved in Japan.  
 
 
2.2.4. Clinical Overview
Overseas Clinical Study Data
TBE vaccine has to date been investigated in numerous clinical studies in adults and 
children, all of which were conducted in Europe.  Data from these studies were used to select 
the dose and administration schedule with which TBE vaccine was confirmed to be safe and 
immunogenic and, accordingly, approved in European countries.
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Furthermore, the benefit/risk of TBE vaccine for adult and pediatric populations remains 
positive for individuals at risk of exposure to TBEV based on the database of postmarketing 
adverse drug reactions.
2.3. Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of TBE vaccine may be found in the IB, which is the SRSD for this study.

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2.3.1. Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Intervention(s) [TBE Vaccine] 
Potential risks associated with TBE vaccine include 
but are not limited to the following: local reactions 
(injection site pain or tenderness, redness, and 
swelling) and systemic events (fever, irritability, 
decreased appetite, and increased sleep).
As with any vaccine, an allergic reaction can occur.  
The allergic reaction can vary from skin rash to 
swelling of the face or lips, wheezing, and/or 
shortness of breath.  A severe allergic reaction 
(anaphylactic shock, collapse, or shock-like state 
[hypotonic-hyporesponsive episode]) may also 
occur.  There may also be additional risks related to 
the vaccines administered in the study that are not 
known at this time.
The potential risks are based on the IB for TBE 
vaccine.
Safety assessments (ie, local reactions, systemic 
events, AEs [including observation for 30 minutes 
after vaccination], and SAEs) 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.
Study Procedures
Risks that may be associated with study procedures 
include risks from blood draws, including pain, 
swelling, bruising, and infection where blood is 
taken.
Risks and possible discomforts from the study 
procedures such as pain, swelling, bruising, 
infection around the vein where the child’s blood is 
collected may also occur, although this is very 
uncommon.
The volume and frequency of blood draws required 
during the study has been minimized as far as 
possible.

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2.3.2. Benefit Assessment
TBE is a rare but potentially fatal disease in Japan.10,11  In endemic countries where the 
vaccine has been approved, field effectiveness studies of TBE vaccine have demonstrated its 
efficacy.7,8,9  Thus, participants are expected to be protected from TBEV infection by 
receiving TBE vaccine in this study.  Moreover, TBE vaccine is a vaccine requested by 
MHLW for development in Japan because of high medical need.12  Participants will 
contribute to a growing body of knowledge regarding the effectiveness and safety of this 
vaccine in an area of high medical need.
2.3.3. Overall Benefit/Risk Conclusion
The potential risks and benefits demonstrated with TBE vaccine reflect a positive benefit/risk 
profile.
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS
Primary Immunogenicity 
Objectives
Estimands
Primary Immunogenicity 
Endpoints

To evaluate the 
immunogenicity of TBE 
vaccine 0.5 mL by NT.

To evaluate the 
immunogenicity of TBE 
vaccine 0.25 mL by NT.

In healthy Japanese adult 
participants 16 years of age and 
older who received 3-dose TBE 
vaccine 0.5 mL in compliance 
with the key protocol criteria 
(evaluable participants): The 
proportion who are seropositive
(achieving NT titer ≥1:10) 
4 weeks after the third dose.

In healthy Japanese pediatric 
participants ≥1 to <16 years of 
age who received 3-dose TBE 
vaccine 0.25 mL in compliance 
with the key protocol criteria 
(evaluable participants): The 
proportion who are seropositive
(achieving NT titer ≥1:10) 
4 weeks after the third dose.
TBEV-neutralizing antibody 
titers.
Primary Safety Objectives
Estimands
Primary Safety Endpoints

To evaluate the safety profile 
of TBE vaccine 0.5 mL.

To evaluate the safety profile 
of TBE vaccine 0.25 mL.
In healthy Japanese participants 
from each age group receiving at 
least 1 dose of investigational 
product:

The percentage of participants 
reporting local reactions within 
7 days after each vaccination

The percentage of participants 
reporting systemic events 
within 7 days after each 
vaccination.

Prespecified local reactions 
(redness, swelling, and pain at 
the injection site).

Prespecified systemic events 
(fever, decreased appetite, 
drowsiness, and irritability for 
participants 1 to ≤2 years of 
age; fever, fatigue, headache, 
vomiting, diarrhea, muscle 
pain, and joint pain for 
participants >2 years of age).

AEs within 1 month after 
vaccination.

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
The percentage of participants 
reporting AEs within 1 month 
after each dose.

The percentage of participants 
reporting SAEs during the study 
period.

SAEs throughout the study.
Secondary Immunogenicity 
Objectives
Estimands
Secondary Immunogenicity 
Endpoints

To describe the 
immunogenicity of TBE 
vaccine 0.5 mL by NT.

To describe the 
immunogenicity of TBE 
vaccine 0.25 mL by NT.
In healthy Japanese adult 
participants 16 years of age and 
older who received 3-dose TBE 
vaccine 0.5 mL in compliance with 
the key protocol criteria (evaluable 
participants):

The proportion who are
seropositive (achieving NT titer 
≥1:10) 4 weeks after the second 
dose.

NT GMTs 4 weeks after the 
second and 4 weeks after the 
third dose.

NT GMFRs 4 weeks after the 
second and 4 weeks after the 
third dose as compared to 
baseline.

NT GMFR 4 weeks after the 
third dose as compared to 
4 weeks after the second dose.
In healthy Japanese pediatric 
participants 1 through 15 years of 
age who received 3-dose TBE 
vaccine 0.25 mL in compliance 
with the key protocol criteria 
(evaluable participants):

The proportion who are
seropositive (achieving NT titer 
≥1:10) 4 weeks after the second 
dose.

NT GMTs 4 weeks after the 
second and 4 weeks after the 
third dose.

NT GMFRs 4 weeks after the 
second and 4 weeks after the 
third dose as compared to 
baseline.

NT GMFR 4 weeks after the 
third dose as compared to 
4 weeks after the second dose.
TBEV-neutralizing antibody 
titers.

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4. STUDY DESIGN
4.1. Overall Design
This Phase 3, multicenter, single-arm, open-label study will be conducted at investigator sites 
in Japan.  This study is part of the Phase 3 clinical development plan to support use of TBE 
vaccine 0.5 mL and 0.25 mL in healthy Japanese adults (≥16 years of age) and the pediatric 
population (≥1 and <16 years of age).  The purpose of this study is to provide key safety and 
immunogenicity data in Japanese participants.  Study duration is approximately 7 to 15 
months for each participant.
Approximately 100 adults (≥16 years of age at the time of consent) and 65 children (≥1 to 
<16 years of age at the time of consent) will be enrolled to receive study intervention such 
that approximately 150 evaluable participants complete the study.
4.2. Scientific Rationale for Study Design
TBE vaccine has been approved in many countries for adults (≥16 years of age) and children 
(≥1 to <16 years of age) at the 2 dosages assessed in this study.  This study will assess TBE 
vaccine in Japanese adult and pediatric populations at the dose and administration schedule 
equivalent to what has been approved overseas.
Human reproductive safety data are limited for TBE vaccine; however, based on the few 
cases of exposure during pregnancy and lactation, no overt safety signal was identified.  
Therefore, given the paucity of information regarding safety of vaccination during pregnancy 
or lactation, the use of a highly effective method of contraception is required for this trial 
(see Appendix 4).
4.3. Justification for Dose
TBE vaccine is the inactivated vaccine containing formaldehyde-inactivated TBEV.  As 
mentioned in Section 2.2.4, based on abundant clinical study data, the approved dosage and 
administration of TBE vaccine has been demonstrated to be safe and immunogenic.  Pfizer 
considers that the same dosage and administration is appropriate in the Japanese population 
because there is no precedent where an inactivated vaccine, introduced from overseas, has 
needed an alternate dosage in Japanese as compared to non-Japanese participants.
4.4. End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases of 
the study, including the last visit.
The end of the study is defined as the date of the last visit of the last participant in the study.

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5. STUDY POPULATION
This study can fulfill its objectives only if appropriate participants are enrolled.  The 
following eligibility criteria are designed to select participants for whom participation in the 
study is considered appropriate.  All relevant medical and nonmedical conditions should be 
taken into consideration when deciding whether a particular participant is suitable for this 
protocol.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
Pfizer will review eligibility criteria verified by the investigator or qualified designee to 
confirm that participants meet study eligibility criteria before they are enrolled into the study.  
The enrollment approval process will be initiated for a participant after an informed consent 
document has been signed and the investigator or qualified designee has assessed the 
participant as eligible.  The enrollment approval will be based on review of CRF/system data.
5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Group 1: Participants ≥16 Years of Age
Age and Sex:
1. Japanese male or female participants ≥16 years of age at Visit 1 (the time of consent).

Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female 
(Section 10.4.2) participants.
Type of Participant and Disease Characteristics:
2. Participants (and a legally acceptable representative/parent/legal guardian if the 
participant is 16 to <20 years of age) who are willing and able to comply with all 
scheduled visits, vaccination plan, and other study procedures including completion 
of the e-diary for 7 days for participants after each of 3 vaccinations.
3. Participants (and/or a legally acceptable representative/parent/legal guardian if the 
participant is 16 to <20 years of age) must be able to be contacted by telephone 
during study participation.
Informed Consent:
4. Participants (and a legally acceptable representative/parent/legal guardian if the 
participant is 16 to <20 years of age) are capable of giving signed informed consent 
as described in Appendix 1, which includes compliance with the requirements and 
restrictions listed in the ICD and in this protocol.

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Group 2: Participants 1 to <16 Years of Age
1. Japanese male or female participants between the ages of ≥1 and <16 years, inclusive 
(ie, <16 years), at Visit 1 (the time of consent).

Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female 
(Section 10.4.2) participants.
Type of Participant and Disease Characteristics:
2. Participants whose parent(s)/legal guardian(s) is willing and able to comply with all 
scheduled visits, vaccination plan, and other study procedures including completion 
of the e-diary for 7 days for participants after each of 3 vaccinations.
3. The legally acceptable representative/parent/legal guardian must be able to be 
contacted by telephone during study participation.
Informed Consent:
4. Participants whose parent(s)/legal guardian(s) are capable of giving signed informed 
consent as described in Appendix 1, which includes compliance with the 
requirements and restrictions listed in the ICD and in this protocol.
5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Common for Groups 1 and 2
Medical Conditions:
1. Medical or psychiatric condition including recent (within the past year) or active 
suicidal ideation/behavior or laboratory abnormality that may increase the risk of 
study participation or, in the investigator’s judgment, make the participant 
inappropriate for the study.
2. History of severe adverse reaction associated with a vaccine and/or severe allergic 
reaction (eg, anaphylaxis) to any component of the vaccines being administered in the 
study.  History of severe hypersensitivity to egg and chicken proteins (anaphylactic 
reaction after oral ingestion of egg protein).
3. Significant neurological disorder or history of seizure including febrile seizure, or 
significant stable or evolving disorders such as cerebral palsy, encephalopathy, 
hydrocephalus, or other significant neurological disorders.  Does not include history 
of resolving syndromes due to birth trauma, such as Erb’s palsy and/or hypotonic-
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4. Major known congenital malformation or serious chronic disorder.
5. Known history of TBEV infection.
6. Known history of other flavivirus infection (eg, dengue fever, yellow fever, JEV, 
West Nile virus).
7. Known history of infection with HIV, HCV, or HBV.
8. Immunocompromised participants with known or suspected immunodeficiency, as 
determined by history and/or laboratory/physical examination.
9. History of autoimmune disease or an active autoimmune disease requiring therapeutic 
intervention including but not limited to: systemic or cutaneous lupus erythematosus, 
autoimmune arthritis/rheumatoid arthritis, Guillain-Barré syndrome, multiple 
sclerosis, Sjögren’s syndrome, idiopathic thrombocytopenia purpura, 
glomerulonephritis, autoimmune thyroiditis, giant cell arteritis (temporal arteritis), 
psoriasis, and/or insulin-dependent diabetes mellitus (type 1).
10. Other acute or chronic medical or psychiatric condition including recent (within the 
past year) or active suicidal ideation or behavior 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 participants inappropriate for entry into 
this study.
11. Bleeding diathesis or condition associated with prolonged bleeding time that would 
contraindicate any type of injection.
Prior/Concomitant Therapy:
12. Previous vaccination with any licensed or investigational TBE vaccine, or planned 
receipt of other flavivirus vaccines apart from JEV vaccine (eg, yellow fever, dengue 
fever) during the study.  (Note: Administration of JEV vaccine is prohibited during a 
participant’s participation in this study.)
13. Participants who receive treatment with immunosuppressive therapy, including 
cytotoxic agents or systemic corticosteroids, eg, for cancer or an autoimmune disease, 
or planned receipt throughout the study.  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.  
Intra-articular, intrabursal, inhaled/nebulized, or topical (skin or eyes) corticosteroids 
are permitted.

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14. Receipt of blood/plasma products or immunoglobulin, from 60 days before 
investigational product administration or planned receipt throughout the study.
Prior/Concurrent Clinical Study Experience:
15. Previous administration with an investigational drug within 30 days prior to study 
entry and/or during study participation.  Participation in purely observational studies 
is acceptable.
Diagnostic Assessments:
Not applicable.
Other Exclusions:
16. Investigator site staff or Pfizer employees directly involved in the conduct of the 
study, site staff otherwise supervised by the investigator, and their respective family 
members.
17. Females who are pregnant or breastfeeding.
5.3. Lifestyle Considerations
5.3.1. Contraception
The investigator or his or her designee, in consultation with the participant, will confirm that 
the participant has selected an appropriate method of contraception for the individual 
participant and his/her partner(s) 
 
 and will confirm that the participant has been instructed in its 
consistent and correct use.  At time points indicated in the SoA, the investigator or designee 
will inform the participant of the need to use highly effective contraception consistently and 
correctly and document the conversation and the participant’s affirmation in the participant’s 
chart (participants need to affirm their consistent and correct use of at least 1 of the selected 
methods of contraception).  In addition, the investigator or designee will instruct the 
participant to call immediately if the selected contraception method is discontinued or if 
pregnancy is known or suspected in the participant or partner.
5.4. Screen Failures
Screen failures are defined as participants who consent (or whose legally acceptable 
representative/parent/legal guardian consent if the participant is 1 to <20 years of age) to 
participate in the clinical study but are not subsequently enrolled in the study.  A minimal set 
of screen failure information is required to ensure transparent reporting of screen failure 
participants to meet the CONSORT publishing requirements and to respond to queries from 
regulatory authorities.  Minimal information includes demography, screen failure details, 
eligibility criteria, and any SAEs.
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5.5. Criteria for Temporarily Delaying Enrollment/Randomization/Study Intervention 
Administration
The following conditions may allow a participant to be enrolled/started on study intervention 
once the conditions have resolved and the participant is otherwise eligible:

Current febrile illness (axillary temperature 37.5°C) or other acute illness within 
48 hours before investigational product administration.

Receipt of systemic antibiotic therapy for other acute illness within 72 hours before 
investigational product administration.

Receipt of any inactivated vaccine within 14 days or any live vaccine within 28 days 
before or anticipated receipt of any vaccine within the 14 days (in the case of 
inactivated vaccine) or 28 days (in the case of live vaccine) after investigational 
product administration.

Receipt of short-term (<14 days) systemic corticosteroids.  Investigational product 
administration should be delayed until systemic corticosteroid use has been 
discontinued for at least 28 days.  Inhaled/nebulized, intra-articular, intrabursal, or 
topical (skin or eyes) corticosteroids are permitted.
6. STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, medical device(s), or study procedure(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.

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6.1. Study Intervention(s) Administered
Intervention Name
Tick-borne encephalitis vaccine, PF-06830414
Type
Biologic
Dose Formulation
Suspension for injection in a pre-filled syringe
Composition of TBE Vaccines
Composition of a Single Dose 
FSME-IMMUN 
0.25 mL
FSME-IMMUN 0.5 
mL
Formaldehyde-inactivated 
TBEVa
Target 1.2 µg
(range 1.00-1.38 µg)
Target 2.4 µg 
(range 2.00-2.75 µg)
Aluminum hydroxide, hydrated
0.17 mg Al³+
0.35 mg Al³+
Human serum albumin
0.25 mg
0.5 mg
Sodium chloride
1.725 mg
3.45 mg
Disodium hydrogen phosphate
0.11 mg
0.22.mg
Potassium dihydrogen phosphate 0.023 mg
0.045 mg
Water for injection
ad 0.25 mL
ad 0.5 mL
a.
Produced using a CC working virus seed and consisting of a sterile suspension of 
formaldehyde-inactivated and sucrose gradient purified TBEV antigen.
Unit Dose Strength(s)
•
2.4 µg/0.5 mL (for participants ≥16 years of age)
•
1.2 µg/0.25 mL (for participants ≥1 to <16 years of age)
Dosage Level(s)
1st dose 0.5 mL or 0.25 mL
2nd dose (21-35 days after 1st dose) 0.5 mL or 0.25 mL
3rd dose (150-365 days after 2nd dose) 0.5 mL or 0.25 mL
Route of 
Administration
Intramuscular
IMP or NIMP
IMP
Sourcing
Provided centrally by the sponsor 
Packaging and 
Labeling
Study intervention will be provided in an open-label carton that includes 
1 prefilled syringe.  Each carton will be labeled as required per country 
requirement.
6.1.1. Administration
Participants will receive 1 dose of TBE vaccine at each vaccination visit (Visits 1, 2, and 4) 
in accordance with the study’s SoA.
TBE Vaccine 2.4 µg/0.5 mL
In participants ≥16 years of age, TBE vaccine should be administered intramuscularly by 
injecting 0.5 mL into the deltoid muscle of the right or left arm (preferably the nondominant 
arm).
TBE Vaccine 1.2 µg/0.25 mL
In participants <16 years of age, TBE vaccine should be administered intramuscularly by 
injecting 0.25 mL into the deltoid muscle of the right or left arm (preferably the nondominant 
arm), except for children up to 18 months of age or when dependent on a child’s 
development and nutrition status.  For children ≤18 months of age, TBE vaccine should be 

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administered intramuscularly by injecting 0.25 mL into the anterolateral thigh muscle of the 
leg at the vaccination visits.
Standard vaccination practices must be observed and vaccine must not be injected into blood 
vessels.  Appropriate medication and other supportive measures for management of an acute 
hypersensitivity reaction should be available in accordance with local guidelines for standard 
immunization practices.
Administration of study interventions should be performed by an appropriately qualified, 
GCP-trained, and vaccine-experienced member of the study staff (eg, physician, nurse, 
physician’s assistant, nurse practitioner, pharmacist, or medical assistant) as allowed by 
local, state, and institutional guidance.
Study intervention administration details will be recorded on the CRF.
6.1.2. Medical Devices
1. Instructions for medical device use as a prefilled syringe are provided in the IP 
manual.
2. All medical device deficiencies (including malfunction, use error, and inadequate 
labeling) shall be documented and reported by the investigator throughout the clinical 
investigation (see Section 8.3.9) and appropriately managed by the sponsor.
6.2. Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm that 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.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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6.2.1. Preparation and Dispensing
See the IP manual for instructions on how to prepare the study intervention for 
administration.  Study intervention should be prepared and dispensed by an appropriately 
qualified and experienced member of the study staff (eg, physician, nurse, physician’s 
assistant, nurse practitioner, pharmacy assistant/technician, or pharmacist) as allowed by 
local, state, and institutional guidance.  A second staff member will verify the dispensing
6.3. Measures to Minimize Bias: Randomization and Blinding
6.3.1. Allocation to Study Intervention
This is an open-label study; however, the specific study intervention dispensed to the 
participant will be assigned using an IRT.  The site will contact the IRT prior to the start of 
study intervention administration for each participant.  The site will record the study 
intervention assignment on the applicable CRF, if required.
The investigator’s knowledge of the study intervention should not influence the decision to 
enroll a particular participant or affect the order in which participants are enrolled.
Study intervention will be dispensed at the study visits summarized in the SoA.
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Dispensed and unused study intervention must not be redispensed to other participants.
The study-specific IRT reference manual and IP manual will provide the contact information 
and further details on the use of the IRT system.
6.4. Study Intervention Compliance
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision.  The date and time of each dose
administered in the clinic will be recorded in the source documents and recorded in the CRF.  
The dose of study intervention and study participant identification will be confirmed at the 
time of dosing by a member of the study site staff other than the person administering the 
study intervention.
The site will complete the required dosage preparation record located in the IP manual.  The 
use of the preparation record is preferred, but it does not preclude the use of an existing 
appropriate clinical site documentation system.  The existing clinical site's documentation 
system should capture all pertinent/required information on the preparation and 
administration of the dose.  This may be used in place of the preparation record after 
approval from the sponsor and/or designee.
6.5. Concomitant Therapy
Hormonal contraceptives that meet the requirements of this study are allowed to be used in 
participants who are WOCBP (see Appendix 4).
6.5.1. Prohibited Concomitant Vaccines and Treatments Prior to the Study

Licensed or investigational TBE vaccines.

Any inactivated vaccine within 14 days or any live vaccine within 28 days before or after 
investigational product administration.

Prior receipt of flavivirus vaccines (eg, yellow fever, dengue fever) apart from JEV 
vaccine, which is permitted if received prior to the study.
6.5.2. Prohibited Concomitant Vaccines and Treatments During the Study

Nonstudy investigational vaccines, investigational drugs, or investigational medical 
devices.

Licensed or investigational TBE vaccines.

Blood/plasma products or immunoglobulins.

Other flavivirus vaccines (eg, yellow fever, dengue fever, JEV) during the study.

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
Systemic immunosuppressive therapy is prohibited during the study; however, topical 
corticosteroids (eg, intra-articular, inhaled/nebulized, intrabursal, skin, or eyes, etc) is 
permitted.

Unless administration is considered immediately medically necessary, no vaccines should 
be administered until at least 14 days after investigational product administration in the 
case of inactivated vaccines, or at least 28 days after in the case of live vaccines.
6.5.3. Permitted Concomitant Vaccines and Treatments During the Study

If medically necessary (eg, pandemic or outbreak with pandemic potential), influenza or 
other pandemic vaccines may be given at any time (however, an interval of >14 days 
prior to or >14 days after investigational product administration is preferred).

Any licensed vaccine other than flavivirus vaccine is permitted but may not be 
administered concurrently with the investigational product.  Whenever possible, any 
licensed vaccine should be administered at least 14 days for inactivated vaccines, or at 
least 28 days for live vaccines, before or after study vaccination.

The use of antipyretics and other pain medication to treat symptoms associated with 
investigational product administration is permitted during participation in the study. The 
use of prophylactic antipyretic/pain medication, while permitted, is not recommended on 
the day of vaccination.

A topical anesthetic is permitted only for blood sample collection.

Medications other than those described as prohibited are permitted.
6.5.4. Recording Prior and Concomitant Vaccines and Treatments
The name and date of administration for any nonstudy vaccinations received from the time of 
signing of the ICD until the final visit will be collected and recorded in the CRF.
History of JEV vaccination of participants will be collected at Visit 1 as far as possible.
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.

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7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention (definitive discontinuation).  Reasons for definitive discontinuation of study 
intervention include the following: a participant no longer meets the eligibility criteria during 
the vaccination period of the study (eg, pregnancy).
Note that discontinuation of study intervention does not represent withdrawal from the study.  
Per the study estimands, if study intervention is definitively discontinued, the participant will 
remain in the study to be evaluated for safety.  See the SRM for data to be collected at the 
time of discontinuation of study intervention and follow-up for any further evaluations that 
need to be completed.
In the event of discontinuation of study intervention, it must be documented on the 
appropriate CRF/in the medical records whether the participant is discontinuing further 
receipt of study intervention or also from study procedures, postvaccination study follow-up, 
and/or future collection of additional information.
7.2. Participant Discontinuation/Withdrawal From the Study
A participant (or legally acceptable representative/parent/legal guardian if the participant is 
1 to <20 years of age) may withdraw from the study at any time at his/her own request.  
Reasons for discontinuation from the study may include the following:

Refused further follow-up;

Lost to follow-up;

Death;

Study terminated by sponsor;

AEs/SAEs;

Protocol deviation;

Physician decision;

Request by the participant or participant’s legally acceptable 
representative/parent/legal guardian;

No longer meets eligibility criteria;

Pregnancy.

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If a participant does not return for a scheduled visit, every effort should be made to contact 
the participant or participant’s parent(s)/legal guardian(s).  All attempts to contact the 
participant or participant’s parent(s)/legal guardian(s) and information received during 
contact attempts must be documented in the participant’s source document.  In any 
circumstance, every effort should be made to document participant outcome, if possible.
At the time of discontinuation, please refer to the ISF and SRM 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 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.
If a participant withdraws from the study, he/she or the participant’s parent(s)/legal 
guardian(s) may request destruction of any remaining samples taken and not tested, and the 
investigator must document any such requests in the site study records and notify the sponsor 
accordingly.
If the participant withdraws from the study and also withdraws consent (see Section 7.2.1) 
for disclosure of future information, no further evaluations 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.
Lack of completion of all or any of the withdrawal/early termination procedures will not be 
viewed as protocol deviations so long as the participant’s safety was preserved.
7.2.1. Withdrawal of Consent
Participants who request to discontinue receipt of study intervention will remain in the study 
and must continue to be followed for protocol-specified follow-up procedures.  The only 
exception to this is when a participant specifically withdraws consent for any further contact 
with him or her or persons previously authorized by the participant to provide this 
information.  Participants should notify the investigator in writing of the decision to 
withdraw consent from future follow-up, whenever possible.  The withdrawal of consent 
should be explained in detail in the medical records by the investigator, as to whether the 
withdrawal is only from further receipt of study intervention or also from study procedures 
and/or postvaccination study follow-up, and entered on the appropriate CRF page.  In the 
event that vital status (whether the participant is alive or dead) is being measured, publicly 
available information should be used to determine vital status only as appropriately directed 
in accordance with local law.

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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 is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study;

Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods).  These contact attempts should be documented 
in the participant’s medical record;

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.
8. STUDY ASSESSMENTS AND PROCEDURES
The investigator (or an appropriate delegate at the investigator site) must obtain a signed and 
dated ICD (and assent, if applicable) before performing any study-specific procedures.
The date of birth will be collected to critically evaluate the immune response and safety 
profile by age.
Study procedures and their timing are summarized in the SoA.  Protocol waivers or 
exemptions are not allowed.
Safety issues should be discussed with the sponsor immediately upon occurrence or 
awareness to determine whether the participant should continue or discontinue study 
intervention.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria.  The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.

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Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICD may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
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 
10 mL (for participants ≥1 to <16 years of age; the minimum is 5 mL).  The actual collection 
times of blood sampling may change.  Additional blood samples may be taken for safety 
assessments at times specified by Pfizer, provided the total volume taken during the study 
does not exceed 550 mL during any period of 60 consecutive days.
8.1. Efficacy and/or Immunogenicity Assessments
The immunogenicity samples must be processed and shipped as indicated in the instructions 
provided to the investigator site to maintain sample integrity.  Any deviations from the 
immunogenicity sample handling procedure (eg, sample collection and processing steps, 
interim storage, or shipping conditions), including any actions taken, must be documented 
and reported to the sponsor.  On a case-by-case basis, the sponsor may make a determination 
as to whether sample integrity has been compromised.
8.1.1. Immunogenicity Assessments
Blood samples will be collected from all participants at Visit 1 (Day 1), Visit 3 (21-35 days 
after the second vaccination), Visit 4 (150-365 days after the second vaccination), and Visit 5 
(21-35 days after the third vaccination).  These are the immunogenicity time points.
Group 1: Participants ≥16 Years of Age
The volume of the blood sample is approximately 10 mL at each blood sample collection 
visit.
Group 2: Participants ≥1 to <16 Years of Age
Considering the difficulty of blood sample collection, the volume of the blood sample is 
approximately 10 mL (the minimum is 5 mL) at each blood sample collection visit.

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8.1.1.1. TBEV Antibody Testing
Sera will be assayed for TBEV-neutralizing antibody levels, 
 
at baseline, 4 weeks after the second vaccination, and prior to and 4 weeks after the 
third vaccination. At the third vaccination visit, the blood sample will be collected prior to 
vaccination.
NT titers ≥10
are considered seropositive.13,
TBE antibody response will be determined 
 
 by means of NT.15
 
The tests will be performed at the following laboratories:
•
Serological and Biochemical Control, Quality Control Vaccines, Pfizer QC / 
Biological Lab I, Austria.
 
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 may request that his or her 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.
CCI
CCI
CCI
CCI
CCI
CCI
CCI

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8.2. Safety Assessments
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 issues.  Medical history, temperature, physical examination (as clinically 
indicated for the second and third doses), and assessment of eligibility will be conducted for 
all participants before administration of each dose of TBE vaccine.  The participants will be 
observed for at least 30 minutes after vaccination and any acute (immediate) reactions will be 
assessed and recorded.
Common for Groups 1 and 2
Local reactions, systemic events, temperature, and antipyretic and/or pain medication use 
will be prompted for and collected daily in an e-diary from Day 1 to Day 7 after each dose of 
vaccination.
8.2.1. Participant Electronic Diary
The participant (or participant’s parent[s]/legal guardian[s] if the participants is ≥1 to 
<16 years of age) 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.  The use of prophylactic 
antipyretic/pain medication, while permitted to treat symptoms associated with 
investigational product administration, is not recommended on the day of investigational 
product administration (before or after vaccination).  For participants 16 to <20 years of age, 
the participant's parent(s)/legal guardian(s) should monitor the participant's compliance with 
data entry.
8.2.2. Grading Scale for Prompted Events
The grading scales used in this study to assess prompted events as described below are based 
on concepts outlined in the FDA CBER guidelines on toxicity grading scales for adults and
adolescent volunteers enrolled in preventive vaccine clinical trials, but have been adapted for
applicability to healthy infants.
8.2.2.1. Local Reactions
Local reactions, including pain, redness, and swelling at the injection site on the deltoid or 
anterolateral thigh, will be prompted for and collected daily for the first 7 days following 
each vaccination (Days 1 through 7, where Day 1 is the day of vaccination) in an e-diary 
according to the grading scale in Table 1 (≥16 years of age), Table 2 (1 to ≤2 years of age), 
Table 3 (>2 to <12 years of age), or Table 4 (≥12 to <16 years of age).  The participant or 
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.

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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.
Group 1: Participants ≥16 Years of Age
Redness and swelling will be measured and recorded in caliper units (range: 1 to 21) by the 
participant, and then categorized as mild, moderate, or severe based on the grading scale in 
Table 1 for participants ≥16 years of age.  Measuring device units can be converted to 
centimeters according to the following scale: 1 measuring device unit = 0.5 cm.  Participants’ 
legally acceptable representative/parent/legal guardian should monitor the participants’ 
compliance of data entry for participants 16 through 19 years of age.
Table 1.
Grading Scale for Local Reactions (Participants ≥16 Years of Age)
Mild 
Grade 1
Moderate
Grade 2
Severe
Grade 3a
Grade 4b
Redness
>2.0 cm to 5.0 cm 
(5 to 10 measuring 
device units)
>5.0 cm to 10.0 cm 
(11 to 20 measuring 
device units)
>10 cm 
(>20 measuring 
device units)
Necrosis or exfoliative 
dermatitisb
Swelling
>2.0 cm to 5.0 cm 
(5 to 10 measuring 
device units)
>5.0 cm to 10.0 cm 
(11 to 20 measuring 
device units)
>10 cm 
(>20 measuring 
device units)
Necrosisb
Pain at the 
injection site
Does not interfere 
with activity
Interferes with 
activity
Prevents daily 
activity
Emergency room visit or 
hospitalization for severe 
pain at the injection site
a.
Participants experiencing local reactions >20 caliper units (>10 cm) are to be seen by or contact the study 
site; an unscheduled visit may be required.
b.
Grade 4 assessment must be made by an investigator; Grade 4 will not be collected in the e-diary but will 
be collected in the case report form.  The severity of the local reaction should be graded using the AE 
severity grading scale provided in the protocol.
Group 2: Participants ≥1 to <16 Years of Age
Participants 1 to ≤2 Years of Age
Redness and swelling will be measured and recorded in caliper units (range: 1 to 14) by the 
participant’s legally acceptable representative/parent/legal guardian, and then categorized as 
mild, moderate, or severe based on the grading scale in Table 2 for participants 1 to ≤2 years 
of age.  Measuring device units can be converted to centimeters according to the following 
scale: 1 measuring device unit = 0.5 cm.

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Table 2.
Grading Scale for Local Reactions (Participants 1 to ≤2 Years of Age)
Mild
Grade 1
Moderate
Grade 2
Severe
Grade 3a
Grade 4b
Redness
>0.5 cm to 2.0 cm 
(1 to 4 measuring 
device units)
>2.0 cm to 7.0 cm 
(5 to 14 measuring 
device units)
>7.0 cm 
(>14 measuring 
device units)
Necrosis or exfoliative 
dermatitisb
Swelling
>0.5 cm to 2.0 cm 
(1 to 4 measuring 
device units)
>2.0 cm to 7.0 cm 
(5 to 14 measuring 
device units)
>7.0 cm 
(>14 measuring 
device units)
Necrosisb
Pain at the 
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 at the 
injection site
a.
Participants experiencing local reactions >14 caliper units (>7.0 cm) are to be seen by or contact the study 
site; an unscheduled visit may be required.
b.
Grade 4 assessment must be made by an investigator; Grade 4 will not be collected in the e-diary but will 
be collected in the case report form.  The severity of the local reaction should be graded using the AE 
severity grading scale provided in the protocol.
Participants >2 to <12 Years of Age
Redness and swelling will be measured and recorded in caliper units (range: 1 to 14) by the 
participant’s legally acceptable representative/parent/legal guardian, and then categorized as 
mild, moderate, or severe based on the grading scale in Table 3 for participants 2 to 
12 years of age.  Measuring device units can be converted to centimeters according to the 
following scale: 1 measuring device unit = 0.5 cm.
Table 3.
Grading Scale for Local Reactions (Participants >2 to <12 Years of Age)
Mild
Grade 1
Moderate
Grade 2
Severe
Grade 3a
Grade 4b
Redness
>0.5 cm to 2.0 cm 
(1 to 4 measuring 
device units)
>2.0 cm to 7.0 cm 
(5 to 14 measuring 
device units)
>7.0 cm 
(>14 measuring 
device units)
Necrosis or exfoliative 
dermatitisb
Swelling
>0.5 cm to 2.0 cm 
(1 to 4 measuring 
device units)
>2.0 cm to 7.0 cm 
(5 to 14 measuring 
device units)
>7.0 cm 
(>14 measuring
device units)
Necrosisb
Pain at the 
injection site
Does not interfere 
with activity
Interferes with 
activity
Prevents daily 
activity
Emergency room visit or 
hospitalization for severe 
pain at the injection site
a.
Participants experiencing local reactions >14 caliper units (>7.0 cm) are to be seen by or contact the study 
site; an unscheduled visit may be required.
b.
Grade 4 assessment must be made by an investigator; Grade 4 will not be collected in the e-diary but will 
be collected in the case report form.  The severity of the local reaction should be graded using the AE 
severity grading scale provided in the protocol.

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Participants ≥12 to <16 Years of Age
Redness and swelling will be measured and recorded in caliper units (range: 1 to 20) by the 
participant’s legally acceptable representative/parent/legal guardian, and then categorized as 
mild, moderate, or severe based on the grading scale in Table 4 for participants ≥12 to 
16 years of age.  Measuring device units can be converted to centimeters according to the 
following scale: 1 measuring device unit = 0.5 cm.
Table 4.
Grading Scale for Local Reactions (Participants ≥12 to 16 Years of Age)
Mild
Grade 1
Moderate
Grade 2
Severe
Grade 3a
Grade 4b
Redness
>2.0 cm to 5.0 cm 
(5 to 10 measuring 
device units)
>5.0 cm to 10.0 cm 
(11 to 20 measuring 
device units)
>10 cm 
(>20 measuring 
device units)
Necrosis or exfoliative 
dermatitisb
Swelling
>2.0 cm to 5.0 cm 
(5 to 10 measuring 
device units))
>5.0 cm to 10.0 cm 
(11 to 20 measuring 
device units)
>10 cm 
(>20 measuring 
device units)
Necrosisb
Pain at the 
injection site
Does not interfere 
with activity
Interferes with 
activity
Prevents daily 
activity
Emergency room visit or 
hospitalization for severe 
pain at the injection site
a.
Participants experiencing local reactions >20 caliper units (>10 cm) are to be seen by or contact the study 
site; an unscheduled visit may be required.
b.
Grade 4 assessment must be made by an investigator; Grade 4 will not be collected in the e-diary but will 
be collected in the case report form.  The severity of the local reaction should be graded using the AE 
severity grading scale provided in the protocol.
8.2.2.2. Systemic Events
Group 1: Participants ≥16 Years of Age
For 7 consecutive days starting on the day of each vaccination (eg, study Day 1 to Day 7), 
participants are to assess fatigue, headache, vomiting, diarrhea, muscle pain, and joint pain in 
the e-diary according to the grading scale in Table 5.  Participants’ legally acceptable 
representative/parent/legal guardian should monitor the participants’ compliance of data 
entry for participants 16 through 19 years of age.  Participants 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 fatigue, headache, vomiting, diarrhea, 
muscle pain, or joint pain) within 7 days after vaccination.  Study staff may also contact the 
participant 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.  If 
a participant experiences a Grade 4 systemic event, the investigator must immediately notify 
the sponsor.
The procedure for notification of the sponsor is provided in the ISF or equivalent.

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Table 5.
Grading Scale for Systemic Events (Participants ≥16 Years of Age)
Mild
Grade 1
Moderate
Grade 2
Severe
Grade 3
Grade 4a
Fatigue
(= tiredness in 
diaries)
Does not interfere 
with activity
Some interference 
with activity
Prevents daily 
routine activity
Emergency room visit 
or hospitalization for 
severe fatigue 
Headache
Does not interfere 
with activity
Some interference 
with activity
Prevents daily 
routine activity
Emergency room visit 
or hospitalization for 
severe headache 
Vomiting
1 to 2 times in 
24 hours
>2 times 
in 24 hours
Requires intravenous 
hydration
Emergency room visit 
or hospitalization for 
severe vomiting
Diarrhea
2 to 3 loose stools
in 24 hours
4 to 5 loose stools
in 24 hours
6 or more loose 
stools
in 24 hours
Emergency room visit
or hospitalization for 
severe diarrhea
Muscle pain
Does not interfere 
with activity
Some interference 
with activity
Prevents daily 
routine activity
Emergency room visit 
or hospitalization for 
severe muscle pain
Joint pain
Does not interfere 
with activity
Some interference 
with activity
Prevents daily 
routine activity
Emergency room visit 
or hospitalization for 
severe joint pain
a.
Grade 4 assessment must be made by an investigator; Grade 4 will not be collected in the e-diary but will 
be collected in the case report form.
The participant will be asked to record the use of antipyretic and/or pain medication in the 
e-diary from Day 1 to Day 7 after vaccination.  Participants’ legally acceptable 
representative/parent/legal guardian should monitor the participants’ compliance of data 
entry for participants 16 through 19 years of age.
Group 2: Participants ≥1 to <16 Years of Age
For 7 consecutive days starting on the day of vaccination (eg, study Day 1 to Day 7), 
participants’ parent(s)/legal guardian(s) are to assess fatigue, headache, vomiting, diarrhea, 
muscle pain, joint pain, decreased appetite, drowsiness, and irritability in the e-diary 
according to the grading scale in Table 6, Table 7, or Table 8 according to the participant’s 
age.  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 fatigue, headache, vomiting, diarrhea, muscle pain, or 
joint pain) within 7 days after vaccination.  Study staff may also contact the participant 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.  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.
The participant’s parent(s)/legal guardian(s) will be asked to record the use of antipyretic 
and/or pain medication in the e-diary from Day 1 to Day 7 after vaccination in an e-diary.
Participants 1 to ≤2 Years of Age
Table 6.
Grading Scale for Systemic Events (Participants 1 to ≤2 Years of Age)
Mild
Grade 1
Moderate
Grade 2
Severe
Grade 3
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)
a.
Grade 4 assessment must be made by an investigator; Grade 4 will not be collected in the e-diary but will 
be collected in the case report form.
Participants >2 to <12 Years of Age
Table 7.
Grading Scale for Systemic Events (Participants >2 to <12 Years of Age)
Mild
Grade 1
Moderate
Grade 2
Severe
Grade 3
Grade 4a
Fatigue
(= tiredness in 
diaries)
Does not interfere 
with activity
Some interference 
with activity
Prevents daily 
routine activity
Emergency room visit 
or hospitalization for 
severe fatigue 
Headache
Does not interfere 
with activity
Some interference 
with activity
Prevents daily 
routine activity
Emergency room visit 
or hospitalization for 
severe headache 
Vomiting
1 to 2 times in 
24 hours
>2 times 
in 24 hours
Requires 
intravenous 
hydration
Emergency room visit 
or hospitalization for 
severe vomiting

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Table 7.
Grading Scale for Systemic Events (Participants >2 to <12 Years of Age)
Mild
Grade 1
Moderate
Grade 2
Severe
Grade 3
Grade 4a
Diarrhea
2 to 3 loose stools
in 24 hours
4 to 5 loose stools
in 24 hours
6 or more loose 
stools
in 24 hours
Emergency room visit
or hospitalization for 
severe diarrhea
Muscle pain
Does not interfere 
with activity
Some interference 
with activity
Prevents daily 
routine activity
Emergency room visit 
or hospitalization for 
severe muscle pain
Joint pain
Does not interfere 
with activity
Some interference 
with activity
Prevents daily 
routine activity
Emergency room visit 
or hospitalization for 
severe joint pain
a.
Grade 4 assessment must be made by an investigator; Grade 4 will not be collected in the e-diary but will 
be collected in the case report form.
Participants ≥12 to <16 Years of Age
Table 8.
Grading Scale for Systemic Events (Participants ≥12 to <16 Years of Age)
Mild
Grade 1
Moderate
Grade 2
Severe
Grade 3
Grade 4a
Fatigue
(= tiredness in 
diaries)
Does not interfere 
with activity
Some interference 
with activity
Prevents daily 
routine activity
Emergency room visit 
or hospitalization for 
severe fatigue 
Headache
Does not interfere 
with activity
Some interference 
with activity
Prevents daily 
routine activity
Emergency room visit 
or hospitalization for 
severe headache 
Vomiting
1 to 2 times in 
24 hours
>2 times 
in 24 hours
Requires intravenous 
hydration
Emergency room visit 
or hospitalization for 
severe vomiting
Diarrhea
2 to 3 loose stools
in 24 hours
4 to 5 loose stools
in 24 hours
6 or more loose 
stools
in 24 hours
Emergency room visit
or hospitalization for 
severe diarrhea
Muscle pain
Does not interfere 
with activity
Some interference 
with activity
Prevents daily
routine activity
Emergency room visit 
or hospitalization for 
severe muscle pain
Joint pain
Does not interfere 
with activity
Some interference 
with activity
Prevents daily 
routine activity
Emergency room visit 
or hospitalization for 
severe joint pain
a.
Grade 4 assessment must be made by an investigator; Grade 4 will not be collected in the e-diary but will 
be collected in the case report form.

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8.2.2.2.1. Fever
Common for Groups 1 and 2
In order to record information on fever, a digital thermometer will be given to the participant 
or participant’s parent(s)/legal guardian(s) with instructions on how to measure axillary 
temperature at home.  Temperature will be prompted for and collected in the evening, daily, 
in the e-diary for 7 days following each study vaccination (Day 1 through Day 7, where 
Day 1 is the day of vaccination) and at any time during the 7 days that fever is suspected.  
The highest temperature for each day will be recorded in the e-diary.  Temperature will be 
collected daily until fever has resolved (1 day of temperature less than 37.5°C) in order to 
collect a stop date in the CRF.  A participant or participant’s parent(s)/legal guardian(s) will 
be prompted to contact the investigator if the participant experiences a fever >40.0°C within 
the 7 days following vaccination to assess the fever and perform an unscheduled assessment, 
as applicable (see Section 8.11.6).  Study staff may also contact the participant’s 
parent(s)/legal guardian(s) to obtain additional information if a temperature of >38.9°C is 
entered into an e-diary.  Temperature measured by the axillary route will be recorded to 
1 decimal place and then grouped into ranges for the analysis according to Table 9 below.
Table 9.
Ranges for Fever
Grade 1
Mild
Grade 2
Moderate
Grade 3
Severe
Grade 4
Fever
≥37.5°C; ≤38.4°C
≥38.5°C; ≤38.9°C
≥39.0°C; ≤40.0°C
>40.0°C
8.2.3. Physical Examinations
Physical examination (at Visit 1) will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal, and neurological systems.  Height and weight 
will also be measured and recorded.
Prior to subsequent vaccination (at Visits 2 and 4), physical examination should be 
performed if the clinical assessment indicates that it is necessary to comprehensively evaluate 
the participant.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.2.4. Vital Signs
Axillary temperature will be assessed prior to vaccination and recorded in the CRF.  If 
multiple measurements are taken at the same time point, the most out-of-range (eg, highest) 
value must be recorded.
8.2.5. Clinical Safety Laboratory Assessments
Clinical safety laboratory assessments will not be collected for this study.

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8.2.6. Pregnancy Testing
Pregnancy tests may be urine or serum tests, but must have a sensitivity of at least 
25 mIU/mL.  Pregnancy tests will be performed in WOCBP at the times listed in the SoA, 
immediately before the administration of each vaccine dose.  A negative pregnancy test result 
will be required prior to the participant’s receiving the study intervention.  Pregnancy tests 
may also be repeated if requested by IRBs/ECs or if required by local regulations.  In the 
case of a positive confirmed pregnancy, the participant will be withdrawn from 
administration of study intervention but may remain in the study.
8.3. Adverse Events and Serious Adverse Events
The definitions of an AE and an SAE can be found in Appendix 3.
The definitions of device-related safety events (ADEs and SADEs) can be found in 
Appendix 8.  Device deficiencies are covered in Section 8.3.9.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or 
the participant's legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether the 
event meets the criteria for classification as an SAE or caused the participant to discontinue 
the study intervention (see Section 7.1).
Each participant/parent/legal guardian/legally authorized representative will be questioned 
about the occurrence of AEs in a nonleading manner.
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion.
8.3.1. Time Period and Frequency for Collecting AE and SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant /parent(s)/legal 
guardian/legally authorized representative provides informed consent, which is obtained 
before the participant’s participation in the study (ie, before undergoing any study-related 
procedure and/or receiving study intervention), through and including Visit 3, and from 
Visit 4 to Visit 5.  Between Visit 3 and Visit 4, only SAEs will be reported.
Follow-up by the investigator continues throughout and after the active collection period and 
until the AE or SAE or its sequelae resolve or stabilize at a level acceptable to the 
investigator and Pfizer concurs with that assessment.
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.

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If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn.
If a participant definitively discontinues or temporarily discontinues study intervention 
because of an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE 
reported using the Vaccine SAE Reporting Form.
Investigators are not obligated to actively seek AEs or SAEs after the participant has 
concluded study participation.  However, if the investigator learns of any SAE, including a 
death, at any time after a participant has completed the study, and he/she considers the event 
to be reasonably related to the study intervention, the investigator must promptly report the 
SAE to Pfizer using the Vaccine SAE Reporting Form.
8.3.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period as described in 
Section 8.3.1 are reported to Pfizer Safety on the Vaccine SAE Reporting Form immediately 
upon awareness and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 3.  The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available.
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF
All nonserious AEs and SAEs occurring in a participant during the active collection period, 
which begins after obtaining informed consent as described in Section 8.3.1, will be recorded 
on the AE section of the CRF.
The investigator is to record on the CRF all directly observed and all spontaneously reported 
AEs and SAEs reported by the participant.
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 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.
8.3.4. Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation.  The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/ECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.
An investigator who receives SUSARs or other specific safety information (eg, summary or 
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the 
study 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 study intervention under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness.
8.3.5.1. Exposure During Pregnancy
An EDP occurs if: 

A female participant is found to be pregnant while receiving or after discontinuing 
study intervention.

A male participant who is receiving or has discontinued study intervention exposes a 
female partner prior to or around the time of conception.

A female is found to be pregnant while being exposed or having been exposed to 
study intervention due to environmental exposure.  Below are examples of 
environmental exposure during pregnancy:

A female family member or healthcare provider reports that she is pregnant after 
having been exposed to the study intervention by inhalation or skin contact.

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
A male family member or healthcare provider who has been exposed to the study 
intervention by inhalation or skin contact then exposes his female partner prior to 
or around the time of conception.
The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred.  The initial information submitted 
should include the anticipated date of delivery (see below for information related to 
termination of pregnancy).

If EDP occurs in a participant or a participant’s partner, the investigator must report 
this information to Pfizer Safety on the Vaccine SAE Reporting Form and an EDP 
Supplemental Form, regardless of whether an SAE has occurred.  Details of the 
pregnancy will be collected after the start of study intervention and until delivery.

If EDP occurs in the setting of environmental exposure, the investigator must report 
information to Pfizer Safety using the Vaccine SAE Reporting Form and EDP 
Supplemental Form.  Since the exposure information does not pertain to the 
participant enrolled in the study, the information is not recorded on a CRF; however, 
a copy of the completed Vaccine SAE Reporting Form is maintained in the ISF.
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP Supplemental Form.  In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth.  In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
preprocedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
Abnormal pregnancy outcomes are considered SAEs.  If the outcome of the pregnancy meets 
the criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal 
demise, neonatal death, or congenital anomaly in a live-born baby, a terminated fetus, an 
intrauterine fetal demise, or a neonatal death), the investigator should follow the procedures 
for reporting SAEs.  Additional information about pregnancy outcomes that are reported to 
Pfizer Safety as SAEs follows: 

Spontaneous abortion including miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the study intervention.

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Additional information regarding the EDP may be requested by the sponsor.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays).  In the case of paternal exposure, the 
investigator will provide the participant with the Pregnant Partner Release of Information 
Form to deliver to his partner.  The investigator must document in the source documents that 
the participant was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.3.5.2. Exposure During Breastfeeding
An exposure during breastfeeding occurs if: 

A female participant is found to be breastfeeding while receiving or after 
discontinuing study intervention.

A female is found to be breastfeeding while being exposed or having been exposed to 
study intervention (ie, environmental exposure).  An example of environmental 
exposure during breastfeeding is a female family member or healthcare provider who 
reports that she is breastfeeding after having been exposed to the study intervention 
by inhalation or skin contact.
The investigator must report exposure during breastfeeding to Pfizer Safety within 24 hours 
of the investigator’s awareness, irrespective of whether an SAE has occurred.  The 
information must be reported using the Vaccine SAE Reporting Form.  When exposure 
during breastfeeding occurs in the setting of environmental exposure, the exposure 
information does not pertain to the participant enrolled in the study, so the information is not 
recorded on a CRF.  However, a copy of the completed Vaccine SAE Reporting Form is 
maintained in the ISF.
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, the 
SAE is reported together with the exposure during breastfeeding.
8.3.5.3. Occupational Exposure
An occupational exposure occurs when a person receives unplanned direct contact with the 
study intervention, which may or may not lead to the occurrence of an AE.  Such persons 
may include healthcare providers, family members, and other roles that are involved in the 
trial participant’s care.
The investigator must report occupational exposure to Pfizer Safety within 24 hours of the 
investigator’s awareness, regardless of whether there is an associated SAE.  The information 
must be reported using the Vaccine SAE Reporting Form.  Since the information does not 
pertain to a participant enrolled in the study, the information is not recorded on a CRF; 
however, a copy of the completed Vaccine SAE Reporting Form is maintained in the ISF.

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8.3.6. Cardiovascular and Death Events
Not applicable.
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs
Not applicable.
8.3.8. Adverse Events of Special Interest
Not applicable.
8.3.8.1. Lack of Efficacy
Not applicable.
8.3.9. Medical Device Deficiencies
Medical devices are being provided for use in this study as the study intervention is supplied 
in prefilled syringes.  In order to fulfill regulatory reporting obligations worldwide, the 
investigator is responsible for the detection and documentation of events meeting the 
definitions of device deficiency that occur during the study with such devices.
The definition of a medical device deficiency can be found in Appendix 8.
NOTE: Deficiencies fulfilling the definition of an AE/SAE will also follow the processes 
outlined in Section 8.3.1 through 8.3.4 and Appendix 3 of the protocol.
8.3.9.1. Time Period for Detecting Medical Device Deficiencies
Medical device deficiencies or malfunctions of the device will be detected, documented, and 
reported during all periods of the study in which the medical device is used.
If the investigator learns of any device deficiency at any time after a participant has been 
discharged from the study, and such incident is considered reasonably related to a medical 
device provided for the study, the investigator will promptly notify the sponsor.
The method of documenting medical device deficiencies is provided in Appendix 8.
8.3.9.2. Follow-up of Medical Device Deficiencies
Follow-up applies to all participants, including those who discontinue study intervention.
The 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.

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8.3.9.3. 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.  
Information will be provided to the sponsor as described in the IP manual.  The medical 
device complaint CRF will also be completed.
Any device deficiency that is associated with an SAE must be reported to Pfizer Safety 
within 24 hours upon the investigator’s awareness as outlined in Sections 8.3.1.1 and 8.3.1.2.
The sponsor will be the contact for the receipt of device deficiency information.
8.3.9.4. Regulatory Reporting Requirements for Device Deficiencies
The 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.
8.3.10. Medication Errors
Medication errors may result from the administration or consumption of the study 
intervention by the wrong participant, or at the wrong time, or at the wrong dosage strength.  
Exposures to the study intervention under study may occur in clinical trial settings, such as 
medication errors.
Safety Event
Recorded on the CRF
Reported on the Vaccine SAE 
Reporting Form to Pfizer Safety 
Within 24 Hours of Awareness
Medication errors 
All (regardless of whether 
associated with an AE)
Only if associated with an SAE
Medication errors include:

Medication errors involving participant exposure to the study intervention;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the study participant.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.

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In the event of a medication dosing error, the sponsor should be notified within 24 hours.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and nonserious, are recorded on the AE page of the 
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a Vaccine SAE 
Reporting Form only when associated with an SAE.

The administration of expired study intervention;

The administration of an incorrect study intervention;

The administration of an incorrect dosage;

The administration of study intervention that has undergone temperature excursion 
from the specified storage range, unless it is determined by the sponsor that the study 
intervention under question is acceptable for use.
8.4. Treatment of Overdose
For this study, any dose of TBE vaccine greater than 1 dose (0.5 mL for participants 
≥16 years of age, 0.25 mL for participants ≥1 to <16 years of age) 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 within 24 hours.
2. Closely monitor the participant for any AEs/SAEs.
3. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF.
4. Overdose is reportable to Safety only when associated with an SAE.
8.5. Pharmacokinetics
Pharmacokinetic parameters are not evaluated in this study.
8.6. Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.

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8.9. Immunogenicity Assessments
Immunogenicity assessments are described in Section 8.1.1.
8.10. Health Economics
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study.
8.11. Study Procedures
The study procedures are summarized in the SoA.  The day of Dose 1 is considered to be 
Day 1.
Unless specified in the sections below, the order of key procedures within a given visit may 
have some flexibility.
8.11.1. Visit 1 (Dose 1 Visit, Day 1)
Prior to vaccination:
•
For participants ≥20 years of age: Obtain a personally signed and dated ICD indicating 
that the participant has been informed of all pertinent aspects of the study before 
performing any study-specific procedures.
•
For participants <20 years of age: 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.  Considering the 
participant’s age and the capacity to understand, assent from participant should be 
obtained.
•
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) and physical examination; record any findings on the medical history CRF.
CCI

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
Record vaccine history.

Record concomitant medications used to treat SAEs.

Measure and record the participant’s axillary temperature (°C).

Collect a blood sample of approximately 10 mL (for participants ≥1 to <16 years of age; 
the minimum is 5 mL) for immunogenicity (a topical anesthetic is permitted).

For female participants of childbearing potential: Discuss contraceptive use and perform 
a urine pregnancy test.  The result of the pregnancy test must be confirmed before 
administration of investigational product.

Ensure that all inclusion criteria, none of the exclusion criteria, and none of the temporary 
delay criteria are met.

Assign 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 enrollment:

The investigator or delegated site staff will administer a single 0.5-mL or 0.25-mL 
injection of TBE vaccine into the deltoid muscle (or anterolateral thigh, if the participant 
is <18 months of age).

The investigator or delegated 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.

Issue the participant or participant’s parent(s)/legal guardian(s) a measuring device to 
measure TBE vaccine injection site reactions and a digital thermometer and provide 
instructions on their use.

Issue the participant or 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 or 
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.

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
Ask the participant or participant’s parent(s)/legal guardian(s) to contact the investigator 
site staff or investigator as soon as possible during the 7-day postvaccination period if the 
participant has a fever >40.0°C, redness and/or swelling at the TBE vaccine injection site 
measuring >20 measuring device units (if the participant is ≥12 years of age) or >14 
measuring device units (>7 cm, if the participant is <12 years of age), or severe TBE 
vaccine injection site pain (prevents daily activity [in participants >2 years of age] or 
causes limitation of limb movement [in participants ≤2 years of age]) to determine if the 
event requires further assessment by the investigator.

Ask the participant/participant’s parent(s)/legal guardian(s) to contact the investigator or 
investigator site staff as soon as possible if any significant illness or medical event 
(eg, emergency room visit or hospitalization) occurs.

Provide the participant or participant’s parent(s)/legal guardian(s) with the participant 
contact card containing the study and investigator information (see Section 10.1.10).

Inform the participant or participant’s parent(s)/legal guardian(s) that the use of 
prophylactic antipyretic/pain medication, while permitted, is not recommended on the 
day of investigational product administration (before or after vaccination).

The investigator or an authorized designee completes the CRF and the source documents 
and the site staff will update the investigational product accountability records.

The investigator or appropriately qualified designee reviews the e-diary data online at 
frequent intervals for the 7 days following vaccination to evaluate participant compliance 
and as part of the ongoing safety review.
8.11.2. Visit 2 (Dose 2 Visit, 21-35 Days After Visit 1 [Dose 1])

Ensure and document that the participant continues to be eligible for the study 
(see Section 7.2 for participant discontinuation/withdrawal) and none of the temporary 
delay criteria are met (Section 5.5).

Record nonstudy vaccinations administered since Visit 1, as described in Section 6.5.

Record concomitant medications used to treat SAEs since Visit 1, as described in 
Section 6.5.

Review the participant’s e-diary data with the participant or 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 and SAEs) 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 SAEs.

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
Measure and record the participant’s axillary temperature (°C).

For female participants of childbearing potential: Discuss contraceptive use and perform 
a urine pregnancy test.  The result of pregnancy test must be confirmed before 
administration.

Investigator or delegated site staff will administer a single 0.5-mL or 0.25-mL injection 
of TBE vaccine into the deltoid muscle (or anterolateral thigh, if the participant is 
<18 months of age).
After vaccination:

Investigator or delegated 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.

Confirm that the e-diary is working and review instructions if necessary.  Remind the 
participant or participant’s parent(s)/legal guardian(s) to complete the e-diary for 7 days 
after the day of vaccination.  Provide a thermometer or measuring device if needed.

Ask the participant or participant’s parent(s)/legal guardian(s) to contact the investigator 
site staff or investigator as soon as possible during the 7-day postvaccination period if the 
participant has a fever >40.0°C, redness and/or swelling at the TBE vaccine injection site 
measuring >20 measuring device units (if the participant is ≥12 years of age) or >14 
measuring device units (>7 cm, if the participant is <12 years of age), or severe TBE 
vaccine injection site pain (prevents daily activity [in participants >2 years of age] or 
causes limitation of limb movement [in participants ≤2 years of age]) to determine if the 
event requires further assessment by the investigator.

Remind the participant or participant’s parent(s)/legal guardian(s) to contact the 
investigator or investigator site staff as soon as possible if any significant illness or 
medical event (eg, emergency room visit or hospitalization) occurs during the study 
period.

Confirm whether the participant or participant’s parent(s)/legal guardian(s) still possesses 
the participant contact card.  Provide a participant contact card if needed.

Remind the participant or participant’s parent(s)/legal guardian(s) that the use of 
prophylactic antipyretic/pain medication, while permitted, is not recommended on the 
day of investigational product administration (before or after vaccination).

The investigator or an authorized designees completes the CRF and the source documents 
and the site staff will update the investigational product accountability records.

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
The investigator or appropriately qualified designee reviews the e-diary data online at 
frequent intervals for the 7 days following vaccination to evaluate participant compliance 
and as part of the ongoing safety review.
8.11.3. Visit 3 (Blood Draw Visit, 21-35 Days After Visit 2 [Dose 2])

Ensure and document that the participant continues to be eligible for the study 
(see Section 7.2 for participant discontinuation/withdrawal).

Record nonstudy vaccinations administered since Visit 2, as described in Section 6.5.

Record concomitant medications used to treat SAEs since Visit 2, as described in 
Section 6.5.

Review the participant’s e-diary data with the participant or 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 and SAEs) 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 SAEs.

Collect a blood sample of approximately 10 mL (for participants ≥1 to <16 years; the 
minimum is 5 mL) for immunogenicity (a topical anesthetic is permitted).

Remind the participant or participant’s parent(s)/legal guardian(s) to contact the 
investigator or investigator site staff as soon as possible if any significant illness or 
medical event (eg, emergency room visit or hospitalization) occurs during the study 
period.

Confirm whether the participant’s parent(s)/legal guardian(s) still possesses the 
participant contact card.  Provide a participant contact card if needed.

The investigator or an authorized designee completes the CRF and the source documents 
and updates the investigational product accountability records.
8.11.4. Visit 4 (Dose 3 Visit, 150-365 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 3, as described in Section 6.5.

Record concomitant medications used to treat SAEs since Visit 1, as described in 
Section 6.5.

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
Determine whether any SAEs 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 SAEs.

Measure and record the participant’s axillary temperature (°C).

Collect a blood sample of approximately 10 mL (for participants ≥1 to <16 years; the 
minimum is 5 mL) for immunogenicity (a topical anesthetic is permitted).

For female participants of childbearing potential: Discuss contraceptive use and perform 
a urine pregnancy test.  The result of the pregnancy test must be confirmed before 
administration.

The investigator or delegated site staff will administer a single 0.5-mL or 0.25-mL 
injection of TBE vaccine into the deltoid muscle (or anterolateral thigh, if the participant 
is <18 months of age).
After vaccination:

The investigator or delegated 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.

Issue the participant or 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 or 
participant’s parent(s)/legal guardian(s) to complete the e-diary for 7 days after the day of 
vaccination.

Ask the participant or participant’s parent(s)/legal guardian(s) to contact the investigator 
site staff or investigator as soon as possible during the 7-day postvaccination period if the 
participant has a fever >40.0°C, redness and/or swelling at the TBE vaccine injection site 
measuring >20 measuring device units (if the participant is ≥12 years of age) or >14 
measuring device units (>7 cm, if the participant is <12 years of age), or severe TBE 
vaccine injection site pain (prevents daily activity [in participants >2 years of age] or 
causes limitation of limb movement [in participants ≤2 years of age]) to determine if the 
event requires further assessment by the investigator.

Remind the participant or participant’s parent(s)/legal guardian(s) to contact the 
investigator or investigator site staff as soon as possible if any significant illness or 
medical event (eg, emergency room visit or hospitalization) occurs during the study 
period.

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
Confirm whether the participant or participant’s parent(s)/legal guardian(s) still possesses 
the participant contact card.  Provide a participant contact card if needed.

Remind the participant or participant’s parent(s)/legal guardian(s) that the use of 
prophylactic antipyretic/pain medication, while permitted, is not recommended on the 
day of investigational product administration (before or after vaccination).

The investigator or an authorized designees completes the CRF and the source documents 
and updates the investigational product accountability records.

The investigator or appropriately qualified designee reviews the e-diary data online at 
frequent intervals for the 7 days following vaccination to evaluate participant compliance 
and as part of the ongoing safety review.
8.11.5. Visit 5 (Dose 3 Follow-up Visit, 21-35 Days After Visit 4 [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 5, as described in Section 6.5.

Record concomitant medications used to treat SAEs 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.

Collect the e-diary (if a device was provided).

Determine whether any AEs (includes nonserious AEs and SAEs) 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 SAEs.

Collect a blood sample of approximately 10 mL (for participants ≥1 to <16 years of age; 
the minimum is 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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8.11.6. Unscheduled Visits
If the participant or participant’s parent(s)/legal guardian(s) reports redness and/or swelling 
at the TBE vaccine injection site measuring >20 measuring device units (if the participant is 
≥12 years of age) or >14 measuring device units (>7 cm, if the participant is <12 years of 
age), severe injection site pain, or a fever >40.0°C during the 7-day postvaccination period, a 
telephone contact must occur as soon as possible between the investigator or medically 
qualified designee and the participant/participant’s parent(s)/legal guardian(s) to assess if an 
unscheduled investigator site visit is required.  Note that for a fever >40.0°C, the participant 
or 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 is unable to visit the site for unscheduled visit.

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 or participant’s parent(s)/legal guardian(s) recorded an incorrect value in 
the e-diary (confirmation of an e-diary data entry error).

The PI or authorized designee determined it was not needed.
This telephone contact will be recorded in the participant’s source documentation and the 
CRF.
If the participant is unable to visit the site for unscheduled visit, 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 axillary temperature (°C).

Measure minimum and maximum diameters of redness (if present).

Measure minimum and maximum diameters of swelling (if present).

Assess injection site pain in accordance with the grades provided in Section 8.2.2
(if present).

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
Assess other findings associated with the reaction and record on the AE page of the CRF, 
if appropriate.
The investigator or an authorized designee will complete the unscheduled visit assessment 
page of the CRF.
The participant or 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 or 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 or participant’s parent(s)/legal 
guardian(s) to obtain additional information on Grade 3 events entered into the e-diary.
9. STATISTICAL CONSIDERATIONS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is described here and further detailed in a SAP, which will be maintained by the sponsor.  
The SAP may modify what is outlined in the protocol where appropriate; however, any major 
modifications of the primary endpoint definitions or their analyses will also be reflected in a 
protocol amendment.
9.1. Estimands and Statistical Hypotheses
The primary immunogenicity objective of the study is to assess the immunogenicity of the 
investigational product by NT in healthy Japanese adults (16 years of age and older) and 
children (≥1 to <16 years of age) when administered in a 3-dose schedule.  The null 
hypothesis to be tested concerns the seropositivity rate for the primary endpoint in each age 
group.  The immune response induced by TBE vaccine will be evaluated in each age group, 
testing the hypotheses H0: seropositivity rate ≤90% vs H1: seropositivity rate >90%.  These 
hypotheses will be tested by age group separately and no adjustment of multiplicity will be 
considered.  For each age group, if the lower bound of the 95% CI on the NT seropositivity 
rate among the evaluable population is >90%, the objective is achieved.
9.1.1. Estimands
9.1.1.1. Immunogenicity
9.1.1.1.1. Primary Estimand
The primary estimand is seropositivity rate based on TBEV-neutralizing antibody levels 
(achieving NT titer ≥1:10) 4 weeks after the third dose for the evaluable population 
(Section 9.3).

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This estimand estimates the immunogenicity in the hypothetical setting where participants 
follow the study schedules and protocol requirements as directed.  Missing serology results 
are not imputed, as MCAR is assumed. For participants who discontinue the study or have 
major protocol violations, all postdiscontinuation or postviolation observations will be 
censored.
9.1.1.1.2. Secondary Estimands
The secondary estimands of this study are following for the evaluable population.

Seropositivity rate based on TBEV-neutralizing antibody levels (achieving NT titer 
≥1:10) 4 weeks after the second dose.

NT GMTs 4 weeks after the second and 4 weeks after the third dose.

NT GMFRs 4 weeks after the second and 4 weeks after the third dose as compared to 
baseline.

NT GMFR 4 weeks after the third dose as compared to 4 weeks after the second dose.
These estimands estimate the immunogenicity in the hypothetical setting where participants 
follow the study schedules and protocol requirements as directed.  Missing serology results 
are not imputed, as MCAR is assumed. For participants who discontinue the study or have 
major protocol violations, all postdiscontinuation or postviolation observations will be 
censored.
9.1.1.2. Safety
In participants receiving at least 1 dose of investigational product:

The percentage of participants reporting local reactions within 7 days following each 
vaccination.

The percentage of participants reporting systemic events within 7 days following each
vaccination.

The percentage of participants reporting AEs within 1 month after each vaccination.

The percentage of participants reporting SAEs throughout the study.
Missing e-diary data are not imputed.  Imputation of missing AE dates and missing AE 
severity will be applied following Pfizer safety rules.
9.2. Sample Size Determination
Sample sizes are determined as the number of participants to be enrolled that is expected to 
achieve the criterion of immunogenicity in which the lower limit of 95% CI 
(Clopper-Pearson method) for the seropositivity rate for the primary endpoint is higher than 

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90% for each age population.  Considering 10% dropouts, approximately 65 child 
participants and approximately 100 adult participants are intended to be enrolled as in the 
following, which shows sufficiently high statistical power.
•
Adults
Assuming the expected seropositivity rate among 90 evaluable adults to be 99.4%, the 
statistical power to demonstrate that the lower limit of the 95% CI of the estimate will 
exceed 90% is computed to be >99%.
•
Children
Assuming the expected seropositivity rate among 60 evaluable children to be 99.6%, the 
statistical power to demonstrate that the lower limit of the 95% CI of the estimate will 
exceed 90% is computed to be 97.3%.
9.3. Analysis Sets
For purposes of analysis, the following populations are defined by age group:
Population
Description
Enrolled 
"Enrolled" means that a participant, or his or her legally authorized 
representative, has agreed to participate in a clinical study 
following completion of the informed consent process and is 
deemed eligible to participate.  Potential participants who are 
screened for the purpose of determining eligibility for the study, 
but do not participate in the study, are not considered enrolled, 
unless otherwise specified by the protocol.
Evaluable 
immunogenicity
All participants who are eligible, receive all 3 doses of the 
investigational product, have blood drawn for assay testing within 
the specified time frame for baseline and 4 weeks after the third 
vaccination, have valid and determinate assay result (NT titer) at 
baseline and 4 weeks after the third vaccination visit, are NT 
seronegative at baseline, and have no major protocol violations.
All-available 
immunogenicity
All enrolled participants who receive at least the first 2 doses of 
the investigational product and have valid and determinate assay
results (NT titer
) 4 weeks after the second 
and/or the third vaccination.
Safety
All enrolled participants who receive at least 1 dose of the 
investigational product.
CCI

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9.4. Statistical Analyses
The SAP will be developed and finalized before any analyses are performed and will 
describe the analyses and procedures for accounting for missing, unused, and spurious data.  
This section is a summary of the planned statistical analyses of the primary, secondary, 
 
 endpoints.  All analyses are conducted by age groups.
9.4.1. Immunogenicity Analyses
Endpoint
Statistical Analysis Methods
Primary
Point estimate and the exact 2-sided 95% CI will be calculated using the Clopper-Pearson 
method for the seropositivity rate based on the immune response determined by NT 4 
weeks after the third vaccination.  NT titers ≥1:10 are considered seropositive. The 
evaluable immunogenicity population will be the primary population for the analysis.
Secondary
Point estimate and the exact 2-sided 95% CI will be calculated using the Clopper-Pearson 
method for the seropositivity rate based on the immune response determined by NT 4 
weeks after the second vaccination.
Neutralizing antibody GMT 4 weeks after the second vaccination and 4 weeks after the 
third vaccination will be calculated.  Two-sided 95% CIs for the mean of the 
logarithmically transformed assay results will be computed based on the Student 
t distribution.
GMFRs and associated 2-sided 95% CIs will be provided for neutralizing antibody titer 
from baseline to 4 weeks after the second and 4 weeks the third vaccinations.  In addition, 
GMFR will be provided for neutralizing antibody titer from 4 weeks after the second 
vaccination to 4 weeks after the third vaccination.  The GMFR will be calculated as the 
mean of the difference of logarithmically transformed antibody titers (postvaccination 
minus prevaccination for each participant) and transformed back to the original scale.  
Two-sided 95% CIs will be obtained by constructing CIs using 1-sample Student’s 
t distribution for the mean difference of measures on the logarithmically transformed assay 
results, and transforming the limits back to the original scale.
Empirical RCDCs by time points will be presented for neutralizing antibody titer.
Titers below the LLOQ or denoted as BLQ will be set to 0.5 × LLOQ for analysis.
The above analyses are based on the evaluable immunogenicity population.  An additional 
analysis will be performed based on all-available immunogenicity population if there is 
enough difference between the all-available immunogenicity population and the evaluable 
immunogenicity population.  Missing serology data are not imputed.
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Endpoint
Statistical Analysis Methods
 
 
 
 
 
 
 
 
 
 
 
 
9.4.2. Safety Analyses
All safety analyses will be performed on the safety population.
Endpoint
Statistical Analysis Methods
Primary
Point estimate and the exact 2-sided 95% CIs will be calculated using the Clopper-Pearson 
method for the percentage of participants reporting each event (local reactions, systemic 
events, AEs, and SAEs).
AEs and SAEs will be categorized according to MedDRA terms.
The safety analyses are based on safety population.  Missing e-diary data are not imputed; 
handling missing AE dates and missing AE severity will be applied following the Pfizer 
safety rules.
Secondary
N/A
CCI
CCI

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9.5. Interim Analyses
No formal interim analysis will be conducted for this study.  As this is an open-label
study, the sponsor may conduct unblinded reviews of the data during the course of the study 
for the purpose of safety assessment, and supporting clinical development.
CCI

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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1. Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines;

Applicable ICH GCP guidelines;

Applicable laws and regulations, including applicable privacy laws.
The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents 
(eg, advertisements) must be reviewed and approved by the sponsor and submitted to an 
IRB/EC by the investigator and reviewed and approved by the IRB/EC before the study is 
initiated.
Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.
The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/EC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC;

Notifying the IRB/EC of SAEs or other significant safety findings as required by 
IRB/EC procedures;

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/EC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations.
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the study 
intervention, Pfizer should be informed immediately.
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study participants against any immediate hazard, and 
of any serious breaches of this protocol or of ICH GCP that the investigator becomes aware 
of.

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10.1.2. Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities.  Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
10.1.3. Informed Consent Process
The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally acceptable representative/parent/legal guardian and answer all 
questions regarding the study.  The participant or his/her legally acceptable 
representative/parent/legal guardian should be given sufficient time and opportunity to ask 
questions and to decide whether or not to participate in the trial.
Participants must be informed that their participation is voluntary.  Participants or their
legally acceptable representative/parent/legal guardian will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, ICH 
guidelines, HIPAA requirements, where applicable, and the IRB/EC or study center.
The investigator must ensure that each study participant or his or her legally acceptable 
representative/parent/legal guardian is fully informed about the nature and objectives of the 
study, the sharing of data related to the study, and possible risks associated with 
participation, including the risks associated with the processing of the participant’s personal 
data.
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law.  The level of disclosure must also be 
explained to the participant.
The participant must be informed that his/her 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 or his or her legally 
acceptable representative/parent/legal guardian is fully informed about his or her right to 
access and correct his or her personal data and to withdraw consent for the processing of his 
or her 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.
Participants must be reconsented to the most current version of the ICD(s) during their 
participation in the study.

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A copy of the ICD(s) must be provided to the participant or the participant’s legally 
acceptable representative/parent/legal guardian.
10.1.4. Data Protection
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data.
Participants’ personal data will be stored at the study site in encrypted electronic and/or paper 
form and will be password protected or secured in a locked room to ensure that only 
authorized study staff have access.  The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster.  In the event of a potential personal data breach, the study site will be responsible 
for determining whether a personal data breach has in fact occurred and, if so, providing 
breach notifications as required by law.
To protect the rights and freedoms of participants with regard to the processing of personal 
data, participants will be assigned a single, participant-specific numerical code.  Any 
participant records or data sets that are transferred to the sponsor will contain the numerical 
code; participant names will not be transferred.  All other identifiable data transferred to the 
sponsor will be identified by this single, participant-specific code.  The study site will 
maintain a confidential list of participants who participated in the study, linking each 
participant’s numerical code to his or her actual identity and medical record identification.  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 EudraCT, and/or 
www.pfizer.com, and other public registries in accordance with applicable local 
laws/regulations.  In addition, Pfizer reports study results outside of the requirements of local 
laws/regulations pursuant to its SOPs.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer-sponsored interventional 
studies (conducted in patients) that evaluate the safety and/or efficacy of a product, 
regardless of the geographical location in which the study is conducted.  These results are 
submitted for posting in accordance with the format and timelines set forth by US law.

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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 (CSR synopses in which any data that could be used 
to identify individual participants have been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the corresponding study results are 
posted to www.clinicaltrials.gov.
Documents within marketing authorization packages/submissions
Pfizer complies with the European Union Policy 0070, the proactive publication of clinical 
data to the EMA website.  Clinical data, under Phase 1 of this policy, includes clinical 
overviews, clinical summaries, CSRs, and appendices containing the protocol and protocol 
amendments, sample CRFs, and statistical methods.  Clinical data, under Phase 2 of this 
policy, includes the publishing of individual participant data.  Policy 0070 applies to new 
marketing authorization applications submitted via the centralized procedure since 
01 Jan 2015 and applications for line extensions and for new indications submitted via the 
centralized procedure since 01 Jul 2015.
Data Sharing
Pfizer provides researchers secure access to patient-level data or full CSRs for the purposes 
of “bona-fide scientific research” that contributes to the scientific understanding of the 
disease, target, or compound class.  Pfizer will make available data from these trials 
24 months after study completion.  Patient-level data will be anonymized in accordance with 
applicable privacy laws and regulations.  CSRs will have personally identifiable information 
redacted.
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses.  Research teams must include a biostatistician.  Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.
10.1.6. Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data).  The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.

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The investigator must ensure that the CRFs are securely stored at the study site in encrypted 
electronic and/or paper form and are password protected or secured in a locked room to 
prevent access by unauthorized third parties.
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source data documents.  This 
verification may also occur after study completion.  It is important that the investigator(s) 
and their relevant personnel are available during the monitoring visits and possible audits or 
inspections and that sufficient time is devoted to the process.
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as risk management and mitigation strategies and analytical risk-based monitoring), 
methods, responsibilities, and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring), are provided in the 
monitoring plan.
The sponsor or designee is responsible for the data management of this study, including
quality checking of the data.
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICDs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period.  No records may be destroyed during 
the retention period without the written approval of the sponsor.  No records may be 
transferred to another location or party without written notification to the sponsor.  The 
investigator must ensure that the records continue to be stored securely for as long as they are 
maintained.
When participant data are to be deleted, the investigator will ensure that all copies of such 
data are promptly and irrevocably deleted from all systems.
The investigator(s) will notify the sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study.  Furthermore, the investigator will cooperate 
with the sponsor or its agents to prepare the investigator site for the inspection and will allow 
the sponsor or its agent, whenever feasible, to be present during the inspection.  The 
investigator site and investigator will promptly resolve any discrepancies that are identified 
between the study data and the participant's medical records.  The investigator will promptly 
provide copies of the inspection findings to the sponsor or its agent.  Before response 
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.

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10.1.7. Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected.  Source documents are filed at the investigator site.
Data reported on the CRF or entered in the eCRF that are from source documents must be 
consistent with the source documents or the discrepancies must be explained.  The 
investigator may need to request previous medical records or transfer records, depending on 
the study.  Also, current medical records must be available.
Definition of what constitutes source data can be found in the ISF.
Description of the use of computerized system is documented in the data management plan.
10.1.8. Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The first act of recruitment is the date of the first participant’s first visit and will be the study 
start date.
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor.  Study sites will be closed upon 
study completion.  A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time upon notification to the sponsor 
or designee/CRO if requested to do so by the responsible IRB/EC or if such termination is 
required to protect the health of study participants.
Reasons for the early closure of a study site by the sponsor may include but are not limited 
to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the sponsor's procedures, or GCP guidelines;

Inadequate recruitment of participants by the investigator;

Discontinuation of further study intervention development.
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements.  The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.

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Study termination is also provided for in the clinical study agreement.  If there is any conflict 
between the contract and this protocol, the contract will control as to termination rights.
10.1.9. Publication Policy
The results of this study may be published or presented at scientific meetings by the
investigator after publication of the overall study results or 1 year after the end of the study 
(or study termination), whichever comes first.
The investigator agrees to refer to the primary publication in any subsequent publications 
such as secondary manuscripts, and submits all manuscripts or abstracts to the sponsor 
30 days before submission.  This allows the sponsor to protect proprietary information and to 
provide comments and the investigator will, on request, remove any previously undisclosed 
confidential information before disclosure, except for any study- or Pfizer 
intervention-related information necessary for the appropriate scientific presentation or 
understanding of the study results.
For all publications relating to the study, the investigator will comply with recognized ethical 
standards concerning publications and authorship, including those established by the 
International Committee of Medical Journal Editors.
The sponsor will comply with the requirements for publication of the overall study results 
covering all investigator sites.  In accordance with standard editorial and ethical practice, the 
sponsor will support publication of multicenter studies only in their entirety and not as 
individual site data.  In this case, a coordinating investigator will be designated by mutual 
agreement.
Authorship of publications for the overall study results will be determined by mutual 
agreement and in line with International Committee of Medical Journal Editors authorship 
requirements.
If publication is addressed in the clinical study agreement, the publication policy set out in 
this section will not apply.
10.1.10. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the ISF.
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, participants are provided with a contact card at the time of informed 
consent.  The contact card contains, at a minimum, protocol and study intervention 
identifiers, participant numbers, contact information for the investigator site, and contact 
details for a contact center in the event that the investigator site 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

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problems; however, it should be used only in the event that the established communication 
pathways between the investigator site and the study team are not available.  It is therefore 
intended to augment, but not replace, the established communication pathways between the 
investigator site and the study team for advice on medical questions or problems that may 
arise during the study.  The contact number is not intended for use by the participant directly, 
and if a participant calls that number, he or she will be directed back to the investigator site.
10.2. Appendix 2: Clinical Laboratory Tests
The following safety laboratory tests will be performed at times defined in the SoA section of 
this protocol.

Pregnancy testing

Conducted at Visits 1, 2, and 4 (prior to vaccination).
Investigators must document their review of each laboratory safety report.

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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1. Definition of AE
AE Definition

An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered 
related to the study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital sign measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator.  Any abnormal laboratory test 
results that meet any of the conditions below must be recorded as an AE:

Is associated with accompanying symptoms.

Requires additional diagnostic testing or medical/surgical intervention.

Leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy.

Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.  Overdose per se will not be reported as 
an AE/SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent.  Such overdoses should be reported regardless of 
sequelae.

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Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
10.3.2. Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, death 
due to progression of disease).

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An SAE is defined as any untoward medical occurrence that, at any dose:
a. Results in death
b. Is life-threatening
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event.  It does not refer to an event that 
hypothetically might have caused death if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually involving 
at least an overnight stay) at the hospital or emergency ward for observation 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 

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convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.

Suspected transmission via a Pfizer product of an infectious agent, pathogenic or 
nonpathogenic, is considered serious.  The event may be suspected from clinical 
symptoms or laboratory findings indicating an infection in a patient exposed to a 
Pfizer product.  The terms “suspected transmission” and “transmission” are 
considered synonymous.  These cases are considered unexpected and handled as 
serious expedited cases by pharmacovigilance personnel.  Such cases are also 
considered for reporting as product defects, if appropriate.
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording adverse events on the CRF and 
for reporting serious adverse events on the Vaccine SAE Reporting Form to Pfizer Safety.  
These requirements are delineated for 3 types of events: (1) SAEs; (2) nonserious adverse 
events (AEs); and (3) exposure to the study intervention under study during pregnancy or 
breastfeeding, and occupational exposure.
It should be noted that the Vaccine SAE Reporting Form for reporting of SAE information 
is not the same as the AE page of the CRF.  When the same data are collected, the forms 
must be completed in a consistent manner.  AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the Vaccine SAE 
Reporting Form for reporting of SAE information.
Safety Event
Recorded on the CRF
Reported on the Vaccine 
SAE Reporting Form to 
Pfizer Safety Within 24 
Hours of Awareness
SAE
All
All
Nonserious AE
All
None
Exposure to the study 
intervention under study 
during pregnancy or 
breastfeeding, and 
occupational exposure
All AEs/SAEs associated 
with exposure during 
pregnancy or breastfeeding
Occupational exposure is not 
recorded.
All (and EDP supplemental 
form for EDP) 
Note:  Include all SAEs 
associated with exposure 
during pregnancy or 
breastfeeding.  Include all 
AEs/SAEs associated with 
occupational exposure.

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
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.

There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety.  In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical 
records before submission to Pfizer Safety.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported during 
the study and assign it to 1 of the following categories:

Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities.  An AE that is assessed 
as severe should not be confused with an SAE.  Severe is a category utilized for 
rating the intensity of an event; and both AEs and SAEs can be assessed as severe.
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
GRADE 
If required on the AE page of the CRF, the investigator will use the 
adjectives MILD, MODERATE, SEVERE, or LIFE-THREATENING to 
describe the maximum intensity of the AE.  For purposes of consistency, 
these intensity grades are defined as follows:

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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.
4
LIFE-THREATENI
NG
Life-threatening consequences; urgent intervention 
indicated.
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.

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
If the investigator does not know whether or not the study intervention caused the 
event, then the event will be handled as “related to study intervention” for reporting 
purposes, as defined by the sponsor.  In addition, if the investigator determines that 
an SAE is associated with study procedures, the investigator must record this causal 
relationship in the source documents and CRF, and report such an assessment in the 
dedicated section of the Vaccine SAE Reporting Form and in accordance with the 
SAE reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
sponsor to elucidate the nature and/or causality of the AE or SAE as fully as 
possible.  This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other healthcare providers.

If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide Pfizer Safety with a copy of any 
postmortem findings including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to the sponsor within 24 hours of 
receipt of the information.
10.3.4. Reporting of SAEs
SAE Reporting to Pfizer Safety via an Electronic Data Collection Tool

The primary mechanism for reporting an SAE to Pfizer Safety will be the electronic 
data collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as the data 
become available.

After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data.

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
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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10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments
Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.”  In some participants, transaminase elevations are a harbinger of a 
more serious potential outcome.  These participants fail to adapt and therefore are 
"susceptible" to progressive and serious liver injury, commonly referred to as DILI.  
Participants who experience a transaminase elevation above 3 × ULN should be monitored 
more frequently to determine if they are an “adaptor” or are “susceptible.”
LFTs are not required as a routine safety monitoring procedure in this study.  However, 
should an investigator deem it necessary to assess LFTs because a participant presents with 
clinical signs/symptoms, such LFT results should be managed and followed as described 
below.
In the majority of DILI cases, elevations in AST and/or ALT precede TBili elevations 
(>2 × ULN) by several days or weeks.  The increase in TBili typically occurs while 
AST/ALT is/are still elevated above 3 × ULN (ie, AST/ALT and TBili values will be 
elevated within the same laboratory sample).  In rare instances, by the time TBili elevations 
are detected, AST/ALT values might have decreased.  This occurrence is still regarded as a 
potential DILI.  Therefore, abnormal elevations in either AST OR ALT in addition to TBili 
that meet the criteria outlined below are considered potential DILI (assessed per Hy’s law 
criteria) cases and should always be considered important medical events, even before all 
other possible causes of liver injury have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the 
participant’s individual baseline values and underlying conditions.  Participants who present 
with the following laboratory abnormalities should be evaluated further as potential DILI 
(Hy’s law) cases to definitively determine the etiology of the abnormal laboratory values:

Participants with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available.

For participants with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is 
smaller).

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
Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches 
>3 × ULN (whichever is smaller).
Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor.
The participant should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment.
In addition to repeating measurements of AST and ALT and TBili for suspected cases of 
Hy’s law, additional laboratory tests should include albumin, CK, direct and indirect 
bilirubin, GGT, PT/INR, total bile acids, and alkaline phosphatase.  Consideration should 
also be given to drawing a separate tube of clotted blood and an anticoagulated tube of blood 
for further testing, as needed, for further contemporaneous analyses at the time of the 
recognized initial abnormalities to determine etiology.  A detailed history, including relevant 
information, such as review of ethanol, acetaminophen/paracetamol (either by itself or as a 
coformulated product in prescription or over-the-counter medications), recreational drug, 
supplement (herbal) use and consumption, family history, sexual history, travel history, 
history of contact with a jaundiced person, surgery, blood transfusion, history of liver or 
allergic disease, and potential occupational exposure to chemicals, should be collected.  
Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging (eg, biliary 
tract) and collection of serum samples for acetaminophen/paracetamol drug and/or protein 
adduct levels may be warranted.
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the LFT abnormalities has yet been found.  Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.
10.7. Appendix 7: ECG Findings of Potential Clinical Concern
Not applicable.

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10.8. Appendix 8: Medical Device Adverse Events, Adverse Device Effects, Serious 
Adverse Events, and Device Deficiencies: Definition and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
Definitions of a Medical Device Incident
The definitions and procedures detailed in this appendix are in accordance with ISO 14155.
Both the investigator and the sponsor will comply with all local medical device reporting 
requirements.
The detection and documentation procedures described in this protocol apply to all sponsor 
medical devices provided for use in the study (see Section 6.1.2 for the list of sponsor 
medical devices).
10.8.1. Definition of AE and ADE
AE and ADE Definition

An AE is defined as any untoward medical occurrence, unintended disease or injury, 
or untoward clinical signs (including abnormal laboratory finding) in study 
participants, users, or other persons, whether or not related to the investigational 
medical device.  This definition includes events related to the investigational 
medical device or comparator for study participants, users, and other persons.  This 
definition also includes events considered related to procedures for study 
participants only.

An ADE is defined as an adverse event related to the use of an investigational 
medical device.  This definition includes any adverse events resulting from 
insufficient or inadequate instructions for use, deployment, implantation, 
installation, or operation, or any malfunction of the investigational medical device as 
well as any event resulting from use error or from intentional misuse of the 
investigational medical device.
10.8.2. Definition of SAE, SADE, and Unanticipated Serious Adverse Device Effect
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, death 
due to progression of disease).

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An SAE is an AE that:
a.
Led to death.
b. Led to serious deterioration in the health of the participant, that either resulted in:

A life-threatening illness or injury.  The term “life-threatening” in the definition of 
serious refers to an event in which the participant was at risk of death at the time of 
the event.  It does not refer to an event that hypothetically might have caused death, 
if it were more severe.

A permanent impairment of a body structure or a body function.

Inpatient or prolonged hospitalization.  Planned hospitalization for a preexisting 
condition, or a procedure required by the protocol, without serious deterioration in 
health, is not considered an SAE.

Medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function.
c.
Led to fetal distress, fetal death, or a congenital abnormality or birth defect.
SADE Definition

An SADE is defined as an adverse device effect that has resulted in any of the 
consequences characteristic of a serious adverse event.
USADE Definition

A USADE is a serious adverse device effect which by its nature, incidence, severity, 
or outcome has not been identified in the current version of the risk analysis 
management file.
10.8.3. Definition of Device Deficiency
Device Deficiency Definition

A device deficiency is an inadequacy of a medical device with respect to its identity, 
quality, durability, reliability, safety, or performance.  Device deficiencies include 
malfunctions, use errors, and inadequate labeling.

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10.8.4. Recording/Reporting and Follow-up of AEs and/or SAEs and Device 
Deficiencies
AE, SAE, and Device Deficiency Recording

When an AE/SAE/device deficiency occurs, it is the responsibility of the 
investigator to review all documentation (eg, hospital progress notes, laboratory 
reports, and diagnostic reports) related to the event.

The investigator will then record all relevant AE/SAE/device deficiency information 
in the participant’s medical records, in accordance with the investigator’s normal 
clinical practice and on the appropriate form of the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of following the reporting process described 
in the IP manual and completing the Medical Device Complaint CRF.

There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety.  In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical 
records before submission to Pfizer Safety.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE/SAE.

For device deficiencies, it is very important that the investigator describes any 
corrective or remedial actions taken to prevent recurrence of the incident.

A remedial action is any action other than routine maintenance or servicing of a 
medical device where such action is necessary to prevent recurrence of a device 
deficiency.  This includes any amendment to the device design to prevent 
recurrence.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE/SAE/device deficiency 
reported during the study and assign it to 1 of the following categories:

Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.

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
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.
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE/device deficiency.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.

The investigator will also consult the IB in his/her assessment.

For each AE/SAE/device deficiency, the investigator must document in the medical 
notes that he/she has reviewed the AE/SAE/device deficiency and has provided an 
assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor.  However, it is 
very important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to the sponsor.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.

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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.

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.

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SAE Reporting to Pfizer Safety via Vaccine SAE Reporting Form

Facsimile transmission of the Vaccine SAE Reporting Form is the preferred method 
to transmit this information to Pfizer Safety.

In circumstances when the facsimile is not working, notification by telephone is 
acceptable with a copy of the Vaccine SAE Reporting Form sent by overnight mail 
or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the Vaccine SAE Reporting Form pages within the designated 
reporting time frames.
10.8.6. 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.

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10.9. Appendix 9: Country-Specific Requirements
10.9.1. Japan-Specific Regulatory Requirements
10.9.1.1. Definitions of Serious Adverse Event, Serious Adverse Event Caused by 
Medical Device, and Unanticipated Serious Adverse Event Caused by Medical Device
Definition of Serious Adverse Event Caused by Medical Device
An SAE caused by medical device is defined as an AE caused by a medical device that led to 
an outcome characteristic of SAEs, or a device-related incident whose recurrence might lead 
to death or serious deterioration in health.

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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
ADE
adverse device effect
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BLQ
below the limit of quantitation
CBER
Center for Biologics Evaluation and Research
CC
chick-chick
CFR
Code of Federal Regulations
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
CNS
central nervous system
CONSORT
Consolidated Standards of Reporting Trials
CRF
case report form
CRO
contract research organization
CSR
clinical study report
DILI
drug-induced liver injury
DMC
data monitoring committee
DRE
drug-related event
EC
ethics committee
ECG
electrocardiogram
eCRF
electronic case report form
e-diary
electronic diary
EDP
exposure during pregnancy
EMA
European Medicines Agency
EU
European Union
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GMFR
geometric mean fold rise
GMT
geometric mean titer
HBV
hepatitis B virus
CCI
CCI

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Abbreviation
Term
HCV
hepatitis C virus
HI
hemagglutination inhibition
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HRT
hormone replacement therapy
IB
investigator’s brochure
ICD
informed consent document
ICH
International Council for Harmonisation
ID
identification
IMP
investigational medicinal product
IND
investigational new drug
INR
international normalized ratio
IP manual
investigational product manual
IPAL
Investigational Product Accountability Log
IRB
institutional review board
IRT
interactive response technology
ISF
investigator site file
ISO
International Organization for Standardization
JEV
Japanese encephalitis virus
LFT
liver function test
LLOQ
lower limit of quantitation
MCAR
missing completely at random
MedDRA
Medical Dictionary for Regulatory Activities
MHLW
Ministry of Health, Labour and Welfare
N/A
not applicable
NIMP
noninvestigational medicinal product
NT
neutralization test
PI
principal investigator
PT
prothrombin time
RCDC
reverse cumulative distribution curve
SADE
serious adverse device effect
SAE
serious adverse event
SAP
statistical analysis plan
SoA
schedule of activities
SOP
standard operating procedure
SRM
study reference manual
SRSD
single reference safety document
SUSAR
suspected unexpected serious adverse reaction
TBE
tick-borne encephalitis
TBEV
tick-borne encephalitis virus
CCI

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Abbreviation
Term
TBili
total bilirubin
UK
United Kingdom
ULN
upper limit of normal
US
United States
USADE
unanticipated serious adverse device effect
VIE U
Vienna units
WHO
World Health Organization
WOCBP
woman/women of childbearing potential

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11. REFERENCES
1
Kovalev SY, Mukhacheva TA. Reconsidering the classification of tick-borne 
encephalitis virus within the Siberian subtype gives new insights into its evolutionary 
history. Infect Genet Evol. 2017;55:159-165. 
2
Adelshin RV, Sidorova EA, Bondaryuk AN, et al. "886-84-like" tick-borne encephalitis 
virus strains: Intraspecific status elucidated by comparative genomics. Ticks Tick Borne 
Dis. 2019;10(5):1168-1172.
3
Kozlova IV, Demina TV., Tkachev SE, et al. Characteristics of the baikal subtype of 
tick-borne encephalitis virus circulating in eastern Siberia. Acta Biomedica Scientifica. 
2018;3(4):53-60.
4
Mickiene A, Laiskonis A, Günther G, et al. Tickborne encephalitis in an area of high 
endemicity in Lithuania: disease severity and long-term prognosis. Clin Infect Dis 
2002;35(6):650-8.
5
National Institute of Infectious Diseases, Japan. What is tick-borne encephalitis? 
Available from: https://www.niid.go.jp/niid/ja/kansennohanashi/434-tick-encephalitis-
intro.html. Updated: 27 Aug 2018. Accessed: 02 Oct 2018.
6
World Health Organization. Vaccines against tick-borne encephalitis: WHO position 
paper. Wkly Epidemiol Rec 2011;24(86):241-56.
7
Kunz C. TBE vaccination and the Austrian experience. Vaccine 2003;21 Suppl 1:S50-5.
8
Heinz FX, Holzmann H, Essl A, et al. Field effectiveness of vaccination against tick-
borne encephalitis. Vaccine 2007;25(43):7559-67.
9
Heinz FX, Stiasny K, Holzmann H, et al. Vaccination and tick-borne encephalitis, 
central Europe. Emerg Infect Dis 2013;19(1):69-76.
10
Tuberculosis and Infectious Diseases Control Division, MHLW. Cautions against tick-
borne infections. Available from: https://www.mhlw.go.jp/file/06-Seisakujouhou-
10900000-Kenkoukyoku/0000210709.pdf. Accessed: 01 Jun 2018.
11
Yoshii K, Song JY, Park SB, et al. Tick-borne encephalitis in Japan, Republic of Korea 
and China. Emerg Microbes Infect 2017;6(9):e82. 
 
 
1
CCI

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13
Holzmann H, Kundi M, Stiasny K, et al. Correlation between ELISA, hemagglutination 
inhibition, and neutralization tests after vaccination against tick-borne encephalitis. J 
Med Virol 1996;48(1):102-7.
 
15
Adner N, Leibl H, Enzersberger O, et al. Pharmacokinetics of human tick-borne 
encephalitis virus antibody levels after injection with human tick-borne encephalitis 
immunoglobulin, solvent/detergent treated, FSME-BULIN S/D in healthy volunteers. 
Scand J Infect Dis 2001;33(11):843-7.
CCI

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