An Open Label, Phase 2 Study to Investigate Cell-mediated Immunity and Safety of a Tetravalent Dengue Vaccine Candidate (TDV) Administered Subcutaneously in Healthy Children Aged 4 to 16 Years
Phase: PHASE2
Conditions: Healthy Volunteers
Sponsor: Takeda




Title: An open label, Phase 2 Study to Investigate Cell-mediated Immunity and Safety of a 
Tetravalent Dengue Vaccine Candidate (TDV) Administered Subcutaneously in Healthy 
Children Aged 4 to 16 Years 
NCT Number: NCT02948829
Protocol Approve Date: 01 July 2016 
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.

1.0 TITLE PAGE 
TITLE PAGE 
PROTOCOL 
An open label, Phase 2 Study to Investigate Cell-mediated Immunity and Safety of a Tetravalent 
Dengue Vaccine Candidate (TDV) Administered Subcutaneously in Healthy Children Aged 4 to 
16 Years 
Safety and Immunogenicity of Takeda’s TDV in Healthy Children 
Sponsor: 
Takeda Vaccines, Inc. 
One Takeda Parkway 
Deerfield, IL 60015 
USA 
Study Identifier: 
DEN-313 
IND Number: 
Not applicable 
EudraCT Number: 
Not applicable 
Vaccine Name: 
Tetravalent Dengue Vaccine Candidate (TDV) (formerly DENVax) 
comprised of a molecularly characterized, attenuated dengue serotype 2 
strain (TDV-2), a dengue serotypes 2/1 chimeric strain (TDV-1), a 
dengue serotypes 2/3 chimeric strain (TDV-3), and a dengue serotypes 
2/4 chimeric strain (TDV-4). 
Date: 
01 July 2016 
Version: 
Version 1.0 
 of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

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Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-313 
Page 5 of 79 
Protocol Version 1.0 
01 July 2016 
 
1.3 
Protocol Amendment Summary of Changes 
Not applicable. 
1.3.1 Summary of Changes 
Not applicable. 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-313 
Page 6 of 79 
Protocol Version 1.0 
01 July 2016 
 
TABLE OF CONTENTS 
1.0 
ADMINISTRATIVE INFORMATION ..............................................................................2 
1.1 
Contacts..........................................................................................................................2 
1.2 
Approval ........................................................................................................................2 
1.3 
Protocol Amendment Summary of Changes..................................................................5 
1.3.1 Summary of Changes ...............................................................................................5 
2.0 
STUDY SUMMARY.........................................................................................................11 
2.1 
Schedule of Study Procedures .....................................................................................19 
3.0 
STUDY REFERENCE INFORMATION .........................................................................21 
3.1 
Study-Related Responsibilities ....................................................................................21 
3.2 
Principal Investigator/Coordinating Investigator .........................................................21 
3.3 
List of Abbreviations ...................................................................................................22 
3.4 
Corporate Identification ...............................................................................................24 
4.0 
INTRODUCTION .............................................................................................................25 
4.1 
Background ..................................................................................................................25 
4.2 
Rationale for the Proposed Study ................................................................................26 
5.0 
STUDY OBJECTIVES AND ENDPOINTS .....................................................................28 
5.1 
Objectives ....................................................................................................................28 
5.1.1 Primary Objective ..................................................................................................28 
5.1.2 Secondary Objectives.............................................................................................28 
5.1.3 Exploratory Objectives ..........................................................................................28 
5.2 
Endpoints .....................................................................................................................28 
5.2.1 Primary Endpoint ...................................................................................................28 
5.2.2 Secondary Endpoints .............................................................................................28 
5.2.3 Exploratory Endpoints ...........................................................................................30 
6.0 
STUDY DESIGN AND DESCRIPTION ..........................................................................31 
6.1 
Study Design ................................................................................................................31 
6.2 
Justification for Study Design, Dose, and Endpoints ..................................................34 
6.3 
Duration of Subject’s Expected Participation in the Entire Study ...............................35 
6.4 
Premature Termination or Suspension of Study or Investigational Site ......................35 
6.4.1 Criteria for Premature Termination or Suspension of the Study ...........................35 
6.4.2 Criteria for Premature Termination or Suspension of Investigational Sites ..........36 
6.4.3 Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s)...................................................................36 
7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS ...............37 
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Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-313 
Page 7 of 79 
Protocol Version 1.0 
01 July 2016 
 
7.1 
Inclusion Criteria .........................................................................................................37 
7.2 
Exclusion Criteria ........................................................................................................37 
7.3 
Criteria for Delay of Second Vaccination at Day 90 (Month 3) ..................................39 
7.4 
Criteria for Discontinuation or Withdrawal of a Subject .............................................40 
7.5 
Procedures for Discontinuation or Withdrawal of a Subject .......................................40 
8.0 
CLINICAL STUDY MATERIAL MANAGEMENT .......................................................42 
8.1 
Study Vaccine(s) and Materials ...................................................................................42 
8.1.1 Dosage Form, Manufacturing, Packaging, and Labeling ......................................42 
8.1.2 Storage ...................................................................................................................42 
8.1.3 Dose and Regimen .................................................................................................43 
8.2 
Study Vaccine Assignment and Dispensing Procedures .............................................43 
8.3 
Randomization Code Creation and Storage .................................................................43 
8.4 
Study Vaccine Blind Maintenance ...............................................................................43 
8.5 
Unblinding Procedure ..................................................................................................44 
8.6 
Accountability and Destruction of Sponsor-Supplied Vaccine(s) ...............................44 
9.0 
STUDY PLAN ...................................................................................................................46 
9.1 
Study Procedures .........................................................................................................46 
9.1.1 Informed Consent/Assent.......................................................................................46 
9.1.2 Demographics, Medical History and Prior Medications ........................................46 
9.1.3 Documentation of Study Entrance/Randomization ...............................................47 
9.1.4 Physical Examination.............................................................................................47 
9.1.5 Vital Signs ..............................................................................................................48 
9.1.6 Dengue Baseline Seropositivity Status ..................................................................48 
9.1.7 Immunogenicity and CMI Assessments ................................................................48 
9.1.8 Processing, Labeling and Storage of Peripheral Blood Mononuclear Cell 
Samples ..................................................................................................................49 
9.1.9 Handling of Febrile Illness Cases (Suspected Dengue Cases)...............................49 
9.1.10 Safety Assessments ................................................................................................49 
9.1.11 Contraception and Pregnancy Avoidance Procedure .............................................49 
9.1.12 Pregnancy ...............................................................................................................50 
9.1.13 Documentation of Enrolled Subjects who are not Vaccinated ..............................50 
9.2 
Monitoring Subject Vaccination Compliance ..............................................................50 
9.3 
Schedule of Observations and Procedures ...................................................................51 
9.3.1 Enrolment (Screening: up to 28 days prior to Day 1 [Month 0]) and Vaccination 
Procedures (Day 1 [Month 0] and Day 90 [Month 3]) ..........................................51 
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Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-313 
Page 8 of 79 
Protocol Version 1.0 
01 July 2016 
 
9.3.2 Clinic Visits after Vaccination (Day 1 [Month 0] and Day 90 [Month 3]) for all 
Subjects at Day 30 (Month 1), Day 120 (Month 4), Day 270 (Month 9), and 
Annually for 3 Years Post Second Vaccination. ....................................................52 
9.3.3 Additional Clinic Visit after Vaccination (Day 1 [Month 0]) for Subjects Aged 
Older than 10 Years (Day 14) ................................................................................53 
9.3.4 Contacts During Febrile Illness Surveillance ........................................................53 
9.3.5 Follow-Up Visit .....................................................................................................54 
9.3.6 Post-Study Care .....................................................................................................54 
9.4 
Biological Sample Retention and Destruction .............................................................54 
10.0 
ADVERSE EVENTS .........................................................................................................55 
10.1 
Definitions....................................................................................................................55 
10.1.1 AEs .........................................................................................................................55 
10.1.2 Unsolicited AEs .....................................................................................................55 
10.1.3 MAAEs ..................................................................................................................55 
10.1.4 SAEs ......................................................................................................................56 
10.2 
Causality of AEs ..........................................................................................................56 
10.2.1 Relationship to Study Procedures ..........................................................................56 
10.2.2 Outcome of AEs .....................................................................................................57 
10.3 
Additional Points to Consider for AEs ........................................................................57 
10.4 
Procedures ....................................................................................................................58 
10.4.1 Collection and Reporting of AEs ...........................................................................58 
10.4.2 Collection and Reporting of Unsolicited AEs .......................................................59 
10.4.3 Collection and Reporting of MAAEs and AEs Leading to Subject 
Discontinuation or Withdrawal ..............................................................................59 
10.4.4 Collection and Reporting of SAEs .........................................................................59 
10.5 
Follow-Up Procedures .................................................................................................60 
10.5.1 AEs .........................................................................................................................60 
10.5.2 SAEs ......................................................................................................................60 
10.5.3 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities .....60 
10.5.4 Post-Study Events ..................................................................................................60 
11.0 
STUDY-SPECIFIC REQUIREMENT(S) .........................................................................61 
11.1 
Study-Specific Committees .........................................................................................61 
11.1.1 Data Monitoring Committee ..................................................................................61 
12.0 
DATA HANDLING AND RECORDKEEPING ..............................................................62 
12.1 
Electronic CRFs (eCRF) ..............................................................................................62 
12.2 
Record Retention .........................................................................................................62 
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Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-313 
Page 9 of 79 
Protocol Version 1.0 
01 July 2016 
 
13.0 
STATISTICAL METHODS ..............................................................................................64 
13.1 
Statistical and Analytical Plans ....................................................................................64 
13.1.1 Analysis Sets ..........................................................................................................64 
13.1.2 Analysis of Demographics and Other Baseline Characteristics ............................64 
13.1.3 Immunogenicity Analysis ......................................................................................64 
13.1.4 Safety Analysis ......................................................................................................65 
13.2 
Interim Analysis and Criteria for Early Termination ...................................................65 
13.3 
Determination of Sample Size .....................................................................................65 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................66 
14.1 
Study-Site Monitoring Visits .......................................................................................66 
14.2 
Protocol Deviations ......................................................................................................66 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections ..................................66 
15.0 
ETHICAL ASPECTS OF THE STUDY ...........................................................................67 
15.1 
IRB and/or IEC Approval ............................................................................................67 
15.2 
Subject Information, Informed Consent/Assent, and Subject Authorization ..............68 
15.3 
Subject Confidentiality ................................................................................................69 
15.4 
Publication, Disclosure, and Clinical Study Registration Policy .................................69 
15.4.1 Publication and Disclosure ....................................................................................69 
15.4.2 Clinical Study Registration ....................................................................................69 
15.4.3 Clinical Study Results Disclosure ..........................................................................70 
15.5 
Insurance and Compensation for Injury .......................................................................70 
16.0 
REFERENCES ..................................................................................................................71 
 
LIST OF IN-TEXT TABLES 
Table 1.a 
Contact Information .................................................................................................2 
Table 2.a 
Schedule of Study procedures ................................................................................19 
Table 16.a 
Serology Plan .........................................................................................................79 
 
LIST OF IN-TEXT FIGURES 
Figure 6.a 
Schematic of Study Design ....................................................................................33 
 
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Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-313 
Page 10 of 79 
Protocol Version 1.0 
01 July 2016 
 
LIST OF APPENDICES 
Appendix A 
Responsibilities of the Investigator ........................................................................73 
Appendix B 
Investigator Consent to Use of Personal Information ............................................75 
Appendix C 
Elements of the Subject Informed Consent ...........................................................76 
Appendix D 
Serology Plan .........................................................................................................79 
 
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Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-313 
Page 11 of 79 
Protocol Version 1.0 
01 July 2016 
 
2.0 
STUDY SUMMARY 
Name of Sponsor: 
Takeda Vaccines, Inc. 
One Takeda Parkway 
Deerfield, IL 60015, USA 
Product Name: 
Tetravalent dengue vaccine candidate (TDV) 
Study Title: An open label, Phase 2 Study to Investigate Cell-mediated Immunity and Safety of a Tetravalent Dengue 
Vaccine Candidate (TDV) Administered Subcutaneously in Healthy Children Aged 4 to 16 Years 
IND No.: Not applicable 
EudraCT No.: Not applicable 
Study Identifier: DEN-313 
Phase: 2 
Study Blinding Schema: Open Label 
Background and Rationale: 
Dengue fever is caused by infection with wild type dengue virus (DENV), a ribonucleic acid (RNA) virus that occurs 
as 4 recognized serotypes, DENV-1, DENV-2, DENV-3 or DENV-4. These dengue viruses are transmitted from 
human to human by mosquitoes (primarily Aedes aegypti). The 4 dengue viruses have spread worldwide and are 
endemic in Asia, Central and South America, the Caribbean, the Pacific Islands, and parts of Africa. There are an 
estimated 390 million dengue infections per year worldwide, which is more than 3 times the previous World Health 
Organization estimate of 50 to 100 million cases. Every year, around 500,000 cases of dengue hemorrhagic fever 
(DHF) require hospitalization with an estimated death rate of 2.5%, primarily in children. It is estimated that 
3.9 billion people are at risk of dengue infection. 
Dengue fever is clinically defined as an acute febrile illness with 2 or more manifestations (headache, retro-orbital 
pain, myalgia, arthralgia, rash, hemorrhagic manifestations, or leucopenia) and occurrence at the same location and 
time as other confirmed cases of dengue fever. The most severe forms of dengue infection (ie, DHF and dengue shock 
syndrome [DSS]) are life threatening. Primary infection with any 1 of the 4 dengue serotypes is thought to result in 
life-long protection from re-infection by the same serotype, but does not protect against a secondary infection by 1 of 
the other 3 dengue virus serotypes and may lead to an increased risk of severe disease (DHF/DSS). 
Treatment of dengue fever is based solely on symptoms and signs, with fluid replacement required for hemorrhagic or 
shock cases. An antiviral therapy for dengue virus infection is not available. Preventive measures that rely on 
mosquito control and individual protection, are of limited efficacy, complex to implement and questionable in terms of 
cost-effectiveness. There is a great global public health need for a safe and effective vaccine that will protect against 
all serotypes of dengue infection, and thereby reduce the morbidity and mortality associated with dengue disease. A 
tetravalent dengue vaccine (CYD-TDV) has been recently approved in some countries in Asia and Latin America. 
However, the initial findings suggest an unfavorable risk-benefit profile for younger subjects with the approved 
vaccine. Vaccine efficacy was different between serotypes and depended on dengue Baseline seropositivity status. 
Hence, there is a continued unmet public health need for safer and more efficacious dengue vaccines. Additional 
vaccines are also important to ensure sufficient supply globally. 
Tetravalent Dengue Vaccine Candidate (TDV) - Background: 
Takeda’s TDV consists of 1 molecularly characterized, attenuated dengue virus strain and 3 recombinant dengue virus 
strains expressing surface antigens corresponding to dengue serotypes 1-4. The dengue serotype 2 strain is based upon 
the attenuated laboratory-derived virus, DENV-2 Primary Dog Kidney (PDK)-53, originally isolated at Mahidol 
University, Bangkok, Thailand. The chimeric, attenuated vaccine strains for dengue serotypes 1, 3, and 4 were 
engineered by substituting the structural genes, pre-membrane (prM) and envelope (E), of TDV-2 with the prM and E 
genes of the DENV strains, DENV-1 16007, DENV-3 16562 or DENV-4 1036 virus, respectively. TDV is thus 
comprised of 4 dengue virus strains: a molecularly characterized, attenuated dengue serotype 2 strain (TDV-2), a 
dengue serotypes 2/1 chimeric strain (TDV-1), a dengue serotypes 2/3 chimeric strain (TDV-3), and a dengue 
serotypes 2/4 chimeric strain (TDV-4). 
Nonclinical studies carried out in mice and nonhuman primates demonstrated an acceptable safety, immunogenicity, 
and efficacy profile of Takeda’s TDV. 
Data from 4 completed phase 1 studies, 1 completed phase 2 study, and 2 ongoing phase 2 studies have shown 
satisfactory reactogenicity, safety and immunogenicity of Takeda’s TDV in adults in non-endemic areas as well as in 
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Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-313 
Page 12 of 79 
Protocol Version 1.0 
01 July 2016 
 
adults and children in endemic areas in Asia and Latin America. Currently ongoing and completed phase 2 studies 
have enabled the selection of a final TDV dose (lyophilized formulation), and a 2-dose vaccination regimen for 
subcutaneous (SC) administration 3 months apart for use in the pivotal program. 
The current Investigator Brochure for Takeda’s TDV contains additional product information and a more detailed 
review of pre-clinical and clinical studies. 
Rationale for the Proposed Phase 2 Study: 
Studies investigating the role of cell-mediated immunity (CMI) in natural infections have demonstrated roles in both 
virus clearance and potentiating disease. These investigations have been extended from the exploratory study of CMI 
in natural infection to the study of dengue vaccine recipients. Knowledge about specific CMI correlates of protection 
is incomplete. However, the exploration of CMI is encouraged by the WHO since specific CMI assays may be useful 
for the assessment of immunological memory and durability of protection. Assessments of cytokine responses may 
also assist in the evaluation of vaccine safety and may provide some indication of the potential risk that vaccination 
could predispose subjects to develop severe dengue febrile illness (DHF/DSS) during subsequent natural infection. 
Studies in nonhuman primates have demonstrated that TDV elicits cluster of differentiation (CD)4+ and CD8+ T cell 
responses targeting the nonstructural (NS) proteins NS1, NS3, and NS5 of TDV-2. Both T cell subsets produced 
interleukin-2 (Il-2), interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α), and were multifunctional in 
nature. In addition, CD8+ T cells expressed the CD107α marker, and exhibited cross-reactivity with the NS proteins of 
the other 3TDV serotypes. 
Subsequently, investigations of clinical samples from phase 1 studies have demonstrated generation of multi-lineage 
CMI after administration of TDV. Potent IFN-γ enzyme-linked immunospot (ELISPOT) responses were detected 
against serotype matched antigens which were confirmed by intracellular cytokine staining (ICS). The responses were 
predominantly mediated by CD8+ T cells, but a population of dengue-specific CD4+ T cells was also mobilized by the 
vaccine. Responses were directed against all regions of the TDV-2 proteome and also the TDV-1, -3, and -4 structural 
components of the vaccine. Cross-reactivity of responses to the TDV-2 proteome with DENV-1, -3 and -4 NS1, NS3, 
and NS5, which are not components of the vaccine, was also detected. 
The DEN-313 study is planned to investigate cellular immune responses following TDV vaccination in dengue 
endemic regions and will contribute to immunogenicity data obtained from the ongoing phase 3 efficacy study 
(DEN-301) in a similar population comprised of subjects 4 to 16 years of age living in dengue endemic regions (Asia 
and Latin America). 
This study will be conducted in compliance with the protocol, the International Conference on Harmonization and 
Good Clinical Practice (ICH-GCP) guidelines and applicable regulatory requirement(s). 
Study Design: 
This is an open-label phase 2 study with a single study group. The target sample size is 200 healthy subjects 
(100 subjects aged 4 to 16 years in Latin America; 100 subjects aged 4 to 8 years in Asia). Each subject will receive a 
2-dose schedule of TDV by SC injection into the upper arm at Day 1 (Month 0) and at Day 90 (Month 3). Subjects will 
be screened prior to vaccination to ensure that approximately 40% or more subjects of either dengue Baseline 
seropositivity status are enrolled at each study center. Any withdrawals or screen failures from enrolment until 
vaccination at Day 1 (Month 0) will be replaced. 
Subjects will be followed up for immunogenicity and safety assessments for 3 years after the second vaccination at 
Day 90 (Month 3) including febrile illness surveillance to monitor any febrile illness with potential dengue etiology 
for long term safety. 
Definition of febrile illness 
The subjects and the subject’s parent(s)/legally authorized representative (LAR), as applicable, will be asked to return 
to the study center for dengue fever evaluation of the subjects by the investigator in case of febrile illness (defined as 
fever ≥38°C on any 2 of 3 consecutive days). 
Febrile illness surveillance 
The subjects or the subject’s parent(s)/LAR, as applicable, will be contacted at least weekly (eg, phone calls, home 
visits, or school-based surveillance) to ensure robust identification of febrile illness by reminding subjects or the 
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Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-313 
Page 13 of 79 
Protocol Version 1.0 
01 July 2016 
 
subject’s parent(s)/LAR, as applicable, of their obligation to return to the site in case of febrile illness. 
Handling of febrile illness cases (suspected dengue cases) 
Subjects with febrile illness (defined as fever ≥38°C on any 2 of 3 consecutive days) or clinically suspected dengue 
will have 1 blood sample taken during the acute phase of the disease (ie, as soon as possible and preferably within 
5 days after the onset of fever) to confirm dengue infection. Testing will include dengue reverse transcriptase 
polymerase chain reaction (RT-PCR) and NS1 enzyme-linked immunosorbent assay (ELISA). Additional blood 
samples may be taken for diagnosis and clinical management of the subject as per standard medical practice. RT-PCR 
and NS1 ELISA results from the central laboratory will not be available for real time case management. 
A new episode of febrile illness as described above will require an interval of at least 14 days from a previous febrile 
illness episode (ie, counting from the first day of febrile illness). 
Duration of febrile illness surveillance 
For each subject, surveillance for febrile illness will commence on the day of first vaccination (Day 1 [Month 0]) and 
will end 3 years after the second vaccination at Day 90 (Month 3). 
Procedures 
After informed consent/assent has been obtained, each subject will be assessed for eligibility to participate in the 
study. A dengue immunoglobulin G (IgG) indirect ELISA will be performed during the screening period to ensure that 
approximately 40% or more subjects of either dengue Baseline seropositivity status are enrolled at each study center. 
Enrolment tracking of dengue naïve and dengue exposed subjects will be done using the interactive web response 
system. Subjects may proceed with vaccination in the study prior to availability of the screening dengue IgG indirect 
ELISA result until approximately 60% of subjects (ie, sample size at each study center) are of the same dengue 
Baseline seropositivity status. Once this limit is reached, the dengue Baseline seropositivity status (ie, screening 
dengue IgG ELISA result) will be reviewed before vaccination. At Day 1 (Month 0), a pre-vaccination blood sample 
will be taken and vaccination will occur. A second vaccination will be administered at Day 90 (Month 3). Subjects will 
be followed-up for 3 years post second vaccination. The study design is presented in Figure 1. 
Figure 1: Schematic of Study DEN-313 
 
Febrile  illness  surveillance
ELISA=enzyme-linked immunosorbentassay, IgG=Immunoglobulin G, TDV=tetravalent dengue vaccine candidate
Notes:
(i) Approximately 40% or more subjects of either dengue Baseline seropositivity status at each study center.
(ii) Subjects presenting with febrile illness (defined as fever ≥38°C on any 2 of 3 consecutive days) or clinically suspected dengue will have 1 blood sample taken during the acute phase
of the disease (ie, as soon as possible and preferably within 5 days after the onset of fever). 
(iii) Visits at Day 30 (Month 1) and Day 120 (Month 4) should occur at least  28 days after the first and second vaccination at Day 1 (Month 0) and Day 90 (Month 3), respectively. The 
window period (ie, -1/+7 days) for these visits will be calculated from  the 30th day after each vaccination (ie, day of vaccination + 29 days).
(iv) Visit at Day 14 is for subjects >10 years of age.
(v) For each subject,  additional blood samples will be taken annually for 3 years post-second vaccination at Day 90 (Month 3).
(vi) For each subject,  surveillance for febrile illness and safety follow-up will end 3 years after the second vaccination at Day 90 (Month 3).
Visit 
Day 30 
(Month 1)
Post  first 
vaccination 
blood sample 
Visit 
Day 1 
(Month 0)
200 subjects
Pre-first vaccination 
blood sample
Visit 
Day 90 
(Month 3)
Pre-second 
vaccination 
blood sample
Visit 
Day 270 
(Month 9)
Post  second 
vaccination 
blood sample 
TDV
TDV
Visit 
Screening
by dengue 
IgG indirect 
ELISA
Visit 
Day 14
Post  first 
vaccination 
blood sample
Visit 
Day 120 
(Month 4)
Post  second 
vaccination 
blood sample 
Annual Visits 
for 3 years
Post  second 
vaccination 
blood sample 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

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Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-313 
Page 19 of 79 
Protocol Version 1.0 
01 July 2016 
 
2.1 
Schedule of Study Procedures 
Table 2.a presents the schedule of study procedures. 
Table 2.a 
Schedule of Study procedures 
 
Screening 
(a)  
Day 1 
(Month 0) 
Day 14 (b) 
Day 30 
(Month 1) 
(c) 
Day 90 
(Month 3) 
Day 120 
(Month 4) 
(c) 
Day 270 
(Month 9)  
Annually 
for 3 years 
post second 
vaccination 
Follow-up 
Visit (d) 
Visit window 
Up to 28 
days prior to 
Day 1 
(Month 0) 
 
± 2 
days 
- 1/+ 7 
days 
± 15 
days 
- 1/+ 7 
days 
± 21 
days 
365 days 
from last 
vaccinatio
n ± 45 
days 
 
Visits 
X 
X 
X 
X 
X 
X 
X 
X 
 
Signed informed consent/assent 
X 
 
 
 
 
 
 
 
 
Assessment of eligibility criteria (e) 
X 
X 
 
 
 
 
 
 
 
Check contraindications to 
vaccination 
 
 
 
 
X 
 
 
 
 
Check criteria for delay of 
vaccination 
 
 
 
 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
X 
 
 
 
X 
Concomitant medications/ 
vaccinations history (f) 
X 
X 
 
X 
X 
X 
X 
X 
X 
Complete physical examination (g) 
X 
X 
 
 
X 
 
 
 
 
Targeted physical examination (h) 
 
 
X 
X 
 
X 
X 
X 
X 
Pregnancy test (i) 
X 
X 
 
 
X 
 
 
 
 
Vaccine administration (j) 
 
X 
 
 
X 
 
 
 
 
Blood sample for screening by 
dengue IgG indirect ELISA (3 mL) 
(k) 
X 
 
 
 
 
 
 
 
 
Blood sample (l) 
 
X 
X 
X 
X 
X 
X 
X 
 
Surveillance for dengue fever (m) 
 
X 
Febrile illness blood sample (n) 
 
X 
Documentation of unsolicited 
adverse events (AEs) and medically 
attended AEs (o) 
 
X 
X 
X 
X 
X 
X 
 
 
Serious AEs and AEs leading to 
subject discontinuation or 
withdrawal (p) 
 
X 
(a) Screening and the Day 1 (Month 0) visit may be performed on the same day depending on the availability and requirement of the 
dengue immunoglobulin G indirect enzyme-linked immunosorbent assay (dengue IgG indirect ELISA) result before first 
vaccination. All marked under either Screening or Day 1 (Month 0) is to be performed only once if screening is performed at Day 1 
(Month 0). 
(b) Visit only for subjects >10 years of age. See also footnote (l). 
(c) Visits at Day 30 (Month 1) and Day 120 (Month 4) should occur at least 28 days after the day of the first and second vaccination 
at Day 1 (Month 0) and Day 90 (Month 3), respectively. The window period (ie, -1/+ 7 days) for these visits will be calculated from 
the 30th day after each vaccination (ie, day of vaccination + 29 days). 
(d) Follow-up visit is only applicable if the subject terminates early. The follow-up visit should be performed as soon as possible 
and preferably at least 28 days after the last study vaccination. 
(e) Eligibility by review of inclusion/exclusion criteria will be documented before entry into the study. 
(f) History of vaccination against Japanese Encephalitis or Yellow Fever irrespective of time of administration and including the 
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Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-313 
Page 20 of 79 
Protocol Version 1.0 
01 July 2016 
 
vaccine type as well as any supportive documentation for these vaccinations, all concomitant medications and vaccine history from 
1 month (minimum 28 days) prior to administration of each dose of TDV up to 1 month (minimum 28 days) thereafter, steroids and 
immunostimulants within 60 days prior to Day 1 (Month 0), immunoglobulins and blood products within 3 months prior to Day 1 
(Month 0), and immunosuppressive therapy within 6 months prior to Day 1 (Month 0). 
(g) Physical examination including measurement of weight and height; body mass index will be calculated automatically. 
Measurement of height is only required at Screening and at Day 1 (Month 0). 
(h) Vital signs including (but not limited to) the measurement of systolic blood pressure/diastolic blood pressure, heart rate, body 
temperature, height and weight. Measurement of height is only required at Day 270 (Month 9), and annually for 3 years post second 
vaccination at Day 90 (Month 3). 
(i) Pregnancy testing (serum or urine) for females of childbearing potential. Results must be confirmed and documented as negative 
prior to each study vaccine administration. Additional pregnancy tests may be performed during the study if deemed necessary by 
the investigator. Female of childbearing potential who are sexually active will be reminded during study visits to adhere to 
acceptable contraceptive methods up to 6 weeks post second vaccination. 
(j) Subjects will be observed for at least 30 minutes after administration of each vaccine dose. 
(k) A blood sample (approximately 3 mL) will be collected from all subjects to perform a dengue IgG indirect ELISA during the 
screening period to ensure that approximately 40% or more subjects of either dengue Baseline seropositivity status are enrolled at 
each study center. 
(l) Blood samples for assessment of dengue neutralizing antibodies and cellular immune responses will be collected from all 
subjects at pre-first vaccination (Day 1 [Month 0]), 1 month post first vaccination (Day 30 [Month 1]), pre-second vaccination 
(Day 90 [Month 3]), 1 month and 6 months post second vaccination (Day 120 [Month 4] and Day 270 [Month 9], respectively), and 
annually for 3 years post second vaccination. One additional blood sample will be collected at Day 14 from subjects >10 years of 
age. Blood volumes for assessment of dengue neutralizing antibodies will be 2.5 mL at Day 30 (Month 1) and 5 mL at each of the 
other specified visits. The blood volume for assessment of cellular immune responses will be 20 mL at each specified visit. In 
subjects ≤10 years of age, volumes of blood samples for assessment of cellular immune responses will be adjusted so as not to 
exceed 3 mL/kg or 50 mL in total (whichever is lower) within 8 weeks. In subjects >10 years of age, volumes of blood samples for 
assessment of cellular immune responses will be adjusted so as not to exceed 5 mL/kg within 8 weeks. 
(m) The subjects or the subject’s parent(s)/legally authorized representative (LAR), as applicable, will be contacted at least weekly 
(eg, phone calls, home visits, or school-based surveillance) to ensure robust identification of febrile illness by reminding subjects or 
the subject’s parent(s)/LAR, as applicable, of their obligation to return to the site in case of febrile illness. 
(n) Subjects with febrile illness (defined as fever ≥38°C on any 2 of 3 consecutive days) or clinically suspected dengue will have a 
blood sample (4 mL) taken during the acute phase of the disease (ie, as soon as possible and preferably within 5 days after the onset 
of fever). Additional blood samples may be taken for diagnosis and clinical management of the subject as per standard medical 
practice. 
(o) Unsolicited AEs during the 28-day period (day of vaccination + 27 subsequent days) after administration of each vaccine dose 
will be collected by interview and will be recorded for all subjects at Day 30 (Month 1) and Day 120 (Month 4). Medically attended 
AEs occurring from first vaccination at Day 1 (Month 0) up to 6 months post second vaccination at Day 90 (Month 3) will be 
collected by interview and will be recorded at Day 30 (Month 1), Day 90 (Month 3), Day 120 (Month 4]) and Day 270 (Month 9). 
(p) All serious AEs and AEs leading to subject discontinuation or withdrawal from first vaccination until the end of the study. 
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Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-313 
Page 21 of 79 
Protocol Version 1.0 
01 July 2016 
 
3.0 
STUDY REFERENCE INFORMATION 
3.1 
Study-Related Responsibilities 
The sponsor will perform all study-related activities with the exception of those identified in the 
Study-Related Responsibilities template. The identified vendors in the template for specific 
study-related activities will perform these activities in full or in partnership with the sponsor. 
3.2 
Principal Investigator/Coordinating Investigator 
The sponsor will select a Signatory Principal Investigator / Coordinating Investigator from the 
investigators who participate in the study. Selection criteria for this investigator will include 
significant knowledge of the study protocol, the investigational vaccine, their expertise in the 
therapeutic area and the conduct of clinical research as well as study participation. The Signatory 
Principal Investigator / Coordinating Investigator will be required to review and sign the clinical 
study report and by doing so agrees that it accurately describes the results of the study. 
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Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-313 
Page 22 of 79 
Protocol Version 1.0 
01 July 2016 
 
3.3 
List of Abbreviations 
AE 
Adverse event 
CD 
Cluster of differentiation 
CMI 
Cell-mediated immunity 
Dengue IgG indirect ELISA Dengue immunoglobulin G indirect enzyme-linked immunosorbent 
assay 
DENV 
Wild type dengue virus 
DHF 
Dengue hemorrhagic fever 
DMC 
Data monitoring committee 
DSS 
Dengue shock syndrome 
E 
Envelope 
eCRF 
electronic Case Report Form 
ELISA 
Enzyme-linked immunosorbent assay 
ELISPOT 
Enzyme-linked immunospot 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMT 
Geometric mean titer 
HIV 
Human immunodeficiency virus 
ICH 
International Conference on Harmonization 
ICS 
Intracellular cytokine staining 
IEC 
Independent ethics committee 
IFN-γ 
Interferon-gamma 
IgG 
Immunoglobulin G 
IL-2 
Interleukin-2 
Inc 
Incorporated 
IRB 
Institutional review board 
IWRS 
Interactive web response system 
LAR 
Legally authorized representative 
MAAE 
Medically attended adverse event 
MedDRA 
Medical Dictionary for Regulatory Activities 
MNT 
Microneutralization test 
NS 
Nonstructural 
PBMC 
Peripheral blood mononuclear cells 
PPS 
Per-protocol set 
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Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-313 
Page 23 of 79 
Protocol Version 1.0 
01 July 2016 
 
prM 
pre-membrane  
PT 
Preferred term 
RT-PCR 
Reverse transcriptase polymerase chain reaction 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reactions  
TDV 
Tetravalent dengue vaccine candidate 
TDV-4 
Dengue serotypes 2/4 chimeric strain 
TDV-1 
Dengue serotypes 2/1 chimeric strain 
TDV-3 
Dengue serotypes 2/3 chimeric strain 
TDV-2 
Molecularly characterized, attenuated dengue serotype 2 strain 
TNF-α 
Tumor necrosis factor-alpha 
WHO 
World Health Organization 
 
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Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-313 
Page 24 of 79 
Protocol Version 1.0 
01 July 2016 
 
3.4 
Corporate Identification 
TV 
Takeda Vaccines, Inc. 
 
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Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-313 
Page 25 of 79 
Protocol Version 1.0 
01 July 2016 
 
4.0 
INTRODUCTION 
4.1 
Background 
Dengue fever is caused by infection with wild type dengue virus (DENV), a ribonucleic acid 
(RNA) virus that occurs as 4 recognized serotypes, DENV-1, DENV-2, DENV-3 or DENV-4. 
These dengue viruses are transmitted from human to human by mosquitoes (primarily Aedes 
aegypti). The 4 dengue viruses have spread worldwide and are endemic in Asia, Central and South 
America, the Caribbean, the Pacific Islands, and parts of Africa. There are an estimated 390 
million dengue infections per year worldwide, which is more than 3 times the previous World 
Health Organization estimate of 50 to 100 million cases. Every year, around 500,000 cases of 
dengue hemorrhagic fever (DHF) require hospitalization with an estimated death rate of 2.5%, 
primarily in children. It is estimated that 3.9 billion people are at risk of dengue infection [1-4]. 
Dengue fever is clinically defined as an acute febrile illness with 2 or more manifestations 
(headache, retro-orbital pain, myalgia, arthralgia, rash, hemorrhagic manifestations, or 
leucopenia) and occurrence at the same location and time as other confirmed cases of dengue 
fever. The most severe forms of dengue infection (ie, DHF and dengue shock syndrome [DSS]) are 
life threatening. Primary infection with any 1 of the 4 dengue serotypes is thought to result in 
life-long protection from re-infection by the same serotype, but does not protect against a 
secondary infection by 1 of the other 3 dengue virus serotypes and may lead to an increased risk of 
severe disease (DHF/DSS) [3-6]. 
Treatment of dengue fever is based solely on symptoms and signs, with fluid replacement required 
for hemorrhagic or shock cases. An antiviral therapy for dengue virus infection is not available. 
Preventive measures that rely on mosquito control and individual protection, are of limited 
efficacy, complex to implement and questionable in terms of cost-effectiveness. There is a great 
global public health need for a safe and effective vaccine that will protect against all serotypes of 
dengue infection, and thereby reduce the morbidity and mortality associated with dengue disease 
[1-7]. A tetravalent dengue vaccine (CYD-TDV) has been recently approved in some countries in 
Asia and Latin America [8]. However, the initial findings suggest an unfavorable risk-benefit 
profile for younger subjects with the approved vaccine. Vaccine efficacy was different between 
serotypes and depended on dengue Baseline seropositivity status. Hence, there is a continued 
unmet public health need for safer and more efficacious dengue vaccines. Additional vaccines are 
also important to ensure sufficient supply globally [9,10]. 
Tetravalent Dengue Vaccine Candidate (TDV) - Background: 
Takeda’s TDV consists of 1 molecularly characterized, attenuated dengue virus strain and 3 
recombinant dengue virus strains expressing surface antigens corresponding to dengue serotypes 
1-4. The dengue serotype 2 strain is based upon the attenuated laboratory-derived virus, DENV-2 
Primary Dog Kidney (PDK)-53, originally isolated at Mahidol University, Bangkok, Thailand 
[11]. The chimeric, attenuated vaccine strains for dengue serotypes 1, 3, and 4 were engineered by 
substituting the structural genes, pre-membrane (prM) and envelope (E), of TDV-2 with the prM 
and E genes of the DENV strains, DENV-1 16007, DENV-3 16562 or DENV-4 1036 virus, 
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Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-313 
Page 26 of 79 
Protocol Version 1.0 
01 July 2016 
 
respectively [12]. TDV is thus comprised of 4 dengue virus strains: a molecularly characterized, 
attenuated dengue serotype 2 strain (TDV-2), a dengue serotypes 2/1 chimeric strain (TDV-1), a 
dengue serotypes 2/3 chimeric strain (TDV-3), and a dengue serotypes 2/4 chimeric strain 
(TDV-4). 
Nonclinical studies carried out in mice and nonhuman primates demonstrated an acceptable safety, 
immunogenicity, and efficacy profile of Takeda’s TDV. 
Data from 4 completed phase 1 studies, 1 completed phase 2 study, and 2 ongoing phase 2 studies 
have shown satisfactory reactogenicity, safety and immunogenicity of Takeda’s TDV in adults in 
non-endemic areas as well as in adults and children in endemic areas in Asia and Latin America. 
Currently ongoing and completed phase 2 studies have enabled the selection of a final TDV dose 
(lyophilized formulation), and a 2-dose vaccination regimen for subcutaneous (SC) administration 
3 months apart for use in the pivotal program. 
The current Investigator Brochure for Takeda’s TDV contains additional product information and 
a more detailed review of pre-clinical and clinical studies [13]. 
4.2 
Rationale for the Proposed Study 
Studies investigating the role of cell-mediated immunity (CMI) in natural infections have 
demonstrated roles in both virus clearance and potentiating disease [14]. These investigations have 
been extended from the exploratory study of CMI in natural infection to the study of dengue 
vaccine recipients. Knowledge about specific CMI correlates of protection is incomplete. 
However, the exploration of CMI is encouraged by the World Health Organization (WHO) since 
specific CMI assays may be useful for the assessment of immunological memory and durability of 
protection. Assessments of cytokine responses may also assist in the evaluation of vaccine safety 
and may provide some indication of the potential risk that vaccination could predispose subjects to 
develop severe dengue febrile illness (DHF/DSS) during subsequent natural infection [15]. 
Studies in nonhuman primates have demonstrated that TDV elicits cluster of differentiation 
(CD)4+ and CD8+ T cell responses targeting the nonstructural (NS) proteins NS1, NS3, and NS5 
of TDV-2. Both T cell subsets produced interleukin-2 (Il-2), interferon-gamma (IFN-γ), and tumor 
necrosis factor-alpha (TNF-α), and were multifunctional in nature. In addition, CD8+ T cells 
expressed the CD107α marker, and exhibited cross-reactivity with the NS proteins of the other 
3 TDV serotypes. 
Subsequently, investigations of clinical samples from phase 1 studies have demonstrated 
generation of multi-lineage CMI after administration of TDV. Potent IFN-γ enzyme-linked 
immunospot (ELISPOT) responses were detected against serotype matched antigens which were 
confirmed by intracellular cytokine staining (ICS). The responses were predominantly mediated 
by CD8+ T cells, but a population of dengue-specific CD4+ T cells was also mobilized by the 
vaccine. Responses were directed against all regions of the TDV-2 proteome and also the TDV-1, 
-3, and -4 structural components of the vaccine. Cross-reactivity of responses to the TDV-2 
proteome with DENV-1, -3 and -4 NS1, NS3, and NS5, which are not components of the vaccine, 
was also detected. 
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Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-313 
Page 27 of 79 
Protocol Version 1.0 
01 July 2016 
 
The DEN-313 study is planned to investigate cellular immune responses following TDV 
vaccination in dengue endemic regions and will contribute to immunogenicity data obtained from 
the ongoing phase 3 efficacy study (DEN-301) in a similar population comprised of subjects 4 to 
16 years of age living in dengue endemic regions (Asia and Latin America). 
This study will be conducted in compliance with the protocol, the International Conference on 
Harmonization and Good Clinical Practice (ICH-GCP) guidelines and applicable regulatory 
requirement(s). 
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Use
CCI

Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-313 
Page 31 of 79 
Protocol Version 1.0 
01 July 2016 
 
6.0 
STUDY DESIGN AND DESCRIPTION 
6.1 
Study Design 
This is an open-label phase 2 study with a single study group. The target sample size is 200 healthy 
subjects (100 subjects aged 4 to 16 years in Latin America; 100 subjects aged 4 to 8 years in Asia). 
Each subject will receive a 2-dose schedule of TDV by SC injection into the upper arm at Day 1 
(Month 0) and at Day 90 (Month 3). Subjects will be screened prior to vaccination to ensure that 
approximately 40% or more subjects of either dengue Baseline seropositivity status are enrolled at 
each study center. Any withdrawals or screen failures from enrolment until vaccination at Day 1 
(Month 0) will be replaced. 
Subjects will be followed up for immunogenicity and safety assessments for 3 years after the 
second vaccination at Day 90 (Month 3) including febrile illness surveillance to monitor any 
febrile illness with potential dengue etiology for long term safety. 
Definition of febrile illness: 
The subjects and the subject’s parent(s)/legally authorized representative (LAR), as applicable, 
will be asked to return to the study center for dengue fever evaluation of the subjects by the 
investigator in case of febrile illness (defined as fever ≥38°C on any 2 of 3 consecutive days). 
Febrile illness surveillance: 
The subjects or the subject’s parent(s)/LAR, as applicable, will be contacted at least weekly (eg, 
phone calls, home visits, or school-based surveillance) to ensure robust identification of febrile 
illness by reminding subjects or the subject’s parent(s)/LAR, as applicable, of their obligation to 
return to the site in case of febrile illness. 
Handling of febrile illness cases (suspected dengue cases): 
Subjects with febrile illness (defined as fever ≥38°C on any 2 of 3 consecutive days) or clinically 
suspected dengue will have 1 blood sample taken during the acute phase of the disease (ie, as soon 
as possible and preferably within 5 days after the onset of fever) to confirm dengue infection. 
Testing will include dengue reverse transcriptase polymerase chain reaction (RT-PCR) and NS1 
enzyme-linked immunosorbent assay (ELISA). Additional blood samples may be taken for 
diagnosis and clinical management of the subject as per standard medical practice. RT-PCR and 
NS1 ELISA results from the central laboratory will not be available for real time case 
management. 
A new episode of febrile illness as described above will require an interval of at least 14 days from 
a previous febrile illness episode (ie, counting from the first day of febrile illness). 
Duration of febrile illness surveillance: 
For each subject, surveillance for febrile illness will commence on the day of first vaccination 
(Day 1 [Month 0]) and will end 3 years after the second vaccination at Day 90 (Month 3). 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-313 
Page 32 of 79 
Protocol Version 1.0 
01 July 2016 
 
Procedures 
After informed consent/assent has been obtained, each subject will be assessed for eligibility to 
participate in the study. A dengue immunoglobulin G (IgG) indirect ELISA will be performed 
during the screening period to ensure that approximately 40% or more subjects of either dengue 
Baseline seropositivity status are enrolled at each study center. Enrolment tracking of dengue 
naïve and dengue exposed subjects will be done using the interactive web response system 
(IWRS). Subjects may proceed with vaccination in the study prior to availability of the screening 
IgG indirect ELISA result until approximately 60% of subjects (ie, sample size at each study 
center) are of the same dengue Baseline seropositivity status. Once this limit is reached, the dengue 
Baseline seropositivity status (ie, screening dengue IgG ELISA result) will be reviewed before 
vaccination. At Day 1 (Month 0), a pre-vaccination blood sample will be taken and vaccination 
will occur. A second vaccination will be administered at Day 90 (Month 3). Subjects will be 
followed-up for 3 years post second vaccination. The schematic of the study design is included as 
Figure 6.a. A schedule of study procedures is provided in Section 2.1. 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-313 
Page 33 of 79 
Protocol Version 1.0 
01 July 2016 
1.0 TITLE PAGE 
 
Figure 6.a 
Schematic of Study Design 
 
 
Febrile  illness  surveillance
ELISA=enzyme-linked immunosorbentassay, IgG=Immunoglobulin G, TDV=tetravalent dengue vaccine candidate
Notes:
(i) Approximately 40% or more subjects of either dengue Baseline seropositivity status at each study center.
(ii) Subjects presenting with febrile illness (defined as fever ≥38°C on any 2 of 3 consecutive days) or clinically suspected dengue will have 1 blood sample taken during the acute phase
of the disease (ie, as soon as possible and preferably within 5 days after the onset of fever). 
(iii) Visits at Day 30 (Month 1) and Day 120 (Month 4) should occur at least  28 days after the first and second vaccination at Day 1 (Month 0) and Day 90 (Month 3), respectively. The 
window period (ie, -1/+7 days) for these visits will be calculated from  the 30th day after each vaccination (ie, day of vaccination + 29 days).
(iv) Visit at Day 14 is for subjects >10 years of age.
(v) For each subject,  additional blood samples will be taken annually for 3 years post-second vaccination at Day 90 (Month 3).
(vi) For each subject,  surveillance for febrile illness and safety follow-up will end 3 years after the second vaccination at Day 90 (Month 3).
Visit 
Day 30 
(Month 1)
Post  first 
vaccination 
blood sample 
Visit 
Day 1 
(Month 0)
200 subjects
Pre-first vaccination 
blood sample
Visit 
Day 90 
(Month 3)
Pre-second 
vaccination 
blood sample
Visit 
Day 270 
(Month 9)
Post  second 
vaccination 
blood sample 
TDV
TDV
Visit 
Screening
by dengue 
IgG indirect 
ELISA
Visit 
Day 14
Post  first 
vaccination 
blood sample
Visit 
Day 120 
(Month 4)
Post  second 
vaccination 
blood sample 
Annual Visits 
for 3 years
Post  second 
vaccination 
blood sample 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

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Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-313 
Page 41 of 79 
Protocol Version 1.0 
01 July 2016 
 
discontinue his or her participation without giving a reason at any time during the study. Should a 
subject’s participation be discontinued, the primary criterion for termination must be recorded. In 
addition, efforts should be made to perform all procedures as scheduled for the follow-up visit 
which should be performed as soon as possible and preferably at least 28 days after the last study 
vaccination. Discontinued or withdrawn subjects will not be replaced. 
All withdrawn and discontinued subjects after vaccination at Day 1 (Month 0) will be followed for 
safety monitoring until the end of the study unless subjects are lost to follow-up or specifically 
withdrawn from febrile surveillance and safety follow-up. Those withdrawn or discontinued prior 
to vaccination will not be followed up for safety. 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

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Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-313 
Page 43 of 79 
Protocol Version 1.0 
01 July 2016 
 
working day. Temperature excursions must be reported to the sponsor as soon as possible and use 
of these vaccines requires sponsor approval. 
8.1.3 Dose and Regimen 
Subjects will receive a 2-dose regimen (Day 1 [Month 0]) and Day 90 [Month 3]) with TDV. 
8.2 
Study Vaccine Assignment and Dispensing Procedures 
The investigator or its designee will access the IWRS at subject enrolment to obtain the subject 
number. This number will be used throughout the study. 
The investigator or its designee will utilize the IWRS on the day of first dosing (Day 1 [Month 0]) 
to provide the necessary subject identifying information. 
The investigator or its designee will access the IWRS at each dispensing visit to obtain the 
Vaccination Identification number for the vaccine dose. The vaccines will be prepared and 
administered by the pharmacist or vaccine administrator according to the instructions in the 
Pharmacy Manual or per sponsor instructions. 
The investigator or its designee will be responsible for overseeing the administration of vaccine to 
subjects enrolled in the study according to the procedures stipulated in this study protocol. All 
vaccines will be administered only by personnel who are qualified to perform that function under 
applicable laws and regulations for that specific study. 
If sponsor-supplied vaccine is lost or damaged, the site can request a replacement. Expired 
vaccines must not be administered. 
Eligibility for vaccination prior to first study vaccine administration is determined by evaluating 
the entry criteria outlined in this protocol (Sections 7.1 and 7.2). 
Eligibility for subsequent study vaccination is determined by following the criteria outlined in 
Section 7.3. 
The study vaccine should not be administered to individuals with known hypersensitivity to any 
component of the vaccine. 
As with all injectable vaccines, trained medical personnel and appropriate medical treatment 
should be readily available in case of anaphylactic reactions following vaccination. For example, 
epinephrine 1:1000, diphenhydramine, and/or other medications for treating anaphylaxis should 
be available. 
8.3 
Randomization Code Creation and Storage 
Not applicable. 
8.4 
Study Vaccine Blind Maintenance 
Not applicable. 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

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Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-313 
Page 45 of 79 
Protocol Version 1.0 
01 July 2016 
 
clinical study material for return to the sponsor or its designee for destruction. In the event of 
expiry date extension of supplies already at the study site, supplies may be relabeled with the new 
expiry date at that study site. In such cases, the sponsor or its designee will prepare additional 
labels and all necessary documentation for completion of the procedure at the study site. 
Prior to site closure or at appropriate intervals throughout the study, before any clinical study 
materials are destroyed or returned to the sponsor or its designee for destruction, a representative 
from the sponsor or its designee will perform clinical study material accountability and 
reconciliation. The investigator will retain a copy of the documentation regarding clinical study 
material accountability, return, and/or destruction, and originals will be sent to the sponsor or its 
designee. 
The investigator (or designated individual) at each site will be responsible for vaccine 
accountability and will document receipt, use, return, or destruction of TDV. Vaccine 
accountability documentation will be reviewed by the monitor during clinical monitoring visits. 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-313 
Page 46 of 79 
Protocol Version 1.0 
01 July 2016 
 
9.0 
STUDY PLAN 
9.1 
Study Procedures 
The following sections describe the study procedures and data to be collected. For each procedure, 
subjects are to be assessed by the same investigator or site personnel whenever possible. Screening 
and the Day 1 (Month 0) visit can be performed the same day. The Schedule of Study Procedures is 
located in Section 2.1. 
9.1.1 Informed Consent/Assent 
The requirements of the informed consent/assent are described in Section 15.2. 
Informed consent/assent must be obtained prior to the subject entering into the study, and before 
any protocol-directed procedures are performed. Subjects who attain legal age during their study 
participation will be asked to provide consent as per local regulations. 
A unique subject number will be assigned to each subject after informed consent/assent is obtained 
from the IWRS. If all eligibility criteria are fulfilled, this subject number will be used throughout 
the study. Subject numbers assigned to subjects who fail screening should not be reused 
(Section 9.1.13). 
9.1.2 Demographics, Medical History and Prior Medications 
Demographic information to be obtained will include date of birth, gender, race, and ethnicity as 
described by the subject or subject’s parent(s)/LAR. 
Medical History will also be collected, including but not limited to any medical history that may be 
relevant to subject eligibility for study participation such as prior vaccinations, concomitant 
medications, and previous and ongoing illnesses or injuries. Relevant medical history can also 
include any medical history that contributes to the understanding of an AE that occurs during study 
participation, if it represents an exacerbation of an underlying disease/preexisting problem. 
History of vaccination against Japanese Encephalitis or Yellow Fever will be recorded in the eCRF 
irrespective of time of administration and including the vaccine type as well as any supportive 
documentation for these vaccinations. 
All concomitant medications and vaccine history from 1 month (minimum 28 days) prior to 
administration of each dose of TDV up to 1 month (minimum 28 days) thereafter, steroids and 
immunostimulants within 60 days prior to Day 1 (Month 0), immunoglobulins and blood products 
within 3 months prior to Day 1 (Month 0), and immunosuppressive therapy within 6 months prior 
to Day 1 (Month 0) are to be recorded on the relevant sections of the eCRF (See also Section 7.2). 
The use of antipyretics and/or analgesic medications within 24 hours prior to vaccination must be 
identified and the reason for their use (prophylaxis versus treatment) must be described in the 
source documents or the eCRF. Study vaccination should be delayed if subjects have used 
antipyretics and/or analgesic medication within 24 hours prior to vaccine administration. 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

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Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-313 
Page 48 of 79 
Protocol Version 1.0 
01 July 2016 
 
(Month 0), and prior to vaccination at Day 90 (Month 3). A complete physical examination 
includes but is not limited to: auscultation of heart and lungs, palpation of the abdomen, inspection 
of extremities (including skin over intended vaccination site[s]), and a check of general 
appearance. Additional physical examinations may be performed if indicated by review of the 
subject’s medical history. The findings should be documented in the subject’s source document. 
Targeted physical examination including but not limited to measurement of vital signs (see 
Section 9.1.5) will be performed for all subjects at Day 30 (Month 1), Day 120 (Month 4), 
Day 270 (Month 9), and annually for 3 years post second vaccination or at the follow-up visit 
(ie, when the subject terminates early). Targeted physical examination will also be performed at 
Day 14 for subjects >10 years of age. 
9.1.5 Vital Signs 
These will include (but are not limited to) the measurement of systolic blood pressure/diastolic 
blood pressure, heart rate, body temperature, height and weight. Measurement of height is required 
at Screening, Day 1 (Month 0), Day 270 (Month 9), and annually for 3 years post second 
vaccination. 
Body temperature measurement will be described in the Procedures Manual. 
9.1.6 Dengue Baseline Seropositivity Status 
A blood sample for evaluation of the dengue Baseline seropositivity status by dengue IgG indirect 
ELISA to be performed locally will be taken at Screening or pre-first vaccination at Day 1 
(Month 0) if screening is performed the same day. Refer also to Appendix D. 
The analysis of study endpoints by dengue Baseline seropositivity status will however be based on 
the MNT result of the blood sample taken pre-first vaccination at Day 1 (Month 0) to ensure 
consistent assessments across the program. 
9.1.7 Immunogenicity and CMI Assessments 
All subjects will undergo blood sampling for assessment of cellular immune responses at pre-first 
vaccination (Day 1 [Month 0]), 1 month post first vaccination (Day 30 [Month 1]), pre-second 
vaccination (Day 90 [Month 3]), 1 month and 6 months post second vaccination (Day 120 
[Month 4] and Day 270 [Month 9], respectively), and annually for 3 years post second vaccination. 
One additional blood sample will be collected at Day 14 from subjects >10 years of age. Refer also 
to Appendix D. 
All subjects will undergo blood sampling for assessment of neutralizing antibodies (MNT) at 
pre-first vaccination (Day 1 [Month 0]), 1 month post first vaccination (Day 30 [Month 1]), 
pre-second vaccination (Day 90 [Month 3]), 1 month and 6 months post second vaccination 
(Day 120 [Month 4] and Day 270 [Month 9], respectively), and annually for 3 years post second 
vaccination. Refer also to Appendix D. 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-313 
Page 49 of 79 
Protocol Version 1.0 
01 July 2016 
 
In subjects ≤10 years of age, volumes of blood samples for assessment of cellular immune 
responses will be adjusted so as not to exceed 3 mL/kg or 50 mL in total (whichever is lower) 
within 8 weeks. In subjects >10 years of age, volumes of blood samples for assessment of cellular 
immune responses will be adjusted so as not to exceed 5 mL/kg within 8 weeks [16]. Refer also to 
Appendix D. 
9.1.8 Processing, Labeling and Storage of Peripheral Blood Mononuclear Cell Samples 
Peripheral blood mononuclear cells (PBMC) will be collected, processed, labeled and stored 
according to study site standard operating procedures (SOP). Refer to the SOP for detailed 
instructions. 
All blood samples will be processed, labeled and stored according to the laboratory guideline or 
other appropriate guideline provided to the study site. 
9.1.9 Handling of Febrile Illness Cases (Suspected Dengue Cases) 
Subjects with febrile illness (defined as fever ≥38°C on any 2 of 3 consecutive days) or clinically 
suspected dengue will have 1 blood sample taken during the acute phase of the disease (ie, as soon 
as possible and preferably within 5 days after the onset of fever) to confirm dengue infection. 
Testing will include dengue RT-PCR and NS1 ELISA. Additional blood samples may be taken for 
diagnosis and clinical management of the subject as per standard medical practice. RT-PCR and 
NS1 ELISA results from central the laboratory will not be available for real time case 
management. Refer also to Appendix D. 
A new episode of febrile illness as described above will require an interval of at least 14 days from 
a previous febrile illness episode (ie, counting from the first day of febrile illness). 
9.1.10 Safety Assessments 
Safety assessments will include collection and recording of unsolicited AEs (serious and 
non-serious) and MAAEs. Refer to Section 10.1 for safety definitions. Details on collection and 
reporting of AEs are in Section 10.4. 
9.1.11 Contraception and Pregnancy Avoidance Procedure 
For female subjects of childbearing potential, pregnancy testing (serum or urine) will be 
performed at Screening, prior to vaccination at Day 1 (Month 0), and prior to vaccination at 
Day 90 (Month 3). Additional pregnancy tests may be performed during the study if deemed 
necessary by the investigator. Female of childbearing potential who are sexually active will be 
reminded during study visits to adhere to acceptable contraceptive methods (see Section 7.2) up to 
6 weeks post second vaccination. Subjects will be provided with information on acceptable 
methods of contraception as part of the subject informed consent process and will be asked to sign 
a consent form/assent form stating that they understand the requirements for avoidance of 
pregnancy, donation of ova. Refer also to Section 7.2. 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

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Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-313 
Page 54 of 79 
Protocol Version 1.0 
01 July 2016 
 
9.3.5 Follow-Up Visit 
If a subject is withdrawn or discontinues after vaccination, standard visit procedures should be 
performed if possible. The follow-up visit should be performed as soon as possible and preferably 
at least 28 days after the last study vaccination. 
9.3.6 Post-Study Care 
No post-study care will be provided. 
9.4 
Biological Sample Retention and Destruction 
In this study, specimens for immune response testing will be collected as described in 
Section 9.1.6 through Section 9.1.8. Specimen to confirm dengue infection will be collected from 
subjects with febrile illness as described in Section 9.1.9. Biological samples will be processed and 
stored per the Laboratory Guidelines as provided in the Procedures Manual/Laboratory Manual. 
The samples will be preserved and retained at a central laboratory that was contracted by the 
sponsor for this purpose for up to but not longer than 20 years or as required by applicable law. The 
sponsor has put into place a system to protect the subjects’ personal information to ensure optimal 
confidentiality and defined standard processes for sample and data collection, storage, analysis, 
and destruction. 
Serum and PBMC samples will be used for the analyses defined in this protocol, but can also, with 
permission from the subject or subject’s parent(s)/LAR, be used for research related or unrelated to 
the disease or the vaccine under study. 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-313 
Page 55 of 79 
Protocol Version 1.0 
01 July 2016 
 
10.0 
ADVERSE EVENTS 
10.1 
Definitions 
10.1.1 AEs 
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a study vaccine; it does not necessarily have to have a causal relationship with study 
vaccine administration. 
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the administration of a study 
vaccine whether or not it is considered related to the study vaccine. 
AEs will be graded by the investigator in the following manner: 
Mild 
Grade 1 Awareness of symptoms that are easily tolerated, causing minimal 
discomfort and not interfering with everyday activities. Relieved with or 
without symptomatic treatment. 
Moderate Grade 2 Sufficient discomfort is present to cause interference with normal activity. 
Only partially relieved with symptomatic treatment. 
Severe 
Grade 3 Extreme distress, causing significant impairment of functioning or 
incapacitation. Prevents normal everyday activities. Not relieved with 
symptomatic treatment 
10.1.2 Unsolicited AEs 
Unsolicited AEs during the 28-day period (day of vaccination + 27 subsequent days) after 
administration of each vaccine dose will be collected by interview (ie, at Day 30 [Month 1] and 
Day 120 [Month 4]) and will be recorded for all subjects onto the relevant sections of the eCRF. 
Subjects will be observed for at least 30 minutes after administration of each vaccine dose (Day 1 
[Month 0] and Day 90 [Month 3]). All safety data will be collected in the subject’s source 
documents. 
10.1.3 MAAEs 
MAAEs defined as AEs leading to a medical visit to or by a healthcare professional, including 
visits to an emergency department, but not fulfilling seriousness criteria occurring from first 
vaccination at Day 1 (Month 0) up to 6 months post second vaccination at Day 90 (Month 3) will 
be collected by interview (ie, at Day 30 [Month 1], Day 90 [Month 3], Day 120 [Month 4], and 
Day 270 [Month 9]) and will be recorded onto the relevant section of the eCRF. 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

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1

Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-313 
Page 60 of 79 
Protocol Version 1.0 
01 July 2016 
 
10.5 
Follow-Up Procedures 
10.5.1 AEs 
All AEs will be monitored until resolution or a stable status is reached or until a formal diagnosis 
can be made or until the end of the study, whichever occurs first. This could potentially be 
followed outside of this study or in a planned extension study. 
10.5.2 SAEs 
If information not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up SAE form or provide other written documentation and 
fax it immediately within 24 hours of receipt. Copies of any relevant data from the hospital notes 
(eg, laboratory tests, discharge summary, post-mortem results) should be sent to the sponsor. 
All SAEs should be followed up until resolution or permanent outcome of the event or is otherwise 
explained. The timelines and procedure for follow-up reports are the same as those for the initial 
report. 
10.5.3 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities 
The sponsor or its designee will be responsible for the reporting of all suspected unexpected 
serious adverse reactions (SUSARs) and any other applicable SAEs to regulatory authorities, 
investigators and IRBs or IECs, as applicable, in accordance with national regulations in the 
countries where the study is conducted. Relative to the first awareness of the event by/or further 
provision to the sponsor or sponsor’s designee, SUSARs will be submitted within 7 days for fatal 
and life-threatening events and 15 days for other SUSARs, unless otherwise required by national 
regulations. The sponsor will also prepare an expedited report for other safety issues where these 
might materially alter the current benefit-risk assessment of an investigational medicinal product 
or that would be sufficient to consider changes in the study vaccine administration or in the overall 
conduct of the study. The investigational site also will forward a copy of all expedited reports to 
their IRB or IEC in accordance with national regulations. 
10.5.4 Post-Study Events 
Any AE that occurs outside of the protocol-specified observation period or after the end of the 
study but considered to be caused by the study vaccine(s) must be reported to the sponsor. These 
AEs will be processed by the sponsor’s Pharmacovigilance Department. Instructions for how to 
submit these AEs will be provided in a handout in the Investigator Site File. 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-313 
Page 61 of 79 
Protocol Version 1.0 
01 July 2016 
 
11.0 
STUDY-SPECIFIC REQUIREMENT(S) 
11.1 
Study-Specific Committees 
11.1.1 Data Monitoring Committee 
A DMC will have oversight of this study. The DMC functions at a program level and further 
information is available in the DMC Charter. 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-313 
Page 62 of 79 
Protocol Version 1.0 
01 July 2016 
 
12.0 
DATA HANDLING AND RECORDKEEPING 
The full details of procedures for data handling will be documented in the Data Management Plan. 
AEs, medical history, and concurrent conditions will be coded using the medical dictionary for 
regulatory activities (MedDRA), system organ class (SOC), high level group term (HLGT), high 
level term (HLT), low level term (LLT), preferred term (PT), and their corresponding descriptive 
terms. Drugs will be coded using the WHO Drug Dictionary. 
12.1 
Electronic CRFs (eCRF) 
Completed eCRFs are required for each subject for whom a signed informed assent/consent has 
been obtained. 
The sponsor or its designee will supply investigative sites with access to eCRFs. The sponsor will 
make arrangements to train appropriate site staff in the use of the eCRF. These eCRFs are used to 
transmit the information collected in the performance of this study to the sponsor and regulatory 
authorities. eCRFs must be completed in English. Data are entered directly onto eCRFs. 
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by sponsor 
personnel (or designees) and will be answered by the site. 
Corrections to eCRFs are recorded in an audit trail that captures the old information, the new 
information, identification of the person making the correction, the date the correction was made, 
and the reason for change. 
The principal investigator or its designee must review the eCRFs for completeness and accuracy 
and must sign and date the appropriate eCRFs as indicated. Furthermore, the investigator must 
retain full responsibility for the accuracy and authenticity of all data entered on the eCRFs. 
Electronic CRFs will be reviewed for completeness and acceptability at the study site during 
periodic visits by study monitors. The sponsor or its designee will be permitted to review the 
subject’s medical and hospital records pertinent to the study to ensure accuracy of the eCRFs. The 
completed eCRFs are the sole property of the sponsor and should not be made available in any 
form to third parties, except for authorized representatives of appropriate governmental health or 
regulatory authorities, without written permission of the sponsor. 
12.2 
Record Retention 
The investigator agrees to keep the records stipulated in Section 12.0 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records. Temporary media such as thermal sensitive paper should 
be copied and certified, source worksheets, all original signed and dated informed consent forms 
and assent forms, subject authorization forms regarding the use of personal health information (if 
separate from the informed consent forms), electronic copy of eCRFs, including the audit trail, and 
detailed records of vaccine disposition to enable evaluations or audits from regulatory authorities, 
the sponsor or its designees. Furthermore, ICH E6 Section 4.9.5 requires the investigator to retain 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-313 
Page 63 of 79 
Protocol Version 1.0 
01 July 2016 
 
essential documents specified in ICH E6 (Section 8) until at least 2 years after the last approval of 
a marketing application for a specified vaccine indication being investigated or, if an application is 
not approved, until at least 2 years after the investigation is discontinued and regulatory authorities 
are notified. In addition, ICH E6 Section 4.9.5 states that the study records should be retained until 
an amount of time specified by applicable regulatory requirements or for a time specified in the 
Clinical Study Site Agreement between the investigator and sponsor. 
Refer to the Clinical Study Site Agreement for the sponsor’s requirements on record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of any 
such documents. 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

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CCI

Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-313 
Page 66 of 79 
Protocol Version 1.0 
01 July 2016 
 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 
Study-Site Monitoring Visits 
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and institution guarantee access to source documents by the sponsor or its 
designee (Clinical Research Organization [CRO]) and by the IRB or IEC. 
All aspects of the study and its documentation will be subject to review by the sponsor or its 
designee, including but not limited to the Investigator’s Binder, study vaccine, subject medical 
records, informed consent documentation, documentation of subject authorization to use personal 
health information (if separate from the informed consent forms), and review of eCRFs and 
associated source documents. It is important that the investigator and other study personnel are 
available during the monitoring visits and that sufficient time is devoted to the process. 
14.2 
Protocol Deviations 
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the medical 
monitor (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospective approved deviation) from the inclusion or exclusion criteria. 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections 
The study site also may be subject to quality assurance audits by the sponsor or its designees. In 
this circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the vaccine is stored and prepared, and any other facility used during the study. In addition, 
there is the possibility that this study may be inspected by regulatory agencies, including those of 
foreign governments (eg, the Food and Drug Administration [FDA], the United Kingdom 
Medicines and Healthcare Products Regulatory Agency, the Pharmaceuticals and Medical Devices 
Agency of Japan). If the study site is contacted for an inspection by a regulatory body, the sponsor 
should be notified immediately. The investigator and institution guarantee access for quality 
assurance auditors to all study documents as described in Section 14.1. 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-313 
Page 67 of 79 
Protocol Version 1.0 
01 July 2016 
 
15.0 
ETHICAL ASPECTS OF THE STUDY 
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonized Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable local or regional regulatory requirements and align his or her 
conduct in accordance with the “Responsibilities of the Investigator” that are listed in Appendix A. 
The principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities. 
15.1 
IRB and/or IEC Approval 
IRBs and IECs must be constituted according to the applicable federal/local requirements of each 
participating region. The sponsor or its designee will require documentation noting all names and 
titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC has 
direct participation in this study, written notification regarding his or her abstinence from voting 
must also be obtained. 
The sponsor or its designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of 
the informed consent form/assent form, and, if applicable, subject recruitment materials and/or 
advertisements and other documents required by all applicable laws and regulations, must be 
submitted to a central or local IRB or IEC for approval. The IRB’s or IEC’s written approval of the 
protocol and subject informed consent/assent form must be obtained and submitted to the sponsor 
or its designee before commencement of the study (ie, before shipment of the sponsor-supplied 
vaccine(s) or study specific screening activity). The IRB or IEC approval must refer to the study 
by exact protocol title, number, and version date; identify versions of other documents 
(eg, informed consent form/assent form) reviewed; and state the approval date. The sponsor will 
notify the site once the sponsor has confirmed the adequacy of site regulatory documentation and, 
when applicable, the sponsor has received permission from the competent authority to begin the 
study. Until the site receives [notification] no protocol activities, including screening may occur. 
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the informed consent 
form/assent form, recruitment materials intended for viewing by subjects, local safety reporting 
requirements, reports and updates regarding the ongoing review of the study at intervals specified 
by the respective IRB or IEC, and submission of the investigator’s final status report to IRB or 
IEC. All IRB and IEC approvals and relevant documentation for these items must be provided to 
the sponsor or its designee. 
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor. 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-313 
Page 68 of 79 
Protocol Version 1.0 
01 July 2016 
 
15.2 
Subject Information, Informed Consent/Assent, and Subject Authorization 
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form/assent form, subject authorization 
form (if applicable), and subject information sheet (if applicable) describe the planned and 
permitted uses, transfers, and disclosures of the subject’s personal and personal health information 
for purposes of conducting the study. The informed consent form/assent form and the subject 
information sheet (if applicable) further explain the nature of the study, its objectives, and 
potential risks and benefits, as well as the date informed consent is given. The informed consent 
form will detail the requirements of the participant and the fact that he or she is free to withdraw/ 
the subject’s parent(s)/LAR is free to withdraw their child/ward at any time without giving a 
reason and without prejudice to his or her further medical care. 
The investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent form/assent form and if applicable, the subject authorization form. The informed 
consent form/assent form, subject authorization form (if applicable), and subject information sheet 
(if applicable) must be approved by both the IRB or IEC and the sponsor prior to use. 
The informed consent form/assent form, subject authorization form (if applicable), and subject 
information sheet (if applicable) must be written in a language fully comprehensible to the 
prospective subject/subject’s parent(s)/LAR. It is the responsibility of the investigator to explain 
the detailed elements of the informed consent form/assent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) to the subject/subject’s parent(s)/LAR. 
Information should be given in both oral and written form whenever possible and in the manner 
deemed appropriate by the IRB or IEC. In the event the subject is not capable of rendering 
adequate written informed consent, then the subject’s parent(s)/LAR may provide such consent for 
the subject in accordance with applicable laws and regulations. 
The subject, or the subject’s parent(s)/LAR, must be given ample opportunity to: (1) inquire about 
details of the study and (2) decide whether or not to allow their child/ward to participate in the 
study. If the subject, or the subject’s parent(s)/LAR, determines he or she/their child/their ward 
will participate in the study, then the informed consent form/assent form and subject authorization 
form (if applicable) must be signed and dated by the subject, or the subject’s parent(s)/LAR, at the 
time of consent and prior to the subject entering into the study. The subject or the subject’s 
parent(s)/LAR should be instructed to sign using their legal names, not nicknames, using blue or 
black ballpoint ink. The investigator must also sign and date the informed consent form and 
subject authorization (if applicable) at the time of consent and prior to subject entering into the 
study; however, the sponsor may allow a designee of the investigator to sign to the extent 
permitted by applicable law. 
Once signed, the original informed consent form/assent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) will be stored in the investigator’s site 
file. The investigator must document the date the subject or subject’s parent(s)/LAR signs the 
informed consent in the subject’s medical record and eCRF. Copies of the signed informed consent 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-313 
Page 69 of 79 
Protocol Version 1.0 
01 July 2016 
 
form/assent form, the signed subject authorization form (if applicable), and subject information 
sheet (if applicable) shall be given to the subject. 
All revised informed consent forms/assent forms must be reviewed and signed by the relevant 
subject/the relevant subject’s parent(s)/LAR in the same manner as the original informed 
consent/assent form. The date the revised consent/assent was obtained should be recorded in the 
subject’s medical record and eCRF, and the subject should receive a copy of the revised informed 
consent form/assent form. 
15.3 
Subject Confidentiality 
The sponsor and its designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth, and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number. 
To comply with ICH guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or its designee’s monitor, representatives from any 
regulatory authority (eg, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s study participation, 
and autopsy reports. Access to a subject’s original medical records requires the specific 
authorization of the subject as part of the informed consent process (see Section 15.2). 
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF). 
15.4 
Publication, Disclosure, and Clinical Study Registration Policy 
15.4.1 Publication and Disclosure 
The results of this study are expected to be published in a scientific journal. It is anticipated that 
clinical and laboratory co-investigators will participate in authorship. The order of authorship and 
choice of journal will be determined by the Principal Investigators and the sponsor. The data 
analysis center for this study will provide the analyses needed for publication. Information 
regarding this study will be posted on ClinicalTrials.gov. 
15.4.2 Clinical Study Registration 
In order to ensure that information on clinical studies reaches the public in a timely manner and to 
comply with applicable law, regulation and guidance, the sponsor will, at a minimum register all 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-313 
Page 70 of 79 
Protocol Version 1.0 
01 July 2016 
 
clinical studies conducted in subjects that it sponsors anywhere in the world on ClinicalTrials.gov 
or other publicly accessible websites before study initiation. The sponsor contact information, 
along with investigator’s city, country, and recruiting status will be registered and available for 
public viewing. 
15.4.3 Clinical Study Results Disclosure 
The sponsor will post the results of this clinical study, regardless of outcome, on ClinicalTrials.gov 
or other publicly accessible websites, as required by applicable laws and/or regulations. 
Study completion corresponds to the date on which the final subject was examined or received an 
intervention for the purposes of final collection of data for the primary outcome, whether the 
clinical study concluded according to the pre-specified protocol or was terminated. 
In line with EC Regulation N° 1901/2006, the sponsor will submit a pediatric study within 
6 months of their completion and irrespective of whether it is part of a pediatric investigational 
plan (completed or not yet completed) or not, or whether it is intended for submission later on as 
part of a variation, extension or new stand-alone marketing-authorization application or not. 
15.5 
Insurance and Compensation for Injury 
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to clinical study subjects. 
Refer to the Clinical Study Site Agreement regarding the sponsor’s policy on subject 
compensation and treatment for injury. If the investigator has questions regarding this policy, he or 
she should contact the sponsor or sponsor’s designee. 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

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Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-313 
Page 79 of 79 
Protocol Version 1.0 
01 July 2016 
 
Appendix D Serology Plan 
Table 16.a 
Serology Plan 
Timing 
Blood volume 
Assessments 
Screening or Day 1 (Month 0) 
Approximately 3 mL 
Dengue IgG indirect ELISA 
Day 1 (Month 0), Day 30 (Month 1), Day 90 (Month 3), 
Day 120 (Month 4), Day 270 (Month 9), and annually for 
3 years post second vaccination 
20 mL 
Cellular immune responses 
Day 14 (In subjects >10 years of age) 
Day 1 (Month 0), Day 90 (Month 3), Day 120 (Month 4), 
Day 270 (Month 9), and annually for 3 years post second 
vaccination 
5 mL 
Dengue neutralizing antibodies (MNT) 
Day 30 (Month 1) 
2.5 mL 
Acute phase of the disease (ie, as soon as possible and 
preferably within 5 days after the onset of fever) 
4 mL 
RT-PCR, NS1 ELISA 
ELISA=enzyme-linked immunosorbent assay, IgG=immunoglobulin G, MNT=microneutralization test, RT-PCR= reverse 
transcriptase polymerase chain reaction 
Note: Blood sampling at Screening or pre-first vaccination at Day 1 (Month 0). 
Note: The IgG indirect ELISA is to be performed locally as per local laboratory requirements. The blood sample volume may be 
different as per local laboratory requirements. 
Note: Samples at Day 1 (Month 0) and Day 90 (Month 3) should be collected prior to vaccination. 
Note: In subjects ≤10 years of age, volumes of blood samples for assessment of cellular immune responses will be adjusted so as not 
to exceed 3 mL/kg or 50 mL in total (whichever is lower) within 8 weeks. In subjects >10 years of age, volumes of blood samples 
for assessment of cellular immune responses will be adjusted so as not to exceed 5 mL/kg within 8 weeks [16]. 
Note: Samples will be sent to the central laboratory, as applicable. RT-PCR and NS1 ELISA results from the central laboratory will 
not be available for real time case management. Additional blood samples may be taken for diagnosis and clinical management of 
the subject as per standard medical practice. 
 
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