A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial to Investigate the Immunogenicity and Safety of Subcutaneous Administration of a Tetravalent Dengue Vaccine Candidate in Healthy Adolescent Subjects in Non-Endemic Area(s) for Dengue
Phase: PHASE3
Conditions: Dengue
Sponsor: Takeda



•
Title:  Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial to Investigate the
Immunogenicity and Safety of Subcutaneous Administration of a Tetravalent Dengue Vaccine
Candidate in Healthy Adolescent Subjects in Non-Endemic Area(s) for Dengue
NCT Number: NCT03341637
Protocol Approve Date: 09 March 2019 
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.

 TITLE PAGE 
TITLE PAGE 
PROTOCOL 
A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial to Investigate the 
Immunogenicity and Safety of Subcutaneous Administration of a Tetravalent Dengue Vaccine 
Candidate in Healthy Adolescent Subjects in Non-Endemic Area(s) for Dengue 
Immunogenicity and Safety of TDV in Adolescents in Non-Endemic Area(s) 
Sponsor: 
Takeda Vaccines, Inc. 
40 Landsdowne Street, 
Cambridge, MA 02139, 
USA 
Trial Identifier: 
DEN-315 
IND Number: 
014292 
EudraCT Number: 
Not applicable 
Vaccine Name: 

Investigational vaccine: tetravalent dengue vaccine candidate
(TDV) 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)

Placebo: saline solution
Date: 
09 March 2019 
Version: 
Version 3.0 (supersedes Version 2.0) 
CONFIDENTIAL PROPERTY OF TAKEDA 
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement 
by the recipient that no information contained herein will be published or disclosed without written authorization 
from Takeda except to the extent necessary to obtain assent or informed consent from those persons to whom the 
vaccine may be administered. Furthermore, the information is only meant for review and compliance by the 
recipient, his or her staff, and applicable institutional review committee and regulatory agencies to enable conduct of 
the trial. 

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Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-315 
Page 4 of 77 
Protocol Version 3.0 
09 March 2019 
 
CONFIDENTIAL 
INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, and 
any other product information provided by the Sponsor. I agree to conduct this trial in 
accordance with the requirements of this protocol and also protect the rights, safety, privacy, and 
well-being of trial subjects in accordance with the following: 
 The ethical principles that have their origin in the Declaration of Helsinki. 
 International Council for Harmonization of Technical Requirements for Pharmaceuticals, 
E6 Good Clinical Practice: Consolidated Guideline. 
 All applicable laws and regulations, including, but not limited to those related to data privacy 
and clinical trial disclosure. 
 Regulatory requirements for reporting serious adverse events defined in Section 10.4 of this 
protocol. 
 Terms outlined in the Clinical Trial Site Agreement. 
 Appendix A – Responsibilities of the Investigator. 
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix B of this protocol. 
 
Signature of Investigator 
Date 
Investigator Name (print or type) 
Investigator’s Title 
Location of Facility (City, State) 
Location of Facility (Country) 

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Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-315 
Page 7 of 77 
Protocol Version 3.0 
09 March 2019 
 
CONFIDENTIAL 
TABLE OF CONTENTS 
1.0 
ADMINISTRATIVE INFORMATION ..............................................................................2 
1.1 
Contacts..........................................................................................................................2 
1.2 
Approval ........................................................................................................................3 
1.3 
Protocol Amendment Summary of Changes..................................................................5 
1.3.1 
Amendment History ............................................................................................5 
1.3.2 
Summary of Changes ..........................................................................................5 
2.0 
TRIAL SUMMARY ..........................................................................................................11 
2.1 
Schedule of Trial Procedures .......................................................................................19 
3.0 
TRIAL REFERENCE INFORMATION ...........................................................................21 
3.1 
Trial-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 Trial ..................................................................................26 
5.0 
TRIAL OBJECTIVES AND ENDPOINTS ......................................................................28 
5.1 
Objectives ....................................................................................................................28 
5.1.1 
Primary Objective .............................................................................................28 
5.1.2 
Secondary Objectives........................................................................................28 
5.2 
Endpoints .....................................................................................................................28 
5.2.1 
Primary Endpoint ..............................................................................................28 
5.2.2 
Secondary Endpoints ........................................................................................28 
6.0 
TRIAL DESIGN AND DESCRIPTION ...........................................................................30 
6.1 
Trial Design .................................................................................................................30 
6.2 
Justification for Trial Design, Dose, and Endpoints ....................................................31 
6.3 
Duration of Subject’s Expected Participation in the Entire Trial ................................32 
6.4 
Premature Termination or Suspension of Trial or Investigational Site .......................32 
6.4.1 
Criteria for Premature Termination or Suspension of the Trial ........................32 
6.4.2 
Criteria for Premature Termination or Suspension of Investigational Sites .....32 
6.4.3 
Procedures for Premature Termination or Suspension of the Trial or the 
Participation of Investigational Site(s)..............................................................32 
7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS ...............33 
7.1 
Inclusion Criteria .........................................................................................................33 

Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-315 
Page 8 of 77 
Protocol Version 3.0 
09 March 2019 
 
CONFIDENTIAL 
7.2 
Exclusion Criteria ........................................................................................................33 
7.3 
Criteria for Delay of Vaccination and/or Blood Sampling ..........................................35 
7.4 
Criteria for Early Trial Termination of a Subject ........................................................36 
7.5 
Criteria for Premature Discontinuation of Trial Vaccine Administration ...................37 
8.0 
CLINICAL TRIAL MATERIAL MANAGEMENT .........................................................39 
8.1 
Trial Vaccines and Materials .......................................................................................39 
8.1.1 
Dosage Form, Manufacturing, Packaging, and Labeling .................................39 
8.1.2 
Storage ..............................................................................................................39 
8.1.3 
Dose and Regimen ............................................................................................40 
8.2 
Trial Vaccine Assignment and Dispensing Procedures ...............................................40 
8.3 
Randomization Code Creation and Storage .................................................................41 
8.4 
Trial Vaccine Blind Maintenance ................................................................................41 
8.5 
Unblinding Procedure ..................................................................................................41 
8.6 
Accountability and Destruction of Sponsor-Supplied Vaccine(s) ...............................42 
9.0 
TRIAL PLAN ....................................................................................................................44 
9.1 
Trial Procedures ...........................................................................................................44 
9.1.1 
Informed Consent/Assent Form ........................................................................44 
9.1.2 
Demographics, Medical History and Prior Medications ...................................44 
9.1.3 
Documentation of Trial Entrance/Randomization ............................................45 
9.1.4 
Physical Examination........................................................................................45 
9.1.5 
Vital Signs .........................................................................................................46 
9.1.6 
Immunogenicity Assessments ...........................................................................46 
9.1.7 
Safety Assessments ...........................................................................................46 
9.1.8 
Contraception and Pregnancy Avoidance Procedure ........................................46 
9.1.9 
Pregnancy ..........................................................................................................46 
9.1.10 
Documentation of Subjects who are not Randomized ......................................47 
9.2 
Monitoring Subject Treatment Compliance.................................................................47 
9.3 
Schedule of Observations and Procedures ...................................................................47 
9.3.1 
Pre-Vaccination Procedures (Day 1 [M0] and Day 90 [M3]) ...........................47 
9.3.2 
Vaccination Procedures (Day 1 [M0] and Day 90 [M3]) .................................48 
9.3.3 
Post-Vaccination Procedures (Day 1 [M0] and Day 90 [M3]) .........................48 
9.3.4 
Clinic Visits after Vaccination (Day 30 [M1], Day 120 [M4], and Day 270 
[M9]) .................................................................................................................50 
9.3.5 
Final (End of Trial) Visit ..................................................................................51 
9.3.6 
Post-Trial Care ..................................................................................................51 
9.4 
Biological Sample Retention and Destruction .............................................................51 

Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-315 
Page 9 of 77 
Protocol Version 3.0 
09 March 2019 
 
CONFIDENTIAL 
10.0 
ADVERSE EVENTS .........................................................................................................52 
10.1 
Definitions....................................................................................................................52 
10.1.1 
Adverse Events .................................................................................................52 
10.1.2 
Solicited Adverse Events ..................................................................................52 
10.1.3 
Medically Attended Adverse Events ................................................................53 
10.1.4 
Serious Adverse Events ....................................................................................54 
10.2 
Causality of Adverse Events ........................................................................................54 
10.2.1 
Relationship to Trial Procedures .......................................................................54 
10.2.2 
Outcome of Adverse Events .............................................................................55 
10.3 
Additional Points to Consider for Adverse Events ......................................................55 
10.4 
Procedures ....................................................................................................................56 
10.4.1 
Collection and Reporting of Adverse Events....................................................56 
10.4.2 
Collection and Reporting of Solicited Adverse Events ....................................57 
10.4.3 
Collection and Reporting of Medically Attended Adverse Events ...................57 
10.4.4 
Collection and Reporting of Serious Adverse Events.......................................57 
10.5 
Follow-up Procedures ..................................................................................................58 
10.5.1 
Adverse Events .................................................................................................58 
10.5.2 
Serious Adverse Events ....................................................................................58 
10.5.3 
Safety Reporting to Investigators, Institutional Review Boards or 
International Ethics Committees, and Regulatory Authorities .........................58 
10.5.4 
Post-Trial Events ...............................................................................................58 
11.0 
TRIAL-SPECIFIC REQUIREMENT(S) ...........................................................................59 
11.1 
Data Monitoring Committee ........................................................................................59 
12.0 
DATA HANDLING AND RECORDKEEPING ..............................................................60 
12.1 
Electronic CRFs (eCRF) ..............................................................................................60 
12.2 
Record Retention .........................................................................................................60 
13.0 
STATISTICAL METHODS ..............................................................................................62 
13.1 
Statistical and Analytical Plans ....................................................................................62 
13.1.1 
Analysis Sets .....................................................................................................62 
13.1.2 
Analysis of Demographics and Other Baseline Characteristics .......................62 
13.1.3 
Immunogenicity Analysis .................................................................................63 
13.1.4 
Safety Analysis .................................................................................................63 
13.2 
Interim Analysis and Criteria for Early Termination ...................................................64 
13.3 
Determination of Sample Size .....................................................................................64 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................65 
14.1 
Trial-Site Monitoring Visits .........................................................................................65 

Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-315 
Page 10 of 77 
Protocol Version 3.0 
09 March 2019 
 
CONFIDENTIAL 
14.2 
Protocol Deviations ......................................................................................................65 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections ..................................65 
15.0 
ETHICAL ASPECTS OF THE TRIAL .............................................................................66 
15.1 
IRB and/or IEC Approval ............................................................................................66 
15.2 
Subject Information, Informed Consent and Subject Authorization ...........................66 
15.3 
Subject Confidentiality ................................................................................................68 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy ..................................68 
15.4.1 
Publication and Disclosure ...............................................................................68 
15.4.2 
Clinical Trial Registration.................................................................................68 
15.4.3 
Clinical Trial Results Disclosure ......................................................................69 
15.5 
Insurance and Compensation for Injury .......................................................................69 
16.0 
REFERENCES ..................................................................................................................70 
 
LIST OF IN-TEXT TABLES 
Table 1.a 
Contact Information .................................................................................................2 
Table 8.a 
Sponsor-Supplied Vaccine and Placebo ................................................................40 
Table 10.a 
Solicited Local and Systemic Adverse Events .......................................................52 
Table 10.b 
Severity Scales for Solicited Safety Parameters ....................................................53 
Table 16.a 
Serology Plan .........................................................................................................77 
 
LIST OF IN-TEXT FIGURES 
Figure 2.a 
Schematic of Trial Design .....................................................................................13 
Figure 6.a 
Schematic of Trial Design .....................................................................................30 
 
LIST OF APPENDICES 
Appendix A 
Responsibilities of the Investigator ........................................................................71 
Appendix B 
Investigator Consent to Use of Personal Information ............................................73 
Appendix C 
Elements of the Subject Informed Consent ...........................................................74 
Appendix D 
Serology Plan .........................................................................................................77 

Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-315 
Page 11 of 77 
Protocol Version 3.0 
09 March 2019 
 
CONFIDENTIAL 
2.0 
TRIAL SUMMARY 
Name of Sponsor: 
Takeda Vaccines, Inc. 
40 Landsdowne Street, 
Cambridge, MA 02139, USA 
Product Name: 
Tetravalent Dengue Vaccine Candidate (TDV) 
Trial Title: A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial to Investigate the 
Immunogenicity and Safety of Subcutaneous Administration of a Tetravalent Dengue Vaccine Candidate in 
Healthy Adolescent Subjects in Non-Endemic Area(s) for Dengue 
IND No.: 014292 
EudraCT No.: Not applicable 
Trial Identifier: DEN-315 
Phase: 3 
Trial Blinding Schema: Double-Blind 
Background and Rationale: 
Dengue fever is caused by infection with the wild type dengue virus (DENV), a ribonucleic acid 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 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 (WHO) 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 of the following 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 – DHF and dengue shock syndrome (DSS) – are life threatening. Primary infection with any 
one 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 one of the other 3 dengue serotypes and may lead to an 
increased risk of severe disease (DHF/DSS). 
Treatment of dengue fever is based solely on signs and symptoms, with fluid replacement required for 
hemorrhagic or shock cases. No antiviral therapy for dengue virus infection is 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, unmet global public health need for a safe and 
effective vaccine to reduce the morbidity and mortality associated with dengue disease. Vaccine development 
has focused on tetravalent vaccines that provide protection against all 4 dengue serotypes simultaneously since 
all 4 dengue serotypes commonly co-circulate in endemic areas. A first 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. Additionally, vaccine 
efficacy was different between serotypes and depended on dengue pre-exposure status. Hence, there is a 
continued unmet public health need for safer and more efficacious dengue vaccines. 
Tetravalent Dengue Vaccine Candidate (TDV) - Background: 
Takeda’s TDV consists of 1 molecularly characterized, attenuated dengue serotype 2 virus strain and 3 
chimeric recombinant dengue virus strains expressing surface antigens corresponding to dengue serotypes 1–4. 
The dengue serotype 2 strain (TDV-2) 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 wild type (DENV) virus strains, 
DENV-1 16007, DENV-3 16562 or DENV-4 1036 virus, respectively. Thus, TDV is comprised of 4 dengue 
virus strains: a molecularly characterized, attenuated dengue serotype 2 strain (TDV-2), a dengue serotypes 2/1  

Takeda’s Tetravalent Dengue Vaccine Candidate 
 
Trial No. DEN-315 
Page 12 of 77 
Protocol Version 3.0 
09 March 2019 
 
CONFIDENTIAL 
chimeric strain (TDV-1), a dengue serotypes 2/3 chimeric strain (TDV-3), and a dengue serotypes 2/4 chimeric 
strain (TDV-4). Non-clinical studies carried out in mice and non-human primates have demonstrated an 
acceptable safety, immunogenicity, and efficacy profile of Takeda’s TDV. Additionally, data from completed 
phase 1 and phase 2 trials have shown satisfactory reactogenicity, safety and immunogenicity profiles 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. Ongoing and completed phase 2 trials have enabled the selection of a final TDV dose 
(lyophilized formulation) and a 2-dose vaccination regimen 3 months apart by subcutaneous (SC) injection for 
use in the pivotal program. 
The current Investigator’s Brochure for TDV contains additional product information and a more detailed 
review of pre-clinical and clinical trials. 
Rationale for the Proposed Trial: 
In the TDV development program, adolescent subjects have been enrolled in phase 2 trials conducted in dengue 
endemic and semi-endemic regions to evaluate the safety and immunogenicity of TDV. Adolescent subjects are 
also enrolled into the ongoing phase 3 trial (DEN-301) which investigates the efficacy, safety and 
immunogenicity of TDV in dengue endemic regions. However, since dengue exposure increases with age, most 
of the adolescent subjects in this phase 3 trial are expected to be pre-exposed to dengue. Therefore, although the 
TDV clinical development program will have a large database of adolescent subjects at the conclusion of the 
DEN-301 trial, a limited proportion in this age-group is likely to be dengue naive. TDV is being developed as a 
vaccine for travelers from non-endemic regions intending to travel to endemic regions. Hence, the current trial 
will enroll adolescent subjects in non-endemic area(s) for dengue, thereby contributing to the database of 
dengue naive adolescent subjects included in the clinical development program. 
The trial will be randomized, double-blind, and placebo-controlled to minimize bias. Subjects with a history of 
vaccination against or infection with any flavivirus will be excluded to minimize confounding factors. There 
will be 2 groups in the trial, a TDV group and a placebo (0.9% sodium chloride [NaCl] solution) group. In each 
trial group, 2 doses of either TDV or placebo will be administered 3 months apart. Outside the context of this 
trial, a licensed vaccine will be offered to all subjects, irrespective of their full participation in this trial, after 
the completion of end of trial procedures (Day 270 [Month 9 (M9)]. The choice of this vaccine will be 
discussed between the Sponsor and the Investigator, and will need to be approved by the appropriate ethics 
committee. This vaccine will be used according to the labeling approved in the country. 
Immunogenicity and safety will be assessed in all subjects in each trial group. As the trial will be conducted in 
non-endemic areas, a 6-month follow up period post second dose is considered adequate. The immunogenicity 
assessment for the primary endpoint is planned at 1 month post second dose to coincide with the anticipated 
peak in post-vaccination antibody titers. An immunogenicity assessment is planned at 6 months post second 
dose to evaluate the persistence of the immune response to 2 TDV doses. 
This trial will be conducted in accordance with the protocol, the International Council for Harmonization of 
Technical Requirements for Pharmaceuticals for Human Use and Good Clinical Practice (ICH-GCP) 
Guidelines and applicable regulatory requirements. 
Trial Design: 
This is a randomized, double-blind, placebo-controlled, phase 3 trial in 400 healthy adolescent subjects aged 12 
to 17 years in non-endemic area(s) for dengue with 2 parallel groups to investigate the immunogenicity and 
safety of SC administration of a 2-dose regimen of TDV. 
Subjects will be randomized in a 3:1 ratio (TDV [300 subjects]: placebo [100 subjects]), as follows: 
 
Group 1: SC administration of TDV at Day 1 (Month 0 [M0]) and Day 90 (Month 3 [M3]). 
 
Group 2: SC administration of placebo at Day 1 (M0) and Day 90 (M3). 
All subjects will be followed-up for 6 months post second dose at Day 90 (M3), so the trial duration will be 
approximately 270 days (9 months) for each subject. 
The schematic of the trial design is included as Figure 2.a 

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Figure 2.a 
Schematic of Trial Design 
 
Immunogenicity evaluation: 
Dengue neutralizing antibodies (microneutralization test 50% [MNT50]) will be measured using blood samples 
collected from all subjects at pre-first dose (Day 1 [M0]), and at 1 month and 6 months post second dose 
(Day 120 [Month 4 (M4)]) and Day 270 [M9], respectively). 
Safety evaluation: 
 
Diary cards will be distributed for the recording of: 
 
Solicited local adverse events (AEs) for 7 days following each TDV/placebo dose on Day 1 (M0) and 
Day 90 (M3) (day of vaccination+6 subsequent days). These will include injection site pain, injection 
site erythema, and injection site swelling. 
 
Solicited systemic AEs for 14 days following each TDV/placebo dose on Day 1 (M0) and 
Day 90 (M3) (day of vaccination+13 subsequent days). These will include fever, headache, asthenia, 
malaise, and myalgia. 
 
Unsolicited AEs for 28 days following each TDV/placebo dose on Day 1 (M0) and Day 90 (M3) (day of 
vaccination+27 subsequent days). 
 
Serious adverse events (SAEs) and medically attended AEs (MAAEs) for the trial duration. MAAEs are 
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. 
Data collection will be by electronic Case Report Form (eCRF). 
Primary Objective: 
 
To describe the neutralizing antibody response against each dengue serotype at 1 month post second dose 
of TDV or placebo in dengue-naive adolescent subjects. 
V1
Day 1 (M0)
Enrolment
Randomization
(3:1 [Group 1:Group 2]) 
(N=400)
Pre-vaccination blood 
sample
Vaccination
Safety assessments
Day 1 (M0)
Group 1
TDV
(N=300)
Day 1 (M0)
Group 2
Placebo
(N=100)
V5
Day 270 (M9)
(V3+180 days)
Blood sample
Safety follow-up
(SAEs and medically 
attended AEs)
V2
Day 30 (M1)
Safety assessments
Day 90 (M3)
Group 1
TDV
(N=300)
V4
Day 120 (M4)
(V3+30 days)
Blood sample
Safety assessments
Day 90 (M3)
Group 2
Placebo
(N=100)
V3
Day 90 (M3)
Vaccination
Safety assessments
M=Month, V=Visit

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Secondary Objectives: 
Immunogenicity: 
 
To describe the persistence of the immune response at 6 months post second dose of TDV or placebo in 
dengue-naive adolescent subjects. 
 
To describe the seropositivity rates for all dengue serotypes at 1 month and 6 months post second dose of 
TDV or placebo in dengue-naive adolescent subjects, where seropositivity is defined as a reciprocal 
neutralizing titer ≥10. 
Safety: 
 
To describe the safety profile following a first and second dose of TDV or placebo at Day 1 (M0) and 
Day 90 (M3), respectively. 
Subject Population: 
Healthy Subjects: Yes 
Planned Minimum Age: 12 years 
Planned Maximum Age: 17 years 
Planned Number of Subjects: 400 subjects 
Planned Number of Arms: Two groups in a 3:1 ratio (300 subjects in Group 1 [TDV] and 100 subjects in 
Group 2 [placebo]) 
Estimated Total: 400 randomized subjects 
Criteria for Inclusion: 
1. The subject is aged 12 to 17 years, inclusive. 
2. Individuals who are in good health at the time of entry into the trial as determined by medical history, 
physical examination (including vital signs), and the clinical judgment of the Investigator. 
3. The subject/the subject’s legally authorized representative signs and dates a written informed 
consent/assent form and any required privacy authorization prior to the initiation of any trial procedures, 
after the nature of the trial has been explained according to local regulatory requirements. Assent is 
obtained from the subject where required. 
4. Individuals who can comply with trial procedures and are available for the duration of follow-up. 
Criteria for Exclusion: 
1. Individuals with an elevated oral temperature (≥38°C or 100.4°F) within 3 days of the intended date of 
vaccination (consider whether applicable as an exclusion criterion or criterion for delay, see below). 
2. Known hypersensitivity or allergy to any of the vaccine components (including excipients of the 
investigational vaccines or placebo). 
3. Individuals with behavioral or cognitive impairment or psychiatric disease that, in the opinion of the 
Investigator, may interfere with the subject’s ability to participate in the trial. 
4. Individuals with any history of progressive or severe neurologic disorder, seizure disorder or neuro-
inflammatory disease (eg, Guillain-Barré syndrome). 
5. Individuals with history or any illness that, in the opinion of the Investigator, might interfere with the 
results of the trial or pose additional risk to the subject due to participation in the trial. 

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6. Known or suspected impairment/alteration of immune function, including: 
a. 
Chronic use of oral steroids (equivalent to 20 mg/day prednisone ≥12 weeks/≥2 mg/kg body 
weight/day prednisone ≥2 weeks) within 60 days prior to Day 1 (M0) (use of inhaled, intranasal, or 
topical corticosteroids is allowed). 
b. Receipt of parenteral steroids (equivalent to 20 mg/day prednisone ≥12 weeks/≥ 2 mg/kg body 
weight/day prednisone ≥2 weeks) within 60 days prior to Day 1 (M0). 
c. 
Administration of immunoglobulins and/or any blood products within the 3 months prior to 
Day 1 (M0) or planned administration during the trial. 
d. Receipt of immunostimulants within 60 days prior to Day 1 (M0). 
e. 
Immunosuppressive therapy such as anti-cancer chemotherapy or radiation therapy within 6 months 
prior to Day 1 (M0). 
f. 
Human immunodeficiency virus (HIV) infection or HIV-related disease. 
g. Genetic immunodeficiency. 
7. Abnormalities of splenic or thymic function. 
8. Individuals with a known bleeding diathesis, or any condition that may be associated with a prolonged 
bleeding time. 
9. Individuals with any serious chronic or progressive disease according to judgment of the Investigator (eg, 
neoplasm, insulin dependent diabetes, cardiac, renal or hepatic disease). 
10. Individuals with body mass index (BMI) greater than or equal to 35 kg/m2 (=weight in kg/[height in 
meters2]). 
11. Individuals participating in any clinical trial with another investigational product 30 days prior to 
Day 1 (M0) or intent to participate in another clinical trial at any time during the conduct of this trial. 
12. Individuals who received any other vaccine within 14 days (for inactivated vaccines) or 28 days (for live 
vaccines) prior to enrollment in this trial or who are planning to receive any vaccine within 28 days of trial 
vaccine administration. 
13. Individuals involved in the trial conduct or their first degree relatives. 
14. Individuals with history of substance or alcohol abuse within the past 2 years. 
15. Female subjects who are pregnant or breastfeeding. 
16. Females of childbearing potential1 who are sexually active, and who have not used any of the acceptable 
contraceptive methods2 for at least 2 months prior to Day 1 (M0). 
17. Females of childbearing potential who are sexually active, and who refuse to use an acceptable 
contraceptive method up to 6 weeks after the last dose of trial vaccine (Day 90 [M3]). In addition, they 
must be advised not to donate ova during this period. 
                                                 
1 Defined as status post onset of menarche and not meeting any of the following conditions: bilateral tubal ligation 
(at least 1 year previously), bilateral oophorectomy (at least 1 year previously) or hysterectomy. 
2 One or more of the following: hormonal contraceptive (such as oral, injection, transdermal patch, implant, cervical 
ring), barrier method (condom with spermicide or diaphragm with spermicide) each and every time during 
intercourse, intrauterine device, monogamous relationship with vasectomized partner (partner must have been 
vasectomized for at least 6 months prior to Day 1 [M0]). Other contraceptive methods may be considered in 
agreement with the Sponsor and will be approved by the appropriate ethics committee. 
 
 

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18. Any positive or indeterminate pregnancy test. 
19. Previous and planned vaccination (during the trial conduct), against any flaviviruses including dengue, 
yellow fever (YF), Japanese encephalitis (JE) viruses or tick-borne encephalitis. 
20. Previous participation in any clinical trial of a dengue or other flavivirus (eg, West Nile [WN] virus) 
candidate vaccine, except for subjects who received placebo in those trials. 
21. Subjects with documented or suspected disease caused by a flavivirus such as dengue, Zika, YF, JE, WN 
fever, tick-borne encephalitis or Murray Valley encephalitis. 
There may be instances when individuals meet all entry criteria except one that relates to transient clinical 
circumstances (eg, body temperature elevation or recent use of excluded medication or vaccine). Under these 
circumstances, eligibility for trial enrollment may be considered if the appropriate window for delay has 
passed, inclusion/exclusion criteria have been rechecked, and if the subject is confirmed to be eligible. 
Criteria for Delay of Second Vaccination at Day 90 (M3): 
Subjects may encounter clinical circumstances that warrant a delay in the administration of second trial 
vaccination at Day 90 (M3). These situations are listed below. In the event that a subject meets a criterion for 
delay of vaccination, the subject may receive trial vaccination once the window for delay has passed as long as 
the subject is otherwise eligible for trial participation. The decision to vaccinate in those situations will be made 
by the Investigator. 
1. Body temperature ≥38.0°C (≥100.4°F) within 3 days of intended trial vaccination. 
2. Receipt of any vaccine other than the trial vaccine within 14 days (for inactivated vaccines) or 28 days (for 
live vaccines) of intended trial vaccination. 
3. Known or suspected altered or impaired immune function as specified under the exclusion criteria. 
Criteria for contraindication to vaccination at Day 90 (M3) 
There are also circumstances under which receipt of the second vaccination at Day 90 (M3) is contraindicated 
in this trial. These circumstances include but are not limited to anaphylaxis or severe hypersensitivity reactions 
following administration of the first vaccination at Day 1 (M0). If these reactions occur, the subject must not 
receive the second vaccination at Day 90 (M3), but will be encouraged to continue trial participation for safety 
follow up. 
Trial Vaccine: 
Investigational vaccine 
The investigational vaccine is TDV, a tetravalent dengue vaccine comprised of 1 molecularly characterized, 
attenuated dengue virus strain, and 3 chimeric dengue virus strains with potencies of not less than 3.3, 2.7, 4.0 
and 4.5 log10 plaque forming units per dose of TDV-1, TDV- 2, TDV-3, and TDV-4, respectively. TDV is a 
lyophilized vaccine that will be reconstituted in diluent (37 mM NaCl solution) prior to administration. The 
diluent will be presented in pre-filled syringes. 
Placebo 
Normal saline solution (0.9% NaCl) for injection. 
Duration of the Trial: 
The trial duration for each subject will be approximately 
270 days (9 months). 
Period of Evaluation: 
For the duration of a subject’s participation. 
Main Criteria for Evaluation and Analyses: 
Primary Endpoint: 
 
Geometric mean titers (GMT) of neutralizing antibodies (MNT50) for each of the 4 dengue serotypes at 
1 month post second dose (Day 120 [M4]). 

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Secondary Endpoints: 
Immunogenicity: 
 
GMTs of neutralizing antibodies (MNT50) for each of the 4 dengue serotypes at 6 months post second dose 
(Day 270 [M9]). 
 
Seropositivity rates (% of subjects seropositive) for each of the 4 dengue serotypes at 1 month and 
6 months post second dose (Day 120 [M4]) and Day 270 [M9], respectively). 
 
Seropositivity rates (% of subjects seropositive) for multiple (2, 3, or 4) dengue serotypes at 1 month and 
6 months post second dose (Day 120 [M4]) and Day 270 [M9], respectively). 
Note: Seropositivity is defined as a reciprocal neutralizing titer ≥10. 
Safety: 
 
Frequency and severity of solicited local (injection site) AEs for 7 days (day of vaccination+6 subsequent 
days) and solicited systemic AEs for 14 days (day of vaccination+13 subsequent days) after each 
TDV/placebo dose on Day 1 (M0) and Day 90 (M3). 
 
Percentage of subjects with any unsolicited AEs for 28 days (day of vaccination+27 subsequent days) after 
each TDV/placebo dose on Day 1 (M0) and Day 90 (M3). 
 
Percentage of subjects with MAAEs and SAEs throughout the trial. 
Statistical Considerations: 
Analysis sets 
Safety set: The safety set will consist of all subjects who received at least 1 dose of trial vaccine. 
Full analysis set (FAS): The FAS will include all randomized subjects who received at least 1 dose of trial 
vaccine and for whom a valid pre-dose and at least 1 valid post-dose blood sample have been received for 
immunogenicity. 
Per-protocol set (PPS): The PPS will exclude all subjects seropositive to any serotype of dengue virus at 
Baseline (seropositivity is defined as a reciprocal neutralizing titer ≥10) and will include all subjects in the FAS 
who have no major protocol violations. The major protocol violation criteria will be defined as part of the 
blinded data review prior to the unblinding of subject’s trial vaccine assignment. The categories of major 
protocol violations include: (1) not meeting selected entry criteria, (2) receiving a wrong trial vaccine, 
(3) receiving prohibited therapies, (4) not receiving 2 doses of trial vaccine or receiving the second dose 
inadmissibly outside of the visit window, and (5) other major protocol violations that may be identified during 
blinded data reviews. 
Analysis of demographics and other Baseline characteristics 
Age, gender, race, and other Baseline characteristics will be summarized by trial group for all randomized 
subjects. 
Immunogenicity analysis 
For primary and secondary immunogenicity endpoints (ie, GMTs of neutralizing antibodies, seropositivity rates 
for each of the 4 dengue serotypes, and seropositivity rates for multiple dengue serotypes), descriptive statistics 
and 95% CIs will be provided by trial group for each applicable visit. Seropositivity is defined as a reciprocal 
neutralizing titer ≥10. 
The primary immunogenicity analyses will be based on the PPS; additional immunogenicity analyses may be 
provided based on the FAS. 
Safety analysis 
All safety data will be summarized by trial group using the safety set. 
Solicited AEs 
In all subjects, the presence and severity (Grade) of solicited local (injection site) AEs (pain, erythema, and 

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swelling) and solicited systemic AEs (fever, asthenia, malaise, headache and myalgia) will be collected for 
7 days and 14 days, respectively, following administration of each trial dose (including the day of 
administration) via collection of diary cards. 
For each solicited AE, the number and percentage of subjects with local (injection site) and systemic AEs will 
be summarized by trial group and event severity for each day after each vaccination (ie, Day 1 through Day 7 
for local [injection site] AEs and Day 1 through Day 14 for systemic AEs), and overall. Summaries of first 
onset of each event and the number of days subjects reported experiencing each event will also be provided. 
For subjects with more than 1 episode of the same event, the maximum severity will be used for tabulations. 
Unsolicited AEs 
Unsolicited AEs will be assessed for 28 days following administration of each trial dose (day of 
administration+27 subsequent days). 
In all subjects, unsolicited AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA), and summarized by System Organ Class (SOC) and Preferred Term (PT) for each trial group. AEs 
leading to trial or trial dose discontinuation or withdrawal will also be summarized. 
Unsolicited AEs will be summarized as follows: by PT including events with frequency greater than a pre-
defined frequency (the percentage will be specified in the statistical analysis plan); by SOC and PT; by SOC, 
PT, and severity; and by SOC, PT, and relationship to the trial dose. Subjects reporting more than 1 occurrence 
for the term (level) being summarized will be counted only once. 
MAAEs 
In all subjects, MAAEs will be collected throughout the trial. MAAEs will be coded using MedDRA, and 
summarized by SOC and PT for each trial group. 
SAEs 
In all subjects, SAEs will be collected throughout the trial. SAEs will be coded using MedDRA, and 
summarized by SOC and PT for each trial group. 
Sample Size Justification: 
As the analysis of this trial is descriptive and is not based on testing formal null hypotheses, the sample size 
was not determined based on formal statistical power calculations. The sample size is considered sufficient to 
address the objectives of the trial. 
Interim Analysis: 
No interim analysis is planned. 
Data Monitoring Committee: 
A data monitoring committee (DMC) will have oversight of this trial. The DMC functions at a program level and 
further information is available in the DMC Charter. 
DEN-315 Version 3.0 (09 March 2019) 
 

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2.1 
Schedule of Trial Procedures 
Visit number 
V1 
V2 
V3 
V4 
V5 (a) 
Day 
Day 
1 
M0 
Day 30 
 
M1 
Day 90 
 
M3 
Day 120 
(V3+30 days) 
M4 
Day 270 
(V3+180 days) 
M9 (ET) 
Visit window (days) 
±0 
-1/+7 
-4/+7 
-1/+7 
-7/+14 
Informed consent/assent (b) 
X 
 
 
 
 
Assessment of eligibility criteria (c) 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Medical history 
X 
 
 
 
 
Concomitant medications/vaccinations (d) 
X 
X 
X 
X 
X 
Check criteria for delay of trial vaccination 
X 
 
X 
 
 
Check contraindications to trial vaccination 
 
 
X 
 
 
Complete physical examination (e) 
X 
 
X 
 
 
Targeted physical examination (f) 
 
X 
 
X 
X 
Vital signs (g) 
X 
X 
X 
X 
X 
Pregnancy test (h) 
X 
 
X 
 
 
Pregnancy avoidance guidance (i) 
X 
X 
X 
X 
 
Randomization 
X 
 
 
 
 
Blood sample for dengue neutralizing antibodies 
(5 mL) (j) 
X 
 
 
X 
X 
Trial dose administration (k) 
X 
 
X 
 
 
Injection site evaluation (l) 
X 
 
X 
 
 
Diary card (m) 
Distribution 
X 
 
X 
 
 
Review/collection 
 
X 
 
X 
 
Unsolicited adverse events (AE) (n) 
X 
X 
X 
X 
 
Serious adverse events (SAE) and AEs leading to 
subject discontinuation or withdrawal (o) 
X 
X 
X 
X 
X 
Medically attended AEs (MAAE) (o) 
X 
X 
X 
X 
X 
ET=Early Termination; M=month, V=visit 
Footnotes: 
(a) If the subject terminates early, Day 270 (M9) procedures should be performed. 
(b) Up to 28 days prior to the day of randomization. 
(c) Review of inclusion/exclusion criteria will be performed prior to administration of the first trial dose at Day 1 (M0). After 
eligibility is assessed and written informed consent/assent has been obtained, subjects will be randomized to receive either 2 
doses of TDV or placebo by subcutaneous (SC) injection. 
(d) Any other vaccination against any flavivirus (licensed or investigational, including any other dengue vaccine) during the 
entire trial period, all concomitant medications, vaccine history from 1 month (minimum 28 days) prior to administration of each 
trial dose of TDV or placebo up to 1 month (minimum 28 days) thereafter, steroids and immunostimulants within 60 days prior to 
Day 1 (M0), immunoglobulins and blood products within 3 months prior to Day 1 (M0), and immunosuppressive therapy within 
6 months prior to Day 1 (M0). 
(e) Physical examination including measurement of vital signs (see footnote [g]), weight and height; body mass index (BMI) will 
be calculated automatically. Measurement of height is only required at Day 1 (M0). 
(f) Subjects may undergo a brief symptom-directed physical examination. Clinically significant changes from the Baseline 

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examination should be recorded in the subject’s source documents and electronic Case Report Form (eCRF). 
(g) Vital signs including (but not limited to) the measurement of systolic blood pressure, diastolic blood pressure, heart rate, and 
body temperature. 
(h) Pregnancy testing (serum or urine) for females of childbearing potential. Results must be confirmed and documented as 
negative prior to each trial dose administration. Additional pregnancy tests may be performed during the trial if deemed 
necessary by the Investigator. Females of childbearing potential who are sexually active will be reminded during trial visits to 
adhere to acceptable contraceptive methods up to 6 weeks after the last dose of trial vaccine (Day 90 [M3]). 
(i) Females of childbearing potential who are sexually active will be provided with information on acceptable methods of 
contraception as part of the subject informed consent/assent process and will be asked to sign a consent form/assent form stating 
that they understand the requirements for avoidance of pregnancy and donation of ova. Subjects will be reminded during trial 
visits to adhere to acceptable contraceptive methods and not to donate ova up to 6 weeks after the last dose of trial vaccine (Day 
90 [M3]). 
(j) The blood sample at Day 1 (M0) should be taken prior to administration of the first trial dose. The blood sample at Visit 4 
(Day 120 [M4]) should be taken at least 28 days after the second trial dose at Day 90 (M3). 
(k) TDV (Group 1) or placebo (Group 2). 
(l) Injection site assessed by trial staff for pain, erythema, and swelling for at least 30 minutes following administration of each 
trial dose. 
(m) Diary cards will be distributed for the collection of 1) solicited local (injection site) AEs for 7 days following administration 
of each trial dose (including the day of administration), and 2) solicited systemic AEs for 14 days following administration of 
each trial dose (including the day of administration). 
The Investigator will categorize all events by severity (mild, moderate or severe), and will assess causality to trial dose 
administration for solicited systemic events (related or not related). 
(n) Unsolicited AEs will be collected for 28 days following administration of each trial dose (including the day of administration) 
by interview. The Investigator will categorize events by severity (mild, moderate or severe) and will assess causality to trial dose 
administration (related or not related). 
(o) MAAEs, SAEs, and AEs leading to subject discontinuation or withdrawal will be collected for the trial duration. The 
Investigator will categorize all events by severity (mild, moderate or severe) and will assess causality to trial dose administration 
(related or not related). 

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3.0 
TRIAL REFERENCE INFORMATION 
3.1 
Trial-Related Responsibilities 
The Sponsor will perform all trial-related activities with the exception of those identified in the 
“Trial-Related Responsibilities” template. The identified vendors in the template for specific 
trial-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 trial. Selection criteria for this Investigator will include 
significant knowledge of the trial protocol, the investigational vaccine, their expertise in the 
therapeutic area and the conduct of clinical research as well as trial 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 trial. 

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3.3 
List of Abbreviations 
AE 
Adverse event 
CRO 
Contract research organization 
DENV 
Wild type dengue virus 
DENV-1, -2, -3, -4 
Wild type dengue virus serotypes 1, 2, 3, and 4 
DHF 
Dengue hemorrhagic fever 
DMC 
Data monitoring committee 
DSS 
Dengue shock syndrome 
E 
Envelope 
eCRF 
electronic Case Report Form 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMT 
Geometric mean titer 
HIV 
Human immunodeficiency virus 
ICH 
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
Independent ethics committee 
Inc 
Incorporated 
IND 
Investigational new drug 
IRB 
Institutional review board 
IRT 
Interactive response technology 
JE 
Japanese encephalitis 
LAR 
Legally authorized representative 
M0, 1, 3, 4, 9 
Month 0, 1, 3, 4, 9 
MAAE 
Medically attended adverse event 
MedDRA 
Medical Dictionary for Regulatory Activities 
MNT50 
Microneutralization test 50% 
NaCl 
Sodium chloride 
PFS 
Pre-filled syringe 
PPS 
Per-protocol set 
prM 
pre-membrane 
PT 
Preferred Term 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 

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SC 
Subcutaneous 
SOC 
System Organ Class 
SUSAR 
Suspected unexpected serious adverse reaction 
TDV 
Tetravalent dengue vaccine candidate 
TDV-1 
Dengue serotypes 2/1 chimeric strain 
TDV-2 
Molecularly characterized, attenuated dengue serotype 2 strain 
TDV-3 
Dengue serotypes 2/3 chimeric strain 
TDV-4 
Dengue serotypes 2/4 chimeric strain 
WHO 
World Health Organization 
WN 
West Nile 
YF 
Yellow fever 

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3.4 
Corporate Identification 
TV 
Takeda Vaccines, Inc. 
 

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4.0 
INTRODUCTION 
4.1 
Background 
Dengue fever is caused by infection with the wild type dengue virus (DENV), a ribonucleic acid 
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 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 (WHO) 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 of the following 
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 – DHF and dengue shock 
syndrome (DSS) – are life threatening. Primary infection with any one 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 one of the other 3 dengue serotypes and may lead to an 
increased risk of severe disease (DHF/DSS) [3-6]. 
Treatment of dengue fever is based solely on signs and symptoms, with fluid replacement 
required for hemorrhagic or shock cases. No antiviral therapy for dengue virus infection is 
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, unmet global public health need for a safe and effective vaccine to reduce the morbidity 
and mortality associated with dengue disease [1-7]. Vaccine development has focused on 
tetravalent vaccines that provide protection against all 4 dengue serotypes simultaneously since 
all 4 dengue serotypes commonly co-circulate in endemic areas. A first 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. Additionally, vaccine efficacy was different between serotypes and 
depended on dengue pre-exposure status. Hence, there is a continued unmet public health need 
for safer and more efficacious dengue vaccines [9, 10]. 
Tetravalent Dengue Vaccine Candidate – Background: 
Takeda’s Tetravalent Dengue Vaccine Candidate (TDV) consists of 1 molecularly characterized, 
attenuated dengue serotype 2 virus strain and 3 chimeric recombinant dengue virus strains 
expressing surface antigens corresponding to dengue serotypes 1–4. The dengue serotype 2 strain 
(TDV-2) 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 

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the wild type (DENV) virus strains, DENV-1 16007, DENV-3 16562 or DENV-4 1036 virus, 
respectively [12]. Thus, TDV is 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). 
Non-clinical studies carried out in mice and non-human primates have demonstrated an 
acceptable safety, immunogenicity, and efficacy profile of Takeda’s TDV. Additionally, data 
from completed phase 1 and phase 2 trials have shown satisfactory reactogenicity, safety and 
immunogenicity profiles 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. Ongoing and completed phase 2 trials 
have enabled the selection of a final TDV dose (lyophilized formulation) and a 2-dose 
vaccination regimen 3 months apart by subcutaneous (SC) injection for use in the pivotal 
program. 
The current Investigator’s Brochure for TDV contains additional product information and a more 
detailed review of pre-clinical and clinical trials [13]. 
4.2 
Rationale for the Proposed Trial 
In the TDV development program, adolescent subjects have been enrolled in phase 2 trials 
conducted in dengue endemic and semi-endemic regions to evaluate the safety and 
immunogenicity of TDV. Adolescent subjects are also enrolled into the ongoing phase 3 trial 
(DEN-301) which investigates the efficacy, safety and immunogenicity of TDV in dengue 
endemic regions. However, since dengue exposure increases with age, most of the adolescent 
subjects in this phase 3 trial are expected to be pre-exposed to dengue. Therefore, although the 
TDV clinical development program will have a large database of adolescent subjects at the 
conclusion of the DEN-301 trial, a limited proportion in this age-group is likely to be dengue 
naive. TDV is being developed as a vaccine for travelers from non-endemic regions intending to 
travel to endemic regions. Hence, the current trial will enroll adolescent subjects in non-endemic 
area(s) for dengue, thereby contributing to the database of dengue naive adolescent subjects 
included in the clinical development program. 
The trial will be randomized, double-blind, and placebo-controlled to minimize bias. Subjects 
with a history of vaccination against or infection with any flavivirus will be excluded to 
minimize confounding factors. There will be 2 groups in the trial, a TDV group and a placebo 
(0.9% sodium chloride [NaCl] solution) group. In each trial group, 2 doses of either TDV or 
placebo will be administered 3 months apart. Outside the context of this trial, a licensed vaccine 
will be offered to all subjects, irrespective of their full participation in this trial, after the 
completion of end of trial procedures (Day 270 [Month 9 (M9)]. The choice of this vaccine will 
be discussed between the Sponsor and the Investigator, and will need to be approved by the 
appropriate ethics committee. This vaccine will be used according to the labeling approved in the 
country. 
Immunogenicity and safety will be assessed in all subjects in each trial group. As the trial will be 
conducted in non-endemic areas, a 6-month follow up period post second dose is considered 

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adequate. The immunogenicity assessment for the primary endpoint is planned at 1 month post 
second dose to coincide with the anticipated peak in post-vaccination antibody titers. An 
immunogenicity assessment is planned at 6 months post second dose to evaluate the persistence 
of the immune response to 2 TDV doses. 
This trial will be conducted in accordance with the protocol, the International Council for 
Harmonization of Technical Requirements for Pharmaceuticals for Human Use and Good 
Clinical Practice (ICH-GCP) Guidelines and applicable regulatory requirements. 

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5.0 
TRIAL OBJECTIVES AND ENDPOINTS 
5.1 
Objectives 
5.1.1 Primary Objective 
 To describe the neutralizing antibody response against each dengue serotype at 1 month post 
second dose of TDV or placebo in dengue-naive adolescent subjects. 
5.1.2 Secondary Objectives 
Immunogenicity: 
 To describe the persistence of the immune response at 6 months post second dose of TDV or 
placebo in dengue-naive adolescent subjects. 
 To describe the seropositivity rates for all dengue serotypes at 1 month and 6 months post 
second dose of TDV or placebo in dengue-naive adolescent subjects, where seropositivity is 
defined as a reciprocal neutralizing titer ≥10. 
Safety: 
 To describe the safety profile following a first and second dose of TDV or placebo at 
Day 1 (Month 0 [M0]) and Day 90 (Month 3 [M3]), respectively. 
5.2 
Endpoints 
5.2.1 Primary Endpoint 
 Geometric mean titers (GMT) of neutralizing antibodies (microneutralization test 50% 
[MNT50]) for each of the 4 dengue serotypes at 1 month post second dose 
(Day 120 [Month 4 (M4)]). 
5.2.2 Secondary Endpoints 
Immunogenicity: 
 GMTs of neutralizing antibodies (MNT50) for each of the 4 dengue serotypes at 6 months 
post second dose (Day 270 [M9]). 
 Seropositivity rates (% of subjects seropositive) for each of the 4 dengue serotypes at 
1 month and 6 months post second dose (Day 120 [M4]) and Day 270 [M9], respectively). 
 Seropositivity rates (% of subjects seropositive) for multiple (2, 3, or 4) dengue serotypes at 
1 month and 6 months post second dose (Day 120 [M4]) and Day 270 [M9], respectively). 
Note: Seropositivity is defined as a reciprocal neutralizing titer ≥10. 

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Safety: 
 Frequency and severity of solicited local (injection site) adverse events (AE) for 7 days 
(day of vaccination+6 subsequent days) and solicited systemic AEs for 14 days (day of 
vaccination+13 subsequent days) after each TDV/placebo dose on Day 1 (M0) and 
Day 90 (M3). 
 Percentage of subjects with any unsolicited AEs for 28 days (day of vaccination+27 
subsequent days) after each TDV/placebo dose on Day 1 (M0) and Day 90 (M3). 
 Percentage of subjects with medically attended AEs (MAAE) and serious adverse events 
(SAE) throughout the trial. 

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6.0 
TRIAL DESIGN AND DESCRIPTION 
6.1 
Trial Design 
This is a randomized, double-blind, placebo-controlled, phase 3 trial in 400 healthy adolescent 
subjects aged 12 to 17 years in a non-endemic country(ies) for dengue with 2 parallel groups to 
investigate the immunogenicity and safety of SC administration of a 2-dose regimen of TDV. 
Subjects will be randomized in a 3:1 ratio (TDV [300 subjects]: placebo [100 subjects]), as 
follows: 
 Group 1: SC administration of TDV at Day 1 (M0) and Day 90 (M3). 
 Group 2: SC administration of placebo at Day 1 (M0) and Day 90 (M3). 
All subjects will be followed-up for 6 months post second dose at Day 90 (M3), so the trial 
duration will be approximately 270 days (9 months) for each subject. 
A schematic of the trial design is included as Figure 6.a. A schedule of trial procedures is 
provided in Section 2.1. 
Figure 6.a 
Schematic of Trial Design 
V1
Day 1 (M0)
Enrolment
Randomization
(3:1 [Group 1:Group 2]) 
(N=400)
Pre-vaccination blood 
sample
Vaccination
Safety assessments
Day 1 (M0)
Group 1
TDV
(N=300)
Day 1 (M0)
Group 2
Placebo
(N=100)
V5
Day 270 (M9)
(V3+180 days)
Blood sample
Safety follow-up
(SAEs and medically 
attended AEs)
V2
Day 30 (M1)
Safety assessments
Day 90 (M3)
Group 1
TDV
(N=300)
V4
Day 120 (M4)
(V3+30 days)
Blood sample
Safety assessments
Day 90 (M3)
Group 2
Placebo
(N=100)
V3
Day 90 (M3)
Vaccination
Safety assessments
M=Month, V=Visit
 
 

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Immunogenicity evaluation: 
Dengue neutralizing antibodies (MNT50) will be measured using blood samples collected from 
all subjects at pre-first dose (Day 1 [M0]), and at 1 month and 6 months post second dose 
(Day 120 [M4]) and Day 270 [M9], respectively). 
Safety evaluation: 
 Diary cards will be distributed for the recording of: 
 Solicited local AEs for 7 days following each TDV/placebo dose on Day 1 (M0) and 
Day 90 (M3) (day of vaccination+6 subsequent days). These will include: injection site 
pain, injection site erythema, and injection site swelling. 
 Solicited systemic AEs for 14 days following each TDV/placebo dose on Day 1 (M0) and 
Day 90 (M3) (day of vaccination+13 subsequent days). These will include: fever, 
headache, asthenia, malaise, and myalgia. 
 Unsolicited AEs for 28 days following each TDV/placebo dose on Day 1 (M0) and 
Day 90 (M3) (day of vaccination+27 subsequent days). 
 SAEs and MAAEs for the trial duration. MAAEs are 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. 
Data collection will be by electronic Case Report Form (eCRF). 
6.2 
Justification for Trial Design, Dose, and Endpoints 
The trial design and the collection of solicited AEs, unsolicited AEs (non-serious AEs and 
SAEs), and MAAEs following trial dose administration are consistent with vaccine evaluation 
trials. 
Ongoing and completed phase 2 trials have enabled the selection of a final TDV dose 
(lyophilized formulation) and a 2-dose vaccination regimen 3 months apart by SC injection for 
use in the pivotal program. 
The timing of the primary and secondary endpoints after vaccination is consistent with previous 
trials with TDV. Dengue neutralizing antibodies have been generally accepted as the immune 
response endpoint for dengue vaccine trials. 
In order to maintain the double-blind design, a placebo (0.9% NaCl solution) will be used in this 
trial. Enrollment into the 2 trial groups is unbalanced such that the group receiving TDV is over-
represented. 
As the trial will be conducted in non-endemic areas for dengue, a 6-month follow-up period after 
the second trial dose is considered adequate. 
The rationale for the proposed trial is given in Section 4.2. 

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6.3 
Duration of Subject’s Expected Participation in the Entire Trial 
The trial duration for each subject will be approximately 270 days (9 months) including trial 
dose administration (Day 1 [M0] and Day 90 [M3]) and follow-up through Day 270 (M9). 
6.4 
Premature Termination or Suspension of Trial or Investigational Site 
6.4.1 Criteria for Premature Termination or Suspension of the Trial 
The trial will be completed as planned unless one or more of the following criteria are satisfied 
that require temporary suspension or early termination of the trial. 
 New information or other evaluation regarding the safety or efficacy of the investigational 
vaccine that indicates a change in the known risk/benefit profile, such that the risk/benefit is 
no longer acceptable for subjects participating in the trial. 
 The data monitoring committee (DMC) recommends that the trial should be suspended or 
terminated. 
 Significant deviation from GCP that compromises the ability to achieve the primary trial 
objectives or compromises subject safety. 
6.4.2 Criteria for Premature Termination or Suspension of Investigational Sites 
A trial site may be terminated prematurely or suspended if the site (including the Investigator) is 
found in significant deviation from GCP, protocol, or contractual agreement, is unable to ensure 
adequate performance of the trial, or as otherwise permitted by the contractual agreement. 
6.4.3 Procedures for Premature Termination or Suspension of the Trial or the 
Participation of Investigational Site(s) 
In the event that the Sponsor, an institutional review board (IRB)/independent ethics committee 
(IEC) or regulatory authority elects to terminate or suspend the trial or the participation of an 
investigational site, a trial-specific procedure for early termination or suspension will be 
provided by the Sponsor; the procedure will be followed by applicable investigational sites 
during the course of termination or trial suspension. 

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7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS 
All entry criteria, including test results, need to be confirmed prior to randomization. 
7.1 
Inclusion Criteria 
Subject eligibility is determined according to the following criteria: 
1. The subject is aged 12 to 17 years, inclusive. 
2. Individuals who are in good health at the time of entry into the trial as determined by medical 
history, physical examination (including vital signs) and the clinical judgment of the 
Investigator. 
3. The subject/the subject’s legally authorized representative (LAR) signs and dates a written, 
informed consent/assent form and any required privacy authorization prior to the initiation of 
any trial procedures, after the nature of the trial has been explained according to local 
regulatory requirements (Appendix C). Assent is obtained from the subject where required. 
4. Individuals who can comply with trial procedures and are available for the duration of 
follow-up. 
7.2 
Exclusion Criteria 
Any subject who meets any of the following criteria will not qualify for entry into the trial: 
1. Individuals with an elevated oral temperature (≥38°C or 100.4°F) within 3 days of the 
intended date of vaccination (consider whether applicable as an exclusion criterion or 
criterion for delay, see Section 7.3). 
2. Known hypersensitivity or allergy to any of the vaccine components (including excipients of 
the investigational vaccines or placebo). 
3. Individuals with behavioral or cognitive impairment or psychiatric disease that, in the 
opinion of the Investigator, may interfere with the subject’s ability to participate in the trial. 
4. Individuals with any history of progressive or severe neurologic disorder, seizure disorder or 
neuro-inflammatory disease (eg, Guillain-Barré syndrome). 
5. Individuals with history or any illness that, in the opinion of the Investigator, might interfere 
with the results of the trial or pose additional risk to the subject due to participation in the 
trial. 
6. Known or suspected impairment/alteration of immune function, including: 
a. Chronic use of oral steroids (equivalent to 20 mg/day prednisone ≥12 weeks/≥2 mg/kg 
body weight/day prednisone ≥2 weeks) within 60 days prior to Day 1 (M0) (use of 
inhaled, intranasal, or topical corticosteroids is allowed). 
b. Receipt of parenteral steroids (equivalent to 20 mg/day prednisone ≥12 weeks/≥ 2 mg/kg 
body weight/day prednisone ≥2 weeks) within 60 days prior to Day 1 (M0). 

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c. Administration of immunoglobulins and/or any blood products within the 3 months prior 
to Day 1 (M0) or planned administration during the trial. 
d. Receipt of immunostimulants within 60 days prior to Day 1 (M0). 
e. Immunosuppressive therapy such as anti-cancer chemotherapy or radiation therapy 
within 6 months prior to Day 1 (M0). 
f. Human immunodeficiency virus (HIV) infection or HIV-related disease. 
g. Genetic immunodeficiency. 
7. Abnormalities of splenic or thymic function. 
8. Individuals with a known bleeding diathesis, or any condition that may be associated with a 
prolonged bleeding time. 
9. Individuals with any serious chronic or progressive disease according to judgment of the 
Investigator (eg, neoplasm, insulin dependent diabetes, cardiac, renal or hepatic disease). 
10. Individuals with body mass index (BMI) greater than or equal to 35 kg/m2 (=weight in 
kg/[height in meters2]). 
11. Individuals participating in any clinical trial with another investigational product 30 days 
prior to Day 1 (M0) or intent to participate in another clinical trial at any time during the 
conduct of this trial. 
12. Individuals who received any other vaccine within 14 days (for inactivated vaccines) or 
28 days (for live vaccines) prior to enrollment in this trial or who are planning to receive any 
vaccine within 28 days of trial vaccine administration. 
13. Individuals involved in the trial conduct or their first degree relatives. 
14. Individuals with history of substance or alcohol abuse within the past 2 years. 
15. Female subjects who are pregnant or breastfeeding. 
16. Females of childbearing potential who are sexually active, and who have not used any of the 
acceptable contraceptive methods for at least 2 months prior to Day 1 (M0). 
a. Of childbearing potential is defined as status post onset of menarche and not meeting any 
of the following conditions: bilateral tubal ligation (at least 1 year previously), bilateral 
oophorectomy (at least 1 year previously) or hysterectomy. 
b. Acceptable birth control methods are defined as one or more of the following: 
i. Hormonal contraceptive (such as oral, injection, transdermal patch, implant, cervical 
ring). 
ii. Barrier method (condom with spermicide or diaphragm with spermicide) each and 
every time during intercourse. 
iii. Intrauterine device. 

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iv. Monogamous relationship with vasectomized partner (partner must have been 
vasectomized for at least 6 months prior to Day 1 [M0]). 
Other contraceptive methods may be considered in agreement with the Sponsor and 
will be approved by the appropriate ethics committee. 
17. Females of childbearing potential who are sexually active, and who refuse to use an 
acceptable contraceptive method up to 6 weeks after the last dose of trial vaccine 
(Day 90 [M3]). In addition, they must be advised not to donate ova during this period. 
18. Any positive or indeterminate pregnancy test. 
19. Previous and planned vaccination (during the trial conduct), against any flaviviruses 
including dengue, yellow fever (YF), Japanese encephalitis (JE) viruses or tick-borne 
encephalitis. 
20. Previous participation in any clinical trial of a dengue or other flavivirus (eg, West Nile 
[WN] virus) candidate vaccine, except for subjects who received placebo in those trials. 
21. Subjects with documented or suspected disease caused by a flavivirus such as dengue, Zika, 
YF, JE, WN fever, tick-borne encephalitis or Murray Valley encephalitis. 
There may be instances when individuals meet all entry criteria except one that relates to 
transient clinical circumstances (eg, body temperature elevation or recent use of excluded 
medication or vaccine). Under these circumstances, eligibility for trial enrollment may be 
considered if the appropriate window for delay has passed, inclusion/exclusion criteria have been 
rechecked, and if the subject is confirmed to be eligible. 
7.3 
Criteria for Delay of Vaccination and/or Blood Sampling 
Subjects may encounter clinical circumstances that warrant a delay in the administration of 
second trial vaccination at Day 90 (M3). These situations are listed below. In the event that a 
subject meets a criterion for delay of vaccination, the subject may receive trial vaccination once 
the window for delay has passed as long as the subject is otherwise eligible for trial participation. 
The decision to vaccinate in those situations will be made by the Investigator. 
1. Body temperature ≥38.0°C (≥100.4°F) within 3 days of intended trial vaccination. 
2. Receipt of any vaccine other than the trial vaccine within 14 days (for inactivated vaccines) 
or 28 days (for live vaccines) of intended trial vaccination. 
3. Known or suspected altered or impaired immune function as specified under the exclusion 
criteria. 

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Criteria for contraindication to vaccination at Day 90 (M3): 
There are also circumstances under which receipt of the second vaccination at Day 90 (M3) is 
contraindicated in this trial. These circumstances include but are not limited to anaphylaxis or 
severe hypersensitivity reactions following administration of the first vaccination at Day 1 (M0). 
If these reactions occur, the subject must not receive the second vaccination at Day 90 (M3), but 
will be encouraged to continue trial participation for safety follow up. 
7.4 
Criteria for Early Trial Termination of a Subject 
Under some circumstances, a subject’s trial participation may be terminated early. This means 
that no further trial procedures (including data collection) will be performed on that subject 
beyond the specific date of early termination. The primary reason for early termination of the 
subject’s participation from the trial should be recorded in the eCRF “end of trial visit” page 
using the following categories. For screen failure subjects, refer to Section 9.1.10. 
1. Adverse Event: The subject has experienced an AE (irrespective of being related/unrelated to 
the trial vaccine or trial-related procedures) that requires early termination because continued 
participation imposes an unacceptable risk to the subject’s health and/or the subject is 
unwilling to continue participation because of the AE. If the subject is unwilling to continue 
because of the AE the primary reason for early termination in this case will be “withdrawal 
due to AE” and not “withdrawal of consent”, see below. Any ongoing AEs leading to early 
termination should be followed by the Investigator until resolution or stabilization. 
2. Lost to follow-up: The subject did not return to the clinic and at least 3 attempts to contact 
the subject (or subject’s LAR) were unsuccessful. Attempts to contact the subject must be 
documented. 
3. Withdrawal of consent: The subject (or subject’s LAR) wishes to withdraw from the trial. 
The primary reason for early termination will be “withdrawal of consent” if the subject 
withdraws from participation due to a non-medical reason (ie, reason other than AE). The 
reason for withdrawal, if provided, should be recorded in the eCRF. 
Note: All attempts should be made to determine the underlying reason for the withdrawal 
and, where possible, the primary underlying reason should be recorded. 
4. Premature trial termination by Sponsor, a regulatory agency, the IEC/IRB, or any other 
authority. 
If the clinical trial is prematurely terminated by the Sponsor, the Investigator is to promptly 
inform the trial subjects and local IEC/IRB and should assure appropriate follow up for the 
subjects. The primary reason for early termination in this case will be “trial termination”. 
5. Subject’s death during trial participation. 
6. Other. 
Note: The specific reasons should be recorded in the “specify” field of the eCRF. 

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7.5 
Criteria for Premature Discontinuation of Trial Vaccine Administration 
Early termination of a subject’s participation in the trial will by default prevent the subject from 
continued trial vaccine administration, as the subject will no longer be participating in the trial. 
In addition to early termination (see Section 7.4) criteria, other situations may apply in which 
subjects may continue participating in the trial (e.g., contributing safety data according to 
protocol) but trial vaccine administration is discontinued selectively. Regardless of the reasons 
for discontinuation of the trial vaccine administration, this must be documented as protocol 
deviation. Even if the subject is deemed ineligible to receive trial vaccine, all efforts should be 
made to continue the collection of safety data according to protocol. In addition, the primary 
reason for premature discontinuation of trial vaccine administration should be recorded in the 
eCRF (“end of trial vaccine administration” page) using the following categories: 
1. Adverse Event: The subject has experienced an AE (irrespective of being related/unrelated to 
the trial vaccine or trial-related procedures) for which subsequent trial vaccine 
administrations impose an unacceptable risk to the subject’s health, but the subject may 
continue trial participation for safety, or a subset of other trial procedures. 
2. Lost to follow-up: The subject did not return to the clinic and at least 3 attempts to contact 
the subject (or subject’s LAR) were unsuccessful. Attempts to contact the subject must be 
documented. 
3. Withdrawal of consent: The subject (or subject’s LAR) wishes to withdraw from the trial. 
The primary reason for early termination will be “withdrawal of consent” if the subject 
withdraws from participation due to a non-medical reason (i.e., reason other than AE). The 
reason for withdrawal, if provided, should be recorded in the eCRF. 
4. Premature trial termination by the Sponsor, a regulatory agency, the IEC/IRB, or any other 
authority. 
If the clinical trial is prematurely terminated by the Sponsor, the Investigator is to promptly 
inform the trial subjects and local IEC/IRB and should assure appropriate follow up for the 
subjects. The primary reason for early termination in this case will be “trial termination”. 
5. Subject´s death during trial participation. 
6. Protocol deviation: A protocol deviation is any change, divergence, or departure from the 
trial design or procedures of a trial protocol. The subject may remain in the trial unless 
continuation in the trial jeopardizes the subject’s health, safety, or rights (see Section 7.4). 
7. Pregnancy: Any subject who, despite the requirement for adequate contraception, becomes 
pregnant during the trial will not receive further trial vaccine administrations. Pregnant 
subjects should, however, be asked to continue participating in the trial contributing data to 
the safety follow-up according to protocol. In addition, the site should maintain contact with 
the pregnant subject and complete a “Clinical Trial Pregnancy Form” as soon as possible. 
The subject should be followed-up until the birth of the child, or spontaneous or voluntary 
termination; when pregnancy outcome information becomes available, the information 

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should be captured using the same form. Data obtained from the “Clinical Trial Pregnancy 
Form” will be captured in the safety database. 
8. Receipt of any other dengue vaccines (investigational or licensed) during the trial. 
9. Other 
Note: The specific reasons should be recorded in the “specify” field of the eCRF. 

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CCI

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All clinical trial material must be kept in an appropriate, limited-access, secure place until it is 
used or returned to the Sponsor or designee for destruction. All Sponsor-supplied vaccines must 
be stored under the conditions specified on the label, and remain in the original container until 
dispensed. A daily temperature log of the vaccine storage area must be maintained every 
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 
The trial vaccine doses that will be provided to each trial group are presented in Table 8.a. 
The trial vaccines will be prepared and administered by the unblinded pharmacist or vaccine 
administrator according to the instructions in the Pharmacy Manual or per Sponsor instructions. 
Lyophilized TDV will be reconstituted by adding the entire content of the PFS with diluent to the 
vial containing TDV. Reconstituted TDV will appear as a clear, colorless to yellow solution 
essentially free of foreign particulate. 
The placebo dose will appear as a clear, colorless solution essentially free of foreign particulate. 
TDV and placebo will be administered by the SC route. 
Table 8.a 
Sponsor-Supplied Vaccine and Placebo 
Group 
Number of subjects 
Day 1 (M0) 
Day 90 (M3) 
Group 1 
300 
TDV, SC 
TDV, SC 
Group 2 
100 
Placebo, SC 
Placebo, SC 
M=Month; SC=subcutaneous 
8.2 
Trial Vaccine Assignment and Dispensing Procedures 
The vaccine to be used will be identifiable by a unique identification number and managed by 
interactive response technology (IRT). Refer to Section 8.6 for accountability of Sponsor-
supplied vaccines. 
The Investigator or designee will use the IRT at subject enrollment to obtain the subject number. 
This number will be used throughout the trial. 
The Investigator or designee will use IRT on the day of first dosing (Day1 [M0]) to provide the 
necessary subject identifying information. 
The Investigator or designee will use IRT at each dispensing visit to obtain the vaccination 
identification number for the vaccine dose. 
The Investigator or designee will be responsible for overseeing the administration of vaccine to 
subjects enrolled in the trial according to the procedures stipulated in this trial protocol. The 
vaccine will be administered only by an unblinded site administrator or pharmacist who is 
qualified to perform that function under applicable laws and regulations for that specific trial. 

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If Sponsor-supplied vaccine is lost or damaged, the site can request a replacement. Expired 
vaccines must not be administered. 
Prior to vaccination, a subject must be determined to be eligible for trial vaccination and it must 
be clinically appropriate in the judgment of the Investigator to vaccinate. Eligibility for 
vaccination prior to first trial vaccine administration is determined by evaluating the entry 
criteria outlined in this protocol (Section 7.1 and Section 7.2). 
Eligibility for subsequent trial vaccination is determined by the criteria outlined in Section 7.3. 
Trial vaccines should not be administered to individuals with known hypersensitivity to any 
component of the vaccines. 
Standard immunization practices are to be observed and care should be taken to administer the 
injection subcutaneously. In addition, WHO recommendations to reduce anxiety and pain at the 
time of vaccination should be followed [14]. Before administering the vaccine, the vaccination 
site is to be disinfected with a skin disinfectant (e.g., 70% alcohol). Allow the skin to dry. DO 
NOT inject intravascularly. 
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 
Randomization personnel of the Sponsor or designee will generate the randomization schedules. 
Randomization information will be stored in a secured area, accessible only by authorized 
personnel. 
8.4 
Trial Vaccine Blind Maintenance 
The trial will be conducted in a double-blind manner. The investigational vaccine blind will be 
maintained using IRT. The subjects, data collectors (eg, Investigator), and data evaluators (eg, 
trial statisticians) are blinded. One or more designated pharmacist’s/vaccine administrators at the 
site will be unblinded. These unblinded designees will maintain the investigational vaccine blind 
and will have no role in the assessment of subject safety. 
8.5 
Unblinding Procedure 
The trial vaccine blind shall not be broken by the Investigator unless information concerning the 
trial vaccine is necessary for the medical treatment of the subject. In the event of a medical 
emergency, if possible, the medical monitor should be contacted before the trial vaccine blind is 
broken to discuss the need for unblinding. 
For unblinding a subject, the trial vaccine blind can be obtained by the Investigator, by accessing 
the IRT. 

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The Sponsor’s Pharmacovigilance Department must be notified as soon as possible if the trial 
vaccine blind is broken by the Investigator and the completed SAE form must be sent within 
24 hours. The date, time, and reason the blind is broken must be recorded in the source document 
and the same information (except the time) must be recorded on the eCRF. 
If any subject is unblinded, no further doses of trial vaccine are to be administered and the 
subject must be withdrawn from the trial. 
8.6 
Accountability and Destruction of Sponsor-Supplied Vaccine(s) 
Vaccine supplies will be counted and reconciled at the site before being locally destroyed or 
returned to the Sponsor or designee as noted below. Sites will maintain source documents in 
addition to entering data in the IRT. 
The Investigator or designee must ensure that the Sponsor-supplied vaccines (including TDV 
diluent) are used in accordance with the approved protocol and are administered only to subjects 
enrolled in the trial. To document appropriate use of Sponsor-supplied vaccines (TDV and 
placebo), the Investigator must maintain records of all Sponsor-supplied vaccines (including 
TDV diluent) delivery to the site, site inventory, administration and use by each subject, and 
return to the Sponsor or designee. 
Upon receipt of Sponsor-supplied vaccines (including TDV diluent), the Investigator or designee 
must verify the contents of the shipments against the packing list. The verifier should ensure that 
the quantity is correct, the trial vaccines (including TDV diluent) are received within the labeled 
storage conditions (ie, no cold chain break has occurred during transit), and are in good 
condition. If quantity and conditions are acceptable, the Investigator or the Investigator designees 
will acknowledge receipt of the shipment by recording in the IRT. 
If there are any discrepancies between the packing list versus the actual product received, the 
Sponsor or designee must be contacted to resolve the issue. The packing list should be filed in 
the Investigator’s essential document file by a qualified Investigator designee. 
The Investigator at each site must maintain 100% accountability for all Sponsor-supplied 
vaccines (including TDV diluent) received and administered during their entire participation in 
the trial. Proper vaccine accountability includes, but is not limited to: 
 Verifying that the actual inventory matches the documented inventory. 
 Verifying that the log is completed for the vaccine lot number used to prepare each dose. 
 Verifying that all containers used are documented accurately on the log. 
 Verifying that required fields are completed accurately and legibly. 
If any dispensing errors or discrepancies are discovered, the Sponsor must be notified 
immediately. 
The Investigator at each site must record the current inventory of all sponsor-supplied vaccines 
(TDV and placebo) including TDV diluent on a Sponsor-approved vaccine accountability log. 
The following information will be recorded at a minimum: protocol number and title, name of 

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Investigator, site identifier and number, description of Sponsor-supplied vaccines, expiry date 
and/or retest date, and amount. The log (IRT) should include all required information as a 
separate entry for each subject to whom Sponsor-supplied vaccine is administered. 
Prior to site closure or at appropriate intervals throughout the trial, before any clinical trial 
materials are destroyed locally or returned to the Sponsor or its designee for destruction, a 
representative from the Sponsor or its designee will perform clinical trial material accountability 
and reconciliation. The Investigator will retain a copy of the documentation regarding clinical 
trial material accountability, return, and/or destruction, and originals will be sent to the Sponsor 
or designee. 
The pharmacist (or designated individual) at each site will be responsible for vaccine 
accountability and will document receipt, use, return, or destruction of trial vaccines (TDV and 
placebo) including TDV diluent. Vaccine accountability documentation will be reviewed by the 
unblinded monitor during clinical monitoring visits. 

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9.0 
TRIAL PLAN 
9.1 
Trial Procedures 
The following sections describe the trial procedures and data to be collected. For each procedure, 
subjects are to be assessed by the same Investigator or site personnel whenever possible. The 
Schedule of Trial Procedures is located in Section 2.1. 
9.1.1 Informed Consent/Assent Form 
The requirements of the informed consent/assent form are described in Section 15.2. 
Informed consent/assent must be obtained prior to the subject entering into the trial, and before 
any protocol-directed procedures are performed. 
A unique subject number will be assigned to each subject after informed consent/assent is 
obtained from the IRT. If all eligibility criteria are fulfilled, this subject number will be used 
throughout the trial. Subject numbers assigned to subjects who fail screening should not be 
reused (Section 9.1.10). 
9.1.2 Demographics, Medical History and Prior Medications 
Demographic information to be obtained will include age, sex, race, and ethnicity as described 
by the subject or subject’s LAR. 
Medical history will also be collected, including but not limited to any medical history that may 
be relevant to subject eligibility for trial participation such as prior medications/vaccinations, 
concomitant medications/vaccinations, 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 trial participation, if it represents an exacerbation of an underlying 
disease/pre-existing problem. 
Any other vaccination against any flavivirus (licensed or investigational, including any other 
dengue vaccine) during the entire trial period will be recorded in the eCRF irrespective of time of 
administration, and including the vaccine type. 
All concomitant medications and vaccine history from 1 month (minimum 28 days) prior to 
administration of each trial vaccine dose up to 1 month (minimum 28 days) thereafter, steroids 
and immunostimulants within 60 days prior to Day 1 (M0), immunoglobulins and blood products 
within 3 months prior to Day 1 (M0), and immunosuppressive therapy within 6 months prior to 
Day 1 (M0) are to be recorded on the Prior and Concomitant Medications eCRF and in the 
subject’s source document. 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. Trial vaccination should be delayed if 
subjects have used antipyretics and/or analgesic medication within 24 hours prior to trial dose 
administration. 

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Medications taken for prophylaxis are those intended to prevent the onset of AEs following 
vaccination. Medications taken for treatment are intended to reduce or eliminate the presence of 
symptoms that are present. 
Prohibited therapies (see also Section 7.2): 
 Parenteral immunoglobulin preparation, blood products, and/or blood-derived products 
within the 3 months prior to Day 1 (M0). 
 Immunosuppressive therapy within 6 months or systemic (eg, oral or parenteral) 
corticosteroid treatment within 60 days prior to Day 1 (M0) or immunostimulants within 
60 days prior to Day 1 (M0). 
 Any other vaccines within 14 days (for inactivated vaccines) or 28 days (for live vaccines) 
prior to Day 1 (M0) and Day 90 (M3), and 28 days after each trial vaccination. 
 Any other dengue vaccines (investigational or licensed) for the entire trial period. 
 Receipt of any other clinical trial product for the entire trial period. 
These data must be written in the source documents. 
Medical history (including corresponding medication) to be obtained will include any significant 
conditions or diseases that have disappeared or resolved at or prior to signing of the informed 
consent form/assent form. 
9.1.3 Documentation of Trial Entrance/Randomization 
Only subjects who have signed the informed consent form/assent form, meet all of the inclusion 
criteria and none of the exclusion criteria are eligible for entrance/randomization into the 
vaccination phase. The randomization schedule will be created and controlled by the IRT 
provider. The randomization specification will be approved by the Sponsor’s trial statistician or 
designee. 
If the subject is found to be ineligible for the vaccination phase, the Investigator should record 
the primary reason for failure on the subject enrollment log. 
9.1.4 Physical Examination 
Physical examinations must be performed by a qualified health professional in accordance with 
local regulations and licensing requirements designated within the Site Responsibility Delegation 
Log. Complete physical examination will be performed prior to vaccination at Day 1 (M0) and 
Day 90 (M3). A complete physical examination includes but is not limited to: measurement of 
vital signs (see Section 9.1.5), weight and height (measurement of height is only required at 
Day 1 [M0]), auscultation of heart and lungs, palpation of the abdomen, inspection of extremities 
(including skin over the intended vaccination site), 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. 

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A targeted physical examination including but not limited to measurement of vital signs (see 
Section 9.1.5) will be performed at Day 30 (Month 1 [M1]), Day 120 (M4), and Day 270 (M9). 
Clinically significant changes from the Baseline assessment must be recorded in the subject’s 
source documents and the eCRF. 
9.1.5 Vital Signs 
These will include (but are not limited to) measurement of systolic blood pressure, diastolic 
blood pressure, heart rate, and body temperature at Day 30 (M1), Day 120 (M4), and 
Day 270 (M9). 
9.1.6 Immunogenicity Assessments 
Blood samples for immunogenicity assessments will be collected from all subjects at pre-first 
dose (Day 1 [M0]), and at 1 month and 6 months post second dose (Day 120 [M4)]) and 
Day 270 [M9], respectively). The maximum volume of blood taken at any single visit is 
approximately 5 mL, and the approximate total volume of blood for the trial is maximum 15 ml. 
Refer also to Appendix D. 
All samples will be collected in accordance with acceptable laboratory procedures. Blood 
samples will be processed and stored at the trial site according to the Laboratory Guidelines. 
9.1.7 Safety Assessments 
Safety assessments will include collection and recording of solicited local (injection site) and 
systemic AEs, unsolicited AEs (non-serious AEs and SAEs), and MAAEs. Refer to Section 10.1 
for safety definitions. Details on collection and reporting of AEs are in Section 10.4. 
9.1.8 Contraception and Pregnancy Avoidance Procedure 
For female subjects of childbearing potential, pregnancy testing (urine or serum) will be 
performed prior to vaccination on Day 1 (M0) and Day 90 (M3). Additional pregnancy tests may 
be performed during the trial if deemed necessary by the Investigator. Females of childbearing 
potential who are sexually active will be reminded during trial visits to adhere to acceptable 
contraceptive methods up to 6 weeks after the last dose of trial vaccine (Day 90 [M3]). Subjects 
will be provided with information on acceptable methods of contraception as part of the subject 
informed consent/assent process and will be asked to sign a consent form/assent form stating that 
they understand the requirements for avoidance of pregnancy and donation of ova. The 
Investigator or designee should explain pertinent aspects of the trial in an age appropriate manner 
to subjects in accordance with local policies. Refer also to Section 7.2. 
9.1.9 Pregnancy 
To ensure subject safety and the safety of the unborn child, each pregnancy in a subject having 
received a trial vaccine must be reported to the Sponsor within 24 hours of the site learning of its 
occurrence. If the subject becomes pregnant during the trial, she will not receive any further 
doses of any Sponsor-supplied trial vaccine. The pregnancy must be followed to determine 

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outcome, including spontaneous or voluntary termination, details of birth, and the presence or 
absence of any birth defects, congenital abnormalities, or maternal and/or newborn 
complications. This follow-up should occur even if the intended duration of safety follow-up for 
the trial has ended. 
Any pregnancy occurring following trial dose administration should be reported immediately, 
using a pregnancy notification form, to the contact listed in the Investigator Site File. 
The Investigator must inform the subject of their right to receive treatment information. If the 
subject (or subject’s LAR) chooses to receive unblinded treatment information, the individual 
blind should be broken by the Investigator and procedures must be followed as described in 
Section 8.5. 
9.1.10 Documentation of Subjects who are not Randomized 
Investigators must account for all subjects who sign an informed consent form/assent form. If the 
subject is found to be not eligible at Day 1 (M0), the Investigator should complete the eCRF. The 
IRT supplier should be contacted as a notification of non-randomization. 
The primary reason for non-randomization is to be recorded in the eCRF using the following 
categories: 
 Screen failure (did not meet one or more inclusion criteria or did meet one or more exclusion 
criteria). 
 Withdrawal by subject. 
 Trial terminated by Sponsor. 
Subject numbers assigned to subjects who fail screening should not be reused. 
9.2 
Monitoring Subject Treatment Compliance 
The Investigator records all injections of trial vaccine given to the subject in the eCRF. 
9.3 
Schedule of Observations and Procedures 
The schedule for all trial-related procedures for all evaluations is shown in Section 2.1. 
Assessments should be completed at the designated visit/time point(s). 
9.3.1 Pre-Vaccination Procedures (Day 1 [M0] and Day 90 [M3]) 
1) Before performing any other trial procedure, the signed informed consent form/assent 
form needs to be obtained (Day 1 [M0]). Refer to Section 9.1.1. 
2) Check inclusion and exclusion criteria (Day 1 [M0]). Refer to Section 7.1 and 
Section 7.2. 
3) Collect demographic data (Day 1 [M0]). Refer to Section 9.1.2. 
4) Collect medical history (Day 1 [M0]). Refer to Section 9.1.2. 

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5) Collect concomitant medications/vaccinations. Refer to Section 9.1.2. 
6) Perform a complete physical examination. Refer to Section 9.1.4. 
7) Check vital signs. Refer to Section 9.1.5. 
8) Review of systems: Review of systems is a structured interview that queries the subject 
or the subject’s LAR as to any complaints the subject has experienced across each organ 
system. 
9) Perform pregnancy testing (serum or urine) for female subjects of childbearing potential. 
Refer to Section 9.1.8. 
10) Randomize subject (Day 1 [M0]). Refer to Section 9.1.3. 
11) Collect pre-vaccination blood sample (Day 1 [M0]). Refer to Section 9.1.6. 
Blood should be taken from the subject using an aseptic venipuncture technique for serological 
immunogenicity testing. Refer to the detailed collection and handling procedures outlined in the 
Procedures Manuals. 
9.3.2 Vaccination Procedures (Day 1 [M0] and Day 90 [M3]) 
1. Check criteria for delay of trial vaccination. Refer to Section 7.3. 
2. Check contraindications to trial vaccination (Day 90 [M3]). Refer to Section 9.1.7. 
3. Administer trial dose. Refer to Section 8.1.3. 
9.3.3 Post-Vaccination Procedures (Day 1 [M0] and Day 90 [M3]) 
1. Careful training of the subject or the subject’s LAR on how to measure local (injection site) 
AEs and body temperature, how to complete the diary card and how often to complete the 
diary card. Training should be directed at the individual(s) who will perform the 
measurements of local (injection site) AEs and those who will enter the information into the 
diary card. This individual may or may not be the subject or the subject’s LAR, but if a 
person other than the subject or the subject’s LAR enters information into the diary card, this 
person’s identity must be documented in the trial file and this person must receive training on 
the diary card. Training of the subject or the subject’s LAR on how to measure an injection 
site AE should be performed while the subject is under observation after vaccination. 
Diary card instructions must include the following: 
 The subject or the subject’s LAR must understand that timely completion of the diary card on 
a daily basis is a critical component of trial participation. The subject or the subject’s LAR 
should also be instructed to write clearly and to complete the diary card in pen. Any 
corrections to the diary card that are performed by the person completing the diary card 
should include a single strikethrough line with a brief explanation for any change and be 
initialed and dated. 

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Please note: 
Diary cards will be the only source document allowed for remote collection of solicited local 
(injection site) AEs and solicited systemic AEs (including body temperature measurements). The 
following additional rules apply to the documentation of safety information collected by diary 
card: 
 The diary card should be reviewed with the subject or the subject’s LAR. 
 No corrections or additions to the diary card will be allowed after it is reviewed with the 
Investigator/designee. 
 Any data that are identified as implausible or incorrect, and confirmed by the subject and/or 
the subject’s LAR to be a transcription error should be corrected by the subject or the 
subject’s LAR on the diary card (the correction should include a single strikethrough line and 
should be initialed and dated by the subject and/or the subject’s LAR). 
 Any blank or illegible fields on the diary card not otherwise corrected as above will be 
missing in the eCRF. 
 The site must enter all readable entries on the diary card into the eCRF. 
 Any newly described solicited safety information should be added to the diary card by the 
subject and initialed and dated. Any new unsolicited safety information would be recorded in 
the subject source document as a verbally reported event and therefore captured as an AE and 
recorded in the AE eCRF. 
 Starting on the day of vaccination, the subject or the subject’s LAR will check for specific 
types of events at the injection site (solicited local [injection site] AEs), any specific 
generalized symptoms (solicited systemic AEs), body temperature (any method), any other 
symptoms or change in the subject’s health status, and any medications taken (excluding 
vitamins and minerals). These solicited AEs and body temperature will be recorded on the 
diary card. Assessments should preferably take place in the evening at day’s end. 
 Body temperature measurement is to be performed using the thermometer provided by the 
site. If the subject feels unusually hot or cold during the day, the subject and/or the subject’s 
LAR should check their temperature. If the subject has fever, the highest body temperature 
observed that day should be recorded on the diary card. 
 The measurement of solicited local (injection site) AEs (pain, erythema, and swelling) is to 
be performed using the ruler provided by the site. 
 The collection on the diary card of solicited local (injection site) AEs, and solicited systemic 
AEs (including body temperature) will continue for a total of 7 days and 14 days, 
respectively, following each trial dose administration. 
2. Collect and record solicited AEs. Refer to Section 10.1.2. 
3. Collect and record unsolicited AEs. Refer to Section 10.4.1. 

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4. Collect and record SAEs. Refer to Section 10.4.4. 
5. Collect and record AEs leading to subject discontinuation or withdrawal. Refer to 
Section 10.4.1. 
6. Collect and record MAAEs. Refer to Section 10.4.3. 
7. Provide pregnancy avoidance counseling. Refer to Section 9.1.8. 
After administration of each trial dose, the subject will be observed for at least 30 minutes 
including observation for unsolicited AEs, solicited AEs, and body temperature measurement. 
Information should be recorded in the electronic data capture (EDC) system. The Investigator or 
delegate will take the opportunity to remind the subject or the subject’s LAR how to measure 
solicited AEs and body temperature as part of this observation period. All safety data will be 
collected in the subject’s source documents. 
The site should schedule the next trial activity with the subject or the subject’s LAR. 
The subject or the subject’s LAR will receive a written reminder of the next planned trial 
activity. The subject or the subject’s LAR will be reminded to complete the diary card daily and 
to contact the site if there are any questions and to contact the site immediately (or as soon as the 
subject is medically stable) if the subject has a medical condition that leads to a hospitalization or 
an emergency room visit or is otherwise perceived as serious. All contact details will be provided 
to the subject or subject’s LAR. 
9.3.4 Clinic Visits after Vaccination (Day 30 [M1], Day 120 [M4], and Day 270 [M9]) 
Note: Visits on Day 30 (M1) and Day 120 (M4) should occur 30 days (at least 29 days) after the 
first and second trial vaccination at Day 1 (M0) and Day 90 (M3), respectively. 
1. Collect concomitant medications/vaccinations. Refer to Section 9.1.2. 
2. Perform a targeted physical examination. Refer to Section 9.1.4. 
3. Check vital signs. Refer to Section 9.1.5. 
4. Collect and record unsolicited AEs (Day 30 [M1] and Day 120 [M4]). Refer to 
Section 10.4.1. 
5. Collect and record SAEs. Refer to Section 10.4.4. 
6. Collect and record AEs leading to subject discontinuation or withdrawal. Refer to 
Section 10.4.1. 
7. Collect and record MAAEs. Refer to Section 10.4.3. 
8. Provide pregnancy avoidance counseling (Day 30 [M1] and Day 120 [M4]). Refer to 
Section 9.1.8. 
9. Collect a blood sample (Day 120 [M4] and Day 270 [M9]). Refer to Section 9.1.6. 

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Blood should be taken from the subject using an aseptic venipuncture technique for 
serological immunogenicity testing. Refer to the detailed collection and handling procedures 
outlined in the Procedures Manual. 
The site should schedule the next trial activity with the subject or the subject’s LAR, as 
applicable. 
The subject or the subject’s LAR will receive a written reminder of the next planned trial 
activity, as applicable. The subject or the subject’s LAR will be reminded to contact the site if 
there are any questions and to contact the site immediately (or as soon as the subject is medically 
stable) if the subject has a medical condition that leads to a hospitalization or an emergency room 
visit or is otherwise perceived as serious. 
9.3.5 Final (End of Trial) Visit 
The Final Visit will be made at Day 270 [M9]. If a subject terminates earlier, end of trial visit 
procedures should be performed if possible. For all subjects receiving trial vaccine or placebo, 
the Investigator must complete the “End of Trial” eCRF page. 
9.3.6 Post-Trial Care 
No post-trial care will be provided. 
9.4 
Biological Sample Retention and Destruction 
In this trial, specimens for immune response testing will be collected as described in 
Section 9.1.6. After blood draw and serum processing, the serum samples will be preserved and 
retained at a central laboratory contracted by the Sponsor for this purpose for up to but no 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 samples will be used for the analyses defined in this protocol, but can also, with 
permission from the subject or subject’s LAR, be used to assess, improve or develop tests related 
to the disease(s) or the vaccine(s) under trial that will allow more reliable measurement of the 
response to the vaccine(s). 

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10.0 
ADVERSE EVENTS 
10.1 
Definitions 
10.1.1 Adverse Events 
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a trial vaccine; it does not necessarily have to have a causal relationship with trial 
vaccine administration. 
An AE can therefore be any unfavorable and unintended sign (e.g., a clinically significant 
abnormal laboratory finding), symptom, or disease temporally associated with the administration 
of a trial vaccine whether or not it is considered related to the trial 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 Solicited Adverse Events 
The occurrence of selected indicators of safety as listed in Table 10.a will be measured/collected 
for 7 days (solicited local [injection site] AEs) and 14 days (solicited systemic AEs) following 
administration of each trial vaccine dose (including the day of administration) and will be 
recorded on the “Local and Systemic AEs” eCRF, as applicable. These will be summarized in 
the final report under the category “solicited AEs” to differentiate them from other AEs which 
were not solicited. Any solicited local or systemic AE observed as continuing 8 days and 15 
days, respectively, following each trial vaccination will be recorded as an unsolicited AE on the 
“AE” eCRF. 
Table 10.a 
Solicited Local and Systemic Adverse Events  
Solicited local (injection site) AEs: 
Pain 
Erythema 
Swelling 
Solicited systemic AEs: 
Fever (a) 
Headache 
Asthenia 
Malaise 
Myalgia 
(a) Fever is defined as greater than or equal to 38°C (100.4°F) regardless of method taken [15]. 
The severity of solicited safety parameters will be assessed as described in Table 10.b. 

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Table 10.b 
Severity Scales for Solicited Safety Parameters  
Adverse Event 
Severity grade 
Severity 
Pain at injection site 
0 
None 
1 
Mild: No interference with daily activity 
2 
Moderate: Interference with daily activity with or without treatment 
3 
Severe: Prevents daily activity with or without treatment 
Erythema at injection 
site (a) 
0 
<25 mm 
1 
Mild: >25 – ≤50 mm 
2 
Moderate: >50 – ≤100 mm 
3 
Severe: >100 mm 
Swelling at injection 
site (a) 
0 
<25 mm 
1 
Mild: >25 – ≤50 mm  
2 
Moderate: >50 – ≤100 mm 
3 
Severe: >100 mm 
Headache 
0 
None 
1 
Mild: No interference with daily activity 
2 
Moderate: Interference with daily activity with or without treatment 
3 
Severe: Prevents normal activity with or without treatment 
Asthenia 
0 
None 
1 
Mild: No interference with daily activity 
2 
Moderate: Interference with daily activity 
3 
Severe: Prevents daily activity 
Malaise  
0 
None 
1 
Mild: No interference with daily activity 
2 
Moderate: Interference with daily activity 
3 
Severe: Prevents daily activity 
Myalgia 
0 
None 
1 
Mild: No interference with daily activity 
2 
Moderate: Interference with daily activity 
3 
Severe: Prevents daily activity 
Fever (b) 
Record body temperature in °C/°F 
(a) Subjects are to record greatest surface diameter in mm on the diary card. 
(b) Fever is defined as greater than or equal to 38°C (100.4°F) regardless of method taken [15]. 
10.1.3 Medically Attended Adverse Events 
MAAEs are 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. 

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10.1.4 Serious Adverse Events  
An SAE is defined as any untoward medical occurrence that: 
1. Results in DEATH. 
2. Is LIFE THREATENING. 
 The term “life threatening” refers to an event in which the subject was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have caused 
death if it were more severe. 
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization. 
4. Results in persistent or significant DISABILITY/INCAPACITY. 
5. Leads to a CONGENITAL ANOMALY/BIRTH DEFECT in the offspring of a subject. 
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following: 
 May require intervention to prevent items 1 through 5 above. 
 May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization. 
10.2 
Causality of Adverse Events 
Relatedness (causality) to vaccine will also be assessed by the Investigator. The relationship of 
each AE, including solicited systemic AEs (all solicited local [injection site] AEs are considered 
as related) to the trial vaccine will be assessed using the following categories: 
Related: 
There is suspicion that there is a relationship between the trial vaccine and 
the AE (without determining the extent of probability); there is a reasonable 
possibility that the trial vaccine contributed to the AE. 
Not Related: 
There is no suspicion that there is a relationship between the trial vaccine 
and the AE; there are other more likely causes and administration of the 
trial vaccine is not suspected to have contributed to the AE. 
10.2.1 Relationship to Trial Procedures 
Relationship (causality) to trial procedures should be determined for all AEs. 
The relationship should be assessed as “Yes” if the Investigator considers that there is reasonable 
possibility that an event is due to a trial procedure. Otherwise, the relationship should be 
assessed as “No”. 

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10.2.2 Outcome of Adverse Events 
Resolved: 
The subject has fully recovered from the event or the condition has 
returned to the level observed at Baseline. 
Resolving: 
The event is improving but the subject is still not fully recovered. 
Not resolved: 
The event is ongoing at the time of reporting and the subject has still not 
recovered. 
Resolved with 
sequelae: 
As a result of the AE, the subject suffered persistent and significant 
disability/incapacity (eg, became blind, deaf or paralysed). 
Fatal: 
The subject died due to the event. If the subject died due to other 
circumstances than the event, the outcome of the event per se should be 
stated otherwise (eg, not resolved or resolving). 
Unknown: 
If outcome is not known or not reported. 
10.3 
Additional Points to Consider for Adverse Events 
An untoward occurrence generally may: 
 Indicate a new diagnosis or unexpected worsening of a pre-existing condition. Intermittent 
events for pre-existing conditions or underlying disease should not be considered as AEs. 
 Necessitate therapeutic intervention. 
 Require an invasive diagnostic procedure. 
 Require vaccine discontinuation or a change in concomitant medication. 
 Be considered unfavorable by the Investigator for any reason. 
Diagnoses vs. signs and symptoms: 
 Each event should be recorded to represent a single diagnosis. Accompanying signs 
(including abnormal laboratory values) or symptoms should NOT be recorded as additional 
AEs. If a diagnosis is unknown, signs or symptoms should be recorded appropriately as AEs. 
Worsening of AEs: 
 If the subject experiences a worsening or complication of an AE after starting administration 
of the trial vaccine, the worsening or complication should be recorded as a new AE. 
Investigators should ensure that the AE term recorded captures the change in the condition 
(eg, “worsening of…”). 
 If the subject experiences a worsening or complication of an AE after any change in trial 
vaccine, the worsening or complication should be recorded as a new AE. Investigators should 
ensure that the AE term recorded captures the change in the condition (eg, “worsening 
of…”). 

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Changes in severity of AEs: 
 If the subject experiences changes in severity of an AE, the event should be captured once 
with the maximum severity recorded. 
Preplanned surgeries or procedures: 
 Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent form/assent form are not considered AEs. Complications resulting from 
any planned surgery should be reported as AEs. 
Elective surgeries or procedures: 
 Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as AEs, but should be documented in the subject’s source documents. 
Complications resulting from an elective surgery should be reported as AEs. 
10.4 
Procedures 
10.4.1 Collection and Reporting of Adverse Events 
All AEs, whether considered related to the use of the trial vaccine or not, must be monitored 
until symptoms subside and any abnormal laboratory values have returned to Baseline, or until 
there is a satisfactory explanation for the changes observed, or until death, in which case a full 
pathologist’s report should be supplied, if possible. All findings must be reported on an AE 
eCRF and on the SAE form, if necessary (see Section 10.4.2). All findings in subjects 
experiencing AEs must also be reported in the subject’s source documents. Any unsolicited AEs 
for 28 days (day of vaccination+27 subsequent days) following each TDV/placebo dose will be 
collected during site visits by interview. 
 The following information will be documented for each event: 
 Reported term for the AE. 
 Start and end date. 
 Serious (Y/N). 
 Severity. 
 Investigator’s opinion of the causality (relationship) between the event and administration of 
trial vaccines (“related” or “not related”). 
 Investigator’s opinion of the causality (relationship) to trial procedure(s), including the 
details of the suspected procedure. 
 Action taken with the trial treatment (trial vaccine). 
 Outcome of event. 

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10.4.2 Collection and Reporting of Solicited Adverse Events 
The occurrence of selected indicators of safety will be collected on diary cards by the 
subject/LAR for 7 days (solicited local [injection site] AEs) and 14 days (solicited systemic AEs) 
following administration of each trial vaccine dose (including the day of administration) and will 
be recorded on the “Local and Systemic AEs” eCRF, as appropriate. Any solicited local 
(injection site) or systemic AE observed as continuing 8 days and 15 days, respectively, 
following each trial dose administration, will be recorded as an unsolicited AE on the AE eCRF. 
Any solicited local (injection site) or systemic AE that resolved before 8 days and 15 days, 
respectively, following each trial dose administration, but which recurs at a later time (ie, if 
discontinues), will be recorded as an unsolicited AE on the AE eCRF. 
Any solicited AE that meets any of the following criteria must be entered as an AE on the 
AE eCRF: 
 Solicited local (injection site) or systemic AEs that lead the subject to withdraw from the 
trial. 
 Solicited local (injection site) or systemic AEs that lead to the subject being withdrawn from 
the trial by the Investigator. 
 Solicited local (injection site) and systemic AEs that otherwise meet the definition of an SAE 
(see Section 10.1.2). 
10.4.3 Collection and Reporting of Medically Attended Adverse Events 
MAAEs occurring from first vaccination at Day 1 (M0) until the end of the trial (Day 270 [M9]) 
will be collected during site visits by interview and must be recorded as an AE on the AE eCRF. 
10.4.4 Collection and Reporting of Serious Adverse Events 
Collection of SAEs will commence from the time that the subject is first administered the trial 
vaccine (Day 1 [M0]). Routine collection of SAEs will continue until the end of the trial 
(Day 270 [M9]). 
SAEs should be reported according to the following procedure: 
A Sponsor SAE form must be completed, in English, and signed by the Investigator immediately 
or within 24 hours of first onset or notification of the event. The information should be 
completed as fully as possible but contain, at a minimum: 
 A short description of the event and the reason why the event is categorized as serious. 
 Subject identification number. 
 Investigator’s name. 
 Name of the trial vaccines – if no unblinding is necessary, in a blinded way. 
 Causality assessment. 

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The SAE form should be transmitted within 24 hours to the attention of the contact(s) in the list 
provided to each site. 
10.5 
Follow-up Procedures 
10.5.1 Adverse Events 
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 trial, whichever occurs first. This could potentially be 
followed outside of this trial or in a planned extension trial. 
10.5.2 Serious Adverse Events 
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 
(e.g., laboratory tests, discharge summary, postmortem 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, Institutional Review Boards or International 
Ethics Committees, and Regulatory Authorities 
The Sponsor or designee will be responsible for the reporting of all suspected unexpected serious 
adverse reactions (SUSAR) 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 trial 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 trial vaccine 
administration or in the overall conduct of the trial. 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-Trial Events 
Any SAE that occurs outside of the protocol-specified observation period or after the end of the 
trial but considered to be caused by the trial vaccine(s) must be reported to the Sponsor. These 
SAEs will be processed by the Sponsor’s Pharmacovigilance Department. Instructions for how to 
submit these SAEs will be provided in a handout in the Investigator Site File. 

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11.0 
TRIAL-SPECIFIC REQUIREMENT(S) 
11.1 
Data Monitoring Committee 
A DMC will have oversight of this trial. The DMC functions at a program level and further 
information is available in the DMC Charter. 

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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, High Level Term, Low Level Term, 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 who provides a signed informed consent 
form/assent form. 
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. eCRFs must be 
completed in English. 
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. Reasons for significant corrections should additionally be included. 
The Principal Investigator or 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. 
eCRFs will be reviewed for completeness and acceptability at the trial site during periodic visits 
by trial monitors. The Sponsor or its designee will be permitted to review the subject’s medical 
and hospital records pertinent to the trial 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 trial-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/assent 
forms, subject authorization forms regarding the use of personal health information (if separate 
from the informed consent or assent 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 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 

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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 trial records should be retained until an amount of time specified by applicable regulatory 
requirements or for a time specified in the Clinical Trial Site Agreement between the Investigator 
and Sponsor. 
Refer to the Clinical Trial 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. 

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13.0 
STATISTICAL METHODS 
13.1 
Statistical and Analytical Plans 
A statistical analysis plan (SAP) will be prepared and finalized prior to database lock and trial 
unblinding. This document will provide further details regarding the definition of analysis 
variables and analysis methodology to address all trial objectives. 
A blinded data review will be conducted prior to unblinding of subject’s trial vaccine 
assignment. This review will assess the accuracy and completeness of the trial database, subject 
evaluability, and appropriateness of the planned statistical methods. 
All analyses will be descriptive; no statistical hypotheses will be tested in this trial. Further 
details will be provided in the SAP. 
13.1.1 Analysis Sets 
Safety set: The safety set will consist of all subjects who received at least 1 dose of trial vaccine. 
Full analysis set (FAS): The FAS will include all randomized subjects who received at least 
1 dose of trial vaccine and for whom a valid pre-dose and at least 1 valid post-dose blood sample 
have been received for immunogenicity. 
Per-protocol set (PPS): The PPS will exclude all subjects seropositive to any serotype of 
dengue virus at Baseline (seropositivity is defined as a reciprocal neutralizing titer ≥10) and will 
include all subjects in the FAS who have no major protocol violations. The major protocol 
violation criteria will be defined as part of the blinded data review prior to the unblinding of 
subject’s trial vaccine assignment. The categories of major protocol violations include: (1) not 
meeting selected entry criteria, (2) receiving a wrong trial vaccine, (3) receiving prohibited 
therapies, (4) not receiving 2 doses of trial vaccine or receiving the second dose inadmissibly 
outside of the visit window, and (5) other major protocol violations that may be identified during 
blinded data reviews. 
All summaries and analyses of safety data will be based on subjects in the safety set. The 
primary immunogenicity analyses will be based on the PPS; additional immunogenicity analyses 
may be provided based on the FAS. 
13.1.2 Analysis of Demographics and Other Baseline Characteristics 
Age, gender, race, and other Baseline characteristics will be summarized by trial group for all 
randomized subjects. 
Summary statistics (number of subjects [n], mean, median, SD, minimum, and maximum) will 
be generated for continuous variables, and the number and percentage of subjects within each 
category will be presented for categorical variables. 

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13.1.3 Immunogenicity Analysis 
For primary and secondary immunogenicity endpoints (ie, GMTs of neutralizing antibodies, 
seropositivity rates for each of the 4 dengue serotypes, and seropositivity rates for multiple 
dengue serotypes), descriptive statistics and 95% CIs will be provided by trial group for each 
applicable visit. Seropositivity is defined as a reciprocal neutralizing titer ≥10. 
Handling of missing data, and of values below the lower limit of quantification will described in 
the SAP. 
13.1.4 Safety Analysis 
Solicited AEs 
In all subjects, the presence and severity (Grade) of solicited local (injection site) AEs (pain, 
erythema, and swelling) and solicited systemic AEs (fever, asthenia, malaise, headache and 
myalgia) will be collected for 7 days and 14 days, respectively, following administration of each 
trial dose (including the day of administration) via collection of diary cards. 
For each solicited AE, the number and percentage of subjects with local (injection site) and 
systemic AEs will be summarized by trial group and event severity for each day after each 
vaccination (ie, Day 1 through Day 7 for local [injection site] AEs and Day 1 through Day 14 for 
systemic AEs), and overall. Summaries of first onset of each event and the number of days 
subjects reported experiencing each event will also be provided. For subjects with more than 
1 episode of the same event, the maximum severity will be used for tabulations. 
Unsolicited AEs 
Unsolicited AEs will be assessed for 28 days following administration of each trial dose (day of 
administration+27 subsequent days). 
In all subjects, unsolicited AEs will be coded using the MedDRA, and summarized by SOC and 
PT for each trial group. AEs leading to trial or trial dose discontinuation or withdrawal will also 
be summarized. 
Unsolicited AEs will be summarized as follows: by PT including events with frequency greater 
than a pre-defined frequency (the percentage will be specified in the SAP); by SOC and PT; by 
SOC, PT, and severity; and by SOC, PT, and relationship to the trial dose. Subjects reporting 
more than 1 occurrence for the term (level) being summarized will be counted only once. 
MAAEs 
In all subjects, MAAEs will be collected throughout the trial. MAAEs will be coded using 
MedDRA, and summarized by SOC and PT for each trial group. 
SAEs 
In all subjects, SAEs will be collected throughout the trial. SAEs will be coded using MedDRA, 
and summarized by SOC and PT for each trial group. 

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13.2 
Interim Analysis and Criteria for Early Termination 
No interim analysis is planned. 
13.3 
Determination of Sample Size 
As the analysis of this trial is descriptive and is not based on testing formal null hypotheses, the 
sample size was not determined based on formal statistical power calculations. The sample size 
is considered sufficient to address the objectives of the trial. 

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14.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 
Trial-Site Monitoring Visits 
Monitoring visits to the trial site will be made periodically during the trial 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 (contract research organization [CRO]) and by the IRB or IEC. 
All aspects of the trial and its documentation will be subject to review by the Sponsor or 
designee (as long as blinding is not jeopardized), including but not limited to the Investigator’s 
Binder, trial vaccine, subject medical records, informed consent/assent form documentation, 
documentation of subject authorization to use personal health information (if separate from the 
informed consent/assent forms), and review of eCRFs and associated source documents. It is 
important that the Investigator and other trial 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 trial 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 trial site also may be subject to quality assurance audits by the Sponsor or 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 trial. In addition, 
there is the possibility that this trial 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 trial 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 trial documents as described in Section 14.1. 

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15.0 
ETHICAL ASPECTS OF THE TRIAL 
This trial 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 trial 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 local requirements of each 
participating region. The Sponsor or 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 trial, written notification regarding his or her abstinence from voting 
must also be obtained. 
The Sponsor or 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/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 designee before commencement of the trial (ie, before shipment of the Sponsor-
supplied vaccine or trial-specific screening activity). The IRB or IEC approval must refer to the 
trial by exact protocol title, number, and version date; identify versions of other documents (eg, 
informed consent/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 trial. 
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/assent form, recruitment materials intended for viewing by subjects, local safety 
reporting requirements, reports and updates regarding the ongoing review of the trial 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. 
15.2 
Subject Information, Informed Consent and Subject Authorization 
Written consent documents will embody the elements of informed consent/assent as described in 
the Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 

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applicable laws and regulations. The informed consent/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 trial. The informed consent form and the subject information sheet (if 
applicable) further explain the nature of the trial, its objectives, and potential risks and benefits, 
as well as the date informed consent is given. The informed consent/assent form will detail the 
requirements of the participant and the fact that he or she is free/the subject’s LAR is free to 
withdraw the child 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/assent form and if applicable, the subject authorization form. The informed 
consent/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/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/the subject’s LAR. It is the responsibility of the Investigator to explain the 
detailed elements of the informed consent/assent form, subject authorization form (if applicable), 
and subject information sheet (if applicable) to the subject/the subject’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 LAR may provide such consent for the subject in 
accordance with applicable laws and regulations. 
The subject, or the subject’s LAR, must be given ample opportunity to: (1) inquire about details 
of the trial and (2) decide whether or not to participate in the trial. If the subject or the subject’s 
LAR, determines he or she will participate in the trial, then the informed consent and subject 
authorization form (if applicable) and assent must be signed and dated by the subject or the 
subject’s LAR, as applicable, at the time of consent and prior to the subject entering into the trial. 
The subject or the 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/assent form and subject authorization (if applicable) at the time of consent and prior to 
subject entering into the trial; 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/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/the subject’s LAR signs the informed 
consent/assent form in the subject’s medical record and eCRF. Copies of the signed informed 
consent/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/assent forms must be reviewed and signed by the relevant subject 
or the relevant subject’s LAR in the same manner as the original informed consent/assent form. 

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The date the revised consent 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/assent form. 
15.3 
Subject Confidentiality 
The Sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this trial, a subject’s source data will only be linked to 
the Sponsor’s clinical trial 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 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, electrocardiogram (ECG) 
reports, admission and discharge summaries for hospital admissions occurring during a subject’s 
trial 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/assent form process (see 
Section 15.2). 
Copies of any subject source documents that are provided to the Sponsor must have certain 
personally identifiable information removed (i.e., subject name, address, and other identifier 
fields not collected on the subject’s eCRF). 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy 
15.4.1 Publication and Disclosure 
The results of this trial 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 proposed by the Sponsor to the Principal Investigator(s), to be 
eventually agreed upon by all authors. The data analysis center for this trial will provide the 
analyses needed for publication. Information regarding this trial will be posted on 
ClinicalTrials.gov. 
15.4.2 Clinical Trial Registration 
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable law, regulation and guidance, the Sponsor will, at a minimum register all 
clinical trials conducted in subjects that it Sponsors anywhere in the world on ClinicalTrials.gov 
or other publicly accessible websites before trial initiation. The Sponsor contact information, 
along with Investigator’s city, country, and recruiting status will be registered and available for 
public viewing. 

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15.4.3 Clinical Trial Results Disclosure 
The Sponsor will post the results of this clinical trial, regardless of outcome, on 
ClinicalTrials.gov or other publicly accessible websites, as required by applicable laws and/or 
regulations. 
Trial completion corresponds to the date on which the final subject was examined or received an 
intervention for the purpose of final collection of data (Last Subject Last Visit). 
15.5 
Insurance and Compensation for Injury 
Each subject in the trial 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 trial insurance against the risk of injury to clinical trial 
subjects. Refer to the Clinical Trial 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. 

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16.0 
REFERENCES 
1. Simmons CP, Farrar JJ, Nguyen vV, Wills B. Dengue. N Engl J Med 2012;366(15):1423-32. 
2. Gubler DJ. Epidemic dengue/dengue hemorrhagic fever as a public health, social and 
economic problem in the 21st century. Trends Microbiol 2002;10(2):100-3. 
3. Guzman MG, Kouri G. Dengue: an update. Lancet Infect Dis 2002;2(1):33-42. 
4. World Health Organization, 2016. Dengue and severe dengue. Fact Sheet. Available from 
http://www.who.int/mediacentre/factsheets/fs117/en/. 
5. Dengue hemorrhagic fever: diagnosis, treatment, prevention and control, 2nd Edition. 
Geneva: World Health Organization. Available from 
http://www.who.int/csr/resources/publications/dengue/Denguepublication/en. 
6. Dengue guidelines for diagnosis, treatment, prevention and control. World Health 
Organization. 2009. Available from http://www.who.int/tdr/publications/documents/dengue-
diagnosis.pdf. 
7. Halstead S, Deen J. The future of dengue vaccines. Lancet 2002;360(9341):1243-5. 
8. Available from http://www.dengue.info. 
9. Hadinegoro SR, Arredondo-García JL, Capeding MR, Deseda C, Chotpitayasunondh T, 
Dietze R, et al. Efficacy and long-term safety of a dengue vaccine in regions of endemic 
disease. N Engl J Med 2015;373(13):1195-206. doi: 10.1056/NEJMoa1506223. 
10. Simmons CP. A candidate dengue vaccine walks a tightrope. N Engl J Med 
2015;373(13):1263-4. 
11. Yoksan S, Bhamarapravati N, Halstead SB. Dengue virus vaccine development: study on 
biological markers of uncloned dengue 1-4 viruses serially passaged in primary kidney cells. 
In: TD St. George, BH Kay and J Blok (ed.), Arbovirus research in Australia. Proceedings of 
the 4th Symposium. CSIRO/QIMR, Brisbane, Australia, 1986: 35-8. 
12. Huang CY, Butrapet S, Tsuchiya KR, Bhamarapravati N, Gubler DJ and Kinney RM. 
Dengue 2 PDK-53 virus as a chimeric carrier for tetravalent dengue vaccine development. J. 
Virol 2003;77(21):11436-47. 
13. Tetravalent Dengue Vaccine Candidate (TDV) Investigator’s Brochure (IND 14292), 
Edition 7, April 2016. 
14. Reducing pain at the time of vaccination: WHO position paper – September 2015Wkly 
Epidemiol Rec. 2015;90(39):505-10. 
15. Kohl KS, Marcy M, Blum M, Jones MC, Dagan R, Hansen J, et al. Fever after immunization: 
current concepts and improved future scientific understanding. Clin Infect Dis 2004;39:389-
94. 

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Appendix A Responsibilities of the Investigator 
Clinical research trials sponsored by the Sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. 
The Investigator agrees to assume the following responsibilities: 
1. Conduct the trial in accordance with the protocol. 
2. Personally conduct or supervise the staff who will assist in the protocol. 
3. Ensure that trial-related procedures, including trial-specific (non-routine/non-standard panel) 
screening assessments are NOT performed on potential subjects, prior to the receipt of 
written approval from relevant governing bodies/authorities. 
4. Ensure that all colleagues and employees assisting in the conduct of the trial are informed of 
these obligations. 
5. Secure prior approval of the trial and any changes by an appropriate IRB/IEC that conform to 
ICH, and local regulatory requirements. 
6. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and 
approval of the protocol. Promptly report to the IRB/IEC all changes in research activity and 
all anticipated risks to subjects. Make at least yearly reports on the progress of the trial to the 
IRB/IEC, and issue a final report within 3 months of trial completion. 
7. Ensure that requirements for informed consent/assent, as outlined in ICH and local 
regulations, are met. 
8. Obtain valid informed consent/assent from each subject/the LAR of each subject who 
participates in the trial, and document the date of consent in the subject’s medical chart. 
Valid informed consent/assent form is the most current version approved by the IRB/IEC. 
Each informed consent/assent form should contain a subject authorization section that 
describes the uses and disclosures of a subject’s personal information (including personal 
health information) that will take place in connection with the trial. If an informed 
consent/assent form does not include such a subject authorization, then the Investigator must 
obtain a separate subject authorization form from each subject/the LAR of each subject. 
9. Prepare and maintain adequate case histories of all persons entered into the trial, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the Sponsor that all investigations have been discontinued 
or that the regulatory authority has approved the marketing application. The Investigator 
should contact and receive written approval from the Sponsor before disposing of any such 
documents. 
10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents. 
11. Maintain current records of the receipt, administration, and disposition of Sponsor-supplied 
vaccines, and return all unused Sponsor-supplied vaccines to the Sponsor. 

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12. Report AEs to the Sponsor promptly. In the event of an SAE, notify the Sponsor within 
24 hours. 
13. Review and provide a signature as approval of the content of the clinical study report. 

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Appendix B Investigator Consent to Use of Personal Information 
Takeda will collect and retain personal information of Investigator, including his or her name, 
address, and other personally identifiable information. In addition, Investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following: 
 Takeda, its affiliates, and licensing partners. 
 Business partners assisting Takeda, its affiliates, and licensing partners. 
 Regulatory agencies and other health authorities. 
 IRBs and IECs. 
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following: 
 Assessment of the suitability of Investigator for the trial and/or other clinical trials. 
 Management, monitoring, inspection, and audit of the trial. 
 Analysis, review, and verification of the trial results. 
 Safety reporting and pharmacovigilance relating to the trial. 
 Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the trial. 
 Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other vaccines used in other clinical trials that may contain the 
same chemical compound present in the investigational vaccine. 
 Inspections and investigations by regulatory authorities relating to the trial. 
Self-inspection and internal audit within Takeda, its affiliates, and licensing partners. 
 Archiving and audit of trial records. 
 Posting Investigator site contact information, trial details and results on publicly accessible 
clinical trial registries, databases, and websites. 
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in Investigator’s 
own country. Investigator acknowledges and consents to the use of his or her personal 
information by Takeda and other parties for the purposes described above. 

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Appendix C Elements of the Subject Informed Consent  
In seeking informed consent/assent, the following information shall be provided to each 
subject/the subject’s LAR: 
1. A statement that the trial involves research. 
2. An explanation of the purposes of the research. 
3. The expected duration of the subject’s participation. 
4. A description of the procedures to be followed, including invasive procedures. 
5. The identification of any procedures that are experimental. 
6. The estimated number of subjects involved in the trial. 
7. A description of the subject’s/subject’s LAR’s responsibilities. 
8. A description of the conduct of the trial. 
9. A statement describing the vaccination(s) and the probability for random assignment to each 
trial group. 
10. A description of the possible side effects following vaccine administration that the subject 
may receive. 
11. A description of any reasonably foreseeable risks or discomforts to the subject and, when 
applicable, to an embryo, fetus, or nursing infant. 
12. A description of any benefits to the subject or to others that reasonably may be expected from 
the research. When there is no intended clinical benefit to the subject, the subject/the 
subject’s LAR should be made aware of this. 
13. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might 
be advantageous to the subject and their important potential risks and benefits. 
14. A statement describing the extent to which confidentiality of records identifying the subject 
will be maintained, and a note of the possibility that regulatory agencies, auditor(s), 
IRB/IEC, and the monitor may inspect the records. By signing a written informed 
consent/assent form, the subject/the subject’s LAR is authorizing such access. 
15. For research involving more than minimal risk, an explanation as to whether any 
compensation and an explanation as to whether any medical treatments are available if injury 
occurs and, if so, what they consist of or where further information may be obtained. 
16. The anticipated prorated payment(s), if any, to the subject for participating in the trial. 
17. The anticipated expenses, if any, to the subject for participating in the trial. 
18. An explanation of whom to contact for answers to pertinent questions about the research 
(Investigator), subject’s rights, and IRB/IEC and whom to contact in the event of a research-
related injury to the subject. 

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19. A statement that participation is voluntary, that refusal to participate will involve no penalty 
or loss of benefits to which the subject otherwise is entitled, and that the subject/the subject’s 
LAR may discontinue participation at any time without penalty or loss of benefits to which 
the subject is otherwise entitled. 
20. The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject. 
21. A statement that the subject/the subject’s LAR will be informed in a timely manner if 
information becomes available that may be relevant to the subject’s/LAR’s willingness to 
continue participation in the trial. 
22. A statement that results of pharmacogenomic analysis will not be disclosed to an individual, 
unless prevailing laws require the Sponsor to do so. 
23. The foreseeable circumstances or reasons under which the subject’s participation in the trial 
may be terminated. 
24. A written subject authorization (either contained within the informed consent/assent form or 
provided as a separate document) describing to the subject/the subject’s LAR the 
contemplated and permissible uses and disclosures of the subject’s personal information 
(including personal health information) for purposes of conducting the trial. The subject 
authorization must contain the following statements regarding the uses and disclosures of the 
subject’s personal information: 
a) that personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) Takeda, its affiliates, and 
licensing partners; (2) business partners assisting Takeda, its affiliates, and licensing 
partners; (3) regulatory agencies and other health authorities; and (4) IRBs/IECs; 
b) it is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
subjects the same level of protection as the data protection laws within this country; 
however, Takeda will make every effort to keep your personal information confidential, 
and your name will not be disclosed outside the clinic unless required by law; 
c) that personal information (including personal health information) may be added to 
Takeda’s research databases for purposes of developing a better understanding of the 
safety and effectiveness of the investigational vaccine(s), studying other therapies for 
patients, developing a better understanding of disease, and improving the efficiency of 
future clinical trials; 
d) that subjects agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the trial to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research; and 

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e) that the subject’s identity will remain confidential in the event that trial results are 
published. 
25. Female subjects of childbearing potential (eg, non-sterilized, premenopausal female subjects) 
who are sexually active must use adequate contraception (as defined in the informed 
consent/assent form) from at least 2 months prior to Day 1 (M0) up to 6 weeks after the last 
dose of trial vaccine (Day 90 [M3]). Pregnancy tests will be performed prior to vaccination at 
Day 1 (M0) and Day 90 (M3). Additional pregnancy tests may be performed during the trial 
if deemed necessary by the Investigator. Females of childbearing potential who are sexually 
active will be reminded during trial visits to adhere to acceptable contraceptive methods (see 
Section 7.2) up to 6 weeks after the last dose of trial vaccine (Day 90 [M3]). In addition, they 
must be advised not to donate ova during this period. If a subject is found to be pregnant 
during the trial, no further vaccine doses will be administered. 
26. A statement that clinical trial information from this trial will be publicly disclosed in a 
publicly accessible website, such as ClinicalTrials.gov. 

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Appendix D Serology Plan 
Table 16.a 
Serology Plan 
Timing 
Blood volume 
Assessments 
Day 1 (M0), Day 120 (M4), and Day 270 (M9) 
5 mL 
Dengue neutralizing antibodies (MNT50) 
M=month, MNT50=microneutralization test 50% 
Note: Blood sampling at Day 1 (M0) should be taken prior to administration of the first trial dose. The blood sample 
at Visit 4 (Day 120 [M4]) should be taken at least 28 days after the second trial dose at Day 90 (M3). 

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