Immunogenicity and Safety of a Tetravalent Dengue Vaccine Administered Concomitantly or Sequentially With Adacel® in Healthy Subjects Aged 9 to 60 Years in the Philippines
Phase: PHASE3
Conditions: Dengue Fever, Dengue Hemorrhagic Fever
Sponsor: Sanofi Pasteur, a Sanofi Company

 
 
 
  
 
 
 
 
 
  
 
 
Immunogenicity and Safety of a Tetravalent Dengue Vaccine 
Administered Concomitantly or Sequentially with Adacel® in 
Healthy Subjects Aged 9 to 60 Years in the Philippines 
A phase IIIb, randomized, multicenter, open-label study in 688 subjects aged from 9 to 60 years 
in the Philippines 
 
Clinical Trial Protocol Amendment 1  
 
WHO Universal Trial Number 
(UTN): 
U1111-1161-3294 
Trial Code: 
CYD66 
Development Phase: 
Phase IIIb 
Sponsor: 
Sanofi Pasteur  
14, Espace Henry Vallée,  69007 Lyon, France 
Investigational Products: 
CYD Dengue Vaccine 
Form/Route: 
Powder and solvent for suspension for injection/Subcutaneous 
Indication For This Study: 
Prevention of dengue fever in 9- to 60-year-old subjects 
Manufacturer: 
Same as Sponsor 
Coordinating Investigators: 
This is a multi-center trial with multiple Investigators. Investigators and 
study sites are listed in the “List of Investigators and Centers Involved in 
the Trial” document. 
Principal Investigator: 
Project Manager and Study 
Leader: 
Sponsor's Responsible Medical 
Officer (Sponsor’s Signatory): 
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                                            NCT02992418 
Version and Date of the Protocol: Version 2.0 dated 04 January 2018

 
 
 
  
 
 
 
 
 
  
 
 
Regional Director of Medical 
Affairs 
Global Safety Officer: 
Clinical Trial Manager: 
Version and Date of the Protocol: 
Version 2.0 dated 04 January 2018 
This protocol version 2.0 is the first amendment to the initial trial protocol version 1.0, dated 17 March 2016.  
 
Information contained in this publication is the property of Sanofi Pasteur and is confidential. This information may not be 
disclosed to third parties without written authorization from Sanofi Pasteur. This document may not be reproduced, stored in a 
retrieval system, or transmitted in any form or by any means–electronic, mechanical recording, or otherwise–without prior 
authorization from Sanofi Pasteur. This document must be returned to Sanofi Pasteur upon request. 
 
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Table of Contents 
List of Tables .................................................................................................................................... 8 
Synopsis ............................................................................................................................................ 9 
Table of Study Procedures ............................................................................................................ 23 
List of Abbreviations ..................................................................................................................... 26 
1 
Introduction ..................................................................................................................... 29 
1.1 
Background ..................................................................................................................... 29 
1.2 
Background of the Investigational Product ..................................................................... 30 
1.3 
Potential Benefits and Risks ........................................................................................... 32 
1.3.1 
Potential Benefits to Subjects ....................................................................................... 32 
1.3.2 
Potential Risks to Subjects ........................................................................................... 33 
1.4 
Rational for the Trial ....................................................................................................... 34 
2 
Trial Objectives ............................................................................................................... 37 
2.1 
Primary Objectives .......................................................................................................... 37 
2.2 
Secondary Objectives ...................................................................................................... 37 
3 
Investigators and Trial Organization ............................................................................ 37 
4 
Independent Ethics Committee/Institutional Review Board ...................................... 38 
5 
Investigational Plan ......................................................................................................... 38 
5.1 
Description of the Overall Trial Design and Plan ........................................................... 38 
5.1.1 
Trial Design .................................................................................................................. 38 
5.1.2 
Justification of the Trial Design ................................................................................... 41 
5.1.3 
Trial Plan ...................................................................................................................... 41 
5.1.4 
Visit Procedures ............................................................................................................ 41 
5.1.5 
Planned Trial Calendar ................................................................................................. 46 
5.1.6 
Early Safety Data Review............................................................................................. 46 
5.2 
Enrollment and Retention of Trial Population ................................................................ 46 
5.2.1 
Recruitment Procedures ................................................................................................ 46 
5.2.2 
Informed Consent Procedures ...................................................................................... 47 
5.2.3 
Screening Criteria ......................................................................................................... 47 
5.2.4 
Inclusion Criteria .......................................................................................................... 47 
5.2.5 
Exclusion Criteria ......................................................................................................... 48 
5.2.6 
Medical History ............................................................................................................ 49 
5.2.7 
Contraindications for Subsequent Vaccinations ........................................................... 50 
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5.2.7.1 
Temporary Contraindications ..................................................................................... 50 
5.2.7.2 
Definitive Contraindications ...................................................................................... 50 
5.2.8 
Conditions for Withdrawal ........................................................................................... 50 
5.2.9 
Lost to Follow-up Procedures....................................................................................... 51 
5.2.10 
Classification of Subjects Who Discontinue the Trial.................................................. 51 
5.2.11 
Follow-up of Discontinuations ..................................................................................... 52 
5.2.12 
Follow-up and Reporting of Pregnancies ..................................................................... 52 
5.3 
Modification of the Trial and Protocol ........................................................................... 52 
5.4 
Interruption of the Trial .................................................................................................. 53 
6 
Vaccines Administered ................................................................................................... 53 
6.1 
Identity of the Investigational Products .......................................................................... 53 
6.1.1 
Identity of CYD Dengue Vaccine ................................................................................ 53 
6.1.1.1 
Composition ............................................................................................................... 53 
6.1.1.2 
Preparation and Administration ................................................................................. 54 
6.1.1.3 
Dose Selection and Timing ........................................................................................ 54 
6.1.2 
Identity of Adacel ......................................................................................................... 55 
6.1.2.1 
Composition ............................................................................................................... 55 
6.1.2.2 
Preparation and Administration ................................................................................. 56 
6.1.2.3 
Dose Selection and Timing ........................................................................................ 56 
6.1.3 
Identity of Control Product ........................................................................................... 56 
6.2 
Identity of Other Product ................................................................................................ 56 
6.3 
Product Logistics ............................................................................................................ 56 
6.3.1 
Labeling and Packaging ............................................................................................... 56 
6.3.2 
Product Shipment, Storage, and Accountability ........................................................... 57 
6.3.2.1 
Product Shipment ....................................................................................................... 57 
6.3.2.2 
Product Storage .......................................................................................................... 57 
6.3.2.3 
Product Accountability ............................................................................................... 57 
6.3.3 
Replacement Doses....................................................................................................... 58 
6.3.4 
Disposal of Unused Products ........................................................................................ 58 
6.3.5 
Recall of Products ......................................................................................................... 58 
6.4 
Blinding and Code-breaking Procedures ........................................................................ 58 
6.5 
Randomization and Allocation Procedures ..................................................................... 58 
6.6 
Treatment Compliance .................................................................................................... 59 
6.7 
Concomitant Medications and Other Therapies ............................................................. 59 
7 
Management of Samples ................................................................................................. 60 
7.1 
Sample Collection ........................................................................................................... 60 
7.1.1 
Serum Samples for Neutralizing Ab Assessment ......................................................... 60 
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7.1.2 
Blood Sample for Virological Confirmation of Hospitalized Suspected Dengue 
Case and Assessment of Case Severity ........................................................................ 61 
7.1.3 
Additional Blood Samples ............................................................................................ 62 
7.1.4 
Urine Samples .............................................................................................................. 62 
7.2 
Serum Sample Preparation .............................................................................................. 62 
7.3 
Sample Storage and Shipment ........................................................................................ 62 
7.4 
Future Use of Stored Serum Samples for Research ........................................................ 63 
8 
Clinical Supplies .............................................................................................................. 63 
9 
Endpoints and Assessment Methods ............................................................................. 64 
9.1 
Primary Endpoints and Assessment Methods ................................................................. 64 
9.1.1 
Immunogenicity ............................................................................................................ 64 
9.1.1.1 
Immunogenicity Endpoints ........................................................................................ 64 
9.1.1.2 
Immunogenicity Assessment Methods ...................................................................... 64 
9.1.2 
Safety ............................................................................................................................ 65 
9.1.3 
Efficacy ......................................................................................................................... 65 
9.2 
Secondary Endpoints and Assessment Methods ............................................................. 66 
9.2.1 
Immunogenicity ............................................................................................................ 66 
9.2.1.1 
Immunogenicity Endpoints ........................................................................................ 66 
9.2.1.2 
Immunogenicity Assessment Methods ...................................................................... 66 
9.2.2 
Safety ............................................................................................................................ 66 
9.2.2.1 
Safety Definitions ....................................................................................................... 66 
9.2.2.2 
Safety Endpoints ........................................................................................................ 69 
9.2.2.3 
Safety Assessment Methods ....................................................................................... 70 
9.2.2.3.1 
Immediate Post-vaccination Surveillance Period .................................................... 70 
9.2.2.3.2 
Reactogenicity: Solicited Reactions From Day 0 to Day 7 (injection site 
reactions) or Day 14 (systemic reactions) After Each Vaccination ......................... 70 
9.2.2.3.3 
Unsolicited Non-serious Adverse Events From Day 0 to Day 28 After Each 
Vaccination .............................................................................................................. 75 
9.2.2.3.4 
Serious Adverse Events ........................................................................................... 76 
9.2.2.3.5 
Adverse Events of Special Interest .......................................................................... 76 
9.2.2.3.6 
Assessment of Causality .......................................................................................... 77 
9.2.3 
Methods for Assessing Virological Confirmation of Hospitalized Suspected 
Dengue Case and Assessment of Case Severity ........................................................... 77 
9.2.4 
Efficacy ......................................................................................................................... 79 
9.3 
Observational Endpoints and Assessment Methods ....................................................... 79 
10 
Reporting of Serious Adverse Events ............................................................................ 79 
10.1 
Initial Reporting by the Investigator ............................................................................... 80 
10.2 
Follow-up Reporting by the Investigator ........................................................................ 81 
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10.3 
Reporting of SAEs Occurring After a Subject Has Completed the Study ...................... 81 
10.4 
Assessment of Causality ................................................................................................. 81 
10.5 
Reporting SAEs to Health Authorities and IECs/IRBs................................................... 81 
11 
Data Collection and Management ................................................................................. 82 
11.1 
Data Collection and eCRF Completion .......................................................................... 82 
11.2 
Data Management ........................................................................................................... 83 
11.2.1 
Management of Clinical Data ....................................................................................... 83 
11.2.2 
Data Management of SAEs and Pregnancies ............................................................... 83 
11.2.3 
Data Review ................................................................................................................. 83 
12 
Statistical Methods and Determination of Sample Size ............................................... 84 
12.1 
Statistical Methods .......................................................................................................... 84 
12.1.1 
Hypotheses and Statistical Methods for Primary Objectives ....................................... 84 
12.1.1.1 
Hypotheses ................................................................................................................. 84 
12.1.1.2 
Statistical Methods ..................................................................................................... 86 
12.1.2 
Hypotheses and Statistical Methods for Secondary Objectives ................................... 86 
12.1.2.1 
Hypotheses ................................................................................................................. 86 
12.1.2.2 
Statistical Methods ..................................................................................................... 87 
12.2 
Analysis Sets ................................................................................................................... 88 
12.2.1 
Full Analysis Set ........................................................................................................... 88 
12.2.2 
Per-Protocol Analysis Set ............................................................................................. 89 
12.2.3 
Safety Analysis Set ....................................................................................................... 90 
12.2.4 
Other Analysis Set ........................................................................................................ 91 
12.2.5 
Populations Used in Analyses ...................................................................................... 91 
12.3 
Handling of Missing Data and Outliers .......................................................................... 91 
12.3.1 
Safety ............................................................................................................................ 91 
12.3.2 
Immunogenicity ............................................................................................................ 91 
12.3.3 
Efficacy ......................................................................................................................... 91 
12.4 
Interim/Preliminary Analysis .......................................................................................... 91 
12.5 
Determination of Sample Size and Power Calculation ................................................... 92 
13 
Ethical and Legal Issues and Investigator/Sponsor Responsibilities.......................... 94 
13.1 
Ethical Conduct of the Trial/Good Clinical Practice ...................................................... 94 
13.2 
Source Data and Source Documents ............................................................................... 94 
13.3 
Confidentiality of Data and Access to Subject Records ................................................. 94 
13.4 
Monitoring, Auditing, and Archiving ............................................................................. 95 
13.4.1 
Monitoring .................................................................................................................... 95 
13.4.2 
Audits and Inspections ................................................................................................. 96 
13.4.3 
Archiving ...................................................................................................................... 96 
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13.5 
Financial Contract and Insurance Coverage ................................................................... 96 
13.6 
Stipends for Participation ................................................................................................ 96 
13.7 
Publication Policy ........................................................................................................... 97 
14 
References List ................................................................................................................. 98 
15 
Signature Pages ............................................................................................................. 100 
 
 
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List of Tables 
Table 7.1: Blood sampling volume (mL) per visit .......................................................................... 61 
Table 7.2: Blood sampling volume (mL) for hospitalized suspected dengue case ......................... 61 
Table 9.1: Solicited injection site reactions: terminology, definitions, and intensity scales for 
subjects aged 9 to 11 years .............................................................................................................. 72 
Table 9.2: Solicited injection site reactions: terminology, definitions, and intensity scales for 
subjects aged >= 12 years for all subjects ....................................................................................... 73 
Table 9.3: Solicited systemic reactions: terminology, definitions, and intensity scales ................. 74 
Table 12.1: Powers for Non-inferiority of seroprotection/GMC/GMT for each antigen and 
serotype between groups- Primary objective .................................................................................. 93 
Table 12.2: Powers for Non-inferiority of GMT for each serotype between groups- Secondary 
objective .......................................................................................................................................... 93 
 
 
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Indeed, new supportive clinical data based on the results of supplemental 
exploratory analyses confirmed that the efficacy and safety profile of the CYD 
dengue vaccine was different between subjects previously naturally exposed to the 
dengue virus prior to vaccination (referred hereafter as “exposed subjects”) and 
subjects never exposed to the dengue virus prior to vaccination (referred hereafter 
as “unexposed subjects”). In light of this results, the IDMC involved in the safety 
data review of the CYD dengue vaccine clinical development program concluded, 
in and ad hoc meeting held on 3-4 November 2017, that there is a strong evidence 
that the CYD dengue vaccine protects exposed subjects from symptomatic, 
hospitalized and severe dengue while, in unexposed subjects, the vaccine confers 
limited short term benefit against symptomatic dengue and induces an increased 
risk of hospitalized or severe dengue in the long term starting on the third year after 
the first injection (findings based on follow-up of dengue unexposed subjects 
having received 3 CYD dengue vaccine doses). The IDMC recommended that no 
further vaccination occurred in unexposed subjects in ongoing or future trials, and 
on precautionary basis, including partially vaccinated subjects in ongoing trials.  
Given the IDMC recommendations, Sanofi Pasteur paused all vaccinations in this 
study (CYD66) and amended this study protocol. To determine the basal serostatus 
of the subjects already included in the study, the PRNT assay will be used on blood 
samples provided by the subjects before the first vaccination.  
As per IDMC recommendations, the following changes will be applied to this trial: 
x 
All vaccinated subjects will be informed about their baseline dengue serostatus 
and what it means as soon as possible  
x 
All subjects will be asked about their willingness to continue participating in 
this study, and consent will be formalized by signing an ICF and/or AF 
addendum, as applicable.  
x 
Subjects seropositive at baseline will additionally be asked for consent to 
receive remaining CYD dengue doses.  
x 
Subjects seronegative at baseline will be able to continue in the study for safety 
follow-up if they consent to, but will not receive further injections of CYD 
dengue vaccine.  
x 
Subjects seronegative at baseline who were vaccinated during this study will 
have timely access to appropriate care in the event of suspected dengue, for 10 
years from the date of last dengue vaccination. 
Time between communication of the results from the exploratory analyses and 
approval of Protocol Amendment 1 by the competent authorities and for the 
associated logistic tasks will result into a hold of study activities of several months 
(approximately 4-6 months). Study-hold intervenes after V03, V04 or V05, 
depending on each subject’s visit-calendar at the time of study-hold (see table 
below).  
In order to communicate to each subject his/her dengue serostatus at baseline, there 
will be either 1 unscheduled visit or phone call during the study-hold before the 
next visit initially planned (V06 at the latest): 
The subject will consent to continue participation in the study by signing an ICF/AF 
addendum 1 at subject’s next planned visit (either V04, V05 or V06).  
Thus, dose 2 and 3, or dose 3 only (provided that dose 2 was received, as planned) 
will be administered selectively to those subjects dengue seropositive at baseline 
who consent continue participation in the study and consent receiving the remaining 
CYD dengue doses planned. 
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For all subjects who received at least 1 dose and who consent to continue 
participation in the study, a 6 month safety follow up is planned. This period will 
start after the last CYD dose the subject received (whether 1, 2 or 3 doses).  
At the time vaccinations were paused, subjects already provided 2 or 3 blood 
samples (BL), depending on their allocation group. Only dengue-exposed subjects 
who will continue in the study and choose to receive remaining CYD dengue doses 
will provide 1 subsequent BL, as initially planned in Protocol version 1.0.  
 
The following table summarizes those study procedures (visits, vaccine injections 
and blood sampling) that were carried out as per protocol version 1.0 before 
Protocol amendment 1 and those paused (study hold) and planned during the study.  
 
Visit 
Number 
V01 
V02 
V03 
V04‡ 
V05‡ 
 
V06‡ 
V07‡ 
 
Unscheduled  
visit / phone call† 
study-hold  
 
Timelines 
D0 
M1 
M2 
M7 
M8 
M 13 
M14 
Status at 
study-
hold 
Finished 
Finished 
Finished 
Paused 
(finished 
for some 
subjects) 
Paused 
(finished 
for some 
subjects) 
Planned 
Planned 
Group 1 
 
Blood 
sample 
 
Adacel® 
+ 
CYD 
dengue 
vaccine 
dose 1 
Blood 
sample 
Safety 
data 
collection 
 
 
 
 
CYD 
dengue 
vaccine 
dose 2 
 
 
Safety 
data 
collection 
 
 
 
 
CYD 
dengue 
vaccine 
dose 3 
Blood 
sample 
Safety 
data 
collection 
Group 2 
Blood 
sample 
 
Adacel® 
Blood 
sample 
 
CYD 
dengue 
vaccine 
dose 1 
Blood 
sample 
Safety 
data 
collection 
 
 
CYD 
dengue 
vaccine 
dose 2 
 
Safety 
data 
collection 
 
 
CYD 
dengue 
vaccine 
dose 3 
Blood 
sample 
Safety 
data 
collection 
BL: blood sample 
CYD and Tdap were be administered at 2 different sites, with the CYD dengue vaccine administered in 
one deltoid and Tdap in the other deltoid 
†All subjects will attend an unscheduled visit or have an unscheduled phone call after the hold of 
activities and before their next scheduled visit to be informed about their dengue serostatus at baseline.  
‡ V04 and/or V05 (if they were not carried out) and V06 and V07 will take place, for those subjects 
dengue seropositive at baseline who consent continue participation in the study and consent 
administration of remaining CYD dengue doses. All other subjects will not attend their next scheduled 
visit unless it is to provide consent to study continuation.  
 
Additional BL may be drawn for virological confirmation of hospitalized suspected 
dengue case during the duration of the trial. 
For the 2 vaccines, solicited reactions will be collected after each injection between 
Days 0–7 for injection site reactions and between Days 0–14 for systemic reactions. 
Unsolicited adverse events (AEs) will be collected between Days 0-28 after each 
injection. 
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Serious AEs (SAEs) will be reported throughout the study (from inclusion until 
6 months after the last injection). 
Serious and non-serious AEs of special interest (AESIs) will be collected in defined 
time windows according to the type of AESI.  
In addition, hospitalized suspected dengue cases occurring at any time in the trial 
will be collected and documented. 
Subjects will be followed for safety from the first injection up to 6 months after the 
last injection. 
Independent Data Monitoring Committee 
An Independent Data Monitoring Committee (IDMC) will be involved in the 
regular review of hospitalized virologically-confirmed dengue cases (VCD), 
including assessment of severity. Additionally, any related SAE or death will be 
promptly reviewed by the IDMC. 
Early Safety Data Review: 
This trial will not include an early review of safety data. However, it may be 
interrupted at any time if new data about the investigational product become 
available, and/or on advice of the Sponsor, the Independent Ethic Committees 
(IECs)/Institutional Review Boards (IRBs), or the governing regulatory authorities 
in the Philippines where the trial is taking place.  
If the trial is prematurely terminated or suspended, the Sponsor will promptly 
inform the Investigators, the IECs/IRBs, and the regulatory authorities of the reason 
for termination or suspension.  
If the trial is prematurely terminated for any reason, the Investigator will promptly 
inform the subjects and/or the subjects’ parents/legally acceptable representatives 
and should assure appropriate therapy and follow-up. 
An internal safety evaluation team (SET) will perform a safety analysis on safety 
data during the conduct of the trial. 
Primary Objectives: 
Tdap immunogenicity 
x 
To demonstrate the non-inferiority of the humoral immune response to the 
Tdap booster dose concomitantly administered with the first dose of CYD 
dengue vaccine as compared to sequential administration, measured 28 days 
after Tdap booster dose* 
 
CYD dengue vaccine immunogenicity 
x 
To demonstrate the non-inferiority of the humoral immune response to the 
first dose of CYD dengue vaccine concomitantly administered with Tdap as 
compared to sequential administration, measured 28 days after the first dose 
of CYD dengue vaccine* Providing that the number of evaluable seropositive 
subjects allows a global power of at least 80% (otherwise  analyses will be 
descriptive) 
Primary Endpoints: 
Tdap immunogenicity 
x 
Antibody (Ab) concentrations against pertussis antigens (PT, FHA, PRN, 
FIM2+3) as measured by enzyme-linked immunosorbent assay (ELISA), 
28 days after the dose of Tdap vaccine  
x 
Seroprotection against D and T, defined as anti-D and anti-T Ab 
FRQFHQWUDWLRQV 0.1 international units (IU)/mL, as measured by ELISA for T 
and by Diphtheria Micrometabolic Inhibition Test - Toxin Neutralization 
assay (MIT-TNA) for D, 28 days after the dose of Tdap vaccine  
 
CYD dengue vaccine immunogenicity 
x 
Neutralizing Ab titers against each of the 4 dengue serotypes, as measured 
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by dengue 50% plaque reduction neutralization test (PRNT50), 28 days 
after the first dose of CYD dengue vaccine 
Secondary Objectives: 
CYD dengue vaccine Immunogenicity: 
x 
To demonstrate the non-inferiority of the humoral immune response of 3 
doses of CYD dengue vaccine with the first dose concomitantly administered 
with Tdap as compared to sequential administration, measured 28 days after 
the third dose of CYD dengue vaccine* 
x 
To describe the humoral immune response at baseline and 28 days after the 
first and third doses of CYD dengue vaccine, in each and any group 
 
Tdap Immunogenicity: 
x 
To describe the humoral immune response of Tdap vaccine at baseline and 28 
days after concomitant administration with the first dose of CYD dengue 
vaccine as compared to the sequential administration, in each and any group 
 
Safety 
x 
To describe the safety of the CYD dengue vaccine and of the Tdap booster 
dose after each and any injection in each group 
 
* Providing that the number of evaluable seropositive subjects allows a global 
power of at least 80% (otherwise  analyses will be descriptive) 
Secondary Endpoints: 
CYD dengue vaccine immunogenicity 
x 
Neutralizing Ab titers against each of the 4 dengue serotypes, as measured by 
dengue PRNT50, at baseline (M1) and 28 days after the first and third doses of 
CYD dengue vaccine 
x 
NeutralizinJ$EWLWHUVGLODJDLQVWHDFKRIWKHGHQJXHVHURW\SHVDQG
against at least 1, 2, 3, or 4 dengue serotypes, as measured by dengue PRNT50, 
at baseline (M1) and 28 days after the first and third doses of CYD dengue 
vaccine 
x 
1HXWUDOL]LQJ$EWLWHUVGLIferent thresholds (1/dil) against each of the 4 
dengue serotypes, as measured by dengue PRNT50, at baseline (M1) and 28 
days after the first and third doses of CYD dengue vaccine 
Tdap immunogenicity 
x 
Ab concentrations against PT, FHA, PRN, and FIM2+3, as measured by 
ELISA, at baseline (D0 for Group 2, M1 for Group 1) and 28 days after the 
dose of Tdap vaccine 
x 
Anti-T and anti-'$EFRQFHQWUDWLRQV,8P/DVPHDVXUHGE\(/,6$IRU
T and by MIT-TNA for D, at baseline (D0 for Group 2, M1 for Group 1) and 
28 days after the dose of Tdap vaccine 
Safety 
Tdap and CYD dengue vaccine safety in each group 
x 
Occurrence of immediate AEs reported in the 30 minutes after each/any 
injection 
x 
Occurrence of solicited (i.e., pre-listed in the subject’s diary card [DC] and 
electronic case report form [eCRF]) injection site reactions (pain, erythema, 
and swelling) within 7 days following each/any injection 
x 
Occurrence of solicited systemic reactions (fever, headache, malaise, myalgia, 
and asthenia) occurring up to 14 days following each/any injection 
x 
Occurrence of unsolicited (spontaneously reported) AEs within 28 days 
following each/any injection 
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x 
Occurrence of non-serious AESIs* occurring within 7 days following each 
and any vaccination 
x 
Occurrence of SAEs, including serious AESIs* (with specific time windows 
according to the type of AESI*) throughout the trial** 
x 
Occurrence of hospitalized VCD cases throughout the trial (i.e., from D0 
through the end of the study) 
*   Hypersensitivity/allergic reactions (serious or not) within 7 days after each 
CYD dengue vaccine injection, serious viscerotropic disease within 30 days 
after each CYD dengue vaccine injection, serious neurotropic disease within 30 
days after each CYD dengue vaccine injection; serious dengue cases requiring 
hospitalization (i.e., hospitalized suspected dengue case) occurring in all 
subjects at any time during the study 
** Subjects from Group 1 will not be vaccinated at V01 but will receive the first 
vaccinations at V02. However, SAEs will be recorded from inclusion and 
subjects from Group 1 will receive a SAE-specific DC at V01 that will be 
collected at V02.  
Depending on the item, these could include: nature (Medical Dictionary for 
Regulatory Activities [MedDRA] preferred term), time of onset, duration, number 
of days of occurrence, grade of severity, relationship to vaccine, action taken, 
whether the AE led to early termination from the study, seriousness, or outcome. 
Hospitalized suspected dengue case is defined as an acute febrile illness with 
diagnosis of dengue requiring hospitalization (with bed attribution). In such cases, 
1 unplanned acute blood sample (within the first 5 days after fever onset) will be 
collected for virological confirmation of hospitalized suspected dengue case. A 
hospitalized suspected case will be considered VCD if there is a detection of wild 
type (WT) dengue virus by dengue non-structural protein 1 (NS1) antigen (Ag) 
ELISA and/or dengue reverse transcriptase-polymerase chain reactions (RT-PCRs) 
(at the Global Clinical Immunology [GCI] or GCI designated laboratory).  
Note: Acute blood sample for all hospitalized suspected dengue cases should be 
collected within the pre-specified timeframe as described above. If this cannot be 
accomplished, this sample should still be obtained as soon as possible thereafter, 
for IDMC severity assessment.  
Planned Sample Size: 
As per Protocol version 1.0 , a total of 688 subjects were planned to be enrolled: 
Group 1: 
n = 344 (86 subjects per age group) 
Group 2: 
n = 344 (86 subjects per age group) 
As per Protocol Amendment 1, only dengue-exposed subjects prior to vaccination 
will be eligible to continue and complete dengue study vaccination schedules. 
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Schedule of Study Procedures: 
The study procedures (Visits, vaccinations and BLs) are summarized in the Table 
presented in the Trial Design and Methodology section. 
Visits/phone call: 
As per Protocol version 1.0, all subjects attended 3 visits (V01 to V03), and some 
subjects attended 4 or 5 visits (V01 to V04, or V01 to V05, respectively). All 
subjects had 1 interim phone call approximately 3 months after the first dose of the 
CYD dengue vaccine.  
Upon implementation of Protocol Amendment1: 
x 
All subjects will attend an unscheduled visit or have an unscheduled phone 
call after the hold of activities and before their next scheduled visit to be 
informed about their serostatus at baseline.    
x 
All subjects who consent to continue in the study will attend their next 
scheduled visit to sign the ICF/AF addendum1.  
x 
All subjects who consent continue participation in the study will receive a 6 
months follow up “safety phone call” 6 months after their last vaccine dose 
received.  
x 
Seropositive subjects who consent to continue participation in the study and 
consent to receive remaining CYD dengue doses will attend their next planned 
visits and have interim phone calls as initially planned (per protocol version 
1.0); ie, 7 planned visits overall; V01 to V07, and 2 more interim phone calls 
during the 6-month period after dose 2 and dose 3 of the CYD dengue vaccine 
(approximately 3 months after each vaccine injection).  
Vaccination: 
As per Protocol version 1.0, all subjects, depending on the group they were 
randomized to, received the first dose of the CYD dengue vaccine and the booster 
dose of Tdap as follows: 
x 
Group 1: subjects  were administered the first dose of CYD dengue vaccine 
concomitantly with the booster dose of Tdap vaccine at the second visit (V02; 
M1) 
x 
Group 2: subjects  received Tdap vaccine at the first visit (V01; D0), and then 
CYD dengue vaccine 28 days later at the second visit (V02; M1) 
All but 19 subjects (both, from Group 1 and from Group 2) received the dose 2 of 
the CYD vaccine at V04 (M7), as planned.  
Upon implementation of Protocol Amendment1: 
Only seropositive subjects who provide consent to continue participation in the 
study and to receive remaining CYD doses will be administered dose 2 (applicable 
to subjects who did not receive dose 2 yet), and dose 3 of the CYD dengue 
vaccine, as initially planned. All other subjects will not receive remaining CYD 
dengue doses. 
Blood Sampling: 
As per Protocol version 1.0, all subjects provided 2 (Group 1) or 3 (Group 2) BLs 
before the study hold. 
Note that in Group 2 the BL 28 days after Tdap vaccination corresponds to the BL 
prior to the first dose for CYD dengue vaccine. 
Upon implementation of Protocol Amendment1: 
Only seropositive subjects who consent to continue participation in the study and 
to receive further CYD dengue doses will provide 1 more BL, as initially planned.  
 
 
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Individual samples will not exceed 6 mL: 
x 
for Tdap immunogenicity assessments (2 mL) before the first vaccination 
(D0 for Group 2 and M1 for Group 1) and 28 days after vaccination with 
Tdap vaccine (M1 for Group 2 and M2 for Group 1) 
x 
for CYD dengue vaccine immunogenicity assessments (4 mL) before the 
first vaccination (M1 for both groups) and 28 days after the first and third 
vaccinations with CYD dengue vaccine (M2 and M14 for both groups) 
 
Additional blood samples might be collected:  
x 
In case of hospitalized suspected dengue case, one unplanned BL (=acute 
BL, of approximately 3 mL) will have to be collected within the first 5 
days after fever onset for virological confirmation of dengue disease.  
x 
In case of SAEs (including AESI).  
x 
To assess AEs that may be indicative of viscerotropic or neurotropic 
disease (see Guidelines for Assessing Viscerotropic and Neurotropic AE).  
Urine sampling: 
All female subjects of childbearing potential will provide urine samples for urine 
pregnancy test before each injection.  
Duration of Participation in 
the Trial: 
For seropositive subjects who consent continue participation in the study and 
administration of remaining CYD dengue doses, due to period of study-hold, the 
duration of each subject’s participation in the trial will be approximately 23-25 
months, since it will be extended by 4-6 months with respect to the initial plan (ie, 
as per protocol version1.0: approximately 19 months, including a vaccination 
phase of 12 months for subjects in Group 1 and 13 months for subjects in Group 2, 
followed by a safety follow-up period of 6 months after the third injection of CYD 
dengue vaccine).  
For seropositive subjects who consent continue participation in the study but 
refuse to receive remaining CYD dengue doses and seronegative subjects who 
provide their consent to continue participation in the study, their participation in 
the trial will be less than 19 months as initially planned. (i. e., taking into account 
the study-hold and the 6 months safety follow up  
Subjects declining continue participation in the study will end the study on the date 
this decision is communicated to the Sponsor. 
Investigational Product: 
CYD Dengue Vaccine  
 Form: 
Powder and solvent for suspension for injection. 
 Composition: 
Each 0.5 mL dose of reconstituted vaccine contains: 
Active Ingredients: 
4.5 – 6 log10 cell-culture infectious dose 50% (CCID50) of each live, attenuated, 
recombinant dengue virus serotype 1, 2, 3, 4 
Excipients: 
Essential amino acids, non-essential amino acids, L-arginine chlorhydrate, 
saccharose, D-trehalose dihydrate, D-sorbitol, tris (hydroxymethyl) aminomethane, 
and urea. 
Solvent: 
NaCl 0.4%. 
 Route: 
Subcutaneous (SC) 
 Batch Number: 
TBD  
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Other Product: 
Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine 
Adsorbed (Adacel®, referred to in this protocol as Tdap) 
 Form: 
Vial presentation 
 Composition: 
Each 0.5 mL dose is formulated in sodium phosphate buffered isotonic sodium 
chloride solution to contain the following active ingredients:  
Active Ingredients: 
5 Lf 
 
tetanus toxoid 
2 Lf 
 
diphtheria toxoid 
2.5 μg  
pertussis toxoid  
5 μg 
 
filamentous hemagglutinin  
3 μg 
 
pertactin  
5 μg 
 
fimbriae types 2 and 3  
Excipients: 
1.5 mg   
aluminum phosphate (adjuvant) 
0.6% v/v 
2-phenoxyethanol 
 Route: 
Intramuscular (IM) 
 Batch Number: 
Commercial Batch  
Inclusion Criteria: 
An individual must fulfill all of the following criteria in order to be eligible for 
trial enrollment: 
1) 
Subject aged 9 to 60 years (i.e., from the day of the 9th birthday to the day 
prior to the 61th birthday) on the day of inclusion 
2) 
Subject in good health, based on medical history and physical examination 
3) 
Informed consent form (ICF) or assent form (AF) has been signed and dated 
by the subject (based on local regulations), and/or ICF has been signed and 
dated by the parent(s) or another legally acceptable representative (and by an 
independent witness if required by local regulations) 
4) 
For subject aged 9 to 11 years: known (documented) receipt of at least 
4 previous doses of diphtheria toxoid, tetanus toxoid and acellular pertussis-
containing (DTaP) vaccines, with the last dose not within the last 5 years 
prior to enrolment 
OR 
For subject aged at least 12 years: known (documented or self-reported) 
receipt of at least 3 previous doses of diphtheria toxoid, tetanus toxoid, and 
whole cell pertussis-containing (DTwP) vaccines, with the last dose not 
within the last 5 years prior to enrolment 
5) 
Subject (or subject and parent[s]/legally acceptable representatives) able to 
attend all scheduled visits and to comply with all trial procedures 
Exclusion Criteria: 
An individual fulfilling any of the following criteria is to be excluded from trial 
enrollment: 
1) 
Subject is pregnant, or lactating, or of childbearing potential (to be 
considered of non-childbearing potential, a female must be pre-menarche or 
post-menopausal for at least 1 year, surgically sterile, or using an effective 
method of contraception or abstinence from at least 4 weeks prior to the first 
vaccination until at least 4 weeks after the last vaccination) 
2) 
Participation at the time of study enrollment (or in the 4 weeks preceding the 
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first trial vaccination) or planned participation during the present trial period 
in another clinical trial investigating a vaccine, drug, medical device, or 
medical procedure 
3) 
Planned receipt of any vaccine in the 4 weeks following any trial vaccination 
4) 
Previous vaccination against dengue disease with the trial CYD dengue 
vaccine  
5) 
Receipt of immune globulins, blood or blood-derived products in the past 3 
months, which might interfere with assessment of the immune response 
6) 
Known or suspected congenital or acquired immunodeficiency (including 
HIV infection with impaired immune function); or receipt of 
immunosuppressive therapy such as anti-cancer chemotherapy or radiation 
therapy within the preceding 6 months; or long-term systemic corticosteroids 
therapy (prednisone or equivalent for more than 2 consecutive weeks within 
the past 3 months) 
7) 
A previous severe reaction to pertussis, diphtheria or tetanus vaccine 
including immediate anaphylaxis, encephalopathy within 7 days or seizure 
within 3 days of receiving the vaccine 
8) 
Known systemic hypersensitivity to any of the vaccine components, or 
history of a life-threatening reaction to the vaccine used in the trial or to a 
vaccine containing any of the same substances 
9) 
Thrombocytopenia, contraindicating intramuscular vaccination 
10) Bleeding disorder or receipt of anticoagulants within 3 weeks preceding 
inclusion, which may be a contraindication for intramuscular vaccination, at 
the discretion of the Investigator 
11) Deprived of freedom by administrative or court order, or in an emergency 
setting, or hospitalized involuntarily 
12) Current alcohol abuse or drug addiction that, based on Investigator’s 
judgment, may interfere with the subject’s ability to comply with trial 
procedures 
13) Chronic illness that, in the opinion of the Investigator, is at a stage where it 
might interfere with trial conduct or completion 
14) Identified as an Investigator or employee of the Investigator with direct 
involvement in the proposed study, or identified as an immediate family 
member (i.e., parent, spouse, natural or adopted child) of the Investigator or 
employee with direct involvement in the proposed study 
15) Self-reported Human Immunodeficiency Virus (HIV), Hepatitis B, or 
Hepatitis C infection 
16) Personal history of Guillain-Barré syndrome 
Temporary Exclusion Criteria 
A prospective subject should not be included in the study until the following 
condition and/or symptoms are resolved: 
1) 
Moderate or severe acute illness/infection (according to Investigator 
judgment) or febrile illness (tempeUDWXUH 38.0°C) on the day of first 
vaccination.  
2) 
Receipt of any vaccine in the 4 weeks preceding the trial inclusion 
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Statistical Methods: 
Non inferiority testing will only be carried out with seropositive subjects and 
providing that the number of evaluable subjects attains a global power of at 
least 80%.  This applies to the co-primary objectives, and the secondary 
objective. Otherwise, descriptive analyses will be performed. 
Primary Objectives: 
Tdap immunogenicity 
A non-inferiority testing approach will be used to compare geometric mean 
concentrations (GMCs) for PT, FHA, PRN, FIM2+3, 28 days after the booster 
dose of Tdap, for each antigen “i” based on the following individual hypotheses: 
 
with:  
i, antigen {PT, FHA, PRN, FIM 2+3}. 
įQRQ-inferiority limit is set at 1.5, i.e., 0.176 (=log10 [1.5]), for each antigen “i”. 
Non-inferiority for antigen “i” will be demonstrated if the lower bound of the 2-
sided 95% CI is greater than -į For each of the 4 antigens, the statistical 
methodology will be based on the use of the age-stratified two-sided 95% CI of the 
ratio of GMCs between groups. The age-stratified CI will be calculated using an 
ANOVA model (type II analysis) of log10-transformed titers. The age groups (9 to 
11 years, 12 to 17 years, 18 to 45 years and 46 to 60 years) will be used as the 
stratifying factor in the model. 
Additionally, a non-inferiority testing approach will be used to compare 
seroprotection rates of T and D, 28 days after the booster dose of Adacel®. 
Seroprotection is defined as anti-D and anti-T Ab concentration superior to 
0.1 IU/mL. 
The individual tested hypotheses for the antigen “i” will be as follows: 
 
Where the non-LQIHULRULW\OLPLWįLVVHWDWIRUERWK7DQG'FRQFHQWUDWLRQV
 0.1 IU/mL. 
Non-inferiority for antigen “i” will be demonstrated if the lower bound of the 2-
sided 95% CI is greater than -į 
The non-inferiority test will be performed using the 95% 2-sided CI of the 
difference between Group 1 and Group 2 for seroprotection rates and of the 
differences of the means of the log10 transformed post-vaccination 
concentrations/titers for GMCs Į RQH-sided). The 95% CI will be 
calculated based on the Wilson score method without continuity correction as 
quoted by Newcombe for seroprotection rates and using the normal approximation 
of the log10 transformed post-vaccination titers for GMCs. 
CYD dengue vaccine immunogenicity 
A non-inferiority testing approach will be used to compare geometric mean titers 
(GMTs), for dengue serotypes 1, 2, 3, and 4, 28 days after the first injection of 
CYD dengue vaccine between Group 1 and Group 2 for each serotype “i” based on 
the following individual hypotheses: 
 
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with:  
i, serotypes in {1, 2, 3, 4}. 
įQRQ-inferiority limit is set at 2, i.e., 0.301 (=log10 [2]), for each serotype “i”. 
Non-inferiority for serotype “i” will be demonstrated if the lower bound of the 2-
sided 95% CI is greater than -į 
The statistical methodology will be based on the use of the two-sided 95% CI of 
the differences of the means of the log10 transformed post-vaccination titers 
between Group 1 and Group 2. The CI for differences will be calculated using 
normal approximation of log-transformed titers. 
Overall, non-inferiority among the groups will be demonstrated if, for each antigen 
of Tdap and each serotype of CYD dengue vaccine, the two-sided 95% CI lies 
above - į 
Secondary Objectives 
CYD dengue vaccine immunogenicity (non-inferiority analysis) 
A non-inferiority testing approach will be used to compare GMTs (dengue 
serotypes 1, 2, 3, and 4) 28 days after 3 injections of CYD dengue vaccine between 
Group 1 and Group 2 for each serotype “i” based on the following individual 
hypotheses: 
 
 
with:  
i, serotypes in {1, 2, 3, 4}. 
įQRQ-inferiority limit is set at 2, i.e., 0.301 (=log10 [2]), for each serotype “i”. 
Non-inferiority for serotype “i” will be demonstrated if the lower bound of the 2-
sided 95% CI is greater than -į 
The statistical methodology will be based on the use of the two-sided 95% CI of 
the differences of the means of the log10 transformed post-vaccination titers 
between Group 1 and Group 2. The CI for differences will be calculated using 
normal approximation of log-transformed titers. 
Overall, non-inferiority among the groups will be demonstrated if, for each antigen 
of Tdap and each serotype of CYD dengue vaccine, the two-sided 95% CI lies 
above - į 
Descriptive analysis on CYD dengue vaccine and Tdap vaccine immunogenicity 
No hypotheses will be tested. Immunogenicity point estimates and their 95% CI 
will be presented for each and any group, before and after the first and third 
injections for CYD dengue vaccine and before and after the booster vaccination for 
Tdap. 
A complementary analysis on CYD dengue vaccine and Tdap vaccine 
immunogenicity after each dose will be conducted for each and any group 
according to the age groups (9 to 11 years, 12 to 17 years, 18 to 45 years and 46 to 
60 years). 
A complementary analysis on CYD dengue vaccine immunogenicity after each 
dose will be conducted for each and any group according to the dengue status at 
baseline. 
The 95% CIs will be calculated using: 
x 
The normal approximate method for GMCs/GMTs and geometric mean of 
concentration ratios [GMCRs]/geometric mean of the titer ratios [GMTRs]  
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Assuming that log10 transformation of the titers/concentrations follows a normal 
distribution, at first, the mean and the 95% CI will be calculated on log10 
(titers/concentrations) using the usual calculation for normal distribution (using 
Student’s t distribution with n-1 degree of freedom), then antilog transformations 
will be applied to the results of calculations, in order to provide geometric means 
and their 95% CI using: 
x 
The exact binomial distribution for percentages (Clopper-Pearson’s method, 
quoted by Newcombe) 
In addition, the booster response against pertussis components (PT, FHA, PRN, 
and FIM2+3) will be calculated based on Ab concentration rises between pre- and 
post-vaccination defined as: 
x 
A post-YDFFLQDWLRQ$EFRQFHQWUDWLRQ 4 x the lower limit of quantification 
(LLOQ) when pre-vaccination concentration is < LLOQ 
x 
A post-YDFFLQDWLRQ$EFRQFHQWUDWLRQ 4 x pre-vaccination Ab concentration 
when pre-YDFFLQDWLRQFRQFHQWUDWLRQLV//24EXW 4 x LLOQ 
x 
A post-YDFFLQDWLRQ$EFRQFHQWUDWLRQ 2 x pre-vaccination Ab concentration 
when pre-YDFFLQDWLRQFRQFHQWUDWLRQLV[//24 
Safety 
All analyses will be descriptive; no hypotheses will be tested. Safety will be 
assessed for all subjects after the booster dose of Tdap vaccine and after each and 
any dose of CYD dengue vaccine.  
A complementary analysis will be conducted for each group according to the age 
groups (9 to 11 years, 12 to 17 years, 18 to 45 years and 46 to 60 years). A 
complementary analysis after each and any dose of CYD dengue vaccine will be 
conducted for each and any group according to the dengue status at baseline. 
For the main parameters, 95% CIs of point estimates will be calculated using the 
normal approximation for quantitative data and the exact binomial distribution 
(Clopper-Pearson method) for proportions. 
Calculation of Sample Size: 
A total of 688 subjects will be enrolled: 344 subjects per treatment group 
(86 subjects per age group).  
Considering a potential attrition rate of 10%, it was initially planned that such 
sample size would provide 618 evaluable subjects in the Per-Pprotocol population 
of Tdap and CYD dengue vaccine.  
This sample size (based on SAS proc Power) targeted a global power over 90.0% 
for the non-inferiority testing corresponding to the co-primary objectives (i.e., after 
the booster dose of Tdap and after the first dose of CYD), and over 99.0% for the 
non-inferiority corresponding to the secondary objective (ie, testing after the third 
dose of CYD dengue vaccine)  
However, as per protocol amendment 1, the number of evaluable subjects will be 
reduced since only dengue seropositive subjects will be included in the Per-
Protocol populations. Thus, the non-inferiority testing will be carried out only if a 
global power of at least 80% for the co-primary objectives and secondary objective 
can be attained (i.e., if the number of evaluable subjects is at least 510 for the co-
primary objectives and 324 for the secondary objective). 
 The following assumptions were considered for the non-inferiority of Tdap: an 
alpha level of 2.5% (one-sided hypotheses), a maximum acceptable difference of 
0.176 for GMCs and of 10% for seroprotection rates,  and the following rates and 
standard deviations (SDs): 
 
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x 
7,8P/– 99% of subjects 
x 
',8P/– 99% of subjects 
x 
PT SD – 0.4 
x 
FHA SD– 0.4 
x 
PRN SD – 0.5 
x 
FIM2+3 SD – 0.6 
(Based on TD519, TD506 and TD526 studies and on Keith S. Reisinger). 
The following assumptions were considered for the non-inferiority after the first 
dose of CYD dengue vaccine: an alpha level of 2.5% (one-sided hypotheses), a 
maximum acceptable difference of 0.301 for GMTs, and a SD of 1.0 for serotype 
1, 0.8 for serotypes 2 and 3, 0.7 for serotype 4 (based on CYD22 and CYD47 
studies conducted in Asia Pacific). 
The following assumptions were considered for the non-inferiority after the third 
dose of CYD dengue vaccine: an alpha level of 2.5% (one-sided hypotheses), a 
maximum acceptable difference of 0.301 for GMTs, and a SD of 0.8 for serotypes 
1 and 2, 0.7 for serotypes 3 and 4 (based on studies conducted in Asia Pacific). 
This sample size will also provide a 95% probability of observing an AE that has a 
true incidence > 0.87% in each group (N=344per group). 
Interim analysis: 
Two or three planned statistical analyses will be performed: 
x 
A first interim statistical analysis will be performed on results obtained after a 
partial database lock of data collected up to the 28 days post first dose of CYD 
dengue vaccine (V03; M2). 
x 
A second interim analysis might be performed on results collected up to the 28 
days after the third dose of CYD dengue vaccine (V06; M13). 
x 
The final analysis will be performed on data collected at the end of the study. 
No statistical adjustment is necessary because there will be no repeated analyses of 
the primary objectives (as the primary tests will be performed at the time of the 
first statistical analysis). 
 
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Table of Study Procedures 
Initial design: Phase IIIb Trial, 4 Vaccinations, 7 Visits and 3 or 4 Blood Samples (depending on group allocation), 19 Months Duration Per Subject. 
One Safety Follow-up Phone Call (PC) will be given 6 months after the last injection and 3 Interim phone calls will be given during the 6-month period 
after each CYD dengue vaccine injection (approximately 3 months after vaccination). Modifications introduced as per this protocol amendment 1 are 
included in this table. 
Visit Number (V) 
V01†††† 
V02†††† 
V03†††† 
V04‡‡‡‡ 
V05‡‡‡‡ 
V06‡‡‡‡ 
V07‡‡‡‡ 
Phone call** 
Trial Timelines* (Days/Months) 
D0 
M1 
(V01+28D) 
M2 
(V02+28D) 
M7 
(V02 +6 
months) 
M8 
(V04+28D) 
M13 
(V02 +12 
months) 
M14 
(V06+28D) 
 
Time Windows (Days) 
 
+14 
+14 
±20 
+14 
±20 
+14 
+30 
Intervening study-hold & Protocol Amendment1 
preparation/implementation 
Unscheduled Visit/Phone call****  
 
study-hold  
 
X 
 
Assent or Informed Consent Addendum 1  
at next planned visit after study-hold§§§§ 
 
 
 
X (= V04, V05 or V06)  
 
 
Assent or Informed Consent Protocol version1.0 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X (Group 1) 
 
 
 
 
 
 
Contraindication  
Contraindication at next planned visit after study-hold§§§§ 
X (Group 2) 
X 
 
X 
 
X 
 
 
X (=V04, V05 or V06)  
Significant Medical History  
X 
 
 
 
 
 
 
 
History of Dengue Infection/Vaccination  
X 
 
 
 
 
 
 
 
Temperature  
X (Group 2) 
X 
 
X 
 
X 
 
 
Physical Examination† 
X 
X 
X 
X 
X 
X 
X 
 
Urine Pregnancy Test ‡ 
X (Group 2) 
X 
 
X 
 
X 
 
 
Demography/Body Stature 
X 
 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
Blood Sampling (BL) for Immunogenicity †† 
 
 
 
 
 
 
 
 
     T, D, PT, FHA, PRN, and FIM2+3 
BL (Group 2) 
BL 
BL (Group 1) 
 
 
 
 
 
      Dengue Serotypes 1, 2, 3, and 4 
 
BL 
BL 
 
 
 
BL 
 
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Visit Number (V) 
V01†††† 
V02†††† 
V03†††† 
V04‡‡‡‡ 
V05‡‡‡‡ 
V06‡‡‡‡ 
V07‡‡‡‡ 
Phone call** 
Tdap Vaccination § 
X (Group 2) 
X (Group 1) 
 
 
 
 
 
 
CYD dengue Vaccination § 
 
Dose 1 
 
Dose 2 
 
Dose 3 
 
 
Post-injection phone calls (PC)** 
Interim phone calls during the 6-month period after each CYD dengue vaccine injection; Last phone call 6 months after the last 
injection**  
30-Min. Observation Period 
X (Group 2) 
X 
 
X 
 
X 
 
 
Injection Site and Systemic Events Collected‡‡‡ 
 
X (Group 2) 
X 
X 
X 
X 
X 
 
Diary Card (DC)  
      DC Provided 
 
X (Group 1 
for SAE only, 
and Group 2) 
 
X 
 
 
X 
 
 
X 
 
 
      DC Collected 
 
X 
 
X 
 
X 
X 
 
Memory Aid (MA) 
      MA Provided 
      MA Provided at next planned visit after study-hold§§§§ 
 
 
 
 
 
 
 
 
 
X 
 
X (=V04, V05 or V06) 
      MA Checked 
 
 
 
 
 
 
 
X 
Concomitant Therapy‡‡ 
X 
X 
X 
X 
X 
X 
X 
 
Telephone Contact 
 
 
 
 
 
 
 
X 
Blood Sampling (BL) for virological confirmation of 
hospitalized suspected dengue case§§ 
All acute febrile illness with diagnosis of hospitalized suspected dengue case within the first 5 days after fever onset, anytime throughout 
the trial period 
SAEs and AESIs collected*** 
Throughout the trial period (for SAEs) or in defined time windows according to the type of AESIs 
Termination Record§§§ 
 
 
 
 
 
 
X 
 
AESI: AE of special interest; BL: blood sample; D: Day;; M: Month; MA: Memory Aid; SAE: Serious adverse event; V: Visit 
* 
Timelines must be calculated based on the date of vaccination, not the date of visit. Vaccinations and associated or subsequent procedures may be out of the defined time-windows in dengue-
immune subjects continuing the study due to the pause of vaccine injections (as per Protocol Amendment 1).  
** 
Interim phone calls during the 6-month period after each CYD dengue vaccine injection; 3 months after Visit 2 (PC1: M4 [M1 + 3 months]) already carried out at the time of protocol 
Amendment 1; 3 months after Visit 4 (PC2: M10 [M7 + 3 months], and 3 months after Visit 6 [PC3: M16 M13 + 3 months] will be made to subjects receiving, respectively, dose 2 and Dose 3 
of the CYD dengue vaccine. The last PC will be held 6 months after the last CYD dose the subject received (whether 1, 2 or 3), provided the subject consents to continue in the study.  
† 
Physical examination will be performed if necessary, based on the health status of the subject. 
‡ 
For female subjects of childbearing potential (e.g., a female subject who has reached menarche). 
§ 
CYD and Tdap will be administered in 2 different sites, with the CYD dengue vaccine administered in one deltoid and Tdap in the other deltoid 
‡‡ 
Concomitant therapy and ongoing medication will be collected for Days 0–28 after each injection only 
††  
Blood samples planned during vaccination visits will be taken before vaccination 
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‡‡‡  
Solicited injection site reactions will be collected for Days 0–7 after each injection. Solicited systemic reactions will be collected for Days 0–14 after each injection. Unsolicited events will be 
collected for Days 0-28 after each injection.  
§§ 
In such case, 1 unplanned acute blood sample (approximately 3 mL) will be collected for virological confirmation of hospitalized suspected dengue case 
*** 
SAEs will be reported throughout the study and AESIs will be collected in defined time windows according to the type of AESI (hypersensitivity/allergic reactions [serious or not] within 7 days 
after each CYD dengue vaccine injection, serious viscerotropic within 30 days after each CYD dengue vaccine injection, serious dengue cases requiring hospitalization (hospitalized VCD case) 
will be reported during the entire study). 
§§§ 
Termination form will be completed. 
**** 
All subjects will either attend an unscheduled visit or have an unscheduled phone call after the hold of activities and before their next scheduled visit.   
†††† 
All participants carried out V01-V03 before the start of the study-hold and implementation of Protocol Amendment 1 
‡‡‡‡  
V04 and/or V05 (if they were not carried out) and V06 and V07 will take place for those subjects dengue seropositive at baseline who consent continue participation in the study and consent 
administration of remaining CYD dengue doses. All other subjects who consent to continue in the study will only attend their next planned visit after study-hold (whether V04, V05 or V06).  
§§§§ 
ICF/AF Addendum 1 signature, contraindications check and MA delivery at next planned visit (whether V04, V05 or V06) applies to subjects seropositive who consent continue participation in 
the study and refuse administration of remaining CYD dengue doses, and seronegative subjects who consent continue in the study. 
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List of Abbreviations 
Ab 
antibody 
AE 
adverse event 
AESI 
adverse events of special interest 
AF 
assent form 
Ag 
antigen 
ALT 
alanine transaminase  
ap 
acellular pertussis 
AR 
adverse reactions 
AST 
aspartate aminotransferase 
BL 
blood sample 
CCID50 
cell-culture infectious dose 50% 
CDM 
clinical data management 
CI 
confidence interval 
C&MQO 
Clinical and Medical Quality Operations department 
CRA 
clinical research associate 
CTA 
clinical trial agreement 
CLT 
clinical teal leader 
d 
diphtheria  
D 
day 
DC 
diary card 
dil 
dilution 
DF 
dengue fever 
DHF 
dengue hemorrhagic fever 
DSS 
dengue shock syndrome 
eCRF 
electronic case report form 
EDC 
Electronic Data Capture 
ELISA 
enzyme-linked immunosorbent assay 
EU 
ELISA unit 
FAS 
full analysis set 
FHA 
filamentous hemagglutinin 
FIM 
fimbriae 
FV 
flavivirus 
FVFS 
first visit, first subject 
GCI 
Global Clinical Immunology 
GCP 
Good Clinical Practice 
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GM 
geometric mean 
GMC 
geometric mean of concentration 
GMCR 
Geometric mean of concentration ratio 
GMT 
geometric mean of titer 
GMTR 
Geometric mean of the titer ratio 
GPV 
Global PharmacoVigilance 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IgG 
immunoglobulin G 
IgM 
immunoglobulin M 
IM 
intramuscular 
IRB 
Institutional Review Board 
LLOQ 
lower limit of quantitation 
LLT 
lowest level term 
LVLS 
last visit of last subject 
M 
month 
MA 
memory aid 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIT-TNA 
Micrometabolic Inhibition Test - Toxin Neutralization assay 
mL 
milliliter 
NSAID 
non steroidal anti-inflammatory drug 
NS1 
non-structural protein 1 
PC 
Phone call 
PFU 
plaque-forming unit 
PPT 
per-protocol analysis set for Tdap 
PPC 
per-protocol analysis set for CYD dengue vaccine 
PPAS 
per-protocol analysis set 
PRN 
Pertactin 
PRNT50 
50% plaque reduction neutralization test 
PSO 
Product Safety Officer 
PT 
pertussis toxoid 
RCTM 
Regional Clinical Trial Manager 
RMO 
Responsible Medical Officer 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
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SafAS 
safety analysis set 
SC 
subcutaneous 
SET 
safety evaluation team  
SMT 
safety management team 
T 
tetanus 
TMF 
trial master file 
RT-PCR 
reverse transcriptase-polymerase chain reaction 
UAR 
unexpected adverse reaction 
V 
visit 
VCD 
virologically-confirmed dengue 
VE 
vaccine efficacy 
YF 
yellow fever 
WHO 
World Health Organization 
WT 
wild type 
 
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1 
Introduction 
1.1 
Background 
The study will assess the safety and immunogenicity of CYD dengue vaccine when administered 
concomitantly or sequentially with a single booster dose of the tetanus (T), reduced-dose 
diphtheria (D), and 5-component acellular pertussis vaccine (ap), consisting of pertussis toxoid 
(PT), filamentous hemagglutinin (FHA), pertactin (PRN), and fimbriae types 2 and 3 (FIM2+3); 
known by preferred product trade names ADACEL®/Adacel®/COVAXIS®/Triaxis®/TRIAXIS®, 
and further referred to as Tdap in this document. 
Dengue 
Dengue is the most common mosquito-borne viral disease in humans, found in tropical and sub-
tropical regions around the world. In recent years, transmission has increased predominantly in 
urban and semi urban areas and has become a major international public health concern. Dengue 
virus is essentially transmitted by mosquitoe bites primarily by the female Aedes aegypti, but the 
global spread of dengue due to A. albopictus is increasing. There are four closely related, but 
antigenically distinct, dengue virus serotypes (1, 2, 3, 4) of the genus Flavivirus (FV) that cause 
dengue. All four serotypes can cause the full spectrum of disease from subclinical infection to a 
mild self-limiting disease, dengue fever (DF) and severe disease that may be fatal, due to dengue 
hemorrhagic fever/dengue shock syndrome (DHF/DSS) (1).  
The clinical presentation of acute dengue is non-specific and is characterized by biphasic fever, 
headache, pain in various parts of the body, prostration, rash, and lymphadenopathy for which 
recovery is usually complete in 7 to 10 days. However, 5-10% of patients progress to DHF/DSS 
which is characterized by abnormalities of homeostasis and increased vascular permeability that 
can lead to hypovolemia and hypotension (DSS), often complicated by severe internal bleeding. 
The case fatality rate of DHF can be as high as 10% without therapy, but is below 1% in most 
centers with modern intensive supportive therapy. 
Routine laboratory diagnosis of dengue infections is based on the detection of dengue virus-
specific antibodies (Abs) (immunoglobulin M [IgM]) and/or isolation of the virus or detection of 
viral ribonucleic acid (RNA) by reverse transcription-polymerase chain reaction (RT-PCR) or 
viral non-structural protein 1 (NS1) antigen (Ag) by enzyme-linked immunosorbent assay 
(ELISA) (2) (3) (4). The diagnosis of dengue falls into 2 stages: Stage I, the acute fever period 
lasting a few days when viremia and NS1 Ag may be detected; and Stage II, the early post-febrile 
period lasting a few weeks when IgM and immunoglobulin G (IgG) are increased. 
According to the World Health Organization (WHO), an estimated 3.9 billion people are at risk 
living in dengue endemic countries in Africa, the Americas, the Eastern Mediterranean, South 
East Asia, and the Western Pacific. The American, South East Asian and the Western Pacific 
regions are the most seriously affected. The WHO currently estimates there may be 390 million 
dengue virus infections worldwide every year, of which 96 million are associated with clinical 
manifestations of dengue. An estimated 500,000 people with severe dengue require 
hospitalization each year of which 2.5% of those die (1). The populations most affected by dengue 
are pre-adolescents, adolescents and adults living in dengue endemic areas. All 4 dengue virus 
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serotypes vary unpredictably over time, causing a continuous risk of infection in populations 
living in dengue-endemic regions. No currently available preventative measures have significantly 
impacted dengue disease, thus as recognized by the WHO, the need for a safe and effective 
vaccine against all 4 serotypes of dengue virus to protect people in endemic countries. 
Tetanus 
Tetanus is an acute and often fatal infection caused by an extremely potent neurotoxin produced 
by a bacterium, Clostridium tetani, which is most commonly found in the soil. The disease is not 
communicable but is acquired through environmental contamination of flesh wounds by the 
bacteria which can lead to disease characterized by severe, painful muscle contractions 
accompanied by hypersensitivity, hyperreflexia, and increased autonomic stimulation of the 
affected body part(s). Complications associated with tetanus include laryngospasms, spinal and 
long bone fractures, and hypertension. 
Diphtheria 
Diphtheria is an acute infection caused by toxin-producing strains of the bacterium 
Corynebacterium diphtheriae, which can be transmitted from person to person via respiratory 
droplets. The main site of infection is the upper respiratory tract presenting as a sore throat often 
with a mild fever. Complications associated with severe diphtheria include airway obstruction, 
myocardidits, and aparalysis. The case fatality rate is as high as 30-95%, despite modern medical 
care.  
Pertussis 
Pertussis (whooping cough) is a highly contagious disease of the respiratory tract caused by the 
bacterium Bordetella pertussis, which is transmitted by the respiratory route. The illness is 
characterized by several coughing spasms, which may or may not be associated with classic 
inspiratory ‘whooping’. In severe disease, the coughing spasms can vary in length and severity but 
may become so severe, that respiration is compromised leading to hypoxia and even subsequent 
neurological damage. Pneumonia may also occur in severe cases. Although pertussis is most 
severe and complications most frequent in children < 1 year of age, pertussis can affect persons of 
any age. Antimicrobial therapy is effective in treating disease but does not alter progression of 
disease unless administered early when pertussis is rarely suspected, thus disease control is based 
on vaccine prophylaxis.  
1.2 
Background of the Investigational Product 
Sanofi Pasteur’s tetravalent CYD dengue vaccine, using recombinant technology to obtain a live-
attenuated vaccine, is currently indicated for the prevention of dengue disease caused by all 
4 serotypes (1, 2, 3, 4) in individuals 9-60 years of age living in endemic regions. Immunization 
against dengue is based on a 3-dose immunization schedule, 6 months apart (0, 6, and 12 months) 
administered subcutaneously with CYD dengue vaccine. The indicated population has been 
defined based on a Benefit/Risk evaluation of the overall population included in the clinical 
development plan. 
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In support of this product profile, an extensive clinical development program, compliant with 
WHO and EMA guidelines has been conducted (5), for which the CYD dengue vaccine efficacy, 
immunogenicity and safety has been assessed in various formulations, schedules and populations.  
x In Phase I trials, a total of 396 subjects aged 2-49 years of age were evaluated for safety. 
Subjects were evaluated in both non-endemic and endemic areas and were received at least 
one dose of Phase I lots of CYD dengue vaccine containing either 4 log10 or 5 ± 1 log10 cell-
culture infectious dose 50% (CCID50) per serotype. 
x In Phase II trials, a total of 4903 subjects aged 12 months-45 years were enrolled to evaluate 
safety and immunogenicity in non-endemic and endemic areas including Asia Pacific and 
Latin America which supported the selection of the final formulation of 3 doses of CYD 
dengue vaccine of 5 log10 CCID50 per serotype as 3 injections administered 6 months apart. A 
proof of concept efficacy study (CYD23) in Thailand in 4-11 year olds has been completed in 
2012. Subjects from CYD23 were followed for safety in a long-term follow-up study 
(CYD57) for a total of 5 years post-dose 3. 
x In Phase III trials, a total of 23,140 subjects aged 9 months to 60 years have received at least 
1 dose of Phase III lots of CYD dengue vaccine (4.5 – 6.0 log10 CCID50 per serotype). Two 
pivotal large scale efficacy studies (CYD14 (6) and CYD15 (7) conducted in Asia Pacific 
(10,275 subjects aged 2 to 14 years) and Latin America (20,869 subjects aged 9 to 16 years) 
respectively, have completed the 25-month active phase and the 1st year of the Hospital Phase 
of the long-term follow-up. These efficacy studies were powered to independently 
demonstrate significant vaccine efficacy (VE) of the CYD dengue vaccine and they met their 
primary endpoints (8). To include the totality of efficacy studies (CYD14, CYD15) analyzed 
over the 25 month Active Phase, and the availability of further safety data for an additional 
one year of long term follow-up in the Hospital Phase, post-hoc meta-analyses was performed 
with improved point estimate precision for descriptive outcomes (6). Consistent VE was 
demonstrated during the 25-month active phase for virologically confirmed dengue (VCD) 
65% (95% CI: 60.7-69.9) for any severity of dengue disease, caused by any and each of the 4 
dengue serotypes, severe dengue 93.2 % (95% CI: 77.3-96) and dengue leading to 
hospitalization 80.8% (95% CI: 70.1-87.7). VE was also demonstrated for dengue-seropositive 
81.9% (95% CI: 67.2-90) and dengue-seronegative 52.5% (95% CI: 5.9-76.1) vaccinees (6). 
No safety issues have been identified in subjects 9-16 years of age during the 25 month active 
period or during the first year of long term follow-up in the Hospital Phase (6) (7) (9). This 
included no observed increase in dengue disease severity compared to the placebo group (6). 
 
In interim results of the long term follow-up, for the first year (year 3) of the Hospital 
Phasepooled efficacy results demonstrated a continued benefit in subjects who were 9 years and 
above with lower risk of hospitalized VCD, RR 0.50 in the vaccine compared to the placebo 
group. All subjects who were hospitalized due to dengue fully recovered after receiving 
appropriate supportive treatment. However, in CYD14, in the first year of the Hospital Phase 
(year 3), the relative risk suggests an overall trend to increased risk of hospitalized VCD in the 
vaccine compared to the placebo group among subjects < 9 years of age, RR 1.58; in particular in 
the 2 to 5 years old age group.  
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Up to November 2016, a total of 28 completed or ongoing clinical studies in 15 endemic and non-
endemic countries including Latin America and Asia pacific have been conducted, comprising 
more than 41,500 subjects from 9 months through to 60 years of age. Of these subjects, 21,215 
were aged 9 through to 60 years and received at least 1 dose of CYD dengue vaccine formulation. 
Furthermore, the CYD dengue vaccine has demonstrated a consistent and acceptable safety 
profile, comparable with placebo during its clinical development across many populations (age 
groups, gender, region, and dengue immune status) in subjects 9 to 60 years of age. The high post-
injection neutralizing antibody titers observed in adults living in endemic areas, allows the 
extrapolation of vaccine efficacy through immunological bridging to adult populations living in 
endemic areas.   
Considering the totality of the efficacy and safety of CYD dengue vaccine studies, a favorable 
benefit-risk ratio supports the claimed indication for the prevention of dengue disease caused by 
all 4 serotypes in individuals 9 to 60 years of age living in endemic regions. 
As of October 2017, the CYD dengue vaccine (commercial name Dengvaxia®) has been licensed 
in 19 countries (in alphabetical order): Argentina, Australia, Bangladesh, Bolivia, Brazil, 
Cambodia, Costa Rica, El Salvador, Guatemala, Honduras, Indonesia, Malaysia, Mexico, 
Paraguay, Peru, the Philippines, Singapore, Thailand, and Venezuela for the prevention of dengue 
disease caused by all 4 virus serotypes (1, 2, 3, 4) in individuals 9/12  to 16/45/60 years living in 
endemic areas. 
As of December 2017, the Sanofi label proposal is being reviewed by national regulatory agencies 
in each country where the vaccine is registered or under registration.  
1.3 
Potential Benefits and Risks 
Detailed risk/benefit analysis is presented in the Investigator’s Brochure version 19.0 dated 9 
February 2017, and recent Investigator’s Brochure Amendment version 1.0 dated 21 December 
2017.  
1.3.1 
Potential Benefits to Subjects 
In terms of benefit, the subjects participating in the present clinical trial may develop immunity 
and protection against dengue disease after vaccination with CYD dengue vaccine. 
Results from the two large-scale Phase III efficacy trials showed the potential for CYD dengue 
vaccine to reduce the probability of a subject's having symptomatic VCD, hospitalized VCD due 
to any of the 4 serotypes (vaccine efficacy [VE] estimates against symptomatic VCD during the 
whole Active Phase due to any of the 4 serotypes were 56.5% [95%CI: 43.8; 66.4] for CYD14 
and 60.8% [95%CI: 52.0; 68.0] for CYD15). In addition, efficacy was observed against each of 
the 4 serotypes with high efficacy seen against severe VCD cases and hospitalized VCD cases 
during the Active Phase. 
A number of supplemental exploratory analyses (see section 1.4) have provided strong evidences 
that, for subjects that were dengue seropositive prior to CYD dengue vaccination, the vaccine 
protects against symptomatic dengue, hospitalized dengue, and severe dengue disease. 
The subjects receiving Adacel® may increase their current immunity and protection against 
diphtheria, tetanus and pertussis disease. 
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As with any vaccine, immunological protection may not be elicited in all individuals against the 
disease they are designed to prevent. 
1.3.2 
Potential Risks to Subjects 
CYD Dengue Vaccine 
During the clinical development of dengue vaccine as well as during the Active Phase of the 
Phase III efficacy studies, no safety concerns after administration of the CYD dengue vaccine 
emerged from the pooled safety analysis, providing sufficient evidence that the safety profile of 
the CYD dengue vaccine is acceptable and similar to the safety profile of licensed vaccines in 
similar population. 
Potential unwanted effects also include injection site reactions such as erythema, swelling, 
induration, and pain. General disorders may also be observed such as fever, malaise, asthenia, 
myalgia and headache. As for any drugs, a risk of allergic reaction cannot be excluded. Vasovagal 
malaise linked to the injection procedure may be observed in susceptible individuals. Full list of 
expected adverse events (AEs) can be found in the Investigator’s Brochure. 
As CYD dengue vaccine has a yellow fever (YF) vaccine backbone, and YF vaccination has been 
rarely associated with viscerotropic and neurotropic AEs, this risk has to be considered. This 
theoretical risk linked to viscerotropism and neurotropism is further addressed in the “Guidelines 
for assessing viscerotropic and neurotropic AE” document. In the previous studies conducted with 
the CYD dengue vaccine, no confirmed viscerotropic or neurotropic AEs have been observed.  
Although an unexplained higher incidence of hospitalization for dengue in year 3 of follow-up 
among children younger than 9 years was observed in CYD14 efficacy trial, in particular in 
children from 2 to 5 years old, the combined analysis of the efficacy trials during year 3 showed a 
lower risk of hospitalization for dengue among participants who were 9 years of age or older in 
the vaccine group than among those in the control group. All subjects who were hospitalized due 
to dengue fully recovered after receiving appropriate supportive treatment (6). 
Considering the totality of long-term follow-up data during the Hospital Phase across the 
3 efficacy studies, no evidence of increased severity of dengue disease or increase in frequency of 
hospitalized dengue cases has been observed in subject from 9 to 16 years old vaccinated with the 
dengue vaccine. 
Following a number of supplemental exploratory analyses (see Section 1.4), it was shown that 
subjects that were dengue seronegative prior to CYD dengue vaccination have an increased risk of 
hospitalized or severe disease, as compared to subjects who received the placebo, with an onset 
from the third year after the first injection. 
Tdap vaccine (Adacel®) 
Tdap vaccine (Adacel®) may not protect 100% of vaccinated individuals. Following vaccination 
with Adacel®, the most common local adverse reactions include injection site pain, erythema, and 
swelling; the most common systemic adverse events include headache, body ache, tiredness, and 
fever. Adacel® is contraindicated in persons with known systemic hypersensitivity to any of their 
components or a life-threatening reaction after previous administration of either vaccine or a 
vaccine containing the same substances. Because of uncertainty as to which vaccine component 
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may be responsible, no further vaccination with the diphtheria, tetanus, or pertussis components 
found in Adacel® should be carried out. 
All subjects 
The potential risks associated with blood drawing include local injection site reactions such as 
erythema, swelling, induration, and pain, bruising and, rarely infection. 
General disorders may also be observed such as fever, malaise, asthenia, myalgia and headache.  
The potential risk for vasovagal syncope (fainting) can occur following, or even before, any 
vaccination in this age group (CYD dengue vaccine or Adacel®), as a psychogenic response to the 
needle injection. This is sometimes associated by other neurological signs such as transient visual 
disturbance, paraesthesia and tonic-clonic movements on resolution of syncope.  
The potential risks listed here are not exhaustive; refer to the package inserts of Adacel® for 
additional information regarding potential risks. Full list of expected adverse events (AEs) for the 
CYD dengue vaccine can be found in the Investigator’s Brochure. 
1.4 
Rational for the Trial 
Preventive measures presently rely on mosquito control and personal protection. These measures 
are limited in efficacy, difficult to enforce, and expensive. The best method of prevention lies with 
the development of a safe and effective vaccine directed at the 4 serotypes of dengue virus 
responsible for the disease. 
It is preferable that CYD dengue vaccine is administered at an existing scheduled visit as part of 
the routine immunization schedule. There is currently no data on concomitant administration of 
CYD dengue vaccine with other vaccines in the indicated population aged 9-60 years of age. Co-
administration of CYD dengue vaccine with other vaccines has been assessed in clinical studies 
outside the age indication, in infants and toddlers 9 to 15 months of age at inclusion in dengue 
endemic countries. A Phase II study was conducted to evaluate the co-administration of CYD 
dengue vaccine together with Measles, Mumps and Rubella (MMR, Trimovax®, Live attenuated 
virus vaccine against Measles [Schwartz strain], Mumps [Urabe AM-9 strain] and Rubella [Wistar 
RA 27/3M strain; Sanofi Pasteur) (CYD08) (10), and 2 Phase III studies (CYD29 and CYD33) 
were conducted to evaluate the co-administration of CYD dengue vaccine together with the YF 
vaccine (Stamaril®, Yellow fever vaccine [live]; Sanofi Pasteur) and the DTaP-IPV-PRP-T (Hib) 
(Pentaxim®, Diphtheria, Tetanus, Pertussis [acellular, component], Poliomyelitis [inactivated] 
vaccine [adsorbed] and Haemophilus Influenza Type b Conjugate Vaccine; Sanofi Pasteur). These 
trials demonstrated that the CYD dengue vaccine could be administered concomitantly with these 
pediatric vaccines and no safety concerns or impact on the immune response was observed. 
The present post-licensure Phase IIIb study CYD66 will investigate the immunogenicity and 
safety of CYD dengue vaccine and Tdap vaccine when both vaccines are administered 
concomitantly or sequentially to subjects aged 9 to 60 years living in the Philippines. CYD 
dengue vaccine may be given concomitantly with Tdap. Tdap vaccine is indicated for the 
prophylaxis of diphtheria caused by Corynebacterium diphtheriae, tetanus caused by Clostridium 
tetani, and pertussis (whooping cough) caused by Bordetella pertussis in individuals 4 through 64 
years of age as a booster according to the national vaccination policies. Tdap vaccine is a sterile 
liquid suspension of adsorbed tetanus, low-dose diphtheria toxoids, and acellular pertussis 
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components, intended for intramuscular administration. Tdap vaccine is licensed in a total of 
67 countries, and is administered as a single booster dose in adolescent and adult public and 
private vaccination schedules in the Philippines. Dengvaxia® is currently indicated in subjects 9 to 
45 years of age. In order to generate further data in older subjects, it was decided to also 
administer the Dengvaxia® to 46-60 year-old subjects in the present study. 
As multiple Ags are administered concurrently, it is necessary to demonstrate that there is no 
impact on either the immunogenicity or safety profile of CYD vaccination on Tdap or the inverse. 
Furthermore, the administration of CYD dengue vaccine at the same time as a booster dose of 
Tdap vaccine might reduce the number of vaccination visits, and thereby increase vaccine 
compliance and coverage of co-administered vaccines, and facilitate dengue program. 
implementation. 
Protocol Amendment 1 
This amended protocol introduces important changes to the original protocol of the ongoing 
CYD66 clinical study.  
In July 2016, the WHO issued a position paper on Sanofi Pasteur’s CYD dengue vaccine based on 
the Strategic Advisory Group of Experts’ (SAGE) assessment that recognized its potential public 
health value when introduced in highly endemic countries. In addition, the SAGE also underlined 
the importance of addressing the question of the potential risk, over time, of hospitalized/severe 
dengue in individuals with no prior exposure to dengue before vaccination (11)  (12). Other 
scientific, public health, and regulatory leaders have expressed similar interest in obtaining more 
information on the long-term safety and efficacy of the CYD vaccine in seronegative individuals.  
Sanofi Pasteur recognized this knowledge gap and remained committed to further evaluate the 
performance of the CYD vaccine. 
Analyzing long-term safety according to dengue serostatus at baseline presented an important 
challenge as serostatus had only been assessed in a subset of subjects (the so-called 
immunogenicity subset) in each of the 3 efficacy studies (CYD14, CYD15 and CYD23/57). As a 
consequence of this, and in order to address the question of vaccine performance in seronegative 
individuals, Sanofi Pasteur decided to conduct an Exploratory Case-Cohort study using a time 
point for which a blood sample was collected in all study participants: approximately 1 month 
after the third injection of CYD dengue vaccine or placebo (month [M] 13). The rationale behind 
this approach was that the classification of study participants according to dengue serostatus at 
this time point (as a surrogate of prior natural dengue exposure) could be used as a baseline for the 
evaluation of outcomes that occur later. However, the PRNT assay routinely used to quantify 
neutralizing Ab titers cannot discriminate between neutralizing Abs against wild-type dengue 
virus and chimeric dengue virus. Said otherwise, a positive PRNT assay at M13 can be the result 
of either prior dengue exposure or CYD dengue vaccination. 
To overcome this challenge, Sanofi Pasteur leveraged an assay originally developed at University 
of Pittsburg (Pittsburg, PA, USA) and optimized by Sanofi Pasteur’s Global Clinical Immunology 
(GCI) Department. This assay measures total immunoglobulin G (IgG) antibodies against the non-
structural protein 1 (NS1) of the dengue virus by Enzyme-Linked Immunosorbent Assay 
(ELISA). Because the NS1 protein is not conserved between the dengue virus and the yellow-
fever virus, previous exposure to CYD dengue vaccine is not expected to induce meaningful 
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levels of antibody against the dengue NS1 protein. The application of the Dengue anti-NS1 IgG 
ELISA assay to M13 samples was therefore considered useful for expanding the existing data on 
both VE and potential risk of dengue hospitalization and/or severe dengue according to baseline 
serostatus in the CYD dengue vaccine efficacy trials. Thus, dengue serostatus was used in a 
supplemental case-cohort study as a covariate to assess the effects of CYD dengue vaccine for 
outcomes that occur after M13. In addition, the Dengue anti-NS1 IgG ELISA values were used in 
conjunction with multiple additional variables in imputation models to predict the D0 PRNT50 
serostatus, to evaluate outcomes occurring after M0 and M13 by measured (when available), or 
imputed PRNT50 serostatus. 
Sanofi Pasteur presented the full data of this supplemental analysis to the IDMC in an ad hoc 
meeting held on 3-4 November 2017. During this meeting, the IDMC reviewed the data from 
these extended safety and efficacy analyses. It concluded that, in the case of subjects exposed to 
dengue prior to vaccination (henceforth, ‘exposed subjects’ or seropositive subjects), there is 
strong evidence that the vaccine protects them from symptomatic dengue, hospitalized dengue and 
severe dengue. In the case of subjects not exposed to dengue before vaccination (henceforth, 
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confer limited short-term benefit against symptomatic dengue, it also induces an increased risk of 
severe disease in the longer term. The IDMC stated that these findings are based on follow-up of 
dengue unexposed subjects having received 3 CYD dengue vaccine doses and no data exist to 
conclude if the risk in partially vaccinated dengue unexposed subjects is different from that in 
fully vaccinated dengue unexposed subjects. 
Given these conclusions, the IDMC recommended that no further vaccination occur in unexposed 
subjects in ongoing or future trials, and on precautionary basis, including partially vaccinated 
subjects in ongoing trials. In addition, they recommended making available information on 
baseline serostatus for all vaccinated subjects whenever possible. Finally, for unexposed subjects 
that were vaccinated during a study, the IDMC recommended instituting mechanisms to provide 
timely access to appropriate care in the event of suspected dengue, for 10 years from the date of 
last vaccination. 
Given the IDMC recommendations, Sanofi Pasteur is amending this study protocol.  As a general 
rule, only subjects assessed as dengue exposed at baseline (ie, before receiving the first injection) 
will be eligible to receive any further dose of CYD dengue vaccine in an ongoing study. In this 
study (CYD66), all subjects will be informed about these latest results and their serostatus at 
baseline and what it means. Moreover, all subjects will be asked about their willingness to 
continue participating in this study by signing an updated ICF and/or AF, as applicable. Subjects 
assessed as dengue exposed will confirm their participation in the study and will continue to be 
eligible to receive remaining CYD dengue doses planned. Subjects classified as unexposed at 
baseline, will only be able to continue in the study for a 6-month safety follow-up. Their consent 
will also be asked for. 
To determine the basal serostatus of the subjects already included in the study, the Dengue PNRT 
will be used. 
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2 
Trial Objectives 
2.1 
Primary Objectives 
Tdap immunogenicity 
x 
To demonstrate the non-inferiority of the humoral immune response to the Tdap booster dose 
concomitantly administered with the first dose of CYD dengue vaccine as compared to 
sequential administration, measured 28 days after Tdap booster dose 
CYD dengue vaccine immunogenicity 
x 
To demonstrate the non-inferiority of the humoral immune response to the first dose of CYD 
dengue vaccine concomitantly administered with Tdap as compared to sequential 
administration, measured 28 days after the first dose of CYD dengue vaccine 
The endpoints for the primary objective(s) are presented in Section 9.1. 
2.2 
Secondary Objectives 
CYD dengue vaccine Immunogenicity: 
x 
To demonstrate the non-inferiority of the humoral immune response of 3 doses of CYD 
dengue vaccine with the first dose concomitantly administered with Tdap as compared to 
sequential administration, measured 28 days after the third dose of CYD dengue vaccine 
x 
To describe the humoral immune response at baseline and 28 days after the first and third 
doses of CYD dengue vaccine, in each and any group 
Tdap Immunogenicity: 
x 
To describe the humoral immune response of Tdap vaccine at baseline and 28 days after 
concomitant administration with the first dose of CYD dengue vaccine as compared to the 
sequential administration, in each and any group 
Safety 
x To describe the safety of the CYD dengue vaccine and of the Tdap booster dose after each and 
any injection in each group 
The endpoints for the secondary objective(s) are presented in Section 9.2. 
3 
Investigators and Trial Organization 
This trial will be conducted in approximately 4 centers in the Philippines. The Principal 
Investigators and any sub-Investigators at the individual sites will be coordinated by one 
Coordinating Investigator. Details of the trial centers, the Investigators at each center, and the 
Coordinating Investigator(s) are provided in the “List of Investigators and Centers Involved in the 
Trial” document. 
Independent Data Monitoring Committee 
An Independent Data Monitoring Committee (IDMC) will be involved in the regular review of 
hospitalized VCD cases, including assessment of severity. Additionally, any related serious 
adverse event (SAE) or death will be promptly reviewed by the IDMC. 
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Subjects were randomized according to a 1:1 ratio into one of the 2 following groups with 
stratification on age (9 to 11 years, 12 to 17 years, 18 to 45 years and 46 to 60 years): 
x Group 1: subjects were administered the first dose of CYD dengue vaccine concomitantly 
with the booster dose of Tdap vaccine at the second visit (V02; M1) 
x Group 2: subjects were administered Tdap vaccine at the first visit (V01; D0), and then CYD 
dengue vaccine 28 days later at the second visit (V02; M1) 
The stratification will be considered in order to balance the potential difference in terms of booster 
response by age group for the pertussis antigens (PT, FHA, PRN and FIM2+3).  
Since the CYD dengue is administered according to a 3-dose schedule, given 6 months apart, 
initial trial design included administration of the second and third doses of CYD dengue vaccine 
at V04 (Month 7 [M7] and at V06 (M13) in all subjects.  
All but 19 subjects (from both, Group1 and Group 2) did receive dose 2 of the CYD dengue 
vaccine as planned. However, as per changes in the conduct of the study reflected in this Protocol 
Amendment 1 (see also Section 1.4), the following will be applied: 
x All vaccinated subjects will be informed about their baseline dengue serostatus and what it 
means as soon as possible  
x All subjects will be asked about their willingness to continue participating in this study, and 
consent will be formalized by signing an ICF and/or AF addendum, as applicable.  
x Subjects seropositive at baseline will additionally be asked for consent to receive remaining 
CYD dengue doses.  
x Subjects seronegative at baseline will be able to continue in the study for safety follow-up if 
they consent to, but will not receive further injections of CYD dengue vaccine.  
x Subjects seronegative at baseline who were vaccinated during this study will have timely 
access to appropriate care in the event of suspected dengue, for 10 years from the date of last 
dengue vaccination. 
Time between communication of the results from the exploratory analyses and approval of 
Protocol Amendment 1 by the competent authorities and for the associated logistic tasks will 
result into a hold of study activities of several months (approximately 4-6 months). Study-hold 
intervenes after V03, V04 or V05, depending on each subject’s visit-calendar at the time of study-
hold.  
Blood samples collected before dose 1 of the vaccine (at V01 for Group 2 and at V02 for Group 
1) will be used to determine dengue serostatus at baseline. Dengue serostatus will be determined 
XVLQJWKH'HQJXH3517$³VHURSRVLWLYH´VXEMHFWKDVEHHQJHQHUDOO\GHILQHGE\D3517WLWHU
1:10 to any dengue serotype at baseline, and a “seronegative” subject has been defined by a PRNT 
titer <10 for all four dengue serotypes. Only subjects identified as dengue seropositive will be 
eligible to receive further vaccine injections.  
In order to communicate to each subject his/her dengue serostatus at baseline, there will be either 
1 unscheduled visit and /or phone call during the study-hold, before the next visit initially planned 
(at V06 at the latest): 
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The subject will consent to continue participation in the study by signing an ICF/AF addendum 1 
at subject’s next planned visit (either V04, V05 or V06). 
Thus, dose 2 and 3, or dose 3 only (provided that dose 2 was received, as planned) will be 
administered only to those subjects dengue seropositive at baseline who consent continue 
participation in the study and consent receiving the remaining CYD dengue doses planned.    
A 6 months safety follow up is planned for all subjects who received at least 1 dose and who 
consent to continue participation in the study. This period will start after the last CYD dose the 
subject received (whether 1, 2 or 3 doses).  
At the time vaccinations were paused, subjects had already provided 2 to 3 blood samples (BL), 
depending on the allocation group. Only dengue-exposed subjects who will continue in the study 
and choose to receive remaining CYD dengue doses will provide 1 subsequent BL, as initially 
planned in Protocol Version 1.0.  
Additional blood samples might be collected in case of SAEs (including AEs of special interest 
[AESIs]) and to assess AEs that may be indicative of viscerotropic or neurotropic disease (see 
Guidelines for Assessing Viscerotropic and Neurotropic AE).  
In case of hospitalized suspected dengue case, one unplanned BL (= acute BL) will have to be 
collected within the first 5 days after fever onset for virological confirmation of dengue disease. 
(If this cannot be accomplished, this sample should still be obtained as soon as possible thereafter, 
for IDMC severity assessment).  
All female subjects of childbearing potential will provide urine samples for urine pregnancy test 
before each injection. 
Immunogenicity of the Tdap booster dose will be evaluated before and 28 days after injection in 
both groups. Immunogenicity of the CYD dengue vaccine will be evaluated before the first 
injection and 28 days after the first and the third injections in both groups. The safety of the two 
vaccines will be assessed after each injection in both groups.  
For seropositive subjects who consent continue participation in the study and administration of 
remaining CYD dengue doses, due to period of study-hold, the duration of each subject’s 
participation in the trial will be approximately 23-25 months, since it will be extended by 4-6 
months with respect to the initial plan (ie, as per protocol version1.0: approximately 19 months, 
including a vaccination phase of 12 months for subjects in Group 1 and 13 months for subjects in 
Group 2, followed by a safety follow-up period of 6 months after the third injection of CYD 
dengue vaccine).  
For seropositive subjects who consent continue participation in the study but refuse to receive 
remaining CYD dengue doses and seronegative subjects who provide their consent to continue 
participation in the study, their participation in the trial will be less than 19 months as initially 
planned. (i. e., taking into account the study-hold and the 6 months safety follow up  
Subjects declining continue participation in the study will end the study on the date this decision 
is communicated to the Sponsor. 
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5.1.2 
Justification of the Trial Design 
There is currently no data on concomitant administration of CYD dengue vaccine with other 
vaccines in the indicated population aged 9-60 years of age. Based on the current age indication of 
the dengue vaccine, co-administration with Adacel®, currently used in public sector school-based 
vaccination programs in subjects aged 9 years and above, is needed and will be incorporated into 
the post-licensure plan. Therefore, the present CYD66 study will investigate the immunogenicity 
and safety of the CYD dengue vaccine when it is administered concomitantly or sequentially (at 
least 28 days apart) with Adacel®. In the Philippines, the CYD dengue vaccine received an 
indication for use in the 9-45 year-old subjects. In order to generate further data in older subjects, 
it was decided to also administer the CYD dengue vaccine to 46-60 year-old subjects in the 
present study. 
5.1.3 
Trial Plan 
A schedule of assessments and study vaccinations is provided in the table of study procedures. 
All information collected during the study visits must be reported into the source documents. 
Some of the following information will also be recorded in the electronic case report form 
(eCRF).  
5.1.4 
Visit Procedures 
Visit 1 (Day 0): Inclusion, Randomization, and Vaccination 
The Investigator or designated study personnel will: 
1) Give the subject’s parent/legally acceptable representative information about the trial, obtain 
written informed consent (ICF and AF when applicable), and give him/her a signed copy. 
2) Obtain significant medical history about the subject and history of dengue 
infection/vaccination. 
3) Collect demographic data. 
4) Check concomitant medications and record every reportable medication ongoing at the time 
of vaccination. 
5) Check inclusion and exclusion criteria for eligibility. 
6) Allocate a subject number to the subject.  
7) Scratch-off the randomization list to obtain the group allocation, and sign it. 
8) Perform a physical examination  
9) Record the subject’s axillary temperature (Group 2). 
10) For female subjects of childbearing potentiala, perform a urine pregnancy test (Group 2). 
                                                 
a  To be considered of non-childbearing potential, a female must be pre-menarche or post-menopausal for at least 
1 year, surgically sterile, or using an effective method of contraception or abstinence from at least 4 weeks prior to 
vaccination and until at least 4 weeks after vaccination. 
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11) Obtain blood samplea from subjects in Group 2 (see Section 7.1 for detailed instructions 
regarding the handling of blood samples). Blood is to be taken from the limb opposite to the 
one that will be used for vaccination.  
12) Review temporary and definitive contraindications to vaccination. 
13) Inject Tdap vaccine to subjects from Group 2. 
14) Keep the subject from Group 2 under observation for 30 minutes, and record any immediate 
AE in the source document (Group 2). 
15) Record the date of injection, the site and side of injection and the route of administration, as 
well as the dose number of the vaccine (Group 2). 
16) Give the subject or parent/legally acceptable representative of subjects in Group 2 a diary 
card (DC), a thermometer, and a ruler, and go over the instructions for their use. Subjects 
from Group 1, who will not be vaccinated at V01, will receive a DC for the collection of SAE 
only. 
17) Remind the subject or parent/legally acceptable representative to bring back the DC when 
they return for Visit 2 at a specified date and time. 
18) Remind the subject or parent/legally acceptable representative to notify the site in case of an 
SAE. 
19) Complete the relevant electronic case report form (eCRF) pages for this visit. 
Visit 2 (Month 1; 28 [+14] days after Visit 1) 
The Investigator or designated study personnel will: 
1) Check the information entered into the DC by interviewing the subject/subject’s parent 
(s)/legally acceptable representative(s) and request information concerning any medical 
event, serious or not, that may have occurred since Visit 1. 
2) Review the DC pages. 
3) Recheck inclusion and exclusion criteria for Group 1. 
4) Perform a physical examination  
5) Record the subject’s axillary temperature. 
6) Collect information regarding the subject’s medication status since the previous visit. 
7) For female subjects of childbearing potential, perform a urine pregnancy test. 
8) Obtain blood sample (see Section 7.1 for detailed instructions regarding the handling of blood 
samples). Blood is to be taken from the limb opposite to the one that will be used for 
                                                 
a  It is important to note that, if the attempt(s) to collect blood is (are) unsuccessful, the subject should be given the 
opportunity for another attempt, even on another day. If ultimately a blood sample cannot be obtained, the reason 
will be recorded in the eCRF. In that case, and if the subject wants to participate in the trial, he/she will be 
vaccinated. 
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vaccination for sequential injection (Group 2), or from the limb opposite to the one that will 
be used for CYD dengue vaccine injection for concomitant injection (Group 1). 
9) Review temporary and definitive contraindications to vaccination 
10) Inject the first dose of CYD dengue vaccine to all subjects. 
11) Inject Tdap vaccine to subjects in Group 1 on the opposite side (the one who did not receive 
the CYD dengue vaccine). 
12) Keep the subject under observation for 30 minutes, and record any immediate AE in the 
source document. 
13) Record the date of injection(s), the site and side of injection(s) and the route of 
administration(s), as well as the dose number of the vaccine(s). 
14) Give the subject or parent/legally acceptable representative a DC (both Groups). 
15) Remind the subject or parent/legally acceptable representative to bring back the DC when 
they return for Visit 3 at a specified date and time. 
16) Complete the relevant eCRF pages for this visit. 
Visit 3 (Month 2; 28 [+14] days after Visit 2) 
The Investigator or designated study personnel will: 
1) Check the information entered into the DC by interviewing the subject/subject’s parent 
(s)/legally acceptable representative(s) and request information concerning any medical 
event, serious or not, that may have occurred since Visit 2. 
2) Check concomitant medications and record every reportable medication ongoing at the time 
of vaccination. 
3) Collect information regarding the subject’s medication status since the previous visit. 
4) Perform a physical examination  
5) Obtain blood sample (see Section 7.1 for detailed instructions regarding the handling of blood 
samples). 
6) Remind the subject or parent/legally acceptable representative to bring back the DC when 
they return for Visit 4 at a specified date and time. 
7) Complete the relevant eCRF pages for this visit. 
Phone Call 1 (PC1) (Month 4; initially planned 3 months after Visit 2) 
During this contact, the Investigator or designated study personnel will ask the subject or 
parent/legally acceptable representative if the subject has experienced any SAE, including 
hospitalized suspected dengue case, in the time since vaccination. If it did occur, follow the 
instructions for reporting it. The Investigator or designated study personnel will also remind the 
instructions to the parent/legally acceptable representative and to complete regularly the DC. A 
follow-up visit can be arranged depending on the info recorded during the phone call.  
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Unscheduled visit/phone call comprised between V03 [28+14 days after first dose of CYD 
dengue vaccine] and V06 [initially planned at M13+20 day] 
As per Protocol Amendment 1, this unscheduled visit/phone call is to take place as soon as 
possible after study-hold (between V03 and V06). During this visit/phone call, subjects will be 
informed about their dengue serostatus at baseline, and about the increased risk of hospitalized or 
severe dengue for subjects not exposed to dengue infection prior to the first injection with the 
CYD dengue vaccine. 
The subject will consent to continue participation in the study by signing an ICF/AF 
addendum 1 at subject’s next planned visit (either V04, V05 or V06). At the latest, this visit 
will take place at the same time as V06.  
The scheduled calendar for the next visits and phone calls may be impacted (delayed) by the 
length of the study hold. It will be adapted accordingly.  
Visit 4 (initially planned at Month 7; 6 months [± 20 days] after Visit 2) 
The Investigator or designated study personnel will: 
1) Review the DC pages with the parent/legally acceptable representative. 
2) Perform a physical examination  
3) Record the subject’s axillary temperature. 
4) Collect information regarding the subject’s medication status since the previous visit. 
5) For female subjects of childbearing potential, perform a urine pregnancy test. 
6) Review temporary and definitive contraindications to vaccination. 
7) Inject the second dose of CYD dengue vaccine to all subjects. 
8) Keep the subject under observation for 30 minutes, and record any immediate AE in the 
source document. 
9) Record the date of injection, the site and side of injection and the route of administration, as 
well as the dose number of the vaccine. 
10) Give the subject or parent/legally acceptable representative a DC. 
11) Remind the subject or parent/legally acceptable representative to bring back the DC when 
they return for Visit 5 at a specified date and time. 
12) Complete the relevant eCRF pages for this visit. 
Visit 5 (initially planned at Month 8; 28 [+14] days after Visit 4) 
This visit is performed only to collect safety data post-second injection with CYD dengue 
vaccine. The same procedures as those described for Visit 3 will be followed, except that no blood 
sample will be performed. 
Phone Call 2 (PC2) (initially planned at Month 10;3 months after Visit 4) 
The same procedures as those described for PC1 will be followed. 
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Visit 6 (initially planned at Month 13; 12 months [± 20 days] after Visit 2) 
The same procedures as those described for Visit 4 will be followed. 
Phone Call 3 (PC3) (initially planned at Month 16;3 months after Visit 6) 
The same procedures as those described for PC1 will be followed. 
Visit 7 (initially planned at Month 14; 28 [+14] days after Visit 6) 
The same procedures as those described for Visit 3 will be followed. In addition, subject or 
parent/legally acceptable representative will be given a memory aid (MA). 
6-Month Safety Follow-up After the Last Vaccination 
During the 6-month safety follow-up after the last vaccination, subjects will be highly invited to 
contact the sponsor in case of SAE. In case of hospitalized suspected dengue case, one unplanned 
acute blood sample will have to be collected within the first 5 days after fever onset for 
virological confirmation of dengue disease. If this cannot be accomplished within the first 5 days 
after fever onset, this sample should still be obtained as soon as possible thereafter, for IDMC 
severity assessment. 
Safety Follow-Up Telephone Call (6 months after the last vaccination): Collection of SAEs 
After the last CYD dengue dose received (whether 1, 2 or 3 doses), subjects will still be contacted 
by telephone.  This contact will be made 6 months after the last vaccination or the closest possible 
to that date, considering the potential delay triggered by the study-hold. During this contact, the 
Investigator or designated study personnel will: 
1) Ask the subject or parent/legally acceptable representative if the subject has experienced any 
SAE, including hospitalized suspected dengue case, in the time since vaccination. If it did 
occur, follow the instructions for reporting it. 
2) Complete the relevant eCRF pages for this contact. 
A follow-up visit can be arranged depending on the information recorded during the phone call. 
SAEs and AEs That Are Related to Vaccination or That Led to Discontinuation: 
At any time during the study, a subject who experiences an SAE or an AE must be followed if 
either of the following is true: 
x The SAE or AE is considered by the Investigator to be related to vaccination, and is not 
resolved by the end of the subject’s participation in the trial 
x The subject has been discontinued from the trial because of the SAE or AE 
Any such subject must be followed until the condition resolves, becomes stable, or becomes 
chronic. 
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5.1.5 
Planned Trial Calendar 
The following dates are approximate. The actual dates may differ as they may be impacted by the 
study-hold and they depend on the obtention of the appropriate regulatory and ethical approvals.. 
Planned trial period (FVFS to LCLSa): 
Q3 2016 to Q2 2019 
Planned vaccination period:  
 
Q3 2016 to Q3 2018 
Planned end of trialb:  
 
 
Q2 2019 
Planned date of final clinical study report: Q4 2019 
The initial expected duration of each subject’s participation in the trial is approximately 19 
months, including a safety follow-up period of 6 months after the third injection of CYD dengue 
vaccine.  
 
5.1.6 
Early Safety Data Review 
This trial will not include an early review of safety data. However, it may be interrupted at any 
time if new data about the investigational product become available, and/or on advice of the 
Sponsor, the IECs/IRBs, or the governing regulatory authorities in the Philippines where the trial 
is taking place.  
If the trial is prematurely terminated or suspended, the Sponsor will promptly inform the 
Investigators, the IECs/IRBs, and the regulatory authorities of the reason for termination or 
suspension.  
If the trial is prematurely terminated for any reason, the Investigator will promptly inform the 
subjects and/or the subjects' parents/legally acceptable representatives and should assure 
appropriate therapy and follow-up. 
An internal SET will perform a safety analysis on safety data during the conduct of the trial. 
5.2 
Enrollment and Retention of Trial Population 
5.2.1 
Recruitment Procedures 
Before the start of the trial, the Investigator and/or study staff will determine the recruitment 
strategy to be used for this study (e.g., advertising, database, direct mail, word of mouth referral). 
Using the relevant methods they will contact an appropriate pool of potential subjects and invite 
them to participate in the study. The site will ensure that any advertisements or materials they plan 
to use to recruit subjects (e.g., letters, pamphlets, posters, etc.) are submitted to Sanofi Pasteur for 
review prior to submission to the IEC/IRB for approval. 
                                                 
a  FVFS: first visit of first subject; LCLS: last contact of last subject. 
b  End of trial is defined as the date of the last contact with a trial subject within the scope of the trial. 
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5.2.2 
Informed Consent Procedures 
Informed consent is the process by which a subject and an appropriate and legally acceptable 
representative voluntarily confirms his or her willingness to participate in a particular trial. 
Informed consent must be obtained before any study procedures are performed. The process is 
documented by means of a written, signed, and dated ICF or AF (according to local EC 
regulation). 
Following the amendment of the original protocol, subject/subject's parent(s) or legally acceptable 
representative(s) are to sign an addendum to the AF and /or the ICF, as per local regulations. 
In accordance with GCP, prior to signing and dating the consent form, the subject and an 
appropriate and legally acceptable representative must be informed by appropriate study personnel 
about all aspects of the trial that are relevant to making the decision to participate, and must have 
sufficient time and opportunity to ask any questions. 
If the subject and the appropriate and legally acceptable representative are not able to read and 
sign the ICF, then it must be signed and dated by an impartial witness who is independent of the 
Investigator. A witness who signs and dates the consent form is certifying that the information in 
this form and any other written information had been accurately explained to and understood by 
the subject or his/her representative. 
The actual ICF and AF used at each center may differ, depending on local regulations and 
IEC/IRB requirements. However, all versions must contain the standard information found in the 
sample ICF/AF provided by the Sponsor. Any change to the content of the ICF and/or AF must be 
approved by the Sponsor and the IEC/IRB prior to the form being used. 
If new information becomes available that may be relevant to the subject’s or legally acceptable 
representative’s willingness to continue participation in the trial, this will be communicated to 
him/her in a timely manner. Such information will be provided via a revised ICF and/or AF or an 
addendum to the original ICF and/or AF. 
Informed consent forms will be provided in duplicate, or a photocopy of the signed consent will 
be made. The original will be kept by the Investigator, and the copy will be kept by the subject or 
the subject’s legally acceptable representative. 
Documentation of the consent process should be recorded in the source documents. 
5.2.3 
Screening Criteria 
There are no screening criteria other than the inclusion and exclusion criteria. 
5.2.4 
Inclusion Criteria 
An individual must fulfill all of the following criteria in order to be eligible for trial enrollment: 
1) Subject aged 9 to 60 years (i.e., from the day of the 9th birthday to the day prior to the 61th 
birthday) on the day of inclusion 
2) Subject in good health, based on medical history and physical examination 
3) Informed consent form (ICF) or assent form (AF) has been signed and dated by the subject 
(based on local regulations), and/or ICF has been signed and dated by the parent(s) or another 
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legally acceptable representative (and by an independent witness if required by local 
regulations) 
4) For subject aged 9 to 11 years: known (documented) receipt of at least 4 previous doses of 
diphtheria toxoid, tetanus toxoid and acellular pertussis-containing (DTaP) vaccines, with the 
last dose not within the last 5 years prior to enrolment 
OR 
For subject aged at least 12 years: known (documented or self-reported) receipt of at least 
3 previous doses of diphtheria toxoid , tetanus toxoid, and whole cell pertussis-containing 
(DTwP) vaccines, with the last dose not within the last 5 years prior to enrolment 
5) Subject (or subject and parent[s]/legally acceptable representatives) able to attend all 
scheduled visits and to comply with all trial procedures 
5.2.5 
Exclusion Criteria 
An individual fulfilling any of the following criteria is to be excluded from trial enrollment: 
1) Subject is pregnant, or lactating, or of childbearing potential (to be considered of non-
childbearing potential, a female must be pre-menarchea or post-menopausal for at least 1 year, 
surgically sterile, or using an effective method of contraception or abstinence from at least 4 
weeks prior to the first vaccination until at least 4 weeks after the last vaccination) 
2) Participation at the time of study enrollment (or in the 4 weeks preceding the first trial 
vaccination) or planned participation during the present trial period in another clinical trial 
investigating a vaccine, drug, medical device, or medical procedure 
3) Planned receipt of any vaccine in the 4 weeks following any trial vaccination 
4) Previous vaccination against dengue disease with the trial CYD dengue vaccine 
5) Receipt of immune globulins, blood or blood-derived products in the past 3 months, which 
might interfere with assessment of the immune response 
6) Known or suspected congenital or acquired immunodeficiency (including HIV infection with 
impaired immune function); or receipt of immunosuppressive therapy such as anti-cancer 
chemotherapy or radiation therapy within the preceding 6 months; or long-term systemic 
corticosteroids therapy (prednisone or equivalent for more than 2 consecutive weeks within 
the past 3 months) 
7) A previous severe reaction to pertussis, diphtheria or tetanus vaccine including immediate 
anaphylaxis, encephalopathy within 7 days or seizure within 3 days of receiving the vaccine 
                                                 
a  For pre-menarche females, the young female patients will declare by themselves (and/or their parent(s) or other 
legally acceptable representative) if they have not yet started menstruation. If a young female patient reaches 
menarche during the study, then she is to be considered as a woman of childbearing potential from that time 
forward. Examples of effective methods of contraception include oral contraception (pill), intrauterine device, 
diaphragm or condoms, contraceptive foam or cream, hormonal implants, transdermal patch, or parenteral 
contraception. 
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8) Known systemic hypersensitivity to any of the vaccine componentsa, or history of a life-
threatening reaction to the vaccine used in the trial or to a vaccine containing any of the same 
substances 
9) Thrombocytopenia, contraindicating intramuscular vaccination 
10) Bleeding disorder or receipt of anticoagulants within 3 weeks preceding inclusion, which may 
be a contraindication for intramuscular vaccination, at the discretion of the Investigator 
11) Deprived of freedom by administrative or court order, or in an emergency setting, or 
hospitalized involuntarily 
12) Current alcohol abuse or drug addiction that, based on Investigator’s judgment, may interfere 
with the subject’s ability to comply with trial procedures  
13) Chronic illness that, in the opinion of the Investigator, is at a stage where it might interfere 
with trial conduct or completion 
14) Identified as an Investigator or employee of the Investigator with direct involvement in the 
proposed study, or identified as an immediate family member (i.e., parent, spouse, natural or 
adopted child) of the Investigator or employee with direct involvement in the proposed study 
15) Self-reported Human Immunodeficiency Virus (HIV), Hepatitis B, or Hepatitis C infection 
16) Personal history of Guillain-Barré syndrome 
Temporary Exclusion Criteria: 
A prospective subject should not be included in the study until the following condition and/or 
symptoms are resolved: 
1) Moderate or severe acute illness/infection (according to Investigator judgment) or febrile 
illness (temperaWXUH 38.0°C) on the day of first vaccination.  
2) Receipt of any vaccine in the 4 weeks preceding the trial inclusion 
5.2.6 
Medical History 
Prior to enrollment, subjects will be assessed for pre-existing conditions and illnesses, both past 
and ongoing. Any such conditions will be documented in the source document. Significant 
medical history (reported as diagnosis) including conditions for which the subject is or has been 
followed by a physician or conditions that could resume during the course of the study or lead to 
an SAE or to a repetitive outpatient care will be collected in the eCRF. The significant medical 
history section of the eCRF contains a core list of body systems and disorders that could be used 
to prompt comprehensive reporting, as well as space for the reporting of specific conditions and 
illnesses. 
For each condition, the data collected will be limited to: 
x Diagnosis (this is preferable to reporting signs and symptoms) 
                                                 
a  The components of the vaccines used in the trial are listed in Section 6.1 and in the Investigator’s Brochure or 
summary of product characteristics. 
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x Presence or absence of the condition at enrollment 
The reporting of signs and symptoms is strongly discouraged. 
Dates, medications, and body systems are not to be recorded, and the information collected will not 
be coded. Its purpose is to assist in the later interpretation of safety data collected during the trial. 
5.2.7 
Contraindications for Subsequent Vaccinations 
5.2.7.1 
Temporary Contraindications 
Should a subject experience one of the conditions listed below, the Investigator will postpone 
further vaccination until the condition is resolved. Postponement must still be within the 
timeframe for vaccination indicated in the Table of Study Procedures. 
1) Febrile LOOQHVVWHPSHUDWXUH 38.0°C) or moderate or severe acute illness/infection on the day 
of vaccination, according to Investigator judgment 
2) Receipt of any vaccine other the trial vaccination in the 4 weeks preceding the trial 
vaccination  
5.2.7.2 
Definitive Contraindications 
Should a subject experience one of the conditions listed below, the Investigator will discontinue 
vaccination: 
1) Pregnancy, as indicated by a positive urine test, or lactation 
2) An anaphylactic or other significant allergic reaction to the previous dose of vaccine 
3) 
Individual with acquired immunodeficiency (including HIV infection with impaired immune 
function); or receipt of immunosuppressive therapy, such as anti-cancer chemotherapy, 
radiation therapy or systemic corticosteroid therapy (prednisone or equivalent) 
4) 
Ongoing clinical AE related to the previous trial vaccination, and in the Investigator's 
opinion, contraindicating further vaccination 
5) 
SAE related to the study vaccine following the previous trial vaccination 
6) 
Subject classified as a dengue unexposed subject (seronegative) at baseline 
Subjects will not be withdrawn due to contraindication but will be followed up for safety and 
possibly immunogenicity assessment. 
If a subject has been classified as a “dengue unexposed”, she/he will have the possibility to continue 
participating in the safety follow-up. 
5.2.8 
Conditions for Withdrawal  
Subjects/Parents/Legally acceptable representatives will be informed that they have the right to 
withdraw or withdraw their child from the trial at any time. 
x At the discretion of the Investigator or Sponsor due to safety concerns (withdrawal) without 
the subject’s permission 
x At the request of the subject/parents or legally acceptable representatives (dropout)  
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The following will result in automatic withdrawal or exclusion of a subject from the study: 
x Significant non-compliance with the protocol, based on the Investigator’s judgment 
The reason for a withdrawal or dropout should be clearly documented in the source documents 
and on the eCRF.  
The Investigator must determine whether voluntary withdrawal is due to safety concerns (in 
which case, the reason for discontinuation will be noted as “SAE” or “other AE” as appropriate) 
or for another reason. 
Withdrawn subjects will not be replaced. 
5.2.9 
Lost to Follow-up Procedures 
In the case of subjects who fail to return for a follow-up examination, documented reasonable 
effort (i.e., documented telephone calls and certified mail) should be undertaken to locate or recall 
them, or at least to determine their health status while fully respecting their rights. These efforts 
should be documented in the eCRF and in the source documents. 
5.2.10 Classification of Subjects Who Discontinue the Trial 
For any subject who discontinues the trial prior to completion, the most significant reason for 
early termination will be checked in the eCRF. Reasons are listed below from the most significant 
to the least significant (refer to the eCRF completion guidelines for additional details and 
examples): 
Serious adverse event: To be used when a subject drops out of or is withdrawn from the study by 
the Investigator because of the occurrence of an SAE, as defined in 9.2.2.1. 
Other adverse event: To be used when a subject drops out of or is withdrawn from the study by 
the Investigator because of the occurrence of an AE other than an SAE, as defined in Section 10. 
Non-compliance with protocol: To be used when the Investigator withdraws a subject from the 
study because of failure to follow the protocol, including when it is retrospectively discovered that 
a subject did not fulfill the eligibility criteria. The Investigator will provide a comment as to the 
specific cause of non-compliance. 
Lost to follow-up: To be used when the Investigator withdraws a subject from the study because 
of failure to establish contact, as outlined in Section 5.2.9. The Investigator will provide 
documentation that contact was attempted (i.e., return of unsigned certified letter receipt). 
Voluntary withdrawal not due to an adverse event: To be used when a subject drops out of the 
study for any reason other than those listed above. 
As per Protocol Amendment 1, every effort will be made to contact unexposed subjects who 
discontinued after dengue vaccine injection(s) to inform them about their dengue status and their 
rights to access medical care for 10 years after the last dengue vaccine injection. 
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5.2.11 Follow-up of Discontinuations 
The site should complete all scheduled safety follow-ups and contact any subject who has 
prematurely terminated the trial because of an SAE, other type of AE, non-compliance with the 
protocol, or loss of eligibility, including definite contraindications.  
For subjects where the reason for early termination was lost to follow-up or if the subject 
withdrew informed consent and specified that they do not want to be contacted again and it is 
documented in the source document, the site will not attempt to obtain further safety information. 
For subjects where the reason for early termination is voluntary withdrawal, the site will attempt 
to contact them for the 6-month follow-up, except if they specified that they do not want to be 
contacted again and it is documented in the source document. 
5.2.12 Follow-up and Reporting of Pregnancies 
Pregnancy is an exclusion criterion for enrollment in this study, but a subject could potentially 
become pregnant during her participation. In case of pregnancy and if at least one dose of the 
study vaccine(s) has been administered, the subject will not be discontinued from the trial and will 
be followed for safety assessment (and may be followed for immunogenicity assessment, if 
applicable). However, no additional vaccination will be administered.  
All pregnancy cases should be reported if they occurred during the study and during the 6 month 
follow up period. To report the pregnancy case, the Investigator must fill out an electronic 
Pregnancy Reporting Form in the Electronic Data Capture (EDC) system and inform the Sponsor 
within 1 month after identifying a pregnancy case.  
Study staff must then maintain contact with the subject to obtain information about the outcome—
i.e., details about the delivery and the newborn, or about pregnancy termination—and must update 
the electronic Pregnancy Reporting Form. This information should be provided to the Sponsor 
within 1 month of delivery. Additional follow-up visits may be performed according to the local 
regulations. 
Pregnancy itself is not considered an AE, but any complications during pregnancy are to be 
considered as AEs, and in some cases could be considered SAEs. Spontaneous abortions, fetal 
death, stillbirth, and congenital anomalies reported in the baby are always considered as SAEs, 
and the information should be provided to the Global PharmacoVigilance (GPV) Department 
regardless of when the SAE occurs (e.g., even after the end of the trial). 
5.3 
Modification of the Trial and Protocol 
Any amendments to this trial plan and protocol must be discussed with and approved by the 
Sponsor. If agreement is reached concerning the need for an amendment, it will be produced in 
writing by the Sponsor, and the amended version of the protocol will replace the earlier version. 
All substantial amendments e.g., that affect the conduct of the trial or the safety of subjects, 
require IEC/IRB approval, and must also be forwarded to regulatory authorities. 
An administrative amendment to a protocol is one that modifies some administrative or logistical 
aspect of the trial but does not affect its design or objectives or have an impact on the subjects’ 
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safety. The IECs/IRBs and regulatory authorities must be notified of administrative changes and 
will provide approval according to local regulations. 
The Investigator is responsible for ensuring that changes to an approved trial, during the period 
for which IEC/IRB approval has already been given, are not initiated without IEC/IRB review and 
approval, except to eliminate apparent immediate hazards to subjects. 
5.4 
Interruption of the Trial 
The trial may be discontinued if new data about the investigational product resulting from this or 
any other trials become available; or for administrative reasons; or on advice of the Sponsor, the 
Investigators, and/or the IECs/IRBs. If the trial is prematurely terminated or suspended, the 
Sponsor shall promptly inform the Investigators, the regulatory authorities, and the IECs/IRBs of 
the reason for termination or suspension, as specified by the applicable regulatory requirements. 
The Investigator shall promptly inform the trial subjects and assure appropriate therapy and/or 
follow-up for them. 
6 
Vaccines Administered 
Subjects will receive the CYD dengue vaccine according to a 3-dose schedule, given 6 months 
apart, with the first dose of CYD dengue vaccine administered either concomitantly or 
sequentially with a booster dose of Tdap vaccine (Adacel®). 
6.1 
Identity of the Investigational Products  
6.1.1 
Identity of CYD Dengue Vaccine 
CYD dengue vaccine:  
Live, attenuated, tetravalent dengue virus vaccine 
Presentation:   
 
Monodose 
Form:   
 
 
Powder and solvent for suspension for injection 
Dose:  
 
0.5 milliliters (mL) of the reconstituted vaccine 
Route:  
 
 
Subcutaneous (SC) injection 
Batch number: 
 
To be determined 
6.1.1.1 
Composition 
Each 0.5 mL dose of reconstituted vaccine contains the following components: 
x Active Ingredients: 4.5 – 6 log10 cell-culture infectious dose 50% (CCID50) of each live, 
attenuated, recombinant dengue virus serotype 1, 2, 3, 4 
x Excipients: essential amino acids, non-essential amino acids, L-arginine chlorhydrate, 
saccharose, D-trehalose dihydrate, D-sorbitol, tris (hydroxymethyl) aminomethane, and urea 
x Solvent: NaCl 0.4% 
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6.1.1.2 
Preparation and Administration 
Sanofi Pasteur’s CYD dengue vaccine consists of a powder and solvent for suspension for 
injection and must be stored between +2°C and +8°C. 
The vaccine must be removed from the refrigerator, reconstituted with the solvent supplied for 
this purpose, and used immediately after reconstitution. 
The vaccine is to be administered subcutaneously in the deltoid region of the upper arm in a 
volume of 0.5 mL. 
Prior to administration, all study products must be inspected visually for cracks, broken seals, 
correct label content (see Section 6.3.1), and extraneous particulate matter and/or discoloration, 
whenever solution and container permit. If any of these conditions exists, the vaccine must not be 
administered. Another dose is to be used, and the event is to be reported to the Sponsor. 
Subjects must be kept under observation for 30 minutes after each vaccination to ensure their 
safety, and any reactions during this period will be documented in the eCRF. Appropriate medical 
equipment and emergency medications, including epinephrine (1:1000), must be available on site 
in the event of an anaphylactic or other immediate allergic reaction. 
If a vial or syringe is accidentally broken and the product spilled out, appropriate disinfection 
procedures must be used (please refer to the Operating Guidelines and/or trial center’s 
procedures). 
6.1.1.3 
Dose Selection and Timing 
Tetravalent vaccine: 
CYD01 assessed safety and immunogenicity of a single dose of monovalent dengue virus 
seroptype 2 chimeric vaccine which demonstrated a satisfactory immune response to serotype 2 
but low seropositivity rates to other serotypes thus confirming the need for a tetravalent vaccine. 
In CYD04, CYD05, and CYD06 the choice of a tetravalent vaccine against all 4 serotypes was 
confirmed as assessed by immunogenicity responses in several populations across different age 
group and with different flavivirus background (FV naïve or immune). Furthermore this was 
supported by CYD11, whereby several bivalent formulations did not improve the immune 
response compared to tetravalent formulations. 
5 log10 CCID50 per serotype (5555) Formulation: 
The results of an early Phase I study (CYD02) showed that a tetravalent formulation with 4 log10 
CCID50 per serotype (2 doses given at 5 to 9 month interval) induced moderate but unbalanced Ab 
levels against the four serotypes (13). Based on these results, it was decided to evaluate a 
formulation with a higher virus concentration 5 log10 CCID50 per serotype (5555) and to introduce 
a third injection. The safety and immunogenicity of the 5555 formulation of CYD dengue vaccine 
(5 log10 CCID50 per serotype) was thus evaluated in additional Phase I trials, 
CYD04,CYD05,CYD06,CYD12. The 5555 formulation reliably induced an immune response 
against all 4 serotypes after 3 injections in various populations. 
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Vaccination schedule: 
The schedule was selected based on the results from phase I studies CYD02, CYD04, CYD05, 
and CYD06 in groups receiving tetravalent vaccine at a 3-injection regimen 0,3/4,12 months in 
different age groups (children, adolescents, adults), different regions (non-endemic USA and 
Latin America , and endemic Asia Pacific) and different baseline FV status at baseline. The data 
from initial Phase I studies demonstrated that increasing the interval between injections was 
beneficial. Furthermore, the benefit of the third injection in terms of seropositivity rate was more 
marked in younger children and/or subjects who were FV non-immune at baseline. A potential 
priming effect was also observed following administration of YF vaccine (CYD06) (14). 
The choice of the final 3 dose schedule at 6 month intervals apart of 5555 formulation was based 
on data from phase II studies, especially CYD12. The 3-dose schedule (0, 3–4, and 12 months) 
and 2-dose schedule (0 and 8–9 months) were adapted to adjust for the higher immunogenicity 
that occurred when Dose 2 was delayed, balanced by providing protection as soon as possible. 
CYD12 was the first phase II study testing the final 5555 formulation with the 3 dose schedule 0, 
6, and 12 months demonstrating a satisfactory immune response to all 4 serotypes in FV non-
immune subjects. Overall, 3 injections at 0, 6 and 12 months of 5555 formulation led to consistent 
immune response against all serotypes in all age groups, regardless of baseline FV status (15). 
6.1.2 
Identity of Adacel 
Adacel®:  
 
Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis  
 
 
 
Vaccine Adsorbed 
Form:   
 
Suspension for injection in a vial 
Dose:  
 
0.5 mL 
Route:  
 
Intramuscular (IM) injection 
Batch number: 
 
Commercial 
6.1.2.1 
Composition 
Each 0.5 mL dose of vaccine contains the following components: 
x Active Ingredients: 
o Tetanus toxoid 
 
 
 
5 Lf 
o Diphtheria toxoid 
 
 
 
2 Lf  
o Pertussis toxoid 
 
 
 
2.5 μg 
o Filamentous Hemagglutinin   
 
5 μg 
o Pertactin  
 
 
 
 
5 μg 
o Fimbriae types 2 and 3  
 
 
5 μg 
x Excipients: 
o aluminum phosphate (adjuvant)  
 
1.5 mg 
o 2-phenoxyethanol 
 
 
 
0.6% v/v 
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6.1.2.2 
Preparation and Administration 
Sanofi Pasteur’s Tdap vaccine consists of a powder and solvent for suspension for injection and 
must be stored between +2°C and +8°C. 
The vaccine must be removed from the refrigerator, reconstituted with the solvent supplied for 
this purpose, and used immediately after reconstitution. 
The Tdap vaccine is to be administered intramuscularly in the deltoid region of the upper arm, on 
the opposite side (the one who did not receive the CYD dengue vaccine). 
Prior to administration, all study products must be inspected visually for cracks, broken seals, 
correct label content (see Section 6.3.1), and extraneous particulate matter and/or discoloration, 
whenever solution and container permit. If any of these conditions exists, the vaccine must not be 
administered. Another dose is to be used, and the event is to be reported to the Sponsor. 
Subjects must be kept under observation for 30 minutes after each vaccination to ensure their 
safety, and any reactions during this period will be documented in the eCRF. Appropriate medical 
equipment and emergency medications, including epinephrine (1:1000), must be available on site 
in the event of an anaphylactic or other immediate allergic reaction. 
6.1.2.3 
Dose Selection and Timing 
The recommended dose will be administered (this should follow the leaflet). 
6.1.3 
Identity of Control Product 
Not applicable. 
6.2 
Identity of Other Product 
Not applicable. 
6.3 
Product Logistics 
6.3.1 
Labeling and Packaging 
CYD dengue vaccine will be supplied in vials/syringes and will be labeled and packaged 
according to national regulations. The information on the label will include: 
x Study code 
x Name of product  
x Route of injection (SC) 
x Investigational use only statement (for clinical trial use only) 
x Storage conditions 
x Batch number 
x Dose number 
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x Name of Sponsor 
x Expiry date 
For Adacel®, a commercial batch will be used, and the manufacturer’s packaging will be used and 
labeled with specific clinical mention according to national regulation. 
6.3.2 
Product Shipment, Storage, and Accountability 
6.3.2.1 
Product Shipment 
The Clinical Logistics Coordinator or designee will contact the Investigator or a designee in order 
to determine the dates and times of delivery of products. 
Each vaccine shipment will include a temperature-monitoring device to verify maintenance of the 
cold chain during transit. On delivery of the product to the site, the person in charge of product 
receipt will follow the instructions given in the Operating Guidelines, including checking that the 
cold chain was maintained during shipment (i.e., verification of the temperature recorders). If 
there is an indication that the cold chain was broken, this person should immediately quarantine 
the product, alert the Sanofi Pasteur representative, and request authorization from Sanofi Pasteur 
to use the product. 
6.3.2.2 
Product Storage 
The Investigator will be personally responsible for product management or will designate a staff 
member to assume this responsibility. 
At the site, products must be kept in a secure place with restricted access and must be protected 
from light. Vaccines will be stored in a refrigerator at a temperature ranging from +2°C to +8°C. 
The vaccines must not be frozen. The temperature must be monitored and documented (see the 
Operating Guidelines) for the entire time that the vaccine is at the trial site. In case of accidental 
freezing or disruption of the cold chain, vaccines must not be administered and must be 
quarantined, and the Investigator or authorized designee should contact the Sanofi Pasteur 
representative for further instructions. 
6.3.2.3 
Product Accountability 
The person in charge of product management at the site will maintain records of product delivery 
to the trial site, product inventory at the site, the dose(s) given to each subject, and the disposal of 
or return to the Sponsor of unused doses.  
The necessary information on the product labels is to be entered into the source document and the 
eCRF. If applicable, information may also be entered into the subject’s vaccination card. 
The Sponsor’s monitoring staff will verify the trial site’s product accountability records against 
the record of administered doses in the eCRF. 
In case of any expected or potential shortage of product during the trial, the Investigator or an 
authorized designee should alert the Sanofi Pasteur representative as soon as possible, so that a 
shipment of extra doses can be arranged. 
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6.3.3 
Replacement Doses 
If a replacement dose is required (e.g., because the syringe broke or particulate matter was 
observed in the syringe), the site personnel must follow the instructions given in the Operating 
Guidelines. 
6.3.4 
Disposal of Unused Products 
Unused or wasted products will be either disposed of or returned to the Sponsor in accordance 
with the instructions in the Operating Guidelines. Product accountability will be verified 
throughout the trial period. 
6.3.5 
Recall of Products 
If the Sponsor makes a decision to launch a retrieval procedure, the Investigator(s) will be 
informed of what needs to be done. 
6.4 
Blinding and Code-breaking Procedures 
The study CYD66 will be an open-labeled study, no blinding is required. 
6.5 
Randomization and Allocation Procedures 
Subjects will be randomized in a 1:1 ratio into Group 1 or Group 2. Stratification according to age 
will be applied (9 to 11 years, 12 to 17 years, 18 to 45 years and 46 to 60 years) to balance the 
potential difference in terms of booster response by age group for the pertussis antigens (PT, 
FHA, PRN and FIM2+3). 
The full detailed procedures for randomization are described in the Operating Guidelines. 
Subject numbers will be 8 digits long, with a 3-digit center identifier and a 5-digit subject 
identifier. For example, Subject 001-00001 is the first subject enrolled in center number 1 and 
Subject 002-00001 is the first subject enrolled in center number 2. 
Subject numbers will be an 8-digit string, consisting of a 3-digit study center identifier and a 5-
digit subject identifier. The 5-digit subject identifier will correspond to the age group (the first 
digit will be used to identify the age group, with “0” for subjects aged 9 to 11years, “1” for 
subjects aged 12 to 17 years, “2” for subjects aged 18 to 45 years, and “3” for subjects aged 46 to 
60 years) and to chronological order of enrollment in the center. Subject identifier will be: 
x From 00001 to 09999 for subjects aged 9 months through 11 years 
x From 10001 to 19999 for subjects aged 12 years through 17 years 
x From 20001 to 29999 for subjects aged 18 years through 45 years 
x From 30001 to 39999 for subjects aged 46 years through 60 years 
For example, Subject 001-10001 is the first subject in the 12-17 year-old age group enrolled in the 
study center number 1 and Subject 002-20001 is the first subject from the 18-45 year-old age 
group enrolled in the study center number 2. 
Subject numbers should not be reassigned for any reason.  
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The Statistical Platform of the Sponsor will provide scratchable randomization lists (one per site). 
These lists will mention the randomization number of the subject and the corresponding study 
group covered by a silver-colored patch. After subject number allocation to a subject, the 
Investigator will scratch off the list to know the study group. Once scratched, each randomization 
line will be dated and signed by the Investigator or the sub-Investigator in charge of administering 
the study vaccine(s). 
Each subject will be vaccinated with the product(s) corresponding to the group mentioned on the 
randomization list. If the dose initially taken for the vaccination is broken or cannot be used, the 
Investigator will take another dose of the same vaccine. 
6.6 
Treatment Compliance 
The following measures will ensure that the vaccine doses administered comply with those planned, 
and that any non-compliance is documented so that it can be accounted for in the data analyses: 
x All vaccinations will be administered by qualified trial personnel 
x The person in charge of product management at the site will maintain accountability records 
of product delivery to the trial site, product inventory at the site, dose(s) given to each subject, 
and the disposal of unused or wasted doses 
6.7 
Concomitant Medications and Other Therapies 
At the time of enrollment, ongoing medications including other therapies e.g., blood products, 
should be recorded in the source document as well as new medications prescribed for new 
medical conditions/AEs during trial participation.  
Documentation in the eCRF of concomitant medication will be limited to specific categories of 
medication of interest beginning on the day of vaccination. This may include medications of 
interest that were started prior to the day of vaccination. 
Reportable medications will be collected in the eCRF from the day of vaccination to the end of 
the solicited and unsolicited follow-up period (e.g., 28 day safety follow-up) as they may impact 
the response to the vaccination and impact the consistency of the information collected on 
concomitant medications at any vaccination.  
The “reportable” medications are distributed according to two categories: 
x Category 1 (Restricted therapies): antipyretics, analgesics, non-steroidal anti-inflammatory 
drugs (NSAIDs), corticosteroids, and other immune modulators  
Note: inhaled and topical steroids should not be captured 
x Category 2 (Prohibited therapies for the PP): 
x 
Vaccines (other than the trial vaccines) in the 4 weeks before and after each trial 
vaccination 
x 
Immunosuppressive therapy such as anti-cancer chemotherapy or radiation therapy or 
long-term systemic corticosteroids (for more than 2 consecutive weeks) in the 4 weeks 
after each trial vaccination 
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x 
Immune globulins, blood or blood-derived products in the 4 weeks before and after each 
trial vaccination 
The information reported in the eCRF for each reported medication will be limited to: 
x Trade name 
x Given as treatment or as prophylaxis 
x Medication category 
x Start and stop dates 
Dosage and administration route will not be recorded. Homeopathic medication will not be 
recorded. Topical treatment will not be recorded. 
The fact that a medication was given in response to an AE will be captured in the “Action Taken” 
column of the AE only. No details will be recorded in the concomitant medication module of the 
eCRF unless the medication received belongs to one of the prelisted categories. Medications will 
not be coded. 
7 
Management of Samples 
Blood samples for the assessment of Ab responses will be collected at Visits 1, 2, 3, and 7. See 
the Table of Study Procedures and Section 5.1.3 for details of the sampling schedule. 
7.1 
Sample Collection 
7.1.1 
Serum Samples for Neutralizing Ab Assessment 
At Visits 1, 2, 3, and 7, 2 to 6 mL of blood will be collected in tubes provided by or recommended 
by the Sponsor. Immediately prior to the blood draw, the staff member performing the procedure 
will verify the subject’s identity; will write the assigned subject’s number on the pre-printed label 
that contains that subject’s number and the sampling stage; and will attach the label to the tube. 
Blood is to be taken from the limb opposite to the one that will be used for vaccination for 
sequential injection (Group 1), or from the limb that will be used for Tdap opposite to the one that 
will be used for CYD dengue vaccine for concomitant injection (Group 2). 
At the time of study-hold, subjects already provided 2 or 3 blood samples (BL), depending on 
their allocation group. Blood samples collected before administration of the first dose of CYD 
dengue vaccine will be used for baseline dengue serostatus assessment.  No additional BL will be 
provided by dengue unexposed participants. Dengue exposed subjects will provide the remaining 
BL as initially planned. 
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Table 7.1: Blood sampling volume (mL) per visit 
Visit Number 
V01 
V02 
V03 
V07 
Trial Timelines  (Days/Months) 
D0 
M1 (D0+28D) 
M2 (M1+28D) 
 
M14 (M13+28D)  
Time Windows 
(Days) 
 
+14 
+14 
+14 
Dengue Neutralizing Abs 
 
4 (Group 1) 
4 (Group 2) 
4 (Group 1) 
4 (Group 2) 
4 (Group 1) 
4 (Group 2) 
T, D, PT, FHA, PRN, and FIM2+3 Abs 
0 (Group 1) 
2 (Group 2) 
2 (Group 1) 
2 (Group 2) 
2 (Group 1)  
0 (Group 2) 
- 
TOTAL (mL) 
0 (Group 1) 
2 (Group 2) 
6 (Group 1) 
6 (Group 2) 
6 (Group 1) 
4 (Group 2) 
4 (Group 1) 
4 (Group 2) 
 
7.1.2 
Blood Sample for Virological Confirmation of Hospitalized Suspected Dengue Case 
and Assessment of Case Severity 
In case of hospitalized suspected dengue case, one 3 mL acute blood sample will be collected 
(within the 5 days after the fever onset) as described in Table 7.2. The acute blood sample for all 
hospitalized suspected dengue cases should be collected within the pre-specified timeframe as 
described above. If this cannot be accomplished, this sample should still be obtained as soon as 
possible thereafter, for IDMC severity assessment. This blood sample will be used to confirm 
whether a hospitalized suspected dengue case is dengue disease or not, and upon confirmation of 
infection, to identify dengue virus serotype. 
For all hospitalized suspected dengue cases, the Investigator must ensure that key biological 
parameters (aspartate aminotransferase [AST], alanine transaminase [ALT], creatinine, blood cell 
count, total bilirubin, and hematocrit count) have been checked or are planned to be checked as 
part of local standard of care at the hospital. If these parameters have not been measured, 
additional blood specimens will be taken to perform these tests for the assessment of severity 
according to the WHO/IDMC classification (see Section 9.2.3 for more details). 
Table 7.2 presents the additional serum aliquots to be taken from subject with hospitalized 
suspected dengue case at any time during the trial. Additional details are found in the Operating 
Guidelines. 
Table 7.2: Blood sampling volume (mL) for hospitalized suspected dengue case 
 
In case of hospitalized suspected dengue case 
Blood volume (mL) 
GCI (USA) or GCI outsourced laboratory 
 
 
Dengue Screen RT-PCR &  Simplexa dengue RT-PCR 
1 
 
Serum bank 
1 
 
Dengue NS1 Ag ELISA 
1 
Local laboratory (if needed) 
x 
TOTAL 
 
3 + x 
 
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More detailed instructions are provided in the Operating Guidelines. 
7.1.3 
Additional Blood Samples 
Additional blood samples may be taken to assess AEs that may be indicative of viscerotropic or 
neurotropic disease. More detailed instructions are detailed in the Guidelines for Assessing 
Viscerotropic and Neurotropic AE (16) (17) (18) document.  
7.1.4 
Urine Samples 
Pregnancy tests are applicable only for any female subjects of childbearing potential. Urine 
samples for pregnancy tests at the vaccination visits (V01 [Group 2], V02, V04, and V06) will be 
taken and analyzed at the trial center. 
7.2 
Serum Sample Preparation 
Detailed instructions on how to prepare blood samples for assessment of Ab response are 
contained in the Operating Guidelines provided to the site. An overview of the procedures is 
provided here. 
Following the blood draw, the sampling tube should be stored at room temperature for a minimum 
of 60 minutes and a maximum of 2 hours to allow the blood to clot before centrifugation. The 
tube must be stored vertically and will not be shaken. 
Beyond 2 hours, the sampling tube must be refrigerated at a temperature of +2°C to +8°C and 
must be centrifuged within a maximum of 24 hours. 
After clotting and centrifugation, the serum will be harvested and divided into appropriate number 
of aliquots. Samples will then be handled one subject at a time to avoid a mix-up of subjects’ 
blood tubes. Serum will be transferred to the appropriate number of tubes, pre-labeled with 
adhesive labels that clearly identify the subject’s number and sampling stage or visit number. 
The subject’s identification number and code, the date of sampling, the number of aliquots 
obtained, and the date and time of preparation are to be specified on a sample identification list. 
Space is provided on this list for comments on the quality of samples. 
Serum will be aliquoted in tubes which are specified in the Operating Guidelines. Aliquots will be 
frozen immediately at -20°C or below until testing. 
7.3 
Sample Storage and Shipment 
During storage, serum tubes are to be kept in a freezer whose temperature is set and maintained at 
-20°C or below. The temperature will be monitored and documented on the appropriate form 
during the entire trial. If it rises above -10°C for any period of time, the Clinical Logistics 
Coordinator must be notified. See the Operating Guidelines for further details. 
Shipments to the laboratories will be made only after appropriate monitoring, and following 
notification of the Clinical Logistics Coordinator. Sera will be shipped frozen, using dry ice to 
maintain them in a frozen state, in the packaging container provided by the carrier. Again, 
temperatures will be monitored. Shipments must be compliant with the International Air 
Transport Association (IATA) 602 regulations. 
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Samples will be shipped to GCI at Sanofi Pasteur. The address is provided in the Operating 
Guidelines. 
7.4 
Future Use of Stored Serum Samples for Research 
Any unused part of the serum samples will be securely stored at the Sanofi Pasteur serology 
laboratory (GCI) for at least 5 years after the last license approval in the relevant market areas has 
been obtained for the vaccine being tested. 
Subjects or subjects’ parents/legally representatives will be asked to indicate in the ICF whether 
they will permit the future use of any unused stored serum samples for other tests. If they refuse 
permission, the samples will not be used for any testing other than that directly related to this 
study. If they agree to this use, they will not be paid for giving permission (anonymity of samples 
will be ensured). The aim of any possible future research is unknown today, and may not be 
related to this particular study. It may be to improve the knowledge of vaccines or infectious 
diseases, or to improve laboratory methods. Genetic tests will never be performed on these 
samples without individual informed consent.  
8 
Clinical Supplies 
Sanofi Pasteur will supply the trial sites with protocols, ICFs, AFs, eCRFs, DCs, MAs, and other 
trial documents, as well as with the following trial materials: all study vaccines and injection 
materials, blood collection tubes, cryotubes, cryotube storage boxes, cryotube labels, temperature 
recorders, shipping containers, rulers, and digital thermometers. 
The means for performing Electronic Data Capture (EDC) will be defined by Sanofi Pasteur. If a 
computer is provided by Sanofi Pasteur, it will be retrieved at the end of the trial. 
The Investigator will supply all vaccination supplies, phlebotomy, and centrifugation equipment, 
including biohazard and/or safety supplies. The biohazard and safety supplies include needles and 
syringes, examination gloves, laboratory coats, sharps disposal containers, and absorbent 
countertop paper. The site will ensure that all biohazard wastes are autoclaved and disposed of in 
accordance with local practices. The Investigator will also supply appropriate space in a 
temperature-monitored refrigerator for the storage of the products and for the blood samples, and 
appropriate space in a temperature-monitored freezer for serum aliquots. 
In the event that additional supplies are required, study staff must contact Sanofi Pasteur, 
indicating the quantity required. Contact information is provided in the Operating Guidelines. 
They must allow approximately 1 week for an order to be filled and to have the supplies sent to 
their site. 
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9 
Endpoints and Assessment Methods 
9.1 
Primary Endpoints and Assessment Methods 
9.1.1 
Immunogenicity 
9.1.1.1 
Immunogenicity Endpoints 
The primary endpoints for the evaluation of immunogenicity are: 
Tdap vaccine immunogenicity 
x Ab concentrations against pertussis antigens (PT, FHA, PRN, FIM2+3) as measured by 
ELISA, 28 days after the dose of Tdap vaccine  
x Seroprotection against D and T, defined as anti-D and anti-7$EFRQFHQWUDWLRQV 0.1 
international units (IU)/mL, as measured by ELISA for T and by Diphtheria Micrometabolic 
Inhibition Test - Toxin Neutralization assay (MIT-TNA) for D, 28 days after the dose of Tdap 
vaccine  
CYD dengue vaccine immunogenicity 
x Neutralizing Ab titers against each of the 4 dengue serotypes, as measured by dengue 50% 
plaque reduction neutralization test (PRNT50), 28 days after the first dose of CYD dengue 
vaccine 
9.1.1.2 
Immunogenicity Assessment Methods  
Anti-Bordetella Pertussis Antibodies (US Methods) 
Assays will be performed by ELISA at Sanofi Pasteur. Purified PT, FHA, PRN, or FIM2+3 Ag is 
adsorbed to the wells of a microtiter plate. Diluted serum samples (test samples, reference 
standards, and quality controls) are incubated in the wells. Specific Abs in the serum samples bind 
to the immobilized Ag to form Ag-Ab complexes. Unbound Abs are washed from the wells, and 
enzyme-conjugated anti-human IgG is added. The enzyme conjugate binds to the Ag-Ab complex. 
Excess conjugate is washed away and a specific colorimetric substrate is added. Bound enzyme 
catalyzes a hydrolytic reaction causing color development. The intensity of the generated color is 
proportional to the amount of specific Ab bound to the wells. The results are read on a 
spectrophotometer (ELISA plate reader). An in house reference standard serum assayed on each 
plate is used to calculate the amount of specific PT, FHA, PRN, or FIM2+3 Ab in the test samples 
in ELISA unit (EU)/mL by comparison to the reference standard curves. The LLOQ for the anti-
PT, PRN, and FIM ELISA is 4 EU/mL and the LLOQ for the anti-FHA ELISA is 3 EU/mL. 
Antibodies to Tetanus Toxin  
Assays will be performed by ELISA at Sanofi Pasteur. Purified Tetanus Ag is adsorbed to the 
wells of a microtiter plate. Diluted serum samples (test samples, reference standard, and quality 
control) are incubated in the wells. Specific Abs in the serum samples bind to the immobilized 
Ag. Unbound Abs are washed from the wells, and enzyme-conjugated anti-human IgG is added. 
The enzyme conjugate binds to the Ag-Ab complex. Excess conjugate is washed away and a 
specific colorimetric substrate is added. Bound enzyme catalyzes a hydrolytic reaction, which 
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causes color development. The intensity of the generated color is proportional to the amount of 
specific Ab bound to the wells. The results are read on a spectrophotometer (ELISA plate reader). 
A reference standard assayed on each plate, WHO human standard lot TE3, is used to calculate 
the amount of specific anti-Tetanus Ab in the unitage assigned by the reference standard (IU/mL 
of serum). The LLOQ for the anti-Tetanus ELISA is 0.01 IU/mL. 
Antibodies to Diphtheria Toxin (MIT Method) 
Assays will be performed by an MIT-TNA at Sanofi Pasteur. Serial dilutions of human sera are 
mixed with diphtheria challenge toxin and incubated with Vero cells that are sensitive to the toxin. 
Neutralizing Abs specific to diphtheria toxin contained in the serum samples bind to and 
neutralize the toxin. The neutralized toxin does not affect cellular viability, therefore the cultured 
cells continue to metabolize and release CO2, reducing the pH of the culture medium. Cell 
survival correlates with the change in the color of the pH indicator (phenol red to yellow at pH 
 7.0) contained in the medium. In the absence of neutralizing Abs, the challenge toxin reduces 
cellular metabolism and CO2 production, therefore the pH does not decrease and a color change is 
not detected. The LLOQ is 0.005 IU/mL. 
Dengue Neutralizing Abs 
Dengue neutralizing Ab levels will be measured by PRNT50 (using parental dengue virus strains 
of CYD dengue vaccine constructs) by Sanofi Pasteur GCI, Swiftwater, USA (or outsourced with 
a GCI selected external laboratory). 
Serial, two-fold dilutions of serum to be tested (previously heat-inactivated) are mixed with a 
constant challenge-dose of each dengue virus serotype 1, 2, 3 or 4 (expressed as plaque-forming 
unit [PFU]/mL). The mixtures are inoculated into wells of a microplate with confluent Vero cell 
monolayers. After adsorption, cell monolayers are incubated for a few days. The presence of 
dengue virus infected cells is indicated by formation of plaques. A reduction in virus infectivity 
due to neutralization by Ab present in serum samples is detected. The reported value (end point 
neutralization titer) represents the highest dilution of serum at whicK 50% of dengue challenge 
virus (in plaque counts) is neutralized when compared to the mean viral plaque count in the 
negative control wells which represents the 100% virus load. The end point neutralization titers 
are presented as continuous values. The LLOQ of the assay is 10 (1/[dil]). 
9.1.2 
Safety 
There are no primary objectives for safety. 
9.1.3 
Efficacy 
There are no primary objectives for efficacy. 
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9.2 
Secondary Endpoints and Assessment Methods 
9.2.1 
Immunogenicity 
9.2.1.1 
Immunogenicity Endpoints 
CYD dengue vaccine Immunogenicity: 
x Neutralizing Ab titers against each of the 4 dengue serotypes, as measured by dengue PRNT50, 
at baseline (M1) and 28 days after the first and third doses of CYD dengue vaccine 
x 1HXWUDOL]LQJ$EWLWHUVGLODJDLQVWHDFKRIWKHGHQJXHVHURW\SHVDQGDJDLQVWDWOHDVW
2, 3, or 4 dengue serotypes, as measured by dengue PRNT50, at baseline (M1) and 28 days 
after the first and third doses of CYD dengue vaccine 
x Neutralizing Ab tLWHUVGLIIHUHQWWLWHUWKUHVKROGVGLODJDLQVWHDFKRIWKHGHQJXH
serotypes, as measured by dengue PRNT50, at baseline (M1) and 28 days after the first and 
third doses of CYD dengue vaccine 
Tdap Immunogenicity: 
x Ab concentrations against PT, FHA, PRN, and FIM2+3, as measured by ELISA, at baseline 
(D0 for group 2, M1 for Group 1) and 28 days after the dose of Tdap vaccine 
x Anti-T and anti-'$EFRQFHQWUDWLRQV,8P/DVPHDVXUHGE\(/,6$IRU7DQGE\0,7-
TNA for D, at baseline (D0 for group 2, M1 for Group 1) and 28 days after the dose of Tdap 
vaccine 
9.2.1.2 
Immunogenicity Assessment Methods 
The immunogenicity assessment methods for the secondary endpoints are the same as those 
presented in Section 9.1.1.2. 
9.2.2 
Safety 
9.2.2.1 
Safety Definitions 
The following definitions are taken from the ICH E2A Guideline for Clinical Safety Data 
Management: Definitions and Standards for Expedited Reporting. 
Adverse Event: 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding, for example), symptom or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the medicinal 
product.  
Therefore an AE may be: 
x A new illness 
x The worsening of a concomitant illness 
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x An effect of the vaccination, including the comparator 
x A combination of the above 
All AEs include serious and non-serious AEs. 
Surgical procedures are not AEs; they are the action taken to treat a medical condition. It is the 
condition leading to the action taken that is the AE (if it occurs during the trial period). 
Pre-existing medical conditions are not to be reported as AEs. However, if a pre-existing 
condition worsens in frequency or intensity, or if in the assessment of the treating physician there 
is a change in its clinical significance, this change should be reported as an AE (exacerbation). 
This applies equally to recurring episodes of pre-existing conditions (e.g., asthma) if the 
frequency or intensity increases post-vaccination. 
Serious Adverse Event: 
Serious and severe are not synonymous. The term severe is often used to describe the intensity of 
a specific event as corresponding to Grade 3. This is not the same as serious which is based on 
patient/event outcome or action criteria usually associated with events that pose a threat to a 
patient’s life or functioning. Seriousness, not severity, serves as a guide for defining regulatory 
reporting obligations. 
An SAE is any untoward medical occurrence that at any dose: 
x Results in death 
x Is life-threateninga 
x Requires inpatient hospitalization or prolongation of existing hospitalizationb 
x Results in persistent or significant disability/incapacityc 
x Is a congenital anomaly/birth defect 
x Is an important medical eventd 
                                                 
a  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 which hypothetically might have caused death if it were more severe. 
b  All medical events leading to hospitalizations will be recorded and reported as SAEs, with the exception of: 
hospitalization planned before inclusion into the study or out-patient treatment with no hospitalization.  
c  “Persistent or significant disability or incapacity” means that there is a substantial disruption of a person’s ability 
to carry out normal life functions. 
d  Medical and scientific judgment should be exercised in deciding whether expedited reporting is appropriate in 
other situations, such as important medical events that may not be immediately life-threatening or result in death 
or hospitalization but may jeopardize the health of the subject or may require intervention to prevent one of the 
other outcomes listed in the definition above. These should also usually be considered serious. Examples of such 
events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse, new onset diabetes, or autoimmune disease. 
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Additionally, the following important medical events are to be considered as SAEs and reported 
to the Sponsor according to the procedure described in Section 10: 
Adverse Reaction: 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered adverse reactions (AR). 
(The phrase “responses to a medicinal product” means that a causal relationship between a 
medicinal product and an AE is at least a reasonable possibility) 
Unexpected Adverse Reaction (UAR): 
An UAE is an AR, the nature or severity of which is not consistent with the applicable product 
information (e.g., Investigator’s Brochure for an unapproved investigational medicinal product).  
The following additional definitions are used by Sanofi Pasteur: 
Solicited Reaction: 
A solicited reaction is an event that is prelisted in the eCRF. The assessment of these AEs post-
vaccination is mandatory. A solicited reaction is defined by a combination of: 
x Symptom and 
x Onset post-vaccination 
e.g., injection site pain between D0 and D7 post-vaccination, or headache between D0 and D14. 
A solicited reaction is therefore an AR observed and reported under the conditions (symptom and 
onset) prelisted (i.e., solicited) in the eCRF and considered as related to vaccination. 
Unsolicited AE/AR: 
An unsolicited AE is an observed AE that does not fulfill the conditions prelisted in the eCRF in 
terms of diagnosis and/or onset post-vaccination, i.e., excluding solicited reactions, e.g., if 
headache between D0 and D14 is a solicited reaction (i.e., prelisted in the eCRF), then a headache 
starting on D14 is a solicited reaction, whereas headache starting on D15 post-vaccination is an 
unsolicited AE. 
An unsolicited non-serious AE is an unsolicited AE excluding SAEs. 
Injection Site Reaction: 
An injection site reactiona is an AR at and around the injection site. Injection site reactions are 
commonly inflammatory reactions.  
Systemic AE: 
Systemic AEs are all AEs that are not injection site reactions. They therefore include systemic 
manifestations such as headache, fever, as well as localized or topical manifestations that are not 
associated with the vaccination site, e.g., erythema that is localized but that is not at the injection 
site. 
                                                 
a  All injection site AEs are considered to be related to vaccination and are therefore all injection site reactions. 
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Adverse Events of Special Interest (AESIs): 
AEs of special interest are AEs that are considered by the Sponsor to be relevant for the 
monitoring of the safety profile of the investigational vaccine. 
9.2.2.2 
Safety Endpoints 
Safety endpoints for Tdap vaccine and CYD dengue vaccine safety in each group are: 
x Occurrence of immediate AEs reported in the 30 minutes after each/any injection 
x Occurrence of solicited (i.e., pre-listed in the subject’s DC and eCRF) injection site reactions 
(pain, erythema and swelling) within 7 days following each/any injection 
x Occurrence of solicited systemic reactions (fever, headache, malaise, myalgia, and asthenia) 
occurring up to 14 days following each/any injection 
x Occurrence of unsolicited (spontaneously reported) AEs within 28 days following each/any 
injection 
x Occurrence of non-serious AESIs* occurring up to 7 days following each and any injection 
x Occurrence of SAEs, including serious AESIs* (with specific time windows according to the 
type of AESI*) throughout the trial** 
x Occurrence of hospitalized VCD cases throughout the trial (i.e., from D0 through the end of 
the study) 
*      Hypersensitivity/allergic reactions (serious or not) within 7 days after each CYD dengue 
vaccine injection, serious viscerotropic disease within 30 days after each CYD dengue 
vaccine injection, serious neurotropic disease within 30 days after each CYD dengue vaccine 
injection; serious dengue cases requiring hospitalization (i.e., hospitalized suspected dengue 
case) occurring in all subjects at any time during the study. 
**   Subjects from Group 1 will not be vaccinated at V01 but will receive the first vaccinations at 
V02. However, SAEs will be recorded from inclusion and subjects from Group 1 will receive 
a SAE-specific DC at V01 that will be collected at V02.  
Depending on the item, these could include: nature (Medical Dictionary for Regulatory Activities 
[MedDRA] preferred term), time of onset, duration, number of days of occurrence, grade of 
severity, relationship to vaccine, action taken, whether the AE led to early termination from the 
study, seriousness, or outcome. 
Hospitalized suspected dengue case is defined as an acute febrile illness with diagnosis of dengue 
requiring hospitalization (with bed attribution). In such cases, 1 unplanned acute blood sample 
(within the first 5 days after fever onset) will be collected for virological confirmation of 
hospitalized suspected dengue case. A suspected case will be considered VCD if there is a 
detection of WT dengue virus by dengue NS1 Ag ELISA and/or dengue RT-PCRs (at the GCI or 
GCI designated laboratory).  
Note: Acute blood sample for all hospitalized suspected dengue cases should be collected within 
the pre-specified timeframe as described above. If this cannot be accomplished, this sample 
should still be obtained as soon as possible thereafter, for IDMC severity assessment. 
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9.2.2.3 
Safety Assessment Methods 
At each visit, the Investigator or a delegate will perform a clinical or medically-driven physical 
examination, and will ask the subject or legally acceptable representative about any solicited 
reactions and unsolicited AEs recorded in the DC or MA, as well as about any other AEs that may 
have occurred since the previous visit. All relevant data will be transcribed into the eCRF 
according to the instructions provided by the Sponsor. 
9.2.2.3.1 
Immediate Post-vaccination Surveillance Period 
Subjects will be kept under observation for 30 minutes after each vaccination to ensure their 
safety. The post-vaccination surveillance should be documented in the source document. Any AE 
that occurs during this period will be noted on the source document and recorded in the eCRF, as 
follows: 
x Any unsolicited systemic AE occurring during the first 30 minutes post-vaccination will be 
recorded on the eCRF as immediate unsolicited systemic AE 
x Solicited and unsolicited injection site reactions and solicited systemic reactions will be 
recorded and analyzed as starting on the day of vaccination 
x Any SAE occurred during the first 30 minutes post-vaccination will be reported in the same 
way as any other SAE and to the Sponsor, according to the procedures described in Section 10 
9.2.2.3.2 
Reactogenicity: Solicited Reactions From Day 0 to Day 7 (injection site reactions) 
or Day 14 (systemic reactions) After Each Vaccination 
After each vaccination, subjects or legally acceptable representatives will be provided with a 
safety DC, a digital thermometer, and a flexible ruler, and will be instructed how to use them. The 
following items will be recorded by the subjects in the DC on the day of vaccination and for the 
next 7 days (i.e., D0 to D7) for the solicited injection site reactions and for the next 14 days (i.e., 
D0 to D14) for the solicited systemic reactions, until resolution: 
x Daily temperature, with the route by which it was taken 
x Daily measurement or intensity grade of all other solicited injection site and systemic 
reactions 
x Action taken for each event, if any (e.g., medication) 
The action taken by the subjects or legally acceptable representatives to treat any solicited 
reactions will be classified in the eCRF using the following scale: 
0: None 
1: Medication (self-medication with an existing prescription or over-the-counter medication) 
2: Health care provider contact (no new medication prescribed) 
3: Health care provider contact and prescription of a new medication (health care provider 
instructed subject to take a new medication, either an over-the-counter medication or one 
requiring a written prescription) 
4: Hospitalization (inpatient) 
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Table 9.1 to Table 9.3 present, the injection site reactions and systemic reactions that are prelisted 
in the DCs and eCRF, together with the intensity scales. 
 
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Table 9.1: Solicited injection site reactions: terminology, definitions, and intensity scales for subjects aged 9 to 11 years  
CRF term 
(MedDRA lowest 
level term [LLT]) 
Injection site pain 
Injection site erythema 
Injection site swelling  
DC term 
Pain 
Redness 
Swelling 
Definition 
 
Presence of a redness including the 
approximate point of needle entry 
Swelling at or near the injection site 
Swelling or edema is caused by a fluid 
infiltration in tissue or cavity and, depending 
on the space available for the fluid to 
disperse, swelling may be either soft 
(typically) or firm (less typical) to touch and 
thus can be best described by looking at the 
size of the swelling 
Intensity scale* 
 
Grade 1: Easily tolerated 
Grade 2: Sufficiently discomforting to 
interfere with normal behavior or activities 
Grade 3: Incapacitating, unable to perform 
usual activities 
Grade 1: > 0 to < 25 mm 
Grade  25 to < 50 mm 
Grade  50 mm 
Grade 1: > 0 to < 25 mm 
Grade  25 to < 50 mm 
Grade  50 mm 
*  For the subjective reaction of pain, subjects or parents/legally acceptable representatives will record the intensity level (Grade 1, 2, or 3) in the DC. For the measurable reactions of 
redness and swelling, they will record just the size of the reaction, and the classification as Grade 1, 2, or 3 will be assigned at the time of the statistical analysis. 
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Table 9.2: Solicited injection site reactions: terminology, definitions, and intensity scales for subjects aged >= 12 years for all subjects 
CRF term 
(MedDRA LLT) 
Injection site pain 
Injection site erythema 
Injection site swelling  
DC term 
Pain 
Redness 
Swelling 
Definition 
 
Presence of a redness including the 
approximate point of needle entry 
Swelling at or near the injection site 
Swelling or edema is caused by a fluid 
infiltration in tissue or cavity and, depending 
on the space available for the fluid to 
disperse, swelling may be either soft 
(typically) or firm (less typical) to touch and 
thus can be best described by looking at the 
size of the swelling 
Intensity scale* 
 
Grade 1: No interference with activity 
Grade 2: Some interference with activity 
Grade 3: Significant; prevents daily activity 
Grade  WR 50 mm 
Grade  WR 100 mm 
Grade 3: > 100 mm 
Grade  WR 50 mm 
Grade  WR 100 mm 
Grade 3: > 100 mm 
* For the subjective reaction of pain, subjects/parents/legally acceptable representatives will record the intensity level (Grade 1, 2, or 3) in the DC. For the measurable reactions of 
redness and swelling, they will record just the size of the reaction, and the classification as Grade 1, 2, or 3 will be assigned at the time of the statistical analysis 
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Table 9.3: Solicited systemic reactions: terminology, definitions, and intensity scales 
CRF term 
(MedDRA 
LLT) 
Fever 
Headache 
Malaise 
Myalgia 
Asthenia 
DC term 
Temperature 
Headache 
Feeling unwell 
Muscle aches and pains 
Weakness 
Definition 
Elevation of temperature to 
& 100.4°F) 
Pain or discomfort in the head 
or scalp. Does not include 
migraine. 
General ill feeling. 
Malaise is a generalized 
feeling of discomfort, illness, 
or lack of well-being that can 
be associated with a disease 
state. It can be accompanied 
by a sensation of exhaustion 
or inadequate energy to 
accomplish usual activities. 
Muscle aches and pains are 
common and can involve more 
than one muscle at the same time. 
Muscle pain can also involve the 
soft tissues that surround muscles. 
These structures, which are often 
referred to as connective tissues, 
include ligaments, tendons, and 
fascia (thick bands of tendons). 
Does not apply to muscle pain at 
the injection site which should be 
reported as injection site pain. 
Generalized weakness. 
Intensity scale* 
Grade  38.0°C to 
 38.4°C, 
or  )WR 101.1°F 
Grade 1: No interference with 
activity 
Grade 1: No interference with 
activity 
Grade 1: No interference with 
activity 
Grade 1: No interference 
with activity 
 
Grade  38.5°C to 
 38.9°C, 
or  )WR 102.0°F 
Grade 2: Some interference 
with activity 
Grade 2: Some interference 
with activity 
Grade 2: Some interference with 
activity 
Grade 2: Some 
interference with activity 
 
Grade  39.0°C 
or  102.1°F 
Grade 3: Significant; prevents 
daily activity 
Grade 3: Significant; prevents 
daily activity 
Grade 3: Significant; prevents 
daily activity 
Grade 3: Significant; 
prevents daily activity 
*  For all reactions but fever, subjects or parents/legally acceptable representatives will record the intensity level (Grade 1, 2, or 3) in the DC. For fever, they will record the body 
temperature, and the classification as Grade 1, 2, or 3 will be assigned at the time of the statistical analysis. 
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Important notes for the accurate assessment of temperature: 
Subjects or legally acceptable representatives are to measure body temperature once per day, 
preferably always at the same time. The optimal time for measurement is the evening, when body 
temperature is the highest. Temperature is also to be measured at the time of any apparent fever. 
The observed daily temperature and the route of measurement are to be recorded in the DC/MA, 
and the highest temperature will be recorded by the site in the eCRF. The preferred route for this 
trial is axillary. Pre-vaccination temperature is also systematically collected by the Investigator in 
the eCRF for subjects aged between 9 and 11 years old, and on the source document for other 
subjects. Tympanic thermometers must not be used. 
9.2.2.3.3 
Unsolicited Non-serious Adverse Events From Day 0 to Day 28 After Each 
Vaccination 
In addition to recording solicited reactions, subjects or legally acceptable representatives will be 
instructed to record any other medical events that may occur during the 28-day period after each 
vaccination to be taken as per the trial design. Space will be provided in the DC for this purpose.  
For each unsolicited non-serious AE, the following information is to be recorded: 
Start and stop datesa  
Intensity of the event: 
x For measurable unsolicited non-serious AEs that are part of the list of solicited reactions, 
the size of the AE as well as the temperature for fever will be collected and analyzed based on 
the corresponding scale used for solicited reactions (see Table 9.1 to Table 9.3) 
x Other unsolicited non-serious AEs will be classified according to the following intensity scale: 
x 
Grade 1: No interference with activity 
x 
Grade 2: Some interference with activity 
x 
Grade 3: Significant; prevents daily activity 
Action taken for each AE, if any (e.g., medication) 
The action taken by the subject or legally acceptable representative to treat any unsolicited AEs 
will be classified in the eCRF using the following scale: 
0: None 
1: Medication (self-medication with an existing prescription or over-the-counter medication) 
2: Health care provider contact (no new medication prescribed) 
                                                 
a The stop date of all related AEs will be actively solicited. For other events, the Investigator will provide the stop 
date when it becomes available. AEs for which no stop date was obtained during the course of the trial will be 
considered as ongoing at the end of the trial. 
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3:  Health care provider contact and prescription of a new medication (health care provider 
instructed subject to take a new medication, either an over-the-counter medication or one 
requiring a written prescription) 
x Whether the AE led to discontinuation 
x Whether the AE was related to vaccination (for unsolicited systemic AEs) 
9.2.2.3.4 
Serious Adverse Events 
Information on SAEs will be collected and assessed throughout the trial, from inclusion until 
6 months after the last vaccination. 
Any SAE occurring at any time during the trial will be reported by the Investigator through the 
EDC system and according to the completion guidelines provided by the Sponsor. All information 
concerning the SAE is to be reported, either as part of the initial reporting or during follow-up 
reporting if relevant information became available later (e.g., outcome, medical history, results of 
investigations, copy of hospitalization reports. The Investigator will assess the causal relationship 
between the SAE and the investigational product as either “Not related” or “Related”, as described 
in Section 10.4. 
See Section 10 for further details on SAE reporting. 
9.2.2.3.5 
Adverse Events of Special Interest 
The following AESIs will be considered: 
Non-Serious AESIs 
x Non-serious hypersensitivity/allergic reactions occurring in all subjects within 7 days after 
vaccination. 
Serious AESIs 
x Serious hypersensitivity/allergic reactions occurring in all subjects within 7 days after CYD 
dengue vaccine injection 
x Serious viscerotropica disease occurring in all subjects within 30 days after vaccination CYD 
dengue vaccine injection 
x Serious neurotropica disease occurring in all subjects within 30 days after vaccination CYD 
dengue vaccine injection 
x Serious dengue cases requiring hospitalizationb, occurring in all subjects at any time during 
the study 
                                                 
a Specific guidelines will be provided to the Investigator to help in the assessment of AEs that may be indicative of 
viscerotropic or neurotropic disease (see Guidelines for Assessing Viscerotropic and Neurotropic AE). 
b Serious dengue case requiring hospitalization is a hospitalized suspected dengue case.  
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9.2.2.3.6 
Assessment of Causality  
The Investigator will assess the causal relationship between each unsolicited systemic AE and 
vaccination as either not related or related, based on the following definitionsa: 
0: Not related – The AE is clearly/most probably caused by other etiologies such as subject’s 
underlying condition, therapeutic intervention, or concomitant therapy; or the delay 
between vaccination and the onset of the AE is incompatible with a causal relationship; or 
the AE started before vaccination (screening phase, if applicable) 
1:  Related – There is a “reasonable possibility” that the AE was caused by the vaccination, 
meaning that there is evidence or arguments to suggest a causal relationship 
Note: By convention, all injection site AEs (solicited and unsolicited) and all solicited systemic 
reactions are considered to be related to vaccination and referred to as reactions, and therefore do 
not require the Investigator’s opinion on relatedness. 
AEs likely to be related to the product, whether serious or not, that persist at the end of the trial 
will be followed up by the Investigator until their complete disappearance or the stabilization of 
the subject’s condition. The Investigator will inform the Sponsor of the date of final 
disappearance of the event. 
9.2.3 
Methods for Assessing Virological Confirmation of Hospitalized Suspected Dengue 
Case and Assessment of Case Severity 
In the event of a hospitalized suspected dengue case, the following tests will be performed on the 
acute BL based on the process described below. 
Dengue Screen RT-PCR 
Dengue screen RT-PCR test will be performed by Sanofi Pasteur GCI, Swiftwater, USA or GCI 
designated laboratory. 
Assessment and quantitation of dengue viremia is determined by testing serum samples with a 
nucleic-acid based assay. RNA is extracted from the serum to discard potential Taq polymerase 
inhibitors or interfering factors, using a commercial kit. Then, a RT-PCR is carried out with 
primers from a gene sequence conserved among dengue viruses. Due to a virus standard included 
in each run, results can be expressed as a concentration of log10 plaque forming unit (PFU)/mL. 
Dengue NS1 Ag ELISA  
The NS1 Ag ELISA will be performed using a commercially available kit: “PlateliaTM Dengue 
NS1 Ag” from Bio-Rad (Marnes-la-Coquette, France). The manufacturer’s instructions are 
followed. The Dengue NS1 Ag test is a one-step sandwich-ELISA based assay that enables 
detection of NS1 Ag in serum. The test uses murine monoclonal antibodies (MAbs) for capture 
and revelation. Samples and controls are directly and simultaneously incubated with the conjugate 
within the microplate wells coated with MAb. If NS1 Ag is present in the sample, an immune-
                                                 
a  ICH Guidelines, Clinical Safety Data Management E2A 
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complex MAb-NS1-MAb/peroxidase will be formed. The presence of immune-complex is 
demonstrated by addition of a chromogenic solution that initiates a color development reaction. 
After 30 minutes of incubation at room temperature, the enzymatic reaction is stopped by addition 
of an acid solution. The optical density (OD) reading obtained with a spectrophotometer set at 
450/620 nm is proportional to the amount of NS1 Ag present in the sample. The presence of NS1 
Ag in an individual sample is determined by comparing the OD reading of the sample to the OD 
of the cutoff control serum. 
Sample ratios of <  WR 1.0, and > 1.0 will be indicative of negative, equivocal, and 
positive results, respectively. 
SimplexaTM Dengue RT-PCR 
Serotype identification of post-infectious dengue viremia is determined by testing serum samples 
with a nucleic-acid based assay. Briefly, RNA is extracted from the serum to discard potential 
polymerase inhibitors or interfering factors, using a commercial kit. Then the Simplexa dengue 
RT-PCR assay is carried out which incorporates serotype-specific primers from dengue 
sequences. The results are expressed qualitatively and reported for each dengue serotype as 
detected or not detected.  
This assay will be used on all dengue screen RT-PCR positive or Dengue NS1 Ag ELISA positive 
samples for serotype identification. In addition sequencing analysis may be attempted on isolates 
from the serotyped samples. 
Interpretation of Results 
If a sample is positive for the dengue screen RT-3&5LH LLOQ) and/or the NS1 assay is 
positive and/or the Simplexa dengue RT-PCR is positive, this will be classified as a virologically-
confirmed dengue infection (i.e., the associated AE will be considered as a hospitalized VCD 
case). 
Hematology – Biochemistry 
Hematology and biochemistry parameters (AST, ALT, creatinine, blood cell count, total bilirubin, 
and hematocrit count) will be measured by local laboratories using standard methods as per 
routine standard of care in the Philippines. However, the measurement of any of these biological 
parameters may be undertaken (or repeated), based on the Investigator’s judgment, to ensure the 
adequate evaluation of hospitalized VCD case severity. It is noteworthy that hematocrit and 
platelet counts are required parameters in the WHO/IDMC severity assessment protocol. The 
results will be collected in the eCRF. 
The assessment of biological parameters will be: within normal range or outside normal range. 
Normal ranges for each biological parameter will be provided by the local laboratory and 
collected in the eCRF. 
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Severity of hospitalized VCD cases 
Each hospitalized VCD case will be assessed for severity by an IDMC. 
The following potential manifestations of severity in all hospitalized VCD cases will be 
considered: 
1) 3ODWHOHWFRXQW/and bleeding (tourniquet, petechiae or any bleeding) plus plasma 
leakage (effusion on chest x-ray or clinically apparent ascites including imaging procedures 
RUKHPDWRFULWabove baseline recovery level or standard for age if only one reading) 
2) 6KRFNSXOVHSUHVVXUHPP+JLQDFKLOGRUK\SRWHQVLRQ>PP+J@ZLWKWDFK\FDUGLD
weak pulse and poor perfusion) 
3) Bleeding requiring blood transfusion 
4) Encephalopathy i.e., unconsciousness or poor conscious state or fitting not attributable to 
simple febrile convulsion or focal neurological signs. Poor conscious state or 
unconsciousness must be supported by Glasgow Coma Scale or Blantyre Coma score  
5) Liver impairment (AST > 1000 U/L or prothrombin time International normalized ratio > 1.5) 
6) ,PSDLUHGNLGQH\IXQFWLRQ6HUXPFUHDWLQLQHPJG/ 
7) Myocarditis, pericarditis or heart failure (clinical heart failure) supported by chest X-ray, 
echocardiography, electrocardiogram or cardiac enzymes where these are available 
8) Every effort must be made to identify and document any existing chronic co-morbidity, such 
as uncontrolled epilepsy, chronic liver disease, of existing cardiac disease or acute co-
morbidity, such as acute hepatitis. 
The designation of a hospitalized VCD case as severe will be made on a case by case basis by the 
IDMC. 
9.2.4 
Efficacy 
There are no secondary objectives for efficacy. 
9.3 
Observational Endpoints and Assessment Methods 
There are no observational objectives in this study. 
10 Reporting of Serious Adverse Events  
In order to comply with current regulations on SAE reporting to health authorities, the 
Investigator must document all SAEs regardless of causal relationship, and notify the Sponsor and 
the Clinical Research Associate (CRA) and/or the Regional Clinical Trial Manager (RCTM) 
within the notification timelines stated in the following sections. The Investigator will give access 
and provide the Sponsor and the CRA and/or the RCTM with all necessary information to allow 
the Sponsor to conduct a detailed analysis of the safety of the investigational product(s). It is the 
responsibility of the Investigator to request all necessary documentation (e.g., medical records, 
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discharge summary, autopsy) in order to provide comprehensive safety information. All relevant 
information must then be transcribed into the SAE Reporting Form. 
10.1 Initial Reporting by the Investigator 
SAEs occurring during a subject’s participation in the trial or experiment must be reported within 
24 hours to the Sponsor’s GPV Department and to the CRA. Every SAE must be reported, even if 
the Investigator considers that it is not related to the vaccine. The SAE form must be signed by a 
licensed physician (M.D. or D.O.) for whom the task is listed on the Study Task Delegation and 
Signature List after each update to the Form. 
The Investigator must complete the “eSAE Form” in the EDC application. After validation, an e-
mail alert will automatically be sent to the GPV mailbox, the CRA and the Global Medical 
Expert. This message will include the country, the study code, the subject number, whether the 
report is initial or a follow-up, the diagnosis and/or symptoms, the seriousness criteria, and the 
outcome, if fatal. 
If the EDC system is unavailable, the site must notify the Sponsor using the paper version of the 
SAE Reporting Form, as follows: 
The Investigator must complete the SAE Reporting Form, check off the “Initial Reporting Form” 
box, and send it to the Sponsor by one of the following means: 
x By fax, to the following number: +33 4 37 37 71 32 
x In PDF format to the following e-mail address, using a method of transmission that 
includes password protection: pv.outsourcing@sanofipasteur.com 
x By express mail, to the following address, using a method of transmission that includes 
password protection:  
Sanofi Pasteur SA 
Global Pharmacovigilance Department 
14, Espace Henry Vallée 
69007 Lyon – France 
 
When the system becomes available, the Investigator must transcribe the information from the 
paper version of the eSAE Form into the EDC system. 
If there is need for urgent consultation, the Investigator is to contact a designated Sponsor 
representative. The contact information is provided in the “Investigators and Other Important 
Study Participants” document.  
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10.2 Follow-up Reporting by the Investigator 
The eSAE Form completed initially must be updated within 24 hours after the Investigator has 
become aware of any new relevant information concerning the SAE (e.g., outcome, precise 
description of medical history, results of the investigation). After validation, an e-mail alert will 
be sent automatically to the GPV Department and to the CRA and/or the RCTM. All relevant 
information must be included directly in the eSAE form. Copies of documents (e.g., medical 
records, discharge summary, autopsy) may be requested by the GPV Department.  
The anonymity of the subject must always be respected when forwarding this information. 
10.3 Reporting of SAEs Occurring After a Subject Has Completed the Study 
Any SAE that occurs after a subject has completed the study but that is likely to be related to the 
product or to the experiment must also be reported as soon as possible. In such a case, the 
reporting procedure to be followed is identical to that described in Section 10.1. 
10.4 Assessment of Causality 
The causal relationship between the SAE and the product will first be evaluated by the 
Investigator, using the following definitions: 
0 - Not related: The AE is clearly/most probably caused by other etiologies such as an 
underlying condition, therapeutic intervention, or concomitant therapy; or the delay between 
vaccination and the onset of the SAE is incompatible with a causal relationship; or the SAE 
started before vaccination (screening phase, if applicable). 
1 - Related: There is a “reasonable possibility” that the SAE was caused by the vaccination, 
meaning that there is evidence or arguments to suggest a causal relationship. 
(ICH Guidelines, Clinical Safety Data Management E2A) 
Following this, the Sponsor’s Product Safety Officer (PSO) will also assess the causal relationship 
to the product, based on the available information and current medical knowledge. 
The decision to modify or discontinue the trial may be made after mutual agreement between the 
Sponsor and the Investigator(s). 
10.5 Reporting SAEs to Health Authorities and IECs/IRBs 
The Sponsor will inform the relevant health authorities of any reportable SAEs according to the 
local regulatory requirements. Reporting to the health authorities will be according to the 
Sponsor’s standard operating procedures. 
The Sponsor’s RMO will notify the Investigators in writing of the occurrence of any reportable 
SAEs. The Investigators/Sponsor will be responsible for informing the IECs or IRBs that 
reviewed the trial protocol. 
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11 Data Collection and Management 
11.1 Data Collection and eCRF Completion 
Individual safety DCs, specifically designed for this trial by the Sponsor and provided to the study 
sites, will be given to study participants for the recording of daily safety information as described 
in Section 9.2.2.3. These DCs will include prelisted terms and intensity scales (see Table 9.1 to 
Table 9.3) as well as areas for free text to capture additional safety information or other relevant 
details. Subjects or legally acceptable representatives will also be provided with rulers for 
measuring the size of injection site reactions, and with standard digital thermometers for 
measuring daily temperatures. To ensure consistency of reporting, the study sites will instruct 
subjects or legally acceptable representatives on how to correctly use these tools. 
The 6-month follow-up will be done by interviewing subjects either during a visit or over the 
telephone using a questionnaire to capture SAEs and AESIs, if applicable. A memory aid will be 
provided to the subjects at the preceding trial visit to help them record information on events 
occurring between this visit and the 6-month follow-up. 
Relevant information will be transcribed into the eCRF. Any SAEs captured during this 6-month 
follow-up period will be reported and followed-up as per the normal process for reporting SAEs. 
The clinical team may decide to replace the MA by a DC if a follow-up visit is planned for the 
subjects. 
At specified intervals, the Investigator or an authorized designee will interview the subjects or 
legally acceptable representatives to collect the information recorded in the DC, and will attempt 
to clarify anything that is incomplete or unclear. All clinical trial information gathered by the 
study site will be reported electronically by the Investigator or authorized designee using a web-
based eCRF. (Any information that was not documented in the DC will first be captured in the 
source document and then reported electronically.) The eCRF has been designed specifically for 
this trial under the responsibility of the Sponsor, using a validated Electronic Records/Electronic 
Signature-compliant platform (21 CFR Part 11). 
To ensure the correct and consistent completion of the eCRF, the Sponsor or authorized 
representative will provide all necessary tools, instructions, and training to all site staff involved 
in data entry prior to study start. Additional instructional documents such as training manuals and 
completion guidelines will be provided to assist with data entry during the course of the trial. 
Upon completion of training, each user requiring access to the EDC system will be issued a 
unique username and password. In the event of a change in trial personnel, each newly assigned 
individual will receive a unique username and password; the username and password of a 
previous user may not be reissued. If any trial personnel leave the study, the Investigator is 
responsible for informing the Sponsor immediately so that their access is deactivated. An audit 
trail will be initiated in the EDC system at the time of the first data entry in order to track all 
modifications and to ensure database integrity. 
The Investigator is responsible for the timeliness, completeness, and accuracy of the information 
in the eCRF; must provide explanations for all missing information; and must sign the eCRF 
using an e-signature. 
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11.2 Data Management 
11.2.1 Management of Clinical Data 
Data generated during the trial will be managed following two different processes: 
x Clinical data, defined as all data reported in the eCRF, and laboratory data will be handled 
by the Sponsor’s Clinical Data Management (CDM) platform or authorized representative. 
x Data pertaining to SAEs and pregnancies, which are reported by the Investigator 
respectively on the eSAE Forms or SAE Reporting Forms and e-Pregnancy Forms, will be 
handled by the Sponsor’s GPV Department. 
During the trial, clinical data reported in the eCRF will be integrated into the clinical database 
under the responsibility of the Sanofi Pasteur CDM platform. Data monitoring at the sites and 
quality control in the form of computerized logic and/or consistency checks will be systematically 
applied in order to detect errors or omissions. In addition, data reviews may be performed several 
times by the Sponsor’s staff in the course of the trial. Any questions pertaining to the reported 
clinical data will be submitted to the investigator for resolution using the EDC system. Each step 
of this process will be monitored through the implementation of individual passwords to maintain 
appropriate database access and to ensure database integrity. 
The validation of the immunogenicity data will be performed at the laboratory level following the 
laboratory’s procedures. Information from the laboratory will be checked for consistency before 
integration into the clinical database. 
After integration of all corrections in the complete set of data, and after the SAE information 
available from CDM and the GPV Department has been reconciled, the database will be released for 
statistical analysis. 
11.2.2 Data Management of SAEs and Pregnancies 
During the trial, data pertaining to SAEs reported on eSAE Forms and data pertaining to 
pregnancies reported in e-Pregnancy Form will be integrated into the Sponsor’s centralized GPV 
database. 
Upon receipt of an eSAE Form, the data will be entered into the GPV database after a duplicate 
check. Each SAE case will be assigned a case identification number. Each case will be entered in 
the GPV database and assessed by the case management platform or its delegate before being 
reported to the relevant authorities as necessary. Assessment of related cases will be done in 
collaboration with the PSO and the RMO. Follow-up information concerning a completed case 
will be entered into the GPV database, and a new version of the case will be created. 
The information pertaining to SAEs in the GPV database will be reconciled with that in the 
clinical database. 
11.2.3 Data Review 
A review of the data is anticipated through the data review process led by Data Management 
before each database lock.  
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12 Statistical Methods and Determination of Sample Size 
12.1 Statistical Methods 
All statistical analyses will be performed under the responsibility of the Sponsor’s Biostatistics 
Platform using the SAS® software, at least Version 9.4 (SAS Institute, Cary, NC, USA). 
A detailed Statistical Analysis Plan (SAP) will be written before database lock. In accordance 
with the protocol, the SAP will describe all analyses to be performed, statistical tables, and 
listings including descriptions of the analysis conventions used. 
Non-inferiority testing will only be carried out with seropositive subjects and providing that the 
number of evaluable subjects attains a global power of at least 80%. This applies to the co-
primary objectives and the secondary objective. Otherwise, descriptive analyses will be performed 
12.1.1 Hypotheses and Statistical Methods for Primary Objectives 
12.1.1.1 Hypotheses 
Non-inferiority on Tdap vaccine 
The objective is to demonstrate that the humoral immune response to the Tdap booster dose 
administered concomitantly with the first dose of CYD dengue vaccine is non-inferior to the 
humoral immune response to the Tdap booster dose administered alone 28 days before the first 
dose of CYD dengue vaccine.  
Individual hypotheses on Tdap response for each antigen: 
A non-inferiority testing approach will be used to compare geometric mean concentrations 
(GMCs) for PT, FHA, PRN, FIM2+3, 28 days after the booster dose of Tdap, for each antigen “i” 
based on the following individual hypotheses: 
 
 
with:  
i, antigen {PT, FHA, PRN, FIM 2+3}. 
įQRQ-inferiority limit is set at 1.5, i.e., 0.176 (=log10 [1.5]), for each antigen “i”. 
Non-inferiority for antigen “i” will be demonstrated if the lower bound of the 2-sided 95% 
confidence interval (CI) is greater than įĮ RQH-sided). For each of the 4 antigens, the 
statistical methodology will be based on the use of the age-stratified two-sided 95% CI of the ratio 
of GMCs between groups. The age-stratified CI will be calculated using an ANOVA model (type 
II analysis) of log10-transformed titers. The age groups (9 to 11 years, 12 to 17 years, 18 to 
45 years and 46 to 60 years) will be used as the stratifying factor in the model. 
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Additionally, a non-inferiority testing approach will be used to compare seroprotection rates of T 
and D, 28 days after the booster dose of Tdap vaccine. Seroprotection is defined as anti-D and 
anti-T Ab concentration superior to 0.1 IU/mL. 
The individual tested hypotheses for the antigen “i” will be as follows: 
 
with: 
i, antigen {T, D} 
įQRQ-inferiority limit is set at 10% for both T and D. 
Non-inferiority for antigen “i” will be demonstrated if the lower bound of the 2-sided 95% CI is 
greater than -į 
Global hypotheses for non-inferiority on Tdap response: 
The global hypotheses are: 
H0G: Non inferiority of Tdap booster dose co-administered with the first dose of CYD 
dengue vaccine versus Tdap booster dose administered alone is not demonstrated for at least 
one antigen. 
H1G: Non-inferiority of Tdap booster dose co-administered with the first dose of CYD 
dengue vaccine versus Tdap booster dose administered alone is demonstrated for all the 
antigens. 
 
Non-inferiority on CYD dengue vaccine after 1 dose 
The objective is to demonstrate that the humoral immune response to the first dose of CYD 
dengue vaccine administered concomitantly with Tdap booster dose is non-inferior to the humoral 
immune response to the first dose of CYD dengue vaccine administered sequentially 28 days after 
the Tdap booster dose. 
Individual hypotheses on CYD response after one dose for each serotype: 
A non-inferiority testing approach will be used to compare geometric mean of titers (GMTs), for 
dengue serotypes 1, 2, 3, and 4, 28 days after the first injection of CYD dengue vaccine between 
Group 1 and Group 2 for each serotype “i” based on the following individual hypotheses: 
 
with:  
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i, serotypes in {1, 2, 3, 4}. 
įQRQ-inferiority limit is set at 2, i.e., 0.301 (=log10 [2]), for each serotype “i”. 
Non-inferiority for serotype “i” will be demonstrated if the lower bound of the 2-sided 95% CI is 
greater than -į 
Global hypotheses for non-inferiority on CYD response after one dose: 
 
Overall, non-inferiority among the groups will be demonstrated if, for each antigen of Tdap and 
each serotype of CYD dengue vaccine, the two-sided 95% CI lies above - į 
12.1.1.2 Statistical Methods 
Non-inferiority on Tdap vaccine 
The non-inferiority test will be performed using the 95% 2-sided CI of the difference between 
Group 1 and Group 2 for seroprotection rates and of the differences of the means of the log10 
transformed post-vaccinatiRQFRQFHQWUDWLRQVWLWHUVIRU*0&V*07VĮ RQH-sided). The 
95% CIs will be calculated based on the Wilson score method without continuity correction as 
quoted by Newcombe (19) for seroprotection rates and using normal approximation of log-
transformed titers for GMCs/GMTs.  
Non-inferiority on CYD dengue vaccine after one dose 
The statistical methodology will be based on the use of the two-sided 95% CI of the differences of 
the means of the log10 transformed post-vaccination titers between Group 1 and Group 2. The CI 
for differences will be calculated using normal approximation of log-transformed titers. 
12.1.2 Hypotheses and Statistical Methods for Secondary Objectives 
12.1.2.1 Hypotheses 
Non-inferiority on CYD dengue vaccine after three doses 
The objective is to demonstrate that the humoral immune response of 3 doses of CYD dengue 
vaccine with the first dose administered concomitantly with the Tdap booster dose is non-inferior 
to the humoral immune response of 3 doses of CYD dengue vaccine administered sequentially 
with the Tdap booster dose administered 28 days before the first dose of CYD dengue vaccine. 
Individual hypotheses on CYD response after three doses for each serotype: 
A non-inferiority testing approach will be used to compare GMTs (dengue serotypes 1, 2, 3, and 
4) 28 days after 3 injections of CYD dengue vaccine between Group 1 and Group 2 for each 
serotype “i” based on the following individual hypotheses: 
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with:  
i, serotypes in {1, 2, 3, 4}. 
įQRQ-inferiority limit is set at 2, i.e., 0.301 (=log10 [2]), for each serotype “i”. 
Non-inferiority for serotype “i” will be demonstrated if the lower bound of the 2-sided 95% CI is 
greater than -į 
Global hypotheses for non-inferiority on CYD response after three doses: 
 
 
Overall, non-inferiority among the groups will be demonstrated if, for each serotype of CYD 
dengue vaccine, the two-sided 95% CI lies above -į 
Non-inferiority on Tdap vaccine 
No statistical hypothesis will be tested on Tdap for secondary objectives. 
12.1.2.2 Statistical Methods 
Non-inferiority on CYD dengue vaccine after 3 doses 
The statistical methodology will be based on the use of the two-sided 95% CI of the differences of 
the means of the log10 transformed post-vaccination titers between GURXSDQG*URXSĮ 
one-sided). The CI for differences will be calculated using normal approximation of log-
transformed titers. 
Descriptive analysis on CYD dengue vaccine and Tdap vaccine immunogenicity 
No hypotheses will be tested. Immunogenicity point estimates and their 95% CI will be presented 
for each and any group, before and after the first and third injections for CYD dengue vaccine and 
before and after the booster vaccination for Tdap. 
A complementary analysis on CYD dengue vaccine and Tdap vaccine immunogenicity after each 
dose will be conducted for each and any group according to the age groups (9 to 11 years, 12 to 
17 years, 18 to 45 years and 46 to 60 years). 
A complementary analysis on CYD dengue vaccine immunogenicity after each dose will be 
conducted for each and any group according to the dengue status at baseline. 
The 95% CIs will be calculated using: 
x The normal approximate method for GMCs/GMTs and Geometric mean of concentration 
ratios [GMCRs]/Geometric mean of the titer ratios [GMTRs]  
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Assuming that log10 transformation of the titers/concentrations follows a normal distribution, at 
first, the mean and the 95% CI will be calculated on log10 (titers/concentrations) using the usual 
calculation for normal distribution (using Student’s t distribution with n-1 degree of freedom), 
then antilog transformations will be applied to the results of calculations, in order to provide 
geometric means (GMs) and their 95% CI. 
x 
The exact binomial distribution for percentages (Clopper-Pearson’s method, quoted by 
Newcombe (20)) 
In addition, the booster response against pertussis components (PT, FHA, PRN, and FIM2+3) will 
be calculated based on Ab concentration rises between pre- and post-vaccination defined as: 
x A post-YDFFLQDWLRQ$EFRQFHQWUDWLRQ 4 x the lower limit of quantification (LLOQ) when pre-
vaccination concentration is < LLOQ 
x A post-YDFFLQDWLRQ$EFRQFHQWUDWLRQ 4 x pre-vaccination Ab concentration when pre-
vaccination concentUDWLRQLV//24EXW 4 x LLOQ 
x A post-YDFFLQDWLRQ$EFRQFHQWUDWLRQ 2 x pre-vaccination Ab concentration when pre-
YDFFLQDWLRQFRQFHQWUDWLRQLV[//24 
Safety 
All analyses will be descriptive; no hypotheses will be tested. Safety will be assessed for all 
subjects after the booster dose of Tdap vaccine and after each and any dose of CYD Dengue 
vaccine.  
A complementary analysis will be conducted for each group according to the age groups (9 to 11 
years, 12 to 17 years, 18 to 45 years and 46 to 60 years). A complementary analysis after each and 
any dose of CYD dengue vaccine will be conducted for each and any group according to the 
dengue status at baseline. 
For the main parameters, 95% CIs of point estimates will be calculated using the normal 
approximation for quantitative data and the exact binomial distribution (Clopper-Pearson method, 
quoted by Newcombe (20) ) for proportions. 
12.2 Analysis Sets 
Three analysis sets will be used: the Per-Protocol Analysis Set (PPAS), the Full Analysis Set 
(FAS), and the Safety Analysis Set (SafAS).  
12.2.1 Full Analysis Set 
The FAS is defined as the subset of subjects who received at least one dose of each of the study 
vaccines (CYD and Tdap). Subjects will be analyzed by the vaccine group to which they were 
randomized. 
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12.2.2 Per-Protocol Analysis Set 
Three PPASs will be defined: one for Tdap (PPT), one for CYD dengue vaccine after first dose 
(PPC1) and one for CYD dengue vaccine after the three doses (PPC3).  
PPT 
The subjects presenting with at least one of the following relevant protocol deviations will be 
excluded from the PPT: 
x Subject did not meet all protocol-specified inclusion criteria or met at least one of the 
protocol-specified exclusion criteria 
x Subject had dengue seronegative status at baseline 
x Subject did not complete the vaccination schedule (at V02 for Group 1, V01 for Group 2) 
x Subject received a vaccine other than the one that he/she was randomized to receive (at V02 
for Group 1, V01 for Group 2) 
x Administration of vaccine was not done as per-protocol (site and route of administration) (at 
V02 for Group 1, V01 for Group 2) 
x Subject did not receive vaccine in the proper time window (at V02 for Group 1) 
x Subject did not provide after Tdap injection a post-dose serology sample in the proper time 
window or a post-dose serology sample was not drawn (V03 for Group 1, V02 for Group 2) 
x Subject received a protocol-prohibited medication (prohibited therapies/medications/vaccines 
are indicated in Section 6.7) (until V03 for Group 1, V01 to V02 for Group 2) 
x Subject’s serology sample did not produce a valid test result, i.e., no Tdap Ab concentration 
available (at V03 for Group 1, V02 for Group 2) 
PPC1 
The subjects presenting with at least one of the following relevant protocol deviations will be 
excluded from the PPC1: 
x Subject did not meet all protocol-specified inclusion criteria or met at least one of the 
protocol-specified exclusion criteria 
x Subject had dengue seronegative status at baseline 
x Subject did not complete the vaccination schedule (at V02 for Group 1, at V01 and V02 for 
Group 2) 
x Subject received a vaccine other than the one that he/she was randomized to receive (at V02 
for Group 1, at V01 or V02 for Group 2) 
x Administration of vaccine was not done as per-protocol (site and route of administration) (at 
V02 for Group 1, at V01 and V02 for Group 2) 
x Subject did not receive vaccine in the proper time window (at V02 for Group 1 and Group 2) 
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x Subject did not provide after the first CYD dengue vaccine injection a post-dose serology 
sample in the proper time window or a post-dose serology sample was not drawn (at V03 for 
Group 1 and Group 2) 
x Subject received a protocol-prohibited medication (prohibited therapies/medications/vaccines 
are indicated in Section 6.7) (until V03 for Group 1 and Group 2) 
x Subject’s serology sample did not produce a valid test result, i.e., no Neutralizing Ab titers 
against any of the four parental dengue virus serotypes of CYD dengue vaccine available (at 
V03 for Group 1 and Group 2) 
 
PPC3 
The subjects presenting with at least one of the following relevant protocol deviations will be 
excluded from the PPC3: 
x Subject did not meet all protocol-specified inclusion criteria or met at least one of the 
protocol-specified exclusion criteria 
x Subject had dengue seronegative status at baseline 
x Subject did not complete the vaccination schedule 
x Subject received a vaccine other than the one that he/she was randomized to receive 
x Administration of vaccine was not done as per-protocol (site and route of administration) 
x Subject did not receive vaccine in the proper time window (at V02, V04 or V06) 
x Subject did not provide a post-dose serology sample in the proper time window or a post-dose 
serology sample was not drawn (at V07) 
x Subject received a protocol-prohibited medication (prohibited therapies/medications/vaccines 
are indicated in Section 6.7 (until V07) 
x Subject’s serology sample did not produce a valid test result, i.e., no neutralizing Ab titers 
against any of the four parental dengue virus serotypes of CYD dengue vaccine available (at 
V07) 
12.2.3 Safety Analysis Set 
The SafAS is defined as the subjects who have received at least one dose of the study vaccines. 
All subjects will have their safety analyzed after each dose according to the vaccine they actually 
received, and after any dose according to the vaccine received at the first dose.  
Safety data recorded for a vaccine received out of the protocol design will be excluded from the 
analysis (and listed separately). 
Note: Subject will be included in the “any dose” analysis according to the 1st dose received that 
corresponds to a protocol group. 
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12.2.4 Other Analysis Set 
Randomized subjects 
A randomized subject is a subject for whom an injection group has been allocated. 
12.2.5 Populations Used in Analyses 
The main immunogenicity analyses (non-inferiority tests) will be performed on the PPASs, and 
will be confirmed on the FAS. In the FAS, subjects will be analyzed by the vaccine group to 
which they were randomized. 
All other immunogenicity analyses will be performed on the FAS, and subjects will be analyzed 
by the vaccine group to which they were randomized. 
The SafAS will be performed on the safety analysis set. Subjects will be analyzed according to the 
vaccine they actually received. 
12.3 Handling of Missing Data and Outliers 
12.3.1 Safety 
No replacement will be done. Imputations may be done for a limited number of scenarios. These 
will be described in the SAP.  
12.3.2 Immunogenicity 
For the computation of GMT/GMCs, any titer/concentration reported as < LLOQ will be 
converted to a value of ½ LLOQ. 
While a single approach was used for GMT/GMCs, two different approaches for GMTR/GMCR 
will be applied: 
x For Tdap Vaccine, < LLOQ will be converted to ½ LLOQ for a numerator and < LLOQ will 
be converted to LLOQ for a denominator when only one of either the numerator or 
denominator is < LLOQ. If both the numerator and denominator are < LLOQ, then both will 
be converted in the same way. 
x For CYD dengue vaccine, < LLOQ will be converted to ½ LLOQ for a numerator and 
< LLOQ will be converted to LLOQ for a denominator 
Missing data will not be imputed. No test or search for outliers will be performed. 
12.3.3 Efficacy 
Not applicable. 
12.4 Interim/Preliminary Analysis 
Two or three planned statistical analyses will be performed: 
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x A first interim statistical analysis (interim analysis) will be performed on results obtained after 
a partial database lock of data collected up to the 28 days post first dose of CYD dengue 
vaccine (V03; M2). 
x A second interim analysis might be performed on results collected up to the 28 days after the 
third dose of CYD dengue vaccine (V06; M13). 
x The final analysis will be performed on data collected at the end of the study. 
No statistical adjustment is necessary because there will be no repeated analyses of the primary 
objectives (as the primary tests will be performed at the time of the first statistical analysis). 
12.5 Determination of Sample Size and Power Calculation 
A total of 688 subjects will be enrolled: 344 subjects per treatment group (86 subjects per age 
group).  
Considering a potential attrition rate of 10%, it was initially planned that such sample size would 
provide 618 evaluable subjects in the PPAS of Tdap and CYD dengue vaccine (PPT and PPC1). 
This sample size (based on SAS proc Power) targeted a global power over 90.0% for the non-
inferiority testing corresponding to the co-primary objectives (i.e., after the booster dose of Tdap 
and after the first dose of CYD), and over 99.0% for the non-inferiority corresponding to the 
secondary objective (ie, testing after the third dose of CYD dengue vaccine)  
However, as per this protocol amendment 1, the number of evaluable subjects will be reduced 
since only dengue seropositive subjects will be included in the Per-Protocol populations. Tus, the 
non-inferiority testing will be carried out only if a global power of at least 80% for the co-primary 
objectives and secondary objective can be attained (i.e., if the number of evaluable subjects is at 
least 510 for the co-primary objectives and 324 for the secondary objective). 
The following assumptions were considered for the non-inferiority on Tdap: an alpha level of 
2.5% (one-sided hypotheses), a maximum acceptable difference of 0.176 for GMCs, and of 10% 
for seroprotection rates, and the following rates and standard deviations (SDs): 
x 7,8P/– 99% of subjects 
x ',8P/– 99% of subjects 
x PT SD – 0.4  
x FHA SD– 0.4  
x PRN SD – 0.5  
x FIM2+3 SD – 0.6  
 
(Based on TD519, TD506 and TD526 studies and on Keith S. Reisinger (21) ). 
The following assumptions were considered for the non-inferiority after the first dose of CYD 
dengue vaccine: an alpha level of 2.5% (one-sided hypotheses), a maximum acceptable difference 
of 0.301 for GMTs, and a standard deviation of 1.0 for serotype 1, 0.8 for serotypes 2 and 3, 0.7 
for serotype 4 (based on CYD22 and CYD47 studies conducted in Asia Pacific). 
The following assumptions were considered for the non-inferiority after the third dose of CYD 
dengue vaccine: an alpha level of 2.5% (one-sided hypotheses), a maximum acceptable difference 
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of 0.301 for GMTs, and a standard deviation of 0.8 for serotypes 1 and 2, 0.7 for serotypes 3 and 
4 (based on studies conducted in Asia Pacific). 
The following tables indicate the individual powers for the non-inferiority testing considering a 
number of evaluable subjects of 309 per group for the co-primary and secondary objectives, or 
255 per group for the co-primary objective (Table 12.3) and 162 per group for the secondary 
objective (Table 12.1and Table 12.2).   
Table 12.1: Powers for Non-inferiority of seroprotection/GMC/GMT for each antigen and 
serotype between groups- Primary objective 
Antigen/Serotype 
Alpha 
G
Reference 
rate/SD 
Power (%) for 309 
evaluable subjects per 
group 
Power (%) for 255 
evaluable subjects 
per group 
D 
0.025 
10% 
99% 
> 99.9 
> 99.9 
T 
0.025 
10% 
99% 
> 99.9 
> 99.9 
PT 
0.025 
0.176 
0.4 
> 99.9 
> 99.9 
FHA 
0.025 
0.176 
0.4 
> 99.9 
> 99.9 
PRN 
0.025 
0.176 
0.5 
99.2 
97.8 
FIM2+3 
0.025 
0.176 
0.6 
95.4 
91.1 
Dengue serotype 1 
0.025 
0.301 
1.0 
96.2 
92.4 
Dengue serotype 2 
0.025 
0.301 
0.8 
99.7 
98.9 
Dengue serotype 3 
0.025 
0.301 
0.8 
99.7 
98.9 
Dengue serotype 4 
0.025 
0.301 
0.7 
> 99.9 
99.8 
Global power 
 
 
 
90% 
80% 
Table 12.2: Powers for Non-inferiority of GMT for each serotype between groups- 
Secondary objective 
Serotype 
Alpha 
G
Reference SD 
Power (%) for 
309 evaluable 
subjects per 
group 
Power (%) for 
162 evaluable 
subjects per 
group 
Dengue serotype 1 
0.025 
0.301 
0.8 
99.7 
96.4 
Dengue serotype 2 
0.025 
0.301 
0.8 
99.7 
96.4 
Dengue serotype 3 
0.025 
0.301 
0.7 
> 99.9 
99.0 
Dengue serotype 4 
0.025 
0.301 
0.7 
> 99.9 
99.0 
Global power 
 
 
 
99% 
80% 
 
This sample size will also provide a 95% probability of observing an AE that has a true incidence 
> 0.87% in each group (N=344). 
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13 Ethical and Legal Issues and Investigator/Sponsor Responsibilities 
13.1 Ethical Conduct of the Trial/Good Clinical Practice 
The conduct of this trial will be consistent with the standards established by the Declaration of 
Helsinki and compliant with the ICH guidelines for GCP as well as with all local and/or national 
regulations and directives. 
13.2 Source Data and Source Documents 
“Source data” are the data contained in source documents. Source documents are original 
documents or certified copies, and include, but are not limited to, DCs, medical and hospital 
records, screening logs, informed consent/assent forms, telephone contact logs, and worksheets. 
The purpose of trial source documents is to document the existence of subjects and to substantiate 
the integrity of the trial data collected. Investigators must maintain source documents so that they 
are accurate, complete, legible, and up to date. 
For missing or discrepant data on a DC, the study coordinator will obtain verbal clarification from 
the subject, enter the response into the "investigator’s comment" page of the DC, and transfer the 
information to the eCRF. 
The subject pre-screening log should list all individuals contacted by the Investigators to 
participate in the trial, regardless of the outcome. 
The Investigator must printa any electronic records on an ongoing basis, sign and date them 
immediately after creation, and keep the printouts on file as source documents that can be verified 
by the Sponsor or an inspector against the electronic records. Any later changes of an electronic 
record require the record to be re-printed, dated (with an indication of the date of change), and 
signed. Such records must also be kept together with the original printed copy. 
13.3 Confidentiality of Data and Access to Subject Records 
Prior to initiation of the trial, the Investigator will sign a fully executed confidentiality agreement 
with Sanofi Pasteur. 
Sanofi Pasteur personnel (or designates), the IECs/IRBs, and regulatory agencies, including the 
Food and Drug Administration, require direct access to all study records, and will treat these 
documents in a confidential manner. 
In the event a subject’s medical records are not at the investigational site, it is the responsibility of 
the Investigator to obtain those records if needed. 
                                                 
a  Unless the electronic medical records are managed by validated computerized systems that are compliant with US 
21 CFR Part 11, in which case they are acceptable on their own. 
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13.4 Monitoring, Auditing, and Archiving 
13.4.1 Monitoring  
Before the start of the trial (i.e., before the inclusion of the first subject), the Investigators and the 
Sponsor’s staff or a representative will meet at the site-initiation visit to discuss the trial protocol 
and the detailed trial procedures. Emphasis will be placed on inclusion and exclusion criteria, visit 
timing, safety procedures, informed consent procedures, SAE reporting procedures, eCRF 
completion, and the handling of samples and products. The Sponsor’s staff or a representative will 
ensure and document that all material to be used during the trial has been received at the site; and 
that the study Investigator team and local Sponsor/delegate staff have been properly informed 
about the trial, GCP and regulatory requirements, and the Sponsor’s procedures. Specific training 
sessions for the study Investigator team and the CRAs on these topics may be performed as 
necessary, and should be documented. 
The following instruction manuals will be provided: the eCRF Completion Guidelines for entering 
data into the eCRF, and the Operating Guidelines for detailed trial procedures such as the product 
management and sample-handling procedures. 
After the start of the trial, the Sponsor’s staff or a representative will be in regular contact with the 
investigational team through telephone calls and regular follow-up visits. The Investigator or 
delegate must be available for these visits, and must allow the Sponsor/delegate staff direct access 
to subject medical files and eCRF. During these visits, the Sponsor/delegate staff will: 
x Evaluate the quality of the trial progress (adherence to protocol and any study-specific 
guidelines, quality of data collection and document completion, signature of consent forms, 
occurrence of SAEs, sample and product management, cold-chain monitoring, archiving) 
x Source-verify completed eCRF and any corresponding answered queries. 
x Determine the number of complete or ongoing issues identified at monitoring visits (e.g., 
protocol deviations, SAEs). Any identified problems will be discussed with the Investigator, 
and corrective or preventive actions will be determined, as appropriate. 
x After all protocol procedures have been completed and the data have been entered into the 
eCRF, the Investigator must still be available to answer any queries forwarded by the Sponsor. 
All data-related queries must be completed prior to database lock. 
At the end of the trial, a close-out visit will be performed to ensure that: 
x The center has all the documents necessary for archiving 
x All samples have been shipped to the appropriate laboratories 
x All unused materials and products have been either destroyed or returned to the Sponsor 
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13.4.2 Audits and Inspections 
A quality assurance audit may be performed at any time by the Sponsor’s Clinical and Medical 
Quality Operations department (C&MQO) or by independent auditors to verify that the trial has 
been conducted according to the protocol, GCP and ICH requirements, and other applicable 
regulations. An inspection may be conducted by regulatory authorities. The Investigator must 
allow direct access to trial documents during these inspections and audits. 
13.4.3 Archiving 
The Investigator must keep all trial documents after the completion or discontinuation of the trial, 
whatever the nature of the investigational center (private practice, hospital, or institution), for as 
long as required by applicable laws and regulations. In the absence of any applicable laws or 
regulations, trial documents will be kept at a minimum for the duration indicated on the Clinical 
Trial Agreement (CTA). In no event, should study personnel destroy or permit the destruction of 
any trial documents upon less than 90 days advance written notification to the Sponsor. In 
addition, trial documents should continue to be stored, at Sponsor's sole expense, in the event that 
the Sponsor requests in writing that such storage continues for a period of time that exceeds that 
required by any applicable law or regulation or the CTA. The Investigator will inform Sanofi 
Pasteur of any address change or if they will no longer be able to house the trial documents. 
Archived data may be held on electronic records, provided that a back-up exists and that a hard 
copy can be obtained if required. The protocol, documentation, approvals, and all other 
documents related to the trial, including certificates attesting that satisfactory audit and inspection 
procedures have been carried out, will be kept by the Sponsor in the Trial Master File (TMF). 
Data on AEs are included in the TMF. All data and documents will be made available if requested 
by relevant authorities. 
13.5 Financial Contract and Insurance Coverage 
A CTA will be signed by all the parties involved in the trial’s performance, if relevant. The 
Sponsor has an insurance policy to cover any liabilities that may arise from use of the product 
and/or the study protocol. 
Specifically for the subjects identified as unexposed/seronegative at baseline, Sanofi Pasteur will 
also cover reasonable expenses related to healthcare for dengue illness for 10 years after the last 
dengue vaccine injection received. Details will be communicated to IEC/IRB and to study 
participants. 
13.6 Stipends for Participation 
Expenses that are directly related to the subject’s participation in the trial (for example cost of 
transportation for attending visits) will be compensated. Subjects/parents/legally acceptable 
representatives will not receive any remuneration for participation in the trial. 
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13.7 Publication Policy 
Data derived from this trial are the exclusive property of Sanofi Pasteur. Any publication or 
presentation related to the trial must be submitted to Sanofi Pasteur for review before submission 
of the manuscript. After publication of the results of the trial, any participating center may publish 
or otherwise use its own data provided that any publication of data from the trial gives recognition 
to the trial group. In addition, Sanofi Pasteur shall be offered an association with all such 
publications, it being understood that Sanofi Pasteur is entitled to refuse the association. 
Sanofi Pasteur must have the opportunity to review all proposed abstracts, manuscripts, or 
presentations regarding this trial at least 90 days prior to submission for publication/presentation. 
Any information identified by Sanofi Pasteur as confidential must be deleted prior to submission, 
it being understood that the results of this trial are not to be considered confidential. 
Sanofi Pasteur’s review can be expedited to meet publication guidelines. 
 
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14 References List 
 
1 
World Health Organization. Dengue and dengue haemorrhagic fever, Fact sheet N°117, 
Updated May 2015. Available from URL: 
http://www.who.int/mediacentre/factsheets/fs117/en/ 
2 
Dengue Guidelines For Diagnosis,Treatment, Prevention and Control, 2009, WHO. 
WHO/HTM/NTD/DEN/2009.1.Dengue Guidelines For Diagnosis,Treatment, Prevention 
and Control, 2009, WHO. WHO/HTM/NTD/DEN/2009.1. 
3 
Kumaria R, Chakravarti A. Molecular detection and serotypic characterization of dengue 
viruses by single-tube multiplex reverse transcriptase-polymerase chain reaction. Diagn 
Microbiol Infect Dis. 2005 Aug;52(4):311-6. 
4 
Dussart P, Petit L, Labeau B, Bremand L, Leduc A, Moua D et al. Evaluation of Two New 
Commercial Tests for the Diagnosis of Acute Dengue Virus Infection Using NS1 Antigen 
Detection in Human Serum. PLOS. August 2008. Volume 2/Issue 8/e280. 
5 
Guidelines for the clinical evaluation of dengue vaccines in endemic areas. World Health 
Organization: publication available on 
http://apps.who.int/iris/bitstream/10665/69850/1/WHO_IVB_08.12_eng.pdf 
6 
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 
7 
Villar L, Dayan GH, Arredondo-García JL, Rivera DM, Cunha R, Deseda C, Reynales H, 
Costa MS, Morales-Ramírez JO, Carrasquilla G, Rey LC, Dietze R, Luz K, Rivas E, 
Miranda Montoya MC, Cortés Supelano M, Zambrano B, Langevin E, Boaz M, Tornieporth 
N, Saville M, Noriega F; CYD15 Study Group. Efficacy of a tetravalent dengue vaccine in 
children in Latin America. N Engl J Med. 2015 Jan 8;372(2):113-23. 
8 
Capeding MR, Tran NH, Hadinegoro SR, Ismail HI, Chotpitayasunondh T, Chua MN, 
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