Immunogenicity and Safety of a Tetravalent Dengue Vaccine Administered Concomitantly or Sequentially With Gardasil® in Healthy Subjects Aged 9 to 13 Years in Malaysia
Phase: PHASE3
Conditions: Dengue Fever, Dengue Hemorrhagic Fever, Human Papillomavirus Disease
Sponsor: Sanofi Pasteur, a Sanofi Company

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Immunogenicity and Safety of a Tetravalent Dengue Vaccine 
Administered Concomitantly or Sequentially with Gardasil® in 
Healthy Subjects Aged 9 to 13 Years in Malaysia 
Phase IIIb, randomized, open-label, multicenter study in 528 subjects aged 9 to 13 years in 
Malaysia. 
 
Clinical Trial Protocol Amendment 1 
WHO Universal Trial Number 
(UTN): 
U1111-1161-3376 
Trial Code: 
CYD67 
Development Phase: 
Phase IIIb 
Sponsor: 
Sanofi Pasteur SA 
14, Espace Henry Vallée, F-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 13-year-old children 
Manufacturer: 
Same as Sponsor 
Coordinating Investigator 
  
Project Manager and Study 
Leader: 
Sponsor's Responsible Medical 
Officer (Sponsor’s Signatory): 
Regional Director of Medical 
Affairs 
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                                    NCT02993757 
Version and Date of the Protocol: Version 3.0 dated 05 January 2018

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Product Safety Officers: 
Clinical Trial Manager: 
Version and Date of the Protocol: 
Version 3.0 dated 05 January 2018 
This protocol version 3.0 is the first amendment to the initial trial protocol version 2.0, dated 15 September 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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History of Protocol Versions 
Version* 
Date 
Comments 
1.0 
08 June 2016 
Submitted 
2.0 
15 September 2016 
Original study protocol (first version used in the study) 
3.0 
05 January 2018 
Amendment 1 to original protocol 
 
 
 
* Versions in bold font have been approved by the Independent Ethics Committee(s) (IEC[s]) / Institutional Review 
Board(s) (IRB[s]) and used in the study. 
 
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Table of Contents 
History of Protocol Versions........................................................................................................... 3 
List of Tables .................................................................................................................................... 9 
Synopsis .......................................................................................................................................... 10 
Table of Study Procedures ............................................................................................................ 21 
List of Abbreviations ..................................................................................................................... 25 
1 
Introduction ..................................................................................................................... 28 
1.1 
Background ..................................................................................................................... 28 
1.2 
Background of the Investigational Product ..................................................................... 29 
1.3 
Potential Benefits and Risks ........................................................................................... 31 
1.3.1 
Potential Benefits to Subjects ....................................................................................... 31 
1.3.2 
Potential Risks to Subjects ........................................................................................... 32 
1.4 
Rationale for the Trial ..................................................................................................... 33 
2 
Trial Objectives ............................................................................................................... 36 
2.1 
Primary Objectives .......................................................................................................... 36 
2.2 
Secondary Objectives ...................................................................................................... 36 
3 
Investigators and Trial Organization ............................................................................ 37 
4 
Independent Ethics Committee/Institutional Review Board ...................................... 37 
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 ................................................................................... 38 
5.1.3 
Trial Plan ...................................................................................................................... 38 
5.1.4 
Visit Procedures ............................................................................................................ 41 
5.1.5 
Planned Trial Calendar ................................................................................................. 48 
5.1.6 
Early Safety Data Review............................................................................................. 48 
5.2 
Enrollment and Retention of Trial Population ................................................................ 49 
5.2.1 
Recruitment Procedures ................................................................................................ 49 
5.2.2 
Informed Consent Procedures ...................................................................................... 49 
5.2.3 
Screening Criteria ......................................................................................................... 50 
5.2.4 
Inclusion Criteria .......................................................................................................... 50 
5.2.5 
Exclusion Criteria ......................................................................................................... 50 
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5.2.6 
Medical History ............................................................................................................ 51 
5.2.7 
Contraindications for Subsequent Vaccinations ........................................................... 52 
5.2.7.1 
Temporary Contraindications ..................................................................................... 52 
5.2.7.2 
Definitive Contraindications ...................................................................................... 52 
5.2.8 
Conditions for Withdrawal ........................................................................................... 52 
5.2.9 
Lost to Follow-up Procedures....................................................................................... 53 
5.2.10 
Classification of Subjects Who Discontinue the Trial.................................................. 53 
5.2.11 
Follow-up of Discontinuations ..................................................................................... 54 
5.2.12 
Follow-up and Reporting of Pregnancies ..................................................................... 54 
5.3 
Modification of the Trial and Protocol ........................................................................... 54 
5.4 
Interruption of the Trial .................................................................................................. 55 
6 
Vaccines Administered ................................................................................................... 55 
6.1 
Identity of the Investigational Products .......................................................................... 55 
6.1.1 
Identity of the CYD Dengue Vaccine........................................................................... 55 
6.1.1.1 
Composition ............................................................................................................... 55 
6.1.1.2 
Preparation and Administration ................................................................................. 56 
6.1.1.3 
Dose Selection and Timing ........................................................................................ 56 
6.1.2 
Identity of Gardasil ....................................................................................................... 57 
6.1.2.1 
Composition ............................................................................................................... 57 
6.1.2.2 
Preparation and Administration ................................................................................. 58 
6.1.2.3 
Dose Selection and Timing ........................................................................................ 58 
6.2 
Identity of Other Product ................................................................................................ 58 
6.3 
Product Logistics ............................................................................................................ 58 
6.3.1 
Labeling and Packaging ............................................................................................... 58 
6.3.2 
Product Shipment, Storage, and Accountability ........................................................... 59 
6.3.2.1 
Product Shipment ....................................................................................................... 59 
6.3.2.2 
Product Storage .......................................................................................................... 59 
6.3.2.3 
Product Accountability ............................................................................................... 59 
6.3.3 
Replacement Doses....................................................................................................... 59 
6.3.4 
Disposal of Unused Products ........................................................................................ 60 
6.3.5 
Recall of Products ......................................................................................................... 60 
6.4 
Blinding and Code-breaking Procedures ........................................................................ 60 
6.5 
Randomization and Allocation Procedures ..................................................................... 60 
6.6 
Treatment Compliance .................................................................................................... 60 
6.7 
Concomitant Medications and Other Therapies ............................................................. 61 
7 
Management of Samples ................................................................................................. 62 
7.1 
Sample Collection ........................................................................................................... 62 
7.1.1 
Serum Samples for Neutralizing Ab Assessment ......................................................... 62 
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7.1.2 
Blood Sample for Virological Confirmation of Hospitalized Suspected Dengue 
Case and Assessment of Disease Severity .................................................................... 63 
7.1.3 
Additional Blood Samples ............................................................................................ 63 
7.1.4 
Urine Samples .............................................................................................................. 63 
7.2 
Serum Sample Preparation .............................................................................................. 64 
7.3 
Sample Storage and Shipment ........................................................................................ 64 
7.4 
Future Use of Stored Serum Samples for Research ........................................................ 64 
8 
Clinical Supplies .............................................................................................................. 65 
9 
Endpoints and Assessment Methods ............................................................................. 65 
9.1 
Primary Endpoints and Assessment Methods ................................................................. 65 
9.1.1 
Immunogenicity ............................................................................................................ 65 
9.1.1.1 
Immunogenicity Endpoints ........................................................................................ 65 
9.1.1.2 
Immunogenicity Assessment Methods ...................................................................... 66 
9.1.2 
Safety ............................................................................................................................ 67 
9.1.3 
Efficacy ......................................................................................................................... 67 
9.2 
Secondary Endpoints and Assessment Methods ............................................................. 67 
9.2.1 
Immunogenicity ............................................................................................................ 67 
9.2.1.1 
Immunogenicity Endpoints ........................................................................................ 67 
9.2.1.2 
Immunogenicity Assessment Methods ...................................................................... 68 
9.2.2 
Safety ............................................................................................................................ 68 
9.2.2.1 
Safety Definitions ....................................................................................................... 68 
9.2.2.2 
Safety Endpoints ........................................................................................................ 71 
9.2.2.3 
Safety Assessment Methods ....................................................................................... 71 
9.2.2.3.1 
Immediate Post-vaccination Surveillance Period .................................................... 72 
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 ..................... 72 
9.2.2.3.3 
Unsolicited Non-serious Adverse Events From Day 0 to Day 28After Each 
Vaccination .............................................................................................................. 76 
9.2.2.3.4 
Serious Adverse Events ........................................................................................... 77 
9.2.2.3.5 
Adverse Events of Special Interest .......................................................................... 77 
9.2.2.3.6 
Assessment of Causality .......................................................................................... 78 
9.2.3 
Methods for Assessing Virological Confirmation of Hospitalized Suspected 
Dengue Case and Assessment of Disease Severity ...................................................... 78 
9.2.4 
Efficacy ......................................................................................................................... 80 
9.3 
Observational Endpoints and Assessment Methods ....................................................... 80 
10 
Reporting of Serious Adverse Events ............................................................................ 80 
10.1 
Initial Reporting by the Investigator ............................................................................... 81 
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 ...................... 82 
10.4 
Assessment of Causality ................................................................................................. 82 
10.5 
Reporting SAEs to Health Authorities and IECs/IRBs................................................... 82 
11 
Data Collection and Management ................................................................................. 82 
11.1 
Data Collection and CRF Completion ............................................................................ 82 
11.2 
Data Management ........................................................................................................... 83 
11.3 
Data Review .................................................................................................................... 84 
12 
Statistical Methods and Determination of Sample Size ............................................... 85 
12.1 
Statistical Methods .......................................................................................................... 85 
12.1.1 
Hypotheses and Statistical Methods for Primary Objectives ....................................... 85 
12.1.1.1 
Hypotheses ................................................................................................................. 85 
12.1.1.2 
Statistical Methods ..................................................................................................... 87 
12.1.2 
Hypotheses and Statistical Methods for Secondary Objectives ................................... 87 
12.1.2.1 
Hypotheses ................................................................................................................. 87 
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 ............................................................................................. 88 
12.2.3 
Safety Analysis Set ....................................................................................................... 89 
12.2.4 
Other Analysis Set ........................................................................................................ 90 
12.2.5 
Populations Used in Analyses ...................................................................................... 90 
12.3 
Handling of Missing Data and Outliers .......................................................................... 90 
12.3.1 
Safety ............................................................................................................................ 90 
12.3.2 
Immunogenicity ............................................................................................................ 90 
12.3.3 
Efficacy ......................................................................................................................... 90 
12.4 
Interim/Preliminary Analysis .......................................................................................... 90 
12.5 
Determination of Sample Size and Power Calculation ................................................... 91 
13 
Ethical and Legal Issues and Investigator/Sponsor Responsibilities.......................... 92 
13.1 
Ethical Conduct of the Trial/Good Clinical Practice ...................................................... 92 
13.2 
Source Data and Source Documents ............................................................................... 92 
13.3 
Confidentiality of Data and Access to Subject Records ................................................. 93 
13.4 
Monitoring, Auditing, and Archiving ............................................................................. 93 
13.4.1 
Monitoring .................................................................................................................... 93 
13.4.2 
Audits and Inspections ................................................................................................. 94 
13.4.3 
Archiving ...................................................................................................................... 94 
13.5 
Financial Contract and Insurance Coverage ................................................................... 95 
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13.6 
Stipends for Participation ................................................................................................ 95 
13.7 
Publication Policy ........................................................................................................... 95 
14 
References List ................................................................................................................. 96 
15 
Signature Pages ............................................................................................................... 99 
 
 
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List of Tables 
Table 5.1: Injection and blood sampling schedule by Group .......................................................... 39 
Table 7.1: Blood sampling volume (mL) per visit .......................................................................... 62 
Table 7.2: Blood sampling volume (mL) for hospitalized suspected dengue case ......................... 63 
Table 9.1: Solicited injection site reactions: terminology, definitions, and intensity scales for 
Subjects aged 9 to 11 Years............................................................................................................. 73 
Table 9.2: Solicited injection site reactions: terminology, definitions, and intensity scales for 
subjects aged  12 Years ................................................................................................................. 74 
Table 9.3: Solicited systemic reactions: terminology, definitions, and intensity scales for all 
subjects ............................................................................................................................................ 75 
Table 12.1: Powers for Non-inferiority between GMT for each antigen and serotype ................... 92 
Table 12.2: Powers for Gardasil seroconversion for each antigen .................................................. 92 
 
 
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Given the IDMC recommendations, Sanofi Pasteur has suspended all vaccinations in 
the CYD67 study and amended this study protocol. To determine the baseline 
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 in CYD67.  
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 as 
soon as possible based on blood samples provided by the subjects before the first 
vaccination and what it means.  
x 
Subjects identified as “dengue unexposed” (seronegative, PRNT neutralizing 
antibody titers < 10 (1/dil) for all 4 dengue serotypes) at baseline will not receive 
further CYD dengue vaccine doses. If they consent to, they will only be able to 
continue in the study for safety follow-up at 6 months post last dengue vaccine 
dose, and will have timely access to appropriate care in the event of suspected 
dengue for 10 years from the date of last dengue vaccination whether they remains 
in the study or not. 
x 
Subjects identified as “dengue expose” subjects (seropositive, PRNT neutralizing 
Ab titers  10 (1/dil) for at least 1 dengue serotype) at baseline who are eligible to 
continue dengue vaccination in the study will be additionally asked to consent for 
further CYD dengue vaccine injection(s). Subject’s consent will be formalized by 
signing an ICF and AF addendum, as applicable. 
Based on these recommendations, the first amendment to the original protocol version 
2.0 has been issued. 
A summary of the study vaccination and blood sampling schedules for eligible subjects 
continuing the study is provided in the table below 
 
Table S 1: Injection and blood sampling schedule by Group (Dengue-exposed 
subjects) 
Period 
Prior to Amendment 1 
Post Amendment 1 
Visit 
Visit 1 
Visit 2 Visit 3 
Visit 4 
Visit 5 Visit6 
Visit7 
Visit 8 
Time point 
D0 
M1 
M2 
M6 
M7† 
M8† 
M12† M13† M14† 
Group 1 * 
Gardasil 
+ CYD 
 
 
Gardasil 
+ CYD 
 
 
CYD 
 
 
BL 
BL 
 
 
BL§ 
 
 
BL 
 
Group 2 
Gardasil 
CYD 
 
Gardasil 
CYD 
 
 
CYD 
 
BL 
BL 
BL 
 
BL§ 
BL 
 
 
BL 
D: day; M: month; BL: blood sample; CYD: CYD dengue vaccine 
* When concomitantly administered, the CYD dengue vaccine and Gardasil will be administered in 
2 different sites with the CYD dengue vaccine administered in one deltoid and Gardasil in the other deltoid 
§ If the first visit performed after vaccination pause is Visit 5 (M7), both dengue unexposed and dengue 
exposed subjects who will continue in the study but refuse to receive the next CYD dengue vaccine 
injection(s) will be proposed to be blood sampled for HPV immunogenicity assessment post Gardasil dose 2 
† At the time of Protocol Amendment 1, procedures at M7 (Visit 5) and M8 (Visit 6) were on hold 
depending on subjects’ progression. Time for the approval of Protocol Amendment 1 by the competent 
authorities and completion of the associated logistic tasks will result into a delay of study activities of 
several months (approximately 2 months), and thus to an extension of study duration for dengue exposed 
subjects.  
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At the time of Protocol Amendment 1 writing, all subjects except 8 (all from Group 2) 
have received the second injection of CYD dengue vaccine and all the subjects had 
completed the vaccination schedule for Gardasil. The next study visits are planned at 
following time points: 
x 
For Group 1, M7 (Visit 5) or M12 (Visit 7)  
x 
For Group 2, M7 (Visit 5) for the 8 subjects waiting to receive the second 
CYD dengue injection and M8 (Visit 6) or M13 (Visit 7) for the remaining 
subjects.  
 
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 the systemic 
reactions. Unsolicited adverse events (AEs) will be collected between Days 0–28 after 
each injection. 
Serious adverse events (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 
 
The 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 Ethics Committees (IECs)/ 
Institutional Review Boards (IRBs), or the governing regulatory authorities in 
Malaysia 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 subject’s 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 
after each injection. 
Primary Objectives: 
Immunogenicity 
Gardasil immunogenicity 
x 
To demonstrate that the humoral immune response (in terms of geometric mean 
titers[GMTs]) to Gardasil after concomitant administration is non-inferior to 
sequential administration with the CYD dengue vaccine measured 28 days after 
the last dose of Gardasil* 
 
CYD dengue vaccine immunogenicity 
x 
To demonstrate that the humoral immune response (in terms of GMTs) to the 
CYD dengue vaccine after concomitant administration is non-inferior to 
sequential administration with Gardasil measured 28 days after the last dose of 
the CYD dengue vaccine* 
*Providing that the number of evaluable seropositive subjects allows a global power 
of at least 80% (otherwise  analyses will be descriptive) 
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Primary Endpoints: 
Immunogenicity 
Gardasil immunogenicity 
x 
Ab levels (measured by competitive Luminex immunoassay [cLIA]) against 
each Gardasil HPV antigen (HPV-6, HPV-11, HPV-16, HPV-18) 28 days after 
the last dose of Gardasil 
 
CYD dengue vaccine immunogenicity 
x 
Neutralizing Ab levels (measured by dengue plaque reduction neutralization test 
[PRNT50]) against each of the four parental dengue virus serotypes of the CYD 
dengue vaccine (1, 2, 3, 4) 28 days after the last dose of the CYD dengue 
vaccine 
Secondary Objectives: 
Immunogenicity 
Gardasil immunogenicity: 
x 
To demonstrate that the humoral immune response (in terms of seroconversion) 
to Gardasil after concomitant administration is non-inferior to sequential 
administration with the CYD dengue vaccine measured 28 days after the last 
dose of Gardasil* 
x 
To describe the humoral immune response to Gardasil at baseline and after each 
dose of Gardasil in each and any group 
 
CYD dengue vaccine immunogenicity: 
x 
To describe the humoral immune response to the CYD dengue vaccine at 
baseline and after each dose of the CYD dengue vaccine in each and any group 
*Providing that the number of evaluable seropositive subjects allows a global power 
of at least 80% (otherwise  analyses will be descriptive) 
 
Safety 
Gardasil and CYD dengue vaccine safety 
x 
To describe the safety of Gardasil and the CYD dengue vaccine after each and 
any dose in each group 
Secondary Endpoints: 
Immunogenicity 
Gardasil immunogenicity 
• 
Seroconversion against each Gardasil HPV antigen (HPV-6, HPV-11, HPV-16, 
HPV-18) 28 days after each dose of Gardasil 
Seroconversion is defined as changing serostatus from seronegative at baseline to 
seropositive (> lower limit of quantitation [LLO4] of the assay) or  4-fold rise in 
Ab titer if seropositive at baseline. 
• 
Ab levels (measured by cLIA) against each Gardasil HPV antigen (HPV-6, HPV-
11, HPV-16, HPV-18) at baseline and after each dose of Gardasil 
 
CYD dengue vaccine immunogenicity 
x 
Neutralizing Ab titers against each of the four parental dengue virus serotypes of 
the CYD dengue vaccine as determined by PRNT50 at baseline and after each 
dose of the CYD dengue vaccine  
x 
Neutralizing Ab titers  10 (1/dil) against each of the four and against at least 1, 
2, 3, or 4 parental dengue virus serotypes of the CYD dengue vaccine as 
determined by PRNT50 at baseline and after each dose of the CYD dengue 
vaccine 
x 
Neutralizing Ab titers  different titer thresholds (1/dil) against each of the four 
parental dengue virus serotype of the CYD dengue vaccine as determined by 
PRNT50 at baseline and after each dose of the CYD dengue vaccine  
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Safety  
Gardasil and CYD dengue vaccine safety in each group 
• 
Occurrence of immediate AEs reported within 30 minutes after each and any 
injection 
• 
Occurrence of solicited (i.e., pre-listed in the subject’s diary card [DC] and 
electronic case report form [CRF]) injection site reactions (pain, erythema, and 
swelling) occurring up to 7 days after each and any injection 
• 
Occurrence of solicited systemic reactions (fever, headache, malaise, myalgia, and 
asthenia) occurring up to 14 days after each and any injection 
• 
Occurrence of unsolicited AEs occurring up to 28 days after each and any 
injection 
• 
Occurrence of non-serious AESIs* occurring within 7 days following each and 
any vaccination 
• 
Occurrence of SAEs, including serious AESIs (with specific time windows 
according to the type of AESI*) throughout the trial 
• 
Occurrence of hospitalized VCD cases throughout the trial (i.e., from D0 through 
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) will be reported during 
the entire study 
x 
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 event/reaction led to early termination from the study, seriousness, or 
outcome. 
x 
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 dengue disease. A suspected case will be 
considered a VCD if there is a detection of wild type (WT) dengue virus by 
dengue non-structural protein 1 (NS1) antigen (Ag) enzyme-linked 
immunosorbent assay (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: 
A total of 528 subjects are planned to be enrolled in a 1:1 randomization ratio stratified 
by gender in a 2:1 (female: male) ratio: 
• 
Group 1 (concomitant administration): 264 subjects 
• 
Group 2 (sequential administration): 264 subjects 
At the time of Protocol Amendment 1, the number of dengue exposed subjects per 
group is not known. 
Schedule of Study 
Procedures: 
Dengue unexposed subjects will not receive further dengue vaccine injection. If they 
consent to continue in the study, they will be contacted by phone call for a safety 
follow-up 6 months after the last injection. They will not attend any further study visits 
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(except the unscheduled visit and/or the next schedule visit planned to sign the 
ICF/AF). 
For dengue exposed subjects who consent to continue in the study and receive the next 
CYD dengue vaccine injection(s), procedures will be as follows: 
Visits/phone call: 
Subjects will have 6 (Group 1) or 8 (Group 2) visits. Subjects will be contacted by 
phone 7 days after each injection and 2 months after blood samples during the 6-month 
period after each vaccination. The last phone call will be for the 6-month follow-up 
after the last injection of CYD dengue vaccine. 
 
An unscheduled visit and/or phone call will take place during the study pause in order 
to communicate the new data on the CYD dengue vaccine to each subject. This visit 
will be either before or at the time of the next visit initially planned (V05, V06 or V07, 
depending on the group). Dengue serostatus at baseline may be communicated to the 
subjects at the time of unscheduled visit if available. 
Vaccinations: 
Group 1: Gardasil and CYD dengue vaccine (concomitantly) at D0 and M6, and CYD 
dengue vaccine (alone) at M12 
Group 2: Gardasil (alone) at D0 and M6, and CYD dengue vaccine (alone) at D0+28D 
(M1), M1+6 months (M7), and M1+12 months (M13) 
See Table S 1 for further details 
 
Blood samplings: 
Subjects will provide: 
• 
4 mL, for CYD dengue vaccine immunogenicity assessments by dengue 
neutralizing Abs (4 mL) before the first vaccination (at D0 in Group 1, and M1 in 
Group 2) and 28 days after each vaccination with the CYD dengue vaccine  
• 
2 mL, for HPV immunogenicity assessments by cLIA before the first vaccination 
(at D0) and 28 days after the each vaccination with Gardasil  
See Table S 1 for further details 
Additional blood samples may be collected at any time throughout the study period: 
• 
In the event of a hospitalized suspected dengue case, all subjects, whether dengue 
exposed or not, will be sampled (3 mL approximately), within the first 5 days (or 
as soon as possible if not within the 5 days) of fever onset, for virological 
confirmation by NS1 Ag ELISA, and/or WT dengue RT-PCR. 
• 
In the event of SAEs (including AESIs).  
• 
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: 
The expected duration of subject’s participation in the trial is approximately 18 months 
for Group 1 and 19 months for Group 2, including a safety follow-up period of 6 
months after the third injection of CYD dengue vaccine. 
Time for the approval of Protocol Amendment 1 by the competent authorities and 
completion of the associated logistic tasks will result into a delay of study activities of 
several months (approximately 2 months), and thus, to an extension of study duration 
for dengue exposed subjects 
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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: 
M019601 
Other Product: 
Gardasil 
 Form: 
Suspension 
 Composition: 
• 
Each individual 0.5 mL dose contains: 
• 
20 μg of HPV 6 L1 protein 
• 
40 μg of HPV 11 L1 protein 
• 
40 μg of HPV 16 L1 protein 
• 
20 μg of HPV 18 L1 protein 
• 
225 μg of aluminum (as amorphous aluminum hydroxyphosphate sulfate 
adjuvant) 
• 
9.56 mg of sodium chloride 
• 
0.78 mg of L-histidine 
• 
50 μg of polysorbate 80 
• 
35 μg of sodium borate 
• 
Water for injection 
 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 13 years (i.e., from the day of the 9th birthday to the day prior to 
the 14th birthday) on the day of inclusion 
2) 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) 
3) Subject (or subject and parent[s] or another legally acceptable representative) is 
(are) able to attend all scheduled visits and to comply with all trial procedures 
4) Subject in good health, based on medical history, and physical examination 
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, surgically sterile, or 
using an effective method of contraception or abstinence from at least 4 weeks 
prior to the first vaccination and until at least 4 weeks after the last vaccination) 
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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 vaccine 
5) Previous vaccination against HPV disease with either the trial vaccine or another 
vaccine 
6) Receipt of immune globulins, blood or blood-derived products in the past 
3 months 
7) 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 corticosteroid therapy (prednisone or 
equivalent for more than 2 consecutive weeks within the past 3 months) 
8) History of HPV infection, confirmed either clinically, serologically, or 
microbiologically as reported by subject or parent(s) or another legally acceptable 
representative 
9) Known systemic hypersensitivity to any of the vaccine components, or history of 
a life-threatening reaction to the vaccines used in the trial or to a vaccine 
containing any of the same substances 
10) Thrombocytopenia, contraindicating intramuscular vaccination 
11) Bleeding disorder, or receipt of anticoagulants in the 3 weeks preceding inclusion, 
contraindicating intramuscular vaccination 
12) Deprived of freedom by an administrative or court order, or in an emergency 
setting, or hospitalized involuntarily 
13) Current alcohol abuse or drug addiction that, based on investigator’s judgment, 
may interfere with the subject’s ability to comply with trial procedures  
14) Chronic illness that, in the opinion of the Investigator, is at a stage where it might 
interfere with trial conduct or completion 
15) 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 
16) Self-reported Hepatitis B, Hepatitis C infection 
 
Temporary Exclusion Criteria: 
1) 
A prospective subject must not be included in the study until the following 
conditions and/or symptoms are resolved: 
1) Moderate or severe acute illness/infection (according to Investigator judgment) or 
febrile illness (temperature  38.0°C) on the day of first vaccination.  
2) Receipt of any vaccine in the 4 weeks preceding the first trial vaccination 
Statistical Methods: 
In a general way, Non-inferiority testing will be done if and only if the number of 
evaluable seropositive subjects provided a global power of at least 80% for the co-
primary objectives and secondary objective. Otherwise, only descriptive analyses will 
be performed. 
Non-inferiority on Gardasil 
For co-primary endpoint, a non-inferiority testing approach will be used to compare 
GMTs for the 4 antigens (HPV-6, HPV-11, HPV-16, HPV-18) 28 days after the last 
dose of Gardasil, for each antigen “i” based on the following individual hypotheses: 
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with:  
i, antigen (HPV-6, HPV-11, HPV-16, HPV-18) 
į non-inferiority limit is set at 2, i.e., 0.301 (=log10[2]), 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=2.5% one-sided). 
Additionally, for secondary endpoint, a non-inferiority testing approach will be used to 
compare seroconversion rates for the 4 antigens (HPV-6, HPV-11, HPV-16, HPV-18). 
The individual tested hypotheses for the antigen “i” will be as follows: 
 
Where the non-inferiority limit į is set at 5% for each antigen. 
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 seroconversion rates and of the differences of the 
means of the log10 transformed post-vaccination concentrations/titers for GMTs 
(Į=2.5% one-sided). The 95% CI will be calculated based on the Wilson score method 
without continuity correction as quoted by Newcombe for seroconversion rates and 
using the normal approximation of the log10 transformed post-vaccination titers for 
GMTs. 
 
Global hypotheses for non-inferiority on Gardasil response 
For both primary and secondary objectives, the global hypotheses are: 
H0G: Non inferiority of Gardasil co-administered with the CYD dengue vaccine 
versus Gardasil administered sequentially with CYD dengue vaccine is not 
demonstrated for at least one antigen. 
H1G: Non-inferiority of Gardasil co-administered with the CYD dengue vaccine 
versus Gardasil administered sequentially with CYD dengue vaccine is demonstrated 
for all the antigens. 
 
Non-inferiority on the CYD dengue vaccine 
For co-primary endpoint, a non-inferiority testing approach will be used to compare 
GMTs 28 days after the third injection of the CYD dengue vaccine between groups for 
each serotypes “i”based on the following individual hypotheses: 
 
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with:  
i, serotypes in {1, 2, 3, 4} 
į non-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 2-sided 95% CI of the 
differences of the means of the log10 transformed post-vaccination titers between 
groups. The CI for differences will be calculated using normal approximation of log-
transformed titers. 
Global hypotheses for non-inferiority on CYD response 
 
Overall, non-inferiority among the groups will be demonstrated if, for each antigen of 
Gardasil and each serotype of the CYD dengue vaccine, the 2-sided 95% CIs lie above 
-į. 
The per-protocol analysis set will be used for the main analysis, and will exclude 
seropositive subjects at baseline for Gardasil (i.e., at least one Ab levels against 
Gardasil HPV antigens > LLOQ at baseline), and is to be confirmed using the FAS. 
 
Calculation of Sample Size: 
A total of 528 subjects will be enrolled: 264 subjects in each group. 
The reference standard deviations (SD) considered are the following for Gardasil: 0.6, 
0.4, 0.5 and 0.5 for HPV-6, HPV-11, HPV-16 and HPV-18, respectively. 
The reference seroconversion rates for Gardasil were set to 99% for all of the 4 
antigens. 
The reference SD considered are the following for the CYD dengue vaccine: 0.7 for 
serotypes 1 and 2, 0.5 for serotypes 3 and 4 (based on CYD studies conducted in Asia 
Pacific: CYD14, CYD23, CYD22 and CYD28). 
Considering a potential attrition rate of 15%, it was initially planned that such sample 
size would provide 222 evaluable subjects in the per protocol population per group. 
This will give, for the co-primary objectives, a global power of 98.4% and for 
secondary objectives (in terms of Gardasil seroconversion) a global power over 90.2%. 
This sample size will also provide a 95% probability of observing an AE that has a true 
incidence of 1.1% in each group. 
Following Protocol Amendment 1, the number of evaluable subjects may be difficult 
to achieve (considering only exposed/seropositive subjects at baseline to be included in 
the Per-Protocol populations). Thus the non-inferiority testing will be done only if the 
number of evaluable subjects provides a global power of at least 80% for the co-
primary objectives and secondary objective i.e., if the number of evaluable subjects per 
group is at least 121 per group for the co-primary objectives and 194 per group for the 
secondary objective. 
 
Interim Analysis: 
Two planned statistical analyses will be performed.  
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• 
An interim statistical analysis of the data obtained up to Day 28 post third CYD 
dengue vaccination (V08) might be performed once data are available and a 
database lock has been conducted.  
• 
A final analysis will be performed once the 6 month safety data have been 
collected and the final database lock has occurred. 
No statistical adjustment is necessary because there will be no repeated analyses of the 
primary objective (as the test will be performed at the time of the first analysis).  
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Table of Study Procedures 
Phase IIIb Trial; 5 Injections;  
Group 1: 6 Visits, 1 Safety Follow-up Phone Call, 6 Interim Phone Calls, 4 Blood Samples, 18 Months duration per subject. 
Group 2: 8 Visits, 1 Safety Follow-up Phone Call, 8 Interim Phone Calls, 6 Blood Samples, 19 Months duration per subject.  
Interim phone calls (PCs) will be given 7 days after each injection (PC1, PC2 [Group 2 only], PC4, PC5 [Group 2 only], and PC7) and 2 months after blood samples during the 6-
month period after each vaccination (PC3, PC6, and PC8). The last phone call will be held 6 months after the last injection.  
As per Protocol Amendment 1, only dengue-exposed subjects before the first dengue vaccine injection will be eligible to continue study vaccinations with the CYD dengue vaccine.  
 
Time period prior to Protocol Amendment 1 
Time period post Protocol Amendment 1 _ Dengue Exposed subjects only **** 
Visit (V) Number 
V01 
V02 
V03  
(Group 2) 
V04 
V05** 
**** 
V06 ** 
**** 
(Group 2) 
V07** 
V08** 
Phone Call 
†††† 
Trial Timelines 
D0 
M1 
(V01+28D) 
M2 
(V02+28D) 
M6 
(V01+6M) 
M7 
((V04+28D)  
(Group 1) 
 
(V02+6M)  
(Group 2) 
M8 
(V05+28D) 
M12 
(Group 1)  
(V01+12M) 
 
M13 
(Group 2)  
(V02+12M) 
M13 
(V07+28D)  
(Group 1) 
 
M14 
(V07+28D)  
(Group 2) 
Last 
vacc+6M 
(Group 1) 
 
 
Last 
vacc+6M 
(Group 2) 
Time Windows (days) 
 
+14 
+14 
±20 
+14 
+14 
±20 
+14 
+30 
Informed Consent and assent 
form (if applicable) signed 
X 
 
 
 
 
 
 
 
 
Addendum 1 to Assent and 
Informed Consent 
 
 
 
 
X (Amdt 1) 
(as applicable) 
X (Amdt 1) 
(as applicable) 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
Significant Medical History 
X 
 
 
 
 
 
 
 
 
History of Dengue 
Infection/Vaccination 
X 
 
 
 
 
 
 
 
 
Demography/Body Stature 
X 
 
 
 
 
 
 
 
 
Physical/Clinical† Examination 
X 
X 
X 
X 
X 
X 
X 
X 
 
Temperature 
X 
X (Group 2) 
 
X 
X (Group 2) 
 
X 
 
 
Concomitant Therapy‡ 
X 
X 
X 
X 
X 
X 
X 
X 
 
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Time period prior to Protocol Amendment 1 
Time period post Protocol Amendment 1 _ Dengue Exposed subjects only **** 
Visit (V) Number 
V01 
V02 
V03  
(Group 2) 
V04 
V05** 
**** 
V06 ** 
**** 
(Group 2) 
V07** 
V08** 
Phone Call 
†††† 
Trial Timelines 
D0 
M1 
(V01+28D) 
M2 
(V02+28D) 
M6 
(V01+6M) 
M7 
((V04+28D)  
(Group 1) 
 
(V02+6M)  
(Group 2) 
M8 
(V05+28D) 
M12 
(Group 1)  
(V01+12M) 
 
M13 
(Group 2)  
(V02+12M) 
M13 
(V07+28D)  
(Group 1) 
 
M14 
(V07+28D)  
(Group 2) 
Last 
vacc+6M 
(Group 1) 
 
 
Last 
vacc+6M 
(Group 2) 
Time Windows (days) 
 
+14 
+14 
±20 
+14 
+14 
±20 
+14 
+30 
Urine Pregnancy Test†† 
X 
X (Group 2) 
 
X 
 (Group 2) 
 
X 
 
 
Randomization 
X 
 
 
 
 
 
 
 
 
Contraindications 
 
X (Group 2) 
 
X 
X  
X 
X 
 
 
Blood Sampling § 
 
 
 
 
 
 
 
 
 
Dengue neutralizing Abs 
X (Group 1) 
X 
X (Group 2) 
 
X (Group 1) 
X (Group 2) 
 
X 
 
HPV Abs 
X 
X 
 
 
X*** 
 
 
 
 
Virological confirmation of 
dengue††† 
All acute febrile illness with diagnosis of dengue requiring hospitalization within the first 5 days after fever onset, occurring anytime throughout the trial period 
Vaccine injection 
Gardasil 
Dose 1 
(Groups 1&2) 
+ 
 
 
Gardasil 
Dose 2 
(Groups 1&2) 
+ 
 
 
 
 
 
CYD Dose 1 
(Group 1) 
CYD Dose 1 
(Group 2) 
 
CYD Dose 2 
(Group 1) 
CYD Dose 2 
(Group 2) 
 
CYD Dose 3 
(Groups 1&2) 
 
 
Post-injection phone calls (PCs)*  
Interim phone calls will be given 7 days after each injection and 2 months after blood samples during the 6-month period after each vaccination. The mast phone call will be held 6 months 
after the last injection 
Diary Card (DC) 
 
 
 
 
 
 
 
 
 
Provided 
X 
X (Group 1 for SAE 
only, and Group 2) 
X (Group 2 for 
SAE only) 
X 
X (Group 1 for SAE 
only, and Group 2) 
X (Group2 for 
SAE only) 
X 
 
 
Checked 
 
X 
X (Group 2) 
X 
X 
X (Group 2) 
X 
X 
 
Collected 
 
X 
X (Group 2) 
X 
X 
X (Group 2) 
X 
X 
 
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Time period prior to Protocol Amendment 1 
Time period post Protocol Amendment 1 _ Dengue Exposed subjects only **** 
Visit (V) Number 
V01 
V02 
V03  
(Group 2) 
V04 
V05** 
**** 
V06 ** 
**** 
(Group 2) 
V07** 
V08** 
Phone Call 
†††† 
Trial Timelines 
D0 
M1 
(V01+28D) 
M2 
(V02+28D) 
M6 
(V01+6M) 
M7 
((V04+28D)  
(Group 1) 
 
(V02+6M)  
(Group 2) 
M8 
(V05+28D) 
M12 
(Group 1)  
(V01+12M) 
 
M13 
(Group 2)  
(V02+12M) 
M13 
(V07+28D)  
(Group 1) 
 
M14 
(V07+28D)  
(Group 2) 
Last 
vacc+6M 
(Group 1) 
 
 
Last 
vacc+6M 
(Group 2) 
Time Windows (days) 
 
+14 
+14 
±20 
+14 
+14 
±20 
+14 
+30 
Memory Aid (MA) 
 
 
 
 
 
 
 
 
 
Provided‡‡‡‡ 
 
 
 
 
X 
X 
 
X 
 
Checked  
 
 
 
 
 
 
 
 
X 
30-Min. Observation Period 
X 
X (Group 2) 
 
X 
X (Group 2) 
 
X 
 
 
Injection Site Reactions & 
Systemic Events Assessment§§ 
X 
X 
X (Group 2) 
X 
X 
X (Group 2) 
X 
X 
 
Collection of SAEs, and serious 
AESIs§§ 
Throughout the trial period (for SAEs) or in defined time windows according to the type of AESI 
Termination Record§§§ 
 
 
 
 
 
 
 
X 
 
Abs: antibodies; AE: Adverse event; AESI: AE of special interest; BL: blood sample; CYD: CYD dengue vaccine; D: Day; M: Month; SAE: Serious adverse event; V: Visit 
* Interim phone calls will be given 7 days [+8 days of time window] after each injection (PC1: V01 + 7 days, PC2: V02 + 7 days [Group 2 only], PC4: V04 + 7 days, PC5: V05 + 7 days [Group 2 only], and PC7: V07 + 7 days) 
and approximately 2 months after blood samples (PC3: M3 or M4, PC6: M9 or M10, and PC8: M15 or M16) during the 6-month period after each vaccination with the CYD dengue vaccine. 
**: 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). 
† A full physical and clinical examination will be performed and documented on each vaccination visit (mandatory before vaccination) and at the Investigator’s discretion if necessary based on the health status of the subject for 
the other visits. 
††: In female subjects of childbearing potential: result of urine pregnancy test should be confirmed as negative before vaccination. 
†††: In such case, 1 unplanned acute blood sample (approximately 3 mL) will be collected for virological confirmation of dengue disease by NS1 (nonstructural protein 1) antigen test (ELISA), and/or WT dengue RT-PCR. 
‡: 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. 
§§: 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. Serious adverse events (SAEs) will be reported throughout the study and AEs of special interest (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 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] will be reported during the entire study). 
§§§: Termination record will be checked either during a planned study visit or a phone call. 
***: If the first visit performed after vaccination pause is Visit 5, both dengue unexposed and dengue exposed subjects who will continue in the study but refuse to receive the next CYD dengue vaccine 
injection(s) will be proposed to be blood sampled for HPV immunogenicity assessment post Gardasil dose 2. 
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****: All subjects will either attend an unscheduled visit (V00) or have an unscheduled phone call (PC00) during the study pause and before the next scheduled visit (V05, V06 or V07). During the 
unscheduled visit or phone call, the subject will be informed about the new safety data thanks to a “dear participant letter” and also on their baseline serostatus result. The signature of the ICF/AF by 
the parents/subjects and the check of contraindications to continue in the study will be at the next visit planned, as applicable.  
‡‡‡‡:  MA will be delivered to subjects who will not receive further CYD dengue vaccine injection but consent to continue their participation in the study.  
††††: The 6-month phone call will be given to all subjects who consented to continue in the study whether they were identified “dengue-exposed” or “dengue unexposed” 
 
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List of Abbreviations 
Ab 
antibody 
AE 
adverse event 
AESI 
adverse events of special interest 
AF 
assent form 
Ag 
antigen 
AR 
adverse reactions 
BL 
blood sample 
CCID50 
cell-culture infectious dose 50% 
CDM 
clinical data management 
CI 
confidence interval 
cLIA 
competitive Luminex immunoassay 
C&MQO 
Clinical and Medical Quality Operations department 
CRA 
clinical research associate 
CTA 
clinical trial agreement 
D 
day 
DC 
diary card 
CIN 
cervical intraepithelial neoplasia 
dil 
dilution 
DHF 
dengue hemorrhagic fever 
DSS 
dengue shock syndrome 
CRF 
electronic case report form 
EDC 
Electronic Data Capture 
ELISA 
enzyme-linked immunosorbent assay 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FV 
flavivirus 
FVFS 
first visit, first subject 
FVLS 
first visit, last subject 
GCI 
Global Clinical Immunology 
GCP 
Good Clinical Practice 
GM 
geometric mean 
GMT 
geometric mean of titer 
GMTR 
Geometric mean of the titer ratio 
GPV 
Global PharmacoVigilance 
HPV 
human papillomavirus 
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ICF 
informed consent form 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IgG 
immunoglobulin G 
IgM 
immunoglobulin M 
IRB 
Institutional Review Board 
JE 
Japanese encephalitis 
LLOQ 
lower limit of quantitation 
LLT 
lowest level term 
M 
month 
Mab 
monoclonal antibodies 
MedDRA 
Medical Dictionary for Regulatory Activities 
MFI 
median fluorescent intensity 
mL 
milliliter 
mMU/mL 
mili-Merck Units per mL 
NS1 
non-structural protein 1 
Pap 
Papanicolaou 
PC 
Phone call 
PE 
phycoerythrin 
PPC 
per-protocol analysis set for the CYD dengue vaccine 
PPG 
per-protocol analysis set for Gardasil 
PPAS 
per-protocol analysis set 
PRNT50 
50% plaque reduction neutralization test 
PSO 
Product Safety Officer 
RMO 
Responsible Medical Officer 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SafAS 
safety analysis set 
SC 
subcutaneous 
SD 
standard deviations 
SMT 
safety management team 
TMF 
trial master file 
RT-PCR 
reverse transcriptase-polymerase chain reaction 
UAR 
unexpected adverse reaction 
V 
visit 
VCD 
virologically-confirmed dengue 
VE 
vaccine efficacy 
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VLP 
Virus-like particle 
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 the CYD dengue vaccine when 
administered concomitantly or sequentially with Gardasil® (Human Papillomavirus Quadrivalent 
[Types 6, 11, 16, and 18] Vaccine, Recombinant). 
Dengue Disease 
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 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 died. The populations most affected by dengue 
are pre-adolescents, adolescents and adults living in dengue endemic areas. All 4 dengue virus 
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 
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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. 
Human Papillomavirus Disease (HPV) (5) 
HPV is a common DNA virus the papillomavirus family that can infect different parts of the 
body. Like all papillomaviruses, HPVs establish productive infections only in keratinocytes of the 
skin or mucous membranes. There are over 170 types of HPV and more than 40 types of HPV are 
primarily sexually transmitted and can cause anal and genital warts. Other types may lead to more 
serious consequences such as cervical, penile and anal cancers as well as certain cancers of the 
head and neck. Types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82 are carcinogenic 
"high-risk" sexually transmitted HPVs and may lead to the development of precancerous disease 
and cancer including cervical intraepithelial neoplasia (CIN), vulvar intraepithelial neoplasia, 
penile intraepithelial neoplasia, and/or anal intraepithelial neoplasia. 
Most HPV infections are subclinical, rapidly cleared by the immune system and go away without 
treatment over the course of a few years. However, in some people subclinical infections can 
become clinical through persistence of HPV infections. 70% of clinical HPV infections, in young 
men and women, may regress to subclinical in one year and 90% in two years. In 5% to 10% of 
infected women, persistent HPV infection may cause benign papillomas (such as warts [verrucae] 
or squamous cell papilloma), or cancers of the cervix, vulva, vagina, penis, oropharynx and anus. 
In particular, persistent infection with high-risk" HPV types may progress to precancerous lesions 
and invasive cancer. High-risk HPV infection with HPV16 and HPV18 are known to cause 
around 70% of cervical cancer cases. 
In more developed countries, cervical screening using a Papanicolaou (Pap) test or liquid-based 
cytology is used to detect abnormal cells that may develop into cancer. If abnormal cells are 
found, women are invited to have a colposcopy. During a colposcopic inspection, biopsies can be 
taken and abnormal areas can be removed with a simple procedure, typically with a cauterizing 
loop or, more commonly in the developing world—by freezing (cryotherapy). Treating abnormal 
cells in this way can prevent them from developing into cervical cancer. Pap smears have reduced 
the incidence and fatalities of cervical cancer in the developed world. 
Worldwide in 2002, an estimated 561,200 new cancer cases (5.2% of all new cancers) were 
attributable to HPV, making HPV one of the most important infectious causes of cancer 84% of 
new cervical cancers were in the developing world, compared with about 50% of all new cancers.  
HPV infection is the most frequently sexually transmitted disease in the world. Methods of 
reducing the chances of infection include sexual abstinence, condoms, vaccination and 
microbicides. 
1.2 
Background of the Investigational Product 
As of October 2017, Sanofi Pasteur’s tetravalent CYD dengue vaccine (commercial name 
Dengvaxia®), using recombinant technology to obtain a live-attenuated vaccine, 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 years and above living in 
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endemic areas. 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. 
In support of this product profile, an extensive clinical development program, compliant with 
WHO and European Medicines Agency (EMA) guidelines has been conducted (6), 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 (7). Subjects from CYD23 are being 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 (8) and CYD15 (9)), 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 months of the Active Phase and the 1st year of the 
Hospital Phase (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 (10) (11). 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 (8). 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 (8). 
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 (12) (10) (8). This 
included no observed increase in dengue disease severity compared to the placebo group (8). 
Pooled interim results from CYD14, CYD15 and CYD23/57 demonstrate that for the first year of 
long-term follow-up (Year 3) there is a continued benefit in subjects who were 9 years and above 
at the time of inclusion, with lower risk of hospitalized VCD in the vaccine compared to the 
placebo group (RR: 0.50 [95% CI:0.29; 0.86]) (8). Ongoing cumulative pooled data from these 
studies including the second year of long-term follow-up (Year 4) demonstrates a continued 
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reduction of hospitalized and /or severe VCD in subjects 9 years and above with a RR <1 (13). In 
CYD14, during the first year of the hospital phase (Year 3), the RR demonstrated an increased 
risk of hospitalized VCD in the vaccine compared to the placebo group (randomized 2:1) among 
subjects <9 years of age, with a RR of 1.58 (95% CI: 0.61; 4.83). This increased risk was mostly 
driven by the 2 to 5 years age group, with 15 hospitalized cases in the CYD vaccine group 
compared to 1 hospitalized case in the placebo group, resulting in a RR of 7.5 (95% CI 1.2; 
313.8). However, and although they remained >1, the RRs diminished to 1.4 (95% CI: 0.6; 4.0) 
and 1.5 (95% CI: 0.3; 15.2) during the Year 4 and the Year 5, respectively (13) (14). All subjects 
who were hospitalized due to dengue fully recovered after receiving appropriate supportive 
treatment.  
Therefore, at the time of original protocol issue, ie September 2016, a total of 25 completed or 
ongoing clinical studies in 15 endemic and non-endemic countries including Latin America and 
Asia pacific have been or were being conducted, comprising more than 41,500 subjects from 9 
months through to 60 years of age. Of these subjects, 21,215 were aged 9 to 60 years and received 
at least 1 dose of CYD dengue vaccine formulation. From this database of subjects, an integrated 
safety analysis was performed in the 9 to 60 year old population pooling data from 13 phase II and 
III studies that used the final formulation and final vaccination schedule (CYD12, CYD13, 
CYD22, CYD24, CYD28, CYD30, CYD47, CYD23, CYD17, CYD32, CYD14, CYD15, 
CYD51). This allows detection of very common, common, and uncommon adverse events in 
accordance with WHO guidelines (15). 
In addition, as of December 2017, 6 additional clinical studies including CYD67 are being 
conducted with the CYD dengue vaccine in Asia Pacific and Latin America since the first license 
was obtained (CYD63, CYD64, CYD65, CYD66 and CYD71). These studies are either 
investigating the safety and immunogenicity of the CYD dengue vaccine when co-administered 
with other vaccines (CYD66/67/71) or the need and timing of a booster dose (CYD63/64/65). All 
these studies are being amended in accordance with the IDMC recommendation to vaccinate only 
dengue exposed subjects. 
The CYD dengue vaccine 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 (15). 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.  
As of December 2017, a Sanofi Pasteur 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 
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. 
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The subjects participating in this trial who will receive the 2-dose series of Gardasil (HPV 
vaccine) will likely gain immunological protection against HPV Types 6, 11, 16 and 18. 
A number of exploratory analyses (see Section 1.4, Rationale for Amendment 1) have provided 
strong evidences that, for subjects that were naturally dengue exposed prior to the first CYD 
dengue vaccine injection, the vaccine protects against symptomatic dengue, hospitalized dengue, 
and severe dengue disease.  
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 (8).  
Following a number of exploratory analyses (see Section 1.4, Rationale for Amendment 1) it was 
shown that subjects that were never dengue exposed prior to the first CYD dengue vaccine 
injection have an increased risk of hospitalized or severe disease, as compared to subjects who 
received the placebo. 
Gardasil 
The most common adverse reaction with Gardasil is headache. Common adverse reactions 
(frequency of at least 1.0% and greater than control or saline placebo) are fever, nausea, dizziness; 
and injection-site pain, swelling, erythema, pruritus, and bruising. 
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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. 
The potential risk for vasovagal syncope (fainting) can occur following, or even before, any 
vaccination in this age group (CYD dengue vaccine or Gardasil), 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 Gardasil for 
additional information regarding potential risks. Full list of expected AEs for the CYD dengue 
vaccine can be found in the Investigator’s Brochure. 
1.4 
Rationale 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. 
Gardasil (or Silgard®) is a recombinant quadrivalent HPV (types 6, 11, 16, 18) L1 virus-like 
particle vaccine (Merck & Co., Inc., Whitehouse Station, N.J., USA). Gardasil is indicated for the 
prevention of the following conditions caused by HPV types 6, 11, 16, and 18: precancerous 
lesions in the cervix, vulva or vagina and anus; cervical, vulvar, vaginal and anal cancers; and 
genital warts and persistent infection (16) (17). Gardasil was the first cervical cancer vaccine to 
receive WHO pre-qualification in May 2009, which meant that it was eligible for procurement in 
national immunization programs. Gardasil is currently recommended by WHO for subjects 9-26 
years of age, in ages 9-13 years of age in a 2 dose schedule (0, 6 months) and in ages 14-26 years 
of age, in a 3 dose schedule (0, 2, 6 months) (18). The WHO and the Food and Drug 
Administration (FDA) approve Gardasil for use in boys and men in ages 9-15 or 9-26 years 
respectively. Since 2006, HPV vaccines have been licensed in over 100 countries (19). 
There is currently no data on concomitant administration of the CYD dengue vaccine with other 
vaccines in the population aged 9-60 years of age. Co-administration of the CYD dengue vaccine 
with other vaccines has been assessed in clinical studies outside this age population, in 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 the 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) vaccine 
(CYD08) (20), and 2 Phase III studies (CYD29 and CYD33) were conducted to evaluate the co-
administration of the 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. 
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Based on the current age indication of the dengue vaccine, and to facilitate implementation of 
school-based dengue vaccination programs, co-administration with Gardasil, currently used in 
public sector school-based vaccination programs in several dengue-endemic countries in subjects 
aged 9 years and above, is needed. 
The main purpose of this post-licensure study is to demonstrate that CYD dengue vaccine can be 
safely co-administered with Gardasil without impacting the immune responses to either vaccine. 
The present Phase IIIb randomized, open-label trial (CYD67) will investigate the immunogenicity 
and safety of the CYD dengue vaccine when it is administered concomitantly or sequentially with 
Gardasil at least 28 days apart in subjects aged 9 to 13 years. 
Rationale for Protocol Amendment 1 
This amended protocol introduces one important change to the original protocol of the ongoing 
CYD67 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 (13) (21). 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 
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 
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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 (where 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, 
“unexposed” subjects or seronegative subjects), the conclusion was that although vaccination may 
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. 
The IDMC recommendations led to an amendment of the study protocol. In CYD67, all subjects 
will be informed about 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. To determine the basal serostatus of the subjects already included in the 
study, the PRNT assay will be used.  
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.  
Subjects assessed as unexposed (seronegative) at baseline will only be able to continue in the 
study for a 6-month safety follow-up but will receive no further injections of CYD dengue 
vaccine. They will not receive any further CYD dengue vaccine injection and will be proposed to 
have a blood sample for the assessment of HPV antibodies after the 2 doses of Gardasil if they 
return in study for M7 (Visit 5). 
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2 
Trial Objectives 
2.1 
Primary Objectives 
Immunogenicity: 
Gardasil Immunogenicity 
x To demonstrate that the humoral immune response (in terms of geometric mean titers[GMTs]) 
to Gardasil after concomitant administration is non-inferior to sequential administration with 
the CYD dengue vaccine measured 28 days after the last dose of Gardasil* 
CYD Dengue Vaccine Immunogenicity 
x To demonstrate that the humoral immune response to the CYD dengue vaccine after 
concomitant administration is non-inferior to sequential administration with Gardasil 
measured 28 days after the last dose of the CYD dengue vaccine* 
The endpoints for the primary objective(s) are presented in Section 9.1. 
*Providing that the number of evaluable seropositive subjects allows a global power of at least 
80% (otherwise analyses will be descriptive). 
2.2 
Secondary Objectives 
Immunogenicity 
Gardasil Immunogenicity 
x To demonstrate that the humoral immune response (in terms of seroconversion) to Gardasil 
after concomitant administration is non-inferior to sequential administration with the CYD 
dengue vaccine measured 28 days after the last dose of Gardasil* 
x To describe the humoral immune response to Gardasil at baseline and after each dose of 
Gardasil in each and any group 
CYD Dengue Vaccine Immunogenicity 
x To describe the humoral immune response to the CYD dengue vaccine at baseline and after 
each dose of the CYD dengue vaccine in each and any group 
*Providing that the number of evaluable seropositive subjects allows a global power of at least 
80% (otherwise analyses will be descriptive). 
Safety 
Gardasil and CYD Dengue Vaccine Safety 
x To describe the safety of Gardasil and the CYD dengue vaccine after each and any dose in 
each group 
The endpoints for the secondary objectives are presented in Section 9.2. 
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5 
Investigational Plan 
5.1 
Description of the Overall Trial Design and Plan 
5.1.1 
Trial Design 
This is a Phase IIIb, randomized, open-label, multicenter study in 528 subjects aged 9 to 13 years 
in Malaysia.  
Subjects have been randomized in a 1:1 ratio into one of 2 following groups, stratified by gender 
in a 2:1 (female:male) ratio to receive: 
x Group 1 (N=264): 3 doses of CYD dengue vaccine and 2 doses of Gardasil® (Human 
Papillomavirus Quadrivalent [Types 6, 11, 16, and 18] Vaccine, Recombinant) concomitantly 
to the 2 first doses of CYD dengue vaccine 
x Group 2 (N=264): 3 doses of CYD dengue vaccine and 2 doses of Gardasil sequentially to the 
2 first doses of CYD dengue vaccine 
For both vaccines, each dose is to be administered 6 months apart. 
As per Protocol Amendment 1, only subjects identified as “dengue exposed” (seropositive, See 
Section 9.1.1.1 for definition) before administration of the first CYD dengue injection and who 
consented to receive the remaining injection of dengue vaccine will continue vaccination in the 
study. 
Subjects identified as unexposed (seronegative) at baseline, will only be able to continue in the 
study for a 6-month safety follow-up but will receive no further injections of CYD dengue 
vaccine. They will not receive any further CYD dengue vaccine injection and will be proposed to 
have a blood sample for the assessment of HPV antibodies after the 2 doses of Gardasil if they 
return in study for M7 (Visit 5). 
5.1.2 
Justification of the Trial Design 
There is currently no data on concomitant administration of the CYD dengue vaccine with other 
vaccines in the population aged 9-60 years. Based on the current age indication of the CYD 
dengue vaccine, co-administration with Gardasil, currently used in public sector school-based 
vaccination programs in subjects aged 9 years and above could support implementation of school-
based vaccination programs for the CYD dengue vaccine. Therefore, the present CYD67 study 
will investigate the immunogenicity and safety of the CYD dengue vaccine when it is 
administered concomitantly or sequentially with Gardasil at least 28 days apart in subjects aged 9 
to 13 years. 
5.1.3 
Trial Plan 
A summary of the schedule of study vaccinations and blood samplings for eligible subjects is 
provided in  
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Table 5.1: Injection and blood sampling schedule by Group 
Period 
Prior to Amendment 1 
Post Amendment 1 
Visit 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Time point 
D0 
M1 
M2 
M6 
M7† 
M8† 
M12† 
M13† 
M14† 
Group 1 * 
Gardasil 
+ CYD 
 
 
Gardasil 
+ CYD 
 
 
CYD 
 
 
BL 
BL 
 
 
BL§ 
 
 
BL 
 
Group 2 
Gardasil 
CYD 
 
Gardasil 
CYD 
 
 
CYD 
 
BL 
BL 
BL 
 
BL§ 
BL 
 
 
BL 
D: day; M: month; BL: blood sample; CYD: CYD dengue vaccine 
* When concomitantly administered, the CYD dengue vaccine and Gardasil will be administered in 2 different sites with the CYD 
dengue vaccine administered in one deltoid and Gardasil in the other deltoid 
§: If the first visit performed after vaccination pause is M7 (Visit 5), both dengue unexposed and dengue exposed subjects who will 
continue in the study but refuse to receive the next CYD dengue vaccine injection(s) will be proposed to be blood sampled for 
HPV immunogenicity assessment post Gardasil dose 2. 
† At the time of Protocol Amendment 1, procedures at M7, M8 and M12 were on hold depending on subjects’ progression. Time 
for the approval of Protocol Amendment 1 by the competent authorities and completion of the associated logistic tasks will result 
into a delay of study activities of several months (approximately 2 months), and thus to an extension of study duration for dengue 
exposed subjects.. 
 
At the time of Protocol Amendment 1 writing, all subjects except 8 (all from Group 2) have 
received the second injection of CYD dengue vaccine and all the subjects had completed the 
vaccination schedule for Gardasil. The next study visits are planned at following time points: 
x For Group 1, M7 (Visit 5) or M12 (Visit 7)  
x For Group 2, M7 (Visit 5) for the 8 subjects waiting to receive the second CYD dengue 
injection and M8 (Visit 6) or M13 (Visit 7) for the remaining subjects.  
 
Dengue unexposed subjects (seronegative, See Section 9.1.1.1 for definition) at baseline will not 
receive further dengue vaccine injection. If they consent to continue their participation in the 
study, they will be contacted by phone call for a safety follow-up 6 months after the last injection. 
They will not attend any further study visits, except the unscheduled visit and/or the next schedule 
visit planned to sign the AF and ICF during which they will be proposed to have a blood sample 
for the assessment of HPV antibodies after the 2 doses of Gardasil. 
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For dengue exposed subjects who consent to continue in the study and receive the CYD dengue 
vaccine injection(s), procedures will be as follows: 
Vaccinations 
Subject will receive a total of 5 injections, i.e., 3 doses of the CYD dengue vaccine and 2 doses of 
Gardasil administered either concomitantly (Group 1) or sequentially (Group 2), according to the 
following schedule:  
x Group 1: Gardasil and the CYD dengue vaccine (concomitantly) at Day (D)0 and Month 
(M)6, and CYD dengue vaccine (alone) at M12 
x Group 2: Gardasil (alone) at D0 and M6, and the CYD dengue vaccine (alone) at D0+28D 
(M1), M1+6 months (M7), and M1+12 months (M13) 
Study Visits 
Subjects will have to attend 6 (Group 1) or 8 (Group 2) visits and will have 1 phone call for the 6-
month follow-up after the last injection of the CYD dengue vaccine. Interim phone calls will be 
given 7 days after each injection and 2 months after blood samples during the 6-month period 
after each vaccination. 
An unscheduled visit and/or phone call will take place during the study pause in order to 
communicate the new data on the CYD dengue vaccine to each subject. This visit will be either 
before or at the time of the next visit initially planned (V05, V06 or V07, depending on study 
progression). A “Dear Patient Letter” approved by IEC/IRB will be explained to the subjects to 
share with them the new safety data. Dengue serostatus at baseline may be communicated to the 
subjects at the time of this unscheduled visit if available.  
Subject’s participation in the study is expected to be of 18 or 19 months. Time for the approval of 
Protocol Amendment 1 by the competent authorities and completion of the associated logistic 
tasks will result into a hold of study activities of several months (approximately 2 months), and 
thus, to an extension of study duration for dengue exposed subjects. 
Blood Samples 
Subjects will provide blood samples:  
x for CYD dengue vaccine immunogenicity assessments by dengue neutralizing Abs (4 mL) 
before the first vaccination (at D0 in Group 1, and M1 in Group 2), and 28 days after each 
vaccination with CYD dengue vaccine (M1, M7 and M13 in Group 1, and M2, M8 and M14 
in Group 2) 
x for HPV immunogenicity assessments by competitive Luminex immunoassay (cLIA) (2 mL) 
before the first vaccination at D0, and 28 days after each vaccination with Gardasil (M1 and 
M7) 
Additional blood samples may be collected at any time throughout the study period:  
x In the event of a hospitalized suspected dengue case, all subjects, whether dengue exposed or 
not, will be sampled (3 mL approximately), within the first 5 days after (or as soon as possible 
if not within the 5 days) of fever onset, for virological confirmation by NS1 Ag ELISA, and/or 
WT dengue RT-PCR 
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x In the event of SAEs (including serious AEs of special interest [AESIs]) and  
x To assess AEs that may be indicative of viscerotropic or neurotropic disease (see Guidelines 
for Assessing Viscerotropic and Neurotropic AE).  
Urine samples 
All female subjects of childbearing potential will provide urine samples for urine pregnancy test 
before each injection. 
5.1.4 
Visit 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 CRF. 
Visit 1 (Day 0): Inclusion, Randomization, and Vaccination 
The Investigator or designated study personnel will: 
2) 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. 
3) Check inclusion and exclusion criteria for eligibility. 
4) Obtain significant medical history about the subject and history of dengue infection. 
5) Collect demographic data. 
6) Check concomitant medications and record every reportable medication ongoing at the time 
of vaccination. 
7) For female subjects of childbearing potentiala, perform a urine pregnancy test. 
8) Allocate a subject number to the subject.  
9) Scratch off the randomization list to obtain the group allocation, and sign it. 
10) Perform a physical examination  
11) Record the subject’s axillary temperature. 
                                                 
a  To be considered of non-child-bearing potential, a female must be pre-menarche, 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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12) Obtain blood samplea (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 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). 
13) Inject the first dose of Gardasil to all subjects (from Groups 1 and 2) and the first dose of the 
CYD dengue vaccine to subjects randomized into Group 1 (for concomitant vaccination, the 
injections are made in opposite deltoid). 
14) Keep the subject under observation for 30 minutes, and record any immediate adverse AE in 
the source document. 
15) 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). 
16) Give the parent/legally acceptable representative a diary card (DC), a thermometer, and a 
ruler, and go over the instructions for their use. 
17) Remind the parent/legally acceptable representative to bring back the DC when they return 
for Visit 2 at a specified date and time. 
18) Remind the parent/legally acceptable representative to notify the site in case of an SAE. 
19) Complete the relevant CRF pages for this visit. 
Phone Call 1 (PC1) (7 days [+8 days] after Visit 1)  
All subjects who received vaccination(s) will be contacted 7 days after vaccination(s). 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. 
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) Perform a physical examination 
3) Record the subject’s axillary temperature (Group 2) 
                                                 
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 CRF. In that case, and if the subject wants to participate in the trial, he/she will be 
vaccinated. 
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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 before injection 
(subjects in Group 2 only). 
6) Obtain blood sample (see Section 7.1 for detailed instructions regarding the handling of blood 
samples). 
7) Review temporary and definitive contraindications to vaccination (Group 2). 
8) Inject the first dose of the CYD dengue vaccine to subjects randomized into Group 2. 
9) Keep the subject under observation for 30 minutes, and record any immediate AE in the 
source document (Group 2). 
10) 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). 
11) Give the parent/legally acceptable representative a DC for Group 2 and Group 1 (for Group 1, 
the DC is for SAE collection only).  
12) Remind the parent/legally acceptable representative of subjects in Group 2 to bring back the 
DC when they return for Visit 3 at a specified date and time. 
13) Remind the parent/legally acceptable representative of subjects in Group 1 to bring back the 
DC when they return for Visit 4 at a specified date and time. 
14) Complete the relevant CRF pages for this visit. 
Phone Call 2 (PC2) (7 days [+8 days] after Visit 2) 
The same procedures as those descried for PC1 will be followed. 
Visit 3 (Month 2; 28 [+14] days after Visit 2) 
This visit is applicable only for subjects in Group 2 and only for safety collection (subjects in 
Group 1 will not attend Visit 3). 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) Perform a physical examination  
3) Check concomitant medications and record every reportable medication ongoing at the time 
of vaccination. 
4) Obtain the blood sample (see Section 7.1 for detailed instructions regarding the handling of 
blood samples). 
5) Give the parent/legally acceptable representative a DC for the collection of SAE only. 
6) Remind the 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 CRF pages for this visit. 
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Phone Call 3 (PC3) for Group 1 (2 months [+8 days] after Visit 2) and for Group 2 (2 months 
[+8 days] after Visit 3) 
The same procedures as those described for PC1 will be followed. 
Visit 4 (Month 6; 6 months [± 20 days] after Visit 1) 
The Investigator or designated study personnel will: 
1) Review the pages of the DC 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 before injection. 
6) Review temporary and definitive contraindications to vaccination. 
7) Inject the second dose of Gardasil to all subjects (Groups 1 and 2) and the second dose of the 
CYD dengue vaccine to subjects in Group 1 (6 months post-dose 1). 
8) Keep the subject under observation for 30 minutes, and record any immediate AE in the 
source document. 
9) 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). 
10) Give the parent/legally acceptable representative a DC. 
11) Remind the 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 CRF pages for this visit. 
Phone Call 4 (PC4) (Month 6 + 7 days; 7 days [+8 days] after Visit 4) 
The same procedures as those descried for PC1 will be followed. 
Additional Unscheduled Visit 0 and /or Phone call (PC0)- As per Protocol Amendment 1 
This unscheduled visit is to take place between Visit 4 and Visit 5 or between Visit 5 and Visit 6 
depending on the group and the progression in the study, after approval of the Protocol 
Amendment 1 by the IEC/IRB. During this visit, subjects will be informed about the increased 
risk of hospitalized or severe dengue for those unexposed to dengue infection prior to the first 
injection with the CYD dengue vaccine by the mean of the “Dear Patient Letter “, and will be 
informed about their dengue serostatus at baseline if available  
At the latest, this visit will take place at the same time as next scheduled visit. 
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Visit 5 (Month 7; 28 [+14] days after Visit 4) 
The Investigator or designated study personnel will: 
For subjects who will return at V05 after the suspension of vaccination  
1) Present the changes brought to the study design to the subject/subject's parent (s)/legally 
acceptable representative(s) in more detail, answer any of his/her/their questions, and ensure 
that he/she/they has/have been informed of all aspects that are relevant to their decision to 
continue participating in the study 
2) Have the subject and/or the subject's parent (s)/legally acceptable representative(s), date and 
sign the new AF and/or ICF version, as applicable 
For dengue unexposed or dengue exposed subjects who continue in the study but refuse further 
CYD dengue vaccine injection: 
3) Obtain the blood sample (see Section 7.1 for detailed instructions regarding the handling of 
blood samples) for HPV immunogenicity assessment post Gardasil Dose 2 
For subjects dengue exposed who continued in the study and agree to receive the remaining CYD 
dengue vaccine injection(s): 
4) Review the pages of the DC with the parent/legally acceptable representative, including any 
AEs, medications, or therapy that occurred since vaccination. 
5) Perform a physical examination. 
6) Record the subject’s axillary temperature (Group 2). 
7) Check concomitant medications and record every reportable medication ongoing at the time 
of vaccination. 
8) Obtain the blood sample (see Section 7.1 for detailed instructions regarding the handling of 
blood samples) 
9) For female subjects of childbearing potential, perform a urine pregnancy test before injection 
(subjects in Group 2 only). 
10) Review temporary and definitive contraindications to vaccination (Group 2). 
11) Inject the second dose of the CYD dengue vaccine to eligible subjects in Group 2 (6 months 
post-dose 1). 
12) Keep the subject under observation for 30 minutes, and record any immediate AE in the 
source document (Group 2). 
13) 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). 
14) Give the parent/legally acceptable representative a DC for Group 2 and Group 1 (for Group1, 
the DC is for SAE collection only).  
15) Remind the parent/legally acceptable representative of subjects in Group 2 to bring back the 
DC when they return for Visit 6 at a specified date and time. 
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16) Remind the parent/legally acceptable representative of subject in Group 1 to bring back the 
DC when they return for Visit 7 at a specified date and time. 
17) Complete the relevant CRF pages for this visit. 
Phone Call 5 (PC5) (Month 7 + 7 days; 7 days [+8 days] after Visit 5) 
The same procedures as those descried for PC1 will be followed. 
Visit 6 (Month 8; 28 [+14] days after Visit 5) 
This visit is applicable only for subjects in Group 2 and the same procedures as those described 
for Visit 3 will be followed with in addition: 
For subjects who will return at V06 after the suspension of vaccination  
1) Present the changes brought to the study design to the subject/subject's parent (s)/legally 
acceptable representative(s) in more detail, answer any of his/her/their questions, and ensure 
that he/she/they has/have been informed of all aspects that are relevant to their decision to 
continue participating in the study 
2) Have the subject and/or the subject's parent (s)/legally acceptable representative(s), date and 
sign the new AF and/or ICF version, as applicable 
Phone Call 6 (PC6) for Group 1 (Month 9 [Month 7 + 2 months]; 2 months [+8 days] after 
Visit 5) or Group 2 (Month 10 [Month 8 + 2 months]; 2 months [+8 days] after Visit 6) 
The same procedures as those described for PC1 will be followed. 
Visit 7 (Month 12 (Group 1) or Month 13 (Group 2); 12 or13 months [± 10 days] after Visit 1) 
For subjects who will return at V07 after the suspension of vaccination  
1) Present the changes brought to the study design to the subject/subject's parent (s)/legally 
acceptable representative(s) in more detail, answer any of his/her/their questions, and ensure 
that he/she/they has/have been informed of all aspects that are relevant to their decision to 
continue participating in the study 
2) Have the subject and/or the subject's parent (s)/legally acceptable representative(s), date and 
sign the new AF and/or ICF version, as applicable 
The same procedures as those described for Visit 4 will be followed, except that no dose of 
Gardasil will be injected and the CYD dengue vaccine will be injected to all eligible subjects 
(third and last dose given 6 months post-dose 2).  
Phone Call 7 (PC7) (Month 12 + 7 days [Group 1] or Month 13 + 7 days [Group 2]; 7 days 
[+8 days] after Visit 7) 
The same procedures as those descried for PC1 will be followed. 
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Visit 8 (Month 13 (Group 1) or Month 14 (Group 2); 28 [+14] days after Visit 7) 
The Investigator or designated study personnel will: 
1) Review the pages of the DC with the parent/legally acceptable representative, including any 
AEs, medications, or therapy that occurred since vaccination. 
2) Perform a physical examination and record the subject’s axillary temperature. 
3) Check concomitant medications and record every reportable medication ongoing at the time 
of vaccination. 
4) Obtain a blood sample (see Section 7.1 for detailed instructions regarding the handling of 
blood samples). 
5) Give the parent/legally acceptable representative a memory aid (MA). 
6) Remind the parent/legally acceptable representative to keep the MA available when they will 
be called for Safety Follow-up Telephone Call at a specified date and time. 
7) Complete the relevant CRF pages for this visit. 
8) Complete the termination record of the CRF. 
Phone Call 8 (PC8) (Month 15 [Month 13 + 2 months; Group 1] or Month 16 Month 14 + 
2 months [group 2]; 2 months [+8 days] after Visit 8) 
The same procedures as those described for PC1 will be followed. 
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 completion of the last vaccination, subjects will still be contacted by telephone. 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 CRF pages for this contact. 
3) A follow-up visit can be arranged depending on the information recorded during the phone 
call. 
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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. 
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 obtaining the appropriate regulatory and ethical approvals.  
Planned trial period (FVFS to LCLSa): 
Q4 2016 to Q2 2019 
Planned vaccination period:   
 
Q4 2016 to Q3 2018 
Planned end of trialb:  
 
 
Q2 2019 
Planned date of final clinical study report: Q4 2019 
The expected duration of each subject’s participation in the trial is approximately 18 months 
(Group 1) to 19 months (Group 2), including a safety follow-up period of 6 months after the third 
injection of the 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 Malaysia 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. 
                                                 
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 
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. 
5.2.2 
Informed Consent Procedures 
Informed consent is the process by which a subject and an appropriate and legally acceptable 
representative voluntarily confirm 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. An AF will also be signed and dated by 
subjects or according to local regulations.  
Following the first amendment of the original protocol, subject/subject's parent(s)/legally 
acceptable representative(s) is to sign an Addendum to the AF/ Addendum to 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 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 provided by the Sponsor. Any change to the content of the ICF and 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 AF or an 
addendum to the original ICF and 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. 
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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 13 years (i.e., from the day of the 9th birthday to the day prior to the 14th 
birthday) on the day of inclusion 
2) 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) 
3) Subject (or subject and parent[s] or another legally acceptable representative) is (are) able to 
attend all scheduled visits and to comply with all trial procedures  
4) Subject in good health, based on medical history, and physical examination 
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-menarche, surgically sterile, or using an effective 
method of contraception or abstinence from at least 4 weeks prior to the first vaccination and 
until at least 4 weeks after the last vaccinationa) 
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 vaccine 
5) Previous vaccination against HPV disease with either the trial vaccine or another vaccine 
6) Receipt of immune globulins, blood or blood-derived products in the past 3 months 
7) 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 
corticosteroid therapy (prednisone or equivalent for more than 2 consecutive weeks within the 
past 3 months) 
                                                 
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) History of HPV infection, confirmed either clinically, serologically, or microbiologically as 
reported by subject or parent(s) or another legally acceptable representative 
9) Known systemic hypersensitivity to any of the vaccine componentsa, or history of a life-
threatening reaction to the vaccines used in the trial or to a vaccine containing any of the 
same substances 
10) Thrombocytopenia, contraindicating intramuscular vaccination 
11) Bleeding disorder, or receipt of anticoagulants in the 3 weeks preceding inclusion, 
contraindicating intramuscular vaccination 
12) Deprived of freedom by an administrative or court order, or in an emergency setting, or 
hospitalized involuntarily 
13) Current alcohol abuse or drug addiction that, based on Investigator’s judgment, may interfere 
with the subject’s ability to comply with trial procedures 
14) Chronic illness that, in the opinion of the Investigator, is at a stage where it might interfere 
with trial conduct or completion 
15) 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 
16) Self-reported Hepatitis B, Hepatitis C infection 
Temporary Exclusion Criteria: 
A prospective subject must not be included in the study until the following conditions and/or 
symptoms are resolved: 
1) Moderate or severe acute illness/infection (according to Investigator judgment) or febrile 
illness (temperature  38.0°C) on the day of first vaccination.  
2) Receipt of any vaccine in the 4 weeks preceding the first trial vaccination 
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 CRF. The significant medical 
history section of the CRF 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) 
x 
Presence or absence of the condition at enrollment 
                                                 
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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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 illness (temperature  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 than trial vaccine) 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) If a subject is identified as “dengue unexposed” (seronegative) before the first CYD dengue 
vaccine injection (based on the PRNT test result) issued after the release of Protocol 
Amendment 1 
Subjects will not be withdrawn due to contraindication but will be followed up for safety and 
possibly immunogenicity assessment.  
If a subject has been identified as “dengue unexposed”, she/he will have the possibility to continue 
participating to the study and will be followed up for safety. 
5.2.8 
Conditions for Withdrawal  
Subjects/Parents/Legally acceptable representatives will be informed that they have the right to 
withdraw 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 CRF.  
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 CRF 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 CRF. Reasons are listed below from the most significant 
to the least significant (refer to the CRF completion guidelines for additional details and 
examples): 
x 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 Section 9.2.2.1. 
x 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 9.2.2.1 
x 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. 
x 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). 
x 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 dengue unexposed subjects 
lost to follow-up or who discontinued after having received at least 1 dengue vaccine injection to 
inform them about their dengue status and their rights to access medical care in case of fever 
consistent with dengue illness for 10 years after the last dengue vaccine injection. 
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5.2.11 Follow-up of Discontinuations 
x 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.  
x 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. 
As per Protocol Amendment 1, unexposed subjects before first CYD dengue vaccination who 
discontinued or withdrew their consent after dengue vaccine injection(s) will be contacted and 
informed about their dengue status and their rights to access medical care in case of fever 
consistent with dengue illness for 10 years after the last dengue vaccine injection. 
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 as 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. 
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All substantial amendments e.g., those 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’ 
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 
All subjects will be administered 2 doses of Gardasil 6 months apart, and 3 doses of the CYD 
dengue vaccine 6 months apart. 
6.1 
Identity of the Investigational Products  
6.1.1 
Identity of the 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: 
 
 
M019601 
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 
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x Solvent: NaCl 0.4% 
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 CRF. 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 
serotype 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 FV 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 (22). 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) (23). 
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 (24). 
6.1.2 
Identity of Gardasil 
Product:  
Gardasil, recombinant quadrivalent HPV (types 6, 11, 16, 18) vaccine 
Form:  
suspension for injection 
Dose: 
0.5 mL 
Route:  
Intramuscular (IM) injection 
Batch number: Commercial batch labeled for clinical trials 
6.1.2.1 
Composition 
Each 0.5 mL dose of vaccine contains the following components: 
 20 μg of HPV 6 L1 protein 
 40 μg of HPV 11 L1 protein 
 40 μg of HPV 16 L1 protein 
 20 μg of HPV 18 L1 protein 
 225 μg of aluminum (as amorphous aluminum hydroxyphosphate sulfate adjuvant) 
 9.56 mg of sodium chloride 
 0.78 mg of L-histidine 
 50 μg of polysorbate 80 
 35 μg of sodium borate 
 Water for injection 
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6.1.2.2 
Preparation and Administration 
The product must be stored between +2°C and +8°C and will 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), 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 CRF. 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). 
6.2 
Identity of Other Product 
Not applicable. 
6.3 
Product Logistics 
6.3.1 
Labeling and Packaging 
The 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 
x Storage conditions 
x Batch number 
x Dose number 
x Name of Sponsor 
x Expiry date 
For Gardasil, a commercial batch will be used, and the manufacturer’s packaging will be used and 
labeled with specific clinical mention according to national regulation. 
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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 
CRF. 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 CRFs. 
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. 
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. 
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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 CYD67 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, stratified by gender in a 2:1 
(female:male) ratio. 
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 should not be reassigned for any reason. 
The Statistical Platform of the Sponsor will provide scratchable randomization lists (one per site). 
These lists will mention the randomization order of the subject and the corresponding study group 
covered by a silver-colored patch. 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 
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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 CRF 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 CRF 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 
x 
Immune globulins, blood or blood-derived products in the 4 weeks before and after each 
trial vaccination 
x The information reported in the CRF 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 
CRF unless the medication received belongs to one of the prelisted categories. Medications will 
not be coded. 
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7 
Management of Samples 
Blood samples for the assessment of antibody responses will be collected at Visits 1, 2, 3, 5, 6, 
and 8. 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 
As per protocol version 2.0 dated 15 September 2016, a total of 4 to 6 mL of blood is to be 
collected in all subjects depending on the randomization group: 
x At Visits 1, 2, 5, and 7 in Group 1 
x At Visits 1, 2, 3, 5, 6 and 8 in Group 2 
As per Protocol Amendment 1, dengue exposed subjects who will continue in the study and 
consent to receive the remaining CYD vaccine injection(s) will provide all blood samples as 
initially planned. 
If the first visit performed after vaccination pause is Visit 5, both dengue unexposed and dengue 
exposed subjects who will continue in the study but refuse to receive the next CYD dengue 
vaccine injection(s) will be proposed to be blood sampled for HPV immunogenicity assessment 
post Gardasil dose 2. 
Blood is to 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 2), or 
from the limb opposite to the one that will be used for CYD dengue vaccine for concomitant 
injection (Group 1). 
Table 7.1: Blood sampling volume (mL) per visit 
Visit Number 
V01 
V02 
V03* 
V05† 
V06*† 
V08† 
Trial Timelines  (Days/Months) 
D0 
M1 
(V01+28D) 
M2 
(V02+28D) 
M7 
(V04+28D) 
 
M8 
(V05+28D) 
M13 (V07+28D) 
(Group 1) 
 
M14 (V07+28D) 
(Group 2) 
Time Windows 
(Days) 
 
+14 
+14 
+14 
+14 
+14 
Dengue Neutralizing Abs 
4 (Group 1) 
 
4 (Group 1) 
4 (Group 2) 
 
4 (Group 2) 
4 (Group 1) 
 
 
4 (Group 2) 
4 (Group 1) 
4 (Group 2) 
HPV Abs 
2 (Group 1) 
2 (Group 2) 
2 (Group 1) 
2 (Group 2) 
- 
2 (Group 1) ‡ 
2 (Group 2) ‡ 
- 
- 
TOTAL (mL) 
6 (Group 1) 
2 (Group 2) 
6 (Group 1) 
6 (Group 2) 
 
4 (Group 2) 
6 (Group 1) 
2 (Group 2) 
 
4 (Group 2) 
4 (Group 1) 
4 (Group 2) 
*for Group 2 only 
† BL post Protocol Amendment 1 will be provided only in dengue exposed subjects who consent to continue in the study and 
receive the next injection(s) of CYD dengue vaccine) 
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‡ BL for HPV immunogenicity assessment after the second dose of Gardasil will be proposed both dengue unexposed and dengue 
exposed subjects who will continue in the study but refuse to receive the next CYD dengue vaccine injection(s), if not done before 
Protocol Amendment 1 is approved. 
7.1.2 
Blood Sample for Virological Confirmation of Hospitalized Suspected Dengue Case 
and Assessment of Disease Severity 
In the event of hospitalized suspected dengue case: one 3 mL acute blood sample will be collected 
(within the 5 days after the fever onset) as presented 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 aminotransferase [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 
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 (25) (26) (27) document.  
7.1.4 
Urine Samples 
Pregnancy tests are only applicable to female subjects of childbearing potential. Urine samples for 
at the vaccination visits (V01, V02 [Group 2], V04, V05 [Group 2]), and V07 will be taken and 
analyzed at the trial center. 
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7.2 
Serum Sample Preparation 
Detailed instructions on how to prepare blood samples for assessment of antibody 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. 
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. 
Due to local regulation, any unused stored serum samples are not permitted for future use for 
other tests. The samples will not be used for any testing other than that directly related to this 
study (e.g., retest of dengue neutralizing Abs, tests to detect or rule out the presence of dengue 
viruses and / or of other flavivirus). Genetic tests will never be performed on these samples. 
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8 
Clinical Supplies 
Sanofi Pasteur will supply the trial sites with protocols, ICFs, AFs, CRFs, DCs, memory aids, 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. 
9 
Endpoints and Assessment Methods 
9.1 
Primary Endpoints and Assessment Methods 
9.1.1 
Immunogenicity 
9.1.1.1 
Immunogenicity Endpoints 
The primary endpoint(s) for the evaluation of immunogenicity are: 
Gardasil immunogenicity 
x 
Ab levels (measured by [cLIA]) against each Gardasil HPV antigen (HPV-6, HPV-11, HPV-
16, HPV-18) 28 days after the last dose of Gardasil 
CYD dengue vaccine immunogenicity 
x 
Neutralizing Ab levels (measured by dengue plaque reduction neutralization test [PRNT50]) 
against each of the four parental dengue virus serotypes of the CYD dengue vaccine (1, 2, 3, 
4) 28 days after the last dose of the CYD dengue vaccine 
Definition of dengue serostatus 
The dengue serostatus at baseline is defined as the presence of Abs against at least one dengue 
serotype in the baseline sample (by dengue 50% plaque reduction neutralization test [PRNT50) in 
the blood sample collected at V01 (BL1) from all subjects. The baseline dengue status variable 
will be calculated for each subject as follows: 
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x Dengue immune subjects (dengue exposed) at baseline are defined as those subjects with titers 
10 (1/dil) for at least one serotype with the parental dengue virus strain  
x Dengue non-immune subjects (dengue unexposed) at baseline are defined as those subjects 
with titers <10 (1/dil) (not quantified) for all serotypes with parental dengue virus strains with 
available “valid” results (i.e. different from missing or ”NR”)  
The baseline dengue status will be set to missing when the titer for any serotypes with parental 
dengue virus is either missing or not quantified (except if all are not quantified in which case the 
dengue status is non-immune).” 
In case of limited serum volume, the priority will be given to the testing of the dengue serostatus 
at baseline testing over the other testing (HPV immunogenicity post Gardasil may be not 
performed if not enough blood volume). 
9.1.1.2 
Immunogenicity Assessment Methods  
HPV Abs 
The competitive Luminex immunoassay for HPV 6, 11, 16 and 18 is performed by Merck & Co. 
A reference serum, assay controls (phycoerythrin [PE]-tagged type-specific monoclonal 
antibodies [Mab]) and samples are added to black opaque 96-well microtiter plates. Virus-like 
particle (VLP)-microspheres for types 6, 11, 16 and 18 are added to each well at 5,000 VLP-
microspheres per HPV type. The plates are then covered with foil and incubated for 15 minutes to 
allow antibodies in the sera to bind to the coated microspheres. Next, type-specific PE-tagged 
Mab are added to each well and mixed, and then plates are covered with foil and incubated 
overnight to allow the antibodies in sera samples to compete with the binding of the type-specific 
PE-tagged Mab. After incubation, all samples are transferred to prewet 96-well filter plates and 
the serum samples are washed 3 times with phosphate-buffered saline (PBS) and resuspended in 
PBS plus 1% Bovine Serum Albumin for analysis.  
The fluorescent signal from bound HPV-specific, detection monoclonal antibodies (MAbs) is 
inversely proportional to the patient’s neutralizing antibody titer. The correlation of median 
fluorescent intensity (MFI) units to mili-Merck Units per mL (mMU/mL) is made by serially 
diluting a reference serum and interpolating the MFI data through a 4-parameter logistic curve fit. 
LLOQ values for HPV are 20 mili-Merck Units (mMU)/mL for HPV-6 and HPV-16, 
16 mMU/mL for HPV-11, and 24 mMU/mL for HPV-18. 
This assay will be performed on samples taken at V01, V02, and V05.  
If the first visit performed after vaccination pause is Visit 5, both dengue unexposed and dengue 
exposed subjects who will continue in the study but refuse to receive the next CYD dengue 
vaccine injection(s) will be proposed to be blood sampled at this visit for HPV immunogenicity 
assessment post Gardasil dose 2. While the preferred sample is to be collected 1 month after the 
second dose of Gardasil, antibody levels are relatively stable from 7 to 12 months after the first 
dose (or 1 to 5 months after the second dose) (28) (29)  
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Dengue Neutralizing Abs 
Dengue neutralizing Ab levels will be measured by PRNT50 (using parental dengue virus strains 
of the 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 which  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 lower limit of quantitation (LLOQ) of the assay is 
10 (1/dilution [dil]). 
This assay will be performed on blood samples taken at V01 (Group 1 only), V02, V03 (Group 2 
only), V05 (Group 1 only), V06 (Group 2 only), and V08. 
9.1.2 
Safety 
There are no primary objectives for safety. 
9.1.3 
Efficacy 
There are no primary objectives for efficacy. 
9.2 
Secondary Endpoints and Assessment Methods 
9.2.1 
Immunogenicity 
9.2.1.1 
Immunogenicity Endpoints 
Gardasil immunogenicity: 
x Seroconversion against each Gardasil HPV antigen (HPV-6, HPV-11, HPV-16, HPV-18) 
28 days after each dose of Gardasil 
Seroconversion is defined as changing serostatus from seronegative at baseline to seropositive 
(> lower limit of quantitation [LLOQ] of the assay) or  4-fold rise in Ab titer if seropositive at 
baseline. 
x Ab levels (measured by cLIA) against each Gardasil HPV antigen (HPV-6, HPV-11, HPV-16, 
HPV-18) at baseline and after each dose of Gardasil 
CYD dengue vaccine immunogenicity: 
x Neutralizing Ab titers against each of the four parental dengue virus serotypes of the CYD 
dengue vaccine as determined by PRNT50 at baseline and after each dose of the CYD dengue 
vaccine  
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x Neutralizing Ab titers  10 (1/dil) against each of the four and against at least 1, 2, 3, or 4 
parental dengue virus serotypes of the CYD dengue vaccine as determined by PRNT50at 
baseline and after each dose of the CYD dengue vaccine  
x Neutralizing Ab titers  different titer thresholds (1/dil) against each parental dengue virus 
serotype of the CYD dengue vaccine as determined by PRNT50 at baseline and after each 
dose of the CYD dengue 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 
x An effect of the vaccination, including the comparator 
x A combination of the above 
x All AEs include serious and non-serious AEs. 
x 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 
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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 
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 UAR 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: 
                                                 
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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Solicited Reaction: 
4) A solicited reaction is an event that is prelisted in the CRF. 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 CRF 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 CRF 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 CRF), 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. 
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. 
                                                 
a  All injection site AEs are considered to be related to vaccination and are therefore all injection site reactions. 
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9.2.2.2 
Safety Endpoints 
Safety endpoints for Gardasil and CYD dengue vaccine safety in each group are: 
x Occurrence of immediate AEs reported within 30 minutes after each and any injection 
x Occurrence of solicited (i.e., pre-listed in the subject’s diary card [DC] and electronic case 
report form [CRF]) injection site reactions (pain, erythema, and swelling) occurring up to 
7 days after each and any injection 
x Occurrence of solicited systemic reactions (fever, headache, malaise, myalgia, and asthenia) 
occurring up to 14 days after each and any injection 
x Occurrence of unsolicited AEs occurring up to 28 days after each and any injection 
x Occurrence of non-serious AESIs* occurring within 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 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. 
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 event/reaction 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. 
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 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 CRF according to 
the instructions provided by the Sponsor. 
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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 CRF, as 
follows: 
x 
Any unsolicited systemic AE occurring during the first 30 minutes post-vaccination will 
be recorded on the CRF 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 CRF 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) 
Table 9.1 to Table 9.3 present, the injection site reactions and systemic reactions that are prelisted 
in the DCs and CRF, 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 2:  25 to < 50 mm 
Grade 3:  50 mm 
Grade 1: > 0 to < 25 mm 
Grade 2:  25 to < 50 mm 
Grade 3:  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 
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 1:  25 to  50 mm 
Grade 2:  51 to  100 mm 
Grade 3: > 100 mm 
Grade 1:  25 to  50 mm 
Grade 2:  51 to  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 for all subjects 
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 
°38.0°C ( 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 1:  38.0°C to 
 38.4°C, 
or  100.4°F to  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 2:  38.5°C to 
 38.9°C, 
or  101.2°F to  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 3:  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 CRF. The preferred route for this 
trial is axillary. Pre-vaccination temperature is also systematically collected by the Investigator in 
the CRF, 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 28After 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: 
x Start and stop datesa  
x 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 
x 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 CRF 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 CYD dengue 
vaccine injection 
x Serious neurotropica disease occurring in all subjects within 30 days after 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 Disease 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 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 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-complex MAb-NS1-
                                                 
a  ICH Guidelines, Clinical Safety Data Management E2A 
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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 < 0.5,  0.5 to  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 DS 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-PCR (i.e.,  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 Malaysia. 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 CRF. 
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 CRF. 
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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) Platelet count  100,000 μL and bleeding (tourniquet, petechiae or any bleeding) plus plasma 
leakage (effusion on chest x-ray or clinically apparent ascites including imaging procedures 
or hematocrit  20% above baseline recovery level or standard for age if only one reading) 
2) Shock (pulse pressure  20 mmHg in a child, or hypotension [ 90 mmHg] with tachycardia, 
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) Impaired kidney function (Serum creatinine  1.5 mg/dL) 
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.  
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.  
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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. 
11 Data Collection and Management 
11.1 Data Collection and CRF 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 
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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 AEs of particular interest, 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 CRF. 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 memory aid 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 CRF (Any information that was not documented in the DC will first be captured in the 
source document and then reported electronically). The CRF 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 CRFs, 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 CRFs; must provide explanations for all missing information; and must sign the CRF using 
an e-signature. 
11.2 Data Management 
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 CRF, and laboratory data will be handled by 
the Sponsor’s Clinical Data Management (CDM) platform or authorized representative. 
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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 CRFs 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. 
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-Pregancy 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. 
11.3 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. 
In a general way, non-inferiority testing will be done if the number of evaluable seropositive 
subjects provided a global power of at least 80% for the co-primary objectives and secondary 
objective. Otherwise, only descriptive analyses will be performed. 
12.1.1 Hypotheses and Statistical Methods for Primary Objectives 
12.1.1.1 Hypotheses 
Non-inferiority on Gardasil 
The objective is to demonstrate that the humoral immune response to the Gardasil administered 
concomitantly with the CYD dengue vaccine is non-inferior to the immune response to Gardasil 
administered sequentially with the CYD dengue vaccine.  
Individual hypotheses on Gardasil response for each antigen: 
A non-inferiority testing approach will be used to compare GMTs for the 4 antigens (HPV-6, 
HPV-11, HPV-16, HPV-18) 28 days after the last dose of Gardasil, based on the following 
individual hypotheses: 
 
with:  
i, antigen (HPV-6, HPV-11, HPV-16, HPV-18) 
į non-inferiority limit is set at 2, i.e., 0.301 (=log10[2]), 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=2.5% one-sided). 
Global hypotheses for non-inferiority on Gardasil response 
The global hypotheses are: 
H0G: Non inferiority of Gardasil co-administered with the CYD dengue vaccine versus 
Gardasil administered sequentially with the CYD dengue vaccine is not demonstrated for at 
least one antigen. 
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H1G: Non-inferiority of Gardasil co-administered with the CYD dengue vaccine versus 
Gardasil administered sequentially with the CYD dengue vaccine is demonstrated for all the 
antigens. 
 
 
Non-inferiority on CYD Dengue Vaccine 
The objective is to demonstrate that the humoral immune response to the CYD dengue vaccine 
administered concomitantly with Gardasil is non-inferior to the immune response to the CYD 
dengue vaccine administered sequentially with Gardasil. 
Individual hypotheses on CYD response for each antigen: 
A non-inferiority testing approach will be used to compare GMTs 28 days after the third injection 
of the CYD dengue vaccine between groups for each serotype “i” based on the following 
individual hypotheses: 
 
with:  
i, serotypes in {1, 2, 3, 4} 
į non-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 
 
 
Overall, non-inferiority among the groups will be demonstrated if, for each antigen of Gardasil 
and each serotype of the CYD dengue vaccine, the 2-sided 95% CIs lie above -į. 
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12.1.1.2 Statistical Methods 
The non-inferiority test will be performed using the 95% 2-sided CI of the difference of the means 
of the log10 transformed post-vaccination titers between Group 1 and Group 2 (Į=2.5% one-
sided). 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 Gardasil 
The objective is to demonstrate that the humoral immune response (in terms of seroconversion) to 
Gardasil after concomitant administration is non-inferior to sequential administration with the 
CYD dengue vaccine measured 28 days after the last of dose of Gardasil 
A non-inferiority testing approach will be used to compare seroconversion rates of the 4 antigens 
of Gardasil (HPV-6, HPV-11, HPV-16, HPV-18). 
The individual tested hypotheses for the antigen “i” will be as follows: 
 
Where the non-inferiority limit į is set at 5% for each antigen. 
Non-inferiority on CYD Dengue Vaccine 
No statistical hypothesis will be tested on the CYD dengue vaccine for secondary objectives. 
12.1.2.2 Statistical Methods 
Non-inferiority on Gardasil 
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 
groups (Į=2.5% one-sided). The 95% CI will be calculated based on the Wilson score method 
without continuity correction as quoted by Newcombe (30) for seroconversion rates. 
Descriptive analysis on Gardasil and CYD dengue vaccine immunogenicity  
No hypotheses will be tested. Immunogenicity point estimates and their 95% CI will be presented 
for each and any group, at baseline and after each dose of Gardasil and the CYD dengue vaccine. 
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: 
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x The normal approximate method for GMTs and geometric mean of the titer ratios (GMTRs) 
x Assuming that Log10 transformation of the titers / data follows a normal distribution, at first, 
the mean and the 95% CI will be calculated on Log10 (titers / data) 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 single proportions (Clopper-Pearson’s method, quoted by 
Newcombe) 
 
Safety 
All analyses will be descriptive; no hypotheses will be tested. Safety will be assessed for all after 
each and any dose of Gardasil and the CYD Dengue vaccine.  
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) for single proportions. 
12.2 Analysis Sets 
Three analysis sets will be used: the Per-Protocol set (PPAS), the Full Analysis Set (FAS), and the 
Safety Analysis Set (SafAS). 
12.2.1 Full Analysis Set 
The Full Analysis Set (FAS) is defined as the subset of subjects who received at least one dose of 
each of the study vaccines (CYD and Gardasil). 
Subjects will be analyzed by the vaccine treatment group to which they were randomized. 
12.2.2 Per-Protocol Analysis Set 
Two PPASs will be defined: one for Gardasil (PPG) and one for the CYD dengue vaccine (PPC). 
The PPASs are subsets of the FAS. 
PPG 
The subjects presenting with at least one of the following relevant protocol deviations will be 
excluded from the PPG: 
x Subject did not meet all protocol-specified inclusion criteria or met at least one of the 
protocol-specified exclusion criteria 
x Subjects identified as dengue unexposed (seronegative) at baseline 
x Subject is seropositive at baseline for Gardasil (i.e., at least one Ab levels against Gardasil 
HPV antigens > LLOQ at baseline) 
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x Subject did not complete the vaccination schedule (until V05) 
x Subject received a vaccine other than the one that he/she was randomized to receive (until V05 
for Group 1, V06 for Group 2) 
x Administration of vaccines was not done as per-protocol (site and route of administration) 
(until V05) 
x Subject did not receive vaccines in the proper time window (until V05 for Group 1, V06 for 
Group 2) 
x Subject did not provide after the 2nd dose of Gardasil a post-dose serology sample in the 
proper time window or a post-dose serology sample was not drawn (until V05 for Group 1, 
V06 for Group 2) 
x Subject received a protocol-prohibited medication (prohibited therapies / medications / 
vaccines are indicated in Section 6.7) (until V05 for Group 1, V06 for Group 2) 
x Subject’s serology sample after the 2nd dose of Gardasil did not produce a valid test result, i.e., 
no Gardasil antigen titer available (until V05 for Group 1, V06 for Group 2) 
PPC 
The subjects presenting with at least one of the following relevant protocol deviations will be 
excluded from the PPC: 
x Subject did not meet all protocol-specified inclusion criteria or met at least one of the 
protocol-specified exclusion criteria 
x Subjects identified as dengue unexposed (seronegative) 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 vaccines was not done as per-protocol (site and route of administration) 
x Subject did not receive vaccines in the proper time window 
x Subject did not provide after the 3rd dose of the CYD dengue vaccine a post-dose serology 
sample in the proper time window or a post-dose serology sample was not drawn (V08, M13 
for Group 1 and M14 for Group 2) 
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 the CYD dengue vaccine available 
(at V08, M13 for Group 1 and M14 for Group 2) 
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.  
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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. 
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, subjects will be analyzed by 
the vaccine group to which they were randomized. 
The safety analyses will be performed on the SafAS. 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. 
12.3.2 Immunogenicity 
For the computation of GMTs, any titer reported as < LLOQ will be converted to a value of 
½ LLOQ. 
While a single approach was used for GMTs, two different approaches for GMTR will be applied: 
x For Gardasil, < LLOQ will be converted to ½ LLOQ 
x For the 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 planned statistical analyses will be performed: 
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x An interim statistical analysis of the data obtained up to Day 28 post third CYD dengue 
vaccination (V08) might be performed once data are available and a database lock has been 
conducted. 
x A final analysis will be performed once the 6 month safety data have been collected and the 
final database lock has occurred. 
No statistical adjustment is necessary because there will be no repeated analyses of the primary 
objective (as the test will be performed at the time of the first analysis).  
12.5 Determination of Sample Size and Power Calculation 
As per protocol version 2.0 dated 15 September 2017, a total of 528 subjects was to be enrolled, 
i.e., 264 subjects in each group. 
The reference standard deviations (SD) considered are the following for Gardasil: 0.6, 0.4, 0.5 and 
0.5 for HPV-6, HPV-11, HPV-16 and HPV-18, respectively. 
The reference seroconversion rates for Gardasil were set to 99% for all of the 4 antigens. 
The reference SD considered are the following for the CYD dengue vaccine: 0.7 for serotypes 1 
and 2, 0.5 for serotypes 3 and 4 (based on CYD studies conducted in Asia Pacific: CYD14, 
CYD23, CYD22 and CYD28). 
Considering a potential attrition rate of 15%, such sample size would provide 222 evaluable 
subjects per group in the PPASs. This will give, for the co-primary objectives, a global power of 
98.4% and for secondary objectives (in terms of Gardasil seroconversion) a power of 90.2%. 
Following Protocol Amendment 1, the number of evaluable subjects may be difficult to achieve 
(considering only exposed/seropositive subjects at baseline to be included in the Per-Protocol 
populations). Thus the non-inferiority testing will be done only if the number of evaluable 
subjects provides a global power of at least 80% for the co-primary objectives and secondary 
objective i.e., if the number of evaluable subjects per group is at least 121 per group for the co-
primary objectives and 194 per group for the secondary objective. The power for non-inferiority 
in terms of GMTs per antigen and serotype will be than as follows: 
This sample size will also provide a 95% probability of observing an AE that has a true incidence 
of 1.1% in each group. 
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Table 12.1: Powers for Non-inferiority between GMT for each antigen and serotype 
Antigen/Serotype 
Alpha 
 
References 
SD(s) 
Power (%) for 
222 evaluable 
subjects per 
group 
Power (%) for 
121 evaluable 
subjects per 
group 
HPV-6 
0.025 
0.301 
0.6 
> 99.9 
97.3 
HPV-11 
0.025 
0.301 
0.4 
> 99.9 
> 99.9 
HPV-16 
0.025 
0.301 
0.5 
> 99.9 
99.7 
HPV-18 
0.025 
0.301 
0.5 
> 99.9 
99.7 
Dengue serotype 1 
0.025 
0.301 
0.7 
99.5 
91.5 
Dengue serotype 2 
0.025 
0.301 
0.7 
99.5 
91.5 
Dengue serotype 3 
0.025 
0.301 
0.5 
> 99.9 
99.7 
Dengue serotype 4 
0.025 
0.301 
0.5 
> 99.9 
99.7 
Global power 
 
 
 
98.4% 
80.4% 
 
Table 12.2: Powers for Gardasil seroconversion for each antigen 
Antigen 
Alpha 
 
Power (%) for 222 
evaluable subjects 
per group 
Power (%) for 194 
evaluable subjects 
per group 
HPV-6 
0.025 
5% 
97.4 
94.6 
HPV-11 
0.025 
5% 
97.4 
94.6 
HPV-16 
0.025 
5% 
97.4 
94.6 
HPV-18 
0.025 
5% 
97.4 
94.6 
Global power 
 
 
90.2% 
80% 
This sample size will also provide a 95% probability of observing an AE that has a true incidence 
of 1.51% in each group. 
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 
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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 CRF. 
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 
FDA, 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. 
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, CRF 
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. 
                                                 
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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The following instruction manuals will be provided: the CRF Completion Guidelines for entering 
data into the CRF, 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 CRFs. 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 CRFs and any corresponding answered queriesDetermine 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 
CRF, 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 
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. 
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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 Clinical Trial Agreement 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. 
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 
 
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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. 
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Kumaria R, Chakravarti A. Molecular detection and serotypic characterization of dengue 
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Dussart P, Petit L, Labeau B, Bremand L, Leduc A, Moua D et al. Evaluation of Two New 
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CDC guidelines for sexually transmitted diseases for references. 
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6 
Guidelines for the clinical evaluation of dengue vaccines in endemic areas. World Health 
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Sabchareon A, Wallace D, Sitivichayakul C, et al. Protective efficacy of the recombinant, 
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Hadinegoro SR, Arredondo-García JL, Capeding MR, Deseda C, Chotpitayasunondh T, 
Dietze R, et al. Efficacy and Long-Term Safety of a Dengue Vaccine in Regions of Endemic 
Disease. N Engl J Med. 2015;373(13):1195-206. 
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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. 
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Villar LÁ, Rivera-Medina DM, Arredondo-García JL, Boaz M, Starr-Spires L, Thakur M, 
and al. Safety and immunogenicity of a recombinant tetravalent dengue vaccine in 9-16 year 
olds: a randomized, controlled, phase II trial in Latin America. Pediatr Infect Dis J. 
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Capeding MR, Tran NH, Hadinegoro SR, Ismail HI, Chotpitayasunondh T, Chua MN, 
Luong CQ, Rusmil K, Wirawan DN, Nallusamy R, Pitisuttithum P, Thisyakorn U, Yoon IK, 
van der Vliet D, Langevin E, Laot T, Hutagalung Y, Frago C, Boaz M, Wartel TA, 
Tornieporth NG, Saville M, Bouckenooghe A; CYD14 Study Group. Clinical efficacy and 
safety of a novel tetravalent dengue vaccine in healthy children in Asia: a phase 3, 
randomised, observer-masked, placebo-controlled trial. Lancet. 2014 Oct 
11;384(9951):1358-65.  
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Capeding RZ, Luna IA, Bomasang E, Lupisan S, Lang J, Forrat R, at al. Live-attenuated, 
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13 
WHO. Dengue vaccine: WHO position paper - July 2016. Weekly Epidemiological 
Records. 2016;30(91):349-64. 
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Hadinegoro SR, Wartel, TA, Frago C, Zambrano B, Langevin E, Gailhardou S, Noriega F, 
et al. Long-Term Safety of a CYD-TDV Dengue Vaccine in Asia Dengue Endemic 
Countries. Pan American Dengue Research Network. 5th Meeting; April 20-23 2016, 
Panama City, Panama. 
15 
Gailhardou S, Skipetrova A, Dayan GH, Jezorwski J, Saville M, Van der Vliet D, et al. 
Safety Overview of a Recombinant Live-Attenuated Tetravalent Dengue Vaccine: Pooled 
Analysis of Data from 18 Clinical Trials. PLoS Negl Trop Dis. 2016;10(7):e0004821. 
16 
U.S. Food and Drug Administration. Gardasil. Package insert - revised 04/2015. 
http://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM
111263.pdf. Accessed on 17 June 2015. 
17 
WHO. Gardasil. Package insert - revised June 2014. 
http://www.who.int/immunization_standards/vaccine_quality/PQ_179_HPV_Merck_PI_Fe
b_2015.pdf. S-WHO-PAHO-V501-I-062014.. Accessed on 17 June 2015. 
18 
WHO. Weekly epidemiological record. Relevé épidémiologique hebdomadaire. 2014. 
89:465-92. http://www.who.int/wer/2014/wer8943.pdf?ua=1. Accessed on 22 July 2015. 
19 
Markowitz LE, Tsu V, Deeks SL, et al. Human papillomavirus vaccine introduction--the 
first five years. Vaccine. 2012;30 Suppl 5:F139-48. 
20 
Crevat D, Brion JD, Gailhardou S, Laot TM, Capeding MR. First experience of concomitant 
vaccination against dengue and MMR in toddlers. Pediatr Infect Dis J. 2015;34(8):884-92. 
21 
The SAGE Working Group on Dengue Vaccines and WHO Secretariat. Background paper 
on dengue vaccines. World Health Organization. 17 March 2016. Available at URL: 
http://www.who.int/immunization/sage/meetings/2016/april/1_Background_Paper_Dengue_
Vaccines_2016_03_17.pdf?ua=1 
22 
Final Clinical Study Report CYD02. Randomized, Double-Blind, Placebo Controlled Phase 
I Study of the Safety, Tolerability and Immunogenicity of Live Attenuated Tetravalent 
Chimerivax-Dengue Vaccine and Yellow Fever Vaccine (YF-VAX). Version 1.0 dated 15 
February 2008. 
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