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    Clinical Trial Results:
    Immunogenicity and Safety of a Tetravalent Dengue Vaccine Administered Concomitantly or Sequentially with Gardasil® in Healthy Subjects Aged 9 to 13 Years in Malaysia

    Summary
    EudraCT number
    		 2019-003135-36
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    27 May 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    31 May 2020
    First version publication date
    31 May 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CYD67
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02993757
    WHO universal trial number (UTN)
    		 U1111-1161-3376
    Sponsors
    Sponsor organisation name
    Sanofi Pasteur
    Sponsor organisation address
    14 Espace Henry Vallée, Lyon, France, 69007
    Public contact
    Trial Transparency Team, Sanofi Pasteur, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi Pasteur, Contact-US@sanofi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    26 Feb 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 May 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    - To demonstrate that the humoral immune response (in terms of geometric mean titers [GMTs]) to Gardasil after concomitant administration was non-inferior to sequential administration with the CYD dengue vaccine measured 28 days after the last dose of Gardasil. - To demonstrate that the humoral immune response to the CYD dengue vaccine after concomitant administration was non-inferior to sequential administration with Gardasil measured 28 days after the last dose of the CYD dengue vaccine.
    Protection of trial subjects
    Vaccinations were performed by qualified and trained study personnel. Subjects with allergy to any of the vaccine components were not vaccinated. After vaccination, subjects were also kept under clinical observation for 30 minutes to ensure their safety. Appropriate medical equipment were also available on site in case of any immediate allergic reactions.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Dec 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Malaysia: 528
    Worldwide total number of subjects
    528
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    422
    Adolescents (12-17 years)
    106
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study subjects were enrolled from 01 December 2016 to 16 April 2017 at 5 centres in Malaysia. A total of 528 subjects were enrolled and randomised in this study.

    Pre-assignment
    Screening details
    		 As per protocol amendment 1, only dengue immune subjects at baseline completed the dengue vaccination schedule and received 3 doses of CYD dengue vaccine, whereas most of the dengue non-immune subjects received only 2 doses of CYD dengue vaccine. All subjects were followed for safety up to 6 months after the last vaccination.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 CYD Dengue Vaccine + Gardasil (Concomitant Administration)
    Arm description
    		 Dengue immune subjects (i.e., titers greater than or equal to (>=)10 (1/dilution [dil]) for at least one serotype with the parental dengue virus strains in the baseline sample) received 3 doses of CYD dengue vaccine 0.5 millilitre (mL) subcutaneously (SC) at Day 0, Month 6, and Month 12; whereas dengue non-immune subjects (i.e., titers <10 (1/dil) for all serotypes with parental dengue virus strains with available and "valid" results in the baseline sample) received only 2 doses of CYD vaccine at Day 0 and Month 6. Both immune and non-immune subjects received 2 doses of Gardasil vaccine 0.5 mL Intramuscular (IM), concomitantly with the first 2 doses of CYD dengue vaccine.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CYD Dengue Vaccine
    Investigational medicinal product code
    Other name
    Dengvaxia
    Pharmaceutical forms
    Powder and solvent for suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.5 mL, SC injection at Day 0, Month 6, and Month 12, respectively.

    Investigational medicinal product name
    Gardasil vaccine (recombinant quadrivalent Human Papillomavirus (HPV) [types 6, 11, 16, 18] vaccine)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, IM injection at Day 0 and Month 6, respectively.

    Arm title
    		 CYD Dengue Vaccine + Gardasil (Sequential Administration)
    Arm description
    		 Dengue immune subjects i.e., subjects with titers >=10 (1/dil) for at least one serotype with the parental dengue virus strains in the baseline sample) received 3 doses of CYD dengue vaccine 0.5 mL SC at Month 1, Month 7, and Month 13; whereas dengue non-immune subjects (i.e., subjects with titers <10 (1/dil) for all serotypes with parental dengue virus strains with available and "valid" results in the baseline sample) received only 2 doses of CYD vaccine at Month 1 and Month 7. Both immune and non-immune subjects received 2 doses of Gardasil vaccine 0.5 mL IM at Day 0 and Month 6 sequentially (i.e., one month before) to each of the first 2 doses of CYD dengue vaccine.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CYD Dengue Vaccine
    Investigational medicinal product code
    Other name
    Dengvaxia
    Pharmaceutical forms
    Powder and solvent for suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.5 mL, SC injection at Months 1, 7, and 13, respectively.

    Investigational medicinal product name
    Gardasil vaccine (recombinant quadrivalent HPV [types 6, 11, 16, 18] vaccine)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, IM injection at Day 0 and Month 6, respectively.

    Number of subjects in period 1
    		CYD Dengue Vaccine + Gardasil (Concomitant Administration) CYD Dengue Vaccine + Gardasil (Sequential Administration)
    Started
    266
    262
    Safety Analysis Set (SafAS)
    263
    260
    Completed
    102
    84
    Not completed
    164
    178
         Non compliance with the protocol
    155
    170
         Lost to follow-up
    1
    -
         Voluntary withdrawal not due to an adverse event
    8
    8

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    CYD Dengue Vaccine + Gardasil (Concomitant Administration)
    Reporting group description
    		 Dengue immune subjects (i.e., titers greater than or equal to (>=)10 (1/dilution [dil]) for at least one serotype with the parental dengue virus strains in the baseline sample) received 3 doses of CYD dengue vaccine 0.5 millilitre (mL) subcutaneously (SC) at Day 0, Month 6, and Month 12; whereas dengue non-immune subjects (i.e., titers <10 (1/dil) for all serotypes with parental dengue virus strains with available and "valid" results in the baseline sample) received only 2 doses of CYD vaccine at Day 0 and Month 6. Both immune and non-immune subjects received 2 doses of Gardasil vaccine 0.5 mL Intramuscular (IM), concomitantly with the first 2 doses of CYD dengue vaccine.

    Reporting group title
    CYD Dengue Vaccine + Gardasil (Sequential Administration)
    Reporting group description
    		 Dengue immune subjects i.e., subjects with titers >=10 (1/dil) for at least one serotype with the parental dengue virus strains in the baseline sample) received 3 doses of CYD dengue vaccine 0.5 mL SC at Month 1, Month 7, and Month 13; whereas dengue non-immune subjects (i.e., subjects with titers <10 (1/dil) for all serotypes with parental dengue virus strains with available and "valid" results in the baseline sample) received only 2 doses of CYD vaccine at Month 1 and Month 7. Both immune and non-immune subjects received 2 doses of Gardasil vaccine 0.5 mL IM at Day 0 and Month 6 sequentially (i.e., one month before) to each of the first 2 doses of CYD dengue vaccine.

    Reporting group values
    		 CYD Dengue Vaccine + Gardasil (Concomitant Administration) CYD Dengue Vaccine + Gardasil (Sequential Administration) Total
    Number of subjects
    		 266 262 528
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 10.4 ± 1.20 10.5 ± 1.18 -
    Gender categorical
    Units: Subjects
        Female
    		 175 172 347
        Male
    		 91 90 181
    Dengue Seropositivity Status
    Dengue immune subjects were defined as subjects with titers >=10 (1/dil) for at least one serotype with the parental dengue virus strains in the baseline sample. Dengue non-immune subjects were defined as subjects with titers <10 (1/dil) for all serotypes with parental dengue virus strains with available and “valid” results in the baseline sample.
    Units: Subjects
        Dengue immune
    		 109 88 197
        Dengue non-immune
    		 157 174 331

    End points

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    End points reporting groups
    Reporting group title
    CYD Dengue Vaccine + Gardasil (Concomitant Administration)
    Reporting group description
    		 Dengue immune subjects (i.e., titers greater than or equal to (>=)10 (1/dilution [dil]) for at least one serotype with the parental dengue virus strains in the baseline sample) received 3 doses of CYD dengue vaccine 0.5 millilitre (mL) subcutaneously (SC) at Day 0, Month 6, and Month 12; whereas dengue non-immune subjects (i.e., titers <10 (1/dil) for all serotypes with parental dengue virus strains with available and "valid" results in the baseline sample) received only 2 doses of CYD vaccine at Day 0 and Month 6. Both immune and non-immune subjects received 2 doses of Gardasil vaccine 0.5 mL Intramuscular (IM), concomitantly with the first 2 doses of CYD dengue vaccine.

    Reporting group title
    CYD Dengue Vaccine + Gardasil (Sequential Administration)
    Reporting group description
    		 Dengue immune subjects i.e., subjects with titers >=10 (1/dil) for at least one serotype with the parental dengue virus strains in the baseline sample) received 3 doses of CYD dengue vaccine 0.5 mL SC at Month 1, Month 7, and Month 13; whereas dengue non-immune subjects (i.e., subjects with titers <10 (1/dil) for all serotypes with parental dengue virus strains with available and "valid" results in the baseline sample) received only 2 doses of CYD vaccine at Month 1 and Month 7. Both immune and non-immune subjects received 2 doses of Gardasil vaccine 0.5 mL IM at Day 0 and Month 6 sequentially (i.e., one month before) to each of the first 2 doses of CYD dengue vaccine.

    Primary: Geometric Mean Titers (GMTs) Against Each Gardasil Vaccine HPV Antigen (HPV-6, HPV-11, HPV-16, HPV-18) 28 Days After Last Gardasil Vaccination in the Previously Dengue Immune Subjects

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    End point title
    		 Geometric Mean Titers (GMTs) Against Each Gardasil Vaccine HPV Antigen (HPV-6, HPV-11, HPV-16, HPV-18) 28 Days After Last Gardasil Vaccination in the Previously Dengue Immune Subjects
    End point description
    GMTs (measured in milli-Merck Units per mL [mMU/mL]) against each Gardasil HPV antigen (HPV-6, HPV-11, HPV-16, HPV-18) was assessed using competitive Luminex immunoassay (cLIA) method. Dengue immune subjects at Baseline were defined as subjects with titers >=10 (1/dil) for at least one serotype with the parental dengue virus strains. Analysis was performed on full analysis set (FAS) which included subset of subjects who received at least one dose of each of the study vaccines (CYD and Gardasil), analysed by baseline dengue status and vaccine group randomized. Here, ‘number of subjects analysed’ = subjects evaluable and had available data for this endpoint.
    End point type
    Primary
    End point timeframe
    28 days after the last Gardasil vaccination
    End point values
    		 CYD Dengue Vaccine + Gardasil (Concomitant Administration) CYD Dengue Vaccine + Gardasil (Sequential Administration)
    Number of subjects analysed
    104
    86
    Units: mMU/mL
    geometric mean (confidence interval 95%)
        HPV-6
    420 (327 to 539)
    428 (314 to 583)
        HPV-11
    1288 (1089 to 1522)
    1601 (1323 to 1937)
        HPV-16
    6221 (5093 to 7598)
    7629 (6142 to 9475)
        HPV-18
    829 (682 to 1007)
    1042 (858 to 1266)
    Statistical analysis title
    		 Antigen HPV-6
    Comparison groups
    CYD Dengue Vaccine + Gardasil (Concomitant Administration) v CYD Dengue Vaccine + Gardasil (Sequential Administration)
    Number of subjects included in analysis
    190
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 GMT ratio
    Point estimate
    0.982
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.664
         upper limit
    		 1.45
    Statistical analysis title
    		 Antigen HPV-11
    Comparison groups
    CYD Dengue Vaccine + Gardasil (Concomitant Administration) v CYD Dengue Vaccine + Gardasil (Sequential Administration)
    Number of subjects included in analysis
    190
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 GMT ratio
    Point estimate
    0.804
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.626
         upper limit
    		 1.03
    Statistical analysis title
    		 Antigen HPV-16
    Comparison groups
    CYD Dengue Vaccine + Gardasil (Concomitant Administration) v CYD Dengue Vaccine + Gardasil (Sequential Administration)
    Number of subjects included in analysis
    190
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 GMT ratio
    Point estimate
    0.815
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.608
         upper limit
    		 1.09
    Statistical analysis title
    		 Antigen HPV-18
    Comparison groups
    CYD Dengue Vaccine + Gardasil (Concomitant Administration) v CYD Dengue Vaccine + Gardasil (Sequential Administration)
    Number of subjects included in analysis
    190
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 GMT ratio
    Point estimate
    0.795
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.603
         upper limit
    		 1.05

    Primary: Geometric Mean Titers Against Each Parental Dengue Virus Serotype 28 Days After Third CYD Dengue Vaccination in the Previously Dengue Immune Subjects

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    End point title
    		 Geometric Mean Titers Against Each Parental Dengue Virus Serotype 28 Days After Third CYD Dengue Vaccination in the Previously Dengue Immune Subjects
    End point description
    The GMTs against each of the four parental dengue virus serotypes (1, 2, 3 and 4) of CYD dengue vaccine was assessed using the 50 percent (%) plaque reduction neutralization test (PRNT50) assay. Dengue immune subjects at Baseline were defined as subjects with titers >=10 (1/dil) for at least one serotype with the parental dengue virus strains. Analysis was performed on FAS population. Here, 'number of subjects analysed'=subjects evaluable and had available data for this endpoint.
    End point type
    Primary
    End point timeframe
    28 days after third CYD dengue vaccination
    End point values
    		 CYD Dengue Vaccine + Gardasil (Concomitant Administration) CYD Dengue Vaccine + Gardasil (Sequential Administration)
    Number of subjects analysed
    102
    84
    Units: titer (1/dilution)
    geometric mean (confidence interval 95%)
        Serotype 1
    447 (303 to 659)
    453 (313 to 656)
        Serotype 2
    561 (408 to 771)
    717 (526 to 977)
        Serotype 3
    460 (354 to 596)
    549 (411 to 734)
        Serotype 4
    323 (263 to 398)
    303 (255 to 359)
    Statistical analysis title
    		 Serotype 1
    Comparison groups
    CYD Dengue Vaccine + Gardasil (Concomitant Administration) v CYD Dengue Vaccine + Gardasil (Sequential Administration)
    Number of subjects included in analysis
    186
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 GMT ratio
    Point estimate
    0.987
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.574
         upper limit
    		 1.7
    Statistical analysis title
    		 Serotype 2
    Comparison groups
    CYD Dengue Vaccine + Gardasil (Concomitant Administration) v CYD Dengue Vaccine + Gardasil (Sequential Administration)
    Number of subjects included in analysis
    186
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 GMT ratio
    Point estimate
    0.783
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 1.22
    Statistical analysis title
    		 Serotype 3
    Comparison groups
    CYD Dengue Vaccine + Gardasil (Concomitant Administration) v CYD Dengue Vaccine + Gardasil (Sequential Administration)
    Number of subjects included in analysis
    186
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 GMT ratio
    Point estimate
    0.836
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.568
         upper limit
    		 1.23
    Statistical analysis title
    		 Serotype 4
    Comparison groups
    CYD Dengue Vaccine + Gardasil (Concomitant Administration) v CYD Dengue Vaccine + Gardasil (Sequential Administration)
    Number of subjects included in analysis
    186
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 GMT ratio
    Point estimate
    1.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.813
         upper limit
    		 1.4

    Secondary: Percentage of Subjects With Seroconversion Against Each Gardasil HPV Antigen (HPV-6, HPV-11, HPV-16, HPV-18) 28 Days After Last Dose of Gardasil in the Previously Dengue Immune Subjects

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    End point title
    		 Percentage of Subjects With Seroconversion Against Each Gardasil HPV Antigen (HPV-6, HPV-11, HPV-16, HPV-18) 28 Days After Last Dose of Gardasil in the Previously Dengue Immune Subjects
    End point description
    Neutralising antibodies against each Gardasil HPV antigen (HPV-6, HPV-11, HPV-16, HPV-18) was assessed using cLIA method. Seroconversion was defined as changing serostatus from seronegative at Baseline to seropositive (subjects with a pre-vaccination titer < lower limit of quantification [LLOQ] (mMU/mL) to a post-vaccination titer >= LLOQ) or >=4-fold rise in antibody titer if seropositive at baseline. The LLOQ for HPV-6 and HPV-16 was 11 mMU/mL, 8 mMU/mL for HPV-11, and 10 mMU/mL for HPV-18. Dengue immune subjects at Baseline were defined as subjects with titers >=10 (1/dil) for at least one serotype with the parental dengue virus strains. Analysis was performed on FAS population. Here, 'number of subjects analysed'=subjects evaluable and had available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    28 days after the last Gardasil vaccination
    End point values
    		 CYD Dengue Vaccine + Gardasil (Concomitant Administration) CYD Dengue Vaccine + Gardasil (Sequential Administration)
    Number of subjects analysed
    103
    81
    Units: percentage of subjects
    number (confidence interval 95%)
        HPV-6
    98.1 (93.2 to 99.8)
    100.0 (95.5 to 100.0)
        HPV-11
    100.0 (96.5 to 100.0)
    100.0 (95.5 to 100.0)
        HPV-16
    100.0 (96.5 to 100.0)
    100.0 (95.5 to 100.0)
        HPV-18
    100.0 (96.5 to 100.0)
    100.0 (95.5 to 100.0)
    No statistical analyses for this end point

    Secondary: Geometric Mean Titers Against Each Gardasil HPV Antigen (HPV-6, HPV-11, HPV-16, HPV-18) at Day 0 and 28 Days After Each Dose of Gardasil in the Previously Dengue Immune Subjects

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    End point title
    		 Geometric Mean Titers Against Each Gardasil HPV Antigen (HPV-6, HPV-11, HPV-16, HPV-18) at Day 0 and 28 Days After Each Dose of Gardasil in the Previously Dengue Immune Subjects
    End point description
    The GMTs (measured in mMU/mL) against each Gardasil HPV antigen (HPV-6, HPV-11, HPV-16, HPV-18) was assessed using cLIA method. Dengue immune subjects at Baseline were defined as subjects with titers >=10 (1/dil) for at least one serotype with the parental dengue virus strains. Analysis was performed on FAS. Here, 'number of subjects analysed'=subjects evaluable and had available data for this endpoint and ‘n’=subjects with available data for each specified categories and '99999' signifies that the 95% confidence interval was not computable, since all subjects had the same value.
    End point type
    Secondary
    End point timeframe
    Day 0 (pre-vaccination) and 28 days after Gardasil vaccination 1 and 2
    End point values
    		 CYD Dengue Vaccine + Gardasil (Concomitant Administration) CYD Dengue Vaccine + Gardasil (Sequential Administration)
    Number of subjects analysed
    109
    88
    Units: mMU/mL
    geometric mean (confidence interval 95%)
        HPV-6: Day 0 (n=108,82)
    5.70 (5.46 to 5.95)
    5.61 (5.46 to 5.77)
        HPV-6: 28 days post vaccination 1 (n=107,88)
    54.9 (45.0 to 66.9)
    61.8 (49.7 to 76.9)
        HPV-6: 28 days post vaccination 2 (n=104,86)
    420 (327 to 539)
    428 (314 to 583)
        HPV-11: Day 0 (n=108,82)
    4.16 (3.92 to 4.41)
    4.00 (-99999 to 99999)
        HPV-11: 28 days post vaccination 1 (n=107,88)
    58.1 (47.6 to 71.0)
    78.5 (62.5 to 98.6)
        HPV-11: 28 days post vaccination 2 (n=104,86)
    1288 (1089 to 1522)
    1601 (1323 to 1937)
        HPV-16: Day 0 (n=108,82)
    5.62 (5.38 to 5.87)
    5.50 (-99999 to 99999)
        HPV-16: 28 days post vaccination 1 (n=107,88)
    148 (119 to 185)
    150 (116 to 193)
        HPV-16: 28 days post vaccination 2 (n=104,86)
    6221 (5093 to 7598)
    7629 (6142 to 9475)
        HPV-18: Day 0 (n=108,82)
    5.26 (5.03 to 5.50)
    5.06 (4.94 to 5.18)
        HPV-18: 28 days post vaccination 1 (n=107,88)
    23.5 (18.7 to 29.4)
    31.6 (24.9 to 40.0)
        HPV-18: 28 days post vaccination 2 (n=104,86)
    829 (682 to 1007)
    1042 (858 to 1266)
    No statistical analyses for this end point

    Secondary: Geometric Mean Titers Against Each Dengue Virus Serotype of CYD Dengue Vaccine at Day 0 and 28 Days After Each Dose of CYD Dengue Vaccination in the Previously Dengue Immune Subjects

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    End point title
    		 Geometric Mean Titers Against Each Dengue Virus Serotype of CYD Dengue Vaccine at Day 0 and 28 Days After Each Dose of CYD Dengue Vaccination in the Previously Dengue Immune Subjects
    End point description
    The GMTs against each of the four parental dengue virus serotypes (1, 2, 3, and 4) of CYD dengue vaccine was assessed using the PRNT50 assay. Dengue immune subjects at Baseline were defined as subjects with titers >=10 (1/dil) for at least one serotype with the parental dengue virus strains. Analysis was performed on FAS. Here, 'number of subjects analysed'=subjects evaluable and had available data for this endpoint and ‘n’=subjects with available data for each specified categories.
    End point type
    Secondary
    End point timeframe
    Day 0 (pre-vaccination) and 28 days after each CYD dengue vaccination
    End point values
    		 CYD Dengue Vaccine + Gardasil (Concomitant Administration) CYD Dengue Vaccine + Gardasil (Sequential Administration)
    Number of subjects analysed
    109
    88
    Units: titer (1/dilution)
    geometric mean (confidence interval 95%)
        Serotype 1: Day 0 (n=109,88)
    62.3 (40.7 to 95.5)
    81.5 (49.4 to 135)
        Serotype 1: 28 days post vaccination 1 (n=107,88)
    382 (245 to 597)
    449 (268 to 752)
        Serotype 1: 28 days post vaccination 2 (n=104,87)
    403 (270 to 602)
    529 (342 to 819)
        Serotype 1: 28 days post vaccination 3 (n=102,84)
    447 (303 to 659)
    453 (313 to 656)
        Serotype 2: Day 0 (n=109,88)
    110 (75.5 to 160)
    130 (84.0 to 201)
        Serotype 2: 28 days post vaccination 1 (n=107,88)
    750 (500 to 1124)
    848 (541 to 1330)
        Serotype 2: 28 days post vaccination 2 (n=104,87)
    728 (519 to 1019)
    937 (654 to 1342)
        Serotype 2: 28 days post vaccination 3 (n=102,84)
    561 (408 to 771)
    717 (526 to 977)
        Serotype 3: Day 0 (n=109,87)
    72.3 (52.7 to 99.2)
    96.7 (64.9 to 144)
        Serotype 3: 28 days post vaccination 1 (n=106,88)
    432 (304 to 614)
    517 (355 to 755)
        Serotype 3: 28 days post vaccination 2 (n=104,87)
    389 (299 to 506)
    543 (403 to 731)
        Serotype 3: 28 days post vaccination 3 (n=102,84)
    460 (354 to 596)
    549 (411 to 734)
        Serotype 4: Day 0 (n=109,88)
    26.3 (18.8 to 36.7)
    23.7 (16.2 to 34.8)
        Serotype 4: 28 days post vaccination 1 (n=107,88)
    330 (234 to 464)
    286 (204 to 401)
        Serotype 4: 28 days post vaccination 2 (n=104,87)
    284 (229 to 352)
    282 (225 to 353)
        Serotype 4: 28 days post vaccination 3 (n=102,83)
    323 (263 to 398)
    303 (255 to 359)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Neutralising Antibody Titers Against Each of the 4 Dengue Virus Serotypes of CYD Dengue Vaccine at Day 0 And 28 Days After Each Dose of CYD Dengue Vaccination in the Previously Dengue Immune Subjects

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    End point title
    		 Percentage of Subjects With Neutralising Antibody Titers Against Each of the 4 Dengue Virus Serotypes of CYD Dengue Vaccine at Day 0 And 28 Days After Each Dose of CYD Dengue Vaccination in the Previously Dengue Immune Subjects
    End point description
    Dengue neutralising antibody levels against each of the 4 dengue virus serotypes (1, 2, 3, and 4) was measured by PRNT50. Dengue immune subjects at Baseline were defined as subjects with titers >=10 (1/dil) for at least one serotype with the parental dengue virus strains. Analysis was performed on FAS. Here, 'number of subjects analysed'=subjects evaluable and had available data for this endpoint and ‘n’=subjects with available data for each specified categories.
    End point type
    Secondary
    End point timeframe
    Day 0 (pre-vaccination) and 28 days after each CYD dengue vaccination
    End point values
    		 CYD Dengue Vaccine + Gardasil (Concomitant Administration) CYD Dengue Vaccine + Gardasil (Sequential Administration)
    Number of subjects analysed
    109
    88
    Units: percentage of subjects
    number (confidence interval 95%)
        Serotype 1: Day 0 (n=109,88)
    66.1 (56.4 to 74.9)
    72.7 (62.2 to 81.7)
        Serotype 1: 28 days post vaccination 1 (n=107,88)
    91.6 (84.6 to 96.1)
    90.9 (82.9 to 96.0)
        Serotype 1: 28 days post vaccination 2 (n=104,87)
    96.2 (90.4 to 98.9)
    95.4 (88.6 to 98.7)
        Serotype 1: 28 days post vaccination 3 (n=102,84)
    95.1 (88.9 to 98.4)
    100.0 (95.7 to 100.0)
        Serotype 2: Day 0 (n=109,88)
    83.5 (75.2 to 89.9)
    81.8 (72.2 to 89.2)
        Serotype 2: 28 days post vaccination 1 (n=107,88)
    93.5 (87.0 to 97.3)
    92.0 (84.3 to 96.7)
        Serotype 2: 28 days post vaccination 2 (n=104,87)
    99.0 (94.8 to 100.0)
    97.7 (91.9 to 99.7)
        Serotype 2: 28 days post vaccination 3 (n=102,84)
    97.1 (91.6 to 99.4)
    98.8 (93.5 to 100.0)
        Serotype 3: Day 0 (n=109,87)
    89.0 (81.6 to 94.2)
    86.2 (77.1 to 92.7)
        Serotype 3: 28 days post vaccination 1 (n=106,88)
    96.2 (90.6 to 99.0)
    97.7 (92.0 to 99.7)
        Serotype 3: 28 days post vaccination 2 (n=104,87)
    100.0 (96.5 to 100.0)
    100.0 (95.8 to 100.0)
        Serotype 3: 28 days post vaccination 3 (n=102,84)
    99.0 (94.7 to 100.0)
    100.0 (95.7 to 100.0)
        Serotype 4: Day 0 (n=109,88)
    59.6 (49.8 to 68.9)
    54.5 (43.6 to 65.2)
        Serotype 4: 28 days post vaccination 1 (n=107,88)
    93.5 (87.0 to 97.3)
    98.9 (93.8 to 100.0)
        Serotype 4: 28 days post vaccination 2 (n=104,87)
    100.0 (96.5 to 100.0)
    100.0 (95.8 to 100.0)
        Serotype 4: 28 days post vaccination 3 (n=102,84)
    100.0 (96.4 to 100.0)
    100.0 (95.7 to 100.0)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Neutralising Antibody Titers Above Pre-defined Thresholds Against at Least 1,2,3,or4 Serotypes of CYD Dengue Vaccine at Day 0 And 28 Days After Each Dose of CYD Dengue Vaccination in the Previously Dengue Immune Subjects

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    End point title
    		 Percentage of Subjects With Neutralising Antibody Titers Above Pre-defined Thresholds Against at Least 1,2,3,or4 Serotypes of CYD Dengue Vaccine at Day 0 And 28 Days After Each Dose of CYD Dengue Vaccination in the Previously Dengue Immune Subjects
    End point description
    Dengue neutralising antibody levels against each of the 4 dengue virus serotypes (1, 2, 3, and 4) were measured by PRNT50. Dengue immune subjects at Baseline were defined as subjects with titers >=10 (1/dil) for at least one serotype with the parental dengue virus strains. Percentage of subjects with neutralizing antibody titers above pre-defined thresholds (>=10 and >=100 [1/dil]) against at least 1, 2, 3, or 4 serotypes of CYD dengue vaccine were reported. Analysis was performed on FAS. Here, 'number of subjects analysed'=subjects evaluable and had available data for this endpoint and ‘n’=subjects with available data for each specified categories. Here "vac"=vaccination in the specified categories.
    End point type
    Secondary
    End point timeframe
    Day 0 (pre-vaccination) and 28 days after each CYD dengue vaccination
    End point values
    		 CYD Dengue Vaccine + Gardasil (Concomitant Administration) CYD Dengue Vaccine + Gardasil (Sequential Administration)
    Number of subjects analysed
    109
    88
    Units: percentage of subjects
    number (confidence interval 95%)
        At least 1 Serotype:Day 0:>=10(1/dil)(n=109,88)
    100.0 (96.7 to 100.0)
    100.0 (95.9 to 100.0)
        At least 1 Serotype:Day 0:>=100(1/dil)(n=109,88)
    90.8 (83.8 to 95.5)
    88.6 (80.1 to 94.4)
        At least1 Serotype:post-vac1:>=10(1/dil)(n=107,88)
    97.2 (92.0 to 99.4)
    100.0 (95.9 to 100.0)
        At least1Serotype:post-vac1:>=100(1/dil)(n=107,88)
    95.3 (89.4 to 98.5)
    96.6 (90.4 to 99.3)
        At least1 Serotype:post-vac2:>=10(1/dil)(n=104,87)
    100.0 (96.5 to 100.0)
    100.0 (95.8 to 100.0)
        At least1Serotype:post-vac2:>=100(1/dil)(n=104,87)
    96.2 (90.4 to 98.9)
    98.9 (93.8 to 100.0)
        At least1 Serotype:post-vac3:>=10(1/dil)(n=102,84)
    100.0 (96.4 to 100.0)
    100.0 (95.7 to 100.0)
        At least1Serotype:post-vac3:>=100(1/dil)(n=102,84)
    98.0 (93.1 to 99.8)
    97.6 (91.7 to 99.7)
        At least 2 Serotype:Day 0:>=10(1/dil)(n=109,88)
    84.4 (76.2 to 90.6)
    81.8 (72.2 to 89.2)
        At least 2 Serotype:Day 0:>=100(1/dil)(n=109,88)
    34.9 (26.0 to 44.6)
    39.8 (29.5 to 50.8)
        At least2 Serotype:post-vac1:>=10(1/dil)(n=107,88)
    94.4 (88.2 to 97.9)
    97.7 (92.0 to 99.7)
        At least2Serotype:post-vac1:>=100(1/dil)(n=107,88)
    85.0 (76.9 to 91.2)
    80.7 (70.9 to 88.3)
        At least2 Serotype:post-vac2:>=10(1/dil)(n=104,87)
    100.0 (96.5 to 100.0)
    100.0 (95.8 to 100.0)
        At least2Serotype:post-vac2:>=100(1/dil)(n=104,87)
    84.6 (76.2 to 90.9)
    92.0 (84.1 to 96.7)
        At least2 Serotype:post-vac3:>=10(1/dil)(n=102,84)
    100.0 (96.4 to 100.0)
    100.0 (95.7 to 100.0)
        At least2Serotype:post-vac3:>=100(1/dil)(n=102,84)
    93.1 (86.4 to 97.2)
    94.0 (86.7 to 98.0)
        At least 3 Serotype:Day 0:>=10(1/dil)(n=109,88)
    71.6 (62.1 to 79.8)
    69.3 (58.6 to 78.7)
        At least 3 Serotype:Day 0:>=100(1/dil)(n=109,88)
    23.9 (16.2 to 33.0)
    27.3 (18.3 to 37.8)
        At least3 Serotype:post-vac1:>=10(1/dil)(n=107,88)
    92.5 (85.8 to 96.7)
    92.0 (84.3 to 96.7)
        At least3Serotype:post-vac1:>=100(1/dil)(n=107,88)
    75.7 (66.5 to 83.5)
    73.9 (63.4 to 82.7)
        At least3 Serotype:post-vac2:>=10(1/dil)(n=104,87)
    99.0 (94.8 to 100.0)
    98.9 (93.8 to 100.0)
        At least3Serotype:post-vac2:>=100(1/dil)(n=104,87)
    77.9 (68.7 to 85.4)
    86.2 (77.1 to 92.7)
        At least3 Serotype:post-vac3:>=10(1/dil)(n=102,84)
    97.1 (91.6 to 99.4)
    100.0 (95.7 to 100.0)
        At least3Serotype:post-vac3:>=100(1/dil)(n=102,84)
    83.3 (74.7 to 90.0)
    88.1 (79.2 to 94.1)
        At least 4 Serotype:Day 0:>=10(1/dil)(n=109,87)
    42.2 (32.8 to 52.0)
    43.7 (33.1 to 54.7)
        At least 4 Serotype:Day 0:>=100(1/dil)(n=109,87)
    6.4 (2.6 to 12.8)
    12.6 (6.5 to 21.5)
        At least4 Serotype:post-vac1:>=10(1/dil)(n=106,88)
    90.6 (83.3 to 95.4)
    89.8 (81.5 to 95.2)
        At least4Serotype:post-vac1:>=100(1/dil)(n=106,88)
    60.4 (50.4 to 69.7)
    62.5 (51.5 to 72.6)
        At least4 Serotype:post-vac2:>=10(1/dil)(n=104,87)
    96.2 (90.4 to 98.9)
    94.3 (87.1 to 98.1)
        At least4Serotype:post-vac2:>=100(1/dil)(n=104,87)
    67.3 (57.4 to 76.2)
    75.9 (65.5 to 84.4)
        At least4 Serotype:post-vac3:>=10(1/dil)(n=102,84)
    94.1 (87.6 to 97.8)
    98.8 (93.5 to 100.0)
        At least4Serotype:post-vac3:>=100(1/dil)(n=102,84)
    72.5 (62.8 to 80.9)
    77.4 (67.0 to 85.8)
    No statistical analyses for this end point

    Secondary: Number of Subjects Reporting Immediate Adverse Events (AEs) Following Vaccination With Gardasil or CYD Dengue Vaccine

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    End point title
    		 Number of Subjects Reporting Immediate Adverse Events (AEs) Following Vaccination With Gardasil or CYD Dengue Vaccine
    End point description
    Any unsolicited systemic AE occurred during the first 30 minutes post-vaccination was recorded on the case report form (CRF) as immediate AE. At Visit 1 and Visit 4, subjects from Group 1 received both Gardasil and CYD vaccination and subjects from Group 2 received only Gardasil vaccination. At Visit 2 and Visit 5, only subjects from Group 2 received CYD vaccination whereas the subjects from Group 1 received no vaccination. Analysis was performed on safety analysis set (SafAS) which included subjects who had received at least one dose of the study vaccines. Here, ‘n’=subjects with available data for each specified categories and '99999' signifies that the subjects from Group 1 did not receive any vaccination at Visit 2 and Visit 5 and therefore were not evaluable.
    End point type
    Secondary
    End point timeframe
    Within 30 minutes after any and each vaccination
    End point values
    		 CYD Dengue Vaccine + Gardasil (Concomitant Administration) CYD Dengue Vaccine + Gardasil (Sequential Administration)
    Number of subjects analysed
    263
    260
    Units: subjects
    number (not applicable)
        Post any vaccination (n=263,260)
    0
    3
        Post vaccination 1 (Visit 1) (n=263,260)
    0
    1
        Post CYD vaccination 1 (Visit 2) (n=0,256)
    99999
    1
        Post vaccination 2 (Visit 4) (n=257,256)
    0
    0
        Post CYD vaccination 2 (Visit 5) (n=0,249)
    99999
    1
        Post CYD vaccination 3 (Visit 7) (n=103, 83)
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects Reporting Solicited Injection Site Reactions Following Vaccination With Gardasil or CYD Dengue Vaccine

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    End point title
    		 Number of Subjects Reporting Solicited Injection Site Reactions Following Vaccination With Gardasil or CYD Dengue Vaccine
    End point description
    A solicited reaction (SR) was an adverse reaction (AR) observed and reported under the conditions (symptom and onset) prelisted (i.e., solicited) in the CRF and considered as related to vaccination. Solicited injection site reactions included pain, erythema, and swelling. Analysis was performed on SafAS. Here, ‘n’=subjects with available data for each specified categories.
    End point type
    Secondary
    End point timeframe
    Up to 7 days after any and each vaccination
    End point values
    		 CYD Dengue Vaccine + Gardasil (Concomitant Administration) CYD Dengue Vaccine + Gardasil (Sequential Administration)
    Number of subjects analysed
    263
    260
    Units: subjects
    number (not applicable)
        Pain: Post any CYD/Gardasil vaccine (n=260,258)
    206
    193
        Pain: Post CYD/Gardasil vaccination 1 (n=260,258)
    163
    157
        Pain: Post CYD/Gardasil vaccination 2 (n=256,254)
    151
    141
        Pain: Post CYD vaccination 3 (n=103,83)
    33
    24
        Erythema: Post any CYD/Gardasil vaccine(n=260,258)
    45
    38
        Erythema:Post CYD/Gardasil vaccination1(n=260,258)
    30
    29
        Erythema:Post CYD/Gardasil vaccination2(n=256,254)
    25
    19
        Erythema:Post CYD vaccination 3 (n=103,83)
    9
    2
        Swelling:Post any CYD/Gardasil vaccine (n=260,258)
    43
    31
        Swelling:Post CYD/Gardasil vaccination1(n=260,258)
    22
    22
        Swelling:Post CYD/Gardasil vaccination2(n=256,254)
    30
    18
        Swelling:Post CYD vaccination 3 (n=103,83)
    9
    3
    No statistical analyses for this end point

    Secondary: Number of Subjects Reporting Solicited Systemic Reactions Following Vaccination With Gardasil or CYD Dengue Vaccine

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    End point title
    		 Number of Subjects Reporting Solicited Systemic Reactions Following Vaccination With Gardasil or CYD Dengue Vaccine
    End point description
    A SR was an AR observed and reported under the conditions (symptom and onset) prelisted (i.e., solicited) in the CRF and considered as related to vaccination. Solicited systemic reactions included fever, headache, malaise, myalgia, and asthenia. At Visit 1 and Visit 4, subjects from Group 1 received both Gardasil and CYD vaccination and subjects from Group 2 received only Gardasil vaccination. At Visit 2 and Visit 5, only subjects from Group 2 received CYD vaccination whereas the subjects from Group 1 received no vaccination. Analysis was performed on SafAS. Here, ‘n’=subjects with available data for each specified categories. Here '99999' signifies that the subjects from Group 1 did not receive any vaccination at Visit 2 and Visit 5 and therefore were not evaluable.
    End point type
    Secondary
    End point timeframe
    Up to 14 days after any and each vaccination
    End point values
    		 CYD Dengue Vaccine + Gardasil (Concomitant Administration) CYD Dengue Vaccine + Gardasil (Sequential Administration)
    Number of subjects analysed
    263
    260
    Units: subjects
    number (not applicable)
        Fever: Post any vaccination (n=259,258)
    36
    47
        Fever: Post vaccination 1 (Visit 1) (n=257,258)
    21
    8
        Fever: Post CYD vaccination 1 (Visit 2) (n=0,255)
    99999
    15
        Fever: Post vaccination 2 (Visit 4) (n=252,253)
    10
    11
        Fever: Post CYD vaccination 2 (Visit 5) (n=0,249)
    99999
    12
        Fever: Post CYD vaccination 3 (Visit 7) (n=103,83)
    8
    6
        Headache: Post any vaccination (n=260,258)
    125
    146
        Headache: Post vaccination 1 (Visit 1)(n=260,258)
    99
    93
        Headache: Post CYD vaccination 1(Visit 2)(n=0,255)
    99999
    73
        Headache: Post vaccination 2 (Visit 4)(n=256,254)
    61
    70
        Headache: Post CYD vaccination 2(Visit 5)(n=0,249)
    99999
    51
        Headache:Post CYD vaccination 3(Visit 7)(n=103,83)
    15
    17
        Malaise: Post any vaccination(n=260,258)
    111
    137
        Malaise: Post vaccination 1 (Visit 1)(n=260,258)
    82
    78
        Malaise: Post CYD vaccination 1 (Visit 2)(n=0,255)
    99999
    69
        Malaise: Post vaccination 2 (Visit 4)(n=256,254)
    57
    54
        Malaise:Post CYD vaccination 2 (Visit 5)(n=0,249)
    99999
    40
        Malaise:Post CYD vaccination 3 (Visit 7)(n=103,83)
    20
    17
        Myalgia: Post any vaccination (n=260,258)
    127
    156
        Myalgia: Post vaccination 1 (Visit 1) (n=260,258)
    93
    94
        Myalgia: Post CYD vaccination 1 (Visit 2)(n=0,255)
    99999
    63
        Myalgia: Post vaccination 2 (Visit 4) (n=256,254)
    72
    70
        Myalgia: Post CYD vaccination 2 (Visit 5)(n=0,249)
    99999
    43
        Myalgia:Post CYD vaccination 3 (Visit 7)(n=103,83)
    16
    13
        Asthenia: Post any vaccination(n=260,258)
    133
    132
        Asthenia: Post vaccination 1 (Visit 1) (n=260,258)
    101
    89
        Asthenia:Post CYD vaccination 1 (Visit 2)(n=0,255)
    99999
    63
        Asthenia: Post vaccination 2 (Visit 4)(n=256,254)
    74
    46
        Asthenia:Post CYD vaccination 2 (Visit 5)(n=0,249)
    99999
    35
        Asthenia:Post CYD vaccination 3(Visit 7)(n=103,83)
    19
    16
    No statistical analyses for this end point

    Secondary: Number of Subjects Reporting Unsolicited Adverse Events Following Vaccination With Gardasil or CYD Dengue Vaccine

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    End point title
    		 Number of Subjects Reporting Unsolicited Adverse Events Following Vaccination With Gardasil or CYD Dengue Vaccine
    End point description
    An unsolicited AE was an observed AE that did not fulfill the conditions prelisted in the CRF in terms of diagnosis and/or onset post-vaccination. At Visit 1 and Visit 4, subjects from Group 1 received both Gardasil and CYD vaccination and subjects from Group 2 received only Gardasil vaccination. At Visit 2 and Visit 5, only subjects from Group 2 received CYD vaccination whereas the subjects from Group 1 received no vaccination. Analysis was performed on SafAS. Here, ‘n’=subjects with available data for each specified categories and '99999' signifies that the subjects from Group 1 did not receive any vaccination at Visit 2 and Visit 5 and therefore were not evaluable.
    End point type
    Secondary
    End point timeframe
    Up to 28 days after any and each vaccination
    End point values
    		 CYD Dengue Vaccine + Gardasil (Concomitant Administration) CYD Dengue Vaccine + Gardasil (Sequential Administration)
    Number of subjects analysed
    263
    260
    Units: subjects
    number (not applicable)
        Post any vaccination (n=263, 260)
    54
    91
        Post vaccination 1 (Visit 1) (n=263, 260)
    34
    38
        Post CYD vaccination 1 (Visit 2) (n=0,256)
    99999
    38
        Post vaccination 2 (Visit 4) (n=257,256)
    24
    22
        Post CYD vaccination 2 (Visit 5) (n=0,249)
    99999
    28
        Post CYD vaccination 3 (Visit 7) (n=103,83)
    5
    7
    No statistical analyses for this end point

    Secondary: Number of Subjects Reporting Non-serious Adverse Event of Special Interests (AESIs) Following Vaccination With Gardasil or CYD Dengue Vaccine

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    End point title
    		 Number of Subjects Reporting Non-serious Adverse Event of Special Interests (AESIs) Following Vaccination With Gardasil or CYD Dengue Vaccine
    End point description
    AESI were AEs that were considered by the Sponsor to be relevant for the monitoring of the safety profile of the investigational vaccine. At Visit 1 and Visit 4, subjects from Group 1 received both Gardasil and CYD vaccination and subjects from Group 2 received only Gardasil vaccination. At Visit 2 and Visit 5, only subjects from Group 2 received CYD vaccination whereas the subjects from Group 1 received no vaccination. Analysis was performed on SafAS. Here, ‘n’=subjects with available data for each specified categories and '99999' signifies that the subjects from Group 1 did not receive any vaccination at Visit 2 and Visit 5 and therefore were not evaluable.
    End point type
    Secondary
    End point timeframe
    Within 7 days after any and each vaccination
    End point values
    		 CYD Dengue Vaccine + Gardasil (Concomitant Administration) CYD Dengue Vaccine + Gardasil (Sequential Administration)
    Number of subjects analysed
    263
    260
    Units: subjects
    number (not applicable)
        Post any vaccination (n=263,260)
    0
    0
        Post vaccination 1 (Visit 1) (n=263,260)
    0
    0
        Post CYD vaccination 1 (Visit 2) (n=0,256)
    99999
    0
        Post vaccination 2 (Visit 4) (n=257,256)
    0
    0
        Post CYD vaccination 2 (Visit 5) (n=0,249)
    99999
    0
        Post CYD vaccination 3 (Visit 7) (n=103,83)
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects Reporting Serious Adverse Events (SAEs) Including Serious Adverse Event of Special Interests Following Vaccination With Gardasil or CYD Dengue Vaccine

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    End point title
    		 Number of Subjects Reporting Serious Adverse Events (SAEs) Including Serious Adverse Event of Special Interests Following Vaccination With Gardasil or CYD Dengue Vaccine
    End point description
    SAEs were AEs that resulted in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalisation; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly or a medically important event. An AESIs were AEs that were considered by the Sponsor to be relevant for the monitoring of the safety profile of the investigational vaccine. Analysis was performed on SafAS.
    End point type
    Secondary
    End point timeframe
    From Day 0 up to 6 months after the last Gardasil or CYD vaccination
    End point values
    		 CYD Dengue Vaccine + Gardasil (Concomitant Administration) CYD Dengue Vaccine + Gardasil (Sequential Administration)
    Number of subjects analysed
    263
    260
    Units: subjects
    number (not applicable)
        SAE
    11
    8
        Serious AESI
    1
    2
    No statistical analyses for this end point

    Secondary: Number of Subjects Reporting Cases of Virologically Confirmed Dengue (VCD) Hospitalisation Following Vaccination With Gardasil or CYD Dengue Vaccine

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    End point title
    		 Number of Subjects Reporting Cases of Virologically Confirmed Dengue (VCD) Hospitalisation Following Vaccination With Gardasil or CYD Dengue Vaccine
    End point description
    Hospitalised suspected dengue case was defined as an acute febrile illness with diagnosis of dengue requiring hospitalisation (with bed attribution). In such cases, 1 unplanned acute blood sample (within the first 5 days after fever onset) was collected for virological confirmation of hospitalised suspected dengue case. A suspected case was considered VCD if there was a detection of wild type dengue virus by dengue non-structural protein 1 antigen enzyme-linked immunosorbent assay and/or dengue reverse transcriptase-polymerase chain reactions. Analysis was performed on SafAS.
    End point type
    Secondary
    End point timeframe
    From Day 0 up to 6 months after the last Gardasil or CYD vaccination
    End point values
    		 CYD Dengue Vaccine + Gardasil (Concomitant Administration) CYD Dengue Vaccine + Gardasil (Sequential Administration)
    Number of subjects analysed
    263
    260
    Units: subjects
        number (not applicable)
    1
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The AE data were collected from Day 0 up to Day 28 post any vaccination. SR were collected from Day 0 up to Day 14 post any vaccination. The SAEs were collected throughout the trial, i.e. 6 months after last Gardasil or CYD vaccination.
    Adverse event reporting additional description
    SR was an AE that was prelisted (i.e.,solicited) in the electronic CRF and considered to be related to vaccination (adverse drug reaction). An unsolicited AE was an observed AE that did not fulfill the conditions prelisted in the CRF (i.e.,solicited) in terms of diagnosis and/or onset post-vaccination. Analysis was performed on SafAS.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    CYD Dengue Vaccine + Gardasil (Concomitant Administration)
    Reporting group description
    		 Dengue immune subjects received 3 doses of CYD dengue vaccine 0.5 mL SC at Day 0, Month 6, and Month 12; whereas dengue non-immune subjects received only 2 doses of CYD vaccine at Day 0 and Month 6. Both immune and non-immune subjects received 2 doses of Gardasil vaccine 0.5 mL IM, concomitantly with the first 2 doses of CYD dengue vaccine.

    Reporting group title
    CYD Dengue Vaccine + Gardasil (Sequential Administration)
    Reporting group description
    		 Dengue immune subjects received 3 doses of CYD dengue vaccine 0.5 mL SC at Month 1, Month 7, and Month 13; whereas dengue non-immune subjects received only 2 doses of CYD vaccine at Month 1 and Month 7. Both immune and non-immune subjects received 2 doses of Gardasil vaccine 0.5 mL IM at Day 0 and Month 6 sequentially (i.e., one month before) to each of the first 2 doses of CYD dengue vaccine.

    Serious adverse events
    		 CYD Dengue Vaccine + Gardasil (Concomitant Administration) CYD Dengue Vaccine + Gardasil (Sequential Administration)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 263 (4.18%)
    8 / 260 (3.08%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sports Injury
         subjects affected / exposed
    0 / 263 (0.00%)
    2 / 260 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon Rupture
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    2 / 263 (0.76%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillar Hypertrophy
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Glomerulonephritis Acute
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chikungunya Virus Infection
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dengue Fever
         subjects affected / exposed
    1 / 263 (0.38%)
    2 / 260 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gingival Abscess
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Mycoplasmal
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral Infection
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 CYD Dengue Vaccine + Gardasil (Concomitant Administration) CYD Dengue Vaccine + Gardasil (Sequential Administration)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    233 / 263 (88.59%)
    235 / 260 (90.38%)
    Nervous system disorders
    Headache
    Additional description: Headache events that occurred after 14 days post-vaccination were considered as unsolicited AE.
         subjects affected / exposed
    126 / 263 (47.91%)
    147 / 260 (56.54%)
         occurrences all number
    178
    311
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    133 / 263 (50.57%)
    132 / 260 (50.77%)
         occurrences all number
    194
    249
    Injection Site Erythema
         subjects affected / exposed
    45 / 263 (17.11%)
    38 / 260 (14.62%)
         occurrences all number
    99
    63
    Injection Site Pain
         subjects affected / exposed
    206 / 263 (78.33%)
    193 / 260 (74.23%)
         occurrences all number
    532
    452
    Injection Site Swelling
         subjects affected / exposed
    43 / 263 (16.35%)
    31 / 260 (11.92%)
         occurrences all number
    89
    48
    Malaise
         subjects affected / exposed
    111 / 263 (42.21%)
    137 / 260 (52.69%)
         occurrences all number
    159
    260
    Pyrexia
    Additional description: Pyrexia events that occurred after 14 days post-vaccination were considered as unsolicited AE.
         subjects affected / exposed
    39 / 263 (14.83%)
    53 / 260 (20.38%)
         occurrences all number
    43
    61
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    127 / 263 (48.29%)
    156 / 260 (60.00%)
         occurrences all number
    181
    283
    Infections and infestations
    Upper Respiratory Tract Infection
         subjects affected / exposed
    20 / 263 (7.60%)
    30 / 260 (11.54%)
         occurrences all number
    21
    37

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Jan 2018
    Amendment was prepared following the recommendations from IDMC and the conduct of exploratory analyses, issued in November 2017, showed that the efficacy and safety profile of the CYD dengue vaccine was different between dengue immune (seropositive) and dengue non-immune (seronegative) prior to dengue vaccination. Following changes were made as per Protocol Amendment, only subjects identified as dengue immune (seropositive) at Baseline and who consented to receive the remaining injection of dengue vaccine were to continue vaccination in the study (i.e., 1 additional dose of CYD dengue vaccine). Subjects identified as dengue non-immune (seronegative) at baseline were not to receive further injections of CYD dengue vaccine but were to be able to continue in the study for a 6-month safety follow-up. They were to be proposed to have a blood sample for the assessment of HPV antibodies after the 2 doses of Gardasil vaccine if they returned into the study for Month 7.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Change of population for non-inferiority reduced to dengue immune subjects and time window for 3rd vaccination not reached (study hold), hence non-inferiority analysis not performed and immunogenicity was performed on FAS and not on Per Protocol Set.
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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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