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    Clinical Trial Results:
    Immunogenicity and Safety of a Tetravalent Dengue Vaccine Administered Concomitantly or Sequentially With Cervarix® in Healthy Female Subjects Aged 9 to 14 Years in Mexico

    Summary
    EudraCT number
    		 2019-000994-22
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    25 Mar 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Jan 2020
    First version publication date
    12 Jan 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CYD71
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02979535
    WHO universal trial number (UTN)
    		 U1111-1161-3455
    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
    17 Oct 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Mar 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Cervarix immunogenicity: To demonstrate that the humoral immune response (in terms of geometric mean titers [GMTs]) to Cervarix after concomitant administration with the CYD dengue vaccine is non-inferior to the humoral immune response (in terms of GMTs) after sequential administration with the CYD dengue vaccine measured 28 days after the last dose of Cervarix. CYD dengue vaccine immunogenicity: To demonstrate that the humoral immune response (in terms of GMTs) to the CYD dengue vaccine after concomitant administration with Cervarix is non-inferior to the humoral immune response (in terms of GMTs) to the CYD dengue vaccine after sequential administration with Cervarix 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 was to be descriptive).
    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 was also available on site in case of any immediate allergic reactions.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Nov 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
    Mexico: 480
    Worldwide total number of subjects
    480
    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)
    446
    Adolescents (12-17 years)
    34
    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 16 November 2016 to 13 March 2017 at 3 centres in Mexico.

    Pre-assignment
    Screening details
    		 A total of 480 subjects were enrolled and randomised in this study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 CYD Dengue Vaccine + Cervarix (Concomitant Administration)
    Arm description
    		 Subjects received 3 doses of CYD dengue vaccine at Day 0, Month 6, and Month 12 and 2 doses of Cervarix concomitantly with the 2 first doses of CYD dengue vaccine.
    Arm type
    		 Experimental

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

    Investigational medicinal product name
    Cervarix
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL, intramuscular (IM) injection at Day 0 and Month 6.

    Arm title
    		 CYD Dengue Vaccine + Cervarix (Sequential Administration)
    Arm description
    		 Subjects received 3 doses of CYD dengue vaccine at Month 1, Month 7, and Month 13 along with the 2 doses of Cervarix at Day 0 and Month 6 sequentially (i.e., one month before) to each of the 2 first doses of CYD dengue vaccine.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CYD Dengue Vaccine
    Investigational medicinal product code
    Other name
    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.

    Investigational medicinal product name
    Cervarix
    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.

    Number of subjects in period 1
    		CYD Dengue Vaccine + Cervarix (Concomitant Administration) CYD Dengue Vaccine + Cervarix (Sequential Administration)
    Started
    239
    241
    Completed
    144
    140
    Not completed
    95
    101
         Consent withdrawn by subject
    11
    18
         Non compliance with the protocol
    78
    82
         Lost to follow-up
    6
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    CYD Dengue Vaccine + Cervarix (Concomitant Administration)
    Reporting group description
    		 Subjects received 3 doses of CYD dengue vaccine at Day 0, Month 6, and Month 12 and 2 doses of Cervarix concomitantly with the 2 first doses of CYD dengue vaccine.

    Reporting group title
    CYD Dengue Vaccine + Cervarix (Sequential Administration)
    Reporting group description
    		 Subjects received 3 doses of CYD dengue vaccine at Month 1, Month 7, and Month 13 along with the 2 doses of Cervarix at Day 0 and Month 6 sequentially (i.e., one month before) to each of the 2 first doses of CYD dengue vaccine.

    Reporting group values
    		 CYD Dengue Vaccine + Cervarix (Concomitant Administration) CYD Dengue Vaccine + Cervarix (Sequential Administration) Total
    Number of subjects
    		 239 241 480
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 9.5 ( 1.00 ) 9.56 ( 1.05 ) -
    Gender categorical
    Units: Subjects
        Female
    		 239 241 480
        Male
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    CYD Dengue Vaccine + Cervarix (Concomitant Administration)
    Reporting group description
    		 Subjects received 3 doses of CYD dengue vaccine at Day 0, Month 6, and Month 12 and 2 doses of Cervarix concomitantly with the 2 first doses of CYD dengue vaccine.

    Reporting group title
    CYD Dengue Vaccine + Cervarix (Sequential Administration)
    Reporting group description
    		 Subjects received 3 doses of CYD dengue vaccine at Month 1, Month 7, and Month 13 along with the 2 doses of Cervarix at Day 0 and Month 6 sequentially (i.e., one month before) to each of the 2 first doses of CYD dengue vaccine.

    Primary: Geometric Mean Titers Against Each Cervarix Human Papillomavirus (HPV) Antigen (HPV-16 and HPV-18) 28 Days After Last Cervarix Vaccination in the Previously Dengue Seropositive Subjects

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    End point title
    		 Geometric Mean Titers Against Each Cervarix Human Papillomavirus (HPV) Antigen (HPV-16 and HPV-18) 28 Days After Last Cervarix Vaccination in the Previously Dengue Seropositive Subjects
    End point description
    GMTs against each Cervarix HPV antigen (HPV-16 and HPV-18) were assessed using an enzyme-linked immunosorbent assay (ELISA) method. Dengue seropositive subjects at baseline were defined as those subjects with titers greater than or equal to (>=) 10 (1/dilutions [dil]) for at least one serotype with the parental dengue virus strain. Analysis was performed on per-protocol analysis set for Cervarix (PPX) which included subjects who received at least one dose of Cervarix vaccine and had no relevant protocol deviations.
    End point type
    Primary
    End point timeframe
    28 days after the last Cervarix vaccination 
    End point values
    		 CYD Dengue Vaccine + Cervarix (Concomitant Administration) CYD Dengue Vaccine + Cervarix (Sequential Administration)
    Number of subjects analysed
    118
    114
    Units: Endotoxin Units per millilitre (EU/mL)
    geometric mean (confidence interval 95%)
        HPV-16
    2149 (1877 to 2460)
    2268 (1946 to 2644)
        HPV-18
    833 (727 to 954)
    845 (723 to 987)
    Statistical analysis title
    		 Antigen HPV-16
    Comparison groups
    CYD Dengue Vaccine + Cervarix (Concomitant Administration) v CYD Dengue Vaccine + Cervarix (Sequential Administration)
    Number of subjects included in analysis
    232
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 GMT ratio
    Point estimate
    0.947
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.773
         upper limit
    		 1.16
    Statistical analysis title
    		 Antigen HPV-18
    Comparison groups
    CYD Dengue Vaccine + Cervarix (Concomitant Administration) v CYD Dengue Vaccine + Cervarix (Sequential Administration)
    Number of subjects included in analysis
    232
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 GMT ratio
    Point estimate
    0.986
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.803
         upper limit
    		 1.21

    Primary: GMTs Against Each Dengue Virus Serotype 28 Days After the Third CYD Dengue Vaccination in the Previously Dengue Seropositive Subjects

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    End point title
    		 GMTs Against Each Dengue Virus Serotype 28 Days After the Third CYD Dengue Vaccination in the Previously Dengue Seropositive Subjects
    End point description
    The GMTs against each of the four parental dengue virus serotypes (Serotypes 1, 2, 3, and 4) of CYD dengue vaccine were assessed using the 50% plaque reduction neutralisation test (PRNT50) assay. Dengue seropositive subjects at baseline were defined as those subjects with titers >=10 (1/dil) for at least one serotype with the parental dengue virus strain. Analysis was performed on full analysis set (FAS) which included subjects who received at least one dose of the study vaccine. Here, 'number of subject analysed' signifies subjects evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    28 days after third CYD dengue vaccination 
    End point values
    		 CYD Dengue Vaccine + Cervarix (Concomitant Administration) CYD Dengue Vaccine + Cervarix (Sequential Administration)
    Number of subjects analysed
    143
    140
    Units: titer (1/dilution)
    geometric mean (confidence interval 95%)
        Serotype 1
    384 (291 to 507)
    393 (292 to 528)
        Serotype 2
    670 (535 to 839)
    735 (575 to 940)
        Serotype 3
    357 (305 to 418)
    388 (325 to 463)
        Serotype 4
    247 (213 to 287)
    265 (220 to 320)
    Statistical analysis title
    		 Dengue Virus Serotype 1
    Comparison groups
    CYD Dengue Vaccine + Cervarix (Concomitant Administration) v CYD Dengue Vaccine + Cervarix (Sequential Administration)
    Number of subjects included in analysis
    283
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 GMT ratio
    Point estimate
    0.977
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.653
         upper limit
    		 1.46
    Statistical analysis title
    		 Dengue Virus Serotype 2
    Comparison groups
    CYD Dengue Vaccine + Cervarix (Sequential Administration) v CYD Dengue Vaccine + Cervarix (Concomitant Administration)
    Number of subjects included in analysis
    283
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 GMT ratio
    Point estimate
    0.911
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.654
         upper limit
    		 1.27
    Statistical analysis title
    		 Dengue Virus Serotype 3
    Comparison groups
    CYD Dengue Vaccine + Cervarix (Concomitant Administration) v CYD Dengue Vaccine + Cervarix (Sequential Administration)
    Number of subjects included in analysis
    283
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 GMT ratio
    Point estimate
    0.921
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.727
         upper limit
    		 1.17
    Statistical analysis title
    		 Dengue Virus Serotype 4
    Comparison groups
    CYD Dengue Vaccine + Cervarix (Concomitant Administration) v CYD Dengue Vaccine + Cervarix (Sequential Administration)
    Number of subjects included in analysis
    283
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 GMT ratio
    Point estimate
    0.931
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.733
         upper limit
    		 1.18

    Secondary: GMTs Against Each Cervarix HPV Antigen (HPV-16 and HPV-18) at Day 0 and 28 Days After Each Cervarix Vaccination in the Previously Dengue Seropositive Subjects

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    End point title
    		 GMTs Against Each Cervarix HPV Antigen (HPV-16 and HPV-18) at Day 0 and 28 Days After Each Cervarix Vaccination in the Previously Dengue Seropositive Subjects
    End point description
    The GMTs against each Cervarix HPV antigen (HPV-16 and HPV-18) were assessed using an ELISA method. Dengue seropositive subjects at baseline were defined as those subjects with titers >=10 (1/dil) for at least one serotype with the parental dengue virus strain. Analysis was performed on FAS population. Here, “number of subjects analysed” signifies number of subjects evaluable for this endpoint and 'n' signifies number of subjects with available data for specified categories.
    End point type
    Secondary
    End point timeframe
    Day 0 and 28 days after each Cervarix vaccination
    End point values
    		 CYD Dengue Vaccine + Cervarix (Concomitant Administration) CYD Dengue Vaccine + Cervarix (Sequential Administration)
    Number of subjects analysed
    154
    151
    Units: EU/mL
    geometric mean (confidence interval 95%)
        HPV-16: Day 0 (n= 154, 151)
    1.61 (1.31 to 1.97)
    1.58 (1.29 to 1.93)
        HPV-16: 28 days post vaccination 1 (n= 150, 151)
    118 (98.7 to 142)
    140 (116 to 170)
        HPV-16: 28 days post vaccination 2 (n= 149, 147)
    2089 (1852 to 2356)
    2162 (1869 to 2501)
        HPV-18: Day 0 (n=154, 151)
    1.34 (1.15 to 1.55)
    1.34 (1.16 to 1.54)
        HPV-18: 28 days post vaccination 1 (n= 150, 151)
    53.8 (44.1 to 65.7)
    68.6 (56.5 to 83.4)
        HPV-18: 28 days post vaccination 2 (n= 149, 147)
    846 (752 to 951)
    846 (728 to 984)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Seroconversion Against Each Cervarix HPV Antigen (HPV-16 and HPV-18) 28 Days After Each Dose of Cervarix Vaccination in the Previously Dengue Seropositive Subjects

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    End point title
    		 Percentage of Subjects With Seroconversion Against Each Cervarix HPV Antigen (HPV-16 and HPV-18) 28 Days After Each Dose of Cervarix Vaccination in the Previously Dengue Seropositive Subjects
    End point description
    Neutralising antibodies against each Cervarix HPV antigen (HPV-16 and HPV-18) were assessed using an ELISA method. Seroconversion was defined as changing serostatus from seronegative at baseline to seropositive (greater than [>] lower limit of quantitation [LLOQ] of the assay) or >=4-fold rise in antibody titer if seropositive at baseline (i.e., at least one antibody levels against Cervarix HPV antigens > LLOQ at baseline). The LLOQ for HPV-16 and HPV-18 was <2.0 International Units per millilitres (IU/mL). Analysis was performed on FAS population. Here, “number of subjects analysed” signifies number of subjects evaluable for this endpoint and 'n' signifies number of subjects with available data for specified categories.
    End point type
    Secondary
    End point timeframe
    28 days after each Cervarix vaccination
    End point values
    		 CYD Dengue Vaccine + Cervarix (Concomitant Administration) CYD Dengue Vaccine + Cervarix (Sequential Administration)
    Number of subjects analysed
    154
    151
    Units: percentage of subjects
    number (confidence interval 95%)
        HPV-16: 28 days post-vaccination 1 (n=150, 151)
    98.0 (94.3 to 99.6)
    99.3 (96.4 to 100.0)
        HPV-16: 28 days post-vaccination 2 (n=149, 147)
    98.7 (95.2 to 99.8)
    99.3 (96.3 to 100.0)
        HPV-18: 28 days post-vaccination 1 (n=150, 151)
    100.0 (97.6 to 100.0)
    98.7 (95.3 to 99.8)
        HPV-18: 28 days post-vaccination 2 (n=149, 147)
    99.3 (96.3 to 100.0)
    100.0 (97.5 to 100.0)
    No statistical analyses for this end point

    Secondary: GMTs 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 Seropositive Subjects

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    End point title
    		 GMTs 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 Seropositive Subjects
    End point description
    The GMTs against each of the four parental dengue virus serotypes (Serotypes 1, 2, 3, and 4) of CYD dengue vaccine were assessed using the PRNT50 assay. Dengue seropositive subjects at baseline were defined as those subjects with titers >=10 (1/dil) for at least one serotype with the parental dengue virus strain. Analysis was performed on FAS population. Here, “number of subjects analysed” signifies number of subjects evaluable for this endpoint and 'n' signifies number of subjects with available data for specified categories.
    End point type
    Secondary
    End point timeframe
    Day 0 and 28 days after each CYD dengue vaccine vaccination
    End point values
    		 CYD Dengue Vaccine + Cervarix (Concomitant Administration) CYD Dengue Vaccine + Cervarix (Sequential Administration)
    Number of subjects analysed
    154
    151
    Units: titer (1/dilution)
    geometric mean (confidence interval 95%)
        Serotype 1: Day 0 (n= 154, 151)
    150 (99.7 to 225)
    108 (72.1 to 163)
        Serotype 1:28 days post-vaccination 1(n= 150,148)
    711 (498 to 1016)
    586 (409 to 840)
        Serotype 1: 28 days post-vaccination 2(n= 149,146)
    460 (336 to 630)
    476 (337 to 674)
        Serotype 1: 28 days post-vaccination 3(n= 143,140)
    384 (291 to 507)
    393 (292 to 528)
        Serotype 2: Day 0 (n= 154, 151)
    193 (141 to 263)
    188 (135 to 262)
        Serotype 2:28 days post-vaccination 1(n= 150,148)
    1168 (879 to 1552)
    1163 (847 to 1597)
        Serotype 2: 28 days post-vaccination 2(n= 149,146)
    618 (492 to 776)
    703 (541 to 913)
        Serotype 2: 28 days post-vaccination 3(n= 143,140)
    670 (535 to 839)
    735 (575 to 940)
        Serotype 3: Day 0 (n= 154, 151)
    98.5 (72.2 to 135)
    90.2 (67.2 to 121)
        Serotype 3:28 days post-vaccination 1(n= 150,148)
    499 (386 to 644)
    503 (385 to 656)
        Serotype 3: 28 days post-vaccination 2(n= 149,146)
    299 (251 to 358)
    361 (294 to 445)
        Serotype 3: 28 days post-vaccination 3(n= 143,140)
    357 (305 to 418)
    388 (325 to 463)
        Serotype 4: Day 0 (n= 154, 151)
    47.1 (34.6 to 64.0)
    38.0 (28.4 to 50.9)
        Serotype 4:28 days post-vaccination 1(n= 150,148)
    423 (336 to 532)
    449 (365 to 552)
        Serotype 4: 28 days post-vaccination 2(n= 149,146)
    267 (225 to 316)
    262 (219 to 314)
        Serotype 4: 28 days post-vaccination 3(n= 143,140)
    247 (213 to 287)
    265 (220 to 320)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Neutralising Antibody Titers >=10 (1/dilutions) 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 Seropositive Subjects

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    End point title
    		 Percentage of Subjects With Neutralising Antibody Titers >=10 (1/dilutions) 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 Seropositive Subjects
    End point description
    Dengue neutralizing antibody levels against each of the 4 dengue virus serotypes (Serotypes 1, 2, 3, and 4) were measured by PRNT50. Dengue seropositive subjects at baseline were defined as those subjects with titers >=10 (1/dil) for at least one serotype with the parental dengue virus strain. Analysis was performed on FAS population. Here, “number of subjects analysed” signifies number of subjects evaluable for this endpoint and 'n' signifies number of subjects with available data for specified categories.
    End point type
    Secondary
    End point timeframe
    Day 0 and 28 days after each CYD dengue vaccine vaccination
    End point values
    		 CYD Dengue Vaccine + Cervarix (Concomitant Administration) CYD Dengue Vaccine + Cervarix (Sequential Administration)
    Number of subjects analysed
    154
    151
    Units: percentage of subjects
    number (confidence interval 95%)
        Serotype 1: Day 0 (n= 154, 151)
    74.0 (66.4 to 80.8)
    68.9 (60.8 to 76.2)
        Serotype 1:28 days post-vaccination 1 (n=150, 148)
    94.7 (89.8 to 97.7)
    95.3 (90.5 to 98.1)
        Serotype 1:28 days post-vaccination 2 (n=149, 146)
    97.3 (93.3 to 99.3)
    97.3 (93.1 to 99.2)
        Serotype 1:28 days post-vaccination 3 (n=143, 140)
    99.3 (96.2 to 100.0)
    97.9 (93.9 to 99.6)
        Serotype 2: Day 0 (n= 154, 151)
    92.9 (87.6 to 96.4)
    91.4 (85.7 to 95.3)
        Serotype 2:28 days post-vaccination 1 (n=150, 148)
    96.7 (92.4 to 98.9)
    93.9 (88.8 to 97.2)
        Serotype 2:28 days post-vaccination 2 (n=149, 146)
    100.0 (97.6 to 100.0)
    98.6 (95.1 to 99.8)
        Serotype 2:28 days post-vaccination 3 (n=143, 140)
    100.0 (97.5 to 100.0)
    100.0 (97.4 to 100.0)
        Serotype 3: Day 0 (n= 154, 151)
    82.5 (75.5 to 88.1)
    83.4 (76.5 to 89.0)
        Serotype 3:28 days post-vaccination 1 (n=150, 148)
    96.7 (92.4 to 98.9)
    96.6 (92.3 to 98.9)
        Serotype 3:28 days post-vaccination 2 (n=149, 146)
    99.3 (96.3 to 100.0)
    100.0 (97.5 to 100.0)
        Serotype 3:28 days post-vaccination 3 (n=143, 140)
    99.3 (96.2 to 100.0)
    100.0 (97.4 to 100.0)
        Serotype 4: Day 0 (n= 154, 151)
    68.8 (60.9 to 76.0)
    66.9 (58.8 to 74.3)
        Serotype 4:28 days post-vaccination 1 (n=150, 148)
    97.3 (93.3 to 99.3)
    98.6 (95.2 to 99.8)
        Serotype 4:28 days post-vaccination 2 (n=149, 146)
    100.0 (97.6 to 100.0)
    100.0 (97.5 to 100.0)
        Serotype 4:28 days post-vaccination 3 (n=143, 140)
    100.0 (97.5 to 100.0)
    98.6 (94.9 to 99.8)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Neutralising Antibody Titers >=10 (1/dilutions) Against At Least 1,2,3, or 4 Dengue Virus Serotypes of CYD Dengue Vaccine at Day 0 And 28 Days After Each Dose of CYD Dengue Vaccination in Previously Dengue Seropositive Subjects

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    End point title
    		 Percentage of Subjects With Neutralising Antibody Titers >=10 (1/dilutions) Against At Least 1,2,3, or 4 Dengue Virus Serotypes of CYD Dengue Vaccine at Day 0 And 28 Days After Each Dose of CYD Dengue Vaccination in Previously Dengue Seropositive Subjects
    End point description
    Dengue neutralising antibody levels against each of the 4 dengue virus serotypes (Serotypes 1, 2, 3, and 4) were measured by PRNT50. Dengue seropositive subjects at baseline were defined as those subjects with titers >=10 (1/dil) for at least one serotype with the parental dengue virus strain. Analysis was performed on FAS population. Here, “number of subjects analysed” signifies number of subjects evaluable for this endpoint and 'n' signifies number of subjects with available data for specified categories. Here, "vacc=vaccination" in the data categories.
    End point type
    Secondary
    End point timeframe
    Day 0 and 28 days after each CYD dengue vaccination
    End point values
    		 CYD Dengue Vaccine + Cervarix (Concomitant Administration) CYD Dengue Vaccine + Cervarix (Sequential Administration)
    Number of subjects analysed
    154
    151
    Units: percentage of subjects
    number (confidence interval 95%)
        At least 1 Serotype: Day 0 (n=154, 151)
    100.0 (97.6 to 100.0)
    100.0 (97.6 to 100.0)
        At least 1 Serotype:28 days post-vacc 1(n=150,148)
    99.3 (96.3 to 100.0)
    99.3 (96.3 to 100.0)
        At least 1 Serotype:28 days post-vacc 2(n=149,146)
    100.0 (97.6 to 100.0)
    100.0 (97.5 to 100.0)
        At least 1 Serotype:28 days post-vacc 3(n=143,140)
    100.0 (97.5 to 100.0)
    100.0 (97.4 to 100.0)
        At least 2 Serotype: Day 0 (n=154, 151)
    84.4 (77.7 to 89.8)
    82.8 (75.8 to 88.4)
        At least 2 Serotype:28 days post-vacc 1(n=150,148)
    98.0 (94.3 to 99.6)
    98.0 (94.2 to 99.6)
        At least 2 Serotype:28 days post-vacc 2(n=149,146)
    100.0 (97.6 to 100.0)
    100.0 (97.5 to 100.0)
        At least 2 Serotype:28 days post-vacc 3(n=143,140)
    100.0 (97.5 to 100.0)
    100.0 (97.4 to 100.0)
        At least 3 Serotype: Day 0 (n=154, 151)
    74.0 (66.4 to 80.8)
    72.8 (65.0 to 79.8)
        At least 3 Serotype:28 days post-vacc 1(n=150,148)
    95.3 (90.6 to 98.1)
    94.6 (89.6 to 97.6)
        At least 3 Serotype:28 days post-vacc 2(n=149,146)
    99.3 (96.3 to 100.0)
    98.6 (95.1 to 99.8)
        At least 3 Serotype:28 days post-vacc 3(n=143,140)
    100.0 (97.5 to 100.0)
    98.6 (94.9 to 99.8)
        All 4 Serotypes: Day 0 (n=154, 151)
    59.7 (51.5 to 67.6)
    55.0 (46.7 to 63.1)
        All 4 Serotypes:28 days post-vacc 1(n=150,148)
    92.7 (87.3 to 96.3)
    92.6 (87.1 to 96.2)
        All 4 Serotypes:28 days post-vacc 2(n=149,146)
    97.3 (93.3 to 99.3)
    97.3 (93.1 to 99.2)
        All 4 Serotypes:28 days post-vacc 3(n=143,140)
    98.6 (95.0 to 99.8)
    97.9 (93.9 to 99.6)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Neutralising Antibody Titers Above Pre-defined Thresholds Against Each Dengue Virus Serotypes of CYD at Baseline And 28 Days After Each Dose of CYD Dengue Vaccination in Dengue Seropositive Subjects

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    End point title
    		 Percentage of Subjects With Neutralising Antibody Titers Above Pre-defined Thresholds Against Each Dengue Virus Serotypes of CYD at Baseline And 28 Days After Each Dose of CYD Dengue Vaccination in Dengue Seropositive Subjects
    End point description
    Dengue neutralising antibody levels against each of the 4 dengue virus serotypes (Serotypes 1, 2, 3, and 4) were measured by PRNT50. Dengue seropositive subjects at baseline were defined as those subjects with titers <10, >=10, and >=100 (1/dil) for at least one serotype with the parental dengue virus strain. Analysis was performed on FAS population. Here, “number of subjects analysed” signifies number of subjects evaluable for this endpoint’ and 'n' signifies number of subjects with available data for specified categories. Here "vacc=vaccination" in the data categories.
    End point type
    Secondary
    End point timeframe
    Day 0 and 28 days after each CYD dengue vaccination
    End point values
    		 CYD Dengue Vaccine + Cervarix (Concomitant Administration) CYD Dengue Vaccine + Cervarix (Sequential Administration)
    Number of subjects analysed
    154
    151
    Units: percentage of subjects
    number (confidence interval 95%)
        Serotype 1: Pre-vacc 1 <10 (1/dil)(n=154,151)
    26.0 (19.2 to 33.6)
    31.1 (23.8 to 39.2)
        Serotype 1: Pre-vacc 1 >=10 (1/dil)(n=154,151)
    74.0 (66.4 to 80.8)
    68.9 (60.8 to 76.2)
        Serotype 1: Pre-vacc 1 >=100 (1/dil)(n=154,151)
    61.0 (52.9 to 68.8)
    56.3 (48.0 to 64.3)
        Serotype 1: Post-vacc 1 <10 (1/dil)(n=150,148)
    5.3 (2.3 to 10.2)
    4.7 (1.9 to 9.5)
        Serotype 1: Post-vacc 1 >=10 (1/dil)(n=150,148)
    94.7 (89.8 to 97.7)
    95.3 (90.5 to 98.1)
        Serotype 1: Post-vacc 1 >=100 (1/dil)(n=150,148)
    82.0 (74.9 to 87.8)
    78.4 (70.9 to 84.7)
        Serotype 1: Post-vacc 2 <10 (1/dil)(n=149,146)
    2.7 (0.7 to 6.7)
    2.7 (0.8 to 6.9)
        Serotype 1: Post-vacc 2 >=10 (1/dil)(n=149,146)
    97.3 (93.3 to 99.3)
    97.3 (93.1 to 99.2)
        Serotype 1: Post-vacc 2 >=100 (1/dil)(n=149,146)
    77.2 (69.6 to 83.7)
    72.6 (64.6 to 79.7)
        Serotype 1: Post-vacc 3 <10 (1/dil)(n=143,140)
    0.7 (0.0 to 3.8)
    2.1 (0.4 to 6.1)
        Serotype 1: Post-vacc 3 >=10 (1/dil)(n=143,140)
    99.3 (96.2 to 100.0)
    97.9 (93.9 to 99.6)
        Serotype 1: Post-vacc 3 >=100 (1/dil)(n=143,140)
    74.8 (66.9 to 81.7)
    76.4 (68.5 to 83.2)
        Serotype 2: Pre-vacc 1 <10 (1/dil)(n=154,151)
    7.1 (3.6 to 12.4)
    8.6 (4.7 to 14.3)
        Serotype 2: Pre-vacc 1 >=10 (1/dil)(n=154,151)
    92.9 (87.6 to 96.4)
    91.4 (85.7 to 95.3)
        Serotype 2: Pre-vacc 1 >=100 (1/dil)(n=154,151)
    59.1 (50.9 to 66.9)
    61.6 (53.3 to 69.4)
        Serotype 2: Post-vacc 1 <10 (1/dil)(n=150,148)
    3.3 (1.1 to 7.6)
    6.1 (2.8 to 11.2)
        Serotype 2: Post-vacc 1 >=10 (1/dil)(n=150,148)
    96.7 (92.4 to 98.9)
    93.9 (88.8 to 97.2)
        Serotype 2: Post-vacc 1 >=100 (1/dil)(n=150,148)
    91.3 (85.6 to 95.3)
    91.9 (86.3 to 95.7)
        Serotype 2: Post-vacc 2 <10 (1/dil)(n=149,146)
    0.0 (0.0 to 2.4)
    1.4 (0.2 to 4.9)
        Serotype 2: Post-vacc 2 >=10 (1/dil)(n=149,146)
    100.0 (97.6 to 100.0)
    98.6 (95.1 to 99.8)
        Serotype 2: Post-vacc 2 >=100 (1/dil)(n=149,146)
    90.6 (84.7 to 94.8)
    90.4 (84.4 to 94.7)
        Serotype 2: Post-vacc 3 <10 (1/dil)(n=143,140)
    0.0 (0.0 to 2.5)
    0.0 (0.0 to 2.6)
        Serotype 2: Post-vacc 3 >=10 (1/dil)(n=143,140)
    100.0 (97.5 to 100.0)
    100.0 (97.4 to 100.0)
        Serotype 2: Post-vacc 3 >=100 (1/dil)(n=143,140)
    95.1 (90.2 to 98.0)
    90.7 (84.6 to 95.0)
        Serotype 3: Pre-vacc 1 <10 (1/dil)(n=154,151)
    17.5 (11.9 to 24.5)
    16.6 (11.0 to 23.5)
        Serotype 3: Pre-vacc 1 >=10 (1/dil)(n=154,151)
    82.5 (75.5 to 88.1)
    83.4 (76.5 to 89.0)
        Serotype 3: Pre-vacc 1 >=100 (1/dil)(n=154,151)
    51.3 (43.1 to 59.4)
    49.0 (40.8 to 57.3)
        Serotype 3: Post-vacc 1 <10 (1/dil)(n=150,148)
    3.3 (1.1 to 7.6)
    3.4 (1.1 to 7.7)
        Serotype 3: Post-vacc 1 >=10 (1/dil)(n=150,148)
    96.7 (92.4 to 98.9)
    96.6 (92.3 to 98.9)
        Serotype 3: Post-vacc 1 >=100 (1/dil)(n=150,148)
    88.7 (82.5 to 93.3)
    87.8 (81.5 to 92.6)
        Serotype 3: Post-vacc 2 <10 (1/dil)(n=149,146)
    0.7 (0.0 to 3.7)
    0.0 (0.0 to 2.5)
        Serotype 3: Post-vacc 2 >=10 (1/dil)(n=149,146)
    99.3 (96.3 to 100.0)
    100.0 (97.5 to 100.0)
        Serotype 3: Post-vacc 2 >=100 (1/dil)(n=149,146)
    87.2 (80.8 to 92.1)
    87.0 (80.4 to 92.0)
        Serotype 3: Post-vacc 3 <10 (1/dil)(n=143,140)
    0.7 (0.0 to 3.8)
    0.0 (0.0 to 2.6)
        Serotype 3: Post-vacc 3 >=10 (1/dil)(n=143,140)
    99.3 (96.2 to 100.0)
    100.0 (97.4 to 100.0)
        Serotype 3: Post-vacc 3 >=100 (1/dil)(n=143,140)
    94.4 (89.3 to 97.6)
    90.7 (84.6 to 95.0)
        Serotype 4: Pre-vacc 1 <10 (1/dil)(n=154,151)
    31.2 (24.0 to 39.1)
    33.1 (25.7 to 41.2)
        Serotype 4: Pre-vacc 1 >=10 (1/dil)(n=154,151)
    68.8 (60.9 to 76.0)
    66.9 (58.8 to 74.3)
        Serotype 4: Pre-vacc 1 >=100 (1/dil)(n=154,151)
    33.1 (25.8 to 41.1)
    29.8 (22.6 to 37.8)
        Serotype 4: Post-vacc 1 <10 (1/dil)(n=150,148)
    2.7 (0.7 to 6.7)
    1.4 (0.2 to 4.8)
        Serotype 4: Post-vacc 1 >=10 (1/dil)(n=150,148)
    97.3 (93.3 to 99.3)
    98.6 (95.2 to 99.8)
        Serotype 4: Post-vacc 1 >=100 (1/dil)(n=150,148)
    87.3 (80.9 to 92.2)
    89.9 (83.8 to 94.2)
        Serotype 4: Post-vacc 2 <10 (1/dil)(n=149,146)
    0.0 (0.0 to 2.4)
    0.0 (0.0 to 2.5)
        Serotype 4: Post-vacc 2 >=10 (1/dil)(n=149,146)
    100.0 (97.6 to 100.0)
    100.0 (97.5 to 100.0)
        Serotype 4: Post-vacc 2 >=100 (1/dil)(n=149,146)
    82.6 (75.5 to 88.3)
    80.1 (72.7 to 86.3)
        Serotype 4: Post-vacc 3 <10 (1/dil)(n=143,140)
    0.0 (0.0 to 2.5)
    1.4 (0.2 to 5.1)
        Serotype 4: Post-vacc 3 >=10 (1/dil)(n=143,140)
    100.0 (97.5 to 100.0)
    98.6 (94.9 to 99.8)
        Serotype 4: Post-vacc 3 >=100 (1/dil)(n=143,140)
    83.2 (76.1 to 88.9)
    83.6 (76.4 to 89.3)
    No statistical analyses for this end point

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

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    End point title
    		 Number of Subjects Reporting Immediate Adverse Events (AEs) Following Vaccination With Cervarix 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. Analysis was performed on safety analysis set which included those subjects who had received at least one dose of the study vaccines. Here, 'n' signifies number of subjects with available data for specified categories.
    End point type
    Secondary
    End point timeframe
    Within 30 minutes after each and any vaccination
    End point values
    		 CYD Dengue Vaccine + Cervarix (Concomitant Administration) CYD Dengue Vaccine + Cervarix (Sequential Administration)
    Number of subjects analysed
    237
    241
    Units: subjects
        After any CYD/Cervarix vaccination (n=237,241)
    0
    0
        Post CYD/Cervarix vaccination 1 (n=237,241)
    0
    0
        Post CYD/Cervarix vaccination 2 (n=227,229)
    0
    0
        Post CYD vaccination 3 (n=145,141)
    0
    0
    No statistical analyses for this end point

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

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    End point title
    		 Number of Subjects Reporting Solicited Injection Site Reactions Following Vaccination With Cervarix or CYD Dengue Vaccine
    End point description
    Solicited injection site reactions included pain, erythema, and swelling. Analysis was performed on Safety analysis set. Here, 'n' signifies number of subjects with available data for specified categories.
    End point type
    Secondary
    End point timeframe
    Up to 7 days after each and any vaccination
    End point values
    		 CYD Dengue Vaccine + Cervarix (Concomitant Administration) CYD Dengue Vaccine + Cervarix (Sequential Administration)
    Number of subjects analysed
    237
    241
    Units: subjects
        Pain:Post any CYD/Cervarix vaccine (n=231,234)
    212
    221
        Pain: Post CYD/Cervarix vaccination 1 (n=231,234)
    202
    206
        Pain: Post CYD/Cervarix vaccination 2 (n=226,229)
    173
    169
        Pain: Post CYD vaccination 3 (n=144,140)
    65
    59
        Erythema:Post any CYD/Cervarix vaccine (n=231,234)
    64
    61
        Erythema:Post CYD/Cervarix vaccination1(n=231,234)
    49
    43
        Erythema:Post CYD/Cervarix vaccination2(n=226,229)
    41
    34
        Erythema: Post CYD vaccination 3 (n=144,140)
    6
    11
        Swelling:Post any CYD/Cervarix vaccine (n=231,234)
    73
    60
        Swelling:Post CYD/Cervarix vaccination1(n=231,234)
    55
    44
        Swelling:Post CYD/Cervarix vaccination2(n=226,229)
    48
    35
        Swelling: Post CYD vaccination 3 (n=144,139)
    8
    10
    No statistical analyses for this end point

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

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    End point title
    		 Number of Subjects Reporting Solicited Systemic Reactions Following Vaccination With Cervarix or CYD Dengue Vaccine
    End point description
    Solicited systemic reactions included Fever, Headache, Malaise, Myalgia, and Asthenia. Analysis was performed on Safety analysis set. At Visit 1 and Visit 4, subjects from Group 1 received both Cervarix and CYD vaccination and subjects from Group 2 received only Cervarix 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. Here 'n' signifies number of subjects with available data for specified categories. Here '99999' signifies that the subjects from Group 1 did not receive any vaccination at Visit 2 or 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 + Cervarix (Concomitant Administration) CYD Dengue Vaccine + Cervarix (Sequential Administration)
    Number of subjects analysed
    237
    241
    Units: subjects
        Fever:Post any vaccination (n=230,234)
    25
    35
        Fever:Post vaccination 1 (Visit 1)(n=230,234)
    14
    8
        Fever:Post CYD vaccination 1 (Visit 2)(n=0,230)
    99999
    14
        Fever:Post vaccination 2 (Visit 4)(n=216,228)
    10
    12
        Fever:Post CYD vaccination 2 (Visit 5)(n=0,227)
    99999
    8
        Fever:Post CYD vaccination 3 (Visit 7)(n=143,139)
    5
    3
        Headache:Post any vaccination (n=231,234)
    101
    111
        Headache:Post vaccination 1 (Visit 1)(n=231,234)
    83
    69
        Headache:Post CYD vaccination 1 (Visit 2)(n=0,231)
    99999
    54
        Headache:Post vaccination 2 (Visit 4)(n=226,229)
    47
    48
        Headache:Post CYD vaccination 2 (Visit 5)(n=0,227)
    99999
    36
        Headache:Post CYD vaccination3(Visit 7)(n=144,140)
    18
    15
        Malaise:Post any vaccination (n=231,234)
    113
    133
        Malaise:Post vaccination 1 (Visit 1)(n=231,234)
    84
    84
        Malaise:Post CYD vaccination 1 (Visit 2)(n=0,231)
    99999
    56
        Malaise:Post vaccination 2 (Visit 4)(n=226,229)
    73
    72
        Malaise:Post CYD vaccination 2 (Visit 5)(n=0,227)
    99999
    47
        Malaise:Post CYD vaccination 3(Visit 7)(n=144,140)
    19
    28
        Myalgia:Post any vaccination (n=231,234)
    160
    168
        Myalgia:Post vaccination 1 (Visit 1)(n=231,234)
    129
    124
        Myalgia:Post CYD vaccination 1 (Visit 2)(n=0,231)
    99999
    76
        Myalgia:Post vaccination 2 (Visit 4)(n=226,229)
    96
    95
        Myalgia:Post CYD vaccination 2 (Visit 5)(n=0,227)
    99999
    60
        Myalgia:Post CYD vaccination 3(Visit 7)(n=144,140)
    26
    31
        Asthenia:Post any vaccination (n=231,234)
    93
    95
        Asthenia:Post vaccination 1 (Visit 1)(n=231,234)
    72
    53
        Asthenia:Post CYD vaccination 1 (Visit 2)(n=0,231)
    99999
    47
        Asthenia:Post vaccination 2 (Visit 4)(n=226,229)
    51
    35
        Asthenia:Post CYD vaccination 2 (Visit 5)(n=0,227)
    99999
    30
        Asthenia:Post CYD vaccination 3(Visit7)(n=144,140)
    16
    13
    No statistical analyses for this end point

    Secondary: Number of Subjects Reporting Unsolicited AEs Following Vaccination With Cervarix or CYD Dengue Vaccine

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    End point title
    		 Number of Subjects Reporting Unsolicited AEs Following Vaccination With Cervarix or CYD Dengue Vaccine
    End point description
    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. At Visit 1 and Visit 4, subjects from Group 1 received both Cervarix and CYD vaccination and subjects from Group 2 received only Cervarix 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. Here, 'n' signifies number of subjects with available data for specified categories. Here '99999' signifies that the subjects from Group 1 did not receive any vaccination at Visit 2 or 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 + Cervarix (Concomitant Administration) CYD Dengue Vaccine + Cervarix (Sequential Administration)
    Number of subjects analysed
    237
    241
    Units: subjects
        Post any vaccination (n=237,241)
    50
    76
        Post vaccination 1 (Visit 1)(n=237,241)
    33
    37
        Post CYD vaccination 1 (Visit 2)(n=0,233)
    99999
    25
        Post vaccination 2 (Visit 4)(n=227,229)
    26
    23
        Post CYD vaccination 2 (Visit 5)(n=0,228)
    99999
    15
        Post CYD vaccination 3 (Visit 7)(n=145,141)
    5
    5
    No statistical analyses for this end point

    Secondary: Number of Subjects Reporting Non-serious Adverse Event of Special Interests (AESIs) Following Vaccination With Cervarix 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 Cervarix 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. Analysis was performed on Safety analysis set.
    End point type
    Secondary
    End point timeframe
    Up to 7 days after any and each vaccination
    End point values
    		 CYD Dengue Vaccine + Cervarix (Concomitant Administration) CYD Dengue Vaccine + Cervarix (Sequential Administration)
    Number of subjects analysed
    237
    241
    Units: subjects
        Post any CYD/Cervarix vaccination (n=237,241)
    0
    0
        Post CYD/Cervarix vaccination 1 (n=237,241)
    0
    0
        Post CYD/Cervarix vaccination 2 (n=227,229)
    0
    0
        Post CYD/Cervarix vaccination 3 (n=145,141)
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects Reporting Serious Adverse Events (SAEs) Including Serious AESIs Following Vaccination With Cervarix or CYD Dengue Vaccine

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    End point title
    		 Number of Subjects Reporting Serious Adverse Events (SAEs) Including Serious AESIs Following Vaccination With Cervarix or CYD Dengue Vaccine
    End point description
    An SAEs were AEs resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; 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 Safety analysis set.
    End point type
    Secondary
    End point timeframe
    From Day 0 up to 6 months after the last vaccination
    End point values
    		 CYD Dengue Vaccine + Cervarix (Concomitant Administration) CYD Dengue Vaccine + Cervarix (Sequential Administration)
    Number of subjects analysed
    237
    241
    Units: subjects
        SAE
    6
    0
        Serious AESI
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects Reporting Cases of Virologically Confirmed Dengue (VCD) Hospitalisation Following Vaccination With Cervarix 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 Cervarix 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 ELISA and/or dengue reverse transcriptase-polymerase chain reactions. Analysis was performed on Safety analysis set.
    End point type
    Secondary
    End point timeframe
    From Day 0 up to 6 months after the last vaccination
    End point values
    		 CYD Dengue Vaccine + Cervarix (Concomitant Administration) CYD Dengue Vaccine + Cervarix (Sequential Administration)
    Number of subjects analysed
    237
    241
    Units: subjects
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    An AE data were collected from Day 0 up to Day 28 post any vaccination. Solicited Reaction (SR) were collected from Day 0 up to Day 14 post vaccination. SAEs were collected throughout the trial (up to Month 14, i.e,. 6 months after last 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 eCRF (i.e., solicited) in terms of symptom and/or onset post-vaccination.Analysis was performed on safety analysis set.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    CYD Dengue Vaccine + Cervarix (Sequential Administration)
    Reporting group description
    		 Subjects received 3 doses of CYD dengue vaccine at Month 1, Month 7, and Month 13 along with the 2 doses of Cervarix at Day 0 and Month 6 sequentially (i.e., one month before) to each of the 2 first doses of CYD dengue vaccine.

    Reporting group title
    CYD Dengue Vaccine + Cervarix (Concomitant Administration)
    Reporting group description
    		 Subjects received 3 doses of CYD dengue vaccine at Day 0, Month 6, and Month 12 and 2 doses of Cervarix concomitantly with the 2 first doses of CYD dengue vaccine.

    Serious adverse events
    		 CYD Dengue Vaccine + Cervarix (Sequential Administration) CYD Dengue Vaccine + Cervarix (Concomitant Administration)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 241 (0.00%)
    6 / 237 (2.53%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    Forearm Fracture
         subjects affected / exposed
    0 / 241 (0.00%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gun Shot Wound
         subjects affected / exposed
    0 / 241 (0.00%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius Fracture
         subjects affected / exposed
    0 / 241 (0.00%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Pre-Eclampsia
         subjects affected / exposed
    0 / 241 (0.00%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 241 (0.00%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 241 (0.00%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         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 + Cervarix (Sequential Administration) CYD Dengue Vaccine + Cervarix (Concomitant Administration)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    228 / 241 (94.61%)
    222 / 237 (93.67%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    113 / 241 (46.89%)
    102 / 237 (43.04%)
         occurrences all number
    227
    149
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    95 / 241 (39.42%)
    93 / 237 (39.24%)
         occurrences all number
    178
    139
    Injection Site Erythema
         subjects affected / exposed
    61 / 241 (25.31%)
    64 / 237 (27.00%)
         occurrences all number
    116
    137
    Injection Site Pain
         subjects affected / exposed
    221 / 241 (91.70%)
    212 / 237 (89.45%)
         occurrences all number
    628
    659
    Injection Site Swelling
         subjects affected / exposed
    60 / 241 (24.90%)
    73 / 237 (30.80%)
         occurrences all number
    115
    154
    Malaise
         subjects affected / exposed
    133 / 241 (55.19%)
    113 / 237 (47.68%)
         occurrences all number
    287
    176
    Pyrexia
         subjects affected / exposed
    37 / 241 (15.35%)
    25 / 237 (10.55%)
         occurrences all number
    47
    29
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    168 / 241 (69.71%)
    160 / 237 (67.51%)
         occurrences all number
    386
    251
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    22 / 241 (9.13%)
    8 / 237 (3.38%)
         occurrences all number
    26
    9
    Pharyngitis
         subjects affected / exposed
    20 / 241 (8.30%)
    13 / 237 (5.49%)
         occurrences all number
    21
    13

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Feb 2018
    In November 2017, IDMC recommended not to vaccinate any individuals with no prior dengue infection anymore, and to only continue vaccination in subjects with prior dengue infection. As a consequence, the Sponsor had amended the CYD71 study protocol to implement the recommendation from IDMC on February 2018. The study was put on hold between IDMC recommendation and approval of protocol amendment. It impacted Vaccination 3 for seronegative subjects. According to Amendment 1, the following changes were made: • All vaccinated subjects were informed about their baseline dengue serostatus. • All subjects were asked about their willingness to continue participating in this study and to sign an amended Assent Form or informed consent form. • Subjects identified as seronegative at baseline did not receive further CYD dengue vaccine doses. They continued in the study for a safety follow-up at 6 months post last dengue vaccine, and they had timely access to appropriate care in the event of suspected dengue, for 10 years from the date of last dengue vaccination whether they remained in the study or not. • Subjects identified as seropositive at baseline who were eligible to continue dengue vaccination in the study were asked to consent for further CYD dengue vaccine injection. Subjects that consented to receive the third and last dose of CYD dengue vaccine completed the study as it was initially planned. Subjects that consented to remain in the study but preferred not to receive the last injection were able to continue in the study for safety follow-up at 6 months post last dengue vaccine dose. • The study population for the non-inferiority was reduced to the dengue immune subjects (seropositive) compared to initial sample size.

    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 vaccination not reached (study hold),hence non-inferiority analysis not performed and immunogenicity analysis was performed on FAS,not on per protocol set.
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