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    Clinical Trial Results:
    Immunogenicity and Safety of a Tetravalent Dengue Vaccine Given as a Booster Injection in Adolescents and Adults Who Previously Completed the 3-dose Schedule in a Study Conducted in Singapore

    Summary
    EudraCT number
    		 2019-000993-44
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    18 Jan 2019

    Results information
    Results version number
    		 v2(current)
    This version publication date
    09 Oct 2019
    First version publication date
    01 Aug 2019
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    Addition of follow-up data

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CYD63
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02824198
    WHO universal trial number (UTN)
    		 U1111-1161-2813
    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
    10 May 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Jan 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the non-inferiority, in terms of geometric mean of titer ratios (GTMRs), of a CYD dengue vaccine booster compared to the third CYD dengue vaccine injection in subjects from CYD28 trial (subjects from Group 1 only).
    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
    01 Jul 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
    Singapore: 118
    Worldwide total number of subjects
    118
    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)
    0
    Adolescents (12-17 years)
    11
    Adults (18-64 years)
    107
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Study subjects were enrolled from 01 July 2016 to 18 February 2017 at 3 sites in Singapore.

    Pre-assignment
    Screening details
    		 A total of 118 subjects who received 3 doses of CYD dengue vaccine in study CYD28 (NCT00880893) were enrolled and randomised in this study (CYD63). Results are reported based on the primary completion date of 18 March 2017.

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    An observer-blind procedure was followed for the injection of CYD dengue vaccine or placebo. Neither the blind-observer Investigator nor the subjects (and/or subjects’ parent(s)/legally acceptable representative(s) for subjects aged less than [<] 21 years) knew which product was administered. The “vaccinator” was in charge of preparing and administering the products and was not authorized to collect any safety data.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 CYD Dengue Vaccine Booster Group
    Arm description
    		 Subjects who received 3 doses of the tetravalent dengue vaccine in a previous CYD dengue vaccine study (CYD28), received a booster injection of CYD dengue vaccine at Day 0 in this study (CYD63).
    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 milliliters (mL), subcutaneous, 1 injection at Day 0.

    Arm title
    		 Placebo Group
    Arm description
    		 Subjects who received 3 doses of the tetravalent dengue vaccine in a previous CYD dengue vaccine study (CYD28), received an injection of a placebo at Day 0 in this study (CYD63).
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo (NaCl)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.5 mL, subcutaneous, 1 injection at Day 0.

    Number of subjects in period 1
    		CYD Dengue Vaccine Booster Group Placebo Group
    Started
    89
    29
    Completed
    74
    26
    Not completed
    15
    3
         Consent withdrawn by subject
    5
    -
         Non-compliance with protocol
    5
    1
         Lost to follow-up
    5
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    CYD Dengue Vaccine Booster Group
    Reporting group description
    		 Subjects who received 3 doses of the tetravalent dengue vaccine in a previous CYD dengue vaccine study (CYD28), received a booster injection of CYD dengue vaccine at Day 0 in this study (CYD63).

    Reporting group title
    Placebo Group
    Reporting group description
    		 Subjects who received 3 doses of the tetravalent dengue vaccine in a previous CYD dengue vaccine study (CYD28), received an injection of a placebo at Day 0 in this study (CYD63).

    Reporting group values
    		 CYD Dengue Vaccine Booster Group Placebo Group Total
    Number of subjects
    		 89 29 118
    Age categorical
    Units: Subjects
        <=18 years
    		 11 0 11
        Between 18 and 65 years
    		 78 29 107
        >=65 years
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 28.1 ± 11.18 28.2 ± 9.18 -
    Gender categorical
    Units: Subjects
        Female
    		 43 15 58
        Male
    		 46 14 60

    End points

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    End points reporting groups
    Reporting group title
    CYD Dengue Vaccine Booster Group
    Reporting group description
    		 Subjects who received 3 doses of the tetravalent dengue vaccine in a previous CYD dengue vaccine study (CYD28), received a booster injection of CYD dengue vaccine at Day 0 in this study (CYD63).

    Reporting group title
    Placebo Group
    Reporting group description
    		 Subjects who received 3 doses of the tetravalent dengue vaccine in a previous CYD dengue vaccine study (CYD28), received an injection of a placebo at Day 0 in this study (CYD63).

    Subject analysis set title
    CYD Dengue Vaccine Booster Group: Post Dose 3 in CYD28
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subjects who received 3 doses of tetravalent dengue vaccine in previous study (CYD28) were enrolled in this study (CYD63).

    Subject analysis set title
    CYD Dengue Vaccine Booster Group: Post Booster Dose
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subjects who received 3 doses of the tetravalent dengue vaccine in a previous CYD dengue vaccine study (CYD28), received a booster injection of CYD dengue vaccine at Day 0 in this study (CYD63).

    Primary: Geometric Mean Titers (GMTs) of Antibodies Against Each Dengue Virus Serotype Following Booster Injection (Inj.) With CYD Dengue Vaccine in CYD63 Compared to the Third CYD Dengue Vaccine Injection Received in Study CYD28: CYD Dengue Vaccine Booster Group

    		 Close Top of page
    End point title
    		 Geometric Mean Titers (GMTs) of Antibodies Against Each Dengue Virus Serotype Following Booster Injection (Inj.) With CYD Dengue Vaccine in CYD63 Compared to the Third CYD Dengue Vaccine Injection Received in Study CYD28: CYD Dengue Vaccine Booster Group
    End point description
    GMTs of antibodies against each of the 4 dengue virus serotype (parental strains) were assessed using the plaque reduction neutralization test (PRNT). Analysis was performed on Per-Protocol Analysis Set which included all subjects who had no protocol deviations from the present study (CYD63). Here, ‘n' = subjects with available data for each specified category.
    End point type
    Primary
    End point timeframe
    28 days post-dose 3 in CYD28 and 28 days post-booster injection in CYD63
    End point values
    		 CYD Dengue Vaccine Booster Group: Post Dose 3 in CYD28 CYD Dengue Vaccine Booster Group: Post Booster Dose
    Number of subjects analysed
    75
    75
    Units: titers (1/dilution)
    geometric mean (confidence interval 95%)
        Dengue Virus Serotype 1 (n=74, 75)
    20.3 (13.9 to 29.5)
    37.7 (26.4 to 53.7)
        Dengue Virus Serotype 2 (n=73, 75)
    85.6 (55.7 to 132)
    56.2 (38.5 to 82.1)
        Dengue Virus Serotype 3 (n=72, 75)
    102 (78.4 to 133)
    105 (77.4 to 142)
        Dengue Virus Serotype 4 (n=70, 75)
    92.8 (72.5 to 119)
    123 (93.8 to 161)
    Statistical analysis title
    		 Dengue Virus Serotype 1
    Statistical analysis description
    Analysis was paired t-tests comparing the GMTs at 2 time points for the same subjects. The actual subjects in the analysis were 75.
    Comparison groups
    CYD Dengue Vaccine Booster Group: Post Dose 3 in CYD28 v CYD Dengue Vaccine Booster Group: Post Booster Dose
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 Geometric mean of titer ratio
    Point estimate
    1.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.998
         upper limit
    		 1.79
    Notes
    [1] - The overall non-inferiority of the booster dose was to be demonstrated if the lower limit of the two-sided 95% Confidence Interval (CI) of the Geometric mean of titer ratios (GMTRs) (booster vs post-dose 3) was greater than (>) 1/2 for each serotype.
    Statistical analysis title
    		 Dengue Virus Serotype 2
    Statistical analysis description
    Analysis was paired t-tests comparing the GMTs at 2 time points for the same subjects. The actual subjects in the analysis were 75.
    Comparison groups
    CYD Dengue Vaccine Booster Group: Post Dose 3 in CYD28 v CYD Dengue Vaccine Booster Group: Post Booster Dose
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    Method
    Parameter type
    		 Geometric mean of titer ratio
    Point estimate
    0.603
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.439
         upper limit
    		 0.829
    Notes
    [2] - The overall non-inferiority of the booster dose was to be demonstrated if the lower limit of the two-sided 95% CI of the GMTRs (booster vs post-dose 3) was >1/2 for each serotype.
    Statistical analysis title
    		 Dengue Virus Serotype 3
    Statistical analysis description
    Analysis was paired t-tests comparing the GMTs at 2 time points for the same subjects. The actual subjects in the analysis were 75.
    Comparison groups
    CYD Dengue Vaccine Booster Group: Post Dose 3 in CYD28 v CYD Dengue Vaccine Booster Group: Post Booster Dose
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    Method
    Parameter type
    		 Geometric mean of titer ratio
    Point estimate
    0.979
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.746
         upper limit
    		 1.28
    Notes
    [3] - The overall non-inferiority of the booster dose was to be demonstrated if the lower limit of the two-sided 95% CI of the GMTRs (booster vs post-dose 3) was >1/2 for each serotype.
    Statistical analysis title
    		 Dengue Virus Serotype 4
    Statistical analysis description
    Analysis was paired t-tests comparing the GMTs at 2 time points for the same subjects. The actual subjects in the analysis were 75.
    Comparison groups
    CYD Dengue Vaccine Booster Group: Post Dose 3 in CYD28 v CYD Dengue Vaccine Booster Group: Post Booster Dose
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [4]
    Method
    Parameter type
    		 Geometric mean of titer ratio
    Point estimate
    1.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.918
         upper limit
    		 1.75
    Notes
    [4] - The overall non-inferiority of the booster dose was to be demonstrated if the lower limit of the two-sided 95% CI of the GMTRs (booster vs post-dose 3) was > 1/2 for each serotype.

    Secondary: Geometric Mean Titers of Antibodies Against Each Dengue Virus Serotype Before and Following Booster Injection With Either CYD Dengue Vaccine or Placebo

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    End point title
    		 Geometric Mean Titers of Antibodies Against Each Dengue Virus Serotype Before and Following Booster Injection With Either CYD Dengue Vaccine or Placebo
    End point description
    GMTs of antibodies against each of the 4 dengue virus serotype (parental strains) following booster injection were assessed using PRNT. Analysis was performed on Per-Protocol Analysis Set.
    End point type
    Secondary
    End point timeframe
    Pre-booster injection (Day 0) and 28 days post-booster injection
    End point values
    		 CYD Dengue Vaccine Booster Group Placebo Group
    Number of subjects analysed
    75
    28
    Units: titers (1/dilution)
    geometric mean (confidence interval 95%)
        Dengue Virus Serotype 1: Pre-booster Inj.
    13.5 (9.31 to 19.6)
    16.7 (7.73 to 36.1)
        Dengue Virus Serotype 1: 28 days Post-booster Inj.
    37.7 (26.4 to 53.7)
    18.1 (8.61 to 38.1)
        Dengue Virus Serotype 2: Pre-booster Inj.
    18.4 (12.1 to 28.0)
    23.2 (9.97 to 53.9)
        Dengue Virus Serotype 2: 28 days Post-booster Inj.
    56.2 (38.5 to 82.1)
    21.5 (9.61 to 48.1)
        Dengue Virus Serotype 3: Pre-booster Inj.
    22.4 (15.6 to 32.0)
    27.4 (14.8 to 51.0)
        Dengue Virus Serotype 3: 28 days Post-booster Inj.
    105 (77.4 to 142)
    24.1 (13.6 to 42.6)
        Dengue Virus Serotype 4: Pre-booster Inj.
    28.0 (20.4 to 38.5)
    44.9 (28.3 to 71.3)
        Dengue Virus Serotype 4: 28 days Post-booster Inj.
    123 (93.8 to 161)
    39.8 (23.9 to 66.3)
    No statistical analyses for this end point

    Secondary: Geometric Mean of Titer Ratios of Antibodies Against Each Dengue Virus Serotype Before and Following Booster Injection With Either CYD Dengue Vaccine or Placebo

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    End point title
    		 Geometric Mean of Titer Ratios of Antibodies Against Each Dengue Virus Serotype Before and Following Booster Injection With Either CYD Dengue Vaccine or Placebo
    End point description
    GMTs of antibodies against each of the 4 dengue virus serotype (parental strains) following booster injection were assessed using PRNT. GMTRs were calculated as the ratio of GMTs post-booster injection and pre-booster injection. Analysis was performed on Per-Protocol Analysis Set.
    End point type
    Secondary
    End point timeframe
    Pre-booster injection (Day 0) and 28 days post-booster injection
    End point values
    		 CYD Dengue Vaccine Booster Group Placebo Group
    Number of subjects analysed
    75
    28
    Units: ratio
    geometric mean (confidence interval 95%)
        Dengue Virus Serotype 1
    1.74 (1.33 to 2.28)
    0.676 (0.525 to 0.871)
        Dengue Virus Serotype 2
    2.04 (1.54 to 2.69)
    0.624 (0.523 to 0.745)
        Dengue Virus Serotype 3
    3.52 (2.58 to 4.82)
    0.669 (0.513 to 0.873)
        Dengue Virus Serotype 4
    3.58 (2.61 to 4.90)
    0.822 (0.640 to 1.06)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Seropositivity Against Each Dengue Virus Serotype Before and Following Booster Injection With Either CYD Dengue Vaccine or Placebo

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    End point title
    		 Percentage of Subjects With Seropositivity Against Each Dengue Virus Serotype Before and Following Booster Injection With Either CYD Dengue Vaccine or Placebo
    End point description
    Seropositivity against each dengue virus serotype was measured using dengue PRNT. Seropositive subjects were defined as the subjects with neutralizing antibody titers >=10 (1/dilution). Analysis was performed on Per-Protocol Analysis Set.
    End point type
    Secondary
    End point timeframe
    Pre-booster injection (Day 0) and 28 days post-booster injection
    End point values
    		 CYD Dengue Vaccine Booster Group Placebo Group
    Number of subjects analysed
    75
    28
    Units: percentage of subjects
    number (not applicable)
        Dengue Virus Serotype 1: Pre-booster Inj.
    32.0
    32.1
        Dengue Virus Serotype 1: 28 days Post-booster Inj.
    74.7
    35.7
        Dengue Virus Serotype 2: Pre-booster Inj.
    41.3
    42.9
        Dengue Virus Serotype 2: 28 days Post-booster Inj.
    81.3
    42.9
        Dengue Virus Serotype 3: Pre-booster Inj.
    58.7
    60.7
        Dengue Virus Serotype 3: 28 days Post-booster Inj.
    96.0
    67.9
        Dengue Virus Serotype 4: Pre-booster Inj.
    70.7
    89.3
        Dengue Virus Serotype 4: 28 days Post-booster Inj.
    97.3
    82.1
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Seroconversion Against Each Dengue Virus Serotype Following Booster Injection With Either CYD Dengue Vaccine or Placebo

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    End point title
    		 Percentage of Subjects With Seroconversion Against Each Dengue Virus Serotype Following Booster Injection With Either CYD Dengue Vaccine or Placebo
    End point description
    Seroconversion rates for each serotypes were defined as the percentages of subjects with either a pre-booster titer <10 (1/dilution) and a post-booster titer >=40 (1/dilution), or a pre-booster titer >=10 (1/dilution) and a >=4-fold increase in post-booster titer as determined by PRNT. Analysis was performed on Per-Protocol Analysis Set.
    End point type
    Secondary
    End point timeframe
    28 days post-booster injection
    End point values
    		 CYD Dengue Vaccine Booster Group Placebo Group
    Number of subjects analysed
    75
    28
    Units: percentage of subjects
    number (not applicable)
        Dengue Virus Serotype 1
    29.3
    3.6
        Dengue Virus Serotype 2
    29.3
    0.0
        Dengue Virus Serotype 3
    44.0
    0.0
        Dengue Virus Serotype 4
    38.7
    0.0
    No statistical analyses for this end point

    Secondary: Geometric Mean Titers of Antibodies Against Each Dengue Virus Serotype Following the Third CYD Dengue Vaccine Injection Received In Study CYD28 and Before Booster Injection With Either CYD Dengue Vaccine or Placebo in CYD63

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    End point title
    		 Geometric Mean Titers of Antibodies Against Each Dengue Virus Serotype Following the Third CYD Dengue Vaccine Injection Received In Study CYD28 and Before Booster Injection With Either CYD Dengue Vaccine or Placebo in CYD63
    End point description
    GMTs of antibodies against each of the 4 dengue virus serotype (parental strains) were assessed using the PRNT. Analysis was performed on Per-Protocol Analysis Set. Here, 'n' = subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    28 days post-dose 3 in CYD28 and pre-booster injection (Day 0) in CYD63
    End point values
    		 CYD Dengue Vaccine Booster Group Placebo Group
    Number of subjects analysed
    75
    28
    Units: titers (1/dilution)
    geometric mean (confidence interval 95%)
        Dengue Virus Serotype1:28 D Post-dose 3(n=74,28)
    20.3 (13.9 to 29.5)
    26.8 (12.4 to 57.7)
        Dengue Virus Serotype1:Pre-booster Inj.(n=75,28)
    13.5 (9.31 to 19.6)
    16.7 (7.73 to 36.1)
        Dengue Virus Serotype2:28 D Post-dose 3(n=73,27)
    85.6 (55.7 to 132)
    65.4 (28.3 to 151)
        Dengue Virus Serotype2: Pre-booster Inj.(n=75,28)
    18.4 (12.1 to 28.0)
    23.2 (9.97 to 53.9)
        Dengue Virus Serotype3:28 D Post-dose 3(n=72,27)
    102 (78.4 to 133)
    107 (63.6 to 179)
        Dengue Virus Serotype3: Pre-booster Inj. (n=75,28)
    22.4 (15.6 to 32.0)
    27.4 (14.8 to 51.0)
        Dengue Virus Serotype4:28 D Post-dose 3(n=70,26)
    92.8 (72.5 to 119)
    86.5 (51.0 to 147)
        Dengue Virus Serotype4: Pre-booster Inj. (n=75,28)
    28.0 (20.4 to 38.5)
    44.9 (28.3 to 71.3)
    No statistical analyses for this end point

    Secondary: Geometric Mean of Titer Ratio of Antibodies Against Each Dengue Virus Serotype Following the Third CYD Dengue Vaccine Injection Received in Study CYD28 and Before Booster Injection With Either CYD Dengue Vaccine or Placebo

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    End point title
    		 Geometric Mean of Titer Ratio of Antibodies Against Each Dengue Virus Serotype Following the Third CYD Dengue Vaccine Injection Received in Study CYD28 and Before Booster Injection With Either CYD Dengue Vaccine or Placebo
    End point description
    GMTs of antibodies against each of the 4 dengue virus serotype (parental strains) were assessed using the PRNT. GMTRs were calculated as the ratio of GMTs post-dose 3 in CYD28 and pre-booster injection in CYD63. Analysis was performed on Per-Protocol Analysis Set. Here, 'n' = subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    28 days post-dose 3 in CYD28 and pre-booster injection (Day 0) in CYD63
    End point values
    		 CYD Dengue Vaccine Booster Group Placebo Group
    Number of subjects analysed
    75
    28
    Units: ratio
    geometric mean (confidence interval 95%)
        Dengue Virus Serotype 1 (n=74, 28)
    0.487 (0.390 to 0.609)
    0.441 (0.316 to 0.617)
        Dengue Virus Serotype 2 (n=73, 27)
    0.199 (0.160 to 0.248)
    0.313 (0.224 to 0.437)
        Dengue Virus Serotype 3 (n=72, 27)
    0.207 (0.163 to 0.262)
    0.267 (0.171 to 0.416)
        Dengue Virus Serotype 4 (n=70, 26)
    0.291 (0.217 to 0.391)
    0.474 (0.343 to 0.656)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Seropositivity Against Each Dengue Virus Serotype Following the Third CYD Dengue Vaccine Injection Received in Study CYD28, and Following Booster Injection With Either CYD Dengue Vaccine or Placebo

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    End point title
    		 Percentage of Subjects With Seropositivity Against Each Dengue Virus Serotype Following the Third CYD Dengue Vaccine Injection Received in Study CYD28, and Following Booster Injection With Either CYD Dengue Vaccine or Placebo
    End point description
    Seropositivity against each dengue virus serotype were measured using dengue PRNT. Seropositive subjects were defined as the subjects with neutralizing Antibody titers >=10 (1/dilution). Analysis was performed on Per-Protocol Analysis Set. Here, 'n' = subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    28 days (D) post-dose 3 in CYD28 and 28-D post-booster injection in CYD63
    End point values
    		 CYD Dengue Vaccine Booster Group Placebo Group
    Number of subjects analysed
    75
    28
    Units: percentage of subjects
    number (not applicable)
        Dengue Virus Serotype 1:28 D Post-dose 3 (n=74,28)
    52.7
    50.0
        Dengue Virus Serotype1:28DPostbooster Inj(n=75,28)
    74.7
    35.7
        Dengue Virus Serotype 2:28 D Post-dose 3 (n=73,27)
    89.0
    74.1
        Dengue Virus Serotype2:28DPostbooster Inj(n=75,28)
    81.3
    42.9
        Dengue Virus Serotype 3:28 D Post-dose 3 (n=72,27)
    97.2
    96.3
        Dengue Virus Serotype3:28DPostbooster Inj(n=75,28)
    96.0
    67.9
        Dengue Virus Serotype 4:28 D Post-dose 3 (n=70,26)
    95.7
    88.5
        Dengue Virus Serotype4:28DPostbooster Inj(n=75,28)
    97.3
    82.1
    No statistical analyses for this end point

    Secondary: Geometric Mean Titers of Antibodies Against Each Dengue Virus Serotype Following Booster Injection With Either CYD Dengue Vaccine or Placebo

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    End point title
    		 Geometric Mean Titers of Antibodies Against Each Dengue Virus Serotype Following Booster Injection With Either CYD Dengue Vaccine or Placebo
    End point description
    GMTs of antibodies against each of the 4 dengue virus serotype (parental strains) following booster injection were assessed using PRNT. Analysis was performed on Per-Protocol Analysis Set. Here, 'n' = subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    6 months , 12 months, and 24 months post-booster injection
    End point values
    		 CYD Dengue Vaccine Booster Group Placebo Group
    Number of subjects analysed
    75
    28
    Units: titers (1/dilution)
    geometric mean (confidence interval 95%)
        Serotype 1:6 months Post-booster Inj.(n=72,27)
    25.1 (17.4 to 36.4)
    14.3 (7.42 to 27.6)
        Serotype 1:12 months Post-booster Inj.(n=69,27)
    20.9 (14.0 to 31.1)
    14.6 (7.55 to 28.3)
        Serotype 1:24 months Post-booster Inj.(n=66,26)
    14.4 (9.88 to 21.0)
    13.6 (7.14 to 25.7)
        Serotype 2:6 months Post-booster Inj.(n=72,27)
    44.3 (29.0 to 67.7)
    20.4 (9.07 to 45.9)
        Serotype 2:12 months Post-booster Inj.(n=69,27)
    39.3 (25.3 to 61.2)
    22.1 (9.95 to 49.1)
        Serotype 2:24 months Post-booster Inj.(n=66,26)
    41.6 (25.8 to 67.2)
    21.7 (9.49 to 49.8)
        Serotype 3:6 months Post-booster Inj.(n=72,27)
    65.1 (47.3 to 89.5)
    26.7 (15.3 to 46.7)
        Serotype 3:12 months Post-booster Inj.(n=69,27)
    54.8 (40.1 to 74.9)
    20.6 (11.8 to 36.0)
        Serotype 3:24 months Post-booster Inj.(n=65,26)
    36.5 (25.6 to 51.8)
    16.8 (9.36 to 30.2)
        Serotype 4:6 months Post-booster Inj.(n=72,27)
    75.6 (58.8 to 97.2)
    34.6 (20.5 to 58.5)
        Serotype 4:12 months Post-booster Inj.(n=69,27)
    61.9 (47.2 to 81.2)
    33.1 (21.0 to 52.2)
        Serotype 4:24 months Post-booster Inj.(n=66,26)
    50.1 (38.4 to 65.4)
    24.5 (14.0 to 42.8)
    No statistical analyses for this end point

    Secondary: Geometric Mean of Titer Ratio of Antibodies Against Each Dengue Virus Serotype Following Booster Injection With Either CYD Dengue Vaccine or Placebo

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    End point title
    		 Geometric Mean of Titer Ratio of Antibodies Against Each Dengue Virus Serotype Following Booster Injection With Either CYD Dengue Vaccine or Placebo
    End point description
    GMTs of antibodies against each of the 4 dengue virus serotype (parental strains) following booster injection were assessed using PRNT. GMTRs were calculated as the ratio of GMTs post-booster injection and pre-booster injection. Analysis was performed on Per-Protocol Analysis Set. Here, 'n' = subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Pre-booster injection (Day 0) and 6 months, 12 months, 24 months post-booster injection
    End point values
    		 CYD Dengue Vaccine Booster Group Placebo Group
    Number of subjects analysed
    75
    28
    Units: ratio
    geometric mean (confidence interval 95%)
        Dengue Virus Serotype 1: 6 months/Day 0 (n=72,27)
    1.19 (0.953 to 1.51)
    0.646 (0.544 to 0.767)
        Dengue Virus Serotype 1: 12 months/Day 0 (n=69,27)
    0.983 (0.775 to 1.25)
    0.660 (0.516 to 0.845)
        Dengue Virus Serotype 1: 24 months/Day 0 (n=66,26)
    0.658 (0.528 to 0.818)
    0.594 (0.500 to 0.705)
        Dengue Virus Serotype 2: 6 months/Day 0 (n=72,27)
    1.60 (1.25 to 2.06)
    0.634 (0.525 to 0.766)
        Dengue Virus Serotype 2: 12 months/Day 0 (n=69,27)
    1.42 (1.11 to 1.80)
    0.687 (0.564 to 0.838)
        Dengue Virus Serotype 2: 24 months/Day 0 (n=66,26)
    1.43 (1.12 to 1.84)
    0.646 (0.491 to 0.850)
        Dengue Virus Serotype 3: 6 months/Day 0 (n=72,27)
    2.14 (1.60 to 2.85)
    0.797 (0.606 to 1.05)
        Dengue Virus Serotype 3: 12 months/Day 0 (n=69,27)
    1.76 (1.35 to 2.30)
    0.614 (0.455 to 0.829)
        Dengue Virus Serotype 3: 24 months/Day 0 (n=65,26)
    1.11 (0.876 to 1.42)
    0.479 (0.357 to 0.642)
        Dengue Virus Serotype 4: 6 months/Day 0 (n=72,27)
    2.17 (1.67 to 2.82)
    0.743 (0.530 to 1.04)
        Dengue Virus Serotype 4: 12 months/Day 0 (n=69,27)
    1.70 (1.28 to 2.27)
    0.710 (0.556 to 0.906)
        Dengue Virus Serotype 4: 24 months/Day 0 (n=66,26)
    1.35 (1.04 to 1.75)
    0.529 (0.384 to 0.730)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Seropositivity Against Each Dengue Virus Serotype Following Booster Injection With Either CYD Dengue Vaccine or Placebo

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    End point title
    		 Percentage of Subjects With Seropositivity Against Each Dengue Virus Serotype Following Booster Injection With Either CYD Dengue Vaccine or Placebo
    End point description
    Seropositivity against each dengue virus serotype were measured using dengue PRNT. Seropositive subjects were defined as the subjects with neutralizing Antibody titers >=10 (1/dilution). Analysis was performed on Per-Protocol Analysis Set. Here, 'n' = subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    6 months, 12 months, and 24 months post-booster injection
    End point values
    		 CYD Dengue Vaccine Booster Group Placebo Group
    Number of subjects analysed
    75
    28
    Units: percentage of subjects
    number (not applicable)
        Serotype 1:6 months Post-booster Inj.(n=72,27)
    59.7
    33.3
        Serotype 1:12 months Post-booster Inj.(n=69,27)
    49.3
    33.3
        Serotype 1:24 months Post-booster Inj.(n=66,26)
    37.9
    34.6
        Serotype 2:6 months Post-booster Inj.(n=72,27)
    72.2
    40.7
        Serotype 2:12 months Post-booster Inj.(n=69,27)
    66.7
    44.4
        Serotype 2:24 months Post-booster Inj.(n=66,26)
    65.2
    42.3
        Serotype 3:6 months Post-booster Inj.(n=72,27)
    88.9
    70.4
        Serotype 3:12 months Post-booster Inj.(n=69,27)
    89.9
    63.0
        Serotype 3:24 months Post-booster Inj.(n=65,26)
    76.9
    50.0
        Serotype 4:6 months Post-booster Inj.(n=72,27)
    95.8
    77.8
        Serotype 4:12 months Post-booster Inj.(n=69,27)
    91.3
    85.2
        Serotype 4:24 months Post-booster Inj.(n=66,26)
    89.4
    65.4
    No statistical analyses for this end point

    Secondary: Number of Subjects Reporting Solicited Injection Site Reactions (Pain, Erythema, Swelling) Following Booster Injection With Either CYD Dengue Vaccine or Placebo

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    End point title
    		 Number of Subjects Reporting Solicited Injection Site Reactions (Pain, Erythema, Swelling) Following Booster Injection With Either CYD Dengue Vaccine or Placebo
    End point description
    Solicited injection site reactions: Pain, Erythema, and Swelling. Grade 3 reactions: Pain: significant; prevents daily activity; Erythema and Swelling: >100 mm. Analysis was performed on Safety Analysis Set which included all participants who received either CYD dengue vaccine or placebo. Here, ‘n’ = subjects with available data for specified category.
    End point type
    Secondary
    End point timeframe
    Within 7 days after booster injection
    End point values
    		 CYD Dengue Vaccine Booster Group Placebo Group
    Number of subjects analysed
    89
    29
    Units: subjects
    number (not applicable)
        Injection-site Pain: Any (n=88,28)
    29
    7
        Injection-site Pain: Grade 3 (n=88,28)
    1
    0
        Injection-site Erythema: Any (n=88,28)
    1
    0
        Injection-site Erythema: Grade 3 (n=88,28)
    0
    0
        Injection-site Swelling: Any (n=88,28)
    0
    0
        Injection-site Swelling: Grade 3 (n=88, 28)
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects Reporting Solicited Systemic Reactions (Fever, Headache, Malaise, Myalgia, Asthenia) Following Booster Injection With Either CYD Dengue Vaccine or Placebo

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    End point title
    		 Number of Subjects Reporting Solicited Systemic Reactions (Fever, Headache, Malaise, Myalgia, Asthenia) Following Booster Injection With Either CYD Dengue Vaccine or Placebo
    End point description
    Solicited systemic reactions: Fever, Headache, Malaise, Myalgia, and Asthenia. Grade 3 reactions: Fever: >=39°C; Headache, Malaise, Myalgia, and Asthenia: significant, prevents daily activity. Analysis was performed on Safety Analysis Set. Here, ‘n’ = subjects with available data for specified category.
    End point type
    Secondary
    End point timeframe
    Within 14 days after booster injection
    End point values
    		 CYD Dengue Vaccine Booster Group Placebo Group
    Number of subjects analysed
    89
    29
    Units: subjects
    number (not applicable)
        Fever: Any Grade (n=88, 28)
    2
    0
        Fever: Grade 3 (n=88,28)
    0
    0
        Headache: Any Grade (n=88, 28)
    23
    3
        Headache: Grade 3 (n=88, 28)
    0
    0
        Malaise: Any Grade (n=88,28)
    11
    3
        Malaise: Grade 3 (n=88, 28)
    0
    1
        Myalgia: Any Grade (n=88, 28)
    21
    7
        Myalgia: Grade 3 (n=88,28)
    0
    1
        Asthenia: Any Grade (n=88, 28)
    15
    4
        Asthenia: Grade 3 (n=88, 28)
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse event (AE) data was collected from Day 0 up to 28 days post-booster injection, solicited reaction (SR) within 7 and 14 days after vaccination. Serious adverse event (SAE) data: throughout the study (up to 24 months after booster injection).
    Adverse event reporting additional description
    Safety Analysis Set. A SR was an AE that was prelisted (i.e., solicited) in the electronic case report form (eCRF) and considered to be related to vaccination (adverse drug reaction). An unsolicited AE was an observed AE that did not fulfill the conditions prelisted (i.e., solicited) in the eCRF in terms of symptom and/or onset post-vaccination.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    CYD Dengue Vaccine Booster Group
    Reporting group description
    		 Subjects who received 3 doses of the tetravalent dengue vaccine in a previous CYD dengue vaccine study (CYD28), received a booster injection of CYD dengue vaccine at Day 0 in this study (CYD63).

    Reporting group title
    Placebo Group
    Reporting group description
    		 Subjects who received 3 doses of the tetravalent dengue vaccine in a previous CYD dengue vaccine study (CYD28), received an injection of a placebo at Day 0 in this study (CYD63).

    Serious adverse events
    		 CYD Dengue Vaccine Booster Group Placebo Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 89 (5.62%)
    0 / 29 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Road Traffic Accident
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Pre-Eclampsia
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Ovarian Cyst
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic Pain
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 29 (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
    Influenza
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 29 (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 Booster Group Placebo Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    47 / 89 (52.81%)
    10 / 29 (34.48%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    23 / 89 (25.84%)
    4 / 29 (13.79%)
         occurrences all number
    23
    4
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    15 / 89 (16.85%)
    4 / 29 (13.79%)
         occurrences all number
    15
    4
    Injection Site Pain
         subjects affected / exposed
    29 / 89 (32.58%)
    7 / 29 (24.14%)
         occurrences all number
    29
    7
    Malaise
         subjects affected / exposed
    11 / 89 (12.36%)
    3 / 29 (10.34%)
         occurrences all number
    11
    3
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    21 / 89 (23.60%)
    7 / 29 (24.14%)
         occurrences all number
    21
    7
    Infections and infestations
    Upper Respiratory Tract Infection
         subjects affected / exposed
    6 / 89 (6.74%)
    1 / 29 (3.45%)
         occurrences all number
    7
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 May 2016
    Following changes were made: some mistakes were corrected and some contents in the immunogenicity endpoints, visit procedures, and product storage were clarified.

    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.
    None reported
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    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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