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    Clinical Trial Results:
    A phase III, randomized, multinational study, double-blinded for the immunogenicity and consistency evaluation of 3 Hib-MenCY-TT vaccine lots and single-blinded and controlled for the evaluation of safety and immunogenicity of GSK Biologicals' Haemophilus influenzae type b and Neisseria meningitidis serogroups C and Y-tetanus toxoid conjugate vaccine combined (Hib-MenCY-TT) compared to monovalent Hib vaccine in healthy infants at 2, 4, 6, and 12 to 15 months of age.

    Summary
    EudraCT number
    		 2005-002352-18
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    26 Feb 2008

    Results information
    Results version number
    		 v3(current)
    This version publication date
    08 Apr 2023
    First version publication date
    02 Jul 2015
    Other versions
    		 v1 , v2
    Version creation reason
    • Correction of full data set
    Results have been amended to account for consistency with other registries.

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    103813,105067
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00289783
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline Biologicals
    Sponsor organisation address
    Rue de l’Institut 89, Rixensart, Belgium, B-1330
    Public contact
    Clinical Trials Call Center, GlaxoSmithKline Biologicals, 44 2089904466, GSKClinicalSupportHD@gsk.com
    Scientific contact
    Clinical Trials Call Center, GlaxoSmithKline Biologicals, 44 2089904466, GSKClinicalSupportHD@gsk.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
    21 Apr 2009
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Aug 2007
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Feb 2008
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate: the lot-to-lot consistency of 3 lots of Hib-MenCY-TT co-administered with DTPa-HBV-IPV following 3 doses, in terms of PRP, MenC and MenY; the immune response to PRP in the group that received 3 doses of Hib-MenCY-TT and a 4th dose of Hib-MenCY-TT was non-inferior to the group that received Hib and Hib-OMP. To evaluate the immunogenicity of a 4th dose of Hib-MenCY-TT co-administered with DTPa-HBV-IPV, MMR and Var. To evaluate the effect of a 4th dose of Hib-MenCY-TT co-administered with MMR and Var, in terms of a vaccine response; the non-inferiority of Hib-MenCY-TT compared to Hib, co-administered with DTPa-HBV-IPV, in terms of PRP; the non-inferiority of MMR when co-administered with a 4th dose of Hib-MenCY-TT compared to MMR co-administered with a 4th dose of Hib-OMP, co-administered with Var; the non-inferiority of Var co-administered with a 4th dose of Hib-MenCY-TT compared to Var co-administered with a 4th dose of Hib-OMP, co-administered with MMR.
    Protection of trial subjects
    All subjects were supervised closely for at least 30 minutes following vaccination with appropriate medical treatment readily available. Vaccines were administered by qualified and trained personnel. Vaccines were administered only to eligible subjects that had no contraindications to any components of the vaccines. Subjects were followed-up from the time the subject consents to participate in the study until she/he is discharged.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Feb 2006
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 6 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 3037
    Country: Number of subjects enrolled
    Australia: 604
    Country: Number of subjects enrolled
    Mexico: 800
    Worldwide total number of subjects
    4441
    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)
    4441
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    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
    		 Subjects were randomized at the beginning of the primary phase and kept their group assignment during the fourth dose vaccination phase. The study protocol identified 3 different study cohorts : United States (US) Safety and Immunogenicity (Cohort 1), Safety Only (Cohort 2: from all investigation sites), Non-US Safety and Immunogenicity (Cohort 3).

    Pre-assignment
    Screening details
    		 The data for 261 subjects from one study center in the US were not included in the analyses as vaccine accountability could not be fully reconciled (i.e. treatment group assignment for the different subjects could not be verified).

    Period 1
    Period 1 title
    Primary phase
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer
    Blinding implementation details
    Double-blind for the immunogenicity and consistency evaluation of the 3 Hib-MenCY-TT vaccine lots and single-blind and controlled for the evaluation of safety and immunogenicity of Hib-MenCY-TT compared to monovalent Hib vaccine, randomized study with 4 parallel treatment groups (1:1:1:1).

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Menhibrix Group
    Arm description
    		 Subjects were primed with 3 doses of Menhibrix vaccine Lot A, B or C co-administered with Pediarix and boosted with 1 dose of Menhibrix vaccine, with co-administration of M-M-R II and Varivax. Subjects received vaccination at approximately 2, 4, 6 months and the fourth dose at 12-15 months of age. Menhibrix and Pediarix vaccines were administered intramuscularly in the right or left upper thigh, respectively. M-M-R II and Varivax vaccines were administered subcutaneously respectively in the upper left arm and the upper right arm.
    Arm type
    		 Experimental

    Investigational medicinal product name
    GSK Biologicals’ Haemophilus influenzae type b and Neisseria meningitidis 792014 vaccine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    3-doses administered at 2, 4 and 6 months of age, and 1 booster dose at 12 to 15 months of age.The vaccines were administered intramuscularly in the right upper thigh.

    Investigational medicinal product name
    Pediarix
    Investigational medicinal product code
    Other name
    Infanrix penta
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    A 3-dose injection at 2, 4 and 6 months of age, administered intramuscularly in the left upper thigh.

    Investigational medicinal product name
    Prevnar
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    3-dose intramuscular injection at 2, 4 and 6 months of age, and 1 booster dose by intramuscular injection at 12 to 15 months of age.

    Investigational medicinal product name
    M-M-R II
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1 booster dose by subcutaneous injection at 12 to 15 months of age.

    Investigational medicinal product name
    Varivax
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1 booster dose by subcutaneous injection at 12 to 15 months of age

    Arm title
    		 ActHIB Group
    Arm description
    		 Subjects were primed with 3 doses of ActHIB co-administered with Pediarix and boosted with 1 dose of PedvaxHIB, with co-administration of M-M-R II and Varivax. Subjects received vaccination at approximately 2, 4, 6 months and the fourth dose at 12-15 months of age. ActHIB, PedvaxHIB vaccines were administered intramuscularly in the right upper thigh and Pediarix vaccine in the left upper thigh. M-M-R II and Varivax vaccines were administered subcutaneously respectively in the upper left arm and the upper right arm.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    ActHIB
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    3-dose injection administered at 2, 4 and 6 months of age, intramuscularly in the right upper thigh.

    Investigational medicinal product name
    PedvaxHIB
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    1 booster dose by intramuscular injection at 12 to 15 months of age, administered in the left lower deltoid or tight

    Number of subjects in period 1 [1]
    		Menhibrix Group ActHIB Group
    Started
    3136
    1044
    Completed
    2888
    961
    Not completed
    248
    83
         Adverse event, serious fatal
    7
    -
         Consent withdrawn by subject
    93
    40
         Adverse event, non-fatal
    3
    1
         Unspecified
    32
    12
         Lost to follow-up
    60
    14
         Migration from the study area
    26
    10
         Protocol deviation
    27
    6
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The data for 261 subjects from one study center in the US were not included in the analyses as vaccine accountability could not be fully reconciled (i.e. treatment group assignment for the different subjects could not be verified).
    Period 2
    Period 2 title
    Fourth dose phase
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Menhibrix Group
    Arm description
    		 Subjects were primed with 3 doses of Menhibrix vaccine Lot A, B or C co-administered with Pediarix and boosted with 1 dose of Menhibrix vaccine, with co-administration of M-M-R II and Varivax. Subjects received vaccination at approximately 2, 4, 6 months and the fourth dose at 12-15 months of age. Menhibrix and Pediarix vaccines were administered intramuscularly in the right or left upper thigh, respectively. M-M-R II and Varivax vaccines were administered subcutaneously respectively in the upper left arm and the upper right arm.
    Arm type
    		 Experimental

    Investigational medicinal product name
    GSK Biologicals’ Haemophilus influenzae type b and Neisseria meningitidis 792014 vaccine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    3-doses administered at 2, 4 and 6 months of age, and 1 booster dose at 12 to 15 months of age.The vaccines were administered intramuscularly in the right upper thigh.

    Investigational medicinal product name
    Pediarix
    Investigational medicinal product code
    Other name
    Infanrix penta
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    A 3-dose injection at 2, 4 and 6 months of age, administered intramuscularly in the left upper thigh.

    Investigational medicinal product name
    Prevnar
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    3-dose intramuscular injection at 2, 4 and 6 months of age, and 1 booster dose by intramuscular injection at 12 to 15 months of age.

    Investigational medicinal product name
    M-M-R II
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1 booster dose by subcutaneous injection at 12 to 15 months of age.

    Investigational medicinal product name
    Varivax
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1 booster dose by subcutaneous injection at 12 to 15 months of age

    Arm title
    		 ActHIB Group
    Arm description
    		 Subjects were primed with 3 doses of ActHIB co-administered with Pediarix and boosted with 1 dose of PedvaxHIB, with co-administration of M-M-R II and Varivax. Subjects received vaccination at approximately 2, 4, 6 months and the fourth dose at 12-15 months of age. ActHIB, PedvaxHIB vaccines were administered intramuscularly in the right upper thigh and Pediarix vaccine in the left upper thigh. M-M-R II and Varivax vaccines were administered subcutaneously respectively in the upper left arm and the upper right arm.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    ActHIB
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    3-dose injection administered at 2, 4 and 6 months of age, intramuscularly in the right upper thigh.

    Investigational medicinal product name
    PedvaxHIB
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    1 booster dose by intramuscular injection at 12 to 15 months of age, administered in the left lower deltoid or tight

    Number of subjects in period 2 [2]
    		Menhibrix Group ActHIB Group
    Started
    2769
    923
    Completed
    2682
    899
    Not completed
    87
    24
         Consent withdrawn by subject
    10
    1
         Adverse event
    1
    -
         Unspecified
    22
    10
         Lost to follow-up
    53
    12
         Migration from the study area
    1
    1
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Subjects were randomized at the beginning of the primary phase and kept their group assignment during the fourth dose vaccination phase.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Menhibrix Group
    Reporting group description
    		 Subjects were primed with 3 doses of Menhibrix vaccine Lot A, B or C co-administered with Pediarix and boosted with 1 dose of Menhibrix vaccine, with co-administration of M-M-R II and Varivax. Subjects received vaccination at approximately 2, 4, 6 months and the fourth dose at 12-15 months of age. Menhibrix and Pediarix vaccines were administered intramuscularly in the right or left upper thigh, respectively. M-M-R II and Varivax vaccines were administered subcutaneously respectively in the upper left arm and the upper right arm.

    Reporting group title
    ActHIB Group
    Reporting group description
    		 Subjects were primed with 3 doses of ActHIB co-administered with Pediarix and boosted with 1 dose of PedvaxHIB, with co-administration of M-M-R II and Varivax. Subjects received vaccination at approximately 2, 4, 6 months and the fourth dose at 12-15 months of age. ActHIB, PedvaxHIB vaccines were administered intramuscularly in the right upper thigh and Pediarix vaccine in the left upper thigh. M-M-R II and Varivax vaccines were administered subcutaneously respectively in the upper left arm and the upper right arm.

    Reporting group values
    		 Menhibrix Group ActHIB Group Total
    Number of subjects
    		 3136 1044 4180
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: months
        arithmetic mean (standard deviation)
    		 2.11 ( 0.26 ) 2.11 ( 0.27 ) -
    Gender categorical
    Units: Subjects
        Female
    		 1523 498 2021
        Male
    		 1613 546 2159

    End points

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    End points reporting groups
    Reporting group title
    Menhibrix Group
    Reporting group description
    		 Subjects were primed with 3 doses of Menhibrix vaccine Lot A, B or C co-administered with Pediarix and boosted with 1 dose of Menhibrix vaccine, with co-administration of M-M-R II and Varivax. Subjects received vaccination at approximately 2, 4, 6 months and the fourth dose at 12-15 months of age. Menhibrix and Pediarix vaccines were administered intramuscularly in the right or left upper thigh, respectively. M-M-R II and Varivax vaccines were administered subcutaneously respectively in the upper left arm and the upper right arm.

    Reporting group title
    ActHIB Group
    Reporting group description
    		 Subjects were primed with 3 doses of ActHIB co-administered with Pediarix and boosted with 1 dose of PedvaxHIB, with co-administration of M-M-R II and Varivax. Subjects received vaccination at approximately 2, 4, 6 months and the fourth dose at 12-15 months of age. ActHIB, PedvaxHIB vaccines were administered intramuscularly in the right upper thigh and Pediarix vaccine in the left upper thigh. M-M-R II and Varivax vaccines were administered subcutaneously respectively in the upper left arm and the upper right arm.
    Reporting group title
    Menhibrix Group
    Reporting group description
    		 Subjects were primed with 3 doses of Menhibrix vaccine Lot A, B or C co-administered with Pediarix and boosted with 1 dose of Menhibrix vaccine, with co-administration of M-M-R II and Varivax. Subjects received vaccination at approximately 2, 4, 6 months and the fourth dose at 12-15 months of age. Menhibrix and Pediarix vaccines were administered intramuscularly in the right or left upper thigh, respectively. M-M-R II and Varivax vaccines were administered subcutaneously respectively in the upper left arm and the upper right arm.

    Reporting group title
    ActHIB Group
    Reporting group description
    		 Subjects were primed with 3 doses of ActHIB co-administered with Pediarix and boosted with 1 dose of PedvaxHIB, with co-administration of M-M-R II and Varivax. Subjects received vaccination at approximately 2, 4, 6 months and the fourth dose at 12-15 months of age. ActHIB, PedvaxHIB vaccines were administered intramuscularly in the right upper thigh and Pediarix vaccine in the left upper thigh. M-M-R II and Varivax vaccines were administered subcutaneously respectively in the upper left arm and the upper right arm.

    Subject analysis set title
    Menhibrix A Group
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects were primed with 3 doses of Menhibrix vaccine Lot A co-administered with Pediarix and boosted with 1 dose of Menhibrix vaccine, with co-administration of M-M-R II and Varivax. Subjects received vaccination at approximately 2, 4, 6 months and the fourth dose at 12-15 months of age. Menhibrix and Pediarix vaccines were administered intramuscularly in the right or left upper thigh, respectively. M-M-R II and Varivax vaccines were administered subcutaneously respectively in the upper left arm and the upper right arm.

    Subject analysis set title
    Menhibrix B Group
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects were primed with 3 doses of Menhibrix vaccine Lot B co-administered with Pediarix and boosted with 1 dose of Menhibrix vaccine, with co-administration of M-M-R II and Varivax. Subjects received vaccination at approximately 2, 4, 6 months and the fourth dose at 12-15 months of age. Menhibrix and Pediarix vaccines were administered intramuscularly in the right or left upper thigh, respectively. M-M-R II and Varivax vaccines were administered subcutaneously respectively in the upper left arm and the upper right arm.

    Subject analysis set title
    Menhibrix C Group
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects were primed with 3 doses of Menhibrix vaccine Lot C co-administered with Pediarix and boosted with 1 dose of Menhibrix vaccine, with co-administration of M-M-R II and Varivax. Subjects received vaccination at approximately 2, 4, 6 months and the fourth dose at 12-15 months of age. Menhibrix and Pediarix vaccines were administered intramuscularly in the right or left upper thigh, respectively. M-M-R II and Varivax vaccines were administered subcutaneously respectively in the upper left arm and the upper right arm.

    Primary: Anti-Polyribosyl Ribitol Phosphate (PRP) antibody concentrations

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    End point title
    		 Anti-Polyribosyl Ribitol Phosphate (PRP) antibody concentrations
    End point description
    Concentrations are given as Geometric Mean Concentrations (GMCs) and are expressed in microgram per millilitre (µg/mL) This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis.
    End point type
    Primary
    End point timeframe
    One month after primary vaccination
    End point values
    		 Menhibrix Group ActHIB Group Menhibrix A Group Menhibrix B Group Menhibrix C Group
    Number of subjects analysed
    518
    171
    162
    180
    176
    Units: µg/mL
    geometric mean (confidence interval 95%)
        Anti-PRP
    11.021 (10.027 to 12.114)
    6.463 (5.288 to 7.9)
    10.17 (8.855 to 11.681)
    11.424 (9.71 to 13.441)
    11.438 (9.503 to 13.768)
    Statistical analysis title
    		 GMC ratio anti-PRP LotB / LotA
    Statistical analysis description
    To demonstrate the lot-to-lot consistency of 3 manufacturing lots of Hib-MenCY-TT vaccine co-administered with DTPa-HBV-IPV vaccine following 3 primary doses in terms of immunogenicity for polyribosylribitol phosphate (PRP) as measured by ELISA.
    Comparison groups
    Menhibrix B Group v Menhibrix A Group
    Number of subjects included in analysis
    342
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    Method
    Parameter type
    		 GMC ratio
    Point estimate
    1.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.89
         upper limit
    		 1.42
    Notes
    [1] - Criteria for lot-to-lot consistency (1 month after primary vaccination): For each pair of lots and for the immune response to anti-PRP measured by ELISA the two-sided 95% confidence interval (CI) on the geometric mean concentrations (GMCs) ratio between lots is within the [0.5; 2.0] interval.
    Statistical analysis title
    		 GMC ratio anti-PRP LotC / LotA
    Statistical analysis description
    To demonstrate the lot-to-lot consistency of 3 manufacturing lots of Hib-MenCY-TT vaccine co-administered with DTPa-HBV-IPV vaccine following 3 primary doses in terms of immunogenicity for polyribosylribitol phosphate (PRP) as measured by ELISA.
    Comparison groups
    Menhibrix A Group v Menhibrix C Group
    Number of subjects included in analysis
    338
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    Method
    Parameter type
    		 GMC ratio
    Point estimate
    1.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.89
         upper limit
    		 1.42
    Notes
    [2] - Criteria for lot-to-lot consistency (1 month after primary vaccination): For each pair of lots and for the immune response to anti-PRP measured by ELISA the two-sided 95% confidence interval (CI) on the geometric mean concentrations (GMCs) ratio between lots is within the [0.5; 2.0] interval.
    Statistical analysis title
    		 GMC ratio anti-PRP LotC / LotB
    Statistical analysis description
    To demonstrate the lot-to-lot consistency of 3 manufacturing lots of Hib-MenCY-TT vaccine co-administered with DTPa-HBV-IPV vaccine following 3 primary doses in terms of immunogenicity for polyribosylribitol phosphate (PRP) as measured by ELISA.
    Comparison groups
    Menhibrix B Group v Menhibrix C Group
    Number of subjects included in analysis
    356
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    Method
    Parameter type
    		 GMC ratio
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 1.26
    Notes
    [3] - Criteria for lot-to-lot consistency (1 month after primary vaccination): For each pair of lots and for the immune response to anti-PRP measured by ELISA the two-sided 95% confidence interval (CI) on the geometric mean concentrations (GMCs) ratio between lots is within the [0.5; 2.0] interval.

    Primary: Neisseria meningitidis serogroup C (MenC) serum bactericidal assay using human complement (hSBA) antibody titers

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    End point title
    		 Neisseria meningitidis serogroup C (MenC) serum bactericidal assay using human complement (hSBA) antibody titers
    End point description
    Titers were expressed as Geometric Mean Titers (GMTs). This analysis occured on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis.
    End point type
    Primary
    End point timeframe
    One month after primary vaccination
    End point values
    		 Menhibrix Group ActHIB Group Menhibrix A Group Menhibrix B Group Menhibrix C Group
    Number of subjects analysed
    491
    164
    158
    168
    165
    Units: Titers
    geometric mean (confidence interval 95%)
        hSBA-MenC
    967.6 (864 to 1083.5)
    2.5 (2.2 to 2.9)
    910 (754.6 to 1097.3)
    1118 (931.1 to 1342.5)
    885.7 (712.4 to 1101.2)
    Statistical analysis title
    		 GMT ratio hSBA-MenC Lot B/Lot A
    Statistical analysis description
    To demonstrate the lot-to-lot consistency of 3 manufacturing lots of Hib-MenCY-TT vaccine co-administered with DTPa-HBV-IPV vaccine following 3 primary doses in terms of immunogenicity for N. meningitidis serogroup C (MenC) as measured by a serum bactericidal assay using human complement (hSBA).
    Comparison groups
    Menhibrix A Group v Menhibrix B Group
    Number of subjects included in analysis
    326
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    Method
    Parameter type
    		 GMT ratio
    Point estimate
    1.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.93
         upper limit
    		 1.62
    Notes
    [4] - For each pair of lots and for the immune response to hSBA-MenC, the two-sided 95% confidence interval (CI) on the geometric mean titers (GMTs) ratio between lots is within the [0.5; 2.0] interval.
    Statistical analysis title
    		 GMT ratio hSBA-MenC Lot C/Lot A
    Statistical analysis description
    To demonstrate the lot-to-lot consistency of 3 manufacturing lots of Hib-MenCY-TT vaccine co-administered with DTPa-HBV-IPV vaccine following 3 primary doses in terms of immunogenicity for N. meningitidis serogroup C (MenC) as measured by a serum bactericidal assay using human complement (hSBA).
    Comparison groups
    Menhibrix C Group v Menhibrix A Group
    Number of subjects included in analysis
    323
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    Method
    Parameter type
    		 GMT ratio
    Point estimate
    0.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.74
         upper limit
    		 1.29
    Notes
    [5] - For each pair of lots and for the immune response to hSBA-MenC, the two-sided 95% confidence interval (CI) on the geometric mean titers (GMTs) ratio between lots is within the [0.5; 2.0] interval.
    Statistical analysis title
    		 GMT ratio hSBA-MenC Lot C/Lot B
    Statistical analysis description
    To demonstrate the lot-to-lot consistency of 3 manufacturing lots of Hib-MenCY-TT vaccine co-administered with DTPa-HBV-IPV vaccine following 3 primary doses in terms of immunogenicity for N. meningitidis serogroup C (MenC) as measured by a serum bactericidal assay using human complement (hSBA).
    Comparison groups
    Menhibrix B Group v Menhibrix C Group
    Number of subjects included in analysis
    333
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    Method
    Parameter type
    		 GMT ratio
    Point estimate
    0.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 1.04
    Notes
    [6] - For each pair of lots and for the immune response to hSBA-MenC, the two-sided 95% confidence interval (CI) on the geometric mean titers (GMTs) ratio between lots is within the [0.5; 2.0] interval.

    Primary: Neisseria meningitidis serogroup Y (MenY) serum bactericidal assay using human complement (hSBA) antibody titers

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    End point title
    		 Neisseria meningitidis serogroup Y (MenY) serum bactericidal assay using human complement (hSBA) antibody titers
    End point description
    Titers are expressed as Geometric Mean Titers (GMTs) This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis.
    End point type
    Primary
    End point timeframe
    One month after primary vaccination
    End point values
    		 Menhibrix Group ActHIB Group Menhibrix A Group Menhibrix B Group Menhibrix C Group
    Number of subjects analysed
    481
    162
    150
    168
    163
    Units: Titers
    geometric mean (confidence interval 95%)
        hSBA-MenY
    236.6 (205.7 to 272.1)
    2.2 (2 to 2.4)
    178.9 (136.4 to 234.6)
    288.1 (232.8 to 356.6)
    249.6 (195.6 to 318.7)
    Statistical analysis title
    		 GMT ratio hSBA-MenY Lot B/Lot A
    Statistical analysis description
    To demonstrate the lot-to-lot consistency of 3 manufacturing lots of Hib-MenCY-TT vaccine co-administered with DTPa-HBV-IPV vaccine following 3 primary doses in terms of immunogenicity for N. meningitidis serogroup Y (MenY) as measured by a serum bactericidal assay using human complement (hSBA).
    Comparison groups
    Menhibrix A Group v Menhibrix B Group
    Number of subjects included in analysis
    318
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    Method
    Parameter type
    		 GMT ratio
    Point estimate
    1.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.14
         upper limit
    		 2.27
    Notes
    [7] - For each pair of lots and for the immune response to hSBA-MenY, the two-sided 95% confidence interval (CI) on the geometric mean titers (GMTs) ratio between lots is within the [0.5; 2.0] interval.
    Statistical analysis title
    		 GMT ratio hSBA-MenY Lot C/Lot A
    Statistical analysis description
    To demonstrate the lot-to-lot consistency of 3 manufacturing lots of Hib-MenCY-TT vaccine co-administered with DTPa-HBV-IPV vaccine following 3 primary doses in terms of immunogenicity for N. meningitidis serogroup Y (MenY) as measured by a serum bactericidal assay using human complement (hSBA).
    Comparison groups
    Menhibrix A Group v Menhibrix C Group
    Number of subjects included in analysis
    313
    Analysis specification
    Pre-specified
    Analysis type
    		 other [8]
    Method
    Parameter type
    		 GMT ratio
    Point estimate
    1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.99
         upper limit
    		 1.97
    Notes
    [8] - For each pair of lots and for the immune response to hSBA-MenY, the two-sided 95% confidence interval (CI) on the geometric mean titers (GMTs) ratio between lots is within the [0.5; 2.0] interval.
    Statistical analysis title
    		 GMT ratio hSBA-MenC Lot C/Lot B
    Statistical analysis description
    To demonstrate the lot-to-lot consistency of 3 manufacturing lots of Hib-MenCY-TT vaccine co-administered with DTPa-HBV-IPV vaccine following 3 primary doses in terms of immunogenicity for N. meningitidis serogroup Y (MenY) as measured by a serum bactericidal assay using human complement (hSBA).
    Comparison groups
    Menhibrix B Group v Menhibrix C Group
    Number of subjects included in analysis
    331
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    Method
    Parameter type
    		 GMT ratio
    Point estimate
    0.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.62
         upper limit
    		 1.21
    Notes
    [9] - For each pair of lots and for the immune response to hSBA-MenY, the two-sided 95% confidence interval (CI) on the geometric mean titers (GMTs) ratio between lots is within the [0.5; 2.0] interval.

    Primary: hSBA-MenC antibody titers

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    End point title
    		 hSBA-MenC antibody titers
    End point description
    Titers are expressed as Geometric Mean Titers (GMTs). This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis.
    End point type
    Primary
    End point timeframe
    Prior to the fourth dose vaccination and 42 days after the fourth dose
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    331
    119
    Units: Titers
    geometric mean (confidence interval 95%)
        hSBA-MenC [post-dose 4] (N=331;119)
    2039.8 (1746.3 to 2382.6)
    4.3 (3.2 to 5.8)
        hSBA-MenC [pre-dose 4] (N=329;104)
    180.3 (155.6 to 208.8)
    3 (2.4 to 3.7)
    Statistical analysis title
    		 1.hSBA-MenC GMT ratio - Post-dose 4/Pre-dose 4
    Statistical analysis description
    To evaluate the specific effect of a fourth dose of Menhibrix vaccine co-administered with M-M-R II and Varivax vaccines at 12 to 15 months of age in terms of a fourth dose vaccine response as measured by hSBA-MenC.
    Comparison groups
    Menhibrix Group v ActHIB Group
    Number of subjects included in analysis
    450
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [10]
    Method
    Parameter type
    		 GMT ratio
    Point estimate
    12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 10.4
         upper limit
    		 13.8
    Notes
    [10] - Criteria for immunogenicity of MenC (42 days after the fourth dose): Lower limit of the asymptotic 95% CI for the geometric mean of individual ratio of post-dose 4/pre-dose 4 is ≥ 2.
    Statistical analysis title
    		 2.hSBA-MenC GMT ratio - Post-dose 4/Pre-dose 4
    Statistical analysis description
    To evaluate the specific effect of a fourth dose of Menhibrix vaccine co-administered with M-M-R II and Varivax vaccines at 12 to 15 months of age in terms of a fourth dose vaccine response as measured by hSBA-MenC.
    Comparison groups
    Menhibrix Group v ActHIB Group
    Number of subjects included in analysis
    450
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [11]
    Method
    Parameter type
    		 GMT ratio
    Point estimate
    1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.4
         upper limit
    		 1.4
    Notes
    [11] - Point estimate = Lower limit (LL) = Upper limit (UL) as LL and UL values were not available due to the departure from lognormal distribution (large number of imputed values).

    Primary: hSBA-MenY antibody titers

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    End point title
    		 hSBA-MenY antibody titers
    End point description
    Titers are expressed as Geometric Mean Titers (GMTs) This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis.
    End point type
    Primary
    End point timeframe
    Prior to the fourth dose vaccination and 42 days after the fourth dose
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    342
    120
    Units: Titers
    geometric mean (confidence interval 95%)
        hSBA-MenY [post-dose 4] (N=342;120)
    1389.5 (1205 to 1602.2)
    48.6 (31.9 to 74)
        hSBA-MenY [pre-dose 4] (N=329;103)
    119.1 (101.1 to 140.3)
    2.5 (2.1 to 2.9)
    Statistical analysis title
    		 1.hSBA-MenY GMT ratio - Post-dose 4/Pre-dose 4
    Statistical analysis description
    To evaluate the specific effect of a fourth dose of Menhibrix vaccine co-administered with M-M-R II and Varivax vaccines at 12 to 15 months of age in terms of a fourth dose vaccine response as measured by hSBA-MenY.
    Comparison groups
    Menhibrix Group v ActHIB Group
    Number of subjects included in analysis
    462
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [12]
    Method
    Parameter type
    		 GMT ratio
    Point estimate
    11.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 10.2
         upper limit
    		 13.8
    Notes
    [12] - Criteria for immunogenicity of MenY (42 days after the fourth dose): Lower limit of the asymptotic 95% CI for the geometric mean of individual ratio of post-dose 4/pre-dose 4 is ≥ 2.
    Statistical analysis title
    		 2.hSBA-MenY GMT ratio - Post-dose 4/Pre-dose 4
    Statistical analysis description
    To evaluate the specific effect of a fourth dose of Menhibrix vaccine co-administered with M-M-R II and Varivax vaccines at 12 to 15 months of age in terms of a fourth dose vaccine response as measured by hSBA-MenY.
    Comparison groups
    ActHIB Group v Menhibrix Group
    Number of subjects included in analysis
    462
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [13]
    Method
    Parameter type
    		 GMT ratio
    Point estimate
    21.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 21.1
         upper limit
    		 21.1
    Notes
    [13] - Point estimate = Lower limit (LL) = Upper limit (UL) as LL and UL values were not available due to the departure from lognormal distribution (large number of imputed values).

    Primary: Number of subjects with anti-PRP antibody concentration equal to or above 1.0 microgram per milliliter (µg/mL)

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    End point title
    		 Number of subjects with anti-PRP antibody concentration equal to or above 1.0 microgram per milliliter (µg/mL) [14]
    End point description
    This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis.
    End point type
    Primary
    End point timeframe
    One month after primary vaccination
    Notes
    [14] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The analysis of the primary endpoint was descriptive i.e. no statistical hypothesis test was performed.
    End point values
    		 Menhibrix Group ActHIB Group Menhibrix A Group Menhibrix B Group Menhibrix C Group
    Number of subjects analysed
    518
    171
    162
    180
    176
    Units: Subjects
        Anti-PRP
    499
    156
    158
    175
    166
    No statistical analyses for this end point

    Primary: Number of subjects with hSBA-MenC titer equal to or above 1:8

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    End point title
    		 Number of subjects with hSBA-MenC titer equal to or above 1:8 [15]
    End point description
    This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis.
    End point type
    Primary
    End point timeframe
    42 days after the fourth dose
    Notes
    [15] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The analysis of the primary endpoint was descriptive i.e. no statistical hypothesis test was performed.
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    331
    119
    Units: Subjects
        hSBA-MenC
    326
    26
    No statistical analyses for this end point

    Primary: Number of subjects with hSBA-MenY titer equal to or above 1:8

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    End point title
    		 Number of subjects with hSBA-MenY titer equal to or above 1:8 [16]
    End point description
    This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis.
    End point type
    Primary
    End point timeframe
    42 days after the fourth dose
    Notes
    [16] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The analysis of the primary endpoint was descriptive i.e. no statistical hypothesis test was performed.
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    342
    120
    Units: Subjects
        hSBA-MenY
    338
    87
    No statistical analyses for this end point

    Primary: Number of subjects with anti-measles antibody concentrations equal to or above 150 milli-international units per milliliter (mIU/mL)

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    End point title
    		 Number of subjects with anti-measles antibody concentrations equal to or above 150 milli-international units per milliliter (mIU/mL)
    End point description
    The analysis was performed on initially seronegative subjects. Seronegative subjects are subjects with anti-measles antibody concentrations below 150 mIU/mL. Co-administration with MMR-II vaccine
    End point type
    Primary
    End point timeframe
    42 days after the fourth dose
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    852
    286
    Units: Subjects
        Anti-measles
    815
    274
    Statistical analysis title
    		 Serostatus for anti-measles antibodies
    Statistical analysis description
    To demonstrate the non-inferiority of M-M-R II vaccine when co-administered with a fourth dose of Menhibrix vaccine compared to M-M-R II vaccine co-administered with a fourth dose of PedvaxHIB vaccine, each co-administered with Varivax vaccine.
    Comparison groups
    Menhibrix Group v ActHIB Group
    Number of subjects included in analysis
    1138
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [17]
    Method
    Parameter type
    		 Difference in percentage
    Point estimate
    -0.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.56
         upper limit
    		 3.06
    Notes
    [17] - Lower limit of the standardized asymptotic 95% CI for the difference (Menhibrix vaccine fourth dose group minus ActHIB fourth dose group) in the percentage of subjects with seroconversion ≥ 150 mIU/mL, in initially seronegative subjects (<150 mIU/mL), for anti-measles antibody is ≥-5% (clinical limit for non-inferiority).

    Primary: Number of subjects with anti-PRP antibody concentration equal to or above 1.0 microgram per milliliter

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    End point title
    		 Number of subjects with anti-PRP antibody concentration equal to or above 1.0 microgram per milliliter
    End point description
    This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis.
    End point type
    Primary
    End point timeframe
    42 days after the fourth dose
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    361
    126
    Units: Subjects
        Anti-PRP
    358
    125
    Statistical analysis title
    		 Serostatus for anti-PRP
    Statistical analysis description
    To demonstrate that, following a fourth dose, the immune response to Hib polysaccharide (PRP) in the group that received 3 primary vaccine doses of Menhibrix vaccine and a fourth dose of Menhibrix vaccine coadministered with M-M-R II and Varivax vaccines was non-inferior to the corresponding immune response in the group that received 3 primary vaccine doses of ActHIB vaccine and a fourth dose of PedvaxHIB vaccine co-administered with M-M-R II and Varivax vaccines.
    Comparison groups
    Menhibrix Group v ActHIB Group
    Number of subjects included in analysis
    487
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [18]
    Method
    Parameter type
    		 Difference in percentage
    Point estimate
    -0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.78
         upper limit
    		 3.57
    Notes
    [18] - Criteria for non-inferiority (42 days after the fourth dose): Lower limit of the two-sided standardized asymptotic 95% CI on the difference (Menhibrix vaccine fourth dose group minus ActHIB fourth dose group) in the percentage of subjects with anti-PRP concentration ≥ 1.0 µg/mL is ≥ -10% (clinical limit for non-inferiority).

    Primary: Number of subjects with anti-mumps titer equal to or above 28 estimated dose 50 (ED50)

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    End point title
    		 Number of subjects with anti-mumps titer equal to or above 28 estimated dose 50 (ED50)
    End point description
    The analysis was performed on initially seronegative subjects. Seronegative subjects are subjects with anti-mumps antibody titers below 28 ED50. Co-administration with MMR-II vaccine.
    End point type
    Primary
    End point timeframe
    42 days after the fourth dose
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    601
    191
    Units: Subjects
        Anti-mumps
    595
    191
    Statistical analysis title
    		 Serostatus for anti-mumps antibodies ≥ 28 ED50
    Statistical analysis description
    To demonstrate the non-inferiority of M-M-R II vaccine when co-administered with a fourth dose of Menhibrix vaccine compared to M--M-R II vaccine co-administered with a fourth dose of PedvaxHIB vaccine, each co-administered with Varivax vaccine.
    Comparison groups
    Menhibrix Group v ActHIB Group
    Number of subjects included in analysis
    792
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [19]
    Method
    Parameter type
    		 Difference in percentage
    Point estimate
    -1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.16
         upper limit
    		 0.98
    Notes
    [19] - Criterion for non-inferiority (42 days after fourth dose vaccination): Lower limit of the standardized asymptotic 95% CI for the difference (Menhibrix vaccine fourth dose group minus ActHIB fourth dose group) in the percentage of subjects with a seroconversion ≥28 ED50, in subjects with initial anti-mumps antibody < 28 ED50, for anti-mumps antibody is ≥ -5% (clinical limit for non-inferiority).

    Primary: Number of subjects with anti-rubella antibody concentrations equal to or above 10 international units per millilitre (IU/mL)

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    End point title
    		 Number of subjects with anti-rubella antibody concentrations equal to or above 10 international units per millilitre (IU/mL)
    End point description
    The analysis was performed on initially seronegative subjects. Seronegative subjects are subjects with anti-rubella antibody concentrations below 4 IU/mL. Co-administration with MMR-II vaccine.
    End point type
    Primary
    End point timeframe
    42 days after the fourth dose
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    850
    285
    Units: Subjects
        Anti-rubella
    848
    284
    Statistical analysis title
    		 Serostatus for anti-rubella antibodies ≥ 10 IU/mL
    Statistical analysis description
    To demonstrate the non-inferiority of M-M-R II vaccine when co-administered with a fourth dose of Menhibrix vaccine compared to M-M-R II vaccine co-administered with a fourth dose of PedvaxHIB vaccine, each co-administered with Varivax vaccine.
    Comparison groups
    Menhibrix Group v ActHIB Group
    Number of subjects included in analysis
    1135
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [20]
    Method
    Parameter type
    		 Difference in percentage
    Point estimate
    0.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.57
         upper limit
    		 1.73
    Notes
    [20] - To demonstrate the non-inferiority of M-M-R II vaccine when co-administered with a fourth dose of Menhibrix vaccine compared to M-M-R II vaccine co-administered with a fourth dose of PedvaxHIB vaccine, each co-administered with Varivax vaccine.

    Primary: Number of subjects with anti-varicella titers equal to or above 1:5

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    End point title
    		 Number of subjects with anti-varicella titers equal to or above 1:5
    End point description
    The analysis was performed on initially seronegative subjects. Seronegative subjects are subjects with anti-varicella antibody titers below 1:5. Co-administration with Varivax vaccine.
    End point type
    Primary
    End point timeframe
    42 days after the fourth dose
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    723
    223
    Units: Subjects
        Anti-varicella
    722
    223
    Statistical analysis title
    		 Serostatus for anti-varicella antibodies (≥ 1:5)
    Statistical analysis description
    To demonstrate the non-inferiority of Varivax vaccine co-administered with a fourth dose of Menhibrix vaccine compared to Varivax vaccine co-administered with a fourth dose of PedvaxHIB vaccine, each co-administered with M-M-R II vaccine in terms of immunogenicity to varicella as measured by fluorescent antibody to membrane antigen (FAMA).
    Comparison groups
    Menhibrix Group v ActHIB Group
    Number of subjects included in analysis
    946
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [21]
    Method
    Parameter type
    		 Difference in percentage
    Point estimate
    -0.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.78
         upper limit
    		 1.56
    Notes
    [21] - Criterion for non-inferiority (42 days after the fourth dose vaccination): Lower limit of the standardized asymptotic 95% CI for the difference (Menhibrix vaccine fourth dose group minus ActHIB fourth dose group) in the percentage of subjects with seroconversion ≥ 1:5 dilution, in initially seronegative subjects (< 1:5), for anti-varicella antibody is ≥ -10% (clinical limit for non-inferiority).

    Secondary: Number of subjects with anti-tetanus (anti-T) and anti-diphtheria toxoid (anti-D) antibody concentrations equal to or above 0.1 international units per millilitre (IU/mL)

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    End point title
    		 Number of subjects with anti-tetanus (anti-T) and anti-diphtheria toxoid (anti-D) antibody concentrations equal to or above 0.1 international units per millilitre (IU/mL)
    End point description
    This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis.
    End point type
    Secondary
    End point timeframe
    One month after primary vaccination
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    365
    120
    Units: Subjects
        Anti-D
    365
    120
        Anti-T
    365
    120
    No statistical analyses for this end point

    Secondary: Anti-D and anti-T antibody concentrations

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    End point title
    		 Anti-D and anti-T antibody concentrations
    End point description
    Concentrations are given as Geometric Mean Concentrations (GMCs) and are expressed in international units per milliliter (IU/mL). This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis.
    End point type
    Secondary
    End point timeframe
    One month after primary vaccination
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    365
    120
    Units: IU/mL
    geometric mean (confidence interval 95%)
        Anti-D
    2 (1.9 to 2.2)
    2.2 (2 to 2.5)
        Anti-T
    3.9 (3.7 to 4.1)
    1.9 (1.7 to 2.2)
    No statistical analyses for this end point

    Secondary: Number of subjects with anti hepatitis B surface antigen (anti-HBs) antibody concentrations equal to or above 10.0 milli-international units per millilitre (mIU/mL)

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    End point title
    		 Number of subjects with anti hepatitis B surface antigen (anti-HBs) antibody concentrations equal to or above 10.0 milli-international units per millilitre (mIU/mL)
    End point description
    Results are stratified by the presence or absence of a birth dose of hepatitis B vaccine. This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis.
    End point type
    Secondary
    End point timeframe
    One month after primary vaccination
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    194
    47
    Units: Subjects
        Anti-HBs with Hepatitis B at birth (N=194;47)
    193
    47
        Anti-HBs without Hepatitis B at birth (N=18;8)
    17
    8
    No statistical analyses for this end point

    Secondary: Anti-HBs antibody concentrations

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    End point title
    		 Anti-HBs antibody concentrations
    End point description
    Concentrations are given as Geometric Mean Concentrations (GMCs) and are expressed in milli-International units per milliliter (mIU/mL) Results are stratified by the presence or absence of a birth dose of hepatitis B vaccine. This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis.
    End point type
    Secondary
    End point timeframe
    One month after primary vaccination
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    194
    47
    Units: mIU/mL
    geometric mean (confidence interval 95%)
        Anti-HBs with Hepatitis B at birth (N=194;47)
    1963.2 (1684.8 to 2287.7)
    2187.6 (1551.4 to 3084.5)
        Anti-HBs without Hepatitis B at birth (N=18;8)
    1672.7 (730.9 to 3827.8)
    3593.2 (1499.4 to 8611.1)
    No statistical analyses for this end point

    Secondary: Number of subjects with anti-pertussis toxoid (anti-PT), anti-filamentous hemagglutinin (anti-FHA) and anti-pertactin (anti-PRN) antibody concentrations equal to or above 5 ELISA units per millilitre (EL.U/mL)

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    End point title
    		 Number of subjects with anti-pertussis toxoid (anti-PT), anti-filamentous hemagglutinin (anti-FHA) and anti-pertactin (anti-PRN) antibody concentrations equal to or above 5 ELISA units per millilitre (EL.U/mL)
    End point description
    This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis.
    End point type
    Secondary
    End point timeframe
    One month after primary vaccination
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    327
    101
    Units: Subjects
        Anti-PT (N=327;100)
    327
    100
        Anti-FHA (N=324;97)
    324
    97
        Anti-PRN (N=322;101)
    321
    99
    No statistical analyses for this end point

    Secondary: Anti-PT, anti-FHA and anti-PRN antibody concentrations

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    End point title
    		 Anti-PT, anti-FHA and anti-PRN antibody concentrations
    End point description
    This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis.
    End point type
    Secondary
    End point timeframe
    One month after primary vaccination
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    327
    101
    Units: EL.U/mL
    geometric mean (confidence interval 95%)
        Anti-PT (N=327;100)
    57.7 (54 to 61.7)
    65.6 (58.3 to 73.9)
        Anti-FHA (N=324;97)
    243.8 (227.9 to 260.9)
    293.6 (261.4 to 329.8)
        Anti-PRN (N=322;101)
    98.6 (89.5 to 108.6)
    103.1 (82.8 to 128.4)
    No statistical analyses for this end point

    Secondary: Number of subjects with anti-poliovirus types 1, 2 and 3 equal to or above 8 estimated dose 50 (ED50)

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    End point title
    		 Number of subjects with anti-poliovirus types 1, 2 and 3 equal to or above 8 estimated dose 50 (ED50)
    End point description
    This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis.
    End point type
    Secondary
    End point timeframe
    One month after primary vaccination
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    285
    90
    Units: Subjects
        Anti-Polio 1 (N=285;90)
    285
    90
        Anti-Polio 2 (N=285;90)
    285
    90
        Anti-Polio 3 (N=285;89)
    285
    89
    No statistical analyses for this end point

    Secondary: Anti-poliovirus types 1, 2 and 3 titers

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    End point title
    		 Anti-poliovirus types 1, 2 and 3 titers
    End point description
    Titers are expressed as Geometric Mean Titers (GMTs) This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis.
    End point type
    Secondary
    End point timeframe
    One month after primary vaccination
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    285
    90
    Units: Titers
    geometric mean (confidence interval 95%)
        Anti-Polio 1 (N=285;90)
    591.8 (525 to 667)
    590.7 (462.7 to 754.1)
        Anti-Polio 2 (N=285;90)
    496.7 (435.9 to 566)
    452.7 (360.3 to 568.8)
        Anti-Polio 3 (N=285;89)
    1367.7 (1209.9 to 1546)
    1239.2 (973.5 to 1577.6)
    No statistical analyses for this end point

    Secondary: Number of subjects with antibodies to Neisseria meningitidis serogroup C and Y polysaccharide capsule (anti-PSC and anti-PSY) concentrations equal to or above the cut-off values

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    End point title
    		 Number of subjects with antibodies to Neisseria meningitidis serogroup C and Y polysaccharide capsule (anti-PSC and anti-PSY) concentrations equal to or above the cut-off values
    End point description
    Anti-PSC and anti-PSY antibody cut-off values assessed were >=0.3 microgram per milliliter (µg/mL) and >=2.0 µg/mL. This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis.
    End point type
    Secondary
    End point timeframe
    One month after primary vaccination
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    421
    404
    Units: Subjects
        Anti-PSC >=0.3 µg/mL (N=421;119)
    418
    5
        Anti-PSY >=0.3 µg/mL (N=404;109)
    402
    1
        Anti-PSC >=2.0 µg/mL (N=421;119)
    379
    2
        Anti-PSY >=2.0 µg/mL (N=404;109)
    396
    0
    No statistical analyses for this end point

    Secondary: Anti-PSC and anti-PSY antibody concentrations

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    End point title
    		 Anti-PSC and anti-PSY antibody concentrations
    End point description
    Concentrations are given as Geometric Mean Concentrations (GMCs) and are expressed in microgram per milliliter (µg/mL) This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis.
    End point type
    Secondary
    End point timeframe
    One month after primary vaccination
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    421
    119
    Units: µg/mL
    geometric mean (confidence interval 95%)
        Anti-PSC (N=421;119)
    5.8 (5.3 to 6.2)
    0.2 (0.2 to 0.2)
        Anti-PSY (N=404;109)
    17.5 (16 to 19.1)
    0.2 (0.1 to 0.2)
    No statistical analyses for this end point

    Secondary: Number of subjects with anti-PRP antibody concentrations equal to or above the cut-off values

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    End point title
    		 Number of subjects with anti-PRP antibody concentrations equal to or above the cut-off values
    End point description
    Anti-PRP antibody cut-off values assessed were >=0.15 microgram per milliliter (µg/mL) and >=1.0 µg/mL. The analysis was performed on the cohort 3 (Non-US Safety and Immunogenicity): Cohort 3 was to include the subjects enrolled at 1 center in Mexico. Only descriptive immunogenicity results were reported for this cohort. These subjects also contributed to the safety analysis.
    End point type
    Secondary
    End point timeframe
    One month after the primary vaccination course
    End point values
    		 Menhibrix Group ActHIB Group Menhibrix A Group Menhibrix B Group Menhibrix C Group
    Number of subjects analysed
    134
    46
    49
    42
    43
    Units: Subjects
        Anti-PRP >=0.15 µg/mL
    134
    46
    49
    42
    43
        Anti-PRP >=1.0 µg/mL
    134
    46
    49
    42
    43
    No statistical analyses for this end point

    Secondary: Number of subjects with anti-PRP antibody concentrations equal to or above the cut-off values

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    End point title
    		 Number of subjects with anti-PRP antibody concentrations equal to or above the cut-off values
    End point description
    Anti-PRP antibody cut-off values assessed were >=0.15 microgram per milliliter (µg/mL) and >=1.0 µg/mL. The analysis was performed on the cohort 3 (Non-US Safety and Immunogenicity): Cohort 3 was to include the subjects enrolled at 1 center in Mexico. Only descriptive immunogenicity results were reported for this cohort. These subjects also contributed to the safety analysis.
    End point type
    Secondary
    End point timeframe
    Prior to the fourth dose vaccination and one month after fourth dose vaccination
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    40
    13
    Units: Subjects
        Anti-PRP pre-dose 4 >=0.15 µg/mL (N=38;12)
    38
    12
        Anti-PRP pre-dose 4 >=1.0 µg/mL (N=38;12)
    33
    11
        Anti-PRP post-dose 4 >=0.15 µg/mL (N=40;13)
    40
    13
        Anti-PRP post-dose 4 >=1.0 µg/mL (N=40;13)
    40
    13
    No statistical analyses for this end point

    Secondary: Anti-PRP antibody concentrations

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    End point title
    		 Anti-PRP antibody concentrations
    End point description
    Concentrations are given as Geometric Mean Concentrations (GMCs) and are expressed in microgram per millilitre (µg/mL) The analysis was performed on the cohort 3 (Non-US Safety and Immunogenicity): Cohort 3 was to include the subjects enrolled at 1 center in Mexico. Only descriptive immunogenicity results were reported for this cohort. These subjects also contributed to the safety analysis.
    End point type
    Secondary
    End point timeframe
    One month after the primary vaccination course
    End point values
    		 Menhibrix Group ActHIB Group Menhibrix A Group Menhibrix B Group Menhibrix C Group
    Number of subjects analysed
    134
    46
    49
    42
    43
    Units: µg/mL
    geometric mean (confidence interval 95%)
        Anti-PRP
    23.165 (20.012 to 26.815)
    29.759 (22.729 to 38.965)
    24.984 (19.674 to 31.728)
    24.05 (18.327 to 31.561)
    20.489 (15.653 to 26.819)
    No statistical analyses for this end point

    Secondary: Anti-PRP antibody concentrations

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    End point title
    		 Anti-PRP antibody concentrations
    End point description
    Concentrations are given as Geometric Mean Concentrations (GMCs) and are expressed in microgram per millilitre (µg/mL) The analysis was performed on the cohort 3 (Non-US Safety and Immunogenicity): Cohort 3 was to include the subjects enrolled at 1 center in Mexico. Only descriptive immunogenicity results were reported for this cohort. These subjects also contributed to the safety analysis.
    End point type
    Secondary
    End point timeframe
    Prior to the fourth dose vaccination and one month after fourth dose vaccination
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    40
    13
    Units: µg/mL
    geometric mean (confidence interval 95%)
        Anti-PRP Pre-dose 4 (N=38;12)
    3.34 (2.407 to 4.636)
    4.123 (1.981 to 8.583)
        Anti-PRP Post-dose 4 (N=40;13)
    132.965 (97.131 to 182.019)
    92.8 (45.636 to 188.709)
    No statistical analyses for this end point

    Secondary: Number of subjects with hSBA-MenC and hSBA-MenY titers equal to or above the cut-off values

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    End point title
    		 Number of subjects with hSBA-MenC and hSBA-MenY titers equal to or above the cut-off values
    End point description
    hSBA-MenC/Y antibody cut-off values assessed were >=1:4 and >=1:8. The analysis was performed on the cohort 3 (Non-US Safety and Immunogenicity): Cohort 3 was to include the subjects enrolled at 1 center in Mexico. Only descriptive immunogenicity results were reported for this cohort. These subjects also contributed to the safety analysis.
    End point type
    Secondary
    End point timeframe
    One month after the primary vaccination course
    End point values
    		 Menhibrix Group ActHIB Group Menhibrix A Group Menhibrix B Group Menhibrix C Group
    Number of subjects analysed
    135
    46
    49
    42
    44
    Units: Subjects
        hSBA-MenC >=1:4 (N=134;46;48;42;44)
    133
    2
    47
    42
    44
        hSBA-MenC >=1:8 (N=134;46;48;42;44)
    133
    2
    47
    42
    44
        hSBA-MenY >=1:4 (N=135;45;49;42;44)
    134
    1
    48
    42
    44
        hSBA-MenY >=1:8 (N=135;45;49;42;44)
    134
    1
    48
    42
    44
    No statistical analyses for this end point

    Secondary: Number of subjects with hSBA-MenC and hSBA-MenY titers equal to or above the cut-off values

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    End point title
    		 Number of subjects with hSBA-MenC and hSBA-MenY titers equal to or above the cut-off values
    End point description
    hSBA-MenC/Y antibody cut-off values assessed were >=1:4 and >=1:8. The analysis was performed on the cohort 3 (Non-US Safety and Immunogenicity): Cohort 3 was to include the subjects enrolled at 1 center in Mexico. Only descriptive immunogenicity results were reported for this cohort. These subjects also contributed to the safety analysis.
    End point type
    Secondary
    End point timeframe
    Prior to the fourth dose vaccination and one month after fourth dose vaccination
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    40
    13
    Units: Subjects
        hSBA-MenC pre-dose 4 >=1:4 (N=39;13)
    39
    2
        hSBA-MenC pre-dose 4 >=1:8 (N=39;13)
    39
    2
        hSBA-MenC post-dose 4 >=1:4 (N=39;13)
    39
    1
        hSBA-MenC post-dose 4 >=1:8 (N=39;13)
    39
    1
        hSBA-MenY pre-dose 4 >=1:4 (N=39;13)
    39
    3
        hSBA-MenY pre-dose 4 >=1:8 (N=39;13)
    39
    3
        hSBA-MenY post-dose 4 >=1:4 (N=40;13)
    40
    7
        hSBA-MenY post-dose 4 >=1:8 (N=40;13)
    40
    7
    No statistical analyses for this end point

    Secondary: hSBA-MenC and hSBA-MenY antibody titers

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    End point title
    		 hSBA-MenC and hSBA-MenY antibody titers
    End point description
    Titres are expressed as Geometric Mean Titers (GMTs). The analysis was performed on the cohort 3 (Non-US Safety and Immunogenicity): Cohort 3 was to include the subjects enrolled at 1 center in Mexico. Only descriptive immunogenicity results were reported for this cohort. These subjects also contributed to the safety analysis.
    End point type
    Secondary
    End point timeframe
    One month after the primary vaccination course
    End point values
    		 Menhibrix Group ActHIB Group Menhibrix A Group Menhibrix B Group Menhibrix C Group
    Number of subjects analysed
    135
    46
    49
    42
    44
    Units: Titers
    geometric mean (confidence interval 95%)
        hSBA-MenC (N=134;46;48;42;44)
    3172.6 (2657.9 to 3786.8)
    2.4 (1.8 to 3.1)
    3055.8 (2096.8 to 4453.6)
    3370.7 (2545.4 to 4463.6)
    3119.3 (2418.9 to 4022.4)
        hSBA-MenY (N=135;45;49;42;44)
    837.2 (696.4 to 1006.3)
    2.2 (1.8 to 2.5)
    666.5 (464 to 957.3)
    916.7 (666.9 to 1260.1)
    989.6 (756.7 to 1294.2)
    No statistical analyses for this end point

    Secondary: hSBA-MenC and hSBA-MenY antibody titers

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    End point title
    		 hSBA-MenC and hSBA-MenY antibody titers
    End point description
    Titers are expressed as Geometric Mean Titers (GMTs) The analysis was performed on the cohort 3 (Non-US Safety and Immunogenicity): Cohort 3 was to include the subjects enrolled at 1 center in Mexico. Only descriptive immunogenicity results were reported for this cohort. These subjects also contributed to the safety analysis.
    End point type
    Secondary
    End point timeframe
    Prior to the fourth dose vaccination and one month after fourth dose vaccination
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    40
    13
    Units: Titers
    geometric mean (confidence interval 95%)
        hSBA-MenC pre-dose 4 (N=39;13)
    504.7 (366.2 to 695.5)
    3.6 (1.5 to 8.7)
        hSBA-MenC post-dose 4 (N=39;13)
    10132.9 (8008 to 12821.7)
    2.5 (1.6 to 3.8)
        hSBA-MenY pre-dose 4 (N=39;13)
    446.5 (328.3 to 607.3)
    5.3 (1.7 to 16.7)
        hSBA-MenY post-dose 4 (N=40;13)
    5775.8 (4488.9 to 7431.7)
    27.4 (5.8 to 129)
    No statistical analyses for this end point

    Secondary: Number of subjects with anti-PSC and anti-PSY antibody concentrations equal to or above the cut-off values

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    End point title
    		 Number of subjects with anti-PSC and anti-PSY antibody concentrations equal to or above the cut-off values
    End point description
    Anti-PSC and anti-PSY antibody cut-off values assessed were >=0.3 microgram per milliliter (µg/mL) and >=2.0 µg/mL. The analysis was performed on the cohort 3 (Non-US Safety and Immunogenicity): Cohort 3 was to include the subjects enrolled at 1 center in Mexico. Only descriptive immunogenicity results were reported for this cohort. These subjects also contributed to the safety analysis.
    End point type
    Secondary
    End point timeframe
    One month after the primary vaccination course
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    134
    46
    Units: Subjects
        Anti-PSC >=0.3 µg/mL (N=134;46)
    134
    2
        Anti-PSC >=2.0 µg/mL (N=134;46)
    134
    1
        Anti-PSY >=0.3 µg/mL (N=130;46)
    130
    1
        Anti-PSY >=2.0 µg/mL (N=130;46)
    130
    1
    No statistical analyses for this end point

    Secondary: Number of subjects with anti-PSC and anti-PSY antibody concentrations equal to or above the cut-off values

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    End point title
    		 Number of subjects with anti-PSC and anti-PSY antibody concentrations equal to or above the cut-off values
    End point description
    Anti-PSC and anti-PSY antibody cut-off values assessed were >=0.3 µg/mL and >=2.0 µg/mL. The analysis was performed on the cohort 3 (Non-US Safety and Immunogenicity): Cohort 3 was to include the subjects enrolled at 1 center in Mexico. Only descriptive immunogenicity results were reported for this cohort. These subjects also contributed to the safety analysis.
    End point type
    Secondary
    End point timeframe
    Prior to the fourth dose vaccination and one month after fourth dose vaccination
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    40
    13
    Units: Subjects
        Anti-PSC pre-dose 4 >=0.3 µg/mL (N=40;13)
    40
    0
        Anti-PSC pre-dose 4 >=2.0 µg/mL (N=40;13)
    22
    0
        Anti-PSC post-dose 4 >=0.3 µg/mL (N=39;13)
    39
    0
        Anti-PSC post-dose 4 >=2.0 µg/mL (N=39;13)
    39
    0
        Anti-PSY pre-dose 4 >=0.3 µg/mL (N=40;13)
    40
    0
        Anti-PSY pre-dose 4 >=2.0 µg/mL (N=40;13)
    36
    0
        Anti-PSY post-dose 4 >=0.3 µg/mL (N=40;13)
    40
    0
        Anti-PSY post-dose 4 >=2.0 µg/mL (N=40;13)
    40
    0
    No statistical analyses for this end point

    Secondary: Anti-PSC and anti-PSY antibodies concentrations

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    End point title
    		 Anti-PSC and anti-PSY antibodies concentrations
    End point description
    Concentrations are given as Geometric Mean Concentrations (GMCs) and are expressed in microgram per milliliter (µg/mL). The analysis was performed on the cohort 3 (Non-US Safety and Immunogenicity): Cohort 3 was to include the subjects enrolled at 1 center in Mexico. Only descriptive immunogenicity results were reported for this cohort. These subjects also contributed to the safety analysis.
    End point type
    Secondary
    End point timeframe
    One month after the primary vaccination course
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    134
    46
    Units: µg/mL
    geometric mean (confidence interval 95%)
        Anti-PSC (N=134;46)
    13.4 (12.1 to 15)
    0.2 (0.1 to 0.2)
        Anti-PSY (N=130;46)
    36.7 (32.2 to 41.8)
    0.2 (0.1 to 0.2)
    No statistical analyses for this end point

    Secondary: Anti-PSC and anti-PSY antibody concentrations

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    End point title
    		 Anti-PSC and anti-PSY antibody concentrations
    End point description
    Concentrations are given as Geometric Mean Concentrations (GMCs) and are expressed in microgram per millilitre (µg/mL). The analysis was performed on the cohort 3 (Non-US Safety and Immunogenicity): Cohort 3 was to include the subjects enrolled at 1 center in Mexico. Only descriptive immunogenicity results were reported for this cohort. These subjects also contributed to the safety analysis.
    End point type
    Secondary
    End point timeframe
    Prior to the fourth dose vaccination and one month after fourth dose vaccination
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    40
    13
    Units: µg/mL
    geometric mean (confidence interval 95%)
        Anti-PSC pre-dose 4 (N=40;13)
    2.2 (1.72 to 2.83)
    0.15 (0.15 to 0.15)
        Anti-PSC post-dose 4 (N=39;13)
    15.63 (13.3 to 18.37)
    0.15 (0.15 to 0.15)
        Anti-PSY pre-dose 4 (N=40;13)
    5.7 (4.18 to 7.78)
    0.15 (0.15 to 0.15)
        Anti-PSY post-dose 4 (N=40;13)
    64.66 (52.35 to 79.86)
    0.15 (0.15 to 0.15)
    No statistical analyses for this end point

    Secondary: Number of subjects with anti-PRP antibody concentrations equal to or above the cut-off value

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    End point title
    		 Number of subjects with anti-PRP antibody concentrations equal to or above the cut-off value
    End point description
    Anti-PRP antibody cut-off values assessed were >=0.15 µg/mL. This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis.
    End point type
    Secondary
    End point timeframe
    One month after the primary vaccination course
    End point values
    		 Menhibrix Group ActHIB Group Menhibrix A Group Menhibrix B Group Menhibrix C Group
    Number of subjects analysed
    518
    171
    162
    180
    176
    Units: Subjects
        Anti-PRP post-primary >=0.15 µg/mL
    518
    168
    162
    180
    176
    No statistical analyses for this end point

    Secondary: Anti-PRP antibody concentrations

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    End point title
    		 Anti-PRP antibody concentrations
    End point description
    Concentrations are given as Geometric Mean Concentrations (GMCs) and are expressed in microgram per millilitre (µg/mL). This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis.
    End point type
    Secondary
    End point timeframe
    One month after the primary vaccination course and prior to the fourth dose vaccination
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    469
    160
    Units: µg/mL
    geometric mean (confidence interval 95%)
        Anti-PRP post-primary (N=469;160)
    10.802 (9.767 to 11.947)
    6.086 (4.897 to 7.564)
        Anti-PRP pre-dose 4 (N=441;147)
    1.615 (1.439 to 1.812)
    0.832 (0.664 to 1.042)
    No statistical analyses for this end point

    Secondary: Number of subjects with hSBA-MenC and hSBA-MenY antibody titers equal to or above the cut-off values

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    End point title
    		 Number of subjects with hSBA-MenC and hSBA-MenY antibody titers equal to or above the cut-off values
    End point description
    hSBA-MenC and hSBA-MenY antibody cut-off values assessed were >=1:4 and >=1:8. This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis.
    End point type
    Secondary
    End point timeframe
    One month after the primary vaccination course
    End point values
    		 Menhibrix Group ActHIB Group Menhibrix A Group Menhibrix B Group Menhibrix C Group
    Number of subjects analysed
    491
    164
    158
    168
    165
    Units: Subjects
        hSBA-MenC >=1:4 (N=491;164;158;168;165)
    485
    11
    156
    167
    162
        hSBA-MenC >=1:8 (N=491;164;158;168;165)
    485
    11
    156
    167
    162
        hSBA-MenY >=1:4 (N=481;162;150;168;163)
    463
    3
    141
    165
    157
        hSBA-MenY >=1:8 (N=481;162;150;168;163)
    461
    3
    140
    165
    156
    No statistical analyses for this end point

    Secondary: Number of subjects with anti-PSC and anti-PSY antibody concentrations equal to or above the cut-off values

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    End point title
    		 Number of subjects with anti-PSC and anti-PSY antibody concentrations equal to or above the cut-off values
    End point description
    Anti-PSC and anti-PSY antibody cut-off values assessed were >=0.3 µg/mL and >=2.0 µg/mL. This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis.
    End point type
    Secondary
    End point timeframe
    Prior to the fourth dose vaccination and 42 days after fourth dose vaccination
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    334
    109
    Units: Subjects
        Anti-PSC pre-dose 4 >=0.3 µg/mL (N=327;99)
    300
    3
        Anti-PSC pre-dose 4 >=2.0 µg/mL (N=327;99)
    73
    0
        Anti-PSC post-dose 4 >=0.3 µg/mL (N=316;106)
    313
    9
        Anti-PSC post-dose 4 >=2.0 µg/mL (N=316;106)
    262
    6
        Anti-PSY pre-dose 4 >=0.3 µg/mL (N=325;93)
    320
    1
        Anti-PSY pre-dose 4 >=2.0 µg/mL (N=325;93)
    235
    0
        Anti-PSY post-dose 4 >=0.3 µg/mL (N=334;109)
    332
    6
        Anti-PSY post-dose 4 >=2.0 µg/mL (N=334;109)
    325
    4
    No statistical analyses for this end point

    Secondary: Anti-PSC and anti-PSY antibody concentrations

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    End point title
    		 Anti-PSC and anti-PSY antibody concentrations
    End point description
    Concentrations are given as Geometric Mean Concentrations (GMCs) and are expressed in microgram per millilitre (µg/mL). This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis.
    End point type
    Secondary
    End point timeframe
    Prior to the fourth dose vaccination and 42 days after fourth dose vaccination
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    334
    109
    Units: µg/mL
    geometric mean (confidence interval 95%)
        Anti-PSC pre-dose 4 (N=327;99)
    1.04 (0.94 to 1.16)
    0.16 (0.15 to 0.17)
        Anti-PSC post-dose 4 (N=316;106)
    4.81 (4.33 to 5.34)
    0.19 (0.16 to 0.23)
        Anti-PSY pre-dose 4 (N=325;93)
    3.15 (2.83 to 3.5)
    0.15 (0.15 to 0.15)
        Anti-PSY post-dose 4 (N=334;109)
    18.26 (16.41 to 20.31)
    0.18 (0.15 to 0.21)
    No statistical analyses for this end point

    Secondary: Number of subjects with anti-PRP antibody concentrations equal to or above 0.15 microgram per milliliter (µg/mL)

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    End point title
    		 Number of subjects with anti-PRP antibody concentrations equal to or above 0.15 microgram per milliliter (µg/mL)
    End point description
    This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis.
    End point type
    Secondary
    End point timeframe
    Prior to the fourth dose vaccination and 42 days after fourth vaccination
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    361
    126
    Units: Subjects
        Anti-PRP [post-dose 4] (N=361;126)
    361
    126
        Anti-PRP [pre-dose 4] (N=341;112)
    329
    98
    No statistical analyses for this end point

    Secondary: Anti-PRP antibody concentrations

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    End point title
    		 Anti-PRP antibody concentrations
    End point description
    Concentrations are given as Geometric Mean Concentrations (GMCs) and are expressed in microgram per millilitre (µg/mL) This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis.
    End point type
    Secondary
    End point timeframe
    Prior to the fourth vaccination and 42 days after fourth vaccination
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    361
    126
    Units: µg/mL
    geometric mean (confidence interval 95%)
        Anti-PRP [post-dose 4] (N=361;126)
    34.851 (30.664 to 39.61)
    20.2 (16.373 to 24.92)
        Anti-PRP [pre-dose 4] (N=341;112)
    1.617 (1.42 to 1.842)
    0.759 (0.589 to 0.978)
    No statistical analyses for this end point

    Secondary: Number of subjects with hSBA-MenC and hSBA-MenY antibody concentrations equal to or above 1:4

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    End point title
    		 Number of subjects with hSBA-MenC and hSBA-MenY antibody concentrations equal to or above 1:4
    End point description
    This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis.
    End point type
    Secondary
    End point timeframe
    Prior to the fourth dose vaccination and 42 days after fourth vaccination
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    342
    120
    Units: Subjects
        hSBA-MenC [post-dose 4] (N=331;119)
    326
    26
        hSBA-MenY [post-dose 4](N=342;120)
    338
    87
        hSBA-MenC [pre-dose 4] (N=329;104)
    318
    12
        hSBA-MenY [pre-dose 4](N=329;103)
    309
    6
    No statistical analyses for this end point

    Secondary: Number of subjects with anti-measles antibody concentrations equal to or above 200 milli-international units per millilitre (mIU/mL)

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    End point title
    		 Number of subjects with anti-measles antibody concentrations equal to or above 200 milli-international units per millilitre (mIU/mL)
    End point description
    The analysis was performed on initially seronegative subjects. Seronegative subjects are subjects with anti-measles antibody concentrations below 150 mIU/mL. This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis.
    End point type
    Secondary
    End point timeframe
    42 days after the fourth vaccination
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    852
    286
    Units: Subjects
        Anti-measles
    812
    273
    No statistical analyses for this end point

    Secondary: Anti-measles antibody concentrations

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    End point title
    		 Anti-measles antibody concentrations
    End point description
    Concentrations are given as Geometric Mean Concentrations (GMCs) and are expressed in milli-international units per milliliter (mIU/mL). The analysis was performed on initially seronegative subjects. Seronegative subjects are subjects with anti-measles antibody concentrations below 150 mIU/mL. This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis.
    End point type
    Secondary
    End point timeframe
    42 days after fourth vaccination
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    852
    286
    Units: mIU/mL
    geometric mean (confidence interval 95%)
        Anti-measles
    1990 (1852.2 to 2138)
    1989.5 (1765.4 to 2242.2)
    No statistical analyses for this end point

    Secondary: Number of subjects with anti-mumps titer equal to or above the cut-off values

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    End point title
    		 Number of subjects with anti-mumps titer equal to or above the cut-off values
    End point description
    Anti-mumps antibody cut-off values assessed were >=28 estimated dose 50 (ED50) and >=51 ED50. The analysis was performed on initially seronegative subjects. Seronegative subjects are subjects with anti-mumps antibody titers below 24 ED50. This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis.
    End point type
    Secondary
    End point timeframe
    42 days after fourth vaccination
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    536
    176
    Units: Subjects
        Anti-mumps >=28 ED50
    532
    176
        Anti-mumps >=51 ED50
    490
    160
    No statistical analyses for this end point

    Secondary: Anti-mumps antibody titers

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    End point title
    		 Anti-mumps antibody titers
    End point description
    Titers are expressed as Geometric Mean Titers (GMTs). The analysis was performed on initially seronegative subjects. Seronegative subjects are subjects with anti-measles antibody titers below 24 ED50. This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis.
    End point type
    Secondary
    End point timeframe
    42 days after fourth vaccination
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    536
    176
    Units: Titers
    geometric mean (confidence interval 95%)
        Anti-mumps
    123.9 (116.9 to 131.3)
    114.3 (103.7 to 126)
    No statistical analyses for this end point

    Secondary: Number of subjects with anti-rubella antibody concentrations equal to or above 4 international units per millilitre (IU/mL)

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    End point title
    		 Number of subjects with anti-rubella antibody concentrations equal to or above 4 international units per millilitre (IU/mL)
    End point description
    The analysis was performed on initially seronegative subjects. Seronegative subjects are subjects with anti-rubella antibody concentrations below 4 IU/mL. This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis.
    End point type
    Secondary
    End point timeframe
    42 days after fourth vaccination
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    850
    285
    Units: Subjects
        Anti-rubella
    850
    285
    No statistical analyses for this end point

    Secondary: Anti-rubella antibody concentrations

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    End point title
    		 Anti-rubella antibody concentrations
    End point description
    Concentrations are given as Geometric Mean Concentrations (GMCs) and are expressed in international units per milliliter (IU/mL). The analysis was performed on initially seronegative subjects. Seronegative subjects are subjects with anti-rubella antibody concentrations below 4 IU/mL. This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis.
    End point type
    Secondary
    End point timeframe
    42 days after fourth vaccination
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    850
    285
    Units: IU/mL
    geometric mean (confidence interval 95%)
        Anti-rubella
    81.4 (77.5 to 85.4)
    74.9 (68.9 to 81.4)
    No statistical analyses for this end point

    Secondary: Number of subjects with anti-varicella titer equal to or above 1:40

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    End point title
    		 Number of subjects with anti-varicella titer equal to or above 1:40
    End point description
    The analysis was performed on initially seronegative subjects. Seronegative subjects are subjects with anti-varicella antibody concentrations below 1:5 This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis.
    End point type
    Secondary
    End point timeframe
    42 days after fourth vaccination
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    723
    223
    Units: Subjects
        Anti-varicella
    722
    223
    No statistical analyses for this end point

    Secondary: Anti-varicella antibody titers

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    End point title
    		 Anti-varicella antibody titers
    End point description
    Titers are expressed as Geometric Mean Titers (GMTs) The analysis was performed on initially seronegative subjects. Seronegative subjects are subjects with anti-varicella antibody titers below 1:5 This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis.
    End point type
    Secondary
    End point timeframe
    42 days after fourth vaccination
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    723
    223
    Units: Titers
    geometric mean (confidence interval 95%)
        Anti-varicella
    407.1 (389.4 to 425.5)
    394.1 (364.6 to 426)
    No statistical analyses for this end point

    Secondary: Number of subjects with anti-H1N1, anti-H3N2 and anti-influenza-B (anti B) antibody titers equal to or above 1:40

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    End point title
    		 Number of subjects with anti-H1N1, anti-H3N2 and anti-influenza-B (anti B) antibody titers equal to or above 1:40
    End point description
    Anti-H1N1, anti-H3N2 and anti-influenza-B (anti-B) antibody were measured by hemagglutination inhibition assay (HIA), in subjects who received 2 doses of influenza vaccine within the same influenza season of which at least one dose is concomitant with the study vaccine. For the purposes of this study, concomitant administration of influenza vaccine was defined as administration within 28 days before to 7 days after administration of study vaccines. This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based.
    End point type
    Secondary
    End point timeframe
    Prior to the fourth dose vaccination and one month after the fourth dose vaccination
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    5
    4
    Units: Subjects
        Anti-H1N1 pre-dose 4 (N=5;3)
    0
    0
        Anti-H1N1 post-dose 4 (N=4;4)
    2
    1
        Anti-H3N2 pre-dose 4 (N=5;3)
    0
    0
        Anti-H3N2 post-dose 4 (N=4;4)
    3
    1
        Anti-B pre-dose 4 (N=5;3)
    0
    0
        Anti-B post-dose 4 (N=4;4)
    1
    1
    No statistical analyses for this end point

    Secondary: Number of subjects reporting fever above 39.5 degrees Celsius/103.1 degrees Fahrenheit

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    End point title
    		 Number of subjects reporting fever above 39.5 degrees Celsius/103.1 degrees Fahrenheit
    End point description
    Fever is defined as temperature (rectal or axillary/tympanic) above 39.5 degrees Celsius (°C) or 103.1 degrees Fahrenheit (°F).
    End point type
    Secondary
    End point timeframe
    In the 4-day (Day 0-3) follow-up period after primary vaccination course
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    3089
    1015
    Units: Subjects
        Fever >39.5°C
    46
    16
    No statistical analyses for this end point

    Secondary: Number of subjects reporting fever above 39.5 degrees Celsius/103.1 degrees Fahrenheit

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    End point title
    		 Number of subjects reporting fever above 39.5 degrees Celsius/103.1 degrees Fahrenheit
    End point description
    Fever is defined as temperature (rectal or axillary/tympanic) above 39.5 degrees Celsius (°C) or 103.1 degrees Fahrenheit (°F).
    End point type
    Secondary
    End point timeframe
    In the 4-day (Day0-3) follow-up period after the fourth dose
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    2527
    831
    Units: Subjects
        Fever >39.5°C
    18
    5
    No statistical analyses for this end point

    Secondary: Number of subjects reporting solicited local and general symptoms

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    End point title
    		 Number of subjects reporting solicited local and general symptoms
    End point description
    Solicited local symptoms assessed were pain, redness and swelling. Solicited general symptoms assessed were fever, irritability/fussiness, drowsiness and loss of appetite. Fever is defined as temperature (rectal or axillary/tympanic) equal to or above 38.0°C.
    End point type
    Secondary
    End point timeframe
    Within the 4 days (Day 0-3) following each dose of the primary vaccination course
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    3089
    1016
    Units: Subjects
        Pain Dose 1 (N=3056;1008)
    1849
    672
        Pain Dose 2 (N=2903;954)
    1679
    596
        Pain Dose 3 (N=2740;904)
    1454
    522
        Pain Across Doses (N=3088;1016)
    2419
    819
        Redness Dose 1 (N=3056;1008)
    1152
    401
        Redness Dose 2 (N=2903;954)
    1455
    483
        Redness Dose 3 (N=2740;904)
    1409
    495
        Redness Across Doses (N=3088;1016)
    2052
    691
        Swelling Dose 1 (N=3056;1008)
    893
    281
        Swelling Dose 2 (N=2903;954)
    1091
    350
        Swelling Dose 3 (N=2740;904)
    1110
    381
        Swelling Across Doses (N=3088;1016)
    1707
    568
        Drowsiness Dose 1 (N=3055;1008)
    1864
    655
        Drowsiness Dose 2 (N=2900;952)
    1588
    552
        Drowsiness Dose 3 (N=2736;905)
    1260
    444
        Drowsiness Across doses (N=3088;1015)
    2418
    804
        Temperature Dose 1 (N=3056;1008)
    688
    228
        Temperature Dose 2 (N=2900;951)
    803
    276
        Temperature Dose 3 (N=2736;905)
    609
    206
        Temperature Across doses (N=3089;1015)
    1434
    463
        Irritability Dose 1 (N=3055;1008)
    2156
    782
        Irritability Dose 2 (N=2900;952)
    2074
    708
        Irritability Dose 3 (N=2736;905)
    1771
    600
        Irritability Across doses (N=3088;1015)
    2740
    926
        Loss of appetite Dose 1 (N=3055;1008)
    1024
    375
        Loss of appetite Dose 2 (N=2900;952)
    921
    317
        Loss of appetite Dose 3 (N=2736;905)
    828
    285
        Loss of appetite Across doses (N=3088;1015)
    1764
    609
    No statistical analyses for this end point

    Secondary: Number of subjects reporting solicited local and general symptoms

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    End point title
    		 Number of subjects reporting solicited local and general symptoms
    End point description
    Solicited local symptoms assessed were pain, redness, swelling and an increase in limb circumference. Solicited general symptoms assessed were fever, irritability/fussiness, drowsiness and lost of appetite. Fever is defined as temperature (rectal or axillary/tympanic) equal to or above 38.0°C
    End point type
    Secondary
    End point timeframe
    Within the 4 days (Day 0-3) post-vaccination period following the fourth dose
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    2769
    923
    Units: Subjects
        Pain (N=2528;832)
    1319
    494
        Redness (N=2528;833)
    1213
    463
        Swelling (N=2526;832)
    936
    334
        Increase in limb circumference (N=2769;923)
    1489
    503
        Drowsiness (N=2526;830)
    1088
    381
        Fever (N=2527;831)
    341
    134
        Irritability (N=2526;830)
    1482
    534
        Loss of appetite (N=2526;830)
    825
    287
    No statistical analyses for this end point

    Secondary: Number of subjects reporting unsolicited adverse events (AEs)

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    End point title
    		 Number of subjects reporting unsolicited adverse events (AEs)
    End point description
    Unsolicited AE covers any AE reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms.
    End point type
    Secondary
    End point timeframe
    Within 31 days (Day 0-30) following the primary vaccination course
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    3136
    1044
    Units: Subjects
        AEs
    1820
    602
    No statistical analyses for this end point

    Secondary: Number of subjects reporting unsolicited adverse events (AEs)

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    End point title
    		 Number of subjects reporting unsolicited adverse events (AEs)
    End point description
    Unsolicited AE covers any AE reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms.
    End point type
    Secondary
    End point timeframe
    Within 31 days (Day 0-30) following the fourth dose
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    2769
    923
    Units: Subjects
        AEs
    1010
    334
    No statistical analyses for this end point

    Secondary: Number of subjects reporting increased circumferential swelling at the injection limb(s)

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    End point title
    		 Number of subjects reporting increased circumferential swelling at the injection limb(s)
    End point description
    Increased circumferential swelling defined as either swelling with a diameter of >50 mm or a >50 mm increase in the circumference of the mid-limb when compared to the baseline (pre-vaccination) measurement, or any diffuse swelling that interferes with or prevents everyday activities (for example, active playing, eating, sleeping).
    End point type
    Secondary
    End point timeframe
    Within 4 days (Day 0 to Day 3) after fourth dose vaccination
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    2769
    923
    Units: Subjects
        Increase in circumference
    1489
    503
    No statistical analyses for this end point

    Secondary: Number of subjects reporting general symptoms specific to measles, mumps, rubella and varicella vaccination

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    End point title
    		 Number of subjects reporting general symptoms specific to measles, mumps, rubella and varicella vaccination
    End point description
    Symptoms assessed were fever, rash/exanthem, parotid/salivary gland swelling, and any suspected signs of meningism including febrile convulsions. Fever is defined as temperature (rectal or axillary/tympanic) equal to or above 38.0°C.
    End point type
    Secondary
    End point timeframe
    Within 43 days (Day 0 through Day 42) after vaccination
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    545
    175
    Units: Subjects
        Meningismus (N=541;173)
    0
    0
        Parotiditis (N=541;173)
    0
    0
        Rash (N=544;175)
    59
    19
        Fever (N=545;173)
    211
    70
    No statistical analyses for this end point

    Secondary: Number of subjects reporting Serious Adverse Events (SAEs)

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    End point title
    		 Number of subjects reporting Serious Adverse Events (SAEs)
    End point description
    SAEs assessed include medical occurrences that results in death, are life threatening, require hospitalization or prolongation of hospitalization, results in disability/incapacity or are a congenital anomaly/birth defect in the offspring of a study subjects.
    End point type
    Secondary
    End point timeframe
    From Dose 0 through 6 months after the last primary dose or untill administration of the fourth dose
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    3136
    1044
    Units: Subjects
        SAEs
    126
    50
    No statistical analyses for this end point

    Secondary: Number of subjects reporting Serious Adverse Events (SAEs)

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    End point title
    		 Number of subjects reporting Serious Adverse Events (SAEs)
    End point description
    SAEs assessed include medical occurrences that results in death, are life threatening, require hospitalization or prolongation of hospitalization, results in disability/incapacity or are a congenital anomaly/birth defect in the offspring of a study subjects.
    End point type
    Secondary
    End point timeframe
    From the fourth dose through the end of the 6-month safety follow-up
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    2769
    923
    Units: Subjects
        SAEs
    47
    18
    No statistical analyses for this end point

    Secondary: Number of subjects reporting new onset of chronic illness(es) (NOCIs)

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    End point title
    		 Number of subjects reporting new onset of chronic illness(es) (NOCIs)
    End point description
    NOCIs include autoimmune disorders, asthma, type I diabetes, allergies.
    End point type
    Secondary
    End point timeframe
    From Dose 0 through 6 months after the last primary dose or until administration of the fourth dose
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    3136
    1044
    Units: Subjects
        Any NOCIs
    163
    52
    No statistical analyses for this end point

    Secondary: Number of subjects reporting new onset of chronic illness(es) (NOCIs)

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    End point title
    		 Number of subjects reporting new onset of chronic illness(es) (NOCIs)
    End point description
    NOCIs include autoimmune disorders, asthma, type I diabetes, allergies.
    End point type
    Secondary
    End point timeframe
    From the fourth dose through the end of the 6-month safety follow-up
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    2769
    923
    Units: Subjects
        Any NOCIs
    85
    33
    No statistical analyses for this end point

    Secondary: Number of subjects reporting rash

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    End point title
    		 Number of subjects reporting rash
    End point description
    Rash assessed was hives, idiopathic thrombocytopenic purpura, petechiae.
    End point type
    Secondary
    End point timeframe
    From Dose 0 through 6 months after the last primary dose or until administration of the fourth dose
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    3136
    1044
    Units: Subjects
        Any rash(es)
    470
    154
    No statistical analyses for this end point

    Secondary: Number of subjects reporting rash

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    End point title
    		 Number of subjects reporting rash
    End point description
    Rash assessed was hives, idiopathic thrombocytopenic purpura, petechiae.
    End point type
    Secondary
    End point timeframe
    From the fourth dose through the end of the 6-month safety follow-up
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    2769
    923
    Units: Subjects
        Any rash(es)
    265
    94
    No statistical analyses for this end point

    Secondary: Number of subjects reporting adverse events resulting in emergency room (ER) visits

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    End point title
    		 Number of subjects reporting adverse events resulting in emergency room (ER) visits
    End point description
    Emergency room (ER) visits were not related to well-child care, vaccination, injury or common acute illness such as upper respiratory tract infections; otitis media, pharyngitis, gastroenteritis.
    End point type
    Secondary
    End point timeframe
    From Dose 0 through 6 months after the last primary dose or until administration of the fourth dose
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    3136
    1044
    Units: Subjects
        Any AEs
    217
    72
    No statistical analyses for this end point

    Secondary: Number of subjects reporting adverse events resulting in physicians (MD) office visits.

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    End point title
    		 Number of subjects reporting adverse events resulting in physicians (MD) office visits.
    End point description
    Physicians (MD) office visits were not related to well-child care, vaccination, injury or common acute illness such as upper respiratory tract infections; otitis media, pharyngitis, gastroenteritis.
    End point type
    Secondary
    End point timeframe
    From Dose 0 through 6 months after the last primary dose or until administration of the fourth dose
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    3136
    1044
    Units: Subjects
        Any AEs
    1336
    433
    No statistical analyses for this end point

    Secondary: Number of subjects reporting adverse events resulting in emergency room (ER) visits

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    End point title
    		 Number of subjects reporting adverse events resulting in emergency room (ER) visits
    End point description
    Emergency room (ER) visits were not related to well-child care, vaccination, injury or common acute illness such as upper respiratory tract infections; otitis media, pharyngitis, gastroenteritis.
    End point type
    Secondary
    End point timeframe
    From the fourth dose through the end of the 6-month safety follow-up
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    2769
    923
    Units: Subjects
        Any AEs
    137
    54
    No statistical analyses for this end point

    Secondary: Number of subjects reporting adverse events resulting in physicians (MD) office visits

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    End point title
    		 Number of subjects reporting adverse events resulting in physicians (MD) office visits
    End point description
    Physicians (MD) office visits were not related to well-child care, vaccination, injury or common acute illness such as upper respiratory tract infections; otitis media, pharyngitis, gastroenteritis.
    End point type
    Secondary
    End point timeframe
    From the fourth dose through the end of the 6-month safety follow-up
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    2769
    923
    Units: Subjects
        Any AEs
    668
    205
    No statistical analyses for this end point

    Secondary: Number of subjects with anti-PRP antibody concentration equal to or above 1.0 microgram per milliliter (µg/mL)

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    End point title
    		 Number of subjects with anti-PRP antibody concentration equal to or above 1.0 microgram per milliliter (µg/mL)
    End point description
    This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis.
    End point type
    Secondary
    End point timeframe
    Prior to the fourth dose vaccination
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    341
    112
    Units: Subjects
        Anti-PRP [pre-dose 4] (N=341;112)
    227
    52
    No statistical analyses for this end point

    Secondary: Number of subjects with hSBA-MenC and hSBA-MenY antibody titer equal to or above 1:8

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    End point title
    		 Number of subjects with hSBA-MenC and hSBA-MenY antibody titer equal to or above 1:8
    End point description
    This analysis occurred on the cohort 1: Cohort 1 was to include subjects in the US on which all immunogenicity analyses were to be based. These subjects also contributed to the safety analysis.
    End point type
    Secondary
    End point timeframe
    Prior to the fourth dose vaccination
    End point values
    		 Menhibrix Group ActHIB Group
    Number of subjects analysed
    329
    104
    Units: Subjects
        hSBA-MenC [pre-dose 4] (N=329;104)
    318
    12
        hSBA-MenY [pre-dose 4] (N=329;103)
    306
    6
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    SAEs: From Day 0 after Dose 1 through the day preceding the fourth dose; From the fourth dose phase through the end of the safety follow-up; AEs: within the 31-day (Day 0-30) post vaccination period; Solicited AEs: During the 4-day post vaccination period
    Adverse event reporting additional description
    Results are presented for the primary phase and the fourth dose phase.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    11.1
    Reporting groups
    Reporting group title
    Menhibrix Group
    Reporting group description
    		 Subjects were primed with 3 doses of Menhibrix vaccine Lot A, B or C co-administered with Pediarix and boosted with 1 dose of Menhibrix vaccine, with co-administration of M-M-R II and Varivax. Subjects received vaccination at approximately 2, 4, 6 months and the fourth dose at 12-15 months of age. Menhibrix and Pediarix vaccines were administered intramuscularly in the right or left upper thigh, respectively. M-M-R II and Varivax vaccines were administered subcutaneously respectively in the upper left arm and the upper right arm.

    Reporting group title
    ActHIB Group
    Reporting group description
    		 Subjects were primed with 3 doses of ActHIB co-administered with Pediarix and boosted with 1 dose of PedvaxHIB, with co-administration of M-M-R II and Varivax. Subjects received vaccination at approximately 2, 4, 6 months and the fourth dose at 12-15 months of age. ActHIB, PedvaxHIB vaccines were administered intramuscularly in the right upper thigh and Pediarix vaccine in the left upper thigh. M-M-R II and Varivax vaccines were administered subcutaneously respectively in the upper left arm and the upper right arm.

    Serious adverse events
    		 Menhibrix Group ActHIB Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    126 / 3136 (4.02%)
    50 / 1044 (4.79%)
         number of deaths (all causes)
    4
    1
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Haemangioma
         subjects affected / exposed
    2 / 3136 (0.06%)
    0 / 1044 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuroblastoma
         subjects affected / exposed
    1 / 3136 (0.03%)
    0 / 1044 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 3136 (0.03%)
    0 / 1044 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    5 / 3136 (0.16%)
    1 / 1044 (0.10%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Irritability
         subjects affected / exposed
    1 / 3136 (0.03%)
    0 / 1044 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden infant death syndrome
         subjects affected / exposed
    1 / 3136 (0.03%)
    0 / 1044 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Immune system disorders
    Hypersensitivity (primary)
         subjects affected / exposed
    1 / 3136 (0.03%)
    0 / 1044 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity (fourth dose)
         subjects affected / exposed [1]
    1 / 2769 (0.04%)
    0 / 923 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory distress (primary)
         subjects affected / exposed
    5 / 3136 (0.16%)
    0 / 1044 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma (primary)
         subjects affected / exposed
    3 / 3136 (0.10%)
    1 / 1044 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial hyperreactivity (primary)
         subjects affected / exposed
    3 / 3136 (0.10%)
    1 / 1044 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    3 / 3136 (0.10%)
    1 / 1044 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Apparent life threatening event
         subjects affected / exposed
    2 / 3136 (0.06%)
    0 / 1044 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 3136 (0.00%)
    1 / 1044 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Apnoea
         subjects affected / exposed
    1 / 3136 (0.03%)
    0 / 1044 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 3136 (0.03%)
    0 / 1044 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory disorder
         subjects affected / exposed
    1 / 3136 (0.03%)
    0 / 1044 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stridor
         subjects affected / exposed
    1 / 3136 (0.03%)
    0 / 1044 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wheezing (primary)
         subjects affected / exposed
    1 / 3136 (0.03%)
    0 / 1044 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma (fourth dose)
         subjects affected / exposed [2]
    4 / 2769 (0.14%)
    1 / 923 (0.11%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial hyperreactivity (fourth dose)
         subjects affected / exposed [3]
    1 / 2769 (0.04%)
    1 / 923 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress (fourth dose)
         subjects affected / exposed [4]
    1 / 2769 (0.04%)
    1 / 923 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wheezing (fourth dose)
         subjects affected / exposed [5]
    1 / 2769 (0.04%)
    0 / 923 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Aspiration bronchial
         subjects affected / exposed
    0 / 3136 (0.00%)
    1 / 1044 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Injury, poisoning and procedural complications
    Respiratory syncytial virus bronchiolitis
         subjects affected / exposed
    8 / 3136 (0.26%)
    2 / 1044 (0.19%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Child maltreatment syndrome
         subjects affected / exposed
    1 / 3136 (0.03%)
    0 / 1044 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Foreign body trauma
         subjects affected / exposed
    1 / 3136 (0.03%)
    0 / 1044 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury (primary)
         subjects affected / exposed
    1 / 3136 (0.03%)
    0 / 1044 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury (fourth dose)
         subjects affected / exposed [6]
    1 / 2769 (0.04%)
    2 / 923 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Accidental drug intake by child
         subjects affected / exposed [7]
    0 / 2769 (0.00%)
    1 / 923 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Accidental exposure
         subjects affected / exposed [8]
    1 / 2769 (0.04%)
    0 / 923 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Burns first degree
         subjects affected / exposed [9]
    1 / 2769 (0.04%)
    0 / 923 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Burns second degree
         subjects affected / exposed [10]
    1 / 2769 (0.04%)
    0 / 923 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple injuries
         subjects affected / exposed [11]
    1 / 2769 (0.04%)
    0 / 923 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Seroma
         subjects affected / exposed [12]
    1 / 2769 (0.04%)
    0 / 923 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin laceration
         subjects affected / exposed [13]
    1 / 2769 (0.04%)
    0 / 923 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thermal burn
         subjects affected / exposed [14]
    1 / 2769 (0.04%)
    0 / 923 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Coarctation of the aorta
         subjects affected / exposed
    1 / 3136 (0.03%)
    0 / 1044 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tuberous sclerosis
         subjects affected / exposed
    1 / 3136 (0.03%)
    0 / 1044 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular septal defect (primary)
         subjects affected / exposed
    1 / 3136 (0.03%)
    0 / 1044 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular septal defect (fourth dose)
         subjects affected / exposed [15]
    0 / 2769 (0.00%)
    1 / 923 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Febrile convulsion (primary)
         subjects affected / exposed
    2 / 3136 (0.06%)
    2 / 1044 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Convulsion (primary)
         subjects affected / exposed
    2 / 3136 (0.06%)
    1 / 1044 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebellar ataxia
         subjects affected / exposed
    1 / 3136 (0.03%)
    0 / 1044 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotonia
         subjects affected / exposed
    1 / 3136 (0.03%)
    0 / 1044 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infantile spasms
         subjects affected / exposed
    1 / 3136 (0.03%)
    0 / 1044 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Convulsion (fourth dose)
         subjects affected / exposed [16]
    2 / 2769 (0.07%)
    1 / 923 (0.11%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile convulsion (fourth dose)
         subjects affected / exposed [17]
    1 / 2769 (0.04%)
    0 / 923 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Lymphoid tissue hyperplasia
         subjects affected / exposed
    1 / 3136 (0.03%)
    0 / 1044 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Idiopathic thrombocytopenic purpura
         subjects affected / exposed [18]
    1 / 2769 (0.04%)
    0 / 923 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenitis
         subjects affected / exposed [19]
    0 / 2769 (0.00%)
    1 / 923 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed [20]
    1 / 2769 (0.04%)
    0 / 923 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed [21]
    1 / 2769 (0.04%)
    0 / 923 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    0 / 3136 (0.00%)
    1 / 1044 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dacryostenosis acquired
         subjects affected / exposed
    1 / 3136 (0.03%)
    0 / 1044 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Intussusception
         subjects affected / exposed
    4 / 3136 (0.13%)
    2 / 1044 (0.19%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting (primary)
         subjects affected / exposed
    2 / 3136 (0.06%)
    2 / 1044 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain (primary)
         subjects affected / exposed
    1 / 3136 (0.03%)
    0 / 1044 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 3136 (0.03%)
    0 / 1044 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 3136 (0.00%)
    1 / 1044 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hiatus hernia
         subjects affected / exposed
    0 / 3136 (0.00%)
    1 / 1044 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 3136 (0.00%)
    1 / 1044 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain (fourth dose)
         subjects affected / exposed [22]
    1 / 2769 (0.04%)
    0 / 923 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting (fourth dose)
         subjects affected / exposed [23]
    1 / 2769 (0.04%)
    0 / 923 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Erythema multiforme
         subjects affected / exposed
    1 / 3136 (0.03%)
    0 / 1044 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash papular
         subjects affected / exposed [24]
    1 / 2769 (0.04%)
    0 / 923 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed [25]
    1 / 2769 (0.04%)
    0 / 923 (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
    Gastroenteritis (primary)
         subjects affected / exposed
    19 / 3136 (0.61%)
    7 / 1044 (0.67%)
         occurrences causally related to treatment / all
    0 / 19
    0 / 7
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Bronchiolitis (primary)
         subjects affected / exposed
    18 / 3136 (0.57%)
    5 / 1044 (0.48%)
         occurrences causally related to treatment / all
    0 / 18
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis media (primary)
         subjects affected / exposed
    8 / 3136 (0.26%)
    4 / 1044 (0.38%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection (primary)
         subjects affected / exposed
    11 / 3136 (0.35%)
    1 / 1044 (0.10%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis rotavirus (primary)
         subjects affected / exposed
    8 / 3136 (0.26%)
    2 / 1044 (0.19%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia (primary)
         subjects affected / exposed
    8 / 3136 (0.26%)
    2 / 1044 (0.19%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection (primary)
         subjects affected / exposed
    8 / 3136 (0.26%)
    1 / 1044 (0.10%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    4 / 3136 (0.13%)
    4 / 1044 (0.38%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Croup infectious (primary)
         subjects affected / exposed
    2 / 3136 (0.06%)
    3 / 1044 (0.29%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    1 / 3136 (0.03%)
    3 / 1044 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection (primary)
         subjects affected / exposed
    4 / 3136 (0.13%)
    0 / 1044 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis (primary)
         subjects affected / exposed
    2 / 3136 (0.06%)
    1 / 1044 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral upper respiratory tract infection (primary)
         subjects affected / exposed
    2 / 3136 (0.06%)
    1 / 1044 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia viral (primary)
         subjects affected / exposed
    2 / 3136 (0.06%)
    0 / 1044 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 3136 (0.03%)
    1 / 1044 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral skin infection
         subjects affected / exposed
    2 / 3136 (0.06%)
    0 / 1044 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal wall abscess
         subjects affected / exposed
    0 / 3136 (0.00%)
    1 / 1044 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess (primary)
         subjects affected / exposed
    1 / 3136 (0.03%)
    0 / 1044 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acarodermatitis
         subjects affected / exposed
    1 / 3136 (0.03%)
    0 / 1044 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis viral
         subjects affected / exposed
    1 / 3136 (0.03%)
    0 / 1044 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Campylobacter gastroenteritis
         subjects affected / exposed
    1 / 3136 (0.03%)
    0 / 1044 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 3136 (0.03%)
    0 / 1044 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis adenovirus
         subjects affected / exposed
    0 / 3136 (0.00%)
    1 / 1044 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral (primary)
         subjects affected / exposed
    0 / 3136 (0.00%)
    1 / 1044 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Group b streptococcus neonatal sepsis
         subjects affected / exposed
    1 / 3136 (0.03%)
    0 / 1044 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HIV infection
         subjects affected / exposed
    1 / 3136 (0.03%)
    0 / 1044 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 3136 (0.00%)
    1 / 1044 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lobar pneumonia (primary)
         subjects affected / exposed
    1 / 3136 (0.03%)
    0 / 1044 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis viral
         subjects affected / exposed
    0 / 3136 (0.00%)
    1 / 1044 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    0 / 3136 (0.00%)
    1 / 1044 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pertussis
         subjects affected / exposed
    1 / 3136 (0.03%)
    0 / 1044 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 3136 (0.00%)
    1 / 1044 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection (primary)
         subjects affected / exposed
    1 / 3136 (0.03%)
    0 / 1044 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Typhoid fever
         subjects affected / exposed
    0 / 3136 (0.00%)
    1 / 1044 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vulval abscess
         subjects affected / exposed
    1 / 3136 (0.03%)
    0 / 1044 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis (fourth dose)
         subjects affected / exposed [26]
    5 / 2769 (0.18%)
    4 / 923 (0.43%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection (fourth dose)
         subjects affected / exposed [27]
    5 / 2769 (0.18%)
    0 / 923 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Croup infectious (fourth dose)
         subjects affected / exposed [28]
    4 / 2769 (0.14%)
    0 / 923 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiolitis (fourth dose)
         subjects affected / exposed [29]
    2 / 2769 (0.07%)
    0 / 923 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis media (fourth dose)
         subjects affected / exposed [30]
    1 / 2769 (0.04%)
    1 / 923 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia viral (fourth dose)
         subjects affected / exposed [31]
    1 / 2769 (0.04%)
    1 / 923 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection (fourth dose)
         subjects affected / exposed [32]
    2 / 2769 (0.07%)
    0 / 923 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess (fourth dose)
         subjects affected / exposed [33]
    1 / 2769 (0.04%)
    0 / 923 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess neck
         subjects affected / exposed [34]
    1 / 2769 (0.04%)
    0 / 923 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenoviral upper respiratory infection
         subjects affected / exposed [35]
    0 / 2769 (0.00%)
    1 / 923 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis (fourth dose)
         subjects affected / exposed [36]
    1 / 2769 (0.04%)
    0 / 923 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis of male external genital organ
         subjects affected / exposed [37]
    1 / 2769 (0.04%)
    0 / 923 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis rotavirus (fourth dose)
         subjects affected / exposed [38]
    1 / 2769 (0.04%)
    0 / 923 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis salmonella
         subjects affected / exposed [39]
    0 / 2769 (0.00%)
    1 / 923 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral (fourth dose)
         subjects affected / exposed [40]
    1 / 2769 (0.04%)
    0 / 923 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lobar pneumonia (fourth dose)
         subjects affected / exposed [41]
    1 / 2769 (0.04%)
    0 / 923 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection (fourth dose)
         subjects affected / exposed [42]
    0 / 2769 (0.00%)
    1 / 923 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymph node abscess
         subjects affected / exposed [43]
    0 / 2769 (0.00%)
    1 / 923 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed [44]
    0 / 2769 (0.00%)
    1 / 923 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia (fourth dose)
         subjects affected / exposed [45]
    1 / 2769 (0.04%)
    0 / 923 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed [46]
    0 / 2769 (0.00%)
    1 / 923 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed [47]
    1 / 2769 (0.04%)
    0 / 923 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection (fourth dose)
         subjects affected / exposed [48]
    1 / 2769 (0.04%)
    0 / 923 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection (fourth dose)
         subjects affected / exposed [49]
    1 / 2769 (0.04%)
    0 / 923 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral upper respiratory tract infection (fourth dose)
         subjects affected / exposed [50]
    0 / 2769 (0.00%)
    1 / 923 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration (primary)
         subjects affected / exposed
    15 / 3136 (0.48%)
    2 / 1044 (0.19%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    2 / 3136 (0.06%)
    0 / 1044 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acidosis
         subjects affected / exposed
    1 / 3136 (0.03%)
    0 / 1044 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration (fourth dose)
         subjects affected / exposed [51]
    3 / 2769 (0.11%)
    2 / 923 (0.22%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [4] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [5] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [6] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [7] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [8] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [9] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [10] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [11] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [12] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [13] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [14] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [15] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [16] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [17] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [18] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [19] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [20] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [21] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [22] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [23] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [24] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [25] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [26] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [27] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [28] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [29] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [30] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [31] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [32] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [33] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [34] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [35] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [36] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [37] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [38] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [39] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [40] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [41] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [42] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [43] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [44] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [45] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [46] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [47] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [48] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [49] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [50] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [51] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Menhibrix Group ActHIB Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3034 / 3136 (96.75%)
    998 / 1044 (95.59%)
    General disorders and administration site conditions
    Pyrexia (primary)
         subjects affected / exposed
    176 / 3136 (5.61%)
    73 / 1044 (6.99%)
         occurrences all number
    176
    73
    Pyrexia (fourth dose)
         subjects affected / exposed [52]
    176 / 2769 (6.36%)
    64 / 923 (6.93%)
         occurrences all number
    176
    64
    Pain (primary)
         subjects affected / exposed [53]
    2419 / 3088 (78.34%)
    819 / 1016 (80.61%)
         occurrences all number
    2419
    819
    Redness (primary)
         subjects affected / exposed [54]
    2052 / 3088 (66.45%)
    691 / 1016 (68.01%)
         occurrences all number
    2052
    691
    Swelling (primary)
         subjects affected / exposed [55]
    1707 / 3088 (55.28%)
    568 / 1016 (55.91%)
         occurrences all number
    1707
    568
    Drowsiness (primary)
         subjects affected / exposed [56]
    2418 / 3088 (78.30%)
    804 / 1015 (79.21%)
         occurrences all number
    2418
    804
    Fever (primary)
         subjects affected / exposed [57]
    1434 / 3089 (46.42%)
    463 / 1015 (45.62%)
         occurrences all number
    1434
    463
    Irritability (primary)
         subjects affected / exposed [58]
    2740 / 3088 (88.73%)
    926 / 1015 (91.23%)
         occurrences all number
    2740
    926
    Loss of appetite (primary)
         subjects affected / exposed [59]
    1764 / 3088 (57.12%)
    609 / 1015 (60.00%)
         occurrences all number
    1764
    609
    Pain (fourth dose)
         subjects affected / exposed [60]
    1319 / 2528 (52.18%)
    494 / 832 (59.38%)
         occurrences all number
    1319
    494
    Redness (fourth dose)
         subjects affected / exposed [61]
    1213 / 2528 (47.98%)
    463 / 833 (55.58%)
         occurrences all number
    1213
    463
    Swelling (fourth dose)
         subjects affected / exposed [62]
    936 / 2526 (37.05%)
    334 / 832 (40.14%)
         occurrences all number
    936
    334
    Increase in limb circumference
         subjects affected / exposed [63]
    1489 / 2769 (53.77%)
    503 / 923 (54.50%)
         occurrences all number
    1489
    503
    Drowsiness (fourth dose)
         subjects affected / exposed [64]
    1088 / 2526 (43.07%)
    381 / 830 (45.90%)
         occurrences all number
    1088
    381
    Fever (fourth dose)
         subjects affected / exposed [65]
    341 / 2527 (13.49%)
    134 / 831 (16.13%)
         occurrences all number
    341
    134
    Irritability (fourth dose)
         subjects affected / exposed [66]
    1482 / 2526 (58.67%)
    534 / 830 (64.34%)
         occurrences all number
    1482
    534
    Loss of appetite (fourth dose)
         subjects affected / exposed [67]
    825 / 2526 (32.66%)
    287 / 830 (34.58%)
         occurrences all number
    825
    287
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    197 / 3136 (6.28%)
    65 / 1044 (6.23%)
         occurrences all number
    197
    65
    Diarrhoea
         subjects affected / exposed
    185 / 3136 (5.90%)
    57 / 1044 (5.46%)
         occurrences all number
    185
    57
    Teething (primary)
         subjects affected / exposed
    180 / 3136 (5.74%)
    55 / 1044 (5.27%)
         occurrences all number
    180
    55
    Teething (fourth dose)
         subjects affected / exposed [68]
    115 / 2769 (4.15%)
    46 / 923 (4.98%)
         occurrences all number
    115
    46
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    163 / 3136 (5.20%)
    50 / 1044 (4.79%)
         occurrences all number
    163
    50
    Nasal congestion
         subjects affected / exposed
    146 / 3136 (4.66%)
    53 / 1044 (5.08%)
         occurrences all number
    146
    53
    Infections and infestations
    Upper respiratory tract infection (primary)
         subjects affected / exposed
    524 / 3136 (16.71%)
    173 / 1044 (16.57%)
         occurrences all number
    524
    173
    Otitis media (primary)
         subjects affected / exposed
    335 / 3136 (10.68%)
    104 / 1044 (9.96%)
         occurrences all number
    335
    104
    Upper respiratory tract infection (fourth dose)
         subjects affected / exposed [69]
    152 / 2769 (5.49%)
    50 / 923 (5.42%)
         occurrences all number
    152
    50
    Otitis media (fourth dose)
         subjects affected / exposed [70]
    135 / 2769 (4.88%)
    47 / 923 (5.09%)
         occurrences all number
    135
    47
    Notes
    [52] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [53] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [54] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [55] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [56] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [57] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [58] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [59] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [60] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [61] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [62] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [63] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [64] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [65] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [66] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [67] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [68] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [69] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.
    [70] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The analysis was performed only on subjects who received a fourth dose of Hib-MenCY-TT vaccine.

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Mar 2006
    The aims of this trial are to demonstrate the consistency of 3 manufacturing lots of GSK Biologicals' Hib-MenCY-TT candidate vaccine in terms of immunogenicity, the immunogenicity of Hib-MenCY-TT vaccine against N. meningitidis serogroups C and Y and the non-inferiority of GSK Biologicals' Hib-MenCY-TT vaccine with respect to immunogenicity and safety compared to the control vaccine (ActHIB) when each are co-administered with Pediarix to healthy infants at 2, 4, and 6 months of age. The study will also evaluate the safety of a booster dose of Hib-MenCY-TT vaccine at 12 to 15 months of age as compared to PedvaxHIB. Finally, immunogenicity of a booster dose of Hib-MenCY-TT vaccine at 12 to 15 months co-administered with M-M-R II and Varivax will be evaluated. The booster immunogenicity will be performed on data from 2 studies: the current study and a second study with the same design, the non-US study, Hib-MenCY-TT-007/008, which is being conducted under US Investigational New Drug (IND) application.
    05 Oct 2006
    The aims of this trial are to demonstrate the consistency of 3 manufacturing lots of GSK Biologicals' Hib-MenCY-TT candidate vaccine in terms of immunogenicity, the immunogenicity of Hib-MenCY-TT vaccine against N. meningitidis serogroups C and Y and the non-inferiority of GSK Biologicals' Hib-MenCY-TT vaccine with respect to immunogenicity and safety compared to the control vaccine (ActHIB) when each are co-administered with Pediarix to healthy infants at 2, 4, and 6 months of age. The study will also evaluate the safety of a fourth dose of Hib-MenCY-TT vaccine at 12 to 15 months of age as compared to PedvaxHIB. Finally, immunogenicity of a fourth dose of Hib-MenCY-TT vaccine at 12 to 15 months coadministered with M-M-R II and Varivax will be evaluated. The M-M-R II and Varivax co-administration analysis will be performed on data from 2 studies: the current study and a second study with the same design, the non-US study, Hib-MenCY-TT-007/008, which is being conducted under US Investigational New Drug (IND) application.

    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
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