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    Clinical Trial Results:
    Assessment of post booster antibody responses in UK infants given a reduced priming schedule of meningococcal serogroup B and 13 valent pneumococcal conjugate vaccines

    Summary
    EudraCT number
    		 2015-000817-32
    Trial protocol
    		 GB  
    Global end of trial date
    01 Jun 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Feb 2022
    First version publication date
    11 Feb 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    2015/03
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02482636
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Oxford, Clinical Trials and Research Governance (CTRG)
    Sponsor organisation address
    Boundary Brook House, Oxford, United Kingdom, OX3 7GB
    Public contact
    Oxford Vaccine Group, University of Oxford, 44 1865611400, info@ovg.ox.ac.uk
    Scientific contact
    Oxford Vaccine Group, University of Oxford, 44 1865611400, info@ovg.ox.ac.uk
    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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    26 Oct 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Jun 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Technical - To assess geometric mean concentrations (GMC) of serotype specific pneumococcal antibody responses measured in the blood sample taken after the final infant vaccinations, usually at 13 months of age, following two or three doses of 13 valent pneumococcal conjugate vaccine (PCV13) at 3 and 12 months or at 2, 4, and 12 months of age Lay - To assess how much antibody can be detected in the blood sample taken a month after the final infant vaccinations, usually taken at 13 months of age, after two or three doses of the routinely used pneumococcal vaccine, called Prevenar13.
    Protection of trial subjects
    The blood sampling may be uncomfortable but the clinical study staff are very experienced at drawing blood samples and not more than two attempts will be made. Finger or heel (in infants) prick may be attempted if venepuncture proves difficult. For infants under 3 months of age, oral sucrose solution (such as Sweet-Ease®) may be offered to minimise discomfort (subject to local practice/preference). The parents will be asked if she/he wishes to feed the infant during the procedure to minimise discomfort. An anaesthetic cream (such as EMLA®, Denela or Ametop®), cryogenic spray may be offered for infants one month or older. As per JCVI recommendation, parents will be advised to give their baby three doses of paracetamol (infant formula) prophylactically in the 24 hours after each primary MenB vaccination. Any stress and discomfort is also reduced by using distraction techniques. Every effort will be made to protect the participants’ identity. The study will comply with the Data Protection Act, which requires data to be anonymised as soon as it is practical to do so.
    Background therapy
    		 All participants receive: Bexsero (MenB) at 2, 4 and 12 months of age Infanrix/IPV/Hib at 2,3 and 4 month MenC conjugate vaccination at 12 months given as the combined Hib/MenC conjugate vaccine, Menitorix Rotarix orally at 2 and 3 months Infants may receive one of 2 licensed MMR vaccines depending on local availability and parental consent: Priorix or MMR®II (live attenuated vaccines that protects against measles, mumps and rubella) at 13 months Infant doses of paracetamol are also provided to families to give following the MenB vaccinations at 2 and 4 months of age.
    Evidence for comparator
    		 The Department of Heath JCVI has recommended that the Bexsero vaccine, designed to protect against meningococcal B and other serogroups not covered by the MenC conjugate vaccine, may be cost effective if given as a 2+1 schedule and if the current MenC conjugate vaccine dose given at 3 months is removed. There are no published immunogenicity data for Bexsero when given at 2, 4 and 12 months (the ages at which a 2+1 schedule would be implemented in the UK) and with concomitant Infanrix/IPV/Hib. The MenC conjugate vaccine currently given for primary immunisation at 3 months of age is a tetanus based conjugate which was shown to enhance the response to the Hib component of Infanrix/IPV/Hib. Removal of MenC conjugate vaccine from the infant schedule would raise uncertainty as to the adequacy of the Hib response to Infanrix/IPV/Hib. Another uncertainty about the 2+1 Bexsero schedule is that it would be given at the same appointments currently used for PCV13 (13 valent pneumococcal conjugate vaccine), thus necessitating 3 injections at the first and third infant visits and just one injection at the second. Past experience has shown that there is reluctance among parents, and some health professionals, to give 3 injections at one visit to a very young infant. An option is to reduce PCV13 to a 1+1 schedule, giving a single priming dose at 3 months. Though the immunogenicity of one dose in infancy will be lower than two doses, a prior study with PCV9 showed higher booster responses with fewer priming doses. With the rapidly reducing incidence of PCV13 disease in young children in the UK, and highly effective herd protection, the potentially increased risk of an invasive pneumococcal infection between 4 and 12 months in a child who has only received one dose of PCV13 instead of two will be very low and unlikely to outweigh the cost savings from reducing the number of PCV13 doses from 3 to 2. This study includes two arms defined by their PCV13 schedule as 1+1 or 2+1.
    Actual start date of recruitment
    22 Sep 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 213
    Worldwide total number of subjects
    213
    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)
    213
    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
    		 Healthy infants aged up to 13 weeks, due to receive their primary vaccinations as per the UK immunisation schedule with the exception of PCV13, were recruited via child health database mailouts in Oxfordshire and via GP surgeries in Gloucestershire and Hertfordshire, and were assesses for eligibility between 22/09/2015 and 1/11/2017.

    Pre-assignment
    Screening details
    		 376 infants were assessed for eligibility and 163 infants were excluded before randomisation. Infants with bleeding disorders, at risk of invasive pneumococcal disease, or with a history of allergic reactions to any of the vaccine components were excluded. 213 eligible infants were enrolled.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group 1 (2+1 PCV13)
    Arm description
    		 PCV13 schedule 2+1; both arms receive Bexsero 2+1 and Infanrix/IPV/Hib with one MenC conjugate vaccination at 12 months given as the combined Hib/MenC conjugate vaccine, Menitorix
    Arm type
    		 Active comparator

    Investigational medicinal product name
    PCV13
    Investigational medicinal product code
    Other name
    Prevenar13
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Injection , Intramuscular use
    Dosage and administration details
    13 valent pneumococcal conjugate vaccine (PCV13) IM 0.5ml at 2, 4 and 12 months

    Investigational medicinal product name
    DTaP/IPV/Hib
    Investigational medicinal product code
    Other name
    Infanrix-IPV-Hib
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Injection , Intramuscular use
    Dosage and administration details
    DTaP/IPV/Hib vaccine IM 0.5ml at 2, 3 and 4 months

    Investigational medicinal product name
    Rotavirus vaccine
    Investigational medicinal product code
    Other name
    Rotarix
    Pharmaceutical forms
    Oral suspension in pre-filled oral applicator
    Routes of administration
    Oral use
    Dosage and administration details
    Rotavirus vaccine oral 1.5ml at 2 and 3 months

    Investigational medicinal product name
    4CMenB
    Investigational medicinal product code
    Other name
    Bexsero
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Injection , Intramuscular use
    Dosage and administration details
    4-component Meningococcal B (4CMenB) vaccine IM 0.5ml given at 2, 4 and 12 months

    Investigational medicinal product name
    Meningococcal C/Hib vaccine
    Investigational medicinal product code
    Other name
    Menitorix
    Pharmaceutical forms
    Powder and solvent for solution for injection in cartridge
    Routes of administration
    Injection , Intramuscular use
    Dosage and administration details
    Meningococcal C/Hib vaccine IM 0.5ml at 12 months

    Investigational medicinal product name
    Measles/Mumps/Rubella (MMR) vaccine
    Investigational medicinal product code
    Other name
    Priorix or MMR II
    Pharmaceutical forms
    Powder and solvent for solution for injection in pre-filled syringe
    Routes of administration
    Injection , Intramuscular use
    Dosage and administration details
    Measles/Mumps/Rubella (MMR) vaccine IM 0.5ml at 13 months - Priorix or MMR II vaccine - depending on local availability and parental consent.

    Arm title
    		 Group 2 (1+1 PCV13)
    Arm description
    		 PCV13 schedule 1+1; both arms receive Bexsero and Infanrix/IPV/Hib with one MenC conjugate vaccination at 12 months given as the combined Hib/MenC conjugate vaccine, Menitorix
    Arm type
    		 Active comparator

    Investigational medicinal product name
    PCV13
    Investigational medicinal product code
    Other name
    Prevenar13
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Injection , Intramuscular use
    Dosage and administration details
    13 valent pneumococcal conjugate vaccine (PCV13) IM 0.5ml at 3 and 12 months (instead of current routine schedule of 2,4 and 12 months)

    Investigational medicinal product name
    DTaP/IPV/Hib
    Investigational medicinal product code
    Other name
    Infanrix-IPV-Hib
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Injection , Intramuscular use
    Dosage and administration details
    DTaP/IPV/Hib vaccine IM 0.5ml at 2, 3 and 4 months

    Investigational medicinal product name
    Rotavirus vaccine
    Investigational medicinal product code
    Other name
    Rotarix
    Pharmaceutical forms
    Oral suspension in pre-filled oral applicator
    Routes of administration
    Oral use
    Dosage and administration details
    Rotavirus vaccine oral 1.5ml at 2 and 3 months

    Investigational medicinal product name
    4CMenB
    Investigational medicinal product code
    Other name
    Bexsero
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Injection , Intramuscular use
    Dosage and administration details
    4-component Meningococcal B (4CMenB) vaccine IM 0.5ml given at 2, 4 and 12 months

    Investigational medicinal product name
    Meningococcal C/Hib vaccine
    Investigational medicinal product code
    Other name
    Menitorix
    Pharmaceutical forms
    Powder and solvent for solution for injection in cartridge
    Routes of administration
    Injection , Intramuscular use
    Dosage and administration details
    Meningococcal C/Hib vaccine IM 0.5ml at 12 months

    Investigational medicinal product name
    Measles/Mumps/Rubella (MMR) vaccine
    Investigational medicinal product code
    Other name
    Priorix or MMR II
    Pharmaceutical forms
    Powder and solvent for solution for injection in pre-filled syringe
    Routes of administration
    Injection , Intramuscular use
    Dosage and administration details
    Measles/Mumps/Rubella (MMR) vaccine IM 0.5ml at 13 months - Priorix or MMR II vaccine - depending on local availability and parental consent.

    Number of subjects in period 1
    		Group 1 (2+1 PCV13) Group 2 (1+1 PCV13)
    Started
    106
    107
    Completed
    101
    96
    Not completed
    5
    11
         Consent withdrawn by subject
    5
    11

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group 1 (2+1 PCV13)
    Reporting group description
    		 PCV13 schedule 2+1; both arms receive Bexsero 2+1 and Infanrix/IPV/Hib with one MenC conjugate vaccination at 12 months given as the combined Hib/MenC conjugate vaccine, Menitorix

    Reporting group title
    Group 2 (1+1 PCV13)
    Reporting group description
    		 PCV13 schedule 1+1; both arms receive Bexsero and Infanrix/IPV/Hib with one MenC conjugate vaccination at 12 months given as the combined Hib/MenC conjugate vaccine, Menitorix

    Reporting group values
    		 Group 1 (2+1 PCV13) Group 2 (1+1 PCV13) Total
    Number of subjects
    		 106 107 213
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 106 107 213
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Age at first PCV dose
    Units: days
        median (full range (min-max))
    		 60 (55 to 88) 91 (84 to 114) -
    Gender categorical
    Units: Subjects
        Female
    		 46 58 104
        Male
    		 60 49 109
    Maternal vaccination
    Units: Subjects
        Yes
    		 76 86 162
        No
    		 23 18 41
        Not known
    		 7 3 10
    Age at booster
    Units: day
        median (full range (min-max))
    		 371 (359 to 406) 371 (366 to 416) -
    Interval from last primary PCV dose to blood sample
    Units: day
        median (full range (min-max))
    		 30 (21 to 57) 62 (50 to 92) -

    End points

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    End points reporting groups
    Reporting group title
    Group 1 (2+1 PCV13)
    Reporting group description
    		 PCV13 schedule 2+1; both arms receive Bexsero 2+1 and Infanrix/IPV/Hib with one MenC conjugate vaccination at 12 months given as the combined Hib/MenC conjugate vaccine, Menitorix

    Reporting group title
    Group 2 (1+1 PCV13)
    Reporting group description
    		 PCV13 schedule 1+1; both arms receive Bexsero and Infanrix/IPV/Hib with one MenC conjugate vaccination at 12 months given as the combined Hib/MenC conjugate vaccine, Menitorix

    Primary: Pneumococcal serotype specific GMCs - post booster

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    End point title
    		 Pneumococcal serotype specific GMCs - post booster
    End point description
    Pneumococcal serotype specific geometric mean concentrations (GMCs) in blood samples following the completion of either a 2, 4 and 12 month schedule of PCV13 vaccination, or only 3 and 12 month PCV13 vaccination
    End point type
    Primary
    End point timeframe
    13 months of age
    End point values
    		 Group 1 (2+1 PCV13) Group 2 (1+1 PCV13)
    Number of subjects analysed
    91
    86
    Units: concentration µg/mL
    geometric mean (confidence interval 95%)
        serotype 1
    3.07 (2.58 to 3.64)
    8.92 (7.42 to 10.73)
        serotype 3
    0.61 (0.51 to 0.74)
    0.62 (0.52 to 0.74)
        serotype 4
    2.55 (2.15 to 3.04)
    3.43 (2.86 to 4.12)
        serotype 5
    1.74 (1.49 to 2.03)
    2.11 (1.81 to 2.45)
        serotype 6A
    8.62 (7.29 to 10.21)
    6.36 (5.34 to 7.58)
        serotype 6B
    6.19 (5.10 to 7.50)
    2.39 (1.94 to 2.94)
        serotype 7F
    3.98 (3.42 to 4.62)
    3.36 (2.93 to 3.86)
        serotype 9V
    2.34 (2.00 to 2.73)
    2.50 (2.16 to 2.88)
        serotype 14
    10.49 (8.84 to 12.44)
    16.9 (13.54 to 21.08)
        serotype 18C
    1.98 (1.70 to 2.30)
    1.63 (1.42 to 1.87)
        serotype 19A
    8.38 (7.17 to 9.80)
    8.83 (7.4 to 10.52)
        serotype 19F
    11.12 (9.46 to 13.07)
    14.76 (12.54 to 17.37)
        serotype 23F
    2.87 (2.38 to 3.46)
    1.72 (1.44 to 2.05)
    Statistical analysis title
    		 Adjusted p-value
    Statistical analysis description
    Adjusted in regression for sex and interval to blood
    Comparison groups
    Group 1 (2+1 PCV13) v Group 2 (1+1 PCV13)
    Number of subjects included in analysis
    177
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001 [1]
    Method
    		 Regression, Logistic
    Confidence interval
    Notes
    [1] - Serotype (S) 1: <0.0001; S3: 0.57; S4: 0.047; S5: 0.20; S6A: 0.002; S6B: <0.0001; S7F: 0.059; S9V: 0.85; S14: 0.002; S18C: 0.017; S19A: 0.98; S19F: 0.035; S23F: <0.0001.

    Secondary: GMC of serotype specific pneumococcal antibody responses and proportions ≥ 0.35 µg/mL - post primary vaccination

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    End point title
    		 GMC of serotype specific pneumococcal antibody responses and proportions ≥ 0.35 µg/mL - post primary vaccination
    End point description
    assess GMC of serotype specific pneumococcal antibody responses and proportions ≥ 0.35 µg/mL measured in the blood samples taken at 5 months of age, following one or two doses of 13 valent pneumococcal conjugate vaccine (PCV13) at 3 months or at 2 and 4 months of age
    End point type
    Secondary
    End point timeframe
    5 months of age
    End point values
    		 Group 1 (2+1 PCV13) Group 2 (1+1 PCV13)
    Number of subjects analysed
    97
    102
    Units: percentage IgG concentr. ≥ 0.35 µg/mL
    geometric mean (confidence interval 95%)
        serotype 1
    95.9 (89.8 to 98.9)
    74.0 (64.3 to 82.3)
        serotype 3
    34.5 (24.5 to 45.7)
    39.5 (29.2 to 50.7)
        serotype 4
    92.8 (85.7 to 97.0)
    64.4 (54.2 to 73.6)
        serotype 5
    89.6 (81.7 to 94.9)
    39.2 (29.7 to 49.4)
        serotype 6A
    84.4 (75.5 to 91.0)
    12.9 (7.0 to 21.0)
        serotype 6B
    34.0 (24.7 to 44.3)
    1.0 (0 to 5.3)
        serotype 7F
    97.9 (92.7 to 99.7)
    86.1 (77.8 to 92.2)
        serotype 9V
    79.4 (70.0 to 86.9)
    16.8 (10.1 to 25.6)
        serotype 14
    94.8 (88.4 to 98.3)
    86.3 (78.0 to 92.3)
        serotype 18C
    81.4 (72.3 to 88.6)
    33.7 (24.6 to 43.8)
        serotype 19A
    91.8 (84.4 to 96.4)
    44.1 (34.3 to 54.3)
        serotype 19F
    100 (96.3 to 100)
    79.2 (70.0 to 86.6)
        serotype 23F
    57.7 (47.3 to 67.7)
    5.9 (2.2 to 12.4)
    No statistical analyses for this end point

    Secondary: GMC of serotype specific pneumococcal antibody responses and proportions ≥ 0.35 µg/mL - post booster

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    End point title
    		 GMC of serotype specific pneumococcal antibody responses and proportions ≥ 0.35 µg/mL - post booster
    End point description
    assess GMC of serotype specific pneumococcal antibody responses and proportions ≥ 0.35 µg/mL measured in the blood samples taken at 13 months of age, following one or two doses of 13 valent pneumococcal conjugate vaccine (PCV13) at 3 months or at 2 and 4 months of age and a booster at 12 months of age
    End point type
    Secondary
    End point timeframe
    13 months of age
    End point values
    		 Group 1 (2+1 PCV13) Group 2 (1+1 PCV13)
    Number of subjects analysed
    91
    86
    Units: percentage IgG concentr. ≥ 0.35 µg/mL
    geometric mean (confidence interval 95%)
        serotype 1
    100 (96.0 to 100)
    100 (95.8 to 100)
        serotype 3
    75.9 (65.5 to 84.4)
    78.8 (68.6 to 86.9)
        serotype 4
    98.9 (94.0 to 100)
    100 (95.8 to 100)
        serotype 5
    98.9 (94.0 to 100)
    100 (95.8 to 100)
        serotype 6A
    100 (96.0 to 100)
    100 (95.8 to 100)
        serotype 6B
    100 (96.0 to 100)
    97.7 (91.9 to 99.7)
        serotype 7F
    100 (96.0 to 100)
    100 (95.8 to 100)
        serotype 9V
    100 (96.0 to 100)
    100 (95.8 to 100)
        serotype 14
    100 (96.0 to 100)
    100 (95.8 to 100)
        serotype 18C
    100 (96.0 to 100)
    100 (95.8 to 100)
        serotype 19A
    100 (96.0 to 100)
    100 (95.8 to 100)
        serotype 19F
    100 (96.0 to 100)
    100 (95.8 to 100)
        serotype 23F
    100 (96.0 to 100)
    95.3 (88.5 to 98.7)
    No statistical analyses for this end point

    Secondary: antibody responses to MenB vaccination: % hSBA titres ≥4 - post primary vaccination

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    End point title
    		 antibody responses to MenB vaccination: % hSBA titres ≥4 - post primary vaccination
    End point description
    antibody responses to MenB vaccination using proportions achieving hSBA titres ≥4 for the three main MenB vaccine antigen target strains, 5/99 (NadA), NZ98/254 (PorA) and 44/76-SL (fHbp) in the blood samples taken at 5 months of age
    End point type
    Secondary
    End point timeframe
    5 months
    End point values
    		 Group 1 (2+1 PCV13) Group 2 (1+1 PCV13)
    Number of subjects analysed
    89
    97
    Units: percentage hSBA titres ≥4
    geometric mean (confidence interval 95%)
        strain 5/99 (NadA)
    100 (95.8 to 100)
    100 (96.2 to 100)
        strain 44/76-SL (fHbp)
    95.3 (88.5 to 98.7)
    97.9 (92.7 to 99.7)
        strain NZ98/254 (PorA)
    88.5 (79.9 to 94.3)
    86.5 (78.0 to 92.6)
    No statistical analyses for this end point

    Secondary: antibody responses to MenB vaccination: % hSBA titres ≥4 - post booster

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    End point title
    		 antibody responses to MenB vaccination: % hSBA titres ≥4 - post booster
    End point description
    antibody responses to MenB vaccination using proportions achieving hSBA titres ≥4 for the three main MenB vaccine antigen target strains, 5/99 (NadA), NZ98/254 (PorA) and 44/76-SL (fHbp) in the blood samples taken at 13 months of age
    End point type
    Secondary
    End point timeframe
    13 months of age
    End point values
    		 Group 1 (2+1 PCV13) Group 2 (1+1 PCV13)
    Number of subjects analysed
    81
    80
    Units: percentage hSBA titres ≥4
    geometric mean (confidence interval 95%)
        strain 5/99 (NadA)
    100 (95.4 to 100)
    100 (95.4 to 100)
        strain 44/76-SL (fHbp)
    92.4 (84.2 to 97.2)
    93.8 (86.0 to 97.9)
        strain NZ98/254 (PorA)
    88.6 (79.5 to 94.7)
    92.1 (83.6 to 97.0)
    No statistical analyses for this end point

    Secondary: antibody responses to MenB vaccination: GMT - post primary vaccination

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    End point title
    		 antibody responses to MenB vaccination: GMT - post primary vaccination
    End point description
    antibody responses to MenB vaccination using GMTs for the three main MenB vaccine antigen target strains, 5/99 (NadA), NZ98/254 (PorA) and 44/76-SL (fHbp) in the blood samples taken at 5 months of age
    End point type
    Secondary
    End point timeframe
    5 months of age
    End point values
    		 Group 1 (2+1 PCV13) Group 2 (1+1 PCV13)
    Number of subjects analysed
    89
    97
    Units: titre
    geometric mean (confidence interval 95%)
        strain 5/99 (NadA)
    528.6 (420.1 to 665.0)
    587.3 (476.8 to 723.4)
        strain 44/76-SL (fHbp)
    39.5 (29.8 to 52.3)
    51.3 (41.9 to 62.8)
        strain NZ98/254 (PorA)
    14.1 (10.4 to 19.1)
    13.7 (10.4 to 18.1)
    No statistical analyses for this end point

    Secondary: antibody responses to MenB vaccination: GMT - post booster

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    End point title
    		 antibody responses to MenB vaccination: GMT - post booster
    End point description
    antibody responses to MenB vaccination using GMTs for the three main MenB vaccine antigen target strains, 5/99 (NadA), NZ98/254 (PorA) and 44/76-SL (fHbp) in the blood samples taken at 13 months of age
    End point type
    Secondary
    End point timeframe
    13 months of age
    End point values
    		 Group 1 (2+1 PCV13) Group 2 (1+1 PCV13)
    Number of subjects analysed
    81
    80
    Units: titre
    geometric mean (confidence interval 95%)
        strain 5/99 (NadA)
    1454.5 (1054.5 to 2007.3)
    1336.8 (1001.8 to 1784.0)
        strain 44/76-SL (fHbp)
    34.0 (24.4 to 47.4)
    44.5 (33.1 to 59.8)
        strain NZ98/254 (PorA)
    26.6 (18.3 to 38.7)
    28.7 (21.2 to 38.8)
    No statistical analyses for this end point

    Secondary: meningococcal serogroup C rSBA proportion titres ≥8 - post primary vaccination

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    End point title
    		 meningococcal serogroup C rSBA proportion titres ≥8 - post primary vaccination
    End point description
    assess meningococcal serogroup C rSBA: proportion of infants with titres ≥8 from blood samples taken at 5 months of age
    End point type
    Secondary
    End point timeframe
    5 months of age
    End point values
    		 Group 1 (2+1 PCV13) Group 2 (1+1 PCV13)
    Number of subjects analysed
    84
    95
    Units: percentage titres ≥8
        geometric mean (confidence interval 95%)
    2.4 (0.3 to 8.3)
    2.1 (0.3 to 7.4)
    No statistical analyses for this end point

    Secondary: meningococcal serogroup C rSBA proportion titres ≥8 - post booster

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    End point title
    		 meningococcal serogroup C rSBA proportion titres ≥8 - post booster
    End point description
    assess meningococcal serogroup C rSBA: proportion of infants with titres ≥8 from blood samples taken at 13 months of age
    End point type
    Secondary
    End point timeframe
    13 months of age
    End point values
    		 Group 1 (2+1 PCV13) Group 2 (1+1 PCV13)
    Number of subjects analysed
    77
    78
    Units: percentage titres ≥8
    geometric mean (confidence interval 95%)
        MenC
    98.7 (93.0 to 100)
    97.4 (91.0 to 99.7)
    No statistical analyses for this end point

    Secondary: meningococcal serogroup C rSBA GMT - post primary vaccination

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    End point title
    		 meningococcal serogroup C rSBA GMT - post primary vaccination
    End point description
    assess meningococcal serogroup C rSBA GMTs from blood samples taken at 5 months of age
    End point type
    Secondary
    End point timeframe
    5 months of age
    End point values
    		 Group 1 (2+1 PCV13) Group 2 (1+1 PCV13)
    Number of subjects analysed
    84
    95
    Units: titre
    geometric mean (confidence interval 95%)
        MenC
    2.2 (1.9 to 2.4)
    2.2 (2.0 to 2.5)
    No statistical analyses for this end point

    Secondary: meningococcal serogroup C rSBA GMT - post booster

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    End point title
    		 meningococcal serogroup C rSBA GMT - post booster
    End point description
    assess meningococcal serogroup C rSBA GMTs from blood samples taken at 13 months of age
    End point type
    Secondary
    End point timeframe
    13 months of age
    End point values
    		 Group 1 (2+1 PCV13) Group 2 (1+1 PCV13)
    Number of subjects analysed
    77
    78
    Units: titre
    geometric mean (confidence interval 95%)
        MenC
    888.3 (640.0 to 1232.8)
    540.4 (404.1 to 722.8)
    No statistical analyses for this end point

    Secondary: antibody responses IgG GMC to Infanrix-IPV-Hib vaccine - post primary vaccination

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    End point title
    		 antibody responses IgG GMC to Infanrix-IPV-Hib vaccine - post primary vaccination
    End point description
    assess antibody responses, by IgG GMC to the tetanus and diphtheria components, as well as IgG GMCs against pertussis components (pertussis toxin (PT), pertactin (PRN), filamentous haemagglutinin (FHA) and fimbrial antigens (fims) 2 and 3), polyribosyl ribitol phosphate-Haemophilus influenzae type b (PRP-Hib) of Infanrix-IPV-Hib vaccine after three doses at 2, 3 and 4 months of age, from the blood sample taken at 5 months of age
    End point type
    Secondary
    End point timeframe
    5 months of age
    End point values
    		 Group 1 (2+1 PCV13) Group 2 (1+1 PCV13)
    Number of subjects analysed
    73
    84
    Units: IgG concentration
    geometric mean (confidence interval 95%)
        Anti-diphtheria toxoid IgG IU/ml
    0.47 (0.40 to 0.55)
    0.32 (0.27 to 0.38)
        Anti-tetanus toxoid IgG IU/ml
    1.26 (1.08 to 1.46)
    1.38 (1.21 to 1.57)
        Anti-PRP-Hib IgG µg/mL
    1.01 (0.72 to 1.41)
    0.71 (0.54 to 0.94)
        Anti-PT IgG IU/mL
    28.94 (25.43 to 32.93)
    26.32 (22.86 to 30.31)
        Anti-PRN IgG IU/mL
    44.05 (35.72 to 54.31)
    42.08 (34.58 to 51.21)
        Anti-FHA IgG IU/mL
    61.78 (53.75 to 71.00)
    58.35 (50.57 to 67.32)
        FIM 2 and 3 IgG U/mL
    2.71 (2.15 to 3.42)
    5.17 (3.93 to 6.80)
    No statistical analyses for this end point

    Secondary: antibody responses IgG GMC to Infanrix-IPV-Hib vaccine - post booster

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    End point title
    		 antibody responses IgG GMC to Infanrix-IPV-Hib vaccine - post booster
    End point description
    assess antibody responses by IgG GMC to the tetanus and diphtheria components, as well as IgG GMCs against pertussis components (pertussis toxin (PT), pertactin (PRN), filamentous haemagglutinin (FHA) and fimbrial antigens (fims) 2 and 3), polyribosyl ribitol phosphate-Haemophilus influenzae type b (PRP-Hib) of Infanrix-IPV-Hib vaccine after three doses at 2, 3 and 4 months of age, from the blood sample taken at 13 months of age
    End point type
    Secondary
    End point timeframe
    13 months of age
    End point values
    		 Group 1 (2+1 PCV13) Group 2 (1+1 PCV13)
    Number of subjects analysed
    73
    74
    Units: IgG concentration
    geometric mean (confidence interval 95%)
        Anti-diphtheria toxoid IgG IU/ml
    0.68 (0.58 to 0.81)
    0.58 (0.47 to 0.71)
        Anti-tetanus toxoid IgG IU/ml
    4.37 (3.28 to 5.84)
    3.88 (2.97 to 5.07)
        Anti-PRP-Hib IgG µg/mL
    35.77 (26.77 to 47.80)
    28.00 (22.00 to 35.64)
        Anti-PT IgG IU/mL
    3.19 (2.56 to 3.98)
    2.67 (2.16 to 3.28)
        Anti-PRN IgG IU/mL
    5.42 (4.22 to 6.98)
    3.99 (3.22 to 4.94)
        Anti-FHA IgG IU/mL
    12.94 (9.99 to 16.76)
    10.57 (8.57 to 13.03)
        FIM 2 and 3 IgG U/mL
    1.44 (1.15 to 1.79)
    1.31 (1.10 to 1.55)
    No statistical analyses for this end point

    Secondary: antibody responses proportions above correlates of protection to Infanrix-IPV-Hib vaccine - post primary vaccination

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    End point title
    		 antibody responses proportions above correlates of protection to Infanrix-IPV-Hib vaccine - post primary vaccination
    End point description
    assess antibody responses, presented as percentage of participants with IgG to Diphtheria-toxoid, Tetanus-toxoid and polyribosyl ribitol phosphate (PRP - Hib) above correlates of protection, of Infanrix-IPV-Hib vaccine after three doses at 2, 3 and 4 months of age, from the blood sample taken at 5 months of age
    End point type
    Secondary
    End point timeframe
    5 month of age
    End point values
    		 Group 1 (2+1 PCV13) Group 2 (1+1 PCV13)
    Number of subjects analysed
    71
    82
    Units: proport. above correlates of protection
    geometric mean (confidence interval 95%)
        Anti-diphtheria toxoid IgG ≥ 0.1 IU/mL
    98.5 (92.1 to 100)
    95.1 (88.0 to 98.7)
        Anti-diphtheria toxoid IgG ≥ 1 IU/mL
    13.2 (6.2 to 23.6)
    11.0 (5.1 to 19.8)
        Anti-tetanus toxoid IgG ≥ 0.1 IU/mL
    100 (94.8 to 100)
    100 (95.6 to 100)
        Anti-tetanus toxoid IgG ≥ 1 IU/mL
    65.2 (52.8 to 76.3)
    67.1 (55.8 to 77.1)
        Anti PRP-Hib IgG ≥ 0.15µg/mL
    93.0 (84.3 to 97.7)
    100 (95.6 to 100)
        Anti PRP-Hib IgG ≥ 1 µg/mL
    49.3 (37.2 to 61.4)
    67.1 (55.8 to 77.1)
    No statistical analyses for this end point

    Secondary: antibody responses proportions above correlates of protection to Infanrix-IPV-Hib vaccine - post booster

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    End point title
    		 antibody responses proportions above correlates of protection to Infanrix-IPV-Hib vaccine - post booster
    End point description
    assess antibody responses, presented as percentage of participants with IgG to Diphtheria-toxoid, Tetanus-toxoid and polyribosyl ribitol phosphate (PRP - Hib) above correlates of protection, of Infanrix-IPV-Hib vaccine after three doses at 2, 3 and 4 months of age, from the blood sample taken at 13 months of age
    End point type
    Secondary
    End point timeframe
    13 months of age
    End point values
    		 Group 1 (2+1 PCV13) Group 2 (1+1 PCV13)
    Number of subjects analysed
    73
    74
    Units: proport. above correlates of protection
    geometric mean (confidence interval 95%)
        Anti-diphtheria toxoid IgG ≥ 0.1 IU/mL
    100 (95.1 to 100)
    94.6 (86.7 to 98.5)
        Anti-diphtheria toxoid IgG ≥ 1 IU/mL
    34.2 (23.5 to 46.3)
    25.7 (16.3 to 37.2)
        Anti-tetanus toxoid IgG ≥ 0.1 IU/mL
    100 (95.1 to 100)
    100 (95.1 to 100)
        Anti-tetanus toxoid IgG ≥ 1 IU/mL
    89.0 (79.5 to 95.1)
    91.9 (83.2 to 97.0)
        Anti PRP-Hib IgG ≥ 0.15µg/mL
    100 (95.1 to 100)
    100 (95.1 to 100)
        Anti PRP-Hib IgG ≥ 1 µg/mL
    98.6 (92.6 to 100)
    100 (95.1 to 100)
    No statistical analyses for this end point

    Secondary: reactogenicity using a daily health diary for a week following vaccination

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    End point title
    		 reactogenicity using a daily health diary for a week following vaccination
    End point description
    assess reactogenicity using a daily health diary for a week following vaccination at 2, 3, 4 and 12 months of age to record local reactions and systemic symptoms, particularly with reference to the use of paracetamol as indicated when the MenB vaccine, Bexsero, is administered. Temperature will also be recorded and analysed from the iButton system
    End point type
    Secondary
    End point timeframe
    for a week following vaccination at 2, 3, 4 and 12 months of age
    End point values
    		 Group 1 (2+1 PCV13) Group 2 (1+1 PCV13)
    Number of subjects analysed
    106
    107
    Units: number
    106
    107
    Attachments
    		 Local and systemic reactions
    No statistical analyses for this end point

    Secondary: Pneumococcal serotype specific GMCs - post primary vaccination

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    End point title
    		 Pneumococcal serotype specific GMCs - post primary vaccination
    End point description
    Pneumococcal serotype specific geometric mean concentrations (GMC) in blood samples at 5 months of age (1 month post the primary series of PCV13 vaccination for group 1 and 2 months post the single priming dose for group 2)
    End point type
    Secondary
    End point timeframe
    5 months of age
    End point values
    		 Group 1 (2+1 PCV13) Group 2 (1+1 PCV13)
    Number of subjects analysed
    97
    102
    Units: concentration µg/mL
    geometric mean (confidence interval 95%)
        serotype 1
    1.25 (1.07 to 1.45)
    0.57 (0.47 to 0.69)
        serotype 3
    0.28 (0.23 to 0.33)
    0.27 (0.21 to 0.34)
        serotype 4
    1.08 (0.93 to 1.26)
    0.43 (0.36 to 0.51)
        serotype 5
    0.90 (0.77 to 1.07)
    0.29 (0.24 to 0.35)
        serotype 6A
    1.25 (1.00 to 1.56)
    0.13 (0.11 to 0.15)
        serotype 6B
    0.26 (0.20 to 0.33)
    0.09 (0.08 to 0.09)
        serotype 7F
    2.46 (2.11 to 2.88)
    0.81 (0.69 to 0.95)
        serotype 9V
    0.73 (0.60 to 0.89)
    0.18 (0.16 to 0.21)
        serotype 14
    4.19 (3.23 to 5.43)
    1.13 (0.90 to 1.40)
        serotype 18C
    0.90 (0.73 to 1.11)
    0.22 (0.19 to 0.27)
        serotype 19A
    1.56 (1.25 to 1.96)
    0.33 (0.27 to 0.39)
        serotype 19F
    4.54 (3.80 to 5.42)
    0.64 (0.54 to 0.76)
        serotype 23F
    0.43 (0.34 to 0.54)
    0.09 (0.08 to 0.10)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    for a week following each vaccination appointment at 2, 3, 4 and 12 months of age
    Adverse event reporting additional description
    Safety data in terms of SAEs, is collected at each visit for the preceding period, with details verified from GP notes. Parents are asked to complete a health diary for the week following each vaccination appointment to document local reactions (redness/swelling/ pain at the injection site) as well as any systemic symptoms and use of paracetamol.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 Protocol
    Dictionary version
    v6.0
    Reporting groups
    Reporting group title
    Group 1 (2+1 PCV13)
    Reporting group description
    		 PCV13 schedule 2+1 and all participants in both arms receiving Bexsero 2+1 and Infanrix/IPV/Hib with one MenC conjugate vaccination at 12 months given as the combined Hib/MenC conjugate vaccine, Menitorix

    Reporting group title
    Group 2 (1+1 PCV13)
    Reporting group description
    		 PCV13 schedule 1+1 and all participants at both arms receiving Bexsero and Infanrix/IPV/Hib with one MenC conjugate vaccination at 12 months given as the combined Hib/MenC conjugate vaccine, Menitorix

    Serious adverse events
    		 Group 1 (2+1 PCV13) Group 2 (1+1 PCV13)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 106 (12.26%)
    8 / 107 (7.48%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Mild concussion secondary to fall
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lacerated ear requiring sutures
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Burns
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Congenital Lymphangioma
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Irritability/ALTE
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurodevelopmental delay + feeding difficulties
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Fever related to vaccines
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mild acute gastroenteritis
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal bleeding
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchiolitis
         subjects affected / exposed
    3 / 106 (2.83%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RSV bronchiolitis
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wheezing/respiratory infection
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 107 (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
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia, wheezing
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest infection
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Croup
         subjects affected / exposed
    1 / 106 (0.94%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Abnormal liver function
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Kidney infection and sepsis
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 107 (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
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 107 (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
    Tonsillitis
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septicaemia
         subjects affected / exposed
    2 / 106 (1.89%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Group 1 (2+1 PCV13) Group 2 (1+1 PCV13)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    106 / 106 (100.00%)
    107 / 107 (100.00%)
    General disorders and administration site conditions
    Feeding
    Additional description: Diary 1 to 4
         subjects affected / exposed [1]
    82 / 95 (86.32%)
    75 / 87 (86.21%)
         occurrences all number
    82
    75
    Less active
    Additional description: Diary 1 to 4
         subjects affected / exposed [2]
    82 / 96 (85.42%)
    78 / 87 (89.66%)
         occurrences all number
    82
    78
    Irritability
    Additional description: Diary 1 to 4
         subjects affected / exposed [3]
    95 / 96 (98.96%)
    81 / 87 (93.10%)
         occurrences all number
    95
    81
    Crying
    Additional description: Diary 1 to 4
         subjects affected / exposed [4]
    88 / 96 (91.67%)
    74 / 87 (85.06%)
         occurrences all number
    88
    74
    Redness
    Additional description: Diary 1 to 4
         subjects affected / exposed [5]
    71 / 90 (78.89%)
    58 / 81 (71.60%)
         occurrences all number
    71
    58
    Swelling
    Additional description: Diary 1 to 4
         subjects affected / exposed [6]
    51 / 89 (57.30%)
    45 / 81 (55.56%)
         occurrences all number
    51
    45
    Tenderness
    Additional description: Diary 1 to 4
         subjects affected / exposed [7]
    67 / 91 (73.63%)
    64 / 79 (81.01%)
         occurrences all number
    67
    64
    Immune system disorders
    Temperature
    Additional description: Diary 1 to 4
         subjects affected / exposed [8]
    85 / 97 (87.63%)
    78 / 88 (88.64%)
         occurrences all number
    85
    78
    Gastrointestinal disorders
    Sickness
    Additional description: Diary 1 to 4
         subjects affected / exposed [9]
    61 / 96 (63.54%)
    55 / 87 (63.22%)
         occurrences all number
    61
    55
    Diarrhoea
    Additional description: Diary 1 to 4
         subjects affected / exposed [10]
    72 / 96 (75.00%)
    70 / 87 (80.46%)
         occurrences all number
    72
    70
    Notes
    [1] - 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 number of subjects does not match due to combination of withdrawal and missing diary card data.
    [2] - 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 number of subjects does not match due to combination of withdrawal and missing diary card data.
    [3] - 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 number of subjects does not match due to combination of withdrawal and missing diary card data.
    [4] - 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 number of subjects does not match due to combination of withdrawal and missing diary card data.
    [5] - 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 number of subjects does not match due to combination of withdrawal and missing diary card data.
    [6] - 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 number of subjects does not match due to combination of withdrawal and missing diary card data.
    [7] - 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 number of subjects does not match due to combination of withdrawal and missing diary card data.
    [8] - 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 number of subjects does not match due to combination of withdrawal and missing diary card data.
    [9] - 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 number of subjects does not match due to combination of withdrawal and missing diary card data.
    [10] - 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 number of subjects does not match due to combination of withdrawal and missing diary card data.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Oct 2015
    .The principal investigators have been updated on page 1 .The type of laboratory assays performed for meningococcal serogroup C and W at 5 months of age (secondary objectives and endpoints) have been revised on pages 9,11,18 and 38 .Clarification of the timings to assess antibody responses to Men B, tetanus, diphtheria and pertussis on pages 9,11,18 and 38 .The titre thresholds for different type of assays have been clarified on pages 9, 11, 18 and 38 .Clarification that reactogenicity data will only be collected following immunizations at 2, 3, 4 and 12 months of age on pages 10, 12, 18, 28 and 38 .Clarification of the references used to define the protective levels of antibodies to Men B vaccine and PCV13 on page 28 .Clarification of the laboratory responsible for processing NP swabs on pages 31 and 32 .Removal of functional pertussis antibody studies on page 31 .Clarification of the name of the sample storage facility at PHE on page 32 .Clarification of the data analysis, including an interim analysis on page 40 .Clarification of the location of the Clinical Trial Data Manager on page 41 .The guidelines followed by the study laboratories have been updated on page 43 .Update of references on page45. .Clarification of PHE recruitment methods on page 23.
    12 Jan 2018
    .The study has been extended. The final visit (visit 8) will now be when participants are 21-33months of age (instead of 18 months of age). The extension involves an additional visit and a blood test. This will allow an extended description of antibody responses to the vaccines given in this trial, which has been listed as an additional secondary endpoint. .Participants will be recruited from all study areas (Thames Valley, Gloucestershire and Hertfordshire). .The PI for the PHE sites in Gloucestershire and Hertfordshire has also changed.
    12 Feb 2018
    .Increase maximal blood volume taken at visit 8 from 5mL to 8mL. .Remove increased body temperature from the temporary exclusion criteria for visit 8. .Change laboratory processes for visit 8, now all samples will be shipped to OVG, spun, frozen and then either stored or sent to other sites for analysis.

    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.
    Follow up results are confidential and not reported. Paper is in draft, will be published soon and distributed to participants.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/29174323
    http://www.ncbi.nlm.nih.gov/pubmed/33428870
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