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    Clinical Trial Results:
    A Phase 2, Randomized, Observer-Blind, Multicenter Study to Evaluate the Immunogenicity and Safety of Several Doses of Antigen and MF59 Adjuvant Content in a Monovalent H5N1 Pandemic Influenza Vaccine in Healthy Pediatric Subjects 6 Months to < 9 Years of Age

    Summary
    EudraCT number
    		 2016-001898-32
    Trial protocol
    		 EE   Outside EU/EEA  
    Global end of trial date
    15 Apr 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Oct 2022
    First version publication date
    14 Oct 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    V87_30
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04669691
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Seqirus UK Ltd.
    Sponsor organisation address
    The Point, 29 Market Street, Maidenhead, United Kingdom, SL6 8AA
    Public contact
    Clinical Trial Disclosure Manager, Seqirus Inc., Seqirus.ClinicalTrials@seqirus.com
    Scientific contact
    Clinical Trial Disclosure Manager, Seqirus Inc., Seqirus.ClinicalTrials@seqirus.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001830-PIP01-15 EMEA-000599-PIP01-09
    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
    15 Apr 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Apr 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Apr 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary Safety Objective: • To evaluate the safety in each study vaccine group from Day 1 through Day 387, by total population and by age cohort. Primary Immunogenicity Objective: • To assess by total population and by age cohort, the antibody responses to each of the study vaccines prior to (Day 1) and at 3 weeks after the first or second vaccination (Day 22 or Day 43), as measured by hemagglutination inhibition (HI) and microneutralization (MN) assays.
    Protection of trial subjects
    This clinical study was designed, implemented, and reported in accordance with the ICH Harmonized Tripartite Guidelines for GCP, with applicable local regulations, including European Directive 2001/20/EC, US Code of Federal Regulations Title 21, ICH E6 (R2), and Japanese Ministry of Health, Labor, and Welfare, the sponsor codes on protection of human rights, and with the ethical principles laid down in the Declaration of Helsinki.
    Background therapy
    		 Not applicable
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    19 Dec 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Estonia: 100
    Country: Number of subjects enrolled
    Philippines: 320
    Worldwide total number of subjects
    420
    EEA total number of subjects
    100
    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)
    115
    Children (2-11 years)
    305
    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 enrolled from 2 centers in Estonia and 5 centers in the Philippines

    Pre-assignment
    Screening details
    		 All enrolled subjects were included in the study

    Period 1
    Period 1 title
    overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A
    Arm description
    		 1.875 µg H5N1 HA/50% MF59
    Arm type
    		 Experimental

    Investigational medicinal product name
    H5N1 Pandemic influenza vaccine (surface antigen, inactivated, adjuvanted)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    The aH5N1 vaccine formulation evaluated in Arm A contained 1.875 µg H5N1 hemagglutinin (HA)/0.125 mL MF59 (=50% MF59) 2 intramuscular injections administered 3 weeks apart (Day 1 and Day 22), in the anterolateral thigh for children <2 years of age and in the deltoid for children ≥2 years of age, unless the deltoid mass was insufficient

    Arm title
    		 Arm B
    Arm description
    		 3.75 µg H5N1 HA/50% MF59
    Arm type
    		 Experimental

    Investigational medicinal product name
    H5N1 Pandemic influenza vaccine (surface antigen, inactivated, adjuvanted)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    The aH5N1 vaccine formulation evaluated in Arm B contained 3.75 µg H5N1 HA/0.125 mL MF59 (=50% MF59) 2 intramuscular injections administered 3 weeks apart (Day 1 and Day 22), in the anterolateral thigh for children <2 years of age and in the deltoid for children ≥2 years of age, unless the deltoid mass was insufficient

    Arm title
    		 Arm C
    Arm description
    		 7.5 µg H5N1 HA/50% MF59
    Arm type
    		 Experimental

    Investigational medicinal product name
    H5N1 Pandemic influenza vaccine (surface antigen, inactivated, adjuvanted)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    The aH5N1 vaccine formulation evaluated in Arm C contained 7.5 µg H5N1 HA/0.125 mL MF59 (=50% MF59) 2 intramuscular injections administered 3 weeks apart (Day 1 and Day 22), in the anterolateral thigh for children <2 years of age and in the deltoid for children ≥2 years of age, unless the deltoid mass was insufficient

    Arm title
    		 Arm D
    Arm description
    		 1.875 µg H5N1 HA/100% MF59
    Arm type
    		 Experimental

    Investigational medicinal product name
    H5N1 Pandemic influenza vaccine (surface antigen, inactivated, adjuvanted)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    The aH5N1 vaccine formulation evaluated in Arm D contained 1.875 µg H5N1 HA/0.25 mL MF59 (=100% MF59) 2 intramuscular injections administered 3 weeks apart (Day 1 and Day 22), in the anterolateral thigh for children <2 years of age and in the deltoid for children ≥2 years of age, unless the deltoid mass was insufficient

    Arm title
    		 Arm E
    Arm description
    		 3.75 µg H5N1 HA/100% MF59
    Arm type
    		 Experimental

    Investigational medicinal product name
    H5N1 Pandemic influenza vaccine (surface antigen, inactivated, adjuvanted)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    The aH5N1 vaccine formulation evaluated in Arm E contained 3.75 µg H5N1 HA/0.25 mL MF59 (=100% MF59) 2 intramuscular injections administered 3 weeks apart (Day 1 and Day 22), in the anterolateral thigh for children <2 years of age and in the deltoid for children ≥2 years of age, unless the deltoid mass was insufficient

    Arm title
    		 Arm F
    Arm description
    		 7.5 µg H5N1 HA/100% MF59
    Arm type
    		 Experimental

    Investigational medicinal product name
    H5N1 Pandemic influenza vaccine (surface antigen, inactivated, adjuvanted)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    The aH5N1 vaccine formulation evaluated in Arm F contained 7.5 µg H5N1 HA/0.25 mL MF59 (=100% MF59) 2 intramuscular injections administered 3 weeks apart (Day 1 and Day 22), in the anterolateral thigh for children <2 years of age and in the deltoid for children ≥2 years of age, unless the deltoid mass was insufficient

    Number of subjects in period 1
    		Arm A Arm B Arm C Arm D Arm E Arm F
    Started
    69
    72
    70
    70
    69
    70
    Completed
    69
    71
    70
    70
    69
    70
    Not completed
    0
    1
    0
    0
    0
    0
         Adverse event, serious fatal
    -
    1
    -
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 1.875 µg H5N1 HA/50% MF59

    Reporting group title
    Arm B
    Reporting group description
    		 3.75 µg H5N1 HA/50% MF59

    Reporting group title
    Arm C
    Reporting group description
    		 7.5 µg H5N1 HA/50% MF59

    Reporting group title
    Arm D
    Reporting group description
    		 1.875 µg H5N1 HA/100% MF59

    Reporting group title
    Arm E
    Reporting group description
    		 3.75 µg H5N1 HA/100% MF59

    Reporting group title
    Arm F
    Reporting group description
    		 7.5 µg H5N1 HA/100% MF59

    Reporting group values
    		 Arm A Arm B Arm C Arm D Arm E Arm F Total
    Number of subjects
    		 69 72 70 70 69 70 420
    Age categorical
    Units: Subjects
        6 months to <36 months
    		 35 35 35 35 36 34 210
        3 years to <9 years
    		 34 37 35 35 33 36 210
    Age continuous
    Units: months
        arithmetic mean (standard deviation)
    		 48.2 ± 28.8 50.9 ± 31.6 47.1 ± 30.9 48.8 ± 31.8 49.9 ± 30.8 50.6 ± 31.8 -
    Gender categorical
    Units: Subjects
        Female
    		 31 26 33 31 31 40 192
        Male
    		 38 46 37 39 38 30 228
    Race
    Units: Subjects
        Asian
    		 52 56 53 53 52 53 319
        Black or African American
    		 0 0 0 0 0 1 1
        White
    		 17 16 17 17 17 16 100
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
    		 69 72 70 70 69 70 420
    Received an influenza vaccination in the past 2 years
    Units: Subjects
        Yes
    		 1 0 3 3 3 2 12
        No
    		 68 72 67 67 66 68 408
    Country
    Units: Subjects
        Estonia
    		 17 16 17 17 17 16 100
        Philippines
    		 52 56 53 53 52 54 320
    Body mass index
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 16.3 ± 2.7 16.3 ± 2.7 16.5 ± 2.9 15.7 ± 2.0 15.6 ± 1.9 16.1 ± 2.6 -

    End points

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    End points reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 1.875 µg H5N1 HA/50% MF59

    Reporting group title
    Arm B
    Reporting group description
    		 3.75 µg H5N1 HA/50% MF59

    Reporting group title
    Arm C
    Reporting group description
    		 7.5 µg H5N1 HA/50% MF59

    Reporting group title
    Arm D
    Reporting group description
    		 1.875 µg H5N1 HA/100% MF59

    Reporting group title
    Arm E
    Reporting group description
    		 3.75 µg H5N1 HA/100% MF59

    Reporting group title
    Arm F
    Reporting group description
    		 7.5 µg H5N1 HA/100% MF59

    Subject analysis set title
    PPS Immunogenicity
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PPS Immunogenicity is all subjects in the Full Analysis Set (FAS) immunogenicity who: correctly received the vaccine; provided at least the baseline and one postbaseline blood sample, with evaluable immunogenicity data; had no protocol deviations leading to exclusion as defined prior to unblinding/analysis.

    Subject analysis set title
    Solicited Safety Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects in the All Exposed Set with any solicited AE data collected, including temperature measurements or use of analgesics/antipyretics.

    Subject analysis set title
    Unsolicited Safety Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects in the All Exposed Set with unsolicited AE data.

    Primary: Pre- and postvaccination GMTs and GMRs (HI assay against the homologous H5N1 strain) in the overall study population (PPS Immunogenicity)

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    End point title
    		 Pre- and postvaccination GMTs and GMRs (HI assay against the homologous H5N1 strain) in the overall study population (PPS Immunogenicity) [1]
    End point description
    Geometric mean titers (GMTs) on Day 1 and Day 22 (3 weeks after the first vaccination) or Day 43 (3 weeks after the second vaccination) as determined by HI assay against the homologous H5N1 pandemic influenza strain. Geometric mean ratios (GMRs) calculated as follows: Day 22/Day 1 or Day 43/Day 1 as determined by HI assay against the homologous H5N1 pandemic influenza strain. Subject Analysis Set: PPS Immunogenicity (overall study population)
    End point type
    Primary
    End point timeframe
    Day 1 to Day 43
    Notes
    [1] - 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 statistical analysis was mainly descriptive in nature without any prespecified inferential analyses.
    End point values
    		 Arm A Arm B Arm C Arm D Arm E Arm F
    Number of subjects analysed
    67
    71
    67
    66
    69
    67
    Units: Titer / ratio
    geometric mean (confidence interval 95%)
        GMT Day 1
    5.05 (4.8 to 5.3)
    5.00 (4.8 to 5.2)
    5.21 (5.0 to 5.4)
    5.05 (4.8 to 5.3)
    5.00 (4.8 to 5.2)
    5.24 (5.0 to 5.5)
        GMT Day 22
    5.61 (4.9 to 6.4)
    6.21 (5.5 to 7.0)
    5.98 (5.3 to 6.8)
    6.17 (5.4 to 7.0)
    6.47 (5.7 to 7.3)
    5.78 (5.1 to 6.6)
        GMR Day 22/Day 1
    1.11 (1.0 to 1.3)
    1.24 (1.1 to 1.4)
    1.15 (1.0 to 1.3)
    1.22 (1.1 to 1.4)
    1.29 (1.1 to 1.5)
    1.11 (1.0 to 1.3)
        GMT Day 43
    81.10 (58.3 to 112.8)
    68.06 (49.4 to 93.8)
    86.70 (62.3 to 120.7)
    122.43 (87.8 to 170.7)
    123.37 (89.1 to 170.8)
    123.61 (88.8 to 172.1)
        GMR Day 43/Day 1
    16.14 (11.5 to 22.6)
    13.77 (9.9 to 19.1)
    16.38 (11.7 to 23.0)
    24.35 (17.3 to 34.2)
    24.98 (17.9 to 34.8)
    23.14 (16.5 to 32.4)
    No statistical analyses for this end point

    Primary: Pre- and postvaccination GMTs and GMRs (HI assay against the homologous H5N1 strain) in the 6 months to <36 months age cohort (PPS Immunogenicity)

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    End point title
    		 Pre- and postvaccination GMTs and GMRs (HI assay against the homologous H5N1 strain) in the 6 months to <36 months age cohort (PPS Immunogenicity) [2]
    End point description
    GMTs on Day 1 and Day 22 (3 weeks after the first vaccination) or Day 43 (3 weeks after the second vaccination) as determined by HI assay against the homologous H5N1 pandemic influenza strain. GMRs calculated as follows: Day 22/Day 1 or Day 43/Day 1 as determined by HI assay against the homologous H5N1 pandemic influenza strain. Subject Analysis Set: PPS Immunogenicity (6 months to <36 months age cohort)
    End point type
    Primary
    End point timeframe
    Day 1 to Day 43
    Notes
    [2] - 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 statistical analysis was mainly descriptive in nature without any prespecified inferential analyses.
    End point values
    		 Arm A Arm B Arm C Arm D Arm E Arm F
    Number of subjects analysed
    34
    34
    34
    33
    36
    31
    Units: Titer / ratio
    geometric mean (confidence interval 95%)
        GMT Day 1
    5.10 (4.9 to 5.3)
    5.00 (4.8 to 5.2)
    5.42 (5.2 to 5.7)
    5.11 (4.9 to 5.3)
    5.00 (4.8 to 5.2)
    5.00 (4.8 to 5.2)
        GMT Day 22
    5.59 (4.7 to 6.6)
    6.14 (5.2 to 7.3)
    5.51 (4.6 to 6.6)
    6.23 (5.2 to 7.4)
    6.55 (5.5 to 7.8)
    5.78 (4.8 to 6.9)
        GMR Day 22/Day 1
    1.10 (0.9 to 1.3)
    1.21 (1.0 to 1.4)
    1.05 (0.9 to 1.3)
    1.22 (1.0 to 1.5)
    1.30 (1.1 to 1.5)
    1.14 (1.0 to 1.4)
        GMT Day 43
    93.22 (56.5 to 153.7)
    98.37 (59.6 to 162.4)
    102.28 (61.5 to 170.1)
    129.72 (78.1 to 215.5)
    157.44 (96.7 to 256.3)
    120.07 (71.0 to 202.9)
        GMR Day 43/Day 1
    18.27 (11.1 to 30.1)
    19.62 (11.9 to 32.4)
    19.02 (11.5 to 31.4)
    25.41 (15.3 to 42.2)
    31.39 (19.3 to 51.1)
    23.94 (14.2 to 40.4)
    No statistical analyses for this end point

    Primary: Pre- and postvaccination GMTs and GMRs (HI assay against the homologous H5N1 strain) in the 3 years to <9 years age cohort (PPS Immunogenicity)

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    End point title
    		 Pre- and postvaccination GMTs and GMRs (HI assay against the homologous H5N1 strain) in the 3 years to <9 years age cohort (PPS Immunogenicity) [3]
    End point description
    GMTs on Day 1 and Day 22 (3 weeks after the first vaccination) or Day 43 (3 weeks after the second vaccination) as determined by HI assay against the homologous H5N1 pandemic influenza strain. GMRs calculated as follows: Day 22/Day 1 or Day 43/Day 1 as determined by HI assay against the homologous H5N1 pandemic influenza strain. Subject Analysis Set: PPS Immunogenicity (3 years to <9 years age cohort)
    End point type
    Primary
    End point timeframe
    Day 1 to Day 43
    Notes
    [3] - 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 statistical analysis was mainly descriptive in nature without any prespecified inferential analyses.
    End point values
    		 Arm A Arm B Arm C Arm D Arm E Arm F
    Number of subjects analysed
    33
    37
    33
    33
    33
    36
    Units: Titer / ratio
    geometric mean (confidence interval 95%)
        GMT Day 1
    5.00 (4.6 to 5.4)
    5.00 (4.7 to 5.4)
    5.00 (4.6 to 5.4)
    5.00 (4.6 to 5.4)
    5.00 (4.6 to 5.4)
    5.45 (5.1 to 5.9)
        GMT Day 22
    5.61 (4.6 to 6.8)
    6.32 (5.3 to 7.6)
    6.29 (5.2 to 7.6)
    6.10 (5.0 to 7.4)
    6.42 (5.3 to 7.8)
    5.91 (4.9 to 7.1)
        GMR Day 22/Day 1
    1.12 (0.9 to 1.4)
    1.26 (1.0 to 1.5)
    1.26 (1.0 to 1.5)
    1.22 (1.0 to 1.5)
    1.29 (1.0 to 1.6)
    1.08 (0.9 to 1.3)
        GMT Day 43
    70.21 (45.5 to 108.4)
    48.35 (32.1 to 72.9)
    69.40 (44.9 to 107.2)
    114.85 (74.4 to 177.4)
    97.17 (62.9 to 150.1)
    129.15 (84.9 to 196.6)
        GMR Day 43/Day 1
    14.27 (9.0 to 22.6)
    9.83 (6.4 to 15.2)
    14.10 (8.9 to 22.3)
    23.34 (14.7 to 37.0)
    19.75 (12.5 to 31.3)
    21.98 (14.2 to 34.1)
    No statistical analyses for this end point

    Primary: Percentage of subjects with seroconversion and percentage of subjects with HI titer ≥1:40 (HI assay against the homologous H5N1 strain) in the overall study population (PPS Immunogenicity)

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    End point title
    		 Percentage of subjects with seroconversion and percentage of subjects with HI titer ≥1:40 (HI assay against the homologous H5N1 strain) in the overall study population (PPS Immunogenicity) [4]
    End point description
    Percentage of subjects achieving seroconversion (non-detectable to ≥1:40, or 4-fold increase from a detectable Day 1 titer) on Day 22 or 43. Percentage of subjects achieving seroconversion with a titer ≥1:40 on Days 1, 22 or 43. Subject Analysis Set: PPS Immunogenicity (overall study population)
    End point type
    Primary
    End point timeframe
    Day 1 to Day 43
    Notes
    [4] - 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 statistical analysis was mainly descriptive in nature without any prespecified inferential analyses.
    End point values
    		 Arm A Arm B Arm C Arm D Arm E Arm F
    Number of subjects analysed
    67
    71
    67
    66
    69
    67
    Units: Percentage of subjects
    number (confidence interval 95%)
        % of subjects with seroconversion at Day 22
    0.0 (0.00 to 5.36)
    4.2 (0.88 to 11.86)
    3.0 (0.36 to 10.37)
    4.5 (0.95 to 12.71)
    1.4 (0.04 to 7.81)
    3.0 (0.36 to 10.37)
        % of subjects with seroconversion at Day 43
    82.1 (70.80 to 90.39)
    74.6 (62.92 to 84.23)
    77.6 (65.78 to 86.89)
    90.9 (81.26 to 96.59)
    87.0 (76.68 to 93.86)
    86.6 (76.03 to 93.67)
        % of subjects with HI titer ≥1:40 at Day 1
    0.0 (0.00 to 5.36)
    0.0 (0.00 to 5.06)
    0.0 (0.00 to 5.36)
    0.0 (0.00 to 5.44)
    0.0 (0.00 to 5.21)
    1.5 (0.04 to 8.04)
        % of subjects with HI titer ≥1:40 at Day 22
    0.0 (0.00 to 5.36)
    4.2 (0.88 to 11.86)
    3.0 (0.36 to 10.37)
    4.5 (0.95 to 12.71)
    1.4 (0.04 to 7.81)
    3.0 (0.36 to 10.37)
        % of subjects with HI titer ≥1:40 at Day 43
    82.1 (70.80 to 90.39)
    74.6 (62.92 to 84.23)
    77.6 (65.78 to 86.89)
    90.9 (81.26 to 96.59)
    87.0 (76.68 to 93.86)
    86.6 (76.03 to 93.67)
    No statistical analyses for this end point

    Primary: Percentage of subjects with seroconversion and percentage of subjects with HI titer ≥1:40 (HI assay against the homologous H5N1 strain) in the 6 months to <36 months age cohort (PPS Immunogenicity)

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    End point title
    		 Percentage of subjects with seroconversion and percentage of subjects with HI titer ≥1:40 (HI assay against the homologous H5N1 strain) in the 6 months to <36 months age cohort (PPS Immunogenicity) [5]
    End point description
    Percentage of subjects achieving seroconversion (non-detectable to ≥1:40, or 4-fold increase from a detectable Day 1 titer) on Day 22 or 43. Percentage of subjects achieving seroconversion with a titer ≥1:40 on Days 1, 22 or 43. Subject Analysis Set: PPS Immunogenicity (6 months to <36 months age cohort)
    End point type
    Primary
    End point timeframe
    Day 1 to Day 43
    Notes
    [5] - 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 statistical analysis was mainly descriptive in nature without any prespecified inferential analyses.
    End point values
    		 Arm A Arm B Arm C Arm D Arm E Arm F
    Number of subjects analysed
    34
    34
    34
    33
    36
    31
    Units: Percentage of subjects
    number (confidence interval 95%)
        % of subjects with seroconversion at Day 22
    0.0 (0.00 to 10.28)
    2.9 (0.07 to 15.33)
    0.0 (0.00 to 10.28)
    3.0 (0.08 to 15.76)
    0.0 (0.00 to 9.74)
    3.2 (0.08 to 16.70)
        % of subjects with seroconversion at Day 43
    79.4 (62.10 to 91.30)
    82.4 (65.47 to 93.24)
    79.4 (62.10 to 91.30)
    93.9 (79.77 to 99.26)
    86.1 (70.50 to 95.33)
    87.1 (70.17 to 96.37)
        % of subjects with HI titer ≥1:40 at Day 1
    0.0 (0.00 to 10.28)
    0.0 (0.00 to 10.28)
    0.0 (0.00 to 10.28)
    0.0 (0.00 to 10.58)
    0.0 (0.00 to 9.74)
    0.0 (0.00 to 11.22)
        % of subjects with HI titer ≥1:40 at Day 22
    0.0 (0.00 to 10.28)
    2.9 (0.07 to 15.33)
    0.0 (0.00 to 10.28)
    3.0 (0.08 to 15.76)
    0.0 (0.00 to 9.74)
    3.2 (0.08 to 16.70)
        % of subjects with HI titer ≥1:40 at Day 43
    79.4 (62.10 to 91.30)
    82.4 (65.47 to 93.24)
    79.4 (62.10 to 91.30)
    93.9 (79.77 to 99.26)
    86.1 (70.50 to 95.33)
    87.1 (70.17 to 96.37)
    No statistical analyses for this end point

    Primary: Percentage of subjects with seroconversion and percentage of subjects with HI titer ≥1:40 (HI assay against the homologous H5N1 strain) in the 3 years to <9 years age cohort (PPS Immunogenicity)

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    End point title
    		 Percentage of subjects with seroconversion and percentage of subjects with HI titer ≥1:40 (HI assay against the homologous H5N1 strain) in the 3 years to <9 years age cohort (PPS Immunogenicity) [6]
    End point description
    Percentage of subjects achieving seroconversion (non-detectable to ≥1:40, or 4-fold increase from a detectable Day 1 titer) on Day 22 or 43. Percentage of subjects achieving seroconversion with a titer ≥1:40 on Days 1, 22 or 43. Subject Analysis Set: PPS Immunogenicity (3 years to <9 years age cohort)
    End point type
    Primary
    End point timeframe
    Day 1 to Day 43
    Notes
    [6] - 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 statistical analysis was mainly descriptive in nature without any prespecified inferential analyses.
    End point values
    		 Arm A Arm B Arm C Arm D Arm E Arm F
    Number of subjects analysed
    33
    37
    33
    33
    33
    36
    Units: Percentage of subjects
    number (confidence interval 95%)
        % of subjects with seroconversion at Day 22
    0.0 (0.00 to 10.58)
    5.4 (0.66 to 18.19)
    6.1 (0.74 to 20.23)
    6.1 (0.74 to 20.23)
    3.0 (0.08 to 15.76)
    2.8 (0.07 to 14.53)
        % of subjects with seroconversion at Day 43
    84.8 (68.10 to 94.89)
    67.6 (50.21 to 81.99)
    75.8 (57.74 to 88.91)
    87.9 (71.80 to 96.60)
    87.9 (71.80 to 96.60)
    86.1 (70.50 to 95.33)
        % of subjects with HI titer ≥1:40 at Day 1
    0.0 (0.00 to 10.58)
    0.0 (0.00 to 9.49)
    0.0 (0.00 to 10.58)
    0.0 (0.00 to 10.58)
    0.0 (0.00 to 10.58)
    2.8 (0.07 to 14.53)
        % of subjects with HI titer ≥1:40 at Day 22
    0.0 (0.00 to 10.58)
    5.4 (0.66 to 18.19)
    6.1 (0.74 to 20.23)
    6.1 (0.74 to 20.23)
    3.0 (0.08 to 15.76)
    2.8 (0.07 to 14.53)
        % of subjects with HI titer ≥1:40 at Day 43
    84.8 (68.10 to 94.89)
    67.6 (50.21 to 81.99)
    75.8 (57.74 to 88.91)
    87.9 (71.80 to 96.60)
    87.9 (71.80 to 96.60)
    86.1 (70.50 to 95.33)
    No statistical analyses for this end point

    Primary: Pre- and postvaccination GMTs and GMRs (MN assay against the homologous H5N1 strain) in the overall study population (PPS Immunogenicity)

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    End point title
    		 Pre- and postvaccination GMTs and GMRs (MN assay against the homologous H5N1 strain) in the overall study population (PPS Immunogenicity) [7]
    End point description
    GMTs on Day 1 and Day 22 (3 weeks after the first vaccination) or Day 43 (3 weeks after the second vaccination) as determined by MN assay against the homologous H5N1 pandemic influenza strain. GMRs calculated as follows: Day 22/Day 1 or Day 43/Day 1 as determined by MN assay against the homologous H5N1 pandemic influenza strain. Subject Analysis Set: PPS Immunogenicity (overall study population)
    End point type
    Primary
    End point timeframe
    Day 1 to Day 43
    Notes
    [7] - 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 statistical analysis was mainly descriptive in nature without any prespecified inferential analyses.
    End point values
    		 Arm A Arm B Arm C Arm D Arm E Arm F
    Number of subjects analysed
    67
    71 [8]
    67
    66 [9]
    69 [10]
    67
    Units: Titer / ratio
    geometric mean (confidence interval 95%)
        GMT Day 1
    5.19 (4.9 to 5.5)
    5.27 (5.0 to 5.6)
    5.38 (5.1 to 5.7)
    5.16 (4.9 to 5.5)
    5.13 (4.9 to 5.4)
    5.31 (5.0 to 5.6)
        GMT Day 22
    31.42 (24.7 to 40.0)
    34.83 (27.5 to 44.2)
    40.61 (31.9 to 51.7)
    46.08 (36.0 to 59.0)
    54.66 (42.9 to 69.7)
    52.81 (41.5 to 67.2)
        GMR Day 22/Day 1
    6.02 (4.7 to 7.7)
    6.62 (5.2 to 8.4)
    7.66 (6.0 to 9.8)
    8.85 (6.9 to 11.3)
    10.52 (8.2 to 13.4)
    10.02 (7.9 to 12.8)
        GMT Day 43
    531.04 (424.7 to 664.1)
    667.86 (536.7 to 831.1)
    610.37 (488.0 to 763.4)
    619.44 (494.5 to 775.9)
    864.91 (693.8 to 1078.2)
    766.18 (612.6 to 958.2)
        GMR Day 43/Day 1
    102.26 (81.4 to 128.5)
    126.71 (101.4 to 158.4)
    113.98 (90.7 to 143.2)
    119.78 (95.2 to 150.7)
    168.06 (134.2 to 210.5)
    144.55 (115.0 to 181.6)
    Notes
    [8] - n=69 at Day 22; n=70 at Day 43
    [9] - n=64 at Day 22
    [10] - n=66 at Day 22
    No statistical analyses for this end point

    Primary: Pre- and postvaccination GMTs and GMRs (MN assay against the homologous H5N1 strain) in the 6 months to <36 months age cohort (PPS Immunogenicity)

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    End point title
    		 Pre- and postvaccination GMTs and GMRs (MN assay against the homologous H5N1 strain) in the 6 months to <36 months age cohort (PPS Immunogenicity) [11]
    End point description
    GMTs on Day 1 and Day 22 (3 weeks after the first vaccination) or Day 43 (3 weeks after the second vaccination) as determined by MN assay against the homologous H5N1 pandemic influenza strain. GMRs calculated as follows: Day 22/Day 1 or Day 43/Day 1 as determined by MN assay against the homologous H5N1 pandemic influenza strain. Subject Analysis Set: PPS Immunogenicity (6 months to <36 months age cohort)
    End point type
    Primary
    End point timeframe
    Day 1 to Day 43
    Notes
    [11] - 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 statistical analysis was mainly descriptive in nature without any prespecified inferential analyses.
    End point values
    		 Arm A Arm B Arm C Arm D Arm E Arm F
    Number of subjects analysed
    34
    34
    34
    33 [12]
    36 [13]
    31
    Units: Titer / ratio
    geometric mean (confidence interval 95%)
        GMT Day 1
    5.00 (4.7 to 5.3)
    5.00 (4.7 to 5.3)
    5.26 (4.9 to 5.6)
    5.21 (4.9 to 5.6)
    5.10 (4.8 to 5.4)
    5.29 (4.9 to 5.7)
        GMT Day 22
    29.27 (21.0 to 40.8)
    33.14 (23.8 to 46.2)
    24.93 (17.9 to 34.7)
    45.78 (32.3 to 64.8)
    69.41 (49.8 to 96.7)
    42.07 (29.7 to 59.6)
        GMR Day 22/Day 1
    5.76 (4.1 to 8.0)
    6.52 (4.7 to 9.1)
    4.80 (3.4 to 6.7)
    8.84 (6.2 to 12.5)
    13.54 (9.7 to 18.9)
    8.09 (5.7 to 11.4)
        GMT Day 43
    618.77 (448.2 to 854.3)
    910.32 (659.3 to 1256.9)
    717.83 (520.0 to 991.0)
    725.06 (522.8 to 1005.5)
    1094.07 (800.0 to 1496.2)
    863.94 (616.3 to 1211.2)
        GMR Day 43/Day 1
    122.81 (88.8 to 169.9)
    180.68 (130.6 to 250.0)
    137.36 (99.3 to 190.0)
    139.62 (100.4 to 194.1)
    214.16 (156.2 to 293.6)
    164.74 (117.3 to 231.4)
    Notes
    [12] - n=31 at Day 22
    [13] - n=34 at Day 22
    No statistical analyses for this end point

    Primary: Pre- and postvaccination GMTs and GMRs (MN assay against the homologous H5N1 strain) in the 3 years to 9 years age cohort (PPS Immunogenicity)

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    End point title
    		 Pre- and postvaccination GMTs and GMRs (MN assay against the homologous H5N1 strain) in the 3 years to 9 years age cohort (PPS Immunogenicity) [14]
    End point description
    GMTs on Day 1 and Day 22 (3 weeks after the first vaccination) or Day 43 (3 weeks after the second vaccination) as determined by MN assay against the homologous H5N1 pandemic influenza strain. GMRs calculated as follows: Day 22/Day 1 or Day 43/Day 1 as determined by MN assay against the homologous H5N1 pandemic influenza strain. Subject Analysis Set: PPS Immunogenicity (3 years to 9 years age cohort)
    End point type
    Primary
    End point timeframe
    Day 1 to Day 43
    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 statistical analysis was mainly descriptive in nature without any prespecified inferential analyses.
    End point values
    		 Arm A Arm B Arm C Arm D Arm E Arm F
    Number of subjects analysed
    33
    37 [15]
    33
    33
    33 [16]
    36
    Units: Titer / ratio
    geometric mean (confidence interval 95%)
        GMT Day 1
    5.38 (4.9 to 5.9)
    5.54 (5.1 to 6.0)
    5.49 (5.0 to 6.0)
    5.11 (4.7 to 5.6)
    5.16 (4.7 to 5.7)
    5.35 (4.9 to 5.8)
        GMT Day 22
    33.70 (24.0 to 47.4)
    36.69 (26.3 to 51.1)
    66.97 (47.6 to 94.2)
    46.59 (33.1 to 65.6)
    42.11 (29.8 to 59.6)
    65.11 (47.0 to 90.2)
        GMR Day 22/Day 1
    6.29 (4.5 to 8.9)
    6.73 (4.8 to 9.4)
    12.37 (8.8 to 17.4)
    8.90 (6.3 to 12.5)
    8.00 (5.7 to 11.3)
    12.18 (8.8 to 16.9)
        GMT Day 43
    458.11 (334.2 to 627.9)
    495.77 (366.4 to 670.9)
    518.46 (378.2 to 710.8)
    527.09 (384.3 to 723.0)
    680.71 (496.4 to 933.4)
    670.67 (495.9 to 907.0)
        GMR Day 43/Day 1
    85.22 (61.6 to 118.0)
    89.57 (65.6 to 122.3)
    94.64 (68.4 to 131.0)
    102.76 (74.2 to 142.3)
    131.50 (95.0 to 182.0)
    125.44 (91.9 to 171.3)
    Notes
    [15] - n=35 at Day 22; n=36 at Day 43
    [16] - n=32 at Day 22
    No statistical analyses for this end point

    Primary: Percentage of subjects with seroconversion and percentage of subjects with MN titer ≥1:40 (MN assay against the homologous H5N1 strain) in the overall study population (PPS Immunogenicity)

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    End point title
    		 Percentage of subjects with seroconversion and percentage of subjects with MN titer ≥1:40 (MN assay against the homologous H5N1 strain) in the overall study population (PPS Immunogenicity) [17]
    End point description
    Percentage of subjects achieving seroconversion (non-detectable to ≥1:40, or 4-fold increase from a detectable Day 1 titer) on Day 22 or 43. Percentage of subjects achieving seroconversion with a titer ≥1:40 on Days 1, 22 or 43. Subject Analysis Set: PPS Immunogenicity (overall study population)
    End point type
    Primary
    End point timeframe
    Day 1 to Day 43
    Notes
    [17] - 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 statistical analysis was mainly descriptive in nature without any prespecified inferential analyses.
    End point values
    		 Arm A Arm B Arm C Arm D Arm E Arm F
    Number of subjects analysed
    67
    71 [18]
    67
    66 [19]
    69 [20]
    67
    Units: Percentage of subjects
    number (confidence interval 95%)
        % of subjects with seroconversion at Day 22
    44.8 (32.60 to 57.42)
    56.5 (44.04 to 68.42)
    58.2 (45.52 to 70.15)
    67.2 (54.31 to 78.41)
    72.7 (60.36 to 82.97)
    68.7 (56.16 to 79.44)
        % of subjects with seroconversion at Day 43
    100.0 (94.64 to 100.00)
    100.0 (94.87 to 100.00)
    100.0 (94.64 to 100.00)
    100.0 (94.56 to 100.00)
    100.0 (94.79 to 100.00)
    100.0 (94.64 to 100.00)
        % of subjects with MN titer ≥1:40 at Day 1
    0.0 (0.00 to 5.36)
    0.0 (0.00 to 5.06)
    0.0 (0.00 to 5.36)
    0.0 (0.00 to 5.44)
    0.0 (0.00 to 5.21)
    0.0 (0.00 to 5.36)
        % of subjects with MN titer ≥1:40 at Day 22
    44.8 (32.60 to 57.42)
    56.5 (44.04 to 68.42)
    58.2 (45.52 to 70.15)
    67.2 (54.31 to 78.41)
    72.7 (60.36 to 82.97)
    68.7 (56.16 to 79.44)
        % of subjects with MN titer ≥1:40 at Day 43
    100.0 (94.64 to 100.00)
    100.0 (94.87 to 100.00)
    100.0 (94.64 to 100.00)
    100.0 (94.56 to 100.00)
    100.0 (94.79 to 100.00)
    100.0 (94.64 to 100.00)
    Notes
    [18] - n=69 at Day 22; n=70 at Day 43
    [19] - n=64 at Day 22
    [20] - n=66 at Day 22
    No statistical analyses for this end point

    Primary: Percentage of subjects with seroconversion and percentage of subjects with MN titer ≥1:40 (MN assay against the homologous H5N1 strain) in the 6 months to <36 months age cohort (PPS Immunogenicity)

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    End point title
    		 Percentage of subjects with seroconversion and percentage of subjects with MN titer ≥1:40 (MN assay against the homologous H5N1 strain) in the 6 months to <36 months age cohort (PPS Immunogenicity) [21]
    End point description
    Percentage of subjects achieving seroconversion (non-detectable to ≥1:40, or 4-fold increase from a detectable Day 1 titer) on Day 22 or 43. Percentage of subjects achieving seroconversion with a titer ≥1:40 on Days 1, 22 or 43. Subject Analysis Set: PPS Immunogenicity (6 months to <36 months age cohort)
    End point type
    Primary
    End point timeframe
    Day 1 to Day 43
    Notes
    [21] - 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 statistical analysis was mainly descriptive in nature without any prespecified inferential analyses.
    End point values
    		 Arm A Arm B Arm C Arm D Arm E Arm F
    Number of subjects analysed
    34
    34
    34
    33 [22]
    36 [23]
    31
    Units: Percentage of subjects
    number (confidence interval 95%)
        % of subjects with seroconversion at Day 22
    35.3 (19.75 to 53.51)
    55.9 (37.89 to 72.81)
    35.3 (19.75 to 53.51)
    71.0 (51.96 to 85.78)
    82.4 (65.47 to 93.24)
    58.1 (39.08 to 75.45)
        % of subjects with seroconversion at Day 43
    100.0 (89.72 to 100.00)
    100.0 (89.72 to 100.00)
    100.0 (89.72 to 100.00)
    100.0 (89.42 to 100.00)
    100.0 (90.26 to 100.00)
    100.0 (88.78 to 100.00)
        % of subjects with MN titer ≥1:40 at Day 1
    0.0 (0.00 to 10.28)
    0.0 (0.00 to 10.28)
    0.0 (0.00 to 10.28)
    0.0 (0.00 to 10.58)
    0.0 (0.00 to 9.74)
    0.0 (0.00 to 11.22)
        % of subjects with MN titer ≥1:40 at Day 22
    35.3 (19.75 to 53.51)
    55.9 (37.89 to 72.81)
    35.3 (19.75 to 53.51)
    71.0 (51.96 to 85.78)
    82.4 (65.47 to 93.24)
    58.1 (39.08 to 75.45)
        % of subjects with MN titer ≥1:40 at Day 43
    100.0 (89.72 to 100.00)
    100.0 (89.72 to 100.00)
    100.0 (89.72 to 100.00)
    100.0 (89.42 to 100.00)
    100.0 (90.26 to 100.00)
    100.0 (88.78 to 100.00)
    Notes
    [22] - n=31 at Day 22
    [23] - n=34 at Day 22
    No statistical analyses for this end point

    Primary: Percentage of subjects with seroconversion and percentage of subjects with MN titer ≥1:40 (MN assay against the homologous H5N1 strain) in the 3 years to <9 years age cohort (PPS Immunogenicity)

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    End point title
    		 Percentage of subjects with seroconversion and percentage of subjects with MN titer ≥1:40 (MN assay against the homologous H5N1 strain) in the 3 years to <9 years age cohort (PPS Immunogenicity) [24]
    End point description
    Percentage of subjects achieving seroconversion (non-detectable to ≥1:40, or 4-fold increase from a detectable Day 1 titer) on Day 22 or 43. Percentage of subjects achieving seroconversion with a titer ≥1:40 on Days 1, 22 or 43. Subject Analysis Set: PPS Immunogenicity (3 years to < 9 years age cohort)
    End point type
    Primary
    End point timeframe
    Day 1 to Day 43
    Notes
    [24] - 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 statistical analysis was mainly descriptive in nature without any prespecified inferential analyses.
    End point values
    		 Arm A Arm B Arm C Arm D Arm E Arm F
    Number of subjects analysed
    33
    37 [25]
    33
    33
    33 [26]
    36
    Units: Percentage of subjects
    number (confidence interval 95%)
        % of subjects with seroconversion at Day 22
    54.5 (36.35 to 71.89)
    57.1 (39.35 to 73.68)
    81.8 (64.54 to 93.02)
    63.6 (45.12 to 79.60)
    62.5 (43.69 to 78.90)
    77.8 (60.85 to 89.88)
        % of subjects with seroconversion at Day 43
    100.0 (89.42 to 100.00)
    100.0 (90.26 to 100.00)
    100.0 (89.42 to 100.00)
    100.0 (89.42 to 100.00)
    100.0 (89.42 to 100.00)
    100.0 (90.26 to 100.00)
        % of subjects with MN titer ≥1:40 at Day 1
    0.0 (0.00 to 10.58)
    0.0 (0.00 to 9.49)
    0.0 (0.00 to 10.58)
    0.0 (0.00 to 10.58)
    0.0 (0.00 to 10.58)
    0.0 (0.00 to 9.74)
        % of subjects with MN titer ≥1:40 at Day 22
    54.5 (36.35 to 71.89)
    57.1 (39.35 to 73.68)
    81.8 (64.54 to 93.02)
    63.6 (45.12 to 79.60)
    62.5 (43.69 to 78.90)
    77.8 (60.85 to 89.88)
        % of subjects with MN titer ≥1:40 at Day 43
    100.0 (89.42 to 100.00)
    100.0 (90.26 to 100.00)
    100.0 (89.42 to 100.00)
    100.0 (89.42 to 100.00)
    100.0 (89.42 to 100.00)
    100.0 (90.26 to 100.00)
    Notes
    [25] - n=35 at Day 22; n=36 at Day 43
    [26] - n=32 at Day 22
    No statistical analyses for this end point

    Primary: Percentages of subjects with solicited adverse events (AEs) from Day 1 through Day 7 after any vaccination in the overall study population (Solicited Safety Set)

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    End point title
    		 Percentages of subjects with solicited adverse events (AEs) from Day 1 through Day 7 after any vaccination in the overall study population (Solicited Safety Set) [27]
    End point description
    Percentages of subjects with solicited local and systemic AEs that occurred within 7 days following each vaccination. Subject Analysis Set: Solicited Safety Set (overall study population)
    End point type
    Primary
    End point timeframe
    Day 1 through Day 7 after any vaccination
    Notes
    [27] - 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 statistical analysis was mainly descriptive in nature without any prespecified inferential analyses.
    End point values
    		 Arm A Arm B Arm C Arm D Arm E Arm F
    Number of subjects analysed
    69
    72
    70
    70
    69
    70
    Units: Percentage of subjects
    number (not applicable)
        Any solicited AE
    46.4
    45.8
    45.7
    48.6
    53.6
    44.3
        Solicited local AEs
    27.5
    22.2
    22.9
    30.0
    27.5
    24.3
        Solicited systemic AEs
    30.4
    33.3
    28.6
    34.3
    42.0
    25.7
        Analgesic/antipyretic use
    13.0
    9.7
    8.6
    7.1
    7.2
    12.9
    No statistical analyses for this end point

    Primary: Percentages of subjects with solicited adverse events (AEs) from Day 1 through Day 7 after any vaccination in the 6 months to <36 months age cohort (Solicited Safety Set)

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    End point title
    		 Percentages of subjects with solicited adverse events (AEs) from Day 1 through Day 7 after any vaccination in the 6 months to <36 months age cohort (Solicited Safety Set) [28]
    End point description
    Percentages of subjects with solicited local and systemic AEs that occurred within 7 days following each vaccination. Subject Analysis Set: Solicited Safety Set (6 months to <36 months age cohort)
    End point type
    Primary
    End point timeframe
    Day 1 through Day 7 after any vaccination
    Notes
    [28] - 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 statistical analysis was mainly descriptive in nature without any prespecified inferential analyses.
    End point values
    		 Arm A Arm B Arm C Arm D Arm E Arm F
    Number of subjects analysed
    35
    35
    35
    35
    36
    34
    Units: Percentage of subjects
    number (not applicable)
        Any solicited AE
    42.9
    57.1
    51.4
    57.1
    58.3
    44.1
        Solicited local AEs
    20.0
    28.6
    17.1
    31.4
    22.2
    11.8
        Solicited systemic AEs
    40.0
    42.9
    45.7
    45.7
    50.0
    32.4
        Analgesic/antipyretic use
    14.3
    11.4
    11.4
    8.6
    8.3
    17.6
    No statistical analyses for this end point

    Primary: Percentages of subjects with solicited adverse events (AEs) from Day 1 through Day 7 after any vaccination in the 3 years to <9 years age cohort (Solicited Safety Set)

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    End point title
    		 Percentages of subjects with solicited adverse events (AEs) from Day 1 through Day 7 after any vaccination in the 3 years to <9 years age cohort (Solicited Safety Set) [29]
    End point description
    Percentages of subjects with solicited local and systemic AEs that occurred within 7 days following each vaccination. Subject Analysis Set: Solicited Safety Set (3 years to <9 years age cohort)
    End point type
    Primary
    End point timeframe
    Day 1 through Day 7 after any vaccination
    Notes
    [29] - 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 statistical analysis was mainly descriptive in nature without any prespecified inferential analyses.
    End point values
    		 Arm A Arm B Arm C Arm D Arm E Arm F
    Number of subjects analysed
    34
    37
    35
    35
    33
    36
    Units: Percentage of subjects
    number (not applicable)
        Any solicited AE
    50.0
    35.1
    40.0
    40.0
    48.5
    44.4
        Solicited local AEs
    35.3
    16.2
    28.6
    28.6
    33.3
    36.1
        Solicited systemic AEs
    20.6
    24.3
    11.4
    22.9
    33.3
    19.4
        Analgesic/antipyretic use
    11.8
    8.1
    5.7
    5.7
    6.1
    8.3
    No statistical analyses for this end point

    Primary: Percentages of subjects with any unsolicited AEs reported within 21 days after each vaccination in the overall study population (Unsolicited Safety Set)

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    End point title
    		 Percentages of subjects with any unsolicited AEs reported within 21 days after each vaccination in the overall study population (Unsolicited Safety Set) [30]
    End point description
    Percentages of subjects with any unsolicited AEs reported within 21 days after each vaccination within each vaccine group. Subject Analysis Set: Unsolicited Safety Set (overall study population)
    End point type
    Primary
    End point timeframe
    Within 21 days after any vaccination
    Notes
    [30] - 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 statistical analysis was mainly descriptive in nature without any prespecified inferential analyses.
    End point values
    		 Arm A Arm B Arm C Arm D Arm E Arm F
    Number of subjects analysed
    69
    72
    70
    70
    69
    70
    Units: Percentage of subjects
    number (not applicable)
        Unsolicited AEs, Any
    26.1
    20.8
    28.6
    14.3
    21.7
    17.1
        Unsolicited AEs, Mild
    26.1
    19.4
    28.6
    14.3
    17.4
    12.9
        Unsolicited AEs, Moderate
    0
    1.4
    0
    0
    4.3
    2.9
        Unsolicited AEs, Severe
    0
    0
    0
    0
    0
    1.4
        Unsolicited AEs, Related
    2.9
    2.8
    2.9
    0
    2.9
    1.4
    No statistical analyses for this end point

    Primary: Percentages of subjects with any unsolicited AEs reported within 21 days after each vaccination in the 6 months to <36 months age cohort (Unsolicited Safety Set)

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    End point title
    		 Percentages of subjects with any unsolicited AEs reported within 21 days after each vaccination in the 6 months to <36 months age cohort (Unsolicited Safety Set) [31]
    End point description
    Percentages of subjects with any unsolicited AEs reported within 21 days after each vaccination within each vaccine group. Subject Analysis Set: Unsolicited Safety Set (6 months to <36 months age cohort)
    End point type
    Primary
    End point timeframe
    Within 21 days after any vaccination
    Notes
    [31] - 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 statistical analysis was mainly descriptive in nature without any prespecified inferential analyses.
    End point values
    		 Arm A Arm B Arm C Arm D Arm E Arm F
    Number of subjects analysed
    35
    35
    35
    35
    36
    34
    Units: Percentage of subjects
    number (not applicable)
        Unsolicited AEs, Any
    34.3
    31.4
    37.1
    22.9
    22.2
    20.6
        Unsolicited AEs, Mild
    34.3
    28.6
    37.1
    22.9
    19.4
    14.7
        Unsolicited AEs, Moderate
    0
    2.9
    0
    0
    2.8
    5.9
        Unsolicited AEs, Severe
    0
    0
    0
    0
    0
    0
        Unsolicited AEs, Related
    2.9
    5.7
    5.7
    0
    2.8
    0
    No statistical analyses for this end point

    Primary: Percentages of subjects with any unsolicited AEs reported within 21 days after each vaccination in the 3 years to <9 years age cohort (Unsolicited Safety Set)

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    End point title
    		 Percentages of subjects with any unsolicited AEs reported within 21 days after each vaccination in the 3 years to <9 years age cohort (Unsolicited Safety Set) [32]
    End point description
    Percentages of subjects with any unsolicited AEs reported within 21 days after each vaccination within each vaccine group. Subject Analysis Set: Unsolicited Safety Set (3 years to <9 years age cohort)
    End point type
    Primary
    End point timeframe
    Within 21 days after any vaccination
    Notes
    [32] - 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 statistical analysis was mainly descriptive in nature without any prespecified inferential analyses.
    End point values
    		 Arm A Arm B Arm C Arm D Arm E Arm F
    Number of subjects analysed
    34
    37
    35
    35
    33
    36
    Units: Percentage of subjects
    number (not applicable)
        Unsolicited AEs, Any
    17.6
    10.8
    20.0
    5.7
    21.2
    13.9
        Unsolicited AEs, Mild
    17.6
    10.8
    20.0
    5.7
    15.2
    11.1
        Unsolicited AEs, Moderate
    0
    0
    0
    0
    6.1
    0
        Unsolicited AEs, Severe
    0
    0
    0
    0
    0
    2.8
        Unsolicited AEs, Related
    2.9
    0
    0
    0
    3.0
    2.8
    No statistical analyses for this end point

    Primary: Percentages of subjects reporting serious adverse events (SAEs), new onset of chronic disease (NOCD), adverse events of special interest (AESIs), and AEs leading to vaccine and/or study withdrawal in the overall study population (Unsolicited Safety Set)

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    End point title
    		 Percentages of subjects reporting serious adverse events (SAEs), new onset of chronic disease (NOCD), adverse events of special interest (AESIs), and AEs leading to vaccine and/or study withdrawal in the overall study population (Unsolicited Safety Set) [33]
    End point description
    Percentages of subjects reporting SAEs, NOCD, AESIs, and AEs leading to vaccine and/or study withdrawal, as collected from Day 1 through Day 387. Subject Analysis Set: Unsolicited Safety Set (overall study population)
    End point type
    Primary
    End point timeframe
    Day 1 through Day 387
    Notes
    [33] - 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 statistical analysis was mainly descriptive in nature without any prespecified inferential analyses.
    End point values
    		 Arm A Arm B Arm C Arm D Arm E Arm F
    Number of subjects analysed
    69
    72
    70
    70
    69
    70
    Units: Percentage of subjects
    number (not applicable)
        SAE
    0
    1.4
    4.3
    0
    1.4
    4.3
        Related SAE
    0
    0
    0
    0
    0
    0
        NOCD
    0
    1.4
    0
    0
    0
    0
        AESI
    0
    0
    0
    0
    0
    0
        AE leading to withdrawal
    0
    0
    0
    0
    0
    0
        Death
    0
    1.4
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Percentages of subjects reporting SAEs, NOCD, AESIs, and AEs leading to vaccine and/or study withdrawal in the 6 months to <36 months age (Unsolicited Safety Set)

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    End point title
    		 Percentages of subjects reporting SAEs, NOCD, AESIs, and AEs leading to vaccine and/or study withdrawal in the 6 months to <36 months age (Unsolicited Safety Set) [34]
    End point description
    Percentages of subjects reporting SAEs, NOCD, AESIs, and AEs leading to vaccine and/or study withdrawal, as collected from Day 1 through Day 387. Subject Analysis Set: Unsolicited Safety Set (6 months to <36 months age cohort)
    End point type
    Primary
    End point timeframe
    Day 1 through Day 387
    Notes
    [34] - 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 statistical analysis was mainly descriptive in nature without any prespecified inferential analyses.
    End point values
    		 Arm A Arm B Arm C Arm D Arm E Arm F
    Number of subjects analysed
    35
    35
    35
    35
    36
    34
    Units: Percentage of subjects
    number (not applicable)
        SAE
    0
    2.9
    2.9
    0
    2.8
    5.9
        Related SAE
    0
    0
    0
    0
    0
    0
        NOCD
    0
    0
    0
    0
    0
    0
        AESI
    0
    0
    0
    0
    0
    0
        AE leading to withdrawal
    0
    0
    0
    0
    0
    0
        Death
    0
    2.9
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Percentages of subjects reporting SAEs, NOCD, AESIs, and AEs leading to vaccine and/or study withdrawal in the 3 years to <9 years age (Unsolicited Safety Set)

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    End point title
    		 Percentages of subjects reporting SAEs, NOCD, AESIs, and AEs leading to vaccine and/or study withdrawal in the 3 years to <9 years age (Unsolicited Safety Set) [35]
    End point description
    Percentages of subjects reporting SAEs, NOCD, AESIs, and AEs leading to vaccine and/or study withdrawal, as collected from Day 1 through Day 387. Subject Analysis Set: Unsolicited Safety Set (3 years to <9 years age cohort)
    End point type
    Primary
    End point timeframe
    Day 1 through Day 387
    Notes
    [35] - 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 statistical analysis was mainly descriptive in nature without any prespecified inferential analyses.
    End point values
    		 Arm A Arm B Arm C Arm D Arm E Arm F
    Number of subjects analysed
    34
    37
    35
    35
    33
    36
    Units: Percentage of subjects
    number (not applicable)
        SAE
    0
    0
    5.7
    0
    0
    2.8
        Related SAE
    0
    0
    0
    0
    0
    0
        NOCD
    0
    2.7
    0
    0
    0
    0
        AESI
    0
    0
    0
    0
    0
    0
        AE leading to withdrawal
    0
    0
    0
    0
    0
    0
        Death
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Persistence of antibody responses at Day 202 - GMTs and GMRs (HI assay against the homologous H5N1 strain) in the overall study population (PPS Immunogenicity)

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    End point title
    		 Persistence of antibody responses at Day 202 - GMTs and GMRs (HI assay against the homologous H5N1 strain) in the overall study population (PPS Immunogenicity)
    End point description
    GMTs on Day 1 and Day 202 (6 months after the second vaccination) as determined by HI assay. GMRs calculated as follows: Day 202/Day 1 as determined by HI assay. Subject Analysis Set: PPS Immunogenicity (overall study population)
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 202
    End point values
    		 Arm A Arm B Arm C Arm D Arm E Arm F
    Number of subjects analysed
    67
    71
    67
    66
    69
    67
    Units: Titer / ratio
    geometric mean (confidence interval 95%)
        GMT Day 1
    5.05 (4.8 to 5.3)
    5.00 (4.8 to 5.2)
    5.21 (5.0 to 5.4)
    5.05 (4.8 to 5.3)
    5.00 (4.8 to 5.2)
    5.24 (5.0 to 5.5)
        GMT Day 202
    7.92 (6.3 to 9.9)
    8.90 (7.2 to 11.0)
    8.81 (7.1 to 11.0)
    10.19 (8.2 to 12.7)
    12.90 (10.4 to 16.1)
    13.15 (10.5 to 16.4)
        GMR Day 202/Day 1
    1.57 (1.3 to 2.0)
    1.78 (1.4 to 2.2)
    1.69 (1.3 to 2.1)
    2.02 (1.6 to 2.5)
    2.59 (2.1 to 3.2)
    2.50 (2.0 to 3.1)
    No statistical analyses for this end point

    Secondary: Persistence of antibody responses at Day 202 - GMTs and GMRs (HI assay against the homologous H5N1 strain) in the 6 months to <36 months age cohort (PPS Immunogenicity)

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    End point title
    		 Persistence of antibody responses at Day 202 - GMTs and GMRs (HI assay against the homologous H5N1 strain) in the 6 months to <36 months age cohort (PPS Immunogenicity)
    End point description
    GMTs on Day 1 and Day 202 (6 months after the second vaccination) as determined by HI assay. GMRs calculated as follows: Day 202/Day 1 as determined by HI assay. Subject Analysis Set: PPS Immunogenicity (6 months to <36 months age cohort)
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 202
    End point values
    		 Arm A Arm B Arm C Arm D Arm E Arm F
    Number of subjects analysed
    34
    34
    34
    33
    36
    31
    Units: Titer / ratio
    geometric mean (confidence interval 95%)
        GMT Day 1
    5.10 (4.9 to 5.3)
    5.00 (4.8 to 5.2)
    5.42 (5.2 to 5.7)
    5.11 (4.9 to 5.3)
    5.00 (4.8 to 5.2)
    5.00 (4.8 to 5.2)
        GMT Day 202
    9.11 (6.3 to 13.3)
    12.57 (8.6 to 18.3)
    11.60 (7.9 to 17.0)
    13.55 (9.3 to 19.8)
    19.12 (13.3 to 27.6)
    19.00 (12.8 to 28.2)
        GMR Day 202/Day 1
    1.79 (1.2 to 2.6)
    2.50 (1.7 to 3.6)
    2.17 (1.5 to 3.2)
    2.65 (1.8 to 3.9)
    3.81 (2.6 to 5.5)
    3.78 (2.5 to 5.6)
    No statistical analyses for this end point

    Secondary: Persistence of antibody responses at Day 202 - GMTs and GMRs (HI assay against the homologous H5N1 strain) in the 3 years to <9 years age cohort (PPS Immunogenicity)

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    End point title
    		 Persistence of antibody responses at Day 202 - GMTs and GMRs (HI assay against the homologous H5N1 strain) in the 3 years to <9 years age cohort (PPS Immunogenicity)
    End point description
    GMTs on Day 1 and Day 202 (6 months after the second vaccination) as determined by HI assay. GMRs calculated as follows: Day 202/Day 1 as determined by HI assay. Subject Analysis Set: PPS Immunogenicity (3 years to <9 years age cohort)
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 202
    End point values
    		 Arm A Arm B Arm C Arm D Arm E Arm F
    Number of subjects analysed
    33
    37
    33
    33
    33
    36
    Units: Titer / ratio
    geometric mean (confidence interval 95%)
        GMT Day 1
    5.00 (4.6 to 5.4)
    5.00 (4.7 to 5.4)
    5.00 (4.6 to 5.4)
    5.00 (4.6 to 5.4)
    5.00 (4.6 to 5.4)
    5.45 (5.1 to 5.9)
        GMT Day 202
    6.90 (5.4 to 8.8)
    6.36 (5.1 to 8.0)
    6.55 (5.2 to 8.3)
    7.66 (6.0 to 9.7)
    8.69 (6.8 to 11.0)
    9.30 (7.4 to 11.7)
        GMR Day 202/Day 1
    1.38 (1.1 to 1.8)
    1.28 (1.0 to 1.6)
    1.31 (1.0 to 1.7)
    1.54 (1.2 to 2.0)
    1.74 (1.4 to 2.2)
    1.68 (1.3 to 2.1)
    No statistical analyses for this end point

    Secondary: Persistence of antibody responses at Day 202 - percentage of subjects with seroconversion and percentage of subjects with HI titer ≥1:40 (HI assay against the homologous H5N1 strain) in the overall study population (PPS Immunogenicity)

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    End point title
    		 Persistence of antibody responses at Day 202 - percentage of subjects with seroconversion and percentage of subjects with HI titer ≥1:40 (HI assay against the homologous H5N1 strain) in the overall study population (PPS Immunogenicity)
    End point description
    Percentage of subjects achieving seroconversion (non-detectable to ≥1:40, or 4-fold increase from a detectable Day 1 titer) on Day 202. Percentage of subjects achieving seroconversion with a titer of ≥1:40 on Day 202. Subject Analysis Set: PPS Immunogenicity (overall study population)
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 202
    End point values
    		 Arm A Arm B Arm C Arm D Arm E Arm F
    Number of subjects analysed
    67
    71
    67
    66
    69
    67
    Units: Percentage of subjects
    number (confidence interval 95%)
        % of subjects with seroconversion at Day 202
    10.4 (4.30 to 20.35)
    14.1 (6.97 to 24.38)
    11.9 (5.30 to 22.18)
    15.2 (7.51 to 26.10)
    21.7 (12.71 to 33.31)
    25.4 (15.53 to 37.49)
        % of subjects with HI titer ≥1:40 at Day 1
    0.0 (0.00 to 5.36)
    0.0 (0.00 to 5.06)
    0.0 (0.00 to 5.36)
    0.0 (0.00 to 5.44)
    0.0 (0.00 to 5.21)
    1.5 (0.04 to 8.04)
        % of subjects with HI titer ≥1:40 at Day 202
    10.4 (4.30 to 20.35)
    14.1 (6.97 to 24.38)
    11.9 (5.30 to 22.18)
    15.2 (7.51 to 26.10)
    21.7 (12.71 to 33.31)
    25.4 (15.53 to 37.49)
    No statistical analyses for this end point

    Secondary: Persistence of antibody responses at Day 202 - percentage of subjects with seroconversion and percentage of subjects with HI titer ≥1:40 (HI assay against the homologous H5N1 strain) in the 6 months to <36 months age cohort (PPS Immunogenicity)

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    End point title
    		 Persistence of antibody responses at Day 202 - percentage of subjects with seroconversion and percentage of subjects with HI titer ≥1:40 (HI assay against the homologous H5N1 strain) in the 6 months to <36 months age cohort (PPS Immunogenicity)
    End point description
    Percentage of subjects achieving seroconversion (non-detectable to ≥1:40, or 4-fold increase from a detectable Day 1 titer) on Day 202. Percentage of subjects achieving seroconversion with a titer of ≥1:40 on Day 202. Subject Analysis Set: PPS Immunogenicity (6 months to <36 months age cohort)
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 202
    End point values
    		 Arm A Arm B Arm C Arm D Arm E Arm F
    Number of subjects analysed
    34
    34
    34
    33
    36
    31
    Units: Percentage of subjects
    number (confidence interval 95%)
        % of subjects with seroconversion at Day 202
    17.6 (6.76 to 34.53)
    26.5 (12.88 to 44.36)
    23.5 (10.75 to 41.17)
    27.3 (13.30 to 45.52)
    33.3 (18.56 to 50.97)
    41.9 (24.55 to 60.92)
        % of subjects with HI titer ≥1:40 at Day 1
    0.0 (0.00 to 10.28)
    0.0 (0.00 to 10.28)
    0.0 (0.00 to 10.28)
    0.0 (0.00 to 10.58)
    0.0 (0.00 to 9.74)
    0.0 (0.00 to 11.22)
        % of subjects with HI titer ≥1:40 at Day 202
    17.6 (6.76 to 34.53)
    26.5 (12.88 to 44.36)
    23.5 (10.75 to 41.17)
    27.3 (13.30 to 45.52)
    33.3 (18.56 to 50.97)
    41.9 (24.55 to 60.92)
    No statistical analyses for this end point

    Secondary: Persistence of antibody responses at Day 202 - percentage of subjects with seroconversion and percentage of subjects with HI titer ≥1:40 (HI assay against the homologous H5N1 strain) in the 3 years to <9 years age cohort (PPS Immunogenicity)

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    End point title
    		 Persistence of antibody responses at Day 202 - percentage of subjects with seroconversion and percentage of subjects with HI titer ≥1:40 (HI assay against the homologous H5N1 strain) in the 3 years to <9 years age cohort (PPS Immunogenicity)
    End point description
    Percentage of subjects achieving seroconversion (non-detectable to ≥1:40, or 4-fold increase from a detectable Day 1 titer) on Day 202. Percentage of subjects achieving seroconversion with a titer of ≥1:40 on Day 202. Subject Analysis Set: PPS Immunogenicity (3 years to <9 years age cohort)
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 202
    End point values
    		 Arm A Arm B Arm C Arm D Arm E Arm F
    Number of subjects analysed
    33
    37
    33
    33
    33
    36
    Units: Percentage of subjects
    number (confidence interval 95%)
        % of subjects with seroconversion at Day 202
    3.0 (0.08 to 15.76)
    2.7 (0.07 to 14.16)
    0.0 (0.00 to 10.58)
    3.0 (0.08 to 15.76)
    9.1 (1.92 to 24.33)
    11.1 (3.11 to 26.06)
        % of subjects with HI titer ≥1:40 at Day 1
    0.0 (0.00 to 10.58)
    0.0 (0.00 to 9.49)
    0.0 (0.00 to 10.58)
    0.0 (0.00 to 10.58)
    0.0 (0.00 to 10.58)
    2.8 (0.07 to 14.53)
        % of subjects with HI titer ≥1:40 at Day 202
    3.0 (0.08 to 15.76)
    2.7 (0.07 to 14.16)
    0.0 (0.00 to 10.58)
    3.0 (0.08 to 15.76)
    9.1 (1.92 to 24.33)
    11.1 (3.11 to 26.06)
    No statistical analyses for this end point

    Secondary: Persistence of antibody responses at Day 202 - GMTs and GMRs (MN assay against the homologous H5N1 strain) in the overall study population (PPS Immunogenicity)

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    End point title
    		 Persistence of antibody responses at Day 202 - GMTs and GMRs (MN assay against the homologous H5N1 strain) in the overall study population (PPS Immunogenicity)
    End point description
    GMTs on Day 1 and Day 202 (6 months after the second vaccination) as determined by MN assay. GMRs calculated as follows: Day 202/Day 1 as determined by MN assay. Subject Analysis Set: PPS Immunogenicity (overall study population)
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 202
    End point values
    		 Arm A Arm B Arm C Arm D Arm E Arm F
    Number of subjects analysed
    67
    71
    67
    66
    69
    67 [36]
    Units: Titer / ratio
    geometric mean (confidence interval 95%)
        GMT Day 1
    5.19 (4.9 to 5.5)
    5.27 (5.0 to 5.6)
    5.38 (5.1 to 5.7)
    5.16 (4.9 to 5.5)
    5.13 (4.9 to 5.4)
    5.31 (5.0 to 5.6)
        GMT Day 202
    113.24 (94.7 to 135.4)
    146.98 (123.6 to 174.8)
    146.41 (122.4 to 175.1)
    150.56 (125.7 to 180.3)
    183.15 (153.6 to 218.4)
    195.57 (163.3 to 234.2)
        GMR Day 202/Day 1
    21.77 (18.1 to 26.1)
    27.94 (23.4 to 33.4)
    27.45 (22.9 to 33.0)
    29.04 (24.2 to 34.9)
    35.47 (29.6 to 42.5)
    36.95 (30.7 to 44.4)
    Notes
    [36] - n=66 at Day 202
    No statistical analyses for this end point

    Secondary: Persistence of antibody responses at Day 202 - GMTs and GMRs (MN assay against the homologous H5N1 strain) in the 6 months to <36 months age cohort (PPS Immunogenicity)

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    End point title
    		 Persistence of antibody responses at Day 202 - GMTs and GMRs (MN assay against the homologous H5N1 strain) in the 6 months to <36 months age cohort (PPS Immunogenicity)
    End point description
    GMTs on Day 1 and Day 202 (6 months after the second vaccination) as determined by MN assay. GMRs calculated as follows: Day 202/Day 1 as determined by MN assay. Subject Analysis Set: PPS Immunogenicity (6 months to <36 months age cohort)
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 202
    End point values
    		 Arm A Arm B Arm C Arm D Arm E Arm F
    Number of subjects analysed
    34
    34
    34
    33
    36
    31
    Units: Titer / ratio
    geometric mean (confidence interval 95%)
        GMT Day 1
    5.00 (4.7 to 5.3)
    5.00 (4.7 to 5.3)
    5.26 (4.9 to 5.6)
    5.21 (4.9 to 5.6)
    5.10 (4.8 to 5.4)
    5.29 (4.9 to 5.7)
        GMT Day 202
    144.60 (111.8 to 187.0)
    217.84 (168.4 to 281.7)
    175.31 (135.6 to 226.7)
    174.21 (134.2 to 226.1)
    245.52 (191.3 to 315.1)
    268.31 (205.0 to 351.3)
        GMR Day 202/Day 1
    28.49 (22.0 to 36.9)
    42.91 (33.2 to 55.5)
    33.76 (26.1 to 43.7)
    33.68 (25.9 to 43.7)
    47.95 (37.3 to 61.6)
    51.56 (39.4 to 67.5)
    No statistical analyses for this end point

    Secondary: Persistence of antibody responses at Day 202 - GMTs and GMRs (MN assay against the homologous H5N1 strain) in the 3 years to <9 years age cohort (PPS Immunogenicity)

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    End point title
    		 Persistence of antibody responses at Day 202 - GMTs and GMRs (MN assay against the homologous H5N1 strain) in the 3 years to <9 years age cohort (PPS Immunogenicity)
    End point description
    GMTs on Day 1 and Day 202 (6 months after the second vaccination) as determined by MN assay. GMRs calculated as follows: Day 202/Day 1 as determined by MN assay. Subject Analysis Set: PPS Immunogenicity (3 years to <9 years age cohort)
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 202
    End point values
    		 Arm A Arm B Arm C Arm D Arm E Arm F
    Number of subjects analysed
    33
    37
    33
    33
    33
    36 [37]
    Units: Titer / ratio
    geometric mean (confidence interval 95%)
        GMT Day 1
    5.38 (4.9 to 5.9)
    5.54 (5.1 to 6.0)
    5.49 (5.0 to 6.0)
    5.11 (4.7 to 5.6)
    5.16 (4.7 to 5.7)
    5.35 (4.9 to 5.8)
        GMT Day 202
    89.38 (69.6 to 114.8)
    101.19 (79.8 to 128.2)
    122.19 (95.1 to 157.0)
    129.11 (100.4 to 165.9)
    136.08 (105.9 to 174.9)
    142.59 (111.8 to 181.8)
        GMR Day 202/Day 1
    16.64 (12.8 to 21.6)
    18.41 (14.4 to 23.5)
    22.38 (17.3 to 29.0)
    25.04 (19.3 to 32.5)
    26.18 (20.2 to 34.0)
    26.63 (20.7 to 34.3)
    Notes
    [37] - n=35 at Day 202
    No statistical analyses for this end point

    Secondary: Persistence of antibody responses at Day 202 - percentage of subjects with seroconversion and percentage of subjects with MN titer ≥1:40 (MN assay against the homologous H5N1 strain) in the overall study population (PPS Immunogenicity)

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    End point title
    		 Persistence of antibody responses at Day 202 - percentage of subjects with seroconversion and percentage of subjects with MN titer ≥1:40 (MN assay against the homologous H5N1 strain) in the overall study population (PPS Immunogenicity)
    End point description
    Percentage of subjects achieving seroconversion (non-detectable to ≥1:40, or 4-fold increase from a detectable Day 1 titer) on Day 202. Percentage of subjects achieving seroconversion with a titer of ≥1:40 on Day 202. Subject Analysis Set: PPS Immunogenicity (overall study population)
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 202
    End point values
    		 Arm A Arm B Arm C Arm D Arm E Arm F
    Number of subjects analysed
    67
    71
    67
    66
    69
    67 [38]
    Units: Percentage of subjects
    number (confidence interval 95%)
        % of subjects with seroconversion at Day 202
    95.5 (87.47 to 99.07)
    97.2 (90.19 to 99.66)
    100.0 (94.64 to 100.00)
    97.0 (89.48 to 99.63)
    98.6 (92.19 to 99.96)
    97.0 (89.48 to 99.63)
        % of subjects with MN titer ≥1:40 at Day 1
    0.0 (0.00 to 5.36)
    0.0 (0.00 to 5.06)
    0.0 (0.00 to 5.36)
    0.0 (0.00 to 5.44)
    0.0 (0.00 to 5.21)
    0.0 (0.00 to 5.36)
        % of subjects with MN titer ≥1:40 at Day 202
    95.5 (87.47 to 99.07)
    98.6 (92.40 to 99.96)
    100.0 (94.64 to 100.00)
    97.0 (89.48 to 99.63)
    98.6 (92.19 to 99.96)
    98.5 (91.84 to 99.96)
    Notes
    [38] - n=66 at Day 202
    No statistical analyses for this end point

    Secondary: Persistence of antibody responses at Day 202 - percentage of subjects with seroconversion and percentage of subjects with MN titer ≥1:40 (MN assay against the homologous H5N1 strain) in the 6 months to 36 months age cohort (PPS Immunogenicity)

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    End point title
    		 Persistence of antibody responses at Day 202 - percentage of subjects with seroconversion and percentage of subjects with MN titer ≥1:40 (MN assay against the homologous H5N1 strain) in the 6 months to 36 months age cohort (PPS Immunogenicity)
    End point description
    Percentage of subjects achieving seroconversion (non-detectable to ≥1:40, or 4-fold increase from a detectable Day 1 titer) on Day 202. Percentage of subjects achieving seroconversion with a titer of ≥1:40 on Day 202. Subject Analysis Set: PPS Immunogenicity (6 months to <36 months age cohort)
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 202
    End point values
    		 Arm A Arm B Arm C Arm D Arm E Arm F
    Number of subjects analysed
    34
    34
    34
    33
    36
    31
    Units: Percentage of subjects
    number (confidence interval 95%)
        % of subjects with seroconversion at Day 202
    97.1 (84.67 to 99.93)
    100.0 (89.72 to 100.00)
    100.0 (89.72 to 100.00)
    97.0 (84.24 to 99.92)
    100.0 (90.26 to 100.00)
    100.0 (88.78 to 100.00)
        % of subjects with MN titer ≥1:40 at Day 1
    0.0 (0.00 to 10.28)
    0.0 (0.00 to 10.28)
    0.0 (0.00 to 10.28)
    0.0 (0.00 to 10.58)
    0.0 (0.00 to 9.74)
    0.0 (0.00 to 11.22)
        % of subjects with MN titer ≥1:40 at Day 202
    97.1 (84.67 to 99.93)
    100.0 (89.72 to 100.00)
    100.0 (89.72 to 100.00)
    97.0 (84.24 to 99.92)
    100.0 (90.26 to 100.00)
    100.0 (88.78 to 100.00)
    No statistical analyses for this end point

    Secondary: Persistence of antibody responses at Day 202 - percentage of subjects with seroconversion and percentage of subjects with MN titer ≥1:40 (MN assay against the homologous H5N1 strain) in the 3 years to <9 years age cohort (PPS Immunogenicity)

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    End point title
    		 Persistence of antibody responses at Day 202 - percentage of subjects with seroconversion and percentage of subjects with MN titer ≥1:40 (MN assay against the homologous H5N1 strain) in the 3 years to <9 years age cohort (PPS Immunogenicity)
    End point description
    Percentage of subjects achieving seroconversion (non-detectable to ≥1:40, or 4-fold increase from a detectable Day 1 titer) on Day 202. Percentage of subjects achieving seroconversion with a titer of ≥1:40 on Day 202. Subject Analysis Set: PPS Immunogenicity (3 years to <9 years age cohort)
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 202
    End point values
    		 Arm A Arm B Arm C Arm D Arm E Arm F
    Number of subjects analysed
    33
    37
    33
    33
    33
    36 [39]
    Units: Percentage of subjects
    number (confidence interval 95%)
        % of subjects with seroconversion at Day 202
    93.9 (79.77 to 99.26)
    94.6 (81.81 to 99.34)
    100.0 (89.42 to 100.00)
    97.0 (84.24 to 99.92)
    97.0 (84.24 to 99.92)
    94.3 (80.84 to 99.30)
        % of subjects with MN titer ≥1:40 at Day 1
    0.0 (0.00 to 10.58)
    0.0 (0.00 to 9.49)
    0.0 (0.00 to 10.58)
    0.0 (0.00 to 10.58)
    0.0 (0.00 to 10.58)
    0.0 (0.00 to 9.74)
        % of subjects with MN titer ≥1:40 at Day 202
    93.9 (79.77 to 99.26)
    97.3 (85.84 to 99.93)
    100.0 (89.42 to 100.00)
    97.0 (84.24 to 99.92)
    97.0 (84.24 to 99.92)
    97.1 (85.08 to 99.93)
    Notes
    [39] - n=35 at Day 202
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 through Day 387
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 1.875 μg H5N1 HA/50% MF59

    Reporting group title
    Arm B
    Reporting group description
    		 3.75 μg H5N1 HA/50% MF59

    Reporting group title
    Arm C
    Reporting group description
    		 7.5 μg H5N1 HA/50% MF59

    Reporting group title
    Arm D
    Reporting group description
    		 1.875 μg H5N1 HA/100% MF59

    Reporting group title
    Arm E
    Reporting group description
    		 3.75 μg H5N1 HA/100% MF59

    Reporting group title
    Arm F
    Reporting group description
    		 7.5 μg H5N1 HA/100% MF59

    Serious adverse events
    		 Arm A Arm B Arm C Arm D Arm E Arm F
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 72 (1.39%)
    3 / 70 (4.29%)
    0 / 70 (0.00%)
    1 / 69 (1.45%)
    3 / 70 (4.29%)
         number of deaths (all causes)
    0
    1
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    1
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Brain neoplasm
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 72 (1.39%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 69 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Animal bite
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 72 (0.00%)
    2 / 70 (2.86%)
    0 / 70 (0.00%)
    0 / 69 (0.00%)
    2 / 70 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thermal burn
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 72 (0.00%)
    1 / 70 (1.43%)
    0 / 70 (0.00%)
    0 / 69 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Febrile convulsion
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 72 (0.00%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    1 / 69 (1.45%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Klebsiella infection
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 72 (1.39%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 69 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 72 (0.00%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    1 / 69 (1.45%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 72 (1.39%)
    0 / 70 (0.00%)
    0 / 70 (0.00%)
    0 / 69 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Arm A Arm B Arm C Arm D Arm E Arm F
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 69 (10.14%)
    4 / 72 (5.56%)
    14 / 70 (20.00%)
    5 / 70 (7.14%)
    5 / 69 (7.25%)
    9 / 70 (12.86%)
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 69 (8.70%)
    4 / 72 (5.56%)
    12 / 70 (17.14%)
    1 / 70 (1.43%)
    5 / 69 (7.25%)
    5 / 70 (7.14%)
         occurrences all number
    6
    4
    13
    1
    5
    5
    Nasopharyngitis
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 72 (0.00%)
    2 / 70 (2.86%)
    4 / 70 (5.71%)
    0 / 69 (0.00%)
    4 / 70 (5.71%)
         occurrences all number
    1
    0
    2
    4
    0
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Oct 2019
    Version 1.0 to Version 2.0 The main reasons for the protocol amendment were the following: 1. Removal of the cohort of adolescents aged 9 years to <18 years of age, such that the age range of the study population is 6 months to <9 years. In line with this change, all subjects were scheduled to receive 2 doses of vaccine in the study, instead of 1 or 2 doses, based on the subject’s age. 2. Removal of the vaccine group that was planned to receive a single dose of study vaccine on Day 1 and saline placebo on Day 22. In line with this change, the overall sample size was reduced from 450 subjects to 420 subjects. Removal of the antigenic challenge dose of non-adjuvanted 7.5 μg H5N1 pandemic influenza antigen planned for all subjects on Day 202. 3. Reduction in the number of blood samples collected, from blood samples being collected on Day 1, Day 22, Day 43, Day 204, and Day 225 to blood samples being collected on Day 1, Day 22, Day 43, and Day 202. 4. Removal of CMI testing as an exploratory objective. 5. Reduction in the number of clinic visits/calls. 6. Alignment of objectives/endpoints with the key binding elements of PIP.
    07 Nov 2019
    Version 2.0 to Version 3.0 The main reasons for the protocol amendment were the following: 1. Changes in vaccine formulation, necessitating updating of the description of the dose formulation to reflect the correct volume to be used as reference for vaccine label documentation. Specifically, the description of the dose for Arm C was changed from “7.5 μg + 50% MF59 0.5 mL” to “7.5 μg + 50% MF59 0.25 mL”. 2. Updating the Time and Events table to provide clarification on prevaccination/Visit 1 procedures, including addition of explanatory footnotes.
    20 Dec 2019
    Version 3.0 to Version 4.0 The main reasons for the protocol amendment were the following: 1. Addition of collection of a baseline blood sample within 10 days prior to the Day 1 vaccination as an inclusion criterion. This change was made because assessment of two of the primary endpoints requires a baseline blood sample. The burden of the study for subjects in the age range 6 months to <9 years of age without a baseline blood sample, who would not be included in the evaluation of these primary endpoints, was considered unreasonable. In line with this change, the timing of the collection of the baseline blood sample was changed from “before vaccination” to “before randomization”. 2. Deletion of the restricted use of antiviral medication with anti-flu properties.
    24 Jun 2020
    Version 4.0 to Version 5.0 The main reasons for the protocol amendment were the following: 1. Introduction of the possibility of home visits to mitigate risks associated with the SARS-CoV-2 pandemic. In the exceptional case that the site staff was not able to perform visits at the clinic due to COVID-19 restrictions, home visits (physical examination and blood draw) could be considered. These visits would only be considered if sites had appropriate SOPs/Instructions for conducting home visits in place, reviewed, and approved by Seqirus. In addition, sites had to instruct subjects on return of the Subject Diary Card if a clinic visit was not feasible. 2. Introduction of the permitted use of a topical analgesic/anesthetic/icepack to reduce the discomfort and pain of the blood draws in this pediatric study, as a mitigation strategy for non-compliance with blood draws.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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