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    Clinical Trial Results:
    A master phase 1/2/3 protocol to investigate the safety, tolerability, and immunogenicity of variant- adapted BNT162b2 RNA-based vaccine candidates(s) in healthy children

    Summary
    EudraCT number
    		 2024-000001-33
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date

    Results information
    Results version number
    		 v1
    This version publication date
    06 Mar 2024
    First version publication date
    06 Mar 2024
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    C4591048
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05543616
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    BioNTech SE
    Sponsor organisation address
    An der Goldgrube 12, Mainz, Germany, 55131
    Public contact
    BioNTech SE, BioNTech clinical trials patient information, +49 6131 90840, patients@biontech.de
    Scientific contact
    BioNTech SE, BioNTech clinical trials patient information, +49 6131 90840, patients@biontech.de
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-002861-PIP02-20
    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
    Interim
    Date of interim/final analysis
    25 Oct 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    SSD: To describe the safety and tolerability profiles of prophylactic bivalent BNT162b2 given as a third or fourth dose in participants >=5 to <12 years of age. To descriptively compare the anti–Omicron BA.4/BA.5 immune response between participants >=5 to <12 years of age who received 3 prior doses of BNT162b2 10 microgram (μg) and received bivalent BNT162b2 as a fourth dose in Group 2 and Study C4591007 Phase 2/3 participants >=5 to <12 years of age who received 3 doses of BNT162b2 10 μg.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Council for Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trials participants were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Sep 2022
    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 States: 134
    Worldwide total number of subjects
    134
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    134
    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
    		 -

    Pre-assignment
    Screening details
    		 A total of 136 participants were randomized in sub-study D(SSD) of which 2 participants were not vaccinated and 134 participants received at least 1 dose of vaccination.Data is reported at study completion date for SSD.PCD for SS A, B, C and E have not been reached and data collection is still ongoing,hence no data is reported for SS A, B, C and E.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group 1: 2 prior doses of BNT162b2
    Arm description
    		 Participants aged 5 to11 years who had received two prior doses of BNT162b2 10 microgram (mcg) 90 to 240 days before enrollment in the study were included. Participants received a single dose of BNT162b2 10 mcg via intramuscular route on Day 1 of the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bivalent BNT162b2 (original/Omicron BA.4/BA.5)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    10 micrograms (original BNT162b2 5 mcg and BNT162b2 Omicron [B.1.1.529 sublineage BA.4/BA.5] 5 mcg) administered intramuscularly.

    Arm title
    		 Group 2: 3 prior doses of BNT162b2
    Arm description
    		 Participants aged 5 to11 years who had received three prior doses of BNT162b2 10 mcg 90 to 240 days before enrollment in the study were included. Participants received a single dose of BNT162b2 10 mcg via intramuscular route on Day 1 of the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bivalent BNT162b2 (original/Omicron BA.4/BA.5)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    10 micrograms (original BNT162b2 5 mcg and BNT162b2 Omicron [B.1.1.529 sublineage BA.4/BA.5] 5 mcg) administered intramuscularly.

    Arm title
    		 Group 3: Participants from study C4591007 Phase 1
    Arm description
    		 Participants from C4591007 (NCT04816643) phase 1 trial, aged 5 to 11 years who had received three prior doses of BNT162b2 10 mcg at least 90 days before enrollment in the study were included. Participants received a single dose of BNT162b2 10 mcg via intramuscular route on Day 1 of the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bivalent BNT162b2 (original/Omicron BA.4/BA.5)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    10 micrograms (original BNT162b2 5 mcg and BNT162b2 Omicron [B.1.1.529 sublineage BA.4/BA.5] 5 mcg) administered intramuscularly.

    Number of subjects in period 1
    		Group 1: 2 prior doses of BNT162b2 Group 2: 3 prior doses of BNT162b2 Group 3: Participants from study C4591007 Phase 1
    Started
    2
    113
    19
    Completed
    2
    111
    19
    Not completed
    0
    2
    0
         Consent withdrawn by subject
    -
    1
    -
         Withdrawal by parents/guardian
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group 1: 2 prior doses of BNT162b2
    Reporting group description
    		 Participants aged 5 to11 years who had received two prior doses of BNT162b2 10 microgram (mcg) 90 to 240 days before enrollment in the study were included. Participants received a single dose of BNT162b2 10 mcg via intramuscular route on Day 1 of the study.

    Reporting group title
    Group 2: 3 prior doses of BNT162b2
    Reporting group description
    		 Participants aged 5 to11 years who had received three prior doses of BNT162b2 10 mcg 90 to 240 days before enrollment in the study were included. Participants received a single dose of BNT162b2 10 mcg via intramuscular route on Day 1 of the study.

    Reporting group title
    Group 3: Participants from study C4591007 Phase 1
    Reporting group description
    		 Participants from C4591007 (NCT04816643) phase 1 trial, aged 5 to 11 years who had received three prior doses of BNT162b2 10 mcg at least 90 days before enrollment in the study were included. Participants received a single dose of BNT162b2 10 mcg via intramuscular route on Day 1 of the study.

    Reporting group values
    		 Group 1: 2 prior doses of BNT162b2 Group 2: 3 prior doses of BNT162b2 Group 3: Participants from study C4591007 Phase 1 Total
    Number of subjects
    		 2 113 19 134
    Age Categorical
    Units: Participants
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 2 113 19 134
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 0 0 0 0
        From 65-84 years
    		 0 0 0 0
        85 years and over
    		 0 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 5.0 ( 0.00 ) 8.6 ( 1.65 ) 8.4 ( 2.19 ) -
    Gender Categorical
    Units: Participants
        Female
    		 0 56 11 67
        Male
    		 2 57 8 67
    Race
    Units: Subjects
        White
    		 2 66 12 80
        Black or African American
    		 0 9 2 11
        Asian
    		 0 13 2 15
        Multiracial
    		 0 22 3 25
        Not reported
    		 0 3 0 3
        Native Hawaiian or other Pacific Islander
    		 0 0 0 0
    Ethinicity
    Units: Subjects
        Hispanic/Latino
    		 0 23 0 23
        Non-Hispanic/non-Latino
    		 2 90 19 111
    Subject analysis sets

    Subject analysis set title
    Historical cohort: C4591007 BNT162b2 10 μg
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants aged >=5 to <12 years from study C4591007 (NCT04816643) who received 3 doses of original BNT162b2 10 mcg were included.

    Subject analysis sets values
    		 Historical cohort: C4591007 BNT162b2 10 μg
    Number of subjects
    113
    Age Categorical
    Units: Participants
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
        Newborns (0-27 days)
    0
        Infants and toddlers (28 days-23 months)
    0
        Children (2-11 years)
    113
        Adolescents (12-17 years)
    0
        Adults (18-64 years)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    8.6 ( 1.65 )
    Gender Categorical
    Units: Participants
        Female
    50
        Male
    63
    Race
    Units: Subjects
        White
    91
        Black or African American
    4
        Asian
    11
        Multiracial
    4
        Not reported
    1
        Native Hawaiian or other Pacific Islander
    2
    Ethinicity
    Units: Subjects
        Hispanic/Latino
    16
        Non-Hispanic/non-Latino
    97

    End points

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    End points reporting groups
    Reporting group title
    Group 1: 2 prior doses of BNT162b2
    Reporting group description
    		 Participants aged 5 to11 years who had received two prior doses of BNT162b2 10 microgram (mcg) 90 to 240 days before enrollment in the study were included. Participants received a single dose of BNT162b2 10 mcg via intramuscular route on Day 1 of the study.

    Reporting group title
    Group 2: 3 prior doses of BNT162b2
    Reporting group description
    		 Participants aged 5 to11 years who had received three prior doses of BNT162b2 10 mcg 90 to 240 days before enrollment in the study were included. Participants received a single dose of BNT162b2 10 mcg via intramuscular route on Day 1 of the study.

    Reporting group title
    Group 3: Participants from study C4591007 Phase 1
    Reporting group description
    		 Participants from C4591007 (NCT04816643) phase 1 trial, aged 5 to 11 years who had received three prior doses of BNT162b2 10 mcg at least 90 days before enrollment in the study were included. Participants received a single dose of BNT162b2 10 mcg via intramuscular route on Day 1 of the study.

    Subject analysis set title
    Historical cohort: C4591007 BNT162b2 10 μg
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants aged >=5 to <12 years from study C4591007 (NCT04816643) who received 3 doses of original BNT162b2 10 mcg were included.

    Primary: SSD: Percentage of Participants With Local Reactions Within 7 Days After Study Vaccination

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    End point title
    		 SSD: Percentage of Participants With Local Reactions Within 7 Days After Study Vaccination [1]
    End point description
    Local reactions recorded by participants/parents/legal guardians in electronic diary(e-diary).Redness&swelling recorded in measuring device units(mdu)converted to centimeter(cm).1 mdu=0.5 cm&graded mild:(greater than[>]0.5 to 2.0cm),moderate:>2.0 to 7.0cm,severe:>7.0 cm,Grade 4(G4): necrosis/exfoliative dermatitis(redness)&necrosis(swelling).Pain at injection site graded mild:did not interfere with daily activity,moderate:interfered with daily activity,severe: prevented daily activity&G4:emergency room[ER]visit/hospitalisation.G4 classified by investigator/medically qualified person.Percentage of participants with local reactions within 7days after study vaccination and associated 2-sided 95% confidence interval(CI) based on Clopper and Pearson method.Safety population=all participants receiving at least 1dose of study intervention.Number of Participants Analysed(N)’= participants evaluable.99999=data could not be generated since it was not part of specified analysis in the protocol.
    End point type
    Primary
    End point timeframe
    Day 1 up to Day 7 after study vaccination
    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: Only descriptive analysis was planned for this endpoint.
    End point values
    		 Group 1: 2 prior doses of BNT162b2 Group 2: 3 prior doses of BNT162b2 Group 3: Participants from study C4591007 Phase 1
    Number of subjects analysed
    2
    111
    19
    Units: Percentage of participants
    number (confidence interval 95%)
        Redness: Any
    0 (-99999 to 99999)
    7.2 (3.2 to 13.7)
    10.5 (1.3 to 33.1)
        Redness: Mild
    0 (-99999 to 99999)
    4.5 (1.5 to 10.2)
    10.5 (1.3 to 33.1)
        Redness: Moderate
    0 (-99999 to 99999)
    2.7 (0.6 to 7.7)
    0 (0.0 to 17.6)
        Redness: Severe
    0 (-99999 to 99999)
    0 (0.0 to 3.3)
    0 (0.0 to 17.6)
        Redness: Grade 4
    0 (-99999 to 99999)
    0 (0.0 to 3.3)
    0 (0.0 to 17.6)
        Swelling: Any
    0 (-99999 to 99999)
    4.5 (1.5 to 10.2)
    10.5 (1.3 to 33.1)
        Swelling: Mild
    0 (-99999 to 99999)
    0.9 (0.0 to 4.9)
    10.5 (1.3 to 33.1)
        Swelling: Moderate
    0 (-99999 to 99999)
    3.6 (1.0 to 9.0)
    0 (0.0 to 17.6)
        Swelling: Severe
    0 (-99999 to 99999)
    0 (0.0 to 3.3)
    0 (0.0 to 17.6)
        Swelling: Grade 4
    0 (-99999 to 99999)
    0 (0.0 to 3.3)
    0 (0.0 to 17.6)
        Pain at the injection site: Any
    0 (-99999 to 99999)
    64.0 (54.3 to 72.9)
    68.4 (43.4 to 87.4)
        Pain at the injection site: Mild
    50.0 (-99999 to 99999)
    45.0 (35.6 to 54.8)
    52.6 (28.9 to 75.6)
        Pain at the injection site: Moderate
    0 (-99999 to 99999)
    18.9 (12.1 to 27.5)
    15.8 (3.4 to 39.6)
        Pain at the injection site: Severe
    0 (-99999 to 99999)
    0 (0.0 to 3.3)
    0 (0.0 to 17.6)
        Pain at the injection site: Grade 4
    0 (-99999 to 99999)
    0 (0.0 to 3.3)
    0 (0.0 to 17.6)
    No statistical analyses for this end point

    Primary: SSD: Percentage of Participants With Systemic Events Within 7 Days After Study Vaccination

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    End point title
    		 SSD: Percentage of Participants With Systemic Events Within 7 Days After Study Vaccination [2]
    End point description
    Systemic events recorded by participants/parents/legal guardians in e-diary. Fever: oral temperature >= 38.0 degree Celsius(deg C)&categorised as >=38.0-38.4 deg C,>38.4-38.9 deg C,>38.9-40.0 deg C & >40.0 deg C.Fatigue,headache,chills,new/worsened muscle pain&new/worsened joint pain:mild:did not interfere with activity,moderate:some interference with activity&severe: prevented daily routine activity.Vomiting:mild: 1-2 times in 24hours(h),moderate:>2 times in 24h,severe:required intravenous hydration.Diarrhea:mild: 2-3 loose stools in 24h,moderate:4-5 loose stools in 24h&severe:6 or more loose stools in 24h.Except fever,G4=ER visit/hospitalisation.G4 events classified by investigator/medically qualified person. Exact 95% CI based on Clopper & Pearson method.Safety population=all participants receiving at least 1 dose of study intervention.N= participants evaluable for this endpoint.99999=data could not be generated since it was not part of specified analysis in the protocol.
    End point type
    Primary
    End point timeframe
    Day 1 up to Day 7 after study vaccination
    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: Only descriptive analysis was planned for this endpoint.
    End point values
    		 Group 1: 2 prior doses of BNT162b2 Group 2: 3 prior doses of BNT162b2 Group 3: Participants from study C4591007 Phase 1
    Number of subjects analysed
    2
    111
    19
    Units: Percentage of participants
    number (confidence interval 95%)
        Fever: Any
    0 (-99999 to 99999)
    4.5 (1.5 to 10.2)
    10.5 (1.3 to 33.1)
        Fever: ≥38.0 to 38.4 deg C
    0 (-99999 to 99999)
    1.8 (0.2 to 6.4)
    0 (0.0 to 17.6)
        Fever: >38.4 to 38.9 deg C
    0 (-99999 to 99999)
    0.9 (0.0 to 4.9)
    5.3 (0.1 to 26.0)
        Fever: >38.9 to 40.0 deg C
    0 (-99999 to 99999)
    1.8 (0.2 to 6.4)
    5.3 (0.1 to 26.0)
        Fever: >40.0 deg C
    0 (-99999 to 99999)
    0 (0.0 to 3.3)
    0 (0.0 to 17.6)
        Fatigue: Any
    0 (-99999 to 99999)
    40.5 (31.3 to 50.3)
    57.9 (33.5 to 79.7)
        Fatigue: Mild
    0 (-99999 to 99999)
    23.4 (15.9 to 32.4)
    36.8 (16.3 to 61.6)
        Fatigue: Moderate
    0 (-99999 to 99999)
    16.2 (9.9 to 24.4)
    15.8 (3.4 to 39.6)
        Fatigue: Severe
    0 (-99999 to 99999)
    0.9 (0.0 to 4.9)
    5.3 (0.1 to 26.0)
        Fatigue: Grade 4
    0 (-99999 to 99999)
    0 (0.0 to 3.3)
    0 (0.0 to 17.6)
        Headache: Any
    0 (-99999 to 99999)
    25.2 (17.5 to 34.4)
    36.8 (16.3 to 61.6)
        Headache: Mild
    0 (-99999 to 99999)
    18.0 (11.4 to 26.4)
    26.3 (9.1 to 51.2)
        Headache: Moderate
    0 (-99999 to 99999)
    6.3 (2.6 to 12.6)
    10.5 (1.3 to 33.1)
        Headache: Severe
    0 (-99999 to 99999)
    0.9 (0.0 to 4.9)
    0 (0.0 to 17.6)
        Headache: Grade 4
    0 (-99999 to 99999)
    0 (0.0 to 3.3)
    0 (0.0 to 17.6)
        Chills: Any
    0 (-99999 to 99999)
    9.0 (4.4 to 15.9)
    10.5 (1.3 to 33.1)
        Chills: Mild
    0 (-99999 to 99999)
    6.3 (2.6 to 12.6)
    10.5 (1.3 to 33.1)
        Chills: Moderate
    0 (-99999 to 99999)
    2.7 (0.6 to 7.7)
    0 (0.0 to 17.6)
        Chills: Severe
    0 (-99999 to 99999)
    0 (0.0 to 3.3)
    0 (0.0 to 17.6)
        Chills: Grade 4
    0 (-99999 to 99999)
    0 (0.0 to 3.3)
    0 (0.0 to 17.6)
        Vomiting: Any
    0 (-99999 to 99999)
    3.6 (1.0 to 9.0)
    0 (0.0 to 17.6)
        Vomiting: Mild
    0 (-99999 to 99999)
    3.6 (1.0 to 9.0)
    0 (0.0 to 17.6)
        Vomiting: Moderate
    0 (-99999 to 99999)
    0 (0.0 to 3.3)
    0 (0.0 to 17.6)
        Vomiting: Severe
    0 (-99999 to 99999)
    0 (0.0 to 3.3)
    0 (0.0 to 17.6)
        Vomiting: Grade 4
    0 (-99999 to 99999)
    0 (0.0 to 3.3)
    0 (0.0 to 17.6)
        Diarrhea: Any
    0 (-99999 to 99999)
    3.6 (1.0 to 9.0)
    0 (0.0 to 17.6)
        Diarrhea: Mild
    0 (-99999 to 99999)
    3.6 (1.0 to 9.0)
    0 (0.0 to 17.6)
        Diarrhea: Moderate
    0 (-99999 to 99999)
    0 (0.0 to 3.3)
    0 (0.0 to 17.6)
        Diarrhea: Severe
    0 (-99999 to 99999)
    0 (0.0 to 3.3)
    0 (0.0 to 17.6)
        Diarrhea: Grade 4
    0 (-99999 to 99999)
    0 (0.0 to 3.3)
    0 (0.0 to 17.6)
        New or worsened muscle pain: Any
    0 (-99999 to 99999)
    13.5 (7.8 to 21.3)
    21.1 (6.1 to 45.6)
        New or worsened muscle pain: Mild
    0 (-99999 to 99999)
    7.2 (3.2 to 13.7)
    10.5 (1.3 to 33.1)
        New or worsened muscle pain: Moderate
    0 (-99999 to 99999)
    6.3 (2.6 to 12.6)
    10.5 (1.3 to 33.1)
        New or worsened muscle pain: Severe
    0 (-99999 to 99999)
    0 (0.0 to 3.3)
    0 (0.0 to 17.6)
        New or worsened muscle pain: Grade 4
    0 (-99999 to 99999)
    0 (0.0 to 3.3)
    0 (0.0 to 17.6)
        New or worsened joint pain: Any
    0 (-99999 to 99999)
    9.0 (4.4 to 15.9)
    10.5 (1.3 to 33.1)
        New or worsened joint pain: Mild
    0 (-99999 to 99999)
    7.2 (3.2 to 13.7)
    5.3 (0.1 to 26.0)
        New or worsened joint pain: Moderate
    0 (-99999 to 99999)
    1.8 (0.2 to 6.4)
    5.3 (0.1 to 26.0)
        New or worsened joint pain: Severe
    0 (-99999 to 99999)
    0 (0.0 to 3.3)
    0 (0.0 to 17.6)
        New or worsened joint pain: Grade 4
    0 (-99999 to 99999)
    0 (0.0 to 3.3)
    0 (0.0 to 17.6)
    No statistical analyses for this end point

    Primary: SSD: Percentage of Participants Reporting Adverse Events (AEs) 1 Month After Study Vaccination

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    End point title
    		 SSD: Percentage of Participants Reporting Adverse Events (AEs) 1 Month After Study Vaccination [3]
    End point description
    An AE was defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. Percentage of participants reporting AEs within 1 month after study vaccination were reported in this endpoint. Exact 2-sided CI was calculated using the Clopper and Pearson method. Only AEs collected by non-systematic assessment (i.e., excluding local reactions and systemic events) were reported in this endpoint. Safety population included all participants who received at least 1 dose of the study intervention. 99999= data could not be generated since it was not part of specified analysis in the protocol.
    End point type
    Primary
    End point timeframe
    From study vaccination on Day 1 up to 1 month after study vaccination
    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: Only descriptive analysis was planned for this endpoint.
    End point values
    		 Group 1: 2 prior doses of BNT162b2 Group 2: 3 prior doses of BNT162b2 Group 3: Participants from study C4591007 Phase 1
    Number of subjects analysed
    2
    113
    19
    Units: Percentage of participants
        number (confidence interval 95%)
    0.0 (-99999 to 99999)
    3.5 (1.0 to 8.8)
    15.8 (3.4 to 39.6)
    No statistical analyses for this end point

    Primary: SSD: Percentage of Participants Reporting Serious Adverse Events (SAEs) Within 6 Months After Study Vaccination

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    End point title
    		 SSD: Percentage of Participants Reporting Serious Adverse Events (SAEs) Within 6 Months After Study Vaccination [4]
    End point description
    An SAE was defined as any untoward medical occurrence that at any dose resulted in death, was life-threatening; resulted in persistent disability/incapacity; constituted a congenital anomaly/birth defect; was important medical event; required inpatient hospitalisation or prolongation of existing hospitalisation. Safety population included all participants who received at least 1 dose of the study intervention.
    End point type
    Primary
    End point timeframe
    From study vaccination on Day 1 up to 6 months after study vaccination
    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: Only descriptive analysis was planned for this endpoint.
    End point values
    		 Group 1: 2 prior doses of BNT162b2 Group 2: 3 prior doses of BNT162b2 Group 3: Participants from study C4591007 Phase 1
    Number of subjects analysed
    2
    113
    19
    Units: Percentage of participants
        number (not applicable)
    0
    0
    0
    No statistical analyses for this end point

    Primary: SSD:Geometric Mean Ratio(GMR)Based on Geometric Mean Titers of Severe Acute Respiratory Syndrome Coronavirus 2(SARS‑CoV‑2)Omicron(BA.4/BA.5)-Neutralizing Titers at 1 Month After Dose 4 for Group 2 and C4591007 Phase 2/3 Participants(1 Month After Dose 3)

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    End point title
    		 SSD:Geometric Mean Ratio(GMR)Based on Geometric Mean Titers of Severe Acute Respiratory Syndrome Coronavirus 2(SARS‑CoV‑2)Omicron(BA.4/BA.5)-Neutralizing Titers at 1 Month After Dose 4 for Group 2 and C4591007 Phase 2/3 Participants(1 Month After Dose 3) [5]
    End point description
    GMTs and the corresponding 2-sided CIs were calculated by exponentiating the least square means and the corresponding CIs based on analysis of log-transformed assay results using a linear regression model with baseline log-transformed neutralizing titers, postbaseline infection status, and vaccine group as covariates. Evaluable immunogenicity population included all eligible randomised participants who received the study intervention to which they were randomised, had a valid and determinate immunogenicity result within 28-42 days after the study vaccination, and had no other important protocol deviations as determined by the clinician. Results include those from a comparator group of C4591007 (NCT04816643) Phase 2/3 participants of the same age who received 3 doses of original BNT162b2 10 μg as of the data cutoff date of 27 May 2022.Participants with or without evidence of prior infection were included in the analysis.'N'=participants evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    1 month after Dose 4 for Group 2 and 1 month after Dose 3 for C4591007 control arm
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be analysed only for the specified reporting arms.
    End point values
    		 Group 2: 3 prior doses of BNT162b2 Historical cohort: C4591007 BNT162b2 10 μg
    Number of subjects analysed
    101
    112
    Units: Titers
        geometric mean (confidence interval 95%)
    1836.1 (1593.8 to 2115.2)
    1632.5 (1427.5 to 1867.0)
    Statistical analysis title
    		 Group 2 and Historical cohort from C4591007
    Statistical analysis description
    GMRs and 2-sided CIs were calculated by exponentiating the difference of LSMeans for the assay and the corresponding CIs based on a linear regression model with baseline log-transformed neutralizing titers, postbaseline infection status, and vaccine group as covariates.
    Comparison groups
    Group 2: 3 prior doses of BNT162b2 v Historical cohort: C4591007 BNT162b2 10 μg
    Number of subjects included in analysis
    213
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Geometric Mean Ratio
    Point estimate
    1.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.92
         upper limit
    		 1.37

    Primary: SSD: Percentages of Participants With Seroresponse to the Omicron (BA.4/BA.5)– Neutralizing Titers at 1 Month After Dose 4 for Group 2 and C4591007 Phase 2/3 Participants (1 Month After Dose 3)

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    End point title
    		 SSD: Percentages of Participants With Seroresponse to the Omicron (BA.4/BA.5)– Neutralizing Titers at 1 Month After Dose 4 for Group 2 and C4591007 Phase 2/3 Participants (1 Month After Dose 3) [6]
    End point description
    Seroresponse was defined as achieving >= 4-fold rise from baseline (before Dose 4 for C4591048 Substudy D Group 2 and before Dose 3 for C4591007). If the baseline measurement was below the lower limit of quantification (LLOQ), the postvaccination assay result of >= 4 × LLOQ was considered a seroresponse. Exact 2-sided 95% CI was based on the Clopper and Pearson method. Percentage of participants achieving seroresponse at 1 month after study vaccination was reported in this endpoint. Evaluable immunogenicity population was analyzed. Results include those from a comparator group of C4591007 (NCT04816643) Phase 2/3 participants of the same age who received 3 doses of original BNT162b2 10 μg as of the data cutoff date of 27 May 2022.Participants with or without evidence of prior infection were included in the analysis.'N'=participants evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    1 month after Dose 4 for Group 2 and 1 month after Dose 3 for C4591007 control arm
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be analysed only for the specified reporting arms.
    End point values
    		 Group 2: 3 prior doses of BNT162b2 Historical cohort: C4591007 BNT162b2 10 μg
    Number of subjects analysed
    101
    112
    Units: Percentage of participants
        number (confidence interval 95%)
    53.5 (43.3 to 63.5)
    52.7 (43.0 to 62.2)
    Statistical analysis title
    		 Group 2 and Historical cohort from C4591007
    Statistical analysis description
    Adjusted difference in proportions based on the Miettinen and Nurminen method stratified by baseline neutralizing titer category (< median, ≥ median), expressed as a percentage (bivalent BNT162b2 [original/Omi BA.4/BA.5] 10 μg - BNT162b2 10 μg). 2-Sided CI, based on the Miettinen and Nurminen method for the difference in proportions stratified by baseline neutralizing titer category (< median,>= median), expressed as a percentage.
    Comparison groups
    Group 2: 3 prior doses of BNT162b2 v Historical cohort: C4591007 BNT162b2 10 μg
    Number of subjects included in analysis
    213
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Percentage Difference
    Point estimate
    8.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.47
         upper limit
    		 19.99

    Secondary: SSD: Geometric Mean Titers (GMT) of SARS-CoV-2 Omicron BA.4/BA.5–Neutralizing Titers at Baseline and 1 Month After Dose 4 for Group 2 and C4591007 Phase 2/3 Participants (1 Month After Dose 3)

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    End point title
    		 SSD: Geometric Mean Titers (GMT) of SARS-CoV-2 Omicron BA.4/BA.5–Neutralizing Titers at Baseline and 1 Month After Dose 4 for Group 2 and C4591007 Phase 2/3 Participants (1 Month After Dose 3) [7]
    End point description
    GMT of SARS-CoV-2 Omicron strain–neutralizing titers at 1 month after the study vaccination was reported in this endpoint. GMTs and the corresponding 2-sided CIs were calculated by exponentiating the mean logarithm of the titers and the corresponding CIs (based on Student's t distribution). Assay results below the LLOQ were set to 0.5 × LLOQ. Evaluable immunogenicity population was analyzed. Results include those from a comparator group of C4591007 (NCT04816643) Phase 2/3 participants of the same age who received 3 doses of original BNT162b2 10 μg as of the data cutoff date of 27 May 2022.Participants with or without evidence of prior infection were included in the analysis.'N'=participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Group 2: Baseline and 1 month after Dose 4; C4591007 control arm: Baseline and 1 month after Dose 3
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be analysed only for the specified reporting arms.
    End point values
    		 Group 2: 3 prior doses of BNT162b2 Historical cohort: C4591007 BNT162b2 10 μg
    Number of subjects analysed
    102
    113
    Units: Titers
    geometric mean (confidence interval 95%)
        Baseline (n=102,112)
    488.3 (361.9 to 658.8)
    248.3 (187.2 to 329.5)
        1 Month (n=102,113)
    2189.9 (1742.8 to 2751.7)
    1393.6 (1175.8 to 1651.7)
    No statistical analyses for this end point

    Secondary: SSD: Geometric Mean Titers (GMT) of SARS-CoV-2 Reference-Strain–Neutralizing Titers at Baseline and 1 Month After Dose 4 for Group 2 and C4591007 Phase 2/3 Participants (1 Month After Dose 3)

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    End point title
    		 SSD: Geometric Mean Titers (GMT) of SARS-CoV-2 Reference-Strain–Neutralizing Titers at Baseline and 1 Month After Dose 4 for Group 2 and C4591007 Phase 2/3 Participants (1 Month After Dose 3) [8]
    End point description
    GMT of SARS-CoV-2 reference-strain-neutralizing titers before vaccination to 1 month after study vaccination was reported in this endpoint.GMTs and the corresponding 2-sided CIs were calculated by exponentiating the mean logarithm of the titers & the corresponding CIs(based on Student's t distribution).Assay results below the LLOQ were set to 0.5 × LLOQ.Evaluable immunogenicity population was analyzed. Results include those from a comparator group of C4591007(NCT04816643) Phase 2/3 participants of the same age who received 3 doses of original BNT162b2 10 μg as of the data cutoff date of 27 May 2022.Participants with or without evidence of prior infection were included in the analysis.'N'=participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Group 2: Baseline and 1 month after Dose 4; C4591007 control arm: Baseline and 1 month after Dose 3
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be analysed only for the specified reporting arms.
    End point values
    		 Group 2: 3 prior doses of BNT162b2 Historical cohort: C4591007 BNT162b2 10 μg
    Number of subjects analysed
    102
    113
    Units: Titers
    geometric mean (confidence interval 95%)
        Baseline
    2904.0 (2372.6 to 3554.5)
    1323.1 (1055.7 to 1658.2)
        1 Month
    8245.9 (7108.9 to 9564.9)
    7235.1 (6331.5 to 8267.8)
    No statistical analyses for this end point

    Secondary: SSD: Geometric Mean Fold Rise (GMFR) of SARS-CoV-2 Omicron BA.4/BA.5–Neutralizing Titers at 1 Month After Dose 4 for Group 2 and C4591007 Phase 2/3 Participants (1 Month After Dose 3)

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    End point title
    		 SSD: Geometric Mean Fold Rise (GMFR) of SARS-CoV-2 Omicron BA.4/BA.5–Neutralizing Titers at 1 Month After Dose 4 for Group 2 and C4591007 Phase 2/3 Participants (1 Month After Dose 3) [9]
    End point description
    GMFR of SARS-CoV-2 omicron BA.4/BA.5-neutralizing titers at 1 month after study vaccination was reported in this endpoint. GMFRs and 2-sided 95% CIs were calculated by exponentiating the mean logarithm of fold rises and the corresponding CIs (based on the Student t distribution). Assay results below the LLOQ were set to 0.5 × LLOQ in the analysis. Evaluable immunogenicity population was analyzed. Results include those from a comparator group of C4591007 (NCT04816643) Phase 2/3 participants of the same age who received 3 doses of original BNT162b2 10 μg as of the data cutoff date of 27 May 2022.Participants with or without evidence of prior infection were included in the analysis.'N'=participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    1 month after Dose 4 for Group 2 and 1 month after Dose 3 for C4591007 control arm
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be analysed only for the specified reporting arms.
    End point values
    		 Group 2: 3 prior doses of BNT162b2 Historical cohort: C4591007 BNT162b2 10 μg
    Number of subjects analysed
    101
    112
    Units: Fold rise
        geometric mean (confidence interval 95%)
    4.5 (3.8 to 5.4)
    5.6 (4.5 to 6.9)
    No statistical analyses for this end point

    Secondary: SSD: GMFR of SARS-CoV-2 Reference-Strain–Neutralizing Titers at 1 Month After Dose 4 for Group 2 and C4591007 Phase 2/3 Participants (1 Month After Dose 3)

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    End point title
    		 SSD: GMFR of SARS-CoV-2 Reference-Strain–Neutralizing Titers at 1 Month After Dose 4 for Group 2 and C4591007 Phase 2/3 Participants (1 Month After Dose 3) [10]
    End point description
    GMFR of SARS-CoV-2 reference-strain-neutralizing titers before vaccination to 1 month after study vaccination was reported in this endpoint. GMFRs and 2-sided 95% CIs were calculated by exponentiating the mean logarithm of fold rises and the corresponding CIs (based on the Student t distribution). Assay results below the LLOQ were set to 0.5 × LLOQ in the analysis.Evaluable immunogenicity population was analyzed. Results include those from a comparator group of C4591007 (NCT04816643) Phase 2/3 participants of the same age who received 3 doses of original BNT162b2 10 μg as of the data cutoff date of 27 May 2022.Participants with or without evidence of prior infection were included in the analysis.'N'=participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    1 month after Dose 4 for Group 2 and 1 month after Dose 3 for C4591007 control arm
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be analysed only for the specified reporting arms.
    End point values
    		 Group 2: 3 prior doses of BNT162b2 Historical cohort: C4591007 BNT162b2 10 μg
    Number of subjects analysed
    101
    113
    Units: Fold rise
        geometric mean (confidence interval 95%)
    2.8 (2.5 to 3.3)
    5.5 (4.5 to 6.7)
    No statistical analyses for this end point

    Secondary: SSD: Percentages of Participants With Seroresponse to SARS-CoV-2 Omicron BA.4/BA.5–Neutralizing Titers at 1 Month After Dose 4 for Group 2 and C4591007 Phase 2/3 Participants (1 Month After Dose 3)

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    End point title
    		 SSD: Percentages of Participants With Seroresponse to SARS-CoV-2 Omicron BA.4/BA.5–Neutralizing Titers at 1 Month After Dose 4 for Group 2 and C4591007 Phase 2/3 Participants (1 Month After Dose 3) [11]
    End point description
    Seroresponse was defined as achieving >= 4-fold rise from baseline (before Dose 4 for C4591048 Substudy D Group 2 and before Dose 3 for C4591007). If the baseline measurement was below the lower limit of quantification (LLOQ), the postvaccination assay result of >= 4 ×* LLOQ was considered a seroresponse. Exact 2-sided 95% CI, based on the Clopper and Pearson method. Percentage of participants achieving seroresponse at 1 month after study vaccination was reported in this endpoint. Evaluable immunogenicity population was analyzed. Results include those from a comparator group of C4591007 (NCT04816643) Phase 2/3 participants of the same age who received 3 doses of original BNT162b2 10 μg as of the data cutoff date of 27 May 2022.Participants with or without evidence of prior infection were included in the analysis.'N'=participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    1 month after Dose 4 for Group 2 and 1 month after Dose 3 for C4591007 control arm
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be analysed only for the specified reporting arms.
    End point values
    		 Group 2: 3 prior doses of BNT162b2 Historical cohort: C4591007 BNT162b2 10 μg
    Number of subjects analysed
    101
    112
    Units: Percentage of participants
        number (confidence interval 95%)
    53.5 (43.3 to 63.5)
    52.7 (43.0 to 62.2)
    No statistical analyses for this end point

    Secondary: SSD: Percentages of Participants With Seroresponse to Reference-Strain-Neutralizing Titers at 1 Month After Dose 4 for Group 2 and C4591007 Phase 2/3 Participants (1 Month After Dose 3)

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    End point title
    		 SSD: Percentages of Participants With Seroresponse to Reference-Strain-Neutralizing Titers at 1 Month After Dose 4 for Group 2 and C4591007 Phase 2/3 Participants (1 Month After Dose 3) [12]
    End point description
    Seroresponse was defined as achieving >= 4-fold rise from baseline (before Dose 4 for C4591048 Substudy D Group 2 and before Dose 3 for C4591007). If the baseline measurement was below the lower limit of quantification (LLOQ), the postvaccination assay result of >= 4 ×* LLOQ was considered a seroresponse. Exact 2-sided 95% CI, based on the Clopper and Pearson method. Percentage of participants achieving seroresponse at 1 month after study vaccination was reported in this endpoint.Results include those from a comparator group of C4591007 (NCT04816643) Phase 2/3 participants of the same age who received 3 doses of original BNT162b2 10 μg as of the data cutoff date of 27 May 2022.Participants with or without evidence of prior infection were included in the analysis.' N'=participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    1 month after Dose 4 for Group 2 and 1 month after Dose 3 for C4591007 control arm
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be analysed only for the specified reporting arms.
    End point values
    		 Group 2: 3 prior doses of BNT162b2 Historical cohort: C4591007 BNT162b2 10 μg
    Number of subjects analysed
    101
    113
    Units: Percentage of participants
        number (confidence interval 95%)
    30.7 (21.9 to 40.7)
    54.9 (45.2 to 64.2)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Local reactions/systemic events(systematic assessment): up to Day 7 after vaccination. Non-SAEs (non-systematic assessment):From Day 1 up to 1 month after study vaccination.For SAE (non-systematic assessment)from Day 1 to 6 month after study vaccination.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Group 1: 2 prior doses of BNT162b2
    Reporting group description
    		 Participants aged 5 to 11 years who had received two prior doses of BNT162b2 10 microgram (mcg) 90 to 240 days before enrollment in the study were included. Participants received a single dose of BNT162b2 10 mcg via intramuscular route on Day 1 of the study.

    Reporting group title
    Group 3: Participants from study C4591007 Phase 1
    Reporting group description
    		 Participants from C4591007 phase 1 trial, aged 5 to 11 years who had received three prior doses of BNT162b2 10 mcg at least 90 days before enrollment in the study were included. Participants received a single dose of BNT162b2 10 mcg via intramuscular route on Day 1 of the study.

    Reporting group title
    Group 2: 3 prior doses of BNT162b2
    Reporting group description
    		 Participants aged 5 to 11 years who had received three prior doses of BNT162b2 10 mcg 90 to 240 days before enrollment in the study were included. Participants received a single dose of BNT162b2 10 mcg via intramuscular route on Day 1 of the study.

    Serious adverse events
    		 Group 1: 2 prior doses of BNT162b2 Group 3: Participants from study C4591007 Phase 1 Group 2: 3 prior doses of BNT162b2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 19 (0.00%)
    0 / 113 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Group 1: 2 prior doses of BNT162b2 Group 3: Participants from study C4591007 Phase 1 Group 2: 3 prior doses of BNT162b2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 2 (50.00%)
    16 / 19 (84.21%)
    88 / 113 (77.88%)
    Injury, poisoning and procedural complications
    Animal bite
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 19 (5.26%)
    0 / 113 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    Headache
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 2 (0.00%)
    7 / 19 (36.84%)
    28 / 113 (24.78%)
         occurrences all number
    0
    7
    28
    General disorders and administration site conditions
    Injection site haemorrhage
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 19 (5.26%)
    0 / 113 (0.00%)
         occurrences all number
    0
    1
    0
    Injection site erythema
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 19 (10.53%)
    8 / 113 (7.08%)
         occurrences all number
    0
    2
    8
    Fatigue
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 2 (0.00%)
    11 / 19 (57.89%)
    45 / 113 (39.82%)
         occurrences all number
    0
    11
    45
    Chills
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 19 (10.53%)
    10 / 113 (8.85%)
         occurrences all number
    0
    2
    10
    Pyrexia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 19 (10.53%)
    5 / 113 (4.42%)
         occurrences all number
    0
    2
    5
    Injection site pain
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 2 (50.00%)
    13 / 19 (68.42%)
    71 / 113 (62.83%)
         occurrences all number
    1
    13
    71
    Injection site swelling
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 19 (10.53%)
    5 / 113 (4.42%)
         occurrences all number
    0
    2
    5
    Gastrointestinal disorders
    Vomiting
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 19 (0.00%)
    4 / 113 (3.54%)
         occurrences all number
    0
    0
    4
    Diarrhoea
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 19 (0.00%)
    4 / 113 (3.54%)
         occurrences all number
    0
    0
    4
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 19 (5.26%)
    0 / 113 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Myalgia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 2 (0.00%)
    4 / 19 (21.05%)
    15 / 113 (13.27%)
         occurrences all number
    0
    4
    15
    Arthralgia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 19 (10.53%)
    10 / 113 (8.85%)
         occurrences all number
    0
    2
    10
    Infections and infestations
    Upper respiratory tract infections
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 19 (5.26%)
    0 / 113 (0.00%)
         occurrences all number
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Oct 2022
    Amendment 1: Updated section 1.1 :Decreased the number of days since last dose prior to enrollment in Group 3 to 90 days. Updated Sections 10.7.5.2, 10.8.5.2, 10.9.5.2, 10.10.5.2 Exclusion Criteria Substudy A, B,C, D: Added radiotherapy, within 60 days before enrollment. Updated section 10.10.3 Clarified that the primary immunogenicity comparison would be between the SSD Group 1 to C4591007 Phase 2/3 participants and made editorial change to the estimands. Updated section 10.10.9.3.2: Clarified that the primary immunogenicity comparison would be between the SSD Group 2 to C4591007 Phase 2/3 participants and made editorial changes to the estimands and analysis. Updated section 10.10.1.2: Removed 1-month postdose blood draw group 3 only. Updated section 10.10.1.3.2: Added the group numbers to rows specific to blood sample collection. Updated section 10.10.1.3.2: Added row specific to Group 3 blood draw to be collected at baseline only.
    01 Aug 2023
    Amendment 3: Updated section: 10.10.3: Added “at 1 month after Dose 4” to the second primary immunogenicity objective.
    01 Sep 2023
    Amendment 4: Updated section 10.10.3 and 10.10.9.3.2: Removed objectives for immunogenicity comparisons and descriptive summaries related to Group 1.

    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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