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    Clinical Trial Results:
    Immune Responses Induced by Vaccination Against COVID-19 in Dutch healthy subjects

    Summary
    EudraCT number
    		 2021-001357-31
    Trial protocol
    		 NL  
    Global end of trial date
    12 Feb 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Jul 2024
    First version publication date
    24 Jul 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    IIV-478
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 ABR number: NL76440.041.21
    Sponsors
    Sponsor organisation name
    RIVM
    Sponsor organisation address
    PO box 1, Bilthoven, Netherlands, 3720BA
    Public contact
    Clinical Expertise Centre, National Institute of Health and the Environment, mensgebonden-onderzoek@rivm.nl
    Scientific contact
    Clinical Expertise Centre, National Institute of Health and the Environment, mensgebonden-onderzoek@rivm.nl
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Interim
    Date of interim/final analysis
    13 Jun 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Feb 2024
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Feb 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Monitoring & evaluation of immune responses induced by COVID-19 vaccines in the general population in the Netherlands, specifically vaccine (e.g. Spike protein)-specific serum IgG GMC at day 28 after completion of COVID-19 vaccination by multiplex immune assay (MIA).
    Protection of trial subjects
    SARS-CoV-2 vaccines have been granted a conditional marketing authorization. These vaccines are given by the participants’ own GP or the GGD as part of the immunization program provided by the Dutch government and are not part of this study. The products are considered safe, as the products are used in several countries in the same age groups. Furthermore, the risk of sampling of blood via finger pricks and venipuncture, faeces and nasal mucosal fluid is considered low. Blood collection could result in a small bruise at the site of blood withdrawal, which will disappear within a few days. The amount of blood drawn within the study is maximum 269 mL and is well within the standard that is maintained by Sanquin Bloodbank. In case of a booster vaccination additional blood will be collected in up to four visits (three home visits in the subgroup with an additional max. total volume of 132 mL and one fingerprick at B2s of 800 μL) amounting in total to an additional max. volume of 133 mL for the booster amendment, over 1 year. For the children the subset groups will be divided in 2 groups. Half of the children (innate group) will have a home visit at T0 and a home visit at T1 (with smaller amounts of blood volume than the adaptive group). The other half (adaptive group) will have a home visit at T0 and no T1 timepoint. This diminishes the burden for the children. Also the blood volume collected will be age dependent. For the booster vaccination study amendment, all subgroups in children will be considered one adaptive subgroup, with age dependent blood volume collected.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 May 2021
    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
    Netherlands: 1459
    Worldwide total number of subjects
    1459
    EEA total number of subjects
    1459
    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)
    47
    Adolescents (12-17 years)
    143
    Adults (18-64 years)
    1269
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Adults aged 18-60 years and children aged 5-12 and 12-18 years were invited; via the VASCO study or other RIVM studies; by random sampling from the BRP; by spontaneous applications. First inclusion 29-05-2021, last inclusion 22-08-2022. Arm assignment was based on age and vaccination type given in the immunization program by the Dutch Government.

    Pre-assignment
    Screening details
    		 Pre-screening was performed through an online questionnaire were in-/exclusion criteria were checked. The trial was looking for generally healthy participants, in order to generate a comparison group for trials with specific diseases.

    Period 1
    Period 1 title
    COVID immunization primary series
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 5-11 years of age - primary vaccination - Pfizer-BioNTech
    Arm description
    		 Participants 5-11 years of age - primary vaccination - Pfizer-BioNTech COVID-19 vaccine
    Arm type
    		 Experimental

    Investigational medicinal product name
    Comirnaty
    Investigational medicinal product code
    Other name
    Pfizer–BioNTech COVID-19 vaccine
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose (0.2 mL) contains 10 micrograms of tozinameran, a COVID-19 mRNA Vaccine (embedded in lipid nanoparticles). Usually, 2 dosages were given with a interval of 3-4 weeks. According to the national immunization program, there were reasons for receiving one instead of two dosages.

    Arm title
    		 12-17 years of age - primary vaccination - Pfizer-BioNTech
    Arm description
    		 Participants 12 -17 years of age - primary vaccination - Pfizer-BioNTech COVID-19 vaccine
    Arm type
    		 Experimental

    Investigational medicinal product name
    Comirnaty
    Investigational medicinal product code
    Other name
    Pfizer–BioNTech COVID-19 vaccine
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose (0.3 mL) contains 30 micrograms of tozinameran, a COVID-19 mRNA Vaccine (embedded in lipid nanoparticles). Usually, 2 dosages were given with a interval of 3-4weeks. According to the national immunization program, there were reasons for receiving one instead of two dosages.

    Arm title
    		 18-30 years of age - primary vaccination - Pfizer-BioNTech
    Arm description
    		 Participants 18-30 years of age - primary vaccination - Pfizer-BioNTech COVID-19 vaccine
    Arm type
    		 Experimental

    Investigational medicinal product name
    Comirnaty
    Investigational medicinal product code
    Other name
    Pfizer–BioNTech COVID-19 vaccine
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose (0.3 mL) contains 30 micrograms of tozinameran, a COVID-19 mRNA Vaccine (embedded in lipid nanoparticles). Usually, 2 dosages were given with a interval of 4-6 weeks. According to the national immunization program, there were reasons for receiving one instead of two dosages.

    Arm title
    		 31-45 years of age - primary vaccination - Pfizer-BioNTech
    Arm description
    		 Participants 31-45 years of age - primary vaccination - Pfizer-BioNTech COVID-19 vaccine
    Arm type
    		 Experimental

    Investigational medicinal product name
    Comrinaty
    Investigational medicinal product code
    Other name
    Pfizer–BioNTech COVID-19 vaccine
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose (0.3 mL) contains 30 micrograms of tozinameran, a COVID-19 mRNA Vaccine (embedded in lipid nanoparticles). Usually, 2 dosages were given with a interval of 4-6 weeks. According to the national immunization program, there were reasons for receiving one instead of two dosages.

    Arm title
    		 46-60 years of age - primary vaccination - Pfizer-BioNTech
    Arm description
    		 Participants 46-60 years of age - primary vaccination - Pfizer-BioNTech COVID-19 vaccine
    Arm type
    		 Experimental

    Investigational medicinal product name
    Comirnaty
    Investigational medicinal product code
    Other name
    Pfizer–BioNTech COVID-19 vaccine
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose (0.3 mL) contains 30 micrograms of tozinameran, a COVID-19 mRNA Vaccine (embedded in lipid nanoparticles). Usually, 2 dosages were given with a interval of 4-6 weeks. According to the national immunization program, there were reasons for receiving one instead of two dosages.

    Arm title
    		 18-30 years of age - primary vaccination - Moderna
    Arm description
    		 Participants 18-30 years of age - primary vaccination - Moderna COVID-19 vaccine
    Arm type
    		 Experimental

    Investigational medicinal product name
    Moderna COVID-19 Vaccine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose (0.50 mL) contains 100 micrograms of elasomeran, a COVID-19 mRNA Vaccine (embedded in SM-102 lipid nanoparticles). Usually, 2 dosages were given with a interval of 4-6 weeks. According to the national immunization program, there were reasons for receiving one instead of two dosages.

    Arm title
    		 31-45 years of age - primary vaccination - Moderna
    Arm description
    		 Participants 31-45 years of age - primary vaccination - Moderna COVID-19 vaccine
    Arm type
    		 Experimental

    Investigational medicinal product name
    Moderna COVID-19 Vaccine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose (0.50 mL) contains 100 micrograms of elasomeran, a COVID-19 mRNA Vaccine (embedded in SM-102 lipid nanoparticles). Usually, 2 dosages were given with a interval of 4-6 weeks. According to the national immunization program, there were reasons for receiving one instead of two dosages.

    Arm title
    		 46-60 years of age - primary vaccination - Moderna
    Arm description
    		 Participants 46-60 years of age - primary vaccination - Moderna COVID-19 vaccine
    Arm type
    		 Experimental

    Investigational medicinal product name
    Moderna COVID-19 Vaccine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose (0.50 mL) contains 100 micrograms of elasomeran, a COVID-19 mRNA Vaccine (embedded in SM-102 lipid nanoparticles). Usually, 2 dosages were given with a interval of 4-6 weeks. According to the national immunization program, there were reasons for receiving one instead of two dosages.

    Arm title
    		 18-30 years of age - primary vaccination - Jcovden
    Arm description
    		 Participants 18-30 years of age - primary vaccination - Jcovden (previously COVID-19 Vaccine Janssen)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Jcovden (previously COVID-19 Vaccine Janssen)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose (0.5 mL) contains Adenovirus type 26 encoding the SARS-CoV-2 spike glycoprotein (Ad26.COV2-S), not less than 8.92 log10 infectious units (Inf.U).

    Arm title
    		 31-45 years of age - primary vaccination - Jcovden
    Arm description
    		 Participants 31-45 years of age - primary vaccination - Jcovden (previously COVID-19 Vaccine Janssen)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Jcovden (previously COVID-19 Vaccine Janssen)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose (0.5 mL) contains Adenovirus type 26 encoding the SARS-CoV-2 spike glycoprotein (Ad26.COV2-S), not less than 8.92 log10 infectious units (Inf.U).

    Arm title
    		 46-60 years of age - primary vaccination - Jcovden
    Arm description
    		 Participants 46-60 years of age - primary vaccination - Jcovden (previously COVID-19 Vaccine Janssen)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Jcovden (previously COVID-19 Vaccine Janssen)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose (0.5 mL) contains Adenovirus type 26 encoding the SARS-CoV-2 spike glycoprotein (Ad26.COV2-S), not less than 8.92 log10 infectious units (Inf.U).

    Arm title
    		 18-30 years of age unknown vaccine primary vaccination
    Arm description
    		 Participants 18-30 years of age - primary unknown vaccination
    Arm type
    		 Experimental

    Investigational medicinal product name
    Unknown vaccine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    These participants didn't communicate the vaccination they received. Therefore the COVID-19 vaccination is unknown.

    Arm title
    		 31-45 years of age unknown vaccine primary vaccination
    Arm description
    		 Participants 31-45 years of age - primary unknown vaccination
    Arm type
    		 Experimental

    Investigational medicinal product name
    Unknown vaccine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    These participants didn't communicate the vaccination they received. Therefore the COVID-19 vaccination is unknown.

    Arm title
    		 46-60 years of age unknown vaccine primary vaccination
    Arm description
    		 Participants 46-60 years of age - primary unknown vaccination
    Arm type
    		 Experimental

    Investigational medicinal product name
    Unknown vaccine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    These participants didn't communicate the vaccination they received. Therefore the COVID-19 vaccination is unknown.

    Number of subjects in period 1
    		5-11 years of age - primary vaccination - Pfizer-BioNTech 12-17 years of age - primary vaccination - Pfizer-BioNTech 18-30 years of age - primary vaccination - Pfizer-BioNTech 31-45 years of age - primary vaccination - Pfizer-BioNTech 46-60 years of age - primary vaccination - Pfizer-BioNTech 18-30 years of age - primary vaccination - Moderna 31-45 years of age - primary vaccination - Moderna 46-60 years of age - primary vaccination - Moderna 18-30 years of age - primary vaccination - Jcovden 31-45 years of age - primary vaccination - Jcovden 46-60 years of age - primary vaccination - Jcovden 18-30 years of age unknown vaccine primary vaccination 31-45 years of age unknown vaccine primary vaccination 46-60 years of age unknown vaccine primary vaccination
    Started
    47
    32
    351
    439
    167
    25
    48
    22
    34
    15
    11
    6
    5
    3
    1-3 days post 1st COVID immunization(T1)
    0 [1]
    21
    30 [2]
    35 [3]
    3 [4]
    0 [5]
    2 [6]
    1 [7]
    3 [8]
    0 [9]
    1 [10]
    0
    0
    0
    28 days post 1st COVID immunization (T2)
    14 [11]
    57
    347
    391
    145 [12]
    25
    42
    17
    0 [13]
    0 [14]
    0 [15]
    0
    0
    0
    28 days post 2nd COVID immunization (T3)
    37
    137
    361
    420
    174
    22
    50
    30
    35
    15
    12
    0
    0
    0
    6 months post 2nd COVID immunization(T4)
    27
    116
    58 [16]
    78 [17]
    65 [18]
    3 [19]
    15 [20]
    16
    28
    13 [21]
    12
    0
    0
    0
    12 mnths post 2nd COVID immunization(T5)
    27
    81
    181 [22]
    280 [23]
    136 [24]
    15 [25]
    32 [26]
    17
    12 [27]
    7 [28]
    9 [29]
    0
    0
    0
    Completed
    27
    91
    292
    391
    166
    20
    45
    26
    27
    16
    12
    0
    0
    0
    Not completed
    20
    52
    116
    90
    18
    7
    8
    6
    14
    1
    0
    6
    5
    3
         Physician decision
    3
    -
    3
    3
    -
    1
    -
    -
    1
    -
    -
    -
    -
    -
         Logistic issues
    1
    4
    2
    -
    -
    -
    -
    -
    -
    -
    -
    -
    -
    -
         Took a booster before end of study period 1
    1
    2
    6
    6
    2
    -
    -
    1
    -
    -
    -
    -
    -
    -
         Participant discontinuation
    -
    17
    25
    9
    2
    1
    -
    1
    3
    -
    -
    1
    3
    1
         Lost to follow-up
    6
    29
    76
    72
    14
    5
    8
    4
    9
    1
    -
    2
    1
    2
         Participant discontuniation
    9
    -
    -
    -
    -
    -
    -
    -
    -
    -
    -
    -
    -
    -
         Maximum number participants reached
    -
    -
    -
    -
    -
    -
    -
    -
    -
    -
    -
    3
    1
    -
         (temporarily) emigrated
    -
    -
    4
    -
    -
    -
    -
    -
    1
    -
    -
    -
    -
    -
    Joined
    0
    111
    57
    42
    17
    2
    5
    10
    7
    2
    1
    0
    0
    0
         Late recruitment
         Late recruitment reason:
    -
             
    111
             Included after vaccination
    57
             Included after vaccination
    42
             Included after vaccination
    17
             Included after vaccination
    2
             Included after vaccination
    5
             Included after vaccination
    10
             Included after vaccination
    7
             Included after vaccination
    2
             Included after vaccination
    1
             Included after vaccination
    -
             
    -
             
    -
             
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: It is correct that it seems that the number of subjects in the milestones are inconsistent with the total number of subjects in the arm. Because not all participants were included in all of the timepoints (milestones), due to missing data/blood samples for some timepoints.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: It is correct that it seems that the number of subjects in the milestones are inconsistent with the total number of subjects in the arm. Because not all participants were included in all of the timepoints (milestones), due to missing data/blood samples for some timepoints.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: It is correct that it seems that the number of subjects in the milestones are inconsistent with the total number of subjects in the arm. Because not all participants were included in all of the timepoints (milestones), due to missing data/blood samples for some timepoints.
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: It is correct that it seems that the number of subjects in the milestones are inconsistent with the total number of subjects in the arm. Because not all participants were included in all of the timepoints (milestones), due to missing data/blood samples for some timepoints.
    [5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: It is correct that it seems that the number of subjects in the milestones are inconsistent with the total number of subjects in the arm. Because not all participants were included in all of the timepoints (milestones), due to missing data/blood samples for some timepoints.
    [6] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: It is correct that it seems that the number of subjects in the milestones are inconsistent with the total number of subjects in the arm. Because not all participants were included in all of the timepoints (milestones), due to missing data/blood samples for some timepoints.
    [7] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: It is correct that it seems that the number of subjects in the milestones are inconsistent with the total number of subjects in the arm. Because not all participants were included in all of the timepoints (milestones), due to missing data/blood samples for some timepoints.
    [8] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: It is correct that it seems that the number of subjects in the milestones are inconsistent with the total number of subjects in the arm. Because not all participants were included in all of the timepoints (milestones), due to missing data/blood samples for some timepoints.
    [9] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: It is correct that it seems that the number of subjects in the milestones are inconsistent with the total number of subjects in the arm. Because not all participants were included in all of the timepoints (milestones), due to missing data/blood samples for some timepoints.
    [10] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: It is correct that it seems that the number of subjects in the milestones are inconsistent with the total number of subjects in the arm. Because not all participants were included in all of the timepoints (milestones), due to missing data/blood samples for some timepoints.
    [11] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: It is correct that it seems that the number of subjects in the milestones are inconsistent with the total number of subjects in the arm. Because not all participants were included in all of the timepoints (milestones), due to missing data/blood samples for some timepoints.
    [12] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: It is correct that it seems that the number of subjects in the milestones are inconsistent with the total number of subjects in the arm. Because not all participants were included in all of the timepoints (milestones), due to missing data/blood samples for some timepoints.
    [13] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: It is correct that it seems that the number of subjects in the milestones are inconsistent with the total number of subjects in the arm. Because not all participants were included in all of the timepoints (milestones), due to missing data/blood samples for some timepoints.
    [14] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: It is correct that it seems that the number of subjects in the milestones are inconsistent with the total number of subjects in the arm. Because not all participants were included in all of the timepoints (milestones), due to missing data/blood samples for some timepoints.
    [15] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: It is correct that it seems that the number of subjects in the milestones are inconsistent with the total number of subjects in the arm. Because not all participants were included in all of the timepoints (milestones), due to missing data/blood samples for some timepoints.
    [16] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: It is correct that it seems that the number of subjects in the milestones are inconsistent with the total number of subjects in the arm. Because not all participants were included in all of the timepoints (milestones), due to missing data/blood samples for some timepoints.
    [17] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: It is correct that it seems that the number of subjects in the milestones are inconsistent with the total number of subjects in the arm. Because not all participants were included in all of the timepoints (milestones), due to missing data/blood samples for some timepoints.
    [18] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: It is correct that it seems that the number of subjects in the milestones are inconsistent with the total number of subjects in the arm. Because not all participants were included in all of the timepoints (milestones), due to missing data/blood samples for some timepoints.
    [19] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: It is correct that it seems that the number of subjects in the milestones are inconsistent with the total number of subjects in the arm. Because not all participants were included in all of the timepoints (milestones), due to missing data/blood samples for some timepoints.
    [20] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: It is correct that it seems that the number of subjects in the milestones are inconsistent with the total number of subjects in the arm. Because not all participants were included in all of the timepoints (milestones), due to missing data/blood samples for some timepoints.
    [21] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: It is correct that it seems that the number of subjects in the milestones are inconsistent with the total number of subjects in the arm. Because not all participants were included in all of the timepoints (milestones), due to missing data/blood samples for some timepoints.
    [22] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: It is correct that it seems that the number of subjects in the milestones are inconsistent with the total number of subjects in the arm. Because not all participants were included in all of the timepoints (milestones), due to missing data/blood samples for some timepoints.
    [23] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: It is correct that it seems that the number of subjects in the milestones are inconsistent with the total number of subjects in the arm. Because not all participants were included in all of the timepoints (milestones), due to missing data/blood samples for some timepoints.
    [24] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: It is correct that it seems that the number of subjects in the milestones are inconsistent with the total number of subjects in the arm. Because not all participants were included in all of the timepoints (milestones), due to missing data/blood samples for some timepoints.
    [25] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: It is correct that it seems that the number of subjects in the milestones are inconsistent with the total number of subjects in the arm. Because not all participants were included in all of the timepoints (milestones), due to missing data/blood samples for some timepoints.
    [26] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: It is correct that it seems that the number of subjects in the milestones are inconsistent with the total number of subjects in the arm. Because not all participants were included in all of the timepoints (milestones), due to missing data/blood samples for some timepoints.
    [27] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: It is correct that it seems that the number of subjects in the milestones are inconsistent with the total number of subjects in the arm. Because not all participants were included in all of the timepoints (milestones), due to missing data/blood samples for some timepoints.
    [28] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: It is correct that it seems that the number of subjects in the milestones are inconsistent with the total number of subjects in the arm. Because not all participants were included in all of the timepoints (milestones), due to missing data/blood samples for some timepoints.
    [29] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: It is correct that it seems that the number of subjects in the milestones are inconsistent with the total number of subjects in the arm. Because not all participants were included in all of the timepoints (milestones), due to missing data/blood samples for some timepoints.
    Period 2
    Period 2 title
    COVID immunization, first booster
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 12 -17 years of age - 1st Booster - Pfizer–BioNTech
    Arm description
    		 Participants 12 -17 years of age - 1st Booster - Pfizer–BioNTech COVID-19 vaccine
    Arm type
    		 Experimental

    Investigational medicinal product name
    Comirnaty
    Investigational medicinal product code
    Other name
    Pfizer–BioNTech COVID-19 vaccine
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose (0.3 mL) contains 30 micrograms of tozinameran, a COVID-19 mRNA Vaccine (embedded in lipid nanoparticles).

    Arm title
    		 18-30 years of age - 1st booster - Pfizer–BioNTech
    Arm description
    		 Participants 18 -30 years of age - 1st Booster - Pfizer–BioNTech COVID-19 vaccine
    Arm type
    		 Experimental

    Investigational medicinal product name
    Comirnaty
    Investigational medicinal product code
    Other name
    Pfizer–BioNTech COVID-19 vaccine
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose (0.3 mL) contains 30 micrograms of tozinameran, a COVID-19 mRNA Vaccine (embedded in lipid nanoparticles).

    Arm title
    		 31-45 years of age - 1st booster - Pfizer–BioNTech
    Arm description
    		 Participants 31-45 years of age - 1st Booster - Pfizer–BioNTech COVID-19 vaccine
    Arm type
    		 Experimental

    Investigational medicinal product name
    Comirnaty
    Investigational medicinal product code
    Other name
    Pfizer–BioNTech COVID-19 vaccine
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose (0.3 mL) contains 30 micrograms of tozinameran, a COVID-19 mRNA Vaccine (embedded in lipid nanoparticles).

    Arm title
    		 46-60 years of age - 1st booster - Pfizer–BioNTech
    Arm description
    		 Participants 46-60 years of age - 1st Booster - Pfizer–BioNTech COVID-19 vaccine
    Arm type
    		 Experimental

    Investigational medicinal product name
    Comirnaty
    Investigational medicinal product code
    Other name
    Pfizer–BioNTech COVID-19 vaccine
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose (0.3 mL) contains 30 micrograms of tozinameran, a COVID-19 mRNA Vaccine (embedded in lipid nanoparticles).

    Arm title
    		 18-30 years of age - 1st booster - Moderna
    Arm description
    		 Participants 18-30 years of age - 1st Booster - Moderna COVID-19 Vaccine
    Arm type
    		 Experimental

    Investigational medicinal product name
    Moderna COVID-19 Vaccine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose (0.25 mL) contains 50 micrograms of elasomeran, a COVID-19 mRNA Vaccine (embedded in SM-102 lipid nanoparticles).

    Arm title
    		 31-45 years of age - 1st booster - Moderna
    Arm description
    		 Participants 31-45 years of age - 1st Booster - Moderna COVID-19 Vaccine
    Arm type
    		 Experimental

    Investigational medicinal product name
    Moderna COVID-19 Vaccine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose (0.25 mL) contains 50 micrograms of elasomeran, a COVID-19 mRNA Vaccine (embedded in SM-102 lipid nanoparticles).

    Arm title
    		 46-60 years of age - 1st booster - Moderna
    Arm description
    		 Participants 46-60 years of age - 1st Booster - Moderna COVID-19 Vaccine
    Arm type
    		 Experimental

    Investigational medicinal product name
    Moderna COVID-19 Vaccine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose (0.25 mL) contains 50 micrograms of elasomeran, a COVID-19 mRNA Vaccine (embedded in SM-102 lipid nanoparticles).

    Number of subjects in period 2 [30] [31]
    		12 -17 years of age - 1st Booster - Pfizer–BioNTech 18-30 years of age - 1st booster - Pfizer–BioNTech 31-45 years of age - 1st booster - Pfizer–BioNTech 46-60 years of age - 1st booster - Pfizer–BioNTech 18-30 years of age - 1st booster - Moderna 31-45 years of age - 1st booster - Moderna 46-60 years of age - 1st booster - Moderna
    Started
    7
    238
    372
    43
    3
    18
    137
    28 days post booster 1 (B1)
    6
    261
    369
    45
    2
    18
    138
    6 motnhs post booster 1 (B2)
    9
    207
    340
    39
    2
    18
    120
    12 motnhs post booster 1 (B3)
    9
    86
    183
    21
    1
    7
    46
    Completed
    9
    86
    183
    21
    1
    7
    46
    Not completed
    1
    215
    219
    26
    2
    12
    97
         Physician decision
    -
    2
    -
    2
    -
    -
    2
         Transferred to other arm/group
    -
    60
    57
    -
    -
    2
    40
         Crucial measurement missing
    -
    5
    9
    -
    -
    -
    4
         Took a booster before end of study period 1
    -
    31
    56
    13
    -
    6
    17
         Participant discontinuation
    -
    4
    8
    1
    1
    -
    7
         Lost to follow-up
    1
    110
    89
    10
    1
    4
    27
         (temporarily) emigrated
    -
    3
    -
    -
    -
    -
    -
    Joined
    3
    63
    30
    4
    0
    1
    6
         Late recruitment
         Late recruitment reason:
    3
             Included after booster vaccination
    63
             Included after booster vaccination
    30
             Included after booster vaccination
    4
             Included after booster vaccination
    -
             
    1
             Included after booster vaccination
    6
             Included after booster vaccination
    Notes
    [30] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: The trial started with the primary series. Later on, booster vaccinations were available that not all participants took. Each period is a separate part of the trial. Participants could then choose to enroll in the second period and/or the third period. Group allocation in the other periods was based on the booster vaccination, irrespective of the vaccination in the primary series. The number of participants starting another period is thus not equal to the number completing a previous period.
    [31] - The number of subjects transferring in and out of the arms in the period are not the same. It is expected the net number of transfers in and out of the arms in a period, will be zero.
    Justification: The trial started with the primary series. Later on, booster vaccinations were available that not all participants took. Each period is a separate part of the trial. Participants could then choose to enroll in the second period and/or the third period. Group allocation in the other periods was based on the booster vaccination, irrespective of the vaccination in the primary series. The number of participants starting another period is thus not equal to the number completing a previous period.
    Period 3
    Period 3 title
    COVID immunization, repeat vaccination
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 12 -17 years of age - repeat vaccination - Pfizer bivalent
    Arm description
    		 Participants 31-45 years of age - repeat vaccination - Pfizer bivalent COVID-19 vaccine
    Arm type
    		 Experimental

    Investigational medicinal product name
    Comirnaty Original/Omicron BA.1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose (0.3 mL) contains 15 micrograms of tozinameran and 15 micrograms of riltozinameran, a COVID-19 mRNA Vaccine (embedded in lipid nanoparticles).

    Arm title
    		 18-30 years of age - repeat vaccination - Pfizer bivalent
    Arm description
    		 Participants 18-30 years of age - repeat vaccination - Pfizer bivalent COVID-19 vaccine
    Arm type
    		 Experimental

    Investigational medicinal product name
    Comirnaty Original/Omicron BA.1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Not apOne dose (0.3 mL) contains 15 micrograms of tozinameran and 15 micrograms of riltozinameran, a COVID-19 mRNA Vaccine (embedded in lipid nanoparticles).

    Arm title
    		 31-45 years of age - repeat vaccination - Pfizer bivalent
    Arm description
    		 Participants 31-45 years of age - repeat vaccination - Pfizer bivalent COVID-19 vaccine
    Arm type
    		 Experimental

    Investigational medicinal product name
    Comirnaty Original/Omicron BA.1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose (0.3 mL) contains 15 micrograms of tozinameran and 15 micrograms of riltozinameran, a COVID-19 mRNA Vaccine (embedded in lipid nanoparticles).

    Arm title
    		 46-60 years of age - repeat vaccination - Pfizer bivalent
    Arm description
    		 Participants 46-60 years of age - repeat vaccination - Pfizer bivalent COVID-19 vaccine
    Arm type
    		 Experimental

    Investigational medicinal product name
    Comirnaty Original/Omicron BA.1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose (0.3 mL) contains 15 micrograms of tozinameran and 15 micrograms of riltozinameran, a COVID-19 mRNA Vaccine (embedded in lipid nanoparticles).

    Arm title
    		 31-45 years of age - repeat vaccination - Moderna bivalent
    Arm description
    		 Participants 31-45 years of age - repeat vaccination - Moderna bivalent COVID-19 vaccine
    Arm type
    		 Experimental

    Investigational medicinal product name
    Spikevax bivalent Original/Omicron BA.1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Dispersion for infusion
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose (0.5 mL) contains 25 micrograms of elasomeran and 25 micrograms of imelasomeran, a COVID-19 mRNA Vaccine (nucleoside modified) (embedded in lipid nanoparticles).

    Arm title
    		 46-60 years of age - repeat vaccination - Moderna bivalent
    Arm description
    		 Participants 46-60 years of age - repeat vaccination - Moderna bivalent COVID-19 vaccine
    Arm type
    		 Experimental

    Investigational medicinal product name
    Spikevax bivalent Original/Omicron BA.1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose (0.5 mL) contains 25 micrograms of elasomeran and 25 micrograms of imelasomeran, a COVID-19 mRNA Vaccine (nucleoside modified) (embedded in lipid nanoparticles).

    Number of subjects in period 3 [32]
    		12 -17 years of age - repeat vaccination - Pfizer bivalent 18-30 years of age - repeat vaccination - Pfizer bivalent 31-45 years of age - repeat vaccination - Pfizer bivalent 46-60 years of age - repeat vaccination - Pfizer bivalent 31-45 years of age - repeat vaccination - Moderna bivalent 46-60 years of age - repeat vaccination - Moderna bivalent
    Started
    13
    56
    56
    4
    6
    35
    28 days post repeat vaccination (D1)
    14
    53
    47
    3
    4
    27
    6 months post repeat vaccination (D2)
    11
    45
    42
    3
    4
    24
    12 months post repeat vaccination (D3)
    12
    47
    40
    2
    4
    24
    Completed
    12
    47
    40
    2
    4
    24
    Not completed
    3
    15
    18
    2
    2
    14
         Physician decision
    -
    1
    2
    -
    -
    1
         Crucial measurement missing
    1
    9
    11
    1
    2
    12
         Participant discontinuation
    2
    2
    1
    -
    -
    -
         Took a booster before end of study period 1
    -
    -
    2
    1
    -
    1
         Lost to follow-up
    -
    3
    2
    -
    -
    -
    Joined
    2
    6
    2
    0
    0
    3
         Late recruitment
         Late recruitment reason:
    2
             Included after repeat vaccination
    6
             Included after repeat vaccination
    2
             Included after repeat vaccination
    -
             
    -
             
    3
             Included after repeat vaccination
    Notes
    [32] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: The trial started with the primary series. Later on, booster vaccinations were available that not all participants took. Each period is a separate part of the trial. Participants could then choose to enroll in the second period and/or the third period. Group allocation in the other periods was based on the booster vaccination, irrespective of the vaccination in the primary series. The number of participants starting another period is thus not equal to the number completing a previous period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    COVID immunization primary series
    Reporting group description
    		 -

    Reporting group values
    		 COVID immunization primary series Total
    Number of subjects
    		 1459 1459
    Age categorical
    Units: Subjects
        Children (2-11 years)
    		 47 47
        Adolescents (12-17 years)
    		 143 143
        Adults (18-64 years)
    		 1269 1269
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 32.03 (5 to 60) -
    Gender categorical
    Units: Subjects
        Female
    		 935 935
        Male
    		 520 520
        Other
    		 4 4

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    5-11 years of age - primary vaccination - Pfizer-BioNTech
    Reporting group description
    		 Participants 5-11 years of age - primary vaccination - Pfizer-BioNTech COVID-19 vaccine

    Reporting group title
    12-17 years of age - primary vaccination - Pfizer-BioNTech
    Reporting group description
    		 Participants 12 -17 years of age - primary vaccination - Pfizer-BioNTech COVID-19 vaccine

    Reporting group title
    18-30 years of age - primary vaccination - Pfizer-BioNTech
    Reporting group description
    		 Participants 18-30 years of age - primary vaccination - Pfizer-BioNTech COVID-19 vaccine

    Reporting group title
    31-45 years of age - primary vaccination - Pfizer-BioNTech
    Reporting group description
    		 Participants 31-45 years of age - primary vaccination - Pfizer-BioNTech COVID-19 vaccine

    Reporting group title
    46-60 years of age - primary vaccination - Pfizer-BioNTech
    Reporting group description
    		 Participants 46-60 years of age - primary vaccination - Pfizer-BioNTech COVID-19 vaccine

    Reporting group title
    18-30 years of age - primary vaccination - Moderna
    Reporting group description
    		 Participants 18-30 years of age - primary vaccination - Moderna COVID-19 vaccine

    Reporting group title
    31-45 years of age - primary vaccination - Moderna
    Reporting group description
    		 Participants 31-45 years of age - primary vaccination - Moderna COVID-19 vaccine

    Reporting group title
    46-60 years of age - primary vaccination - Moderna
    Reporting group description
    		 Participants 46-60 years of age - primary vaccination - Moderna COVID-19 vaccine

    Reporting group title
    18-30 years of age - primary vaccination - Jcovden
    Reporting group description
    		 Participants 18-30 years of age - primary vaccination - Jcovden (previously COVID-19 Vaccine Janssen)

    Reporting group title
    31-45 years of age - primary vaccination - Jcovden
    Reporting group description
    		 Participants 31-45 years of age - primary vaccination - Jcovden (previously COVID-19 Vaccine Janssen)

    Reporting group title
    46-60 years of age - primary vaccination - Jcovden
    Reporting group description
    		 Participants 46-60 years of age - primary vaccination - Jcovden (previously COVID-19 Vaccine Janssen)

    Reporting group title
    18-30 years of age unknown vaccine primary vaccination
    Reporting group description
    		 Participants 18-30 years of age - primary unknown vaccination

    Reporting group title
    31-45 years of age unknown vaccine primary vaccination
    Reporting group description
    		 Participants 31-45 years of age - primary unknown vaccination

    Reporting group title
    46-60 years of age unknown vaccine primary vaccination
    Reporting group description
    		 Participants 46-60 years of age - primary unknown vaccination
    Reporting group title
    12 -17 years of age - 1st Booster - Pfizer–BioNTech
    Reporting group description
    		 Participants 12 -17 years of age - 1st Booster - Pfizer–BioNTech COVID-19 vaccine

    Reporting group title
    18-30 years of age - 1st booster - Pfizer–BioNTech
    Reporting group description
    		 Participants 18 -30 years of age - 1st Booster - Pfizer–BioNTech COVID-19 vaccine

    Reporting group title
    31-45 years of age - 1st booster - Pfizer–BioNTech
    Reporting group description
    		 Participants 31-45 years of age - 1st Booster - Pfizer–BioNTech COVID-19 vaccine

    Reporting group title
    46-60 years of age - 1st booster - Pfizer–BioNTech
    Reporting group description
    		 Participants 46-60 years of age - 1st Booster - Pfizer–BioNTech COVID-19 vaccine

    Reporting group title
    18-30 years of age - 1st booster - Moderna
    Reporting group description
    		 Participants 18-30 years of age - 1st Booster - Moderna COVID-19 Vaccine

    Reporting group title
    31-45 years of age - 1st booster - Moderna
    Reporting group description
    		 Participants 31-45 years of age - 1st Booster - Moderna COVID-19 Vaccine

    Reporting group title
    46-60 years of age - 1st booster - Moderna
    Reporting group description
    		 Participants 46-60 years of age - 1st Booster - Moderna COVID-19 Vaccine
    Reporting group title
    12 -17 years of age - repeat vaccination - Pfizer bivalent
    Reporting group description
    		 Participants 31-45 years of age - repeat vaccination - Pfizer bivalent COVID-19 vaccine

    Reporting group title
    18-30 years of age - repeat vaccination - Pfizer bivalent
    Reporting group description
    		 Participants 18-30 years of age - repeat vaccination - Pfizer bivalent COVID-19 vaccine

    Reporting group title
    31-45 years of age - repeat vaccination - Pfizer bivalent
    Reporting group description
    		 Participants 31-45 years of age - repeat vaccination - Pfizer bivalent COVID-19 vaccine

    Reporting group title
    46-60 years of age - repeat vaccination - Pfizer bivalent
    Reporting group description
    		 Participants 46-60 years of age - repeat vaccination - Pfizer bivalent COVID-19 vaccine

    Reporting group title
    31-45 years of age - repeat vaccination - Moderna bivalent
    Reporting group description
    		 Participants 31-45 years of age - repeat vaccination - Moderna bivalent COVID-19 vaccine

    Reporting group title
    46-60 years of age - repeat vaccination - Moderna bivalent
    Reporting group description
    		 Participants 46-60 years of age - repeat vaccination - Moderna bivalent COVID-19 vaccine

    Subject analysis set title
    Pre- primary vaccination immune response in adults (T0)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Pre- primary vaccination immune response in adults (T0)

    Subject analysis set title
    1-3 days post 1st primary vaccination response in adults (T1)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    1-3 days post 1st primary vaccination immune response in adults (T1)

    Subject analysis set title
    Pre- primary vaccination immune response in adolescents (T0)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Pre- primary vaccination immune response in adolescents (T0)

    Subject analysis set title
    1-3 days post 1st primary vaccination response in adolescents
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    1-3 days post 1st primary vaccination response in adolescents (T1)

    Subject analysis set title
    VNT 28 days post primary vaccination(s) (T3)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Virus neutralizing capacity of antibodies at T3 (28 days post primary vaccination(s))

    Subject analysis set title
    VNT Pre-booster vaccination (B0)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Virus neutralizing capacity of antibodies at B0 (pre first booster vaccination)

    Subject analysis set title
    VNT 28 days post booster vaccination (B1)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Virus neutralizing capacity of antibodies at B1 (28 days post booster vaccination)

    Subject analysis set title
    VNT Pre-repeat vaccination (D0)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Virus neutralizing capacity of antibodies at D0 (pre repeat vaccination)

    Subject analysis set title
    VNT 28 days post repeat vaccination (D1)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Virus neutralizing capacity of antibodies at D1 (28 days post repeat vaccination)

    Subject analysis set title
    ADCD 28 days post 2nd vaccination (T3)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Complement deposition capacity of antibodies in MFI at T3 (28 days post 2nd COVID-19 vaccination)

    Subject analysis set title
    ADCP 28 days post 2nd vaccination (T3)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Phagocytosis mediating capacity of antibodies in iMFI at T3 (28 days post 2nd COVID-19 vaccination)

    Subject analysis set title
    ADCC 28 days post 2nd vaccination (T3)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    % NK cell activation in cell based (NK-92) assay as a measure for ADCC inducing capacity of antibodies in serum at T3 (28 days post 2nd COVID-19 vaccination)

    Subject analysis set title
    MLF pre-primary COVID immunization (T0)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    MLF pre-primary COVID immunization (T0)

    Subject analysis set title
    MLF 28 days post 2nd COVID immunization (T3)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    MLF 28 days post 2nd COVID immunization (T3)

    Subject analysis set title
    MLF 12 months post 2nd COVID immunization (T5)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    MLF 12 months post 2nd COVID immunization (T5)

    Subject analysis set title
    MLF pre- first booster (B0)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    MLF pre- first booster (B0)

    Subject analysis set title
    MLF 28 days post booster 1 (B1)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    MLF 28 days post booster 1 (B1)

    Subject analysis set title
    MLF 12 months post booster 1 (B3)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    MLF 12 months post booster 1 (B3)

    Subject analysis set title
    MLF pre- repeat vaccination (D0)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    MLF pre- repeat vaccination (D0)

    Subject analysis set title
    MLF 28 days post repeat vaccination (D1)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    MLF 28 days post repeat vaccination (D1)

    Subject analysis set title
    Tcel ELISpot: pre-primary COVID immunization (T0)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Tcel ELISpot: pre-primary COVID immunization (T0)

    Subject analysis set title
    Tcel ELISpot: post 2nd COVID immunization (T3)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Tcel ELISpot: post 2nd COVID immunization (T3)

    Subject analysis set title
    Tcel ELISpot: pre- first booster (B0)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Tcel ELISpot: pre- first booster (B0)

    Subject analysis set title
    Tcel ELISpot: 28 days post first booster (B1)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Tcel ELISpot: 28 days post first booster (B1)

    Subject analysis set title
    Tcel ELISpot: pre-repeat vaccination (D0)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Tcel ELISpot: pre-repeat vaccination (D0)

    Subject analysis set title
    Tcel ELISpot: 28 days post repeat vaccination (D1)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Tcel ELISpot: 28 days post repeat vaccination (D1)

    Subject analysis set title
    Tcel ELISpot: 12 months post repeat vaccination (D3)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Tcel ELISpot: 12 months post repeat vaccination (D3)

    Subject analysis set title
    Bcel ELISpot: pre-primary COVID immunization (T0)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Bcel ELISpot: pre-primary COVID immunization (T0)

    Subject analysis set title
    Bcel ELISpot: post 2nd COVID immunization (T3)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Bcel ELISpot: post 2nd COVID immunization (T3)

    Subject analysis set title
    Bcel ELISpot: pre- first booster (B0)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Bcel ELISpot: pre- first booster (B0)

    Subject analysis set title
    Bcel ELISpot: 28 days post first booster (B1)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Bcel ELISpot: 28 days post first booster (B1)

    Subject analysis set title
    Reactogenicity: first 5 days post primary vaccination
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Reactogenicity; AEs recorded the first 5 days after 1st COVID 19 vaccination or until symptoms subside

    Primary: Vaccine-specific IgG GMC at day 28 after completion of COVID-19 vaccination

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    End point title
    		 Vaccine-specific IgG GMC at day 28 after completion of COVID-19 vaccination
    End point description
    Measuring vaccine (e.g. Spike protein)- specific serum IgG GMC in Dutch healthy subject at day 28 after completion of COVID-19 vaccination by bead-based multiplex immune assay (MIA).
    End point type
    Primary
    End point timeframe
    Period 1 - period 3
    End point values
    		 5-11 years of age - primary vaccination - Pfizer-BioNTech 12-17 years of age - primary vaccination - Pfizer-BioNTech 18-30 years of age - primary vaccination - Pfizer-BioNTech 31-45 years of age - primary vaccination - Pfizer-BioNTech 46-60 years of age - primary vaccination - Pfizer-BioNTech 18-30 years of age - primary vaccination - Moderna 31-45 years of age - primary vaccination - Moderna 46-60 years of age - primary vaccination - Moderna 18-30 years of age - primary vaccination - Jcovden 31-45 years of age - primary vaccination - Jcovden 46-60 years of age - primary vaccination - Jcovden 18-30 years of age unknown vaccine primary vaccination 31-45 years of age unknown vaccine primary vaccination 46-60 years of age unknown vaccine primary vaccination 12 -17 years of age - 1st Booster - Pfizer–BioNTech 18-30 years of age - 1st booster - Pfizer–BioNTech 31-45 years of age - 1st booster - Pfizer–BioNTech 46-60 years of age - 1st booster - Pfizer–BioNTech 18-30 years of age - 1st booster - Moderna 31-45 years of age - 1st booster - Moderna 46-60 years of age - 1st booster - Moderna 12 -17 years of age - repeat vaccination - Pfizer bivalent 18-30 years of age - repeat vaccination - Pfizer bivalent 31-45 years of age - repeat vaccination - Pfizer bivalent 46-60 years of age - repeat vaccination - Pfizer bivalent 31-45 years of age - repeat vaccination - Moderna bivalent 46-60 years of age - repeat vaccination - Moderna bivalent
    Number of subjects analysed
    29
    121 [1]
    313
    347 [2]
    136 [3]
    19
    43
    23 [4]
    26
    11
    8 [5]
    0 [6]
    0 [7]
    0 [8]
    6
    250 [9]
    356 [10]
    40 [11]
    2
    17
    127 [12]
    10
    47
    42
    2
    4
    24
    Units: BAU/ml
    geometric mean (confidence interval 95%)
        Conc_COV19S1
    4427.8 (3222.1 to 5633.5)
    5345.4 (4750.9 to 5939.9)
    3588.9 (3345.9 to 3831.8)
    2537.6 (2358 to 2717.1)
    2699.7 (2297.5 to 3101.8)
    5696 (3964.6 to 7427.3)
    3743.9 (3065.7 to 4422.2)
    3654.1 (2653 to 4655.2)
    1127.5 (334.2 to 1920.8)
    52.1 (40.7 to 63.5)
    779.4 (-317.6 to 1876.4)
    ( to )
    ( to )
    ( to )
    20322.4 (5507.6 to 35137.2)
    7479.4 (6552.9 to 8405.8)
    5962.8 (5398.3 to 6527.4)
    6995.9 (5342.3 to 8649.5)
    19969.5 (-1442056.2 to 181995.2)
    8942.5 (3299.1 to 14586)
    8935.8 (7839.4 to 10032.1)
    9844.7 (6774 to 12915.3)
    9845.2 (8082 to 11608.5)
    9225.5 (7372.8 to 11078.2)
    9591.6 (-11912.4 to 31095.6)
    10448.8 (-1205 to 22102.5)
    15705.9 (12050.7 to 19361.2)
        Conc_COV19N
    173.5 (50.1 to 296.8)
    9.3 (5.5 to 13.1)
    9.9 (5 to 14.8)
    7.1 (5.5 to 8.8)
    16 (9.5 to 22.5)
    8.6 (5.8 to 14.4)
    11 (2.1 to 20)
    48 (-31.8 to 127.8)
    8.6 (3.5 to 13.6)
    2.2 (0.9 to 3.6)
    63.4 (-68.9 to 195.6)
    ( to )
    ( to )
    ( to )
    8.1 (1 to 15.3)
    31.6 (13.6 to 49.7)
    21.2 (7.2 to 35.3)
    76.1 (-27.1 to 179.3)
    3.8 (-31.7 to 39.2)
    5.9 (1.8 to 10.1)
    18.1 (-1.7 to 37.8)
    130.9 (-29.9 to 291.7)
    43.2 (23.8 to 62.6)
    27.4 (16.6 to 38.1)
    136.4 (-1334.2 to 1607)
    9.6 (-4.7 to 23.9)
    37.7 (14.6 to 60.8)
        Conc_COV19RBD
    2599.5 (1809.5 to 3389.5)
    3777.2 (3299.9 to 4254.5)
    2475.5 (2304.5 to 2646.6)
    1824.2 (1691.2 to 1957.2)
    1918.8 (1646.4 to 2191.3)
    3868.9 (2668.6 to 5069.1)
    2814.8 (2301.5 to 3328)
    2686.5 (1975.6 to 3397.4)
    871.2 (308.8 to 1433.5)
    52.5 (35.6 to 69.4)
    697.9 (24.2 to 1371.5)
    ( to )
    ( to )
    ( to )
    10820.9 (4490.1 to 17151.7)
    4680.1 (3948.4 to 5411.7)
    3608.2 (3224.8 to 3991.6)
    4405.7 (3235 to 5576.3)
    15429.9 (-130497.9 to 161357.8)
    5558 (1919.3 to 9196.7)
    5654 (4872.5 to 6435.5)
    5923.9 (3853.8 to 7994)
    6297.1 (5206.9 to 7387.3)
    5965 (4725 to 7205)
    7000.4 (-3488 to 17488.7)
    7006.6 (758.2 to 13255)
    11390.2 (8453.4 to 14327)
    Notes
    [1] - 1 subject was excluded from the analysis due to illness
    [2] - 3 subjects were excluded from the analysis due to illness.
    [3] - 4 subjects were excluded, 1 due to use of medication and 3 due to illnesses
    [4] - 1 subject was excluded due to medication
    [5] - 1 subject was excluded due to illness
    [6] - No MIA data obtained, participants dropped out and no samples were collected.
    [7] - No MIA data obtained, participants dropped out and no samples were collected.
    [8] - No MIA data obtained, participants dropped out and no samples were collected.
    [9] - 1 subject was excluded due to medication
    [10] - 1 subject was excluded due to illness
    [11] - 3 subjects were excluded, 1 due to medication and 2 due to illnesses
    [12] - 3 subjects were excluded, 1 due to medication, 2 due to illnesses
    Statistical analysis title
    		 Vaccine-specific serum IgG pre- vs 28 days post
    Statistical analysis description
    IgG antibody responses to the S1 protein prior to and after primary vaccine doses. Geometric mean IgG concentrations with 95% confidence interval. Differences in antibody levels between time points were analyzed with two-tailed Wilcoxon matched-pairs signed-rank test. Subjects in this analysis = 290, with each 2 timepoints for comparison within group 'Period 1 31-45 years with the Pfizer vaccine'
    Comparison groups
    31-45 years of age - primary vaccination - Pfizer-BioNTech v 5-11 years of age - primary vaccination - Pfizer-BioNTech v 12-17 years of age - primary vaccination - Pfizer-BioNTech v 18-30 years of age - primary vaccination - Pfizer-BioNTech v 46-60 years of age - primary vaccination - Pfizer-BioNTech v 18-30 years of age - primary vaccination - Moderna v 31-45 years of age - primary vaccination - Moderna v 46-60 years of age - primary vaccination - Moderna v 18-30 years of age - primary vaccination - Jcovden v 31-45 years of age - primary vaccination - Jcovden v 46-60 years of age - primary vaccination - Jcovden
    Number of subjects included in analysis
    1076
    Analysis specification
    Pre-specified
    Analysis type
    		 other [13]
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [13] - Only participants with a pre sample (T0) and a 28 days post vaccination sample (T3) were included. Therefore; only 290 subjects were included in the analysis

    Secondary: Humoral, cellular and innate COVID-19 vaccine-induced immune responses in adults

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    End point title
    		 Humoral, cellular and innate COVID-19 vaccine-induced immune responses in adults
    End point description
    Innate COVID-19 vaccine-induced immune responses in adults. The following variables were included in the panel for this analysis: IL-1b IL-6 TNFa IP10* IFNL1 IL-8 IL-12p70 IFNa2 IFNL2_3 GMCSF IFNb IL-10 IFNy IL-8 IP10 _2 Eotaxin TARC MCP1 RANTES MIP1a MIG ENA78 MIP3a GROa ITAC MIP1b IL-5 IL-13 IL-2 IL-6_2 IL-9 IL-10_2 IFNy_2 TNFa_2 IL-17A IL-17F IL-4 IL-22 TSLP IL-1a IL-1b_2 GMCSF_2 IFNa2_2 IL-23 IL-12p40 IL-12p70 _2 IL-15 IL-18 IL-11 IL-27 IL-33 IL-1β IL-6 TNF-α IP-10* IFN-λ1 IL-8 IL-12p70 IFN-α2 IFN-λ2/3 GM-CSF IFN-β IL-10 IFN-γ IL-8 IP-10 Eotaxin TARC MCP-1 RANTES MIP-1α MIG ENA-78 MIP-3α GROα I-TAC MIP-1β *IP10 tested twice (different kits) However, not all variables showed differences between the two timepoints. Therefor, 5 variables are displayed for this end point: CXCL10 (IP10), IFNy, CXCL9 (MIG), CCL20 (Mip3a) and CXCL11 (ITAC).
    End point type
    Secondary
    End point timeframe
    Pre-primary vaccination - 1-3 days post 1st COVID primary vaccination
    End point values
    		 Pre- primary vaccination immune response in adults (T0) 1-3 days post 1st primary vaccination response in adults (T1)
    Number of subjects analysed
    39
    58
    Units: pg/ml
    geometric mean (confidence interval 95%)
        CXCL10 (IP10)
    46.9 (38.6 to 55.2)
    157 (114 to 200)
        IFNy
    9.8 (-8 to 27.7)
    60.5 (-0.5 to 121.5)
        CXCL9 (MIG)
    282.7 (-235 to 800.5)
    296.7 (-73.8 to 667.1)
        CCL20 (Mip3a)
    3.4 (1.4 to 5.4)
    5.8 (3.8 to 7.9)
        CXCL11 (ITAC)
    13.9 (10.3 to 17.6)
    32 (22.5 to 41.6)
    No statistical analyses for this end point

    Secondary: Virus neutralizing capacity of antibodies induced by COVID-19 vaccination

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    End point title
    		 Virus neutralizing capacity of antibodies induced by COVID-19 vaccination
    End point description
    Virus neutralizing capacity of antibodies induced by COVID-19 vaccination
    End point type
    Secondary
    End point timeframe
    28 days post primary vaccination(s) (T3) Pre-booster vaccination (B0) 28 days post booster vaccination (B1) Pre- repeat vaccination (D0) 28 days post repeat vaccination (D1)
    End point values
    		 VNT 28 days post primary vaccination(s) (T3) VNT Pre-booster vaccination (B0) VNT 28 days post booster vaccination (B1) VNT Pre-repeat vaccination (D0) VNT 28 days post repeat vaccination (D1)
    Number of subjects analysed
    57
    23
    39
    11
    11
    Units: VNT50
        geometric mean (confidence interval 95%)
    221.3 (135.5 to 307.2)
    413.4 (124.5 to 702.3)
    1454.3 (1117.5 to 1791)
    439.5 (-33.1 to 912)
    1109.1 (441.1 to 1777.1)
    No statistical analyses for this end point

    Secondary: Fc functionality: Complement deposition capacity of antibodies in MFI

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    End point title
    		 Fc functionality: Complement deposition capacity of antibodies in MFI
    End point description
    Complement deposition capacity of antibodies in MFI
    End point type
    Secondary
    End point timeframe
    28 days post 2nd COVID-19 vaccination (T3)
    End point values
    		 ADCD 28 days post 2nd vaccination (T3)
    Number of subjects analysed
    120
    Units: MFI
    geometric mean (confidence interval 95%)
        experiment AG_044
    5841.9 (5168 to 6515.8)
        experiment AG_052
    1834.8 (1025.1 to 2644.5)
        experiment AG_061
    302.8 (270.1 to 335.6)
    No statistical analyses for this end point

    Secondary: Fc functionality: Phagocytosis mediating capacity of antibodies in iMFI

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    End point title
    		 Fc functionality: Phagocytosis mediating capacity of antibodies in iMFI
    End point description
    Phagocytosis mediating capacity of antibodies in iMFI
    End point type
    Secondary
    End point timeframe
    28 days post 2nd COVID-19 vaccination (T3)
    End point values
    		 ADCP 28 days post 2nd vaccination (T3)
    Number of subjects analysed
    120
    Units: iMFI
    geometric mean (confidence interval 95%)
        experiment AG_036
    445.3 (333.4 to 557.2)
        experiment AG_046
    1187.6 (1054.9 to 1320.3)
        experiment AG_059
    1101.8 (946 to 1257.7)
    No statistical analyses for this end point

    Secondary: Fc functionality: % NK cell activation in cell based (NK-92) assay as a measure for ADCC inducing capacity of antibodies in serum

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    End point title
    		 Fc functionality: % NK cell activation in cell based (NK-92) assay as a measure for ADCC inducing capacity of antibodies in serum
    End point description
    % NK cell activation in cell based (NK-92) assay as a measure for ADCC inducing capacity of antibodies in serum
    End point type
    Secondary
    End point timeframe
    28 days post 2nd COVID-19 vaccination (T3)
    End point values
    		 ADCC 28 days post 2nd vaccination (T3)
    Number of subjects analysed
    120
    Units: %CD107a+
    geometric mean (confidence interval 95%)
        experiment AG_053
    4 (3.7 to 4.4)
        experiment AG_058
    13.3 (11.8 to 14.8)
    No statistical analyses for this end point

    Secondary: COVID-19 vaccine-induced antibodies in nasal mucosal lining fluid

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    End point title
    		 COVID-19 vaccine-induced antibodies in nasal mucosal lining fluid
    End point description
    Measuring vaccine (e.g. Spike protein)-specific nasasl IgG and IgA GMC in Dutch healthy subjects
    End point type
    Secondary
    End point timeframe
    pre- primary COVID immunization (T0) - 28 days post repeat vaccination (D1)
    End point values
    		 MLF pre-primary COVID immunization (T0) MLF 28 days post 2nd COVID immunization (T3) MLF 12 months post 2nd COVID immunization (T5) MLF pre- first booster (B0) MLF 28 days post booster 1 (B1) MLF 12 months post booster 1 (B3) MLF pre- repeat vaccination (D0) MLF 28 days post repeat vaccination (D1)
    Number of subjects analysed
    76
    237
    30
    65
    146
    60
    26
    25
    Units: AU/ml
    geometric mean (confidence interval 95%)
        IgG_Conc_COV19S1
    0.1 (0 to 0.2)
    25.6 (20.6 to 30.5)
    29.7 (18.6 to 40.7)
    6.1 (3.3 to 8.9)
    56.3 (42.1 to 70.6)
    34.9 (24.7 to 45)
    59.3 (20.2 to 98.5)
    108.4 (65.1 to 151.6)
        IgG_Conc_COV19N
    0.6 (0.4 to 0.8)
    2 (1.4 to 2.7)
    33.4 (-8.3 to 75.1)
    2 (1.2 to 2.8)
    4.2 (1.9 to 6.5)
    25.1 (8.5 to 41.8)
    8 (2 to 14)
    8.8 (1.1 to 16.5)
        IgA_Conc_COV19S1
    0.6 (0.3 to 0.8)
    0.7 (0.5 to 0.9)
    10.1 (5.6 to 14.6)
    1 (0.2 to 1.8)
    2.1 (1.3 to 3)
    7.3 (3.4 to 11.2)
    7.4 (2.3 to 12.4)
    4.1 (2.5 to 5.6)
        IgA_Conc_COV19N
    1.9 (1.4 to 2.4)
    1.8 (1.5 to 2.2)
    3 (1.8 to 4.3)
    1.1 (0.9 to 1.3)
    2 (1.2 to 2.8)
    2.7 (1.6 to 3.8)
    2.1 (1.3 to 3)
    2.3 (1.2 to 3.4)
    No statistical analyses for this end point

    Secondary: Measuring antibody-secreting IFN-gamma producing T cells by ELISPOT assays

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    End point title
    		 Measuring antibody-secreting IFN-gamma producing T cells by ELISPOT assays
    End point description
    Measuring IFN-gamma producing T cells by ELISPOT assays
    End point type
    Secondary
    End point timeframe
    pre primary COVID immunization (T0) - 12 months post repeat vaccination (D3)
    End point values
    		 Tcel ELISpot: pre-primary COVID immunization (T0) Tcel ELISpot: post 2nd COVID immunization (T3) Tcel ELISpot: pre- first booster (B0) Tcel ELISpot: 28 days post first booster (B1) Tcel ELISpot: pre-repeat vaccination (D0) Tcel ELISpot: 28 days post repeat vaccination (D1) Tcel ELISpot: 12 months post repeat vaccination (D3)
    Number of subjects analysed
    60 [14]
    118 [15]
    20 [16]
    60
    30
    32
    32
    Units: IFNg spots per 2x10^5 PBMC
    geometric mean (confidence interval 95%)
        Original strain S1+S2 (per 2x10^5 PBMC) - BLANK
    3 (1.7 to 4.3)
    29.5 (23.8 to 35.1)
    8.2 (2.9 to 13.6)
    35.1 (21.3 to 48.9)
    26.6 (18.6 to 34.6)
    40.7 (18.4 to 63.1)
    28.9 (15.4 to 42.4)
    Notes
    [14] - 3 subjects were excluded from the analyses due to low PHA response and low recovery.
    [15] - 2 subjects were excluded from the analyses due to low PHA response and low recovery.
    [16] - 3 subjects were excluded. 1 due to low PHA response, 1 due to no cells, 1 due to high blank
    No statistical analyses for this end point

    Secondary: Measuring antibody-secreting B cells by ELISPOT assays

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    End point title
    		 Measuring antibody-secreting B cells by ELISPOT assays
    End point description
    Measuring antibody-secreting B cells by EISPOT assays
    End point type
    Secondary
    End point timeframe
    pre primary COVID immunization (T0) - 28 days post first booster (B1)
    End point values
    		 Bcel ELISpot: pre-primary COVID immunization (T0) Bcel ELISpot: post 2nd COVID immunization (T3) Bcel ELISpot: pre- first booster (B0) Bcel ELISpot: 28 days post first booster (B1)
    Number of subjects analysed
    8
    40
    8
    19 [17]
    Units: IFNg spots per 2x10^5 PBMC
    geometric mean (confidence interval 95%)
        Original strain S1 (per 2x10^5 PBMC) - BLANK
    1.8 (0 to 3.7)
    9.4 (6.5 to 12.3)
    12 (5.7 to 18.3)
    80.7 (36.5 to 124.8)
    Notes
    [17] - 1 subject was excluded from the analyses due medication taken at this timepoint
    No statistical analyses for this end point

    Secondary: Reactogenicity self-reported in questionnaires shortly after vaccination

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    End point title
    		 Reactogenicity self-reported in questionnaires shortly after vaccination
    End point description
    The standard symptoms asked via the diary were: pyrexia, vaccination site erythema, vaccination site swelling, vaccination site induration, vaccination site bruising, vaccination site pain, vaccination site movement impairment, headache, fatigue, myalgia, arthralgia, malaise. Participants could also rapport other symptoms spontaneously by the diary.
    End point type
    Secondary
    End point timeframe
    Local, AEs recorded the first 5 days after 1st COVID 19 vaccination or until symptoms subside
    End point values
    		 Reactogenicity: first 5 days post primary vaccination
    Number of subjects analysed
    169
    Units: NA
        Pyrexia
    19
        Vaccination site erythema
    35
        Vaccination site swelling
    25
        Vaccination site induration
    33
        Vaccination site bruising
    17
        Vaccination site pain
    151
        Vaccination site movement impairment
    106
        Headache
    70
        Fatigue
    106
        Myalgia
    132
        Arthralgia
    21
        Malaise
    64
        Angioedema
    1
        Axillary pain
    1
        Cough
    1
        Diarrhoea
    1
        Dizziness
    8
        Hypoaesthesia
    1
        Limb discomfort
    1
        Mood swings
    1
        Musculoskeletal stiffness
    5
        Nasopharyngitis
    2
        Nausea
    8
        Night sweats
    1
        Noninfective gingivitis
    1
        Oligomenorrhoea
    2
        Oropharyngeal pain
    6
        Pain in extremity
    2
        Paraesthesia
    3
        Restlessness
    1
        Therapeutic response decreased
    1
        Tremor
    1
        Vaccination site coldness
    1
        Vaccination site hypoaesthesia
    1
        Vaccination site pruritus
    1
        Vaccination site warmth
    2
        Vasoconstriction
    1
        Poor quality sleep
    2
        Migraine
    1
        Hot flush
    2
        Dyspnoea
    1
        Heart rate increased
    1
        Gingival pain
    1
        Body temperature fluctuation
    1
        Toothache
    1
        Rhinorrhoea
    1
        Gingival ulceration
    1
        Eye pain
    1
    No statistical analyses for this end point

    Secondary: Humoral, cellular and innate COVID-19 vaccine-induced immune responses in adolescents

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    End point title
    		 Humoral, cellular and innate COVID-19 vaccine-induced immune responses in adolescents
    End point description
    Innate COVID-19 vaccine-induced immune responses in adolescents. The following variables were included in the panel for this analysis: IL-1b IL-6 TNFa IP10* IFNL1 IL-8 IL-12p70 IFNa2 IFNL2_3 GMCSF IFNb IL-10 IFNy IL-8 IP10 _2 Eotaxin TARC MCP1 RANTES MIP1a MIG ENA78 MIP3a GROa ITAC MIP1b IL-5 IL-13 IL-2 IL-6_2 IL-9 IL-10_2 IFNy_2 TNFa_2 IL-17A IL-17F IL-4 IL-22 TSLP IL-1a IL-1b_2 GMCSF_2 IFNa2_2 IL-23 IL-12p40 IL-12p70 _2 IL-15 IL-18 IL-11 IL-27 IL-33 IL-1β IL-6 TNF-α IP-10* IFN-λ1 IL-8 IL-12p70 IFN-α2 IFN-λ2/3 GM-CSF IFN-β IL-10 IFN-γ IL-8 IP-10 Eotaxin TARC MCP-1 RANTES MIP-1α MIG ENA-78 MIP-3α GROα I-TAC MIP-1β *IP10 tested twice (different kits) However, not all variables showed differences between the two timepoints. Therefor, 3 variables are displayed for this end point: CXCL10 (IP10), CXCL9 (MIG) and CXC11 (ITAC)
    End point type
    Secondary
    End point timeframe
    Pre- primary vaccination - 1-3 days post 1st primary vaccination
    End point values
    		 Pre- primary vaccination immune response in adolescents (T0) 1-3 days post 1st primary vaccination response in adolescents
    Number of subjects analysed
    19
    19
    Units: pg/ml
    geometric mean (confidence interval 95%)
        CXCL10 (IP10)
    65 (55.8 to 74.1)
    191.6 (138 to 245.2)
        CXCL9 (CIG)
    443.4 (341.1 to 545.6)
    716.9 (581.7 to 852)
        CXC11 (ITAC)
    90.6 (73.6 to 107.7)
    192.3 (145.2 to 239.4)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Any adverse event spontaneously reported by the subject related to and occurring within one week after nasal fluid collection or blood sampling.
    Adverse event reporting additional description
    There were no SAEs and SUSARs.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27
    Reporting groups
    Reporting group title
    COVID Immunization
    Reporting group description
    		 237 participants were asked to fill in the diary to report adverse events. The other participants of the whole study population could report AE's spontaneously to the study teams, what was done by 25 participants.

    Serious adverse events
    		 COVID Immunization
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 1459 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 COVID Immunization
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    180 / 1459 (12.34%)
    General disorders and administration site conditions
    Vaccination site pain
         subjects affected / exposed
    151 / 1459 (10.35%)
         occurrences all number
    151
    Vaccination site movement impairment
         subjects affected / exposed
    106 / 1459 (7.27%)
         occurrences all number
    106
    Fatigue
         subjects affected / exposed
    106 / 1459 (7.27%)
         occurrences all number
    106
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    132 / 1459 (9.05%)
         occurrences all number
    132

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 May 2021
    To increase the chance of including enough participants in the study. More and more persons are invited for the corona vaccination. In order to include enough currently unvaccinated persons in the trial we propose to add the following recruitment option: Also persons participating in other RIVM studies can be invited, provided they consented to be contacted for additional research and meet the inclusion criteria.
    03 Jun 2021
    To increase the chance of including enough participants in the study. More and more persons are invited for the corona vaccination. In order to include enough currently unvaccinated persons in the trial we propose to add the following recruitment option: Lastly, also spontaneous applications from interested citizens are allowed. This can occur if they read about this study on the website (which includes the PIF&IC) or in the news or hear from friends.
    25 Jun 2021
    Later inclusion until T3 or T3s (28 days after the last vaccination) where necessary. The IIVAC study follows the national COVID-19 immunization program. The current inclusion into the subgroup, where we look more deeply into the (cellular) immunity, is lower than anticipated. For the general group (5 fingerprick samples in 12 months), the number of inclusions is going well (recruitment was possible all over the Netherlands). As soon as participants are vaccinated we will know the exact distribution over the vaccine groups. For the subgroup, participation is only possible for habitants of the province of Utrecht (or places within one hour drive from the RIVM). Therefore the recruitment covers a smaller part of the population. Participation is currently lower then needed considering the pace of national vaccine roll out. The primary endpoint of the trial is at T3(s) (28 days after the last vaccination). At that timepoint the comparison over all RIVM trials is possible as well as the comparison between the IIVAC study and the risk group studies funded by ZonMW. In order to reach enough participants for the primary endpoint we will allow inclusion in the subgroup up until timepoint T3s. If necessary, we may allow participation in the general group up until timepoint T3 if specific vaccinated (age)segments are underrepresented.
    15 Jul 2021
    To monitor and evaluate immune responses after corona vaccination in children. In the IIVAC study we evaluate immune responses after COVID-19 immunization, following the national vaccination program. The immunization of children 12-18 years of age has started. In order to examine the immune response in these younger age groups we would like to add 2 age groups to the IIVAC study (12-18 years of age and 0-12 years of age). We will study the duration and quality of the immune response and compare these to the adult groups and risk groups. The 0-12 group will only start once vaccines are registered for this age group and vaccination is implemented in the Netherlands We aim to include the children for the general as well as for the subgroup part of the study. In the subset part we made some changes in order to reduce the burden. First, sampling volumes are lower (age dependent), limiting the possibility to fulfil all secondary objectives. At T0s and T1s we split the group in two subsets: the adaptive group with sampling at T0s, not T1s; and the innate group with sampling at T0s and T1s but with lower blood volumes per timepoint.
    05 Aug 2021
    Tto increase (by necessity) the blood volume sampled by venapuncture with 1 ml for children aged 8-18 years old at home visits T0s, T3s and T5s. Due to unforeseen production problems and the world-wide increase in demand of blood collection tubes, the 4 ml serum tubes that we intended to use for children aged 8-18 years are currently not available. Therefore, 5ml serum tubes will necessarily be used for blood collection in this age group. Effectively this means that at home visit T0s for the innate group, total collected blood volume will be 23 ml; for the adaptive group total collected blood volume will be 41 ml. At visit T3s and T5s, total collected blood volume will be 41 ml. This amount is still within the guidelines drafted by the Nederlandse Vereniging voor Klinische Chemie en Laboratoriumgeneeskunde and the Clinical and Labatory Standards institute and thus is unlikely to pose any additional risk in this age group.
    18 Nov 2021
    We intend to follow immune responses after the SARS-CoV-2 booster vaccination, in those participants that take the SARS-CoV-2 booster vaccination. This will result in the following follow up schedule based on the SARS-CoV-2 booster vaccination date: pre booster (B0) and at 28 days (B1), 6 months (B2) and 12 months (B3) post booster vaccination. This study schedule can be repeated in case of additional boosters of similar or other vaccines against COVID-19, e.g. multivalent vaccines against other variants of concern . The data collected will provide insight into vaccine-induced immunity pre and post SARS-CoV-2 booster vaccination. Currently around 150 participants aged 12-18 years have been enrolled in the study. The subjects have been recruited via random sampling from the Basisregistratie Personen (BRP). Inclusion of these subjects was closely monitored. Most subjects applied for participation after one or both vaccinations had been received as part of the Dutch national vaccination program. Inclusion of the subjects until T3(s) has been allowed as described in amendment 4 and a large number of participants already received one to two vaccinations. As a result the total number of T0 (baseline) samples is limited. In addition, the inclusion of subjects in the innate group is not yet completed. Therefore we want to allow the inclusion of additional unvaccinated participants aged 12-18 years to obtain a sufficient number of T0(s) samples. The additional unvaccinated participants can be 11 years of age at the time of enrolment (pre vaccination timepoint), and are 12 years of age at the time of vaccination. They will be asked to sign the 12 years of age IC form at enrolment. in addition, section 8.6 has been adjusted to allow the replacement of subjects (<18 years) in case samples cannot be used for the analysis. A broader window is considered to be acceptable for sample data analyses.
    01 Sep 2022
    Adding letters for the research packages of the timepoints; little adaptations in different used documents; textual adaptations in subject information letter; children 5-12 years of age were recruited for the venipuncture group
    26 Oct 2022
    To include follow-up after a repeat vaccination. Equal to the previous booster vaccination follow up: - Participants who don’t get the repeat vaccination: o Follow the current timepoints of the study o Afterwards, the study is ended - Participants who get the repeat vaccination, but don’t want to participate in the extended study: o The study will be ended. o When a timepoint was planned after the repeat vaccination, this timepoint will be cancelled. Unlike the previous booster vaccination follow-up we decided not to include everyone. The different vaccinations rounds resulted in several groups. Some of these groups are too small. Therefore we decided to make selections for the new follow-up. In making these selections we follow the distributions of the general population as much as possible. Furthermore, we look at the participants with the most complete follow-up/sampling time points. Related to this, some groups will be followed only with self-sampling finger pricks instead of a venepuncture by homevisits.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/35396570
    http://www.ncbi.nlm.nih.gov/pubmed/36680141
    http://www.ncbi.nlm.nih.gov/pubmed/35891550
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