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    Clinical Trial Results:
    Immune responses to influenza and pneumococcal conjugate vaccines in older adults compared to middle-aged adults and adults.

    Summary
    EudraCT number
    		 2019-000836-24
    Trial protocol
    		 NL  
    Global end of trial date
    07 Oct 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Oct 2025
    First version publication date
    29 Oct 2025
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    IIV-406
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 ABR number: NL69701.041.19
    Sponsors
    Sponsor organisation name
    RIVM
    Sponsor organisation address
    PO box 1, Bilthoven, Netherlands, 3720BA
    Public contact
    VITAL studyteam, National Institute of Health and the Environment (RIVM), VITAL-studie@rivm.nl
    Scientific contact
    VITAL studyteam, National Institute of Health and the Environment (RIVM), VITAL-studie@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
    07 Oct 2025
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Oct 2024
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Oct 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To get a better insight in the influence of age and age-related changes by internal and external factors on vaccine-induced immune responses and gain knowledge on the trajectory of immune decline in older adults, pre-elderly (middle-aged) adults in comparison to adults with the ultimate goal to formulate evidence-based strategies to improve immunity to vaccines in the ageing population.
    Protection of trial subjects
    The vaccins used in this trial are registered vaccins which are used according to the indication. The particpants are all eligible for the influenza and (booster) COVID-19 vaccinations. Only the pneumcoccal vaccination will be given as an extra vaccination. However, this vaccin is registered in Europe and in the USA, and is used for several years in children and adults. 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 per two months within the study is maximum 269 mL and is well within the standard that is maintained by Sanquin Bloodbank.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jul 2019
    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: 326
    Worldwide total number of subjects
    326
    EEA total number of subjects
    326
    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)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    160
    From 65 to 84 years
    140
    85 years and over
    26

    Subject disposition

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    Recruitment
    Recruitment details
    		 The older adults were recruited by the wetenschapsbureau of the Spaarne hospital from a previous Influenza-like illness (ILI) study sponsored by the RIVM. Middle-aged and adults subjects were health care workers or laboratory personnel in the Utrecht area recruited via email, flyers and posters.

    Pre-assignment
    Screening details
    		 Screening was performed during visit T0. During this visit, the following tasks were executed: checking of subject information was received and understood; questions were answered; Informed consent (IC) was obtained; An inclusion number was assigned and Inclusion and exclusion criteria were checked.

    Period 1
    Period 1 title
    QIV and PCV13 vaccination
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 25-49 years of age, QIV + PCV13
    Arm description
    		 25-49 years of age, QIV + PCV13
    Arm type
    		 Experimental

    Investigational medicinal product name
    Influvac Tetra
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose of 0,5 mL contains the following strains: - A/Michigan/45/2015 (H1N1)pdm09-like strain (A/Singapore/GP1908/2015, IVR-180): 15 microgram HA - A/Singapore/INFIMH-16-0019/2016 (H3N2)-like strain (A/Singapore/INFIMH-16-0019/2016,NIB-104): 15 microgram HA - B/Colorado/06/2017-like strain (B/Maryland/15/2016,NYMC BX-69A): 15 microgram HA - B/Phuket.3073.2013-like strain (B/Phuket/3073/2013, wild type) 15 microgram HA

    Investigational medicinal product name
    Prevanar 13
    Investigational medicinal product code
    Other name
    Pneumococcal polysaccharide conjugate vaccine (13-valent, adsorbed)
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose (0,5 ml) contains: - Pneumococcal polysaccharide serotype 1: 2,2 µg - Pneumococcal polysaccharide serotype 3: 2,2 µg - Pneumococcal polysaccharide serotype 4: 2,2 µg - Pneumococcal polysaccharide serotype 5: 2,2 µg - Pneumococcal polysaccharide serotype 6A: 2,2 µg - Pneumococcal polysaccharide serotype 6B: 4,4 µg - Pneumococcal polysaccharide serotype 7F: 2,2 µg - Pneumococcal polysaccharide serotype 9V: 2,2 µg - Pneumococcal polysaccharide serotype 14: 2,2 µg - Pneumococcal polysaccharide serotype 18C: 2,2 µg - Pneumococcal polysaccharide serotype 19A: 4,4 µg - Pneumococcal polysaccharide serotype 19F: 2,2 µg - Pneumococcal polysaccharide serotype 23F: 2,2 µg All serotypes are conjugated to CRM197 carrier protein, adsorbed on aluminium phosphate 1 dos (0,5ml) contains approcimately 32 µg CRM 197 carrier proterin and 0,125 mg aluminium

    Arm title
    		 50-64 years of age, QIV + PCV13
    Arm description
    		 50-64 years of age, QIV + PCV13
    Arm type
    		 Experimental

    Investigational medicinal product name
    Influvac Tetra
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose of 0,5 mL contains the following strains: - A/Michigan/45/2015 (H1N1)pdm09-like strain (A/Singapore/GP1908/2015, IVR-180): 15 microgram HA - A/Singapore/INFIMH-16-0019/2016 (H3N2)-like strain (A/Singapore/INFIMH-16-0019/2016,NIB-104): 15 microgram HA - B/Colorado/06/2017-like strain (B/Maryland/15/2016,NYMC BX-69A): 15 microgram HA - B/Phuket.3073.2013-like strain (B/Phuket/3073/2013, wild type) 15 microgram HA

    Investigational medicinal product name
    Prevanar 13
    Investigational medicinal product code
    Other name
    Pneumococcal polysaccharide conjugate vaccine (13-valent, adsorbed)
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose (0,5 ml) contains: - Pneumococcal polysaccharide serotype 1: 2,2 µg - Pneumococcal polysaccharide serotype 3: 2,2 µg - Pneumococcal polysaccharide serotype 4: 2,2 µg - Pneumococcal polysaccharide serotype 5: 2,2 µg - Pneumococcal polysaccharide serotype 6A: 2,2 µg - Pneumococcal polysaccharide serotype 6B: 4,4 µg - Pneumococcal polysaccharide serotype 7F: 2,2 µg - Pneumococcal polysaccharide serotype 9V: 2,2 µg - Pneumococcal polysaccharide serotype 14: 2,2 µg - Pneumococcal polysaccharide serotype 18C: 2,2 µg - Pneumococcal polysaccharide serotype 19A: 4,4 µg - Pneumococcal polysaccharide serotype 19F: 2,2 µg - Pneumococcal polysaccharide serotype 23F: 2,2 µg All serotypes are conjugated to CRM197 carrier protein, adsorbed on aluminium phosphate 1 dos (0,5ml) contains approcimately 32 µg CRM 197 carrier proterin and 0,125 mg aluminium

    Arm title
    		 65+ years of age, QIV + PCV13
    Arm description
    		 65+ years of age, QIV + PCV13
    Arm type
    		 Experimental

    Investigational medicinal product name
    Influvac Tetra
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose of 0,5 mL contains the following strains: - A/Michigan/45/2015 (H1N1)pdm09-like strain (A/Singapore/GP1908/2015, IVR-180): 15 microgram HA - A/Singapore/INFIMH-16-0019/2016 (H3N2)-like strain (A/Singapore/INFIMH-16-0019/2016,NIB-104): 15 microgram HA - B/Colorado/06/2017-like strain (B/Maryland/15/2016,NYMC BX-69A): 15 microgram HA - B/Phuket.3073.2013-like strain (B/Phuket/3073/2013, wild type) 15 microgram HA

    Investigational medicinal product name
    Prevanar 13
    Investigational medicinal product code
    Other name
    Pneumococcal polysaccharide conjugate vaccine (13-valent, adsorbed)
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose (0,5 ml) contains: - Pneumococcal polysaccharide serotype 1: 2,2 µg - Pneumococcal polysaccharide serotype 3: 2,2 µg - Pneumococcal polysaccharide serotype 4: 2,2 µg - Pneumococcal polysaccharide serotype 5: 2,2 µg - Pneumococcal polysaccharide serotype 6A: 2,2 µg - Pneumococcal polysaccharide serotype 6B: 4,4 µg - Pneumococcal polysaccharide serotype 7F: 2,2 µg - Pneumococcal polysaccharide serotype 9V: 2,2 µg - Pneumococcal polysaccharide serotype 14: 2,2 µg - Pneumococcal polysaccharide serotype 18C: 2,2 µg - Pneumococcal polysaccharide serotype 19A: 4,4 µg - Pneumococcal polysaccharide serotype 19F: 2,2 µg - Pneumococcal polysaccharide serotype 23F: 2,2 µg All serotypes are conjugated to CRM197 carrier protein, adsorbed on aluminium phosphate 1 dos (0,5ml) contains approcimately 32 µg CRM 197 carrier proterin and 0,125 mg aluminium

    Number of subjects in period 1
    		25-49 years of age, QIV + PCV13 50-64 years of age, QIV + PCV13 65+ years of age, QIV + PCV13
    Started
    62
    98
    166
    QIV vaccination (T1)
    60
    96
    163
    1 or 2 days post QIV vaccination (T2)
    59
    94
    161
    7 days post QIV vaccination (T3)
    58
    96
    162
    28 days post QIV vaccination (T4)
    59
    95
    159
    6 months post QIV vaccination (TE1)
    42 [1]
    77 [2]
    140 [3]
    5-8 months post QIV+ PCV 13 (T5)
    55
    89
    148
    1 or 2 days post PCV13 vaccination (T6)
    49
    85 [4]
    146
    7 days post PCV13 vaccination (T7)
    48
    84 [5]
    145
    28 days post PCV13 vaccination (T8)
    51
    88
    143 [6]
    12 months pt QIV + 6months pt PCV13 (T9)
    48
    87
    145
    12 months post PCV13 vaccination (T10)
    45
    84 [7]
    143 [8]
    Completed
    45
    87
    145
    Not completed
    17
    11
    21
         Physician decision
    3
    2
    5
         Covid-19 pandemic
    1
    3
    4
         Pregnancy
    1
    -
    -
         Received vaccine via other route
    1
    -
    -
         Participant discontinuation
    2
    5
    9
         Death (unrelated to study)
    -
    -
    1
         Transferred to other period
    3
    -
    -
         Logistical issues
    3
    -
    -
         Lost to follow-up
    2
    -
    -
         Study burden
    1
    1
    2
    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.
    Period 2
    Period 2 title
    COVID vaccination, primary series
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 50-64 years of age, Comirnaty (Pfizer/BioNTech)
    Arm description
    		 50-64 years of age, Comirnaty (Pfizer/BioNTech) Only 2 late inclusions at Tc, no subjects truly started at starting point. Starting point set at 2 instead of 0 due to technical limitations.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Comirnaty
    Investigational medicinal product code
    Other name
    COVID-19 mRNA Vaccine, Pfizer–BioNTech COVID-19 vaccine
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    The vaccine is in a multidose vial and must be diluted before use. One dose (0,3mL) contains 30 micrograms of tozinameran, a COVID-19 mRNA Vaccine (embeded in lipid nanoparticles). 2 dosages were given with an interval of 28 days (+7days).

    Arm title
    		 65+ years of age, Comirnaty (Pfizer/BioNTech)
    Arm description
    		 65+ years of age, Comirnaty (Pfizer/BioNTech)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Comirnaty
    Investigational medicinal product code
    Other name
    COVID-19 mRNA Vaccine, Pfizer–BioNTech COVID-19 vaccine
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    The vaccine is in a multidose vial and must be diluted before use. One dose (0,3mL) contains 30 micrograms of tozinameran, a COVID-19 mRNA Vaccine (embeded in lipid nanoparticles). 2 dosages were given with an interval of 28 days (+7days).

    Arm title
    		 25-49 years of age, Spikevax (Moderna)
    Arm description
    		 25-49 years of age, Spikevax (Moderna)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Spikevax
    Investigational medicinal product code
    Other name
    COIVD-19 mRNA vaccine, Moderna
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose (0,5 mL) contains 100 micrograms of messenger RNA (mRNA) (embedded in SM-102 lipid nanoparticles) Preferred site of administration is the deltoid muscle of the upper arm. 2 dosages were given with an interval of 28 days (+7days).

    Arm title
    		 50-64 years of age, Spikevax (Moderna)
    Arm description
    		 50-64 years of age, Spikevax (Moderna)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Spikevax
    Investigational medicinal product code
    Other name
    COIVD-19 mRNA vaccine, Moderna
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose (0,5 mL) contains 100 micrograms of messenger RNA (mRNA) (embedded in SM-102 lipid nanoparticles) Preferred site of administration is the deltoid muscle of the upper arm. 2 dosages were given with an interval of 28 days (+7days).

    Arm title
    		 65+ years of age, Spikevax (Moderna)
    Arm description
    		 65+ years of age, Spikevax (Moderna)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Spikevax
    Investigational medicinal product code
    Other name
    COIVD-19 mRNA vaccine, Moderna
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose (0,5 mL) contains 100 micrograms of messenger RNA (mRNA) (embedded in SM-102 lipid nanoparticles) Preferred site of administration is the deltoid muscle of the upper arm. 2 dosages were given with an interval of 28 days (+7days).

    Arm title
    		 50-64 years of age, Vaxzevria (AstraZeneca)
    Arm description
    		 50-64 years of age, Vaxzevria (AstraZeneca) Only 1 late inclusions at Tc, no subjects truly started at starting point. Starting point set at 1 instead of 0 due to technical limitations.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vaxzevria
    Investigational medicinal product code
    J07BN02
    Other name
    AstraZeneca
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose (0,5 ml) contains Chimpanzee Adenovirus encoding the SARS-CoV-2 Spike glycoprotein (ChAdOx1-S), not less than 2,5x10^8 infectious units (Inf.U). The product contains genetically modified organisms. Preferable place of administration is the deltoid muscle of the upper arm. 2 dosages were given with an interval of 4 to 12 weeks

    Number of subjects in period 2 [9]
    		50-64 years of age, Comirnaty (Pfizer/BioNTech) 65+ years of age, Comirnaty (Pfizer/BioNTech) 25-49 years of age, Spikevax (Moderna) 50-64 years of age, Spikevax (Moderna) 65+ years of age, Spikevax (Moderna) 50-64 years of age, Vaxzevria (AstraZeneca)
    Started
    2
    2
    44
    76
    91
    1
    28d pt vaccination1 = vaccination2 (Tb)
    0 [10]
    36
    44
    76
    91
    0
    1 month after vaccination 2 (Tc)
    2
    43
    44
    76
    90
    1
    6 months after vaccination 2 (Td)
    2
    41
    42
    75
    89
    1
    12 months after vaccination 2 (Te)
    0 [11]
    0
    2 [12]
    0 [13]
    3 [14]
    0
    Completed
    2
    39
    33
    72
    89
    0
    Not completed
    0
    4
    11
    4
    2
    1
         Physician decision
    -
    -
    -
    -
    1
    -
         Death
    -
    2
    -
    -
    -
    -
         Received additional booster before timepoint
    -
    -
    9
    3
    -
    -
         Participant discontinuation
    -
    2
    -
    -
    -
    -
         Death (unrelated to study)
    -
    -
    -
    1
    1
    -
         Logistical issues
    -
    -
    1
    -
    -
    -
         Lost to follow-up
    -
    -
    1
    -
    -
    1
    Joined
    0
    41
    0
    0
    0
    0
         Late recruitment
         Late recruitment reason:
    -
             
    41
             Logistical issues
    -
             
    -
             
    -
             
    -
             
    Notes
    [9] - 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 QIV +PCV series. COVID + booster vaccinations were later available that not all participants took. Each period is a separate part of the trial. Participants could then choose to enroll in the following period. Group allocation in the other periods was based on the corresponding vaccination, irrespective of former vaccinations. The number of participants starting another period is thus not equal to the number completing a previous period.
    [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.
    Period 3
    Period 3 title
    COVID vaccination, first booster
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 25-49 years of age, first booster, Comirnaty (Pfizer/BioNTech)
    Arm description
    		 25-49 years of age, first booster, Comirnaty (Pfizer/BioNTech)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Comirnaty
    Investigational medicinal product code
    Other name
    COVID-19 mRNA Vaccine, Pfizer–BioNTech COVID-19 vaccine
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    The vaccine is in a multidose vial and must be diluted before use. One dose (0,3mL) contains 30 micrograms of tozinameran, a COVID-19 mRNA Vaccine (embeded in lipid nanoparticles).

    Arm title
    		 50-64 years of age, first booster, Comirnaty (Pfizer/BioNTech)
    Arm description
    		 50-64 years of age, first booster, Comirnaty (Pfizer/BioNTech)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Comirnaty
    Investigational medicinal product code
    Other name
    COVID-19 mRNA Vaccine, Pfizer–BioNTech COVID-19 vaccine
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    The vaccine is in a multidose vial and must be diluted before use. One dose (0,3mL) contains 30 micrograms of tozinameran, a COVID-19 mRNA Vaccine (embeded in lipid nanoparticles).

    Arm title
    		 65+ years of age, first booster, Comirnaty (Pfizer/BioNTech)
    Arm description
    		 65+ years of age, first booster, Comirnaty (Pfizer/BioNTech)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Comirnaty
    Investigational medicinal product code
    Other name
    COVID-19 mRNA Vaccine, Pfizer–BioNTech COVID-19 vaccine
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    The vaccine is in a multidose vial and must be diluted before use. One dose (0,3mL) contains 30 micrograms of tozinameran, a COVID-19 mRNA Vaccine (embeded in lipid nanoparticles).

    Number of subjects in period 3 [15]
    		25-49 years of age, first booster, Comirnaty (Pfizer/BioNTech) 50-64 years of age, first booster, Comirnaty (Pfizer/BioNTech) 65+ years of age, first booster, Comirnaty (Pfizer/BioNTech)
    Started
    28
    73
    123
    28 days post booster 1 vaccination (B1)
    30
    73
    125
    3-5months post booster1 vaccination (B2)
    25
    56
    6 [16]
    6 months post booster 1 vaccination (B3)
    23
    45
    26 [17]
    12months post booster 1 vaccination (B4)
    4
    5 [18]
    9 [19]
    Completed
    4
    43
    124
    Not completed
    27
    31
    2
         Received additional booster before timepoint
    -
    2
    -
         Participant discontinuation
    -
    3
    1
         Death (unrelated to study)
    -
    -
    1
         Logistical issues
    20
    25
    -
         Lost to follow-up
    7
    1
    -
    Joined
    3
    1
    3
         Late recruitment
         Late recruitment reason:
    3
             Logistical issues
    1
             Logistical issues
    3
             Logistical issues
    Notes
    [15] - 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 QIV +PCV series. COVID + booster vaccinations were later available that not all participants took. Each period is a separate part of the trial. Participants could then choose to enroll in the following period. Group allocation in the other periods was based on the corresponding vaccination, irrespective of former vaccinations. The number of participants starting another period is thus not equal to the number completing a previous period.
    [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.
    Period 4
    Period 4 title
    COVID vaccination, second booster
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 50-64 years of age, booster 2, Comirnaty (Pfizer/BioNTech)
    Arm description
    		 50-64 years of age, booster 2, Comirnaty (Pfizer/BioNTech)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Comirnaty
    Investigational medicinal product code
    Other name
    COVID-19 mRNA Vaccine, Pfizer–BioNTech COVID-19 vaccine
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    The vaccine is in a multidose vial and must be diluted before use. One dose (0,3mL) contains 30 micrograms of tozinameran, a COVID-19 mRNA Vaccine (embeded in lipid nanoparticles).

    Arm title
    		 65+ years of age, booster 2, Comirnaty (Pfizer/BioNTech)
    Arm description
    		 65+ years of age, booster 2, Comirnaty (Pfizer/BioNTech)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Comirnaty
    Investigational medicinal product code
    Other name
    COVID-19 mRNA Vaccine, Pfizer–BioNTech COVID-19 vaccine
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    The vaccine is in a multidose vial and must be diluted before use. One dose (0,3mL) contains 30 micrograms of tozinameran, a COVID-19 mRNA Vaccine (embeded in lipid nanoparticles).

    Arm title
    		 50-64 years of age, booster 2, Spikevax (Moderna)
    Arm description
    		 50-64 years of age, booster 2, Spikevax (Moderna)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Spikevax
    Investigational medicinal product code
    Other name
    COIVD-19 mRNA vaccine, Moderna
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose (0,25 mL) contains 50 micrograms of messenger RNA (mRNA) (embedded in SM-102 lipid nanoparticles) Preferred site of administration is the deltoid muscle of the upper arm.

    Arm title
    		 65+ years of age, booster 2, Spikevax (Moderna)
    Arm description
    		 65+ years of age, booster 2, Spikevax (Moderna)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Spikevax
    Investigational medicinal product code
    Other name
    COIVD-19 mRNA vaccine, Moderna
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose (0,25 mL) contains 50 micrograms of messenger RNA (mRNA) (embedded in SM-102 lipid nanoparticles) Preferred site of administration is the deltoid muscle of the upper arm.

    Number of subjects in period 4 [20]
    		50-64 years of age, booster 2, Comirnaty (Pfizer/BioNTech) 65+ years of age, booster 2, Comirnaty (Pfizer/BioNTech) 50-64 years of age, booster 2, Spikevax (Moderna) 65+ years of age, booster 2, Spikevax (Moderna)
    Started
    7
    91
    12
    7
    28 days post booster 12 vaccination (C1)
    9
    91
    14
    7
    6 months post booster 2 vaccination (C2)
    0 [21]
    11 [22]
    3 [23]
    1 [24]
    12 months post booster2 vaccination (C3)
    0 [25]
    9 [26]
    0 [27]
    1 [28]
    Completed
    7
    86
    26
    8
    Not completed
    2
    7
    4
    0
         Physician decision
    -
    1
    -
    -
         Received additional booster before timepoint
    2
    2
    1
    -
         Participant discontinuation
    -
    2
    1
    -
         Missed essential timepoint
    -
    -
    1
    -
         Logistical issues
    -
    1
    -
    -
         Lost to follow-up
    -
    1
    1
    -
    Joined
    2
    2
    18
    1
         Late recruitment
         Late recruitment reason:
    2
             Logistical issues
    2
             Logistical issues
    3
             Logistical issues
    1
             Logistical issues
         Directly started in next period
    -
    -
    15
    -
    Notes
    [20] - 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 QIV +PCV series. COVID + booster vaccinations were later available that not all participants took. Each period is a separate part of the trial. Participants could then choose to enroll in the following period. Group allocation in the other periods was based on the corresponding vaccination, irrespective of former vaccinations. The number of participants starting another period is thus not equal to the number completing a previous period.
    [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.
    Period 5
    Period 5 title
    COVID vaccination, third booster
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 50-64 years of age, Comirnaty Orig/BA.1 (Pfizer/BioNTech)
    Arm description
    		 50-64 years of age, Comirnaty Orig/BA.1 (Pfizer/BioNTech)
    Arm type
    		 Experimental

    Investigational medicinal product name
    COMIRNATY Original/Omicron BA.1 (15/15 microgram)
    Investigational medicinal product code
    Other name
    COVID-19-mRNA-vaccin
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Eén dosis bevat 15 microgram tozinameran en 15 microgram riltozinameran

    Arm title
    		 65+ years of age, Comirnaty Orig/BA.1 (Pfizer/BioNTech)
    Arm description
    		 65+ years of age, Comirnaty Orig/BA.1 (Pfizer/BioNTech)
    Arm type
    		 Experimental

    Investigational medicinal product name
    COMIRNATY Original/Omicron BA.1 (15/15 microgram)
    Investigational medicinal product code
    Other name
    COVID-19-mRNA-vaccin
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Eén dosis bevat 15 microgram tozinameran en 15 microgram riltozinameran

    Arm title
    		 50-64 years of age, Spikevax Orig/BA.1 (Moderna)
    Arm description
    		 50-64 years of age, Spikevax Orig/BA.1 (Moderna)
    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).

    Arm title
    		 65+ years of age, Spikevax Orig/BA.1 (Moderna)
    Arm description
    		 65+ years of age, Spikevax Orig/BA.1 (Moderna)
    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).

    Arm title
    		 50-64 years of age, unknown mRNA vaccine
    Arm description
    		 50-64 years of age, unknown mRNA vaccine
    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
    		 65+ years of age, unknown mRNA vaccine
    Arm description
    		 65+ years of age, unknown mRNA vaccine
    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 5 [29]
    		50-64 years of age, Comirnaty Orig/BA.1 (Pfizer/BioNTech) 65+ years of age, Comirnaty Orig/BA.1 (Pfizer/BioNTech) 50-64 years of age, Spikevax Orig/BA.1 (Moderna) 65+ years of age, Spikevax Orig/BA.1 (Moderna) 50-64 years of age, unknown mRNA vaccine 65+ years of age, unknown mRNA vaccine
    Started
    3
    2
    12
    94
    13
    1
    28 days post booster 3 vaccination (D1)
    5
    2
    15
    93
    7
    1
    6 months post booster 3 vaccination (D2)
    5
    2
    14
    92
    7
    1
    12 months post booster3 vaccination (D3)
    4
    2
    11
    8 [30]
    6
    1
    Completed
    4
    2
    14
    91
    6
    1
    Not completed
    1
    0
    1
    3
    7
    0
         Participant discontinuation
    -
    -
    -
    1
    -
    -
         Death (unrelated to study)
    -
    -
    -
    2
    -
    -
         Missed essential timepoint
    -
    -
    -
    -
    6
    -
         Logistical issues
    -
    -
    1
    -
    -
    -
         Lost to follow-up
    1
    -
    -
    -
    1
    -
    Joined
    2
    0
    3
    0
    0
    0
         Late recruitment
         Late recruitment reason:
    2
             Logistical issues
    -
             
    3
             Logistical issues
    -
             
    -
             
    -
             
    Notes
    [29] - 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 QIV +PCV series. COVID + booster vaccinations were later available that not all participants took. Each period is a separate part of the trial. Participants could then choose to enroll in the following period. Group allocation in the other periods was based on the corresponding vaccination, irrespective of former vaccinations. The number of participants starting another period is thus not equal to the number completing a previous period.
    [30] - 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 6
    Period 6 title
    COVID vaccination, fourth booster
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 50-64 years of age, Comirnaty XBB.1.5 (Pfizer/BioNTech)
    Arm description
    		 50-64 years of age, Comirnaty XBB.1.5 (Pfizer/BioNTech)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Comirnaty Omicron XBB.1.5
    Investigational medicinal product code
    Other name
    COVID-19-mRNA-vaccin
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose (0,3 mL) contains 30 microgram tozinameran. There must been at least 3 months between the vaccination with this vaccin and the last COVID-19 vaccination

    Arm title
    		 65+ years of age, Comirnaty XBB.1.5 (Pfizer/BioNTech)
    Arm description
    		 65+ years of age, Comirnaty XBB.1.5 (Pfizer/BioNTech)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Comirnaty Omicron XBB.1.5
    Investigational medicinal product code
    Other name
    COVID-19-mRNA-vaccin
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose (0,3 mL) contains 30 microgram tozinameran. There must been at least 3 months between the vaccination with this vaccin and the last COVID-19 vaccination

    Number of subjects in period 6 [31]
    		50-64 years of age, Comirnaty XBB.1.5 (Pfizer/BioNTech) 65+ years of age, Comirnaty XBB.1.5 (Pfizer/BioNTech)
    Started
    3
    83
    28 days post booster 4 vaccination (E1)
    3
    83
    12 months post booster4 vaccination (E3)
    3
    79
    Completed
    3
    79
    Not completed
    0
    4
         Received vaccine via other route
    -
    2
         Death (unrelated to study)
    -
    2
    Notes
    [31] - 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 QIV +PCV series. COVID + booster vaccinations were later available that not all participants took. Each period is a separate part of the trial. Participants could then choose to enroll in the following period. Group allocation in the other periods was based on the corresponding vaccination, irrespective of former vaccinations. The number of participants starting another period is thus not equal to the number completing a previous period.

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    QIV and PCV13 vaccination
    Reporting group description
    		 -

    Reporting group values
    		 QIV and PCV13 vaccination Total
    Number of subjects
    		 326 326
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 160 160
        From 65-84 years
    		 140 140
        85 years and over
    		 26 26
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 62.7 (25 to 98) -
    Gender categorical
    Units: Subjects
        Female
    		 146 146
        Male
    		 180 180

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    25-49 years of age, QIV + PCV13
    Reporting group description
    		 25-49 years of age, QIV + PCV13

    Reporting group title
    50-64 years of age, QIV + PCV13
    Reporting group description
    		 50-64 years of age, QIV + PCV13

    Reporting group title
    65+ years of age, QIV + PCV13
    Reporting group description
    		 65+ years of age, QIV + PCV13
    Reporting group title
    50-64 years of age, Comirnaty (Pfizer/BioNTech)
    Reporting group description
    		 50-64 years of age, Comirnaty (Pfizer/BioNTech) Only 2 late inclusions at Tc, no subjects truly started at starting point. Starting point set at 2 instead of 0 due to technical limitations.

    Reporting group title
    65+ years of age, Comirnaty (Pfizer/BioNTech)
    Reporting group description
    		 65+ years of age, Comirnaty (Pfizer/BioNTech)

    Reporting group title
    25-49 years of age, Spikevax (Moderna)
    Reporting group description
    		 25-49 years of age, Spikevax (Moderna)

    Reporting group title
    50-64 years of age, Spikevax (Moderna)
    Reporting group description
    		 50-64 years of age, Spikevax (Moderna)

    Reporting group title
    65+ years of age, Spikevax (Moderna)
    Reporting group description
    		 65+ years of age, Spikevax (Moderna)

    Reporting group title
    50-64 years of age, Vaxzevria (AstraZeneca)
    Reporting group description
    		 50-64 years of age, Vaxzevria (AstraZeneca) Only 1 late inclusions at Tc, no subjects truly started at starting point. Starting point set at 1 instead of 0 due to technical limitations.
    Reporting group title
    25-49 years of age, first booster, Comirnaty (Pfizer/BioNTech)
    Reporting group description
    		 25-49 years of age, first booster, Comirnaty (Pfizer/BioNTech)

    Reporting group title
    50-64 years of age, first booster, Comirnaty (Pfizer/BioNTech)
    Reporting group description
    		 50-64 years of age, first booster, Comirnaty (Pfizer/BioNTech)

    Reporting group title
    65+ years of age, first booster, Comirnaty (Pfizer/BioNTech)
    Reporting group description
    		 65+ years of age, first booster, Comirnaty (Pfizer/BioNTech)
    Reporting group title
    50-64 years of age, booster 2, Comirnaty (Pfizer/BioNTech)
    Reporting group description
    		 50-64 years of age, booster 2, Comirnaty (Pfizer/BioNTech)

    Reporting group title
    65+ years of age, booster 2, Comirnaty (Pfizer/BioNTech)
    Reporting group description
    		 65+ years of age, booster 2, Comirnaty (Pfizer/BioNTech)

    Reporting group title
    50-64 years of age, booster 2, Spikevax (Moderna)
    Reporting group description
    		 50-64 years of age, booster 2, Spikevax (Moderna)

    Reporting group title
    65+ years of age, booster 2, Spikevax (Moderna)
    Reporting group description
    		 65+ years of age, booster 2, Spikevax (Moderna)
    Reporting group title
    50-64 years of age, Comirnaty Orig/BA.1 (Pfizer/BioNTech)
    Reporting group description
    		 50-64 years of age, Comirnaty Orig/BA.1 (Pfizer/BioNTech)

    Reporting group title
    65+ years of age, Comirnaty Orig/BA.1 (Pfizer/BioNTech)
    Reporting group description
    		 65+ years of age, Comirnaty Orig/BA.1 (Pfizer/BioNTech)

    Reporting group title
    50-64 years of age, Spikevax Orig/BA.1 (Moderna)
    Reporting group description
    		 50-64 years of age, Spikevax Orig/BA.1 (Moderna)

    Reporting group title
    65+ years of age, Spikevax Orig/BA.1 (Moderna)
    Reporting group description
    		 65+ years of age, Spikevax Orig/BA.1 (Moderna)

    Reporting group title
    50-64 years of age, unknown mRNA vaccine
    Reporting group description
    		 50-64 years of age, unknown mRNA vaccine

    Reporting group title
    65+ years of age, unknown mRNA vaccine
    Reporting group description
    		 65+ years of age, unknown mRNA vaccine
    Reporting group title
    50-64 years of age, Comirnaty XBB.1.5 (Pfizer/BioNTech)
    Reporting group description
    		 50-64 years of age, Comirnaty XBB.1.5 (Pfizer/BioNTech)

    Reporting group title
    65+ years of age, Comirnaty XBB.1.5 (Pfizer/BioNTech)
    Reporting group description
    		 65+ years of age, Comirnaty XBB.1.5 (Pfizer/BioNTech)

    Subject analysis set title
    QIV serology - Pre QIV timepoint - 25-49 y/o
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subset of participants (25-49 years of age) who received a QIV vaccination in this study. Participants included in this serology analysis selection for the pre-vaccination timepoint are based on availability of per-protocol measurements at pre-vaccination and 28-days post QIV vaccination timepoints.

    Subject analysis set title
    QIV serology - Pre QIV timepoint - 50-64 y/o
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subset of participants (50-64 years of age) who received a QIV vaccination in this study. Participants included in this serology analysis selection for the pre-vaccination timepoint are based on availability of per-protocol measurements at pre-vaccination and 28-days post QIV vaccination timepoints.

    Subject analysis set title
    QIV serology - Pre QIV timepoint - 65+ y/o
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subset of participants (65+ years of age) who received a QIV vaccination in this study. Participants included in this serology analysis selection for the pre-vaccination timepoint are based on availability of per-protocol measurements at pre-vaccination and 28-days post QIV vaccination timepoints.

    Subject analysis set title
    QIV serology - 28-days post QIV timepoint - 25-49 y/o
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subset of participants (25-49 years of age) who received a QIV vaccination in this study. Participants included in this serology analysis selection for the 28-days post QIV vaccination timepoint are based on availability of per-protocol measurements at pre-vaccination and 28-days post QIV vaccination timepoints.

    Subject analysis set title
    QIV serology - 28-days post QIV timepoint - 50-64 y/o
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subset of participants (50-64 years of age) who received a QIV vaccination in this study. Participants included in this serology analysis selection for the 28-days post QIV vaccination timepoint are based on availability of per-protocol measurements at pre-vaccination and 28-days post QIV vaccination timepoints.

    Subject analysis set title
    QIV serology - 28-days post QIV timepoint - 65+ y/o
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subset of participants (65+ years of age) who received a QIV vaccination in this study. Participants included in this serology analysis selection for the 28-days post QIV vaccination timepoint are based on availability of per-protocol measurements at pre-vaccination and 28-days post QIV vaccination timepoints.

    Subject analysis set title
    QIV serology - 6-months post QIV timepoint - 25-49 y/o
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subset of participants (25-49 years of age) who received a QIV vaccination in this study. Participants included in this serology analysis selection for the 6-months post QIV vaccination timepoint are based on availability of per-protocol measurements at this timepoint.

    Subject analysis set title
    QIV serology - 6-months post QIV timepoint - 50-64 y/o
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subset of participants (50-64 years of age) who received a QIV vaccination in this study. Participants included in this serology analysis selection for the 6-months post QIV vaccination timepoint are based on availability of per-protocol measurements at this timepoint.

    Subject analysis set title
    QIV serology - 6-months post QIV timepoint - 65+ y/o
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subset of participants (65+ years of age) who received a QIV vaccination in this study. Participants included in this serology analysis selection for the 6-months post QIV vaccination timepoint are based on availability of per-protocol measurements at this timepoint.

    Subject analysis set title
    PCV-13 serology - Pre PCV-13 timepoint - 25-49 y/o
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subset of participants (25-49 years of age) who received a PCV-13 vaccination in this study. Participants included in this serology analysis selection for the pre-vaccination timepoint are based on availability of per-protocol measurements at pre-vaccination and 28-days post PCV-13 vaccination timepoints.

    Subject analysis set title
    PCV-13 serology - Pre PCV-13 timepoint - 50-64 y/o
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subset of participants (50-64 years of age) who received a PCV-13 vaccination in this study. Participants included in this serology analysis selection for the pre-vaccination timepoint are based on availability of per-protocol measurements at pre-vaccination and 28-days post PCV-13 vaccination timepoints.

    Subject analysis set title
    PCV-13 serology - Pre PCV-13 timepoint - 65+ y/o
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subset of participants (65+ years of age) who received a PCV-13 vaccination in this study. Participants included in this serology analysis selection for the pre-vaccination timepoint are based on availability of per-protocol measurements at pre-vaccination and 28-days post PCV-13 vaccination timepoints.

    Subject analysis set title
    PCV-13 serology - 7-days post PCV-13 timepoint - 25-49 y/o
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subset of participants (25-49 years of age) who received a PCV-13 vaccination in this study. Participants included in this serology analysis selection for the 7-days post PCV-13 vaccination timepoint are based on availability of per-protocol measurements at this timepoint.

    Subject analysis set title
    PCV-13 serology - 7-days post PCV-13 timepoint - 50-64 y/o
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subset of participants (50-64 years of age) who received a PCV-13 vaccination in this study. Participants included in this serology analysis selection for the 7-days post PCV-13 vaccination timepoint are based on availability of per-protocol measurements at this timepoint.

    Subject analysis set title
    PCV-13 serology - 7-days post PCV-13 timepoint - 65+ y/o
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subset of participants (65+ years of age) who received a PCV-13 vaccination in this study. Participants included in this serology analysis selection for the 7-days post PCV-13 vaccination timepoint are based on availability of per-protocol measurements at this timepoint.

    Subject analysis set title
    PCV-13 serology - 28-days post PCV-13 timepoint - 25-49 y/o
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subset of participants (25-49 years of age) who received a PCV-13 vaccination in this study. Participants included in this serology analysis selection for the 28-days post PCV-13 vaccination timepoint are based on availability of per-protocol measurements at pre-vaccination and 28-days post PCV-13 vaccination timepoints.

    Subject analysis set title
    PCV-13 serology - 28-days post PCV-13 timepoint - 50-64 y/o
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subset of participants (50-64 years of age) who received a PCV-13 vaccination in this study. Participants included in this serology analysis selection for the 28-days post PCV-13 vaccination timepoint are based on availability of per-protocol measurements at pre-vaccination and 28-days post PCV-13 vaccination timepoints.

    Subject analysis set title
    PCV-13 serology - 28-days post PCV-13 timepoint - 65+ y/o
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subset of participants (65+ years of age) who received a PCV-13 vaccination in this study. Participants included in this serology analysis selection for the 28-days post PCV-13 vaccination timepoint are based on availability of per-protocol measurements at pre-vaccination and 28-days post PCV-13 vaccination timepoints.

    Subject analysis set title
    PCV-13 serology - 6-months post PCV-13 timepoint - 25-49 y/o
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subset of participants (25-49 years of age) who received a PCV-13 vaccination in this study. Participants included in this serology analysis selection for the 6-months post PCV-13 vaccination timepoint are based on availability of per-protocol measurements at this timepoint.

    Subject analysis set title
    PCV-13 serology - 6-months post PCV-13 timepoint - 50-64 y/o
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subset of participants (50-64 years of age) who received a PCV-13 vaccination in this study. Participants included in this serology analysis selection for the 6-months post PCV-13 vaccination timepoint are based on availability of per-protocol measurements at this timepoint.

    Subject analysis set title
    PCV-13 serology - 6-months post PCV-13 timepoint - 65+ y/o
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subset of participants (65+ years of age) who received a PCV-13 vaccination in this study. Participants included in this serology analysis selection for the 6-months post PCV-13 vaccination timepoint are based on availability of per-protocol measurements at this timepoint.

    Subject analysis set title
    PCV-13 serology - 12-months post PCV-13 timepoint - 25-49 y/o
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subset of participants (25-49 years of age) who received a PCV-13 vaccination in this study. Participants included in this serology analysis selection for the 12-months post PCV-13 vaccination timepoint are based on availability of per-protocol measurements at this timepoint.

    Subject analysis set title
    PCV-13 serology - 12-months post PCV-13 tmepoint - 50-64 y/o
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subset of participants (50-64 years of age) who received a PCV-13 vaccination in this study. Participants included in this serology analysis selection for the 12-months post PCV-13 vaccination timepoint are based on availability of per-protocol measurements at this timepoint.

    Subject analysis set title
    PCV-13 serology - 12-months post PCV-13 timepoint - 65+ y/o
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subset of participants (65+ years of age) who received a PCV-13 vaccination in this study. Participants included in this serology analysis selection for the 12-months post PCV-13 vaccination timepoint are based on availability of per-protocol measurements at this timepoint.

    Subject analysis set title
    QIV ELISpot - Pre QIV timepoint - 25-49y
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subset of participants (25-49 years of age) who received a QIV vaccination in this study. Participants included in this ELISpot analysis selection for the pre-QIV vaccination timepoint only if all measurements are available for this timepoint.

    Subject analysis set title
    QIV ELISpot - Pre QIV timepoint - 50-64y
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subset of participants (50-64 years of age) who received a QIV vaccination in this study. Participants included in this ELISpot analysis selection for the pre-QIV vaccination timepoint only if all measurements are available for this timepoint.

    Subject analysis set title
    QIV ELISpot - Pre QIV timepoint - 65+
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subset of participants (65+ years of age) who received a QIV vaccination in this study. Participants included in this ELISpot analysis selection for the pre-QIV vaccination timepoint only if all measurements are available for this timepoint.

    Subject analysis set title
    QIV ELISpot - 7-days post QIV timepoint - 25-49y
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subset of participants (25-49 years of age) who received a QIV vaccination in this study. Participants included in this ELISpot analysis selection for the 7-days post QIV vaccination timepoint only if all measurements are available for this timepoint.

    Subject analysis set title
    QIV ELISpot - 7-days post QIV timepoint - 50-64y
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subset of participants (50-64 years of age) who received a QIV vaccination in this study. Participants included in this ELISpot analysis selection for the 7-days post QIV vaccination timepoint only if all measurements are available for this timepoint.

    Subject analysis set title
    QIV ELISpot - 7-days post QIV timepoint - 65+
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subset of participants (65+ years of age) who received a QIV vaccination in this study. Participants included in this ELISpot analysis selection for the 7-days post QIV vaccination timepoint only if all measurements are available for this timepoint.

    Subject analysis set title
    QIV ELISpot - 28-days post QIV timepoint - 25-49y
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subset of participants (25-49 years of age) who received a QIV vaccination in this study. Participants included in this ELISpot analysis selection for the 28-days post QIV vaccination timepoint only if all measurements are available for this timepoint.

    Subject analysis set title
    QIV ELISpot - 28-days post QIV timepoint - 50-64y
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subset of participants (50-64 years of age) who received a QIV vaccination in this study. Participants included in this ELISpot analysis selection for the 28-days post QIV vaccination timepoint only if all measurements are available for this timepoint.

    Subject analysis set title
    QIV ELISpot - 28-days post QIV timepoint - 65+
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subset of participants (65+ years of age) who received a QIV vaccination in this study. Participants included in this ELISpot analysis selection for the 28-days post QIV vaccination timepoint only if all measurements are available for this timepoint.

    Subject analysis set title
    QIV ELISpot - 6-months post QIV timepoint - 25-49y
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subset of participants (25-49 years of age) who received a QIV vaccination in this study. Participants included in this ELISpot analysis selection for the 6-months post QIV vaccination timepoint only if all measurements are available for this timepoint.

    Subject analysis set title
    QIV ELISpot - 6-months post QIV timepoint - 50-64y
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subset of participants (50-64 years of age) who received a QIV vaccination in this study. Participants included in this ELISpot analysis selection for the 6-months post QIV vaccination timepoint only if all measurements are available for this timepoint.

    Subject analysis set title
    QIV ELISpot - 6-months post QIV timepoint - 65+
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subset of participants (65+ years of age) who received a QIV vaccination in this study. Participants included in this ELISpot analysis selection for the 6-months post QIV vaccination timepoint only if all measurements are available for this timepoint.

    Subject analysis set title
    PCV-13 ELISpot - Pre PCV-13 timepoint - 25-49y
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subset of participants (25-49 years of age) who received a PCV-13 vaccination in this study. Participants included in this ELISpot analysis selection for the pre-PCV-13 vaccination timepoint only if all measurements are available for this timepoint.

    Subject analysis set title
    PCV-13 ELISpot - Pre PCV-13 timepoint - 50-64y
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subset of participants (50-64 years of age) who received a PCV-13 vaccination in this study. Participants included in this ELISpot analysis selection for the pre-PCV-13 vaccination timepoint only if all measurements are available for this timepoint.

    Subject analysis set title
    PCV-13 ELISpot - Pre PCV-13 timepoint - 65+
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subset of participants (65+ years of age) who received a PCV-13 vaccination in this study. Participants included in this ELISpot analysis selection for the pre-PCV-13 vaccination timepoint only if all measurements are available for this timepoint.

    Subject analysis set title
    PCV-13 ELISpot - 7-days post PCV-13 timepoint - 25-49y
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subset of participants (25-49 years of age) who received a PCV-13 vaccination in this study. Participants included in this ELISpot analysis selection for the 7-days post PCV-13 vaccination timepoint only if all measurements are available for this timepoint.

    Subject analysis set title
    PCV-13 ELISpot - 7-days post PCV-13 timepoint - 50-64y
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subset of participants (50-64 years of age) who received a PCV-13 vaccination in this study. Participants included in this ELISpot analysis selection for the 7-days post PCV-13 vaccination timepoint only if all measurements are available for this timepoint.

    Subject analysis set title
    PCV-13 ELISpot - 7-days post PCV-13 timepoint - 65+
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subset of participants (65+ years of age) who received a PCV-13 vaccination in this study. Participants included in this ELISpot analysis selection for the 7-days post PCV-13 vaccination timepoint only if all measurements are available for this timepoint.

    Subject analysis set title
    PCV-13 ELISpot - 28-days post PCV-13 timepoint - 25-49y
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subset of participants (25-49 years of age) who received a PCV-13 vaccination in this study. Participants included in this ELISpot analysis selection for the 28-days post PCV-13 vaccination timepoint only if all measurements are available for this timepoint.

    Subject analysis set title
    PCV-13 ELISpot - 28-days post PCV-13 timepoint - 50-64y
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subset of participants (50-64 years of age) who received a PCV-13 vaccination in this study. Participants included in this ELISpot analysis selection for the 28-days post PCV-13 vaccination timepoint only if all measurements are available for this timepoint.

    Subject analysis set title
    PCV-13 ELISpot - 28-days post PCV-13 timepoint - 65+
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subset of participants (65+ years of age) who received a PCV-13 vaccination in this study. Participants included in this ELISpot analysis selection for the 28-days post PCV-13 vaccination timepoint only if all measurements are available for this timepoint.

    Subject analysis set title
    PCV-13 ELISpot - 6-months post PCV-13 timepoint - 25-49y
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subset of participants (25-49 years of age) who received a PCV-13 vaccination in this study. Participants included in this ELISpot analysis selection for the 6-months post PCV-13 vaccination timepoint only if all measurements are available for this timepoint.

    Subject analysis set title
    PCV-13 ELISpot - 6-months post PCV-13 timepoint - 50-64y
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subset of participants (50-64 years of age) who received a PCV-13 vaccination in this study. Participants included in this ELISpot analysis selection for the 6-months post PCV-13 vaccination timepoint only if all measurements are available for this timepoint.

    Subject analysis set title
    PCV-13 ELISpot - 6-months post PCV-13 timepoint - 65+
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subset of participants (65+ years of age) who received a PCV-13 vaccination in this study. Participants included in this ELISpot analysis selection for the 6-months post PCV-13 vaccination timepoint only if all measurements are available for this timepoint.

    Subject analysis set title
    FACS analysis - younger adults
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subset of participant 25-45 years of age included in analysis requiring FACS measurement at the timepoint 28-days post primary mRNA vaccination series. Due to participant selection and comparison with other cohorts, the age groups for this analysis differs from the general VITAL age groups.

    Subject analysis set title
    FACS analysis - older adults
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subset of participant 60+ years of age included in analysis requiring FACS measurement at the timepoint 28-days post primary mRNA vaccination series. Due to participant selection and comparison with other cohorts, the age groups for this analysis differs from the general VITAL age groups.

    Subject analysis set title
    SARS-CoV-2 T-cell ELISpot - Pre vaccination timepoint - 25-49y
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subset of participants (25-49 years of age) who received a SARS-CoV-2 mRNA primary vaccination series, included at the pre-vaccination timepoint for T-cell ELISpot analysis.

    Subject analysis set title
    SARS-CoV-2 T-cell ELISpot - Pre vaccination timepoint - 50-64y
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subset of participants (50-64 years of age) who received a SARS-CoV-2 mRNA primary vaccination series, included at the pre-vaccination timepoint for T-cell ELISpot analysis.

    Subject analysis set title
    SARS-CoV-2 T-cell ELISpot - Pre vaccination timepoint - 65+
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subset of participants (65+ years of age) who received a SARS-CoV-2 mRNA primary vaccination series, included at the pre-vaccination timepoint for T-cell ELISpot analysis.

    Subject analysis set title
    SARS-CoV-2 T-cell ELISpot - 28-days post vaccination - 25-49y
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subset of participants (25-49 years of age) who received a SARS-CoV-2 mRNA primary vaccination series, included at the timepoint 28-days post 2nd vaccination of primary series for T-cell ELISpot analysis.

    Subject analysis set title
    SARS-CoV-2 T-cell ELISpot - 28-days post vaccination - 50-64y
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subset of participants (50-64 years of age) who received a SARS-CoV-2 mRNA primary vaccination series, included at the timepoint 28-days post 2nd vaccination of primary series for T-cell ELISpot analysis.

    Subject analysis set title
    SARS-CoV-2 T-cell ELISpot - 28-days post vaccination - 65+
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subset of participants (65+ years of age) who received a SARS-CoV-2 mRNA primary vaccination series, included at the timepoint 28-days post 2nd vaccination of primary series for T-cell ELISpot analysis.

    Subject analysis set title
    SARS-CoV-2 B-cell ELISpot - 28-days post vaccination - 25-49y
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subset of participants (25-49 years of age) who received a SARS-CoV-2 mRNA primary vaccination series, included at the timepoint 28-days post 2nd vaccination of primary series for B-cell ELISpot analysis.

    Subject analysis set title
    SARS-CoV-2 B-cell ELISpot - 28-days post vaccination - 50-64y
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subset of participants (50-64 years of age) who received a SARS-CoV-2 mRNA primary vaccination series, included at the timepoint 28-days post 2nd vaccination of primary series for B-cell ELISpot analysis.

    Subject analysis set title
    SARS-CoV-2 B-cell ELISpot - 28-days post vaccination - 65+
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subset of participants (65+ years of age) who received a SARS-CoV-2 mRNA primary vaccination series, included at the timepoint 28-days post 2nd vaccination of primary series for B-cell ELISpot analysis.

    Subject analysis set title
    SARS-CoV-2 B-cell ELISpot - Pre booster - 25-49y
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subset of participants (25-49 years of age) who received a first SARS-CoV-2 mRNA booster, included at the pre-booster vaccination timepoint for B-cell ELISpot analysis.

    Subject analysis set title
    SARS-CoV-2 B-cell ELISpot - Pre booster - 50-64y
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subset of participants (50-64 years of age) who received a first SARS-CoV-2 mRNA booster, included at the pre-booster vaccination timepoint for B-cell ELISpot analysis.

    Subject analysis set title
    SARS-CoV-2 B-cell ELISpot - Pre booster - 65+
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subset of participants (65+ years of age) who received a first SARS-CoV-2 mRNA booster, included at the pre-booster vaccination timepoint for B-cell ELISpot analysis.

    Subject analysis set title
    SARS-CoV-2 B-cell ELISpot - 28-days post booster - 25-49y
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subset of participants (25-49 years of age) who received a first SARS-CoV-2 mRNA booster, included at the28-days post booster vaccination timepoint for B-cell ELISpot analysis.

    Subject analysis set title
    SARS-CoV-2 B-cell ELISpot - 28-days post booster - 50-64y
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subset of participants (50-64 years of age) who received a first SARS-CoV-2 mRNA booster, included at the28-days post booster vaccination timepoint for B-cell ELISpot analysis.

    Subject analysis set title
    SARS-CoV-2 B-cell ELISpot - 28-days post booster - 65+
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subset of participants (65+ years of age) who received a first SARS-CoV-2 mRNA booster, included at the28-days post booster vaccination timepoint for B-cell ELISpot analysis.

    Subject analysis set title
    mucosal antibody analysis - Pre 1st booster - 25-49y
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subset of participants (25-49 years of age) who received a first SARS-CoV-2 mRNA booster, included at the pre-booster vaccination timepoint for mucosal antibody analysis.

    Subject analysis set title
    mucosal antibody analysis - Pre 1st booster - 50-64y
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subset of participants (50-64 years of age) who received a first SARS-CoV-2 mRNA booster, included at the pre-booster vaccination timepoint for mucosal antibody analysis.

    Subject analysis set title
    mucosal antibody analysis - Pre 1st booster -65+
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subset of participants (65+ years of age) who received a first SARS-CoV-2 mRNA booster, included at the pre-booster vaccination timepoint for mucosal antibody analysis.

    Subject analysis set title
    mucosal antibody analysis - 28-days post 1st booster - 25-49y
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subset of participants (25-49 years of age) who received a first SARS-CoV-2 mRNA booster, included at the timepoint 28-days post first booster for mucosal antibody analysis.

    Subject analysis set title
    mucosal antibody analysis - 28-days post 1st booster -50-64y
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subset of participants (50-64 years of age) who received a first SARS-CoV-2 mRNA booster, included at the timepoint 28-days post first booster for mucosal antibody analysis.

    Subject analysis set title
    mucosal antibody analysis - 28-days post 1st booster - 65+
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subset of participants (65+ years of age) who received a first SARS-CoV-2 mRNA booster, included at the timepoint 28-days post first booster for mucosal antibody analysis.

    Subject analysis set title
    Spikevax serology - Pre primary series - 25-49y
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subset of participants (25-49 years of age) who received a Spikevax (Moderna) mRNA primary series (consisting of 2 vaccinations), included at the pre-vaccination timepoint.

    Subject analysis set title
    Spikevax serology - 28-days post 1st primary vaccine - 25-49y
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subset of participants (25-49 years of age) who received a Spikevax (Moderna) mRNA primary series (consisting of 2 vaccinations), included at the 28-days post 1st vaccination timepoint.

    Subject analysis set title
    Spikevax serology - 28-days post 2nd primary vaccine - 25-49y
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subset of participants (25-49 years of age) who received a Spikevax (Moderna) mRNA primary series (consisting of 2 vaccinations), included at the 28-days post 2nd vaccination timepoint.

    Subject analysis set title
    Spikevax serology - 6-months post primary series - 25-49y
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subset of participants (25-49 years of age) who received a Spikevax (Moderna) mRNA primary series (consisting of 2 vaccinations), included at the 6-months post primary vaccination series timepoint.

    Subject analysis set title
    Spikevax serology - Pre primary series - 50-64y
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subset of participants (50-64 years of age) who received a Spikevax (Moderna) mRNA primary series (consisting of 2 vaccinations), included at the pre-vaccination timepoint.

    Subject analysis set title
    Spikevax serology - 28-days post 1st primary vaccine - 50-64y
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subset of participants (50-64 years of age) who received a Spikevax (Moderna) mRNA primary series (consisting of 2 vaccinations), included at the 28-days post 1st vaccination timepoint.

    Subject analysis set title
    Spikevax serology - 28-days post 2nd primary vaccine - 50-64y
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subset of participants (50-64 years of age) who received a Spikevax (Moderna) mRNA primary series (consisting of 2 vaccinations), included at the 28-days post 2nd vaccination timepoint.

    Subject analysis set title
    Spikevax serology - 6-months post primary series - 50-64y
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subset of participants (50-64 years of age) who received a Spikevax (Moderna) mRNA primary series (consisting of 2 vaccinations), included at the 6-months post primary vaccination series timepoint.

    Subject analysis set title
    Spikevax serology - Pre primary series - 65+
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subset of participants (65+ years of age) who received a Spikevax (Moderna) mRNA primary series (consisting of 2 vaccinations), included at the pre-vaccination timepoint.

    Subject analysis set title
    Spikevax serology - 28-days post 1st primary vaccine - 65+
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subset of participants (65+ years of age) who received a Spikevax (Moderna) mRNA primary series (consisting of 2 vaccinations), included at the 28-days post 1st vaccination timepoint.

    Subject analysis set title
    Spikevax serology - 28-days post 2nd primary vaccine - 65+
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subset of participants (65+ years of age) who received a Spikevax (Moderna) mRNA primary series (consisting of 2 vaccinations), included at the 28-days post 2nd vaccination timepoint.

    Subject analysis set title
    Spikevax serology - 6-months post primary series - 65+
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subset of participants (65+ years of age) who received a Spikevax (Moderna) mRNA primary series (consisting of 2 vaccinations), included at the 6-months post primary vaccination series timepoint.

    Subject analysis set title
    Comirnaty serology - Pre primary series - 65+
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subset of participants (65+ years of age) who received a Comirnaty (Moderna) mRNA primary series (consisting of 2 vaccinations), included at the pre-vaccination timepoint.

    Subject analysis set title
    Comirnaty serology - 28-days post 1st primary vaccine - 65+
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subset of participants (65+ years of age) who received a Comirnaty (Moderna) mRNA primary series (consisting of 2 vaccinations), included at the 28-days post 1st vaccination timepoint.

    Subject analysis set title
    Comirnaty serology - 28-days post 2nd primary vaccine - 65+
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subset of participants (65+ years of age) who received a Comirnaty (Moderna) mRNA primary series (consisting of 2 vaccinations), included at the 28-days post 2nd vaccination timepoint.

    Subject analysis set title
    Comirnaty serology - 6-months post primary series - 65+
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subset of participants (65+ years of age) who received a Comirnaty (Moderna) mRNA primary series (consisting of 2 vaccinations), included at the 6-months post primary vaccination series timepoint.

    Primary: Pneumococcal serotype-specific serum IgG antibody concentrations (GMCs) pre and one-month post PCV13 vaccination.

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    End point title
    		 Pneumococcal serotype-specific serum IgG antibody concentrations (GMCs) pre and one-month post PCV13 vaccination.
    End point description
    Pneumococcal serotype- specific serum IgG antibody concentrations pre-vaccination and one-month post PCV13 vaccination measured by bead-based multiplex immune assay. Full analysis is published in Van der Heiden et al., Nat Commun 2024, https://doi.org/10.1038/s41467-024-50760-9
    End point type
    Primary
    End point timeframe
    Period 1
    End point values
    		 PCV-13 serology - Pre PCV-13 timepoint - 25-49 y/o PCV-13 serology - Pre PCV-13 timepoint - 50-64 y/o PCV-13 serology - Pre PCV-13 timepoint - 65+ y/o PCV-13 serology - 28-days post PCV-13 timepoint - 25-49 y/o PCV-13 serology - 28-days post PCV-13 timepoint - 50-64 y/o PCV-13 serology - 28-days post PCV-13 timepoint - 65+ y/o
    Number of subjects analysed
    51
    84
    140
    51
    84
    140
    Units: ug/mL
    geometric mean (confidence interval 95%)
        Ps1-specific IgG antibody GMC
    0.29 (0.18 to 0.48)
    0.22 (0.14 to 0.32)
    0.12 (0.09 to 0.16)
    9.80 (5.85 to 16.4)
    5.56 (3.62 to 8.53)
    4.11 (2.85 to 5.92)
        Ps3-specific IgG antibody GMC
    0.38 (0.27 to 0.55)
    0.44 (0.32 to 0.59)
    0.17 (0.13 to 0.22)
    2.25 (1.65 to 3.06)
    1.82 (1.39 to 2.37)
    1.48 (1.14 to 1.93)
        Ps4-specific IgG antibody GMC
    0.05 (0.03 to 0.08)
    0.06 (0.04 to 0.07)
    0.05 (0.04 to 0.07)
    4.64 (3.34 to 6.43)
    2.07 (1.47 to 2.94)
    1.37 (1.00 to 1.88)
        Ps5-specific IgG antibody GMC
    0.45 (0.31 to 0.66)
    0.58 (0.45 to 0.76)
    0.54 (0.41 to 0.70)
    17.67 (11.35 to 27.51)
    14.53 (10.00 to 21.13)
    9.18 (6.59 to 12.79)
        Ps6A-specific IgG antibody GMC
    0.18 (0.10 to 0.31)
    0.41 (0.27 to 0.6)
    0.24 (0.17 to 0.34)
    13.35 (8.13 to 21.93)
    7.49 (4.82 to 11.64)
    5.19 (3.67 to 7.33)
        Ps6B-specific IgG antibody GMC
    0.15 (0.09 to 0.24)
    0.24 (0.16 to 0.35)
    0.14 (0.10 to 0.19)
    9.99 (6.37 to 15.65)
    4.46 (2.82 to 7.07)
    2.77 (1.93 to 3.98)
        Ps7F-specific IgG antibody GMC
    0.36 (0.22 to 0.59)
    0.48 (0.34 to 0.68)
    0.44 (0.34 to 0.57)
    16.16 (11.20 to 23.33)
    13.59 (10.23 to 18.07)
    11.62 (8.68 to 15.55)
        Ps9V-specific IgG antibody GMC
    0.19 (0.13 to 0.27)
    0.23 (0.17 to 0.32)
    0.20 (0.15 to 0.27)
    4.75 (3.44 to 6.57)
    3.92 (2.82 to 5.45)
    3.30 (2.36 to 4.60)
        Ps14-specific IgG antibody GMC
    0.21 (0.11 to 0.40)
    0.62 (0.44 to 0.89)
    0.36 (0.25 to 0.50)
    4.84 (2.83 to 8.28)
    4.73 (3.13 to 7.14)
    3.54 (2.42 to 5.19)
        Ps18C-specific IgG antibody GMC
    0.26 (0.17 to 0.41)
    0.33 (0.23 to 0.49)
    0.39 (0.29 to 0.52)
    8.14 (5.09 to 13.03)
    8.05 (5.54 to 11.69)
    10.09 (7.34 to 13.86)
        Ps19A-specific IgG antibody GMC
    0.67 (0.45 to 1.00)
    0.69 (0.49 to 0.99)
    0.71 (0.53 to 0.94)
    12.73 (8.79 to 18.44)
    8.96 (6.46 to 12.43)
    10.07 (7.57 to 13.40)
        Ps19F-specific IgG antibody GMC
    0.41 (0.25 to 0.68)
    0.56 (0.39 to 0.81)
    0.41 (0.32 to 0.52)
    8.47 (5.79 to 12.39)
    6.25 (4.56 to 8.57)
    6.00 (4.48 to 8.05)
        Ps23F-specific IgG antibody GMC
    0.16 (0.10 to 0.25)
    0.26 (0.18 to 0.39)
    0.21 (0.15 to 0.28)
    13.24 (8.61 to 20.38)
    4.87 (2.98 to 7.94)
    3.07 (2.13 to 4.42)
    Statistical analysis title
    		 primary PCV-13 serology
    Comparison groups
    PCV-13 serology - Pre PCV-13 timepoint - 25-49 y/o v PCV-13 serology - Pre PCV-13 timepoint - 50-64 y/o v PCV-13 serology - Pre PCV-13 timepoint - 65+ y/o v PCV-13 serology - 28-days post PCV-13 timepoint - 25-49 y/o v PCV-13 serology - 28-days post PCV-13 timepoint - 50-64 y/o v PCV-13 serology - 28-days post PCV-13 timepoint - 65+ y/o
    Number of subjects included in analysis
    550
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 Kruskal-wallis
    Confidence interval

    Primary: Influenza vaccine strain-specific serum antibody titers (GMTs) pre- and one-month post-influenza vaccination.

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    End point title
    		 Influenza vaccine strain-specific serum antibody titers (GMTs) pre- and one-month post-influenza vaccination.
    End point description
    Influenza vaccine strain-specific serum antibody titers measured pre-vaccination and one-month post-influenza vaccination by Hemagglutinin Inhibition (HI) assay. Full analysis is published in Van der Heiden et al., Nat Commun 2024, https://doi.org/10.1038/s41467-024-50760-9
    End point type
    Primary
    End point timeframe
    Period 1
    End point values
    		 QIV serology - Pre QIV timepoint - 25-49 y/o QIV serology - Pre QIV timepoint - 50-64 y/o QIV serology - Pre QIV timepoint - 65+ y/o QIV serology - 28-days post QIV timepoint - 25-49 y/o QIV serology - 28-days post QIV timepoint - 50-64 y/o QIV serology - 28-days post QIV timepoint - 65+ y/o
    Number of subjects analysed
    56
    94
    157
    56
    94
    157
    Units: titre
    geometric mean (confidence interval 95%)
        HI titer A/Kansas/14/2017 (H3N2)
    82.51 (58.90 to 115.59)
    40.74 (32.32 to 51.36)
    35.23 (29.66 to 41.86)
    105.36 (74.7 to 148.63)
    63.18 (50.04 to 79.78)
    59.06 (50.43 to 69.16)
        HI titer A/Brisbane/02/2018 (H1N1)
    19.90 (14.15 to 27.99)
    16.98 (13.18 to 21.87)
    15.93 (13.18 to 19.26)
    126.61 (93.49 to 171.47)
    108.13 (84.02 to 139.16)
    98.67 (79.25 to 122.84)
    Statistical analysis title
    		 primary QIV serology
    Comparison groups
    QIV serology - Pre QIV timepoint - 50-64 y/o v QIV serology - Pre QIV timepoint - 65+ y/o v QIV serology - 28-days post QIV timepoint - 25-49 y/o v QIV serology - 28-days post QIV timepoint - 50-64 y/o v QIV serology - 28-days post QIV timepoint - 65+ y/o v QIV serology - Pre QIV timepoint - 25-49 y/o
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.05
    Method
    		 Kruskal-wallis
    Confidence interval

    Secondary: Influenza vaccin strain-specific serum antibody titers (GMTs) for additional post-vaccination timepoints.

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    End point title
    		 Influenza vaccin strain-specific serum antibody titers (GMTs) for additional post-vaccination timepoints.
    End point description
    Influenza vaccine strain-specific serum antibody titers measured Hemagglutinin Inhibition (HI) assay. Due to technical limitations during measurements, only H3N2-specific antibody titers at 6-9 months post vaccination are available. Full analysis is published in Van der Heiden et al., Nat Commun 2024, https://doi.org/10.1038/s41467-024-50760-9
    End point type
    Secondary
    End point timeframe
    Period 1
    End point values
    		 QIV serology - 6-months post QIV timepoint - 25-49 y/o QIV serology - 6-months post QIV timepoint - 50-64 y/o QIV serology - 6-months post QIV timepoint - 65+ y/o
    Number of subjects analysed
    52
    87
    142
    Units: titre
    geometric mean (confidence interval 95%)
        HI titer A/Kansas/14/2017 (H3N2)
    77.93 (55.71 to 109.01)
    42.97 (33.27 to 55.51)
    47.00 (37.39 to 59.08)
    No statistical analyses for this end point

    Secondary: Pneumococcal serotype-specific serum IgG antibody concentrations (GMCs) for additional post-vaccination timepoints.

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    End point title
    		 Pneumococcal serotype-specific serum IgG antibody concentrations (GMCs) for additional post-vaccination timepoints.
    End point description
    Pneumococcal serotype- specific serum IgG antibody concentrations (GMCs) at 7 days, 6 months, and 12 months post PCV13 vaccination measured by beadbased multiplex immune assay. Further analysis included in Van der Heiden et al., Nat Commun 2024, https://doi.org/10.1038/s41467-024-50760-9 & Visser et al., npj Vaccines 2025, https://doi.org/10.1038/s41541-025-01152-7
    End point type
    Secondary
    End point timeframe
    Period 1
    End point values
    		 PCV-13 serology - 7-days post PCV-13 timepoint - 25-49 y/o PCV-13 serology - 7-days post PCV-13 timepoint - 50-64 y/o PCV-13 serology - 7-days post PCV-13 timepoint - 65+ y/o PCV-13 serology - 6-months post PCV-13 timepoint - 25-49 y/o PCV-13 serology - 6-months post PCV-13 timepoint - 50-64 y/o PCV-13 serology - 6-months post PCV-13 timepoint - 65+ y/o PCV-13 serology - 12-months post PCV-13 timepoint - 25-49 y/o PCV-13 serology - 12-months post PCV-13 tmepoint - 50-64 y/o PCV-13 serology - 12-months post PCV-13 timepoint - 65+ y/o
    Number of subjects analysed
    45
    78
    134
    45
    78
    134
    40
    73
    128
    Units: ug/mL
    geometric mean (confidence interval 95%)
        Ps1-specific IgG antibody GMC
    2.08 (1.25 to 3.46)
    0.80 (0.51 to 1.25)
    0.32 (0.23 to 0.44)
    6.34 (4.00 to 10.05)
    4.06 (2.58 to 6.39)
    2.54 (1.75 to 3.69)
    5.82 (3.69 to 9.19)
    3.12 (2.03 to 4.82)
    1.88 (1.32 to 2.67)
        Ps3-specific IgG antibody GMC
    1.02 (0.69 to 1.50)
    0.71 (0.54 to 0.95)
    0.28 (0.21 to 0.37)
    1.26 (0.90 to 1.75)
    1.14 (0.84 to 1.53)
    0.73 (0.57 to 0.94)
    0.95 (0.69 to 1.31)
    1.05 (0.77 to 1.44)
    0.64 (0.49 to 0.83)
        Ps4-specific IgG antibody GMC
    0.91 (0.59 to 1.42)
    0.26 (0.17 to 0.38)
    0.14 (0.11 to 0.19)
    1.96 (1.42 to 2.72)
    1.21 (0.86 to 1.72)
    0.89 (0.64 to 1.22)
    1.42 (1.02 to 1.99)
    0.93 (0.65 to 1.32)
    0.64 (0.46 to 0.88)
        Ps5-specific IgG antibody GMC
    2.26 (1.39 to 3.67)
    1.97 (1.33 to 2.92)
    0.98 (0.73 to 1.31)
    8.36 (5.39 to 12.98)
    8.72 (5.89 to 12.91)
    5.83 (4.22 to 8.04)
    6.96 (4.31 to 11.23)
    6.41 (4.27 to 9.61)
    4.16 (3.05 to 5.69)
        Ps6A-specific IgG antibody GMC
    1.31 (0.74 to 2.31)
    1.05 (0.68 to 1.63)
    0.43 (0.31 to 0.6)
    5.63 (3.15 to 10.06)
    4.89 (3.06 to 7.84)
    2.93 (2.03 to 4.23)
    4.33 (2.30 to 8.17)
    4.02 (2.46 to 6.58)
    2.22 (1.55 to 3.18)
        Ps6B-specific IgG antibody GMC
    1.21 (0.73 to 2.00)
    0.68 (0.44 to 1.06)
    0.27 (0.19 to 0.37)
    4.92 (3.04 to 7.97)
    2.55 (1.56 to 4.17)
    1.60 (1.11 to 2.31)
    3.53 (2.08 to 5.98)
    1.92 (1.17 to 3.16)
    1.08 (0.75 to 1.56)
        Ps7F-specific IgG antibody GMC
    2.91 (1.88 to 4.52)
    1.74 (1.25 to 2.41)
    0.95 (0.72 to 1.25)
    7.50 (5.25 to 10.72)
    8.47 (6.29 to 11.4)
    6.75 (5.18 to 8.80)
    5.49 (3.63 to 8.31)
    6.14 (4.57 to 8.25)
    4.52 (3.46 to 5.89)
        Ps9V-specific IgG antibody GMC
    1.16 (0.79 to 1.7)
    0.77 (0.57 to 1.05)
    0.45 (0.32 to 0.63)
    2.81 (1.92 to 4.11)
    2.26 (1.63 to 3.15)
    2.33 (1.69 to 3.20)
    2.15 (1.43 to 3.22)
    1.62 (1.16 to 2.25)
    1.69 (1.22 to 2.33)
        Ps14-specific IgG antibody GMC
    0.72 (0.36 to 1.44)
    1.07 (0.71 to 1.62)
    0.60 (0.41 to 0.86)
    4.67 (2.61 to 8.37)
    3.72 (2.6 to 5.33)
    3.35 (2.36 to 4.74)
    3.85 (2.13 to 6.95)
    3.28 (2.28 to 4.74)
    2.75 (1.96 to 3.87)
        Ps18C-specific IgG antibody GMC
    1.68 (0.94 to 3.00)
    1.10 (0.74 to 1.64)
    0.79 (0.58 to 1.08)
    3.76 (2.40 to 5.90)
    4.78 (3.32 to 6.88)
    6.50 (4.83 to 8.73)
    3.19 (2.01 to 5.04)
    3.70 (2.59 to 5.28)
    4.42 (3.28 to 5.95)
        Ps19A-specific IgG antibody GMC
    3.27 (2.19 to 4.89)
    1.98 (1.39 to 2.82)
    1.44 (1.10 to 1.89)
    5.74 (3.89 to 8.47)
    5.60 (3.90 to 8.04)
    6.03 (4.54 to 8.02)
    4.29 (2.77 to 6.63)
    4.44 (3.10 to 6.35)
    4.27 (3.24 to 5.63)
        Ps19F-specific IgG antibody GMC
    2.01 (1.23 to 3.27)
    1.65 (1.18 to 2.30)
    0.87 (0.67 to 1.12)
    3.72 (2.45 to 5.65)
    3.61 (2.59 to 5.02)
    3.28 (2.49 to 4.33)
    2.93 (1.85 to 4.64)
    2.82 (2.02 to 3.95)
    2.27 (1.71 to 3.02)
        Ps23F-specific IgG antibody GMC
    1.46 (0.86 to 2.50)
    0.67 (0.43 to 1.04)
    0.34 (0.24 to 0.49)
    6.80 (4.24 to 10.89)
    2.82 (1.74 to 4.56)
    1.89 (1.34 to 2.65)
    5.25 (3.19 to 8.66)
    2.40 (1.52 to 3.77)
    1.41 (1.01 to 1.96)
    No statistical analyses for this end point

    Secondary: CRM197-specific serum antibody titers before, at 7 days, at 1 month, and at 6 months post pneumococcal vaccination.

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    End point title
    		 CRM197-specific serum antibody titers before, at 7 days, at 1 month, and at 6 months post pneumococcal vaccination.
    End point description
    CRM197-specific serum antibody titers before, at 7 days, at 1 month, and at 6 months post pneumococcal vaccination.
    End point type
    Secondary
    End point timeframe
    Period 1
    End point values
    		 PCV-13 serology - Pre PCV-13 timepoint - 25-49 y/o PCV-13 serology - Pre PCV-13 timepoint - 50-64 y/o PCV-13 serology - Pre PCV-13 timepoint - 65+ y/o PCV-13 serology - 7-days post PCV-13 timepoint - 25-49 y/o PCV-13 serology - 7-days post PCV-13 timepoint - 50-64 y/o PCV-13 serology - 7-days post PCV-13 timepoint - 65+ y/o PCV-13 serology - 28-days post PCV-13 timepoint - 25-49 y/o PCV-13 serology - 28-days post PCV-13 timepoint - 50-64 y/o PCV-13 serology - 28-days post PCV-13 timepoint - 65+ y/o PCV-13 serology - 6-months post PCV-13 timepoint - 25-49 y/o PCV-13 serology - 6-months post PCV-13 timepoint - 50-64 y/o PCV-13 serology - 6-months post PCV-13 timepoint - 65+ y/o
    Number of subjects analysed
    51
    84
    139 [1]
    45
    78
    134
    51
    83 [2]
    140
    45
    78
    134
    Units: titre
    geometric mean (confidence interval 95%)
        CRM197-specific IgG antibody titer
    0.25 (0.20 to 0.32)
    0.26 (0.22 to 0.32)
    0.17 (0.14 to 0.21)
    0.96 (0.65 to 1.44)
    0.79 (0.59 to 1.07)
    0.44 (0.34 to 0.56)
    2.10 (1.41 to 3.13)
    1.54 (1.15 to 2.07)
    1.10 (0.82 to 1.48)
    0.87 (0.57 to 1.32)
    0.86 (0.66 to 1.12)
    0.53 (0.40 to 0.69)
    Notes
    [1] - 1 excluded: missing measurement
    [2] - 1 excluded: missing measurement
    No statistical analyses for this end point

    Secondary: Influenza-specific T-cells measured by Enzyme-Linked Immunosorbent Spot (ELISPOT) in peripheral blood mononuclear cells (PBMCs) of pre- and post-vaccination samples.

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    End point title
    		 Influenza-specific T-cells measured by Enzyme-Linked Immunosorbent Spot (ELISPOT) in peripheral blood mononuclear cells (PBMCs) of pre- and post-vaccination samples.
    End point description
    Influenza-specific T-cells measured by Enzyme-Linked Immunosorbent Spot (ELISPOT) in peripheral blood mononuclear cells (PBMCs) of pre- and post-vaccination samples. Full analysis will be published, manuscript in preparation.
    End point type
    Secondary
    End point timeframe
    Period 1
    End point values
    		 QIV ELISpot - Pre QIV timepoint - 25-49y QIV ELISpot - Pre QIV timepoint - 50-64y QIV ELISpot - Pre QIV timepoint - 65+ QIV ELISpot - 7-days post QIV timepoint - 25-49y QIV ELISpot - 7-days post QIV timepoint - 50-64y QIV ELISpot - 7-days post QIV timepoint - 65+ QIV ELISpot - 28-days post QIV timepoint - 25-49y QIV ELISpot - 28-days post QIV timepoint - 50-64y QIV ELISpot - 28-days post QIV timepoint - 65+ QIV ELISpot - 6-months post QIV timepoint - 25-49y QIV ELISpot - 6-months post QIV timepoint - 50-64y QIV ELISpot - 6-months post QIV timepoint - 65+
    Number of subjects analysed
    46
    68
    115
    43
    50
    111
    43
    48
    107
    42
    67
    111
    Units: countable unit(s)
    median (confidence interval 95%)
        Influenza A H1N1-specific counts
    24.00 (11.83 to 29.00)
    14.33 (12.33 to 18.42)
    7.00 (4.33 to 11.5)
    29.00 (22.5 to 42.33)
    24.00 (21.5 to 27.83)
    18.33 (11.67 to 24.33)
    25.00 (22.33 to 29)
    18.92 (15.25 to 23.83)
    14.00 (11.33 to 22)
    18.25 (14.08 to 27.25)
    18.00 (13.67 to 23)
    14.33 (10 to 21.33)
        Influenza A H3N2-specific counts
    5.67 (3 to 8.67)
    4.58 (2.33 to 6.50)
    2.00 (0.83 to 3.17)
    12.67 (8 to 20.33)
    14.5 (12.25 to 19.67)
    8.33 (4 to 11.83)
    11.67 (7.33 to 14.67)
    9.83 (7 to 12.5)
    6.50 (3.83 to 10.5)
    5.50 (4.08 to 9.75)
    7.83 (4 to 11)
    7.67 (5.33 to 11.33)
        Influenza B Victoria-specific counts
    28.83 (21 to 42.33)
    21.67 (14.33 to 23.08)
    12.33 (8 to 17.33)
    31.33 (25.33 to 44.33)
    35.17 (28.92 to 43.67)
    25.00 (16 to 30)
    25.50 (20 to 33.67)
    22.67 (14.33 to 30.5)
    20.00 (14.33 to 23.67)
    28.75 (21.83 to 35.42)
    29.00 (16.5 to 36.33)
    18.67 (14.67 to 26.5)
        Influenza B Yamagata-specific counts
    25.83 (19.08 to 39)
    22.17 (15.33 to 27.17)
    15.67 (7.5 to 23)
    34.00 (30.67 to 60)
    37.83 (32.67 to 43)
    29.33 (23 to 36)
    33.00 (24 to 40.67)
    23.33 (19 to 32.33)
    19.50 (15 to 30.33)
    34.83 (25.5 to 40.42)
    27.00 (20.67 to 39)
    20.67 (18.67 to 28.67)
    No statistical analyses for this end point

    Secondary: CRM197-specific T-cells measured by Enzyme-Linked Immunosorbent Spot (ELISPOT) in peripheral blood mononuclear cells (PBMCs) of pre- and post-vaccination samples.

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    End point title
    		 CRM197-specific T-cells measured by Enzyme-Linked Immunosorbent Spot (ELISPOT) in peripheral blood mononuclear cells (PBMCs) of pre- and post-vaccination samples.
    End point description
    CRM197-specific T-cells measured by Enzyme-Linked Immunosorbent Spot (ELISPOT) in peripheral blood mononuclear cells (PBMCs) of pre- and post-vaccination samples. Full analysis will be published, manuscript in preparation.
    End point type
    Secondary
    End point timeframe
    Period 1
    End point values
    		 PCV-13 ELISpot - Pre PCV-13 timepoint - 25-49y PCV-13 ELISpot - Pre PCV-13 timepoint - 50-64y PCV-13 ELISpot - Pre PCV-13 timepoint - 65+ PCV-13 ELISpot - 7-days post PCV-13 timepoint - 25-49y PCV-13 ELISpot - 7-days post PCV-13 timepoint - 50-64y PCV-13 ELISpot - 7-days post PCV-13 timepoint - 65+ PCV-13 ELISpot - 28-days post PCV-13 timepoint - 25-49y PCV-13 ELISpot - 28-days post PCV-13 timepoint - 50-64y PCV-13 ELISpot - 28-days post PCV-13 timepoint - 65+ PCV-13 ELISpot - 6-months post PCV-13 timepoint - 25-49y PCV-13 ELISpot - 6-months post PCV-13 timepoint - 50-64y PCV-13 ELISpot - 6-months post PCV-13 timepoint - 65+
    Number of subjects analysed
    41
    67
    123
    29
    62
    101
    33
    65
    104
    39
    68
    123
    Units: countable unit(s)
    median (confidence interval 95%)
        CRM197-specific counts
    0 (0 to 0)
    0.33 (0 to 0.67)
    0 (0 to 0)
    15.33 (4 to 32)
    9.58 (4.83 to 17.75)
    4.67 (2.33 to 14.67)
    4.67 (2 to 9)
    1 (0.33 to 2.67)
    1 (0.67 to 2.67)
    1.67 (1 to 2.33)
    2.5 (1.42 to 3)
    1 (0.5 to 1.67)
    No statistical analyses for this end point

    Secondary: A deficit accumulation index will be calculated for each subject and the subjects will be ranked based on this index.

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    End point title
    		 A deficit accumulation index will be calculated for each subject and the subjects will be ranked based on this index.
    End point description
    A deficit accumulation index will be calculated for each subject and the subjects will be ranked based on this index. Further details on composition of deficit score and statistics can be found in Van Sleen et al., Immunity & Ageing 2023, https://doi.org/10.1186/s12979-023-00391-3
    End point type
    Secondary
    End point timeframe
    Period 1
    End point values
    		 25-49 years of age, QIV + PCV13 50-64 years of age, QIV + PCV13 65+ years of age, QIV + PCV13
    Number of subjects analysed
    60 [3]
    96 [4]
    163 [5]
    Units: score
    arithmetic mean (confidence interval 95%)
        deficit score
    0.08 (0.06 to 0.09)
    0.11 (0.10 to 0.13)
    0.19 (0.18 to 0.21)
    Notes
    [3] - 2 excluded: missing data
    [4] - 2 excluded: missing data
    [5] - 3 excluded: missing data
    No statistical analyses for this end point

    Secondary: Absolute numbers of immune cell types, a.o. lymphocytes, granulocytes and monocytes, measured in whole blood by Trucount.

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    End point title
    		 Absolute numbers of immune cell types, a.o. lymphocytes, granulocytes and monocytes, measured in whole blood by Trucount.
    End point description
    Absolute numbers of a selection of immune cell subtypes as measured by Trucount. Full analysis and additional subsets are published in Cevirgel et al., Aging Cell 2022, https://doi.org/10.1111/acel.13703
    End point type
    Secondary
    End point timeframe
    Period 1
    End point values
    		 25-49 years of age, QIV + PCV13 50-64 years of age, QIV + PCV13 65+ years of age, QIV + PCV13
    Number of subjects analysed
    60 [6]
    89 [7]
    154 [8]
    Units: absolute numbers
    median (confidence interval 95%)
        absolute numbers of CD19+ subset
    178.48 (161.64 to 199.96)
    161.63 (146.84 to 191.42)
    137.72 (130.53 to 147.49)
        absolute numbers of CD3+ subset
    1076.31 (1036.01 to 1170.49)
    1038.55 (967.27 to 1118.67)
    975.56 (929.79 to 1039.76)
        absolute numbers of CD4+ subset
    688.69 (647.7 to 717.88)
    668.87 (641.67 to 732.92)
    629.96 (597.55 to 671.93)
        absolute numbers of CD56+ subset
    9.34 (8.81 to 10.20)
    8.95 (7.85 to 9.7)
    8.32 (7.95 to 8.76)
        absolute numbers of CD8+ subset
    314.54 (281.36 to 335.37)
    259.71 (228.66 to 284.09)
    217.02 (196.67 to 229.89)
        absolute numbers of granulocytes
    2532.61 (2322.22 to 2841.13)
    2680.28 (2445.7 to 2825.42)
    2933.68 (2792.31 to 3046.82)
        absolute numbers of lymphocytes
    1469.19 (1410.08 to 1617.53)
    1435.74 (1374.82 to 1530.35)
    1427.90 (1316.12 to 1495.76)
        absolute numbers of monocytes+ subset
    308.19 (302.59 to 332.46)
    351.22 (324.83 to 377.09)
    409.10 (388.84 to 425.34)
    Notes
    [6] - 2 excluded: missing Trucount data
    [7] - 6 excluded: missing Trucount data 3 excluded: technical outliers
    [8] - 9 excluded: missing Trucount data 3 excluded: technical outliers
    No statistical analyses for this end point

    Secondary: Measurement of immune and inflammatory profiles in serum, and measurement of biomarkers in plasma.

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    End point title
    		 Measurement of immune and inflammatory profiles in serum, and measurement of biomarkers in plasma.
    End point description
    Measurement of immune and inflammatory profiles in serum, and measurement of biomarkers in plasma. Full analysis is published in Van Sleen et al., Immun Ageing 2023, https://doi.org/10.1186/s12979-023-00391-3
    End point type
    Secondary
    End point timeframe
    Period 1
    End point values
    		 25-49 years of age, QIV + PCV13 50-64 years of age, QIV + PCV13 65+ years of age, QIV + PCV13
    Number of subjects analysed
    60 [9]
    96 [10]
    158 [11]
    Units: concentrations
    geometric mean (confidence interval 95%)
        A1AT-Elastase_ng/mL
    50.61 (38.13 to 67.19)
    63.11 (50.35 to 79.10)
    54.53 (49.37 to 60.22)
        Angiopoeietin-2_pg/mL
    1827.09 (1620.22 to 2060.36)
    1947.27 (1801.56 to 2104.77)
    2396.65 (2235.37 to 2569.58)
        C5a_ng/mL
    19.87 (17.96 to 21.99)
    20.80 (18.96 to 22.82)
    22.07 (20.39 to 23.87)
        Calprotectin_ng/mL
    1504.28 (1231.36 to 1837.7)
    1674.46 (1473.87 to 1902.35)
    1631.19 (1493.54 to 1781.51)
        CathepsinG_ng/mL
    6.17 (5.56 to 6.85)
    6.27 (5.74 to 6.84)
    6.37 (5.85 to 6.93)
        CCL2_pg/mL
    341.97 (318.13 to 367.6)
    409.57 (386.89 to 433.57)
    432.40 (406.87 to 459.53)
        CRP_ng/mL
    0.74 (0.54 to 1.01)
    1.02 (0.81 to 1.27)
    1.54 (1.30 to 1.83)
        CXCL10_pg/mL
    19.17 (17.44 to 21.08)
    23.01 (21.02 to 25.2)
    29.12 (27.43 to 30.93)
        Elastase_ng/mL
    183.88 (159.23 to 212.33)
    217.24 (191.55 to 246.36)
    265.01 (238.59 to 294.37)
        GM-CSF_pg/mL
    0.18 (0.16 to 0.20)
    0.15 (0.12 to 0.19)
    0.15 (0.12 to 0.18)
        iFABP2_pg/mL
    927.92 (807.15 to 1066.77)
    1145.60 (1054.05 to 1245.09)
    1289.26 (1189.78 to 1397.06)
        IFNa_pg/mL
    0.01 (0 to 0.01)
    0.01 (0.01 to 0.01)
    0.01 (0.01 to 0.01)
        IFNy_pg/mL
    0.03 (0.03 to 0.04)
    0.04 (0.03 to 0.05)
    0.05 (0.05 to 0.06)
        IL-10_pg/mL
    0.56 (0.49 to 0.64)
    0.66 (0.58 to 0.74)
    0.56 (0.47 to 0.67)
        IL-1b_pg/mL
    0.02 (0.01 to 0.03)
    0.03 (0.02 to 0.04)
    0.01 (0.01 to 0.02)
        IL-1RA_pg/mL
    738.04 (661.56 to 823.36)
    805.89 (749.49 to 866.54)
    990.09 (931.54 to 1052.31)
        IL-6_g/mL
    0.39 (0.32 to 0.49)
    0.83 (0.69 to 1)
    1.16 (1.02 to 1.32)
        IL8_pg/mL
    17.49 (14.35 to 21.33)
    25.75 (22.13 to 29.96)
    25.26 (22.99 to 27.76)
        Neopterin_nmol/L
    5.87 (5.22 to 6.60)
    7.58 (6.94 to 8.27)
    9.87 (9.13 to 10.68)
        PR3_ng/mL
    30.42 (26.04 to 35.53)
    30.54 (26.69 to 34.94)
    43.15 (38.14 to 48.82)
        PTX3_pg/mL
    5197.44 (4557.69 to 5926.99)
    4853.04 (4271.71 to 5513.48)
    5576.36 (5172.39 to 6011.88)
        SAA_ng/mL
    0.05 (0.03 to 0.09)
    0.06 (0.04 to 0.09)
    0.16 (0.12 to 0.22)
        sCD14_ng/mL
    1331.4 (1268.34 to 1397.59)
    1385.62 (1324.78 to 1449.26)
    1525.07 (1460.53 to 1592.47)
        sCD163_pg/mL
    567.43 (504.95 to 637.64)
    749.76 (675.78 to 831.84)
    859.67 (791.9 to 933.24)
        sCD25_pg/mL
    467.07 (438.66 to 497.32)
    483.09 (454.08 to 513.96)
    603.96 (569.95 to 640.01)
        sGP130_ng/mL
    129.09 (122.44 to 136.12)
    138.47 (133.41 to 143.73)
    143.88 (140.19 to 147.67)
        sIL-6R_ng/mL
    43.42 (41.49 to 45.44)
    46.39 (44.52 to 48.33)
    47.77 (46.48 to 49.1)
        TNFa_pg/mL
    2.09 (1.92 to 2.28)
    2.50 (2.26 to 2.76)
    2.22 (2.10 to 2.34)
        YKL-40_ng/mL
    24.32 (21.93 to 26.97)
    31.42 (28.14 to 35.07)
    61.51 (55.44 to 68.24)
        bl.ALAT_U/L
    16.02 (14.08 to 18.23)
    15.05 (14 to 16.19)
    13.68 (12.92 to 14.49)
        bl.Albumine_g/L
    48.37 (47.72 to 49.02)
    47.57 (47.07 to 48.08)
    43.1 (42.68 to 43.52)
        bl.ASAT_U/L
    23.8 (22.09 to 25.64)
    25.25 (24.18 to 26.36)
    24.67 (23.66 to 25.72)
        bl.Creatinin_umol/L
    73.88 (71.13 to 76.73)
    76.75 (73.77 to 79.86)
    79.55 (76.92 to 82.26)
        bl.HDL.Chol_mmol/L
    1.52 (1.44 to 1.60)
    1.55 (1.48 to 1.64)
    1.42 (1.36 to 1.48)
        bl.LDL.Chol_mmol/L
    3.02 (2.85 to 3.21)
    3.19 (2.96 to 3.43)
    2.69 (2.54 to 2.84)
        bl.Triglyceride_mmol/L
    1.25 (1.1 to 1.41)
    1.46 (1.35 to 1.59)
    1.49 (1.40 to 1.59)
        bl.Ureum_mmol/L
    4.89 (4.55 to 5.25)
    5.82 (5.56 to 6.1)
    6.37 (6.11 to 6.65)
    Notes
    [9] - 2 excluded: missing multiple measurements
    [10] - 2 excluded: missing multiple measurements
    [11] - 8 excluded: missing multiple measurements
    No statistical analyses for this end point

    Secondary: Cell frequency, phenotype and functional capacity of SARS-CoV-2 specific immune cells measured by Fluorescence-Activated Cell Sorting (FACS).

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    End point title
    		 Cell frequency, phenotype and functional capacity of SARS-CoV-2 specific immune cells measured by Fluorescence-Activated Cell Sorting (FACS).
    End point description
    Measurement of cell frequency, phenotype and functional capacity of SARS-CoV-2 specific immune cells by Fluorescence-Activated Cell Sorting (FACS), determined in a subset of participants in their 28-days post 2nd primary SARS-CoV-2 vaccination timepoint. Full analysis will be published, manuscript in preparation.
    End point type
    Secondary
    End point timeframe
    Period 2
    End point values
    		 FACS analysis - younger adults FACS analysis - older adults
    Number of subjects analysed
    15
    28
    Units: frequencies
    median (confidence interval 95%)
        % Spike-specific CD4+ T cells
    0.85 (0.58 to 1.48)
    0.58 (0.28 to 1.18)
        % CD69+CD134+ subset of CD4+ T cells
    0.63 (0.37 to 1.26)
    0.22 (0.10 to 0.32)
        % CD137+CD154+ subset of CD4+ T cells
    0.36 (0.23 to 0.56)
    0.175 (0.097 to 0.26)
        % cytokine+ producing subset of CD4+ T cells
    0.58 (0.36 to 0.75)
    0.225 (0.19 to 0.33)
        % IFNy+ producing subset of CD4+ T cells
    0.18 (0.13 to 0.24)
    0.081 (0.063 to 0.099)
        % TNFa+ producing subset of CD4+ T cells
    0.32 (0.18 to 0.47)
    0.13 (0.11 to 0.22)
        % IL-2+ producing subset of CD4+ T cells
    0.27 (0.17 to 0.34)
    0.11 (0.081 to 0.18)
    No statistical analyses for this end point

    Secondary: SARS-CoV-2 specific IgG GMC in serum at pre- and post- SARS-CoV-2 mRNA vaccination.

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    End point title
    		 SARS-CoV-2 specific IgG GMC in serum at pre- and post- SARS-CoV-2 mRNA vaccination.
    End point description
    SARS-CoV-2 specific IgG GMC in serum at pre- and post- SARS-CoV-2 (booster) vaccination. Full analysis on primary vaccination series is published in Van der Heiden et al., Nat Commun 2024, https://doi.org/10.1038/s41467-024-50760-9. Later timepoints will be included in future publications.
    End point type
    Secondary
    End point timeframe
    Period 2
    End point values
    		 Spikevax serology - Pre primary series - 25-49y Spikevax serology - 28-days post 1st primary vaccine - 25-49y Spikevax serology - 28-days post 2nd primary vaccine - 25-49y Spikevax serology - 6-months post primary series - 25-49y Spikevax serology - Pre primary series - 50-64y Spikevax serology - 28-days post 1st primary vaccine - 50-64y Spikevax serology - 28-days post 2nd primary vaccine - 50-64y Spikevax serology - 6-months post primary series - 50-64y Spikevax serology - Pre primary series - 65+ Spikevax serology - 28-days post 1st primary vaccine - 65+ Spikevax serology - 28-days post 2nd primary vaccine - 65+ Spikevax serology - 6-months post primary series - 65+ Comirnaty serology - Pre primary series - 65+ Comirnaty serology - 28-days post 1st primary vaccine - 65+ Comirnaty serology - 28-days post 2nd primary vaccine - 65+ Comirnaty serology - 6-months post primary series - 65+
    Number of subjects analysed
    43
    43
    43
    41
    75
    75
    75
    73
    84
    84
    84
    82
    42
    33
    41
    38
    Units: BAU/ml
    geometric mean (confidence interval 95%)
        S1-specific IgG antibody GMC
    0.7 (0.44 to 1.09)
    308.51 (178.13 to 534.31)
    2587.76 (2214.12 to 3024.46)
    2.85 (2.13 to 3.82)
    1.01 (0.71 to 1.44)
    245.06 (151.97 to 395.18)
    2217.94 (1879.65 to 2617.12)
    323.89 (264.83 to 396.12)
    0.92 (0.7 to 1.21)
    312.62 (241.82 to 404.15)
    1832.32 (1517.73 to 2212.13)
    257.59 (205.56 to 322.79)
    0.22 (0.16 to 0.3)
    105.98 (56.42 to 199.06)
    717.87 (483.92 to 1064.94)
    90.64 (53.87 to 152.5)
        N-specific IgG antibody GMC
    1.45 (1.04 to 2.01)
    2.41 (1.67 to 3.48)
    414.28 (338.75 to 506.66)
    1.88 (1.46 to 2.43)
    1.58 (1.21 to 2.06)
    1.81 (1.34 to 2.45)
    2.68 (2.14 to 3.35)
    2.02 (1.62 to 2.52)
    1.26 (1.03 to 1.54)
    3.13 (2.57 to 3.81)
    2.1 (1.77 to 2.49)
    1.77 (1.44 to 2.17)
    0.96 (0.69 to 1.35)
    2.69 (1.86 to 3.89)
    1.59 (1.1 to 2.29)
    1.57 (1.02 to 2.4)
    No statistical analyses for this end point

    Secondary: SARS-CoV-2 specific T-cells measured by Enzyme-Linked Immunosorbent Spot (ELISPOT) in peripheral blood mononuclear cells (PBMCs) pre- and post-vaccination.

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    End point title
    		 SARS-CoV-2 specific T-cells measured by Enzyme-Linked Immunosorbent Spot (ELISPOT) in peripheral blood mononuclear cells (PBMCs) pre- and post-vaccination.
    End point description
    SARS-CoV-2 specific T-cells measured by Enzyme-Linked Immunosorbent Spot (ELISPOT) in peripheral blood mononuclear cells (PBMCs) of pre- and post-vaccination samples. Analysis is included in Brummelman et al., Front. Immunol. 2024, https://doi.org/10.1186/s12979-023-00391-3
    End point type
    Secondary
    End point timeframe
    Period 2
    End point values
    		 SARS-CoV-2 T-cell ELISpot - Pre vaccination timepoint - 25-49y SARS-CoV-2 T-cell ELISpot - Pre vaccination timepoint - 50-64y SARS-CoV-2 T-cell ELISpot - Pre vaccination timepoint - 65+ SARS-CoV-2 T-cell ELISpot - 28-days post vaccination - 25-49y SARS-CoV-2 T-cell ELISpot - 28-days post vaccination - 50-64y SARS-CoV-2 T-cell ELISpot - 28-days post vaccination - 65+
    Number of subjects analysed
    10
    18
    28
    16
    25
    34
    Units: countable unit(s)
    median (confidence interval 95%)
        NCAP-specific counts
    0.33 (0 to 0.83)
    0 (0 to 0.17)
    0 (0 to 0.17)
    0.17 (0 to 0.5)
    0 (0 to 0.17)
    0 (0 to 0)
        S1+S2-specific counts
    0.83 (0.33 to 2.58)
    0 (0 to 0.5)
    0 (0 to 0.5)
    22.67 (15.83 to 46)
    24.67 (16.92 to 35.33)
    6.17 (4 to 9.17)
    No statistical analyses for this end point

    Secondary: SARS-CoV-2 specific B-cells measured by Enzyme-Linked Immunosorbent Spot (ELISPOT) in peripheral blood mononuclear cells (PBMCs) pre- and post-vaccination.

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    End point title
    		 SARS-CoV-2 specific B-cells measured by Enzyme-Linked Immunosorbent Spot (ELISPOT) in peripheral blood mononuclear cells (PBMCs) pre- and post-vaccination.
    End point description
    SARS-CoV-2 specific B-cells measured by Enzyme-Linked Immunosorbent Spot (ELISPOT) in peripheral blood mononuclear cells (PBMCs) of pre- and post-vaccination samples. Analysis is included in Verheul et al., Vaccines 2023, https://doi.org/10.3390/vaccines11071196
    End point type
    Secondary
    End point timeframe
    Period 2 - Period 3
    End point values
    		 SARS-CoV-2 B-cell ELISpot - 28-days post vaccination - 25-49y SARS-CoV-2 B-cell ELISpot - 28-days post vaccination - 50-64y SARS-CoV-2 B-cell ELISpot - 28-days post vaccination - 65+ SARS-CoV-2 B-cell ELISpot - Pre booster - 25-49y SARS-CoV-2 B-cell ELISpot - Pre booster - 50-64y SARS-CoV-2 B-cell ELISpot - Pre booster - 65+ SARS-CoV-2 B-cell ELISpot - 28-days post booster - 25-49y SARS-CoV-2 B-cell ELISpot - 28-days post booster - 50-64y SARS-CoV-2 B-cell ELISpot - 28-days post booster - 65+
    Number of subjects analysed
    10
    11
    13
    3
    7
    13
    3
    7
    10
    Units: countable unit(s)
    median (confidence interval 95%)
        NCAP-specific counts
    0 (0 to 0.25)
    0 (0 to 0.5)
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
        S1-specific counts
    10 (7.25 to 12)
    7 (1.3 to 14.3)
    4.3 (1.8 to 9)
    1.8 (1.8 to 7.8)
    12 (8 to 27)
    8 (2.8 to 13.8)
    3.8 (2.3 to 107.6)
    23.8 (23 to 42)
    69.4 (25.05 to 100.75)
    No statistical analyses for this end point

    Secondary: SARS-CoV-2 specific antibody concentrations (GMCs) in nasal lining fluid of pre- and post-vaccination samples.

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    End point title
    		 SARS-CoV-2 specific antibody concentrations (GMCs) in nasal lining fluid of pre- and post-vaccination samples.
    End point description
    SARS-CoV-2 specific antibody concentrations (GMCs) in nasal lining fluid of pre- and post-vaccination samples measured by bead-based multiplex immune assay. Full analysis will be publised, manuscript in preparation.
    End point type
    Secondary
    End point timeframe
    Period 2 - Period 3
    End point values
    		 mucosal antibody analysis - Pre 1st booster - 25-49y mucosal antibody analysis - Pre 1st booster - 50-64y mucosal antibody analysis - Pre 1st booster -65+ mucosal antibody analysis - 28-days post 1st booster - 25-49y mucosal antibody analysis - 28-days post 1st booster -50-64y mucosal antibody analysis - 28-days post 1st booster - 65+
    Number of subjects analysed
    9
    31
    40
    9
    31
    40
    Units: BAU/mL
    geometric mean (confidence interval 95%)
        S1-specific IgG antibody GMC
    1.38 (0.69 to 2.73)
    0.85 (0.42 to 1.72)
    0.28 (0.15 to 0.53)
    19.03 (9.42 to 38.45)
    35.21 (25.65 to 48.32)
    19.75 (12.92 to 30.2)
        N-specific IgG antibody GMC
    0.03 (0.01 to 0.06)
    0.03 (0.02 to 0.06)
    0.03 (0.02 to 0.04)
    0.04 (0.02 to 0.12)
    0.09 (0.05 to 0.17)
    0.06 (0.03 to 0.09)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Any adverse event spontaneously reported by the subject occurring within 28 days after vaccination, or within one week after swab collection or blood sampling.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.1
    Reporting groups
    Reporting group title
    QIV, PCV-13 and SARS-CoV-2 immunization
    Reporting group description
    		 -

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: It is correct that no non-serious adverse events are recorded. As described in the protocol, only adverse events that were reported spontaneously by the subject or observed by the investigator or study staff were recorded. Adverse events were not actively recorded or requested. As a result, no adverse event occurred in more than 5% of participants. Therefore, reporting these data would not provide an accurate or representative overview of the adverse events in this study.
    Serious adverse events
    		 QIV, PCV-13 and SARS-CoV-2 immunization
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 326 (2.76%)
         number of deaths (all causes)
    10
         number of deaths resulting from adverse events
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lymphoma
         subjects affected / exposed
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Periprothetic fracture
         subjects affected / exposed
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Nervous system disorders
    Balance disorder
         subjects affected / exposed
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Miscarriage
         subjects affected / exposed
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 326 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 QIV, PCV-13 and SARS-CoV-2 immunization
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 326 (0.00%)

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Jun 2020
    This amendment concerns: a) Additional small blood sample collection by finger stick for all participants to asses Influenza- specific antibodies. Due to the COVID-19 pandemic, the T5 visits were postponed. Because it was unclear if the T5 visits could be resumed within the 5-8 month follow-up window, it was proposed to collect a small additional blood sample by self-sampling. Hereby, long term follow-up evaluation of influenza specific antibodies 5-9 months after influenza vaccination was still allowed. b) Determine the impact of potential COVID-19 infections on baseline and vaccine induced immune responses in the participants: All participants in the study have been asked to report any influenza like illness symptoms during the influenza season, they will be asked to continue reporting these symptoms during the whole study period to also record COVID related symptoms. In addition, SARS-CoV-2 serology will be included in the analyses. c) Extend the period of Influenza Like Infection (ILI) monitoring due to the COVID-19 pandemic. d) Changes in ILI monitoring form. With the adaptations also COVID-19 specific symptoms were monitored. e) Additional questionnaire “Zorgnetwerk en COVID-19”. This questionnaire will assess changes in healthcare networks due to the COVID19 pandemic and shed light on the impact of the pandemic on healthcare networks and the implications thereof for the participant f) Change in pneumococcal vaccination letter for elderly and their general practitioner. Because of the COVID19 pandemic the State Secretary of Health, Welfare and Sports decided to change the age groups eligible for PPV23 vaccination based on a recent report of the “gezondheidsraad”. g) QIV 2020-2021 vaccination at T8 visit
    14 Jan 2021
    The amendment concerns a change of no longer analyzing the long term effect of PCV13 vaccination on pneumococcal specific cellular immunity and carriage at 12 months post vaccination. Pneumococcal antibody responses will still be evaluated at 12 months post vaccination. This post vaccination analysis can be done in a small blood volume so the T10 (home) visit will be replaced by a fingerstick blood collection performed by the participants themselves. This also has the advantage that there will be one contact moment less between the study participants and members of the study teams in case of the COVID-19 pandemic.
    22 Feb 2021
    An addition of a evaluation of the immune response to COVID-19 vaccination. Humoral and cellular responses in older adults will be compared with the responses elicited in the other adult age groups. Moreover, the immune response to the COVID-19 vaccine will be compared to responses to influenza and pneumococcal vaccinations, that have been analyzed as part of the study protocol, within the different age groups. The COVID-19 vaccination schedule for the the vaccines used in this study, consists of two vaccine doses to be given with a 4 week interval. A total of 5 additional evaluation timepoints, four visits and one self sampling timepoints, will be added to the protocol. At visit Ta and Tb the COVID-19 vaccination will be given. For evaluation of the COVID-19 vaccine induced immune response samples will be collected at 1st and 2nd vaccination visit, during a visit 1 month later as well as 6 and 12 months post second COVID-19 vaccination. At timepoint 6 months after vaccination blood samples will be collected by fingerprick self sampling.
    03 Nov 2021
    Evaluate the immune response induced by a COVID-19 booster vaccination as a measurement for its effectiveness of the Dutch national vaccination program. Determine the SARS-CoV-2 booster vaccination induced humoral and cellular immune response and compare the responses between elderly and younger age groups of a well characterized cohort. This will result in extra timepoints; Pre booster (B0), at 28 days (-7/+14 days; B1), 6 months (+/- 4 weeks; B2) and 12 months (+/- 4 weeks; B3) post booster vaccination. Depending on the timing of the SARS-CoV-2 booster vaccination timepoints after the second vaccination can be skipped. A subgroup of participants will be asked to participate in the analysis of the cellular immune response.
    09 Mar 2022
    Determine the immune response induced by additional COVID-19 booster vaccinations as part of the evaluation of the effectiveness of the Dutch national COVID vaccination program, similar to the scheme as originally planned and compare the 3 month post 1st booster immune response between the different age groups of the Vital cohort. This booster vaccination is followed in persons above 70+ years of age. this will result in extra timepoints for blood sampling; pre booster, at 28 days (-7 till +14 days) post, 6 months (+/- 4 weeks) and 12 months (+/- 4 weeks) post booster vaccination.
    24 Aug 2023
    Determine the immune response induced by additional COVID-19 booster vaccination as part of the evaluation of the effectiveness of the Dutch national COVID vaccination program. Of the healthy population only persons of 60 years and older will be eligible for the autumn 2023 COVID-19 vaccination round. Therefore only participants from the Spaarne Hospital in this age group will be invited for participation in the autumn 2023 COVID-19 vaccine immune response follow-up extension of the study. This will result in extra timepoints; Pre booster (E0), at 28 days (-7/+14 days; E1) and 12 months (+/- 4 weeks; E3) post booster vaccination. The study for the middle-aged and adult subjects will be ended. These groups will not be followed after a booster SARS-CoV-2 vaccination obtained in autumn 2023. To complete the protocol, information about the booster in autumn 2022 was included. The follow up of this booster was covered by amendment 4 and notification from November 2022
    06 Oct 2023
    Correct the age of participants who were eligible for follow-up after the second booster in February 2022, mentioned in amendment 5. Originally individuals of 70 years and older were eligible for the additional booster dose to be given in the spring of 2022. Based on this information protocol amendment 5 added follow-up of the additional booster dose in Vital-corona participants of 70 years and older to the study. However, after submission of amendment 5, the minister decided that persons -70 years of age were also eligible for a second booster dose. Therefore these participants older than 60 years of age were invited for participation in the additional follow-up of this study after the second booster vaccination.
    21 Aug 2024
    Including the collection of nasal lining fluid at timepoint 12 months after booster 2023. Adding the collection of an MLF sample at 12 months post 2023 booster vaccination will give an indication of the duration of the mucosal antibody response.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    12 Mar 2020
    Due to the COVID-19 pandemic the visits were temporarily stopped. The most important reason was the fragility of the participants 70 years and older. Furthermore, the participants who where working at the UMCU/RIVM and who had visits planned at the locations, were asked to work from home. That's why these visits also couldn't continue. Another reason was, the tasks planned at the visits couldn't be executed at 1.5m distance, which was the regulation at that time.
    13 Jul 2020

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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