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    Clinical Trial Results:
    Vaccination of older persons against Sars-Cov-2 and cellular immunogenicity for long term protection (participating in the Doetinchem Cohort Study)

    Summary
    EudraCT number
    		 2021-002363-22
    Trial protocol
    		 NL  
    Global end of trial date
    05 Dec 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Dec 2025
    First version publication date
    18 Dec 2025
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    IIV-482
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 ABR number: NL76719.041.21
    Sponsors
    Sponsor organisation name
    RIVM
    Sponsor organisation address
    Antonie van Leeuwenhoeklaan 9, Bilthoven, Netherlands, 3721 MA
    Public contact
    Clinical expertise centre, National Institute for Public Health and the Environment, mensgebonden-onderzoek@rivm.nl
    Scientific contact
    Clinical expertise centre, National Institute for Public Health and the Environment, mensgebonden-onderzoek@rivm.nl
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    05 Dec 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Dec 2024
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Dec 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The overall aim is to monitor and evaluate the magnitude, quality and persistence of immune responses induced by SARS-CoV-2 vaccination in the general older Dutch population 64-90 years of age. Furthermore, in older individuals inter-individual differences in the presence of frailty will be related to vaccine responsiveness. • Assess the magnitude of systemic antibody responses to the SARS-CoV-2 vaccine in 64-90 years old male and female persons at a month after completion of SARS-CoV-2 vaccination. • To address the magnitude and quality of T-cell and B-cell immune responses induced by the current new SARS-CoV-2 vaccines at a month after completion of SARS-CoV-2 vaccination in older male and female persons (64-90 years of age).
    Protection of trial subjects
    SARS-COV-2 vaccines have been granted a conditional marketing authorization. The products are routinely used in several countries in the same age groups and considered safe. It is therefore unlikely that serious side effects will occur that can lead to premature termination of the study. These vaccines are given by the participants’ own GP or the GGD as part of the routine immunization program for this age group, not as part of this study. Furthermore, the burden and risk of blood sampling is considered low. Collection of finger prick blood is regarded an adequate and safe alternative for full venousblood puncture. The applied lancet is easy to use, sterile and with a pricking needle which is designed to prevent exposure and re-use. Risk of infecting someone via the lancet is therefore very unlikely
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 Mar 2021
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 101
    Worldwide total number of subjects
    101
    EEA total number of subjects
    101
    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)
    0
    From 65 to 84 years
    96
    85 years and over
    5

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 All persons still participating in the DCS who have participated in the ISA substudy of the DCS (n=270) will be invited for participation in the current study. Recruitment was done by a personal letter inviting the subjects to participate. First inclusion: 27-03-2021, Last inclusion: 30-07-2021

    Pre-assignment
    Screening details
    		 Inclusion: - participated in ISA study - receive SARS-CoV-2 vaccine - Sign informed consent Exclusion: - Received 2nd SARS-CoV-2 vaccine dose more than 1 months before signing ICF

    Period 1
    Period 1 title
    SARS-CoV-2 primary immunization
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    No blinding

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 SARS-CoV-2 primary immunization comirnaty
    Arm description
    		 Participants that received their SARS-CoV-2 primary immunization with comirnaty, and participants that only received a single dose comirnaty as SARS-CoV-2 primary immunization.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Comirnaty
    Investigational medicinal product code
    EU/1/20/1528 - J07BN01 - Covid-19, RNA-based vacci
    Other name
    Pharmaceutical forms
    Concentrate for dispersion for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Comirnaty is administered intramuscularly after dilution as a single dose of 0.3 mL for individuals 12 years of age and older regardless of prior COVID-19 vaccination status. For individuals who have previously been vaccinated with a COVID-19 vaccine, Comirnaty should be administered at least 3 months after the most recent dose of a COVID-19 vaccine. Comirnaty 30 micrograms/dose concentrate for dispersion for injection should be administered intramuscularly after dilution. The preferred site is the deltoid muscle of the upper arm.

    Arm title
    		 SARS-CoV-2 primary immunization spikevax
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Spikevax
    Investigational medicinal product code
     EU/1/20/1507 - J07BN01 - Covid-19, RNA-based vacc
    Other name
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    The primary series consists of 2 doses (0.5 ml each, containing 100 mincrograms mRNA). It is recommended to administer the seconde dose 28 days after the first dose. Spikevax may be used to boost individuals 12 years of age and older who have received a primary series with Spikevax or a primary series comprised of another mRNA vaccine or adenoviral vector vaccine at least 3 months after completion of the primary series. The booster dose consists of 1 dose of 0.25 ml, containing 50 micrograms mRNA. The vaccine should be administered intramuscularly. The preferred site is the deltoid muscle of the upper arm or in infants and young children, the anterolateral aspect of the thigh.

    Arm title
    		 SARS-CoV-2 primary immunization Vaxzevria
    Arm description
    		 Participants that received their SARS-CoV-2 primary immunization with Vaxzevria, and participants that received a single dose of Vaxzevria and a single dose of comirnaty as SARS-CoV-2 primary immunization.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vaxzevria
    Investigational medicinal product code
    EU/1/21/1529 - J07BN02, viral vector, non-replicat
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    The Vaxzevria primary vaccination course consists of two separate doses of 0.5 ml each. The second dose should be administered between 4 and 12 weeks (28 to 84 days) after the first dose. Vaxzevria is for intramuscular injection only, preferably in the deltoid muscle of the upper arm.

    Number of subjects in period 1
    		SARS-CoV-2 primary immunization comirnaty SARS-CoV-2 primary immunization spikevax SARS-CoV-2 primary immunization Vaxzevria
    Started
    95
    1
    5
    Pre 1st primary SARS-CoV-2 immunization
    95
    1
    5
    1 month post 1st primary SARS-CoV-2 immu
    94
    1
    5
    1 month post 2nd primary SARS-CoV-2 immu
    94
    1
    5
    6 months post 2nd primary SARS-CoV-2 imm
    90
    1
    4
    1 year post 2nd primary SARS-CoV-2 immun
    87
    1
    4
    Completed
    87
    1
    4
    Not completed
    8
    0
    1
         Participant decided to end participation
    8
    -
    1
    Period 2
    Period 2 title
    SARS-CoV-2 1st booster immunization
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    No blinding

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 SARS-CoV-2 1st booster immunization comirnaty
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Comirnaty
    Investigational medicinal product code
    EU/1/20/1528 - J07BN01 - Covid-19, RNA-based vacci
    Other name
    Pharmaceutical forms
    Concentrate for dispersion for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Comirnaty is administered intramuscularly after dilution as a single dose of 0.3 mL for individuals 12 years of age and older regardless of prior COVID-19 vaccination status. For individuals who have previously been vaccinated with a COVID-19 vaccine, Comirnaty should be administered at least 3 months after the most recent dose of a COVID-19 vaccine. Comirnaty 30 micrograms/dose concentrate for dispersion for injection should be administered intramuscularly after dilution. The preferred site is the deltoid muscle of the upper arm.

    Arm title
    		 SARS-CoV-2 1st booster immunization spikevax
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Spikevax
    Investigational medicinal product code
     EU/1/20/1507 - J07BN01 - Covid-19, RNA-based vacc
    Other name
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    The primary series consists of 2 doses (0.5 ml each, containing 100 mincrograms mRNA). It is recommended to administer the seconde dose 28 days after the first dose. Spikevax may be used to boost individuals 12 years of age and older who have received a primary series with Spikevax or a primary series comprised of another mRNA vaccine or adenoviral vector vaccine at least 3 months after completion of the primary series. The booster dose consists of 1 dose of 0.25 ml, containing 50 micrograms mRNA. The vaccine should be administered intramuscularly. The preferred site is the deltoid muscle of the upper arm or in infants and young children, the anterolateral aspect of the thigh.

    Number of subjects in period 2 [1]
    		SARS-CoV-2 1st booster immunization comirnaty SARS-CoV-2 1st booster immunization spikevax
    Started
    11
    78
    pre 1st SARS-CoV-2 booster immunization
    11
    78
    1 month post 1st SARS-CoV-2 booster immu
    11
    77
    6 months post 1st SARS-CoV-2 booster im
    11
    73
    1 year post 1st SARS-CoV-2 booster immun
    11
    73
    Completed
    11
    73
    Not completed
    0
    5
         Participant decided to end participation
    -
    5
    Notes
    [1] - 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: Several subjects completing the 1st period (primary immunization) did not receive a booster vaccination and therefore did not participate in the 2nd period (1st booster immunization)
    Period 3
    Period 3 title
    SARS-CoV-2 2nd booster immunization
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    No blinding

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 SARS-CoV-2 2nd booster immunization comirnaty
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Comirnaty
    Investigational medicinal product code
    EU/1/20/1528 - J07BN01 - Covid-19, RNA-based vacci
    Other name
    Pharmaceutical forms
    Concentrate for dispersion for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Comirnaty is administered intramuscularly after dilution as a single dose of 0.3 mL for individuals 12 years of age and older regardless of prior COVID-19 vaccination status. For individuals who have previously been vaccinated with a COVID-19 vaccine, Comirnaty should be administered at least 3 months after the most recent dose of a COVID-19 vaccine. Comirnaty 30 micrograms/dose concentrate for dispersion for injection should be administered intramuscularly after dilution. The preferred site is the deltoid muscle of the upper arm.

    Arm title
    		 SARS-CoV-2 2nd booster immunization spikevax
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Spikevax
    Investigational medicinal product code
     EU/1/20/1507 - J07BN01 - Covid-19, RNA-based vacc
    Other name
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    The primary series consists of 2 doses (0.5 ml each, containing 100 mincrograms mRNA). It is recommended to administer the seconde dose 28 days after the first dose. Spikevax may be used to boost individuals 12 years of age and older who have received a primary series with Spikevax or a primary series comprised of another mRNA vaccine or adenoviral vector vaccine at least 3 months after completion of the primary series. The booster dose consists of 1 dose of 0.25 ml, containing 50 micrograms mRNA. The vaccine should be administered intramuscularly. The preferred site is the deltoid muscle of the upper arm or in infants and young children, the anterolateral aspect of the thigh.

    Number of subjects in period 3 [2]
    		SARS-CoV-2 2nd booster immunization comirnaty SARS-CoV-2 2nd booster immunization spikevax
    Started
    24
    51
    1 month post 2nd SARS-CoV-2 booster immu
    24
    51
    6 months post 2nd SARS-CoV-2 booster imm
    23
    49
    1 year post 2nd SARS-CoV-2 booster immun
    21
    49
    Completed
    21
    49
    Not completed
    3
    2
         Participant decided to end participation
    3
    2
    Notes
    [2] - 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: Several subjects completing the 2nd period (1st booster immunization) did not receive a 2nd booster vaccination and therefore did not participate in the 3rd period (2nd booster immunization)
    Period 4
    Period 4 title
    SARS-CoV-2 3rd booster immunization
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    No blinding

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 SARS-CoV-2 3rd booster immunization comirnaty
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Comirnaty Original/Omicron BA.1
    Investigational medicinal product code
    EU/1/20/1528 - J07BN01 - Covid-19, RNA-based vacci
    Other name
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Comirnaty Original/Omicron BA.1 is administered intramuscularly as a single dose of 0.3 mL for individuals 12 years of age and older who have previously received at least a primary vaccination course against COVID-19. It should be administered at least 3 months after the most recent dose of a COVID-19 vaccine. Comirnaty Original/Omicron BA.1 (15/15 micrograms)/dose dispersion for injection should be administered intramuscularly.

    Arm title
    		 SARS-CoV-2 3rd booster immunization spikevax
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Spikevax bivalent origineel/omicron BA.1
    Investigational medicinal product code
     EU/1/20/1507 - J07BN01 - Covid-19, RNA-based vacc
    Other name
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    "The booster consists of 1 dose (0.5 ml, containing 125 micrograms of elasomeran and 25 micrograms of imelasomeran, a COVID-19 mRNA Vaccine (nucleoside modified) (embedded in lipid nanoparticles)). There should be an interval of at least 3 months between administration of Spikevax bivalent Original/Omicron BA.1 and the last prior dose of a COVID-19 vaccine. Spikevax bivalent Original/Omicron BA.1 is only indicated for individuals who have previously received at least a primary vaccination course against COVID-19. The vaccine should be administered intramuscularly. The preferred site is the deltoid muscle of the upper arm."

    Arm title
    		 SARS-CoV-2 3nd booster immunization unknown vaccine
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vaccine unknown
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Vaccine used is either Comirnaty Original/Omicron BA.1 or Spikevax bivalent origineel/omicron BA.1

    Number of subjects in period 4 [3]
    		SARS-CoV-2 3rd booster immunization comirnaty SARS-CoV-2 3rd booster immunization spikevax SARS-CoV-2 3nd booster immunization unknown vaccine
    Started
    1
    64
    1
    pre 3rd SARS-CoV-2 booster immunization
    1
    64
    1
    1 month post 3rd SARS-CoV-2 booster immu
    1
    64
    1
    6 months post 3rd SARS-CoV-2 booster imm
    1
    63
    0
    1 year post 3rd SARS-CoV-2 booster immun
    1
    62
    0
    Completed
    1
    62
    0
    Not completed
    0
    2
    1
         Participant decided to end participation
    -
    2
    1
    Notes
    [3] - 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: Several subjects completing the 3rd period (2nd booster immunization) did not receive a 3rd booster vaccination and therefore did not participate in the 4th period (3rd booster immunization)
    Period 5
    Period 5 title
    SARS-CoV-2 4th booster immunization
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    No blinding

    Arms
    Arm title
    		 SARS-CoV-2 4th booster immunization comirnaty
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Comirnaty JN.1
    Investigational medicinal product code
    EU/1/20/1528 - J07BN01 - Covid-19, RNA-based vacci
    Other name
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Comirnaty JN.1 is administered intramuscularly as a single dose of 0.3 mL for individuals 12 years of age and older independant of prior vaccination against COVID-19. It should be administered at least 3 months after the most recent dose of a COVID-19 vaccine. Comirnaty JN.1 (30 micrograms)/dose dispersion for injection should be administered intramuscularly.

    Number of subjects in period 5 [4]
    		SARS-CoV-2 4th booster immunization comirnaty
    Started
    53
    1 month post 4th SARS-CoV-2 booster immu
    53
    1 year post 4th SARS-CoV-2 booster immun
    53
    Completed
    53
    Notes
    [4] - 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: Several subjects completing the 4th period (3rd booster immunization) did not receive a 4th booster vaccination and therefore did not participate in the 5th period (4th booster immunization)

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    SARS-CoV-2 primary immunization
    Reporting group description
    		 -

    Reporting group values
    		 SARS-CoV-2 primary immunization Total
    Number of subjects
    		 101 101
    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)
    		 0 0
        From 65-84 years
    		 96 96
        85 years and over
    		 5 5
    Gender categorical
    Units: Subjects
        Female
    		 50 50
        Male
    		 51 51
    Subject analysis sets

    Subject analysis set title
    T0
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Pre 1st primary SARS-CoV-2 immunization

    Subject analysis set title
    T1
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    1 month post 1st primary SARS-CoV-2 immunization

    Subject analysis set title
    T2
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    1 month post 2nd primary SARS-CoV-2 immunization

    Subject analysis set title
    T3
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    6 months post 2nd primary SARS-CoV-2 immunization

    Subject analysis set title
    T4
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    1 year post 2nd primary SARS-CoV-2 immunization

    Subject analysis set title
    B0
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    pre 1st SARS-CoV-2 booster immunization

    Subject analysis set title
    B1
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    1 month post 1st SARS-CoV-2 booster immunization

    Subject analysis set title
    B2
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    6 months post 1st SARS-CoV-2 booster immunization

    Subject analysis set title
    B3
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    1 year post 1st SARS-CoV-2 booster immunization

    Subject analysis set title
    C1
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    1 month post 2nd SARS-CoV-2 booster immunization

    Subject analysis set title
    C2
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    6 months post 2nd SARS-CoV-2 booster immunization

    Subject analysis set title
    C3
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    1 year post 2nd SARS-CoV-2 booster immunization

    Subject analysis set title
    D0
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    pre 3rd SARS-CoV-2 booster immunization

    Subject analysis set title
    D1
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    1 month post 3rd SARS-CoV-2 booster immunization

    Subject analysis set title
    D2
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    6 months post 3rd SARS-CoV-2 booster immunization

    Subject analysis set title
    D3
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    1 year post 3rd SARS-CoV-2 booster immunization

    Subject analysis set title
    E1
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    1 month post 4th SARS-CoV-2 booster immunization

    Subject analysis set title
    E3
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    1 year post 4th SARS-CoV-2 booster immunization

    Subject analysis sets values
    		 T0 T1 T2 T3 T4 B0 B1 B2 B3 C1 C2 C3 D0 D1 D2 D3 E1 E3
    Number of subjects
    101
    100
    100
    95
    92
    89
    88
    84
    84
    75
    72
    70
    66
    66
    64
    63
    53
    53
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        Adults (18-64 years)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        From 65-84 years
    96
    95
    95
    91
    88
    86
    85
    82
    82
    74
    71
    69
    65
    65
    63
    62
    52
    52
        85 years and over
    5
    5
    5
    4
    4
    3
    3
    2
    2
    1
    1
    1
    1
    1
    1
    1
    1
    1
    Age continuous
    Units:
        
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    50
    50
    50
    47
    47
    44
    44
    42
    42
    38
    37
    35
    34
    34
    33
    33
    26
    26
        Male
    51
    50
    50
    48
    45
    45
    44
    42
    42
    37
    35
    35
    32
    32
    31
    30
    27
    27

    End points

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    End points reporting groups
    Reporting group title
    SARS-CoV-2 primary immunization comirnaty
    Reporting group description
    		 Participants that received their SARS-CoV-2 primary immunization with comirnaty, and participants that only received a single dose comirnaty as SARS-CoV-2 primary immunization.

    Reporting group title
    SARS-CoV-2 primary immunization spikevax
    Reporting group description
    		 -

    Reporting group title
    SARS-CoV-2 primary immunization Vaxzevria
    Reporting group description
    		 Participants that received their SARS-CoV-2 primary immunization with Vaxzevria, and participants that received a single dose of Vaxzevria and a single dose of comirnaty as SARS-CoV-2 primary immunization.
    Reporting group title
    SARS-CoV-2 1st booster immunization comirnaty
    Reporting group description
    		 -

    Reporting group title
    SARS-CoV-2 1st booster immunization spikevax
    Reporting group description
    		 -
    Reporting group title
    SARS-CoV-2 2nd booster immunization comirnaty
    Reporting group description
    		 -

    Reporting group title
    SARS-CoV-2 2nd booster immunization spikevax
    Reporting group description
    		 -
    Reporting group title
    SARS-CoV-2 3rd booster immunization comirnaty
    Reporting group description
    		 -

    Reporting group title
    SARS-CoV-2 3rd booster immunization spikevax
    Reporting group description
    		 -

    Reporting group title
    SARS-CoV-2 3nd booster immunization unknown vaccine
    Reporting group description
    		 -
    Reporting group title
    SARS-CoV-2 4th booster immunization comirnaty
    Reporting group description
    		 -

    Subject analysis set title
    T0
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Pre 1st primary SARS-CoV-2 immunization

    Subject analysis set title
    T1
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    1 month post 1st primary SARS-CoV-2 immunization

    Subject analysis set title
    T2
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    1 month post 2nd primary SARS-CoV-2 immunization

    Subject analysis set title
    T3
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    6 months post 2nd primary SARS-CoV-2 immunization

    Subject analysis set title
    T4
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    1 year post 2nd primary SARS-CoV-2 immunization

    Subject analysis set title
    B0
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    pre 1st SARS-CoV-2 booster immunization

    Subject analysis set title
    B1
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    1 month post 1st SARS-CoV-2 booster immunization

    Subject analysis set title
    B2
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    6 months post 1st SARS-CoV-2 booster immunization

    Subject analysis set title
    B3
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    1 year post 1st SARS-CoV-2 booster immunization

    Subject analysis set title
    C1
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    1 month post 2nd SARS-CoV-2 booster immunization

    Subject analysis set title
    C2
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    6 months post 2nd SARS-CoV-2 booster immunization

    Subject analysis set title
    C3
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    1 year post 2nd SARS-CoV-2 booster immunization

    Subject analysis set title
    D0
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    pre 3rd SARS-CoV-2 booster immunization

    Subject analysis set title
    D1
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    1 month post 3rd SARS-CoV-2 booster immunization

    Subject analysis set title
    D2
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    6 months post 3rd SARS-CoV-2 booster immunization

    Subject analysis set title
    D3
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    1 year post 3rd SARS-CoV-2 booster immunization

    Subject analysis set title
    E1
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    1 month post 4th SARS-CoV-2 booster immunization

    Subject analysis set title
    E3
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    1 year post 4th SARS-CoV-2 booster immunization

    Primary: Specific serum IgG antibody concentrations at one month after the second vaccination

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    End point title
    		 Specific serum IgG antibody concentrations at one month after the second vaccination [1]
    End point description
    Serum IgG levels voor SARS-CoV-2 S1 protein
    End point type
    Primary
    End point timeframe
    One month after second primary vaccination (T2)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Since participants did not have antibodies to SARSCoV2 at T0, in this observational study just induction of antibody responses at T2, post vaccination, have been analysed. Therefore, no statistical analyses can be specified.
    End point values
    		 T2
    Number of subjects analysed
    97
    Units: BAU/ml
        geometric mean (confidence interval 95%)
    1273.285 (1031.586 to 1571.614)
    No statistical analyses for this end point

    Primary: Frequencies of B-cells at one month after the second SARS-CoV-2 vaccination

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    End point title
    		 Frequencies of B-cells at one month after the second SARS-CoV-2 vaccination [2]
    End point description
    Percentage of B-cells, memory B-cells or plasmablasts in comparison to total amount of PBMCs
    End point type
    Primary
    End point timeframe
    One month after second primary vaccination (T2)
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Since participants did not have memory B-cell responses to SARSCoV2 at T0, in this observational study just induction of B-cell responses at T2, post vaccination, have been analysed. Therefore, no statistical analyses can be specified.
    End point values
    		 T2
    Number of subjects analysed
    40
    Units: Percentage cells
    geometric mean (standard deviation)
        B-cells
    5.51 ( 1.91 )
        Memory B-cells
    0.26 ( 0.16 )
        Plasmablasts
    0.02 ( 0.01 )
    No statistical analyses for this end point

    Primary: Frequencies of the adaptive memory B-cell responses at one month after the second SARS-CoV-2 vaccination

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    End point title
    		 Frequencies of the adaptive memory B-cell responses at one month after the second SARS-CoV-2 vaccination [3]
    End point description
    polyclonal stimulation of PBMCs in vitro followed by virus-protein specific ELISpot assay for spike protein S1
    End point type
    Primary
    End point timeframe
    At one month after primary vaccination (T2)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Since participants did not have memory B-cell responses to SARSCoV2 at T0, in this observational study just induction of B-cell responses at T2, post vaccination, have been analysed. Therefore, no statistical analyses can be specified.
    End point values
    		 T2
    Number of subjects analysed
    42
    Units: spots/100.000 PBMCs
        geometric mean (confidence interval 95%)
    1.096 (0.262 to 4.589)
    No statistical analyses for this end point

    Primary: Frequencies of functional T-cell responses at one month after the second SARS-CoV-2 vaccination

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    End point title
    		 Frequencies of functional T-cell responses at one month after the second SARS-CoV-2 vaccination [4]
    End point description
    in vitro stimulation with viral proteins followed by INF-g ELISpot assay for spike protein S1 and S2
    End point type
    Primary
    End point timeframe
    At one month after primary vaccination (T2)
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Since participants did not have T-cell responses to SARSCoV2 at T0, in this observational study just induction of T-cell responses at T2, post vaccination, have been analysed. Therefore, no statistical analyses can be specified.
    End point values
    		 T2
    Number of subjects analysed
    63
    Units: spots/100.000 PBMCs
        geometric mean (confidence interval 95%)
    2.894 (0.937 to 8.941)
    No statistical analyses for this end point

    Secondary: Longevity of antibody levels at 1 year post (booster)vaccination

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    End point title
    		 Longevity of antibody levels at 1 year post (booster)vaccination
    End point description
    Serum IgG levels voor SARS-CoV-2 S1 protein
    End point type
    Secondary
    End point timeframe
    At 1 year post primary vaccination (T4), and 1 year post booster vaccinations (B3, C3, D3, E3)
    End point values
    		 T4 B3 C3 D3 E3
    Number of subjects analysed
    0 [5]
    6
    3
    63
    52
    Units: BAU/ml
        geometric mean (confidence interval 95%)
    ( to )
    5046.666 (1493.554 to 17052.505)
    6968.184 (3773.825 to 12866.413)
    2736.649 (2112.550 to 3545.122)
    4132.644 (3146.233 to 5428.316)
    Notes
    [5] - All subject received booster vaccination within one year after primary vacc so T4 was not applicable
    No statistical analyses for this end point

    Secondary: Longevity of cellular response (B-cells) at 1 year post (booster)vaccination

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    End point title
    		 Longevity of cellular response (B-cells) at 1 year post (booster)vaccination
    End point description
    polyclonal stimulation of PBMCs in vitro followed by virus-protein specific ELISpot assay for spike protein S1
    End point type
    Secondary
    End point timeframe
    At 1 year post primary vaccination (T4), and 1 year post booster vaccinations (B3, C3, D3, E3)
    End point values
    		 T4 B3 C3 D3 E3
    Number of subjects analysed
    0 [6]
    6
    0 [7]
    0 [8]
    0 [9]
    Units: Spots/100.000 PBMCs
        geometric mean (confidence interval 95%)
    ( to )
    43.647 (36.585 to 52.073)
    ( to )
    ( to )
    ( to )
    Notes
    [6] - All subject received booster vaccination within one year after primary vacc so T4 was not applicable
    [7] - Analysis was not performed
    [8] - Analysis was not performed
    [9] - Analysis was not performed
    No statistical analyses for this end point

    Secondary: Mucosal IgA and IgG antibodies will be determined in nose fluids at T2, T4 and pre and post booster vaccinations

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    End point title
    		 Mucosal IgA and IgG antibodies will be determined in nose fluids at T2, T4 and pre and post booster vaccinations
    End point description
    Mucosal IgA and IgG concentrations specific for SARS-CoV-2 S1 protein
    End point type
    Secondary
    End point timeframe
    At one month and one year post primary vaccination (T2 and T4), and pre and post booster vaccinations (B0, B1, B3, C1, D0, D1)
    End point values
    		 T2 T4 B0 B1 B3 C1 D0 D1
    Number of subjects analysed
    3
    3
    76
    85
    9
    68
    65
    66
    Units: BAUM/ml
    geometric mean (confidence interval 95%)
        IgA
    0.100 (0.056 to 0.179)
    0.610 (0.072 to 5.158)
    0.158 (0.111 to 0.225)
    0.370 (0.279 to 0.491)
    2.361 (0.729 to 7.642)
    0.870 (0.555 to 1.365)
    1.194 (0.754 to 1.893)
    1.276 (0.854 to 1.905)
        IgG
    0.682 (0.082 to 5.655)
    3.949 (0.139 to 112.345)
    0.704 (0.511 to 0.969)
    20.302 (15.356 to 26.842)
    27.614 (6.024 to 126.574)
    39.435 (27.737 to 56.066)
    17.475 (11.664 to 26.183)
    36.075 (27.092 to 48.035)
    No statistical analyses for this end point

    Secondary: IgG antibodies to the SARS-CoV-2 core N protein indicating contact with the virus

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    End point title
    		 IgG antibodies to the SARS-CoV-2 core N protein indicating contact with the virus
    End point description
    End point type
    Secondary
    End point timeframe
    At all timepoints
    End point values
    		 T0 T1 T2 T3 B0 B1 B2 B3 C1 C2 C3 D0 D1 D2 D3 E1 E3
    Number of subjects analysed
    56
    74
    97
    81
    80
    74
    8
    6
    66
    21
    3
    62
    63
    65
    63
    52
    52
    Units: BAU/ml
        geometric mean (confidence interval 95%)
    1.419 (0.953 to 2.113)
    2.111 (1.476 to 3.021)
    2.560 (1.937 to 3.382)
    2.417 (1.751 to 3.337)
    2.670 (1.914 to 3.725)
    3.021 (2.259 to 4.040)
    18.547 (8.226 to 41.817)
    13.440 (3.695 to 48.889)
    6.902 (4.504 to 10.578)
    11.038 (5.537 to 22.002)
    157.299 (12.406 to 1994.372)
    11.042 (7.108 to 17.154)
    13.167 (8.658 to 20.023)
    34.146 (20.134 to 57.909)
    19.319 (11.744 to 31.781)
    16.571 (9.655 to 28.441)
    41.189 (22.654 to 74.886)
    No statistical analyses for this end point

    Secondary: Self-reported experiences possible SARS-CoV-2 infection from answers to short questionnaires at the several timepoints.

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    End point title
    		 Self-reported experiences possible SARS-CoV-2 infection from answers to short questionnaires at the several timepoints.
    End point description
    End point type
    Secondary
    End point timeframe
    At all timepoints
    End point values
    		 T0 T1 T2 T3 T4 B0 B1 B2 B3 C1 C2 C3 D0 D1 D2 D3 E1 E3
    Number of subjects analysed
    56
    74
    97
    81
    0 [10]
    80
    74
    8
    6
    66
    21
    3
    62
    63
    65
    63
    52
    52
    Units: number of participants
    5
    0
    0
    2
    0
    1
    15
    1
    6
    9
    1
    0
    3
    14
    1
    0
    2
    Notes
    [10] - All subject received booster vaccination within one year after primary vacc so T4 was not applicable
    No statistical analyses for this end point

    Secondary: Longevity of cellular response (T-cells) at 1 year post (booster)vaccination

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    End point title
    		 Longevity of cellular response (T-cells) at 1 year post (booster)vaccination
    End point description
    in vitro stimulation with viral proteins followed by INF-g ELISpot assay for spike protein S1 and S2
    End point type
    Secondary
    End point timeframe
    At 1 year post primary vaccination (T4), and 1 year post booster vaccinations (B3, C3, D3, E3)
    End point values
    		 T4 B3 C3 D3 E3
    Number of subjects analysed
    0 [11]
    6
    0 [12]
    25
    0 [13]
    Units: Spots/100.000 PBMCs
        geometric mean (confidence interval 95%)
    ( to )
    1.268 (0.005 to 316.495)
    ( to )
    23.562 (14.735 to 37.678)
    ( to )
    Notes
    [11] - All subject received booster vaccination within one year after primary vacc so T4 was not applicable
    [12] - Analysis was not performed
    [13] - Analysis was not performed
    No statistical analyses for this end point

    Secondary: Antibody virus neutralization for SARS-CoV-2 positive serum samples at 1 month (T2), 6 months (T3) 1 year (T4) post vaccination and pre and post booster vaccination

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    End point title
    		 Antibody virus neutralization for SARS-CoV-2 positive serum samples at 1 month (T2), 6 months (T3) 1 year (T4) post vaccination and pre and post booster vaccination
    End point description
    Selected SARS-CoV-2 positive serum samples will be tested for virus neutralization, providing a functional measure of immune protection
    End point type
    Secondary
    End point timeframe
    At 1 month post primary immunization (T2) and pre and post booster vaccinations (B0, B1, B3, C1, C2, D0, D1). Timepoints T3 and T4 (6 months and 12 months post primary immunization) have not been included in this assay.
    End point values
    		 T2 B0 B1 B3 C1 C2 D0 D1
    Number of subjects analysed
    95
    66
    71
    8
    62
    2
    55
    65
    Units: titre
        geometric mean (confidence interval 95%)
    42.838 (32.975 to 55.652)
    9.611 (7.253 to 12.734)
    429.507 (320.707 to 575.218)
    442.007 (123.519 to 1581.698)
    470.756 (350.617 to 632.062)
    1226.490 (532.111 to 2827.000)
    424.498 (291.418 to 618.351)
    1009.385 (775.295 to 1314.156)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    only adverse events spontaneously reported by the subject related to and occurring within one week after blood sampling were reported
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    28
    Reporting groups
    Reporting group title
    SARS-CoV-2 primary immunization
    Reporting group description
    		 Participants that received SARS-CoV-2 primary immunization

    Serious adverse events
    		 SARS-CoV-2 primary immunization
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 101 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 SARS-CoV-2 primary immunization
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 101 (0.00%)
    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: only adverse events spontaneously reported by the subject related to and occurring within one week after blood sampling were reported

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Aug 2021
    Submission of the VOCAAL study as drug research at the request of the METC
    29 Oct 2021
    Follow the immune responses after SARS-CoV-2 booster vaccination and administration of 3th SARS-CoV-2 vaccination
    09 Mar 2022
    Follow the immune responses after the second and following SARS-CoV-2 booster vaccination
    19 May 2023
    changes secondary endpoint and changes in informed consent procedure
    30 Aug 2023
    Follow the immune responses after the fourth SARS-CoV-2 booster vaccination given in the autumn of 2023
    18 Oct 2024
    Extra blood sample at the end of the study for measuring the status of total SARS-CoV2 antibody responses after multiple vaccinations and possible infections as an endpoint state of the study in relation to the actual status of the immune cell characterization and inflammation markers in the plasma present per person.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    For T-cells cytokine analysis, frequencies and activation analysis has not been performed in this study, but has been performed in a different cohort (2019-000836-24). Furthermore, the avidity of serum antibodies has not been measured.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/37515012
    http://www.ncbi.nlm.nih.gov/pubmed/38774878
    http://www.ncbi.nlm.nih.gov/pubmed/39407293
    http://www.ncbi.nlm.nih.gov/pubmed/36146557
    http://www.ncbi.nlm.nih.gov/pubmed/37880758
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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