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    Clinical Trial Results:
    An International Multicentre, Phase 2, Randomised, Adaptive Protocol to determine the need for, optimal timing of and immunogenicity of administering a booster mRNA vaccination dose against SARS-CoV-2 in the general population (18+ years) already vaccinated against SARS-CoV-2 (EU-COVAT-2 BOOSTAVAC)

    Summary
    EudraCT number
    		 2021-004889-35
    Trial protocol
    		 IE   NO   DE   ES   BE  
    Global end of trial date
    23 Apr 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Apr 2026
    First version publication date
    11 Apr 2026
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    UCDCRC/21/10
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University College Dublin
    Sponsor organisation address
    Centre for Experimental Pathogen Host Research, Belfield Campus, Dublin, Ireland, D04 V1W8
    Public contact
    Department of Infectious Diseases, University College Dublin, paddy.mallon@ucd.ie
    Scientific contact
    Department of Infectious Diseases, University College Dublin, paddy.mallon@ucd.ie
    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
    28 Jan 2025
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Apr 2024
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Apr 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the need for, optimal timing of, and immune response after administering a mRNA booster vaccination dose against SARS-CoV-2 in the general population (18+ years) already vaccinated with the mRNA vaccines.
    Protection of trial subjects
    The trial was conducted in accordance with the valid versions of the trial protocol and the internationally recognised Good Clinical Practice Guidelines (ICH-GCP), including archiving of essential documents. The participants volunteering for this trials were not considered to be at additional risk related to the vaccine selected as the intervention. Participants in this study were exposed to some general risks associated with the study procedures. The participants underwent additional blood sampling, which can be uncomfortable but rarely results in any relevant harm or discomfort. Collection of other samples where indicated, saliva or urine, were considered not to cause any significant harm. These risks are almost always short lived and do not result in any long-term effects. Anxiety-related reactions, including vasovagal reactions (syncope), hyperventilation or stress‐related reactions (e.g. dizziness, palpitations, increases in heart rate, alterations in blood pressure, paraesthesia, hypoaesthesia and sweating) may occur in association with the vaccination process itself. Events of anaphylaxis have been reported following vaccination with COMIRNATY®. Appropriate medical treatment and supervision was always available in case of an anaphylactic reaction following the administration of the vaccine. Cases of myocarditis and pericarditis have been observed following vaccination with COMIRNATY®. These cases have primarily occurred within 14 days following vaccination. Solicited AEs, including local and systemic manifestations as well as of symptoms of myocarditis and pericarditis, were collected by the participants in a study diary. Participants’ identities were protected at all times and personal health information held securely. No directly identifiable data was stored in the clinical trial database, and the participant lists were stored separately, secured, at the local study sites.
    Background therapy
    		 Standard of care as per country guidelines
    Evidence for comparator
    		 -
    Actual start date of recruitment
    09 Mar 2022
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Norway: 6
    Country: Number of subjects enrolled
    Spain: 21
    Country: Number of subjects enrolled
    Sweden: 29
    Country: Number of subjects enrolled
    Belgium: 37
    Country: Number of subjects enrolled
    Germany: 51
    Country: Number of subjects enrolled
    Ireland: 111
    Worldwide total number of subjects
    255
    EEA total number of subjects
    255
    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)
    208
    From 65 to 84 years
    46
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 The first participant was recruited on March 09, 2022, the last one on September 19, 2023. Total recruitment time: 559 days. A total of 255 participant were recruited in 14 centres across Europe. The planned sample size of 500 participants was not reached The last participant completed the study on April 23, 2024 Total study duration: 776 days.

    Pre-assignment
    Screening details
    		 Potential participants were recruited from a European Volunteer Registry for vaccine trials, local site database or local advertising. Elegible participants included adults who had received more than 3 doses of mRNA vaccine as primary vaccination for COVID-19 at least 3 but no more than 7 months prior to enrolment (consent)

    Period 1
    Period 1 title
    Baseline (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm 2: booster at month 0
    Arm description
    		 Participants randomised to Arm 2 received IMP at the baseline visit.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    COVID-19 Vaccine, mRNA
    Investigational medicinal product code
    Other name
    COMIRNATY
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Injection , Intramuscular use
    Dosage and administration details
    Subjects randomised to an intervention will receive a single dose of either Pfizer BNT162b2 or one of the Pfizer Bivalent COVID-19 Vaccines (COMIRNATY® Original/Omicron BA.1 or Original/Omicron BA.4-5) or COMIRNATY® Omicron XBB.1.5, at month 0, 2, 4 or 6 after enrolment as per the allocated study arm. The choice of Pfizer vaccine administered will be determined by what is recommended within the country and/or what is used as standard clinical care at the study site and will be administered at the clinical site by trained study healthcare personnel. The vaccine should be administered intramuscularly. The preferred site is the deltoid muscle of the upper arm. Pharmaceutical form: Concentrate for dispersion for injection Dosage: 1 dose (day 1 at the allocated visit: month 0, 2, 4, or 6)

    Arm title
    		 Arm 3: booster at month 2
    Arm description
    		 Participants randomised to Arm 3 received IMP at the follow-up visit at month 2
    Arm type
    		 Active comparator

    Investigational medicinal product name
    COVID-19 Vaccine, mRNA
    Investigational medicinal product code
    Other name
    COMIRNATY
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Injection , Intramuscular use
    Dosage and administration details
    Subjects randomised to an intervention will receive a single dose of either Pfizer BNT162b2 or one of the Pfizer Bivalent COVID-19 Vaccines (COMIRNATY® Original/Omicron BA.1 or Original/Omicron BA.4-5) or COMIRNATY® Omicron XBB.1.5, at month 0, 2, 4 or 6 after enrolment as per the allocated study arm. The choice of Pfizer vaccine administered will be determined by what is recommended within the country and/or what is used as standard clinical care at the study site and will be administered at the clinical site by trained study healthcare personnel. The vaccine should be administered intramuscularly. The preferred site is the deltoid muscle of the upper arm. Pharmaceutical form: Concentrate for dispersion for injection Dosage: 1 dose (day 1 at the allocated visit: month 0, 2, 4, or 6)

    Arm title
    		 Arm 4: booster at month 4
    Arm description
    		 Participants randomised to Arm 4 received IMP at the follow-up visit at month 4
    Arm type
    		 Active comparator

    Investigational medicinal product name
    COVID-19 Vaccine, mRNA
    Investigational medicinal product code
    Other name
    COMIRNATY
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Injection , Intramuscular use
    Dosage and administration details
    Subjects randomised to an intervention will receive a single dose of either Pfizer BNT162b2 or one of the Pfizer Bivalent COVID-19 Vaccines (COMIRNATY® Original/Omicron BA.1 or Original/Omicron BA.4-5) or COMIRNATY® Omicron XBB.1.5, at month 0, 2, 4 or 6 after enrolment as per the allocated study arm. The choice of Pfizer vaccine administered will be determined by what is recommended within the country and/or what is used as standard clinical care at the study site and will be administered at the clinical site by trained study healthcare personnel. The vaccine should be administered intramuscularly. The preferred site is the deltoid muscle of the upper arm. Pharmaceutical form: Concentrate for dispersion for injection Dosage: 1 dose (day 1 at the allocated visit: month 0, 2, 4, or 6)

    Arm title
    		 Arm 5: booster at month 6
    Arm description
    		 Participants randomised to Arm 5 received IMP at the follow-up visit at month 6
    Arm type
    		 Active comparator

    Investigational medicinal product name
    COVID-19 Vaccine, mRNA
    Investigational medicinal product code
    Other name
    COMIRNATY
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Injection , Intramuscular use
    Dosage and administration details
    Subjects randomised to an intervention will receive a single dose of either Pfizer BNT162b2 or one of the Pfizer Bivalent COVID-19 Vaccines (COMIRNATY® Original/Omicron BA.1 or Original/Omicron BA.4-5) or COMIRNATY® Omicron XBB.1.5, at month 0, 2, 4 or 6 after enrolment as per the allocated study arm. The choice of Pfizer vaccine administered will be determined by what is recommended within the country and/or what is used as standard clinical care at the study site and will be administered at the clinical site by trained study healthcare personnel. The vaccine should be administered intramuscularly. The preferred site is the deltoid muscle of the upper arm. Pharmaceutical form: Concentrate for dispersion for injection Dosage: 1 dose (day 1 at the allocated visit: month 0, 2, 4, or 6)

    Arm title
    		 Arm 1: control
    Arm description
    		 Participants randomised to arm 1 (control) did not receive vaccination as part of the study
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Arm 2: booster at month 0 Arm 3: booster at month 2 Arm 4: booster at month 4 Arm 5: booster at month 6 Arm 1: control
    Started
    51
    53
    50
    51
    50
    Completed
    48
    48
    46
    48
    45
    Not completed
    3
    5
    4
    3
    5
         Consent withdrawn by subject
    3
    2
    2
    2
    4
         Physician decision
    -
    1
    1
    -
    -
         Lost to follow-up
    -
    2
    1
    -
    1
         Protocol deviation
    -
    -
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm 2: booster at month 0
    Reporting group description
    		 Participants randomised to Arm 2 received IMP at the baseline visit.

    Reporting group title
    Arm 3: booster at month 2
    Reporting group description
    		 Participants randomised to Arm 3 received IMP at the follow-up visit at month 2

    Reporting group title
    Arm 4: booster at month 4
    Reporting group description
    		 Participants randomised to Arm 4 received IMP at the follow-up visit at month 4

    Reporting group title
    Arm 5: booster at month 6
    Reporting group description
    		 Participants randomised to Arm 5 received IMP at the follow-up visit at month 6

    Reporting group title
    Arm 1: control
    Reporting group description
    		 Participants randomised to arm 1 (control) did not receive vaccination as part of the study

    Reporting group values
    		 Arm 2: booster at month 0 Arm 3: booster at month 2 Arm 4: booster at month 4 Arm 5: booster at month 6 Arm 1: control Total
    Number of subjects
    		 51 53 50 51 50 255
    Age categorical
    Units: Subjects
        18-49 years
    		 17 18 17 18 18 88
        50-59 years
    		 20 20 19 19 18 96
        ≥60 years
    		 14 15 14 14 14 71
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 52 ( 14 ) 54 ( 14 ) 51 ( 15 ) 51 ( 15 ) 54 ( 14 ) -
    Gender categorical
    Units: Subjects
        Female
    		 33 34 29 30 28 154
        Male
    		 18 19 21 21 22 101
    Race
    Units: Subjects
        White
    		 49 53 48 50 49 249
        Asian
    		 1 0 1 1 1 4
        Other
    		 1 0 1 0 0 2
    Is the participant immunocompromised?
    Units: Subjects
        Yes
    		 50 47 49 51 48 245
        No
    		 1 6 1 0 2 10
    Prior SARS-CoV-2 Infection
    Units: Subjects
        Yes
    		 28 26 25 29 22 130
        No
    		 20 27 23 17 26 113
        Unknown
    		 2 0 2 2 1 7
        Missing
    		 1 0 0 3 1 5
    Number of pre-study vaccination
    Units: Subjects
        3 prior vaccines
    		 12 12 9 14 12 59
        >3 vaccines
    		 39 41 41 37 38 196
    BNT162b2 (Comirnaty)
    Type of vaccine recieved pre-study entry
    Units: Subjects
        Yes
    		 24 32 21 31 33 141
        No
    		 27 21 29 20 17 114
    Last vaccination to randomisation
    Units: day
        arithmetic mean (standard deviation)
    		 163 ( 63 ) 152 ( 40 ) 154 ( 42 ) 150 ( 33 ) 150 ( 39 ) -
    Anti-RBD titres
    Anti-RBD titres at study entry
    Units: IU/mL
        median (inter-quartile range (Q1-Q3))
    		 8278 (3876 to 15647) 8271 (4112 to 18862) 13521 (5627 to 29280) 12441 (4746 to 19261) 10373 (4107 to 17530) -

    End points

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    End points reporting groups
    Reporting group title
    Arm 2: booster at month 0
    Reporting group description
    		 Participants randomised to Arm 2 received IMP at the baseline visit.

    Reporting group title
    Arm 3: booster at month 2
    Reporting group description
    		 Participants randomised to Arm 3 received IMP at the follow-up visit at month 2

    Reporting group title
    Arm 4: booster at month 4
    Reporting group description
    		 Participants randomised to Arm 4 received IMP at the follow-up visit at month 4

    Reporting group title
    Arm 5: booster at month 6
    Reporting group description
    		 Participants randomised to Arm 5 received IMP at the follow-up visit at month 6

    Reporting group title
    Arm 1: control
    Reporting group description
    		 Participants randomised to arm 1 (control) did not receive vaccination as part of the study

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All randomised participants with available anti-RBD antibody titre at baseline and at Day 14 post booster, analyzed according to intention-to-treat principle.

    Primary: Composite primary endpoint

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    End point title
    		 Composite primary endpoint [1]
    End point description
    The primary endpoint comprised a composite endpoint of either an increase in anti-RBD antibody titre to ≥500 IU/mL at day 14 post booster vaccine in those with anti-RBD antibody titre of ≤500 IU/mL immediately before booster vaccination or a 2-fold increase in anti-RBD antibody titre at day 14 following booster dose vaccination in those with anti-RBD titre of ≥500 IU/mL immediately before booster vaccination, as measured by quantitative immunoassay targeting the anti-RBD antibody.
    End point type
    Primary
    End point timeframe
    From baseline to 14-days post booster vaccination
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Trial participants in Arm 1 (control arm - no vaccine group) were offered the booster dose at the end of the study but they were not followed up as the vaccine was administered after study completion. Hence they were excluded in the statistical analysis.
    End point values
    		 Arm 2: booster at month 0 Arm 3: booster at month 2 Arm 4: booster at month 4 Arm 5: booster at month 6
    Number of subjects analysed
    50
    47
    48
    44
    Units: Subjects
    29
    35
    23
    26
    Attachments
    		 Statistical Analysis and Justification
    Statistical analysis title
    		 Primary analysis of the schedule-response relation
    Statistical analysis description
    Since the primary endpoint was analysed using one-sample one-sided hypothesis testing , results presented here points to further analyses that were done if efficacy was met (in the main primary analysis), and this was to determine the optimal timing of a booster dose, by modelling the schedule-response relationship using a logistic regression with fractional polynomials
    Comparison groups
    Arm 2: booster at month 0 v Arm 3: booster at month 2 v Arm 4: booster at month 4 v Arm 5: booster at month 6
    Number of subjects included in analysis
    189
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.48 [3]
    Method
    		 Regression, Logistic
    Confidence interval
    Notes
    [2] - Logistic regression with fractional polynomials to determine trend. Schedule-response relationship by randomisation group.
    [3] - The p-value indicates whether the slope is 0 (i.e. no effect of time)

    Secondary: 2-fold increase in RBD antibody titre

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    End point title
    		 2-fold increase in RBD antibody titre [4]
    End point description
    This endpoint describes subjects who received booster vaccination at each specific time point that achieve a 2-fold in-crease in RBD antibody titre 14 days after the booster vaccine
    End point type
    Secondary
    End point timeframe
    14 days after the booster vaccine
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Trial participants in Arm 1 (control arm - no vaccine group) were offered the booster dose at the end of the study but they were not followed up as the vaccine was administered after study completion. Hence they were excluded in the statistical analysis.
    End point values
    		 Arm 2: booster at month 0 Arm 3: booster at month 2 Arm 4: booster at month 4 Arm 5: booster at month 6
    Number of subjects analysed
    50
    47
    48
    44
    Units: Subjects
    29
    35
    23
    26
    Statistical analysis title
    		 2-fold increase in anti-RBD titre
    Statistical analysis description
    Determining the optimal timing of a booster dose, by modelling the schedule-response relationship using a logistic regression with fractional polynomials (for time point of last vaccine dose) according to the randomisation group
    Comparison groups
    Arm 2: booster at month 0 v Arm 3: booster at month 2 v Arm 4: booster at month 4 v Arm 5: booster at month 6
    Number of subjects included in analysis
    189
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.48 [6]
    Method
    		 Regression, Logistic
    Confidence interval
    Notes
    [5] - Testing for slope using a logistic regression with the best fitting fractional polynomial
    [6] - The p-value indicates whether the slope is 0 (i.e. no effect of time)

    Secondary: Post anti-RBD ≥ 500 IU/mL

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    End point title
    		 Post anti-RBD ≥ 500 IU/mL [7]
    End point description
    This endpoint describes subjects who received the booster vaccination at each specific time point that achieve an anti-RBD antibody titre 500 IU/mL 14 days after the booster vaccine (regardless of the titre level before booster vaccination),
    End point type
    Secondary
    End point timeframe
    From baseline to Day 14 post booster
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Trial participants in Arm 1 (control arm - no vaccine group) were offered the booster dose at the end of the study but they were not followed up as the vaccine was administered after study completion. Hence they were excluded in the statistical analysis.
    End point values
    		 Arm 2: booster at month 0 Arm 3: booster at month 2 Arm 4: booster at month 4 Arm 5: booster at month 6
    Number of subjects analysed
    50
    47
    48
    45
    Units: Subjects
    50
    47
    48
    45
    Statistical analysis title
    		 Post anti-RBD titre > 500 IU/mL
    Statistical analysis description
    Determining the optimal timing of a booster dose, by modelling the schedule-response relationship using a logistic regression with fractional polynomials (for time point of last vaccine dose) according to the randomisation group
    Comparison groups
    Arm 2: booster at month 0 v Arm 3: booster at month 2 v Arm 4: booster at month 4 v Arm 5: booster at month 6
    Number of subjects included in analysis
    190
    Analysis specification
    Pre-specified
    Analysis type
    		 other [8]
    P-value
    		 = 1 [9]
    Method
    		 Regression, Logistic
    Confidence interval
    Notes
    [8] - Testing for slope using a logistic regression with the best fitting fractional polynomial
    [9] - The p value indicates whether the slope is 0. The titre outcomes at each booster point were not estimable hence the p value =1

    Secondary: 2-fold increase in anti-S1 titre

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    End point title
    		 2-fold increase in anti-S1 titre [10]
    End point description
    This endpoint describes subjects with 2-fold RBD antibody titre increase following booster vaccination measured by quantitative immunoassay targeting the spike 1 (S1) antibodies at 14 days after booster vaccine
    End point type
    Secondary
    End point timeframe
    From baseline to Day 14 after booster
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Trial participants in Arm 1 (control arm - no vaccine group) were offered the booster dose at the end of the study but they were not followed up as the vaccine was administered after study completion. Hence they were excluded in the statistical analysis.
    End point values
    		 Arm 2: booster at month 0 Arm 3: booster at month 2 Arm 4: booster at month 4 Arm 5: booster at month 6
    Number of subjects analysed
    50
    47
    48
    44
    Units: Subjects
    31
    32
    27
    27
    Statistical analysis title
    		 2-fold increase in anti-S1 titre
    Statistical analysis description
    Determining the optimal timing of a booster dose, by modelling the schedule-response relationship using a logistic regression with fractional polynomials (for time point of last vaccine dose) according to the randomisation group
    Comparison groups
    Arm 5: booster at month 6 v Arm 2: booster at month 0 v Arm 3: booster at month 2 v Arm 4: booster at month 4
    Number of subjects included in analysis
    189
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    P-value
    		 = 0.67 [12]
    Method
    		 Regression, Logistic
    Confidence interval
    Notes
    [11] - Testing for slope using a logistic regression with the best fitting fractional polynomial.
    [12] - The p value indicates whether the slope is 0 (i.e no effect of time)

    Secondary: 2-fold increase in anti-NC titre

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    End point title
    		 2-fold increase in anti-NC titre [13]
    End point description
    This endpoint describes subjects with 2-fold RBD antibody titre increase following booster vaccination measured by quantitative immunoassay targeting the nucleocapsid (NC) antibodies at 14 days after booster vaccine
    End point type
    Secondary
    End point timeframe
    From baseline to Day 14 after booster
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Trial participants in Arm 1 (control arm - no vaccine group) were offered the booster dose at the end of the study but they were not followed up as the vaccine was administered after study completion. Hence they were excluded in the statistical analysis.
    End point values
    		 Arm 2: booster at month 0 Arm 3: booster at month 2 Arm 4: booster at month 4 Arm 5: booster at month 6
    Number of subjects analysed
    50
    47
    48
    44
    Units: Subjects
    9
    9
    1
    4
    Statistical analysis title
    		 2-fold increase in anti-NC titre
    Statistical analysis description
    Determining the optimal timing of a booster dose, by modelling the schedule-response relationship using a logistic regression with fractional polynomials (for time point of last vaccine dose) according to the randomisation group
    Comparison groups
    Arm 3: booster at month 2 v Arm 4: booster at month 4 v Arm 5: booster at month 6 v Arm 2: booster at month 0
    Number of subjects included in analysis
    189
    Analysis specification
    Pre-specified
    Analysis type
    		 other [14]
    P-value
    		 = 0.038 [15]
    Method
    		 Regression, Logistic
    Confidence interval
    Notes
    [14] - Testing for slope using a logistic regression with the best fitting fractional polynomial
    [15] - The p value indicates whether the slope is 0. (i.e no effect of time)

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Solicited AEs: within 7 days after booster dose. Unsolicited AEs: until the end of trial. SAEs: up to 3 months post-booster or until study completion, whichever occurs first.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24
    Reporting groups
    Reporting group title
    Arm 1: Control
    Reporting group description
    		 Participants in this group received no booster vaccination

    Reporting group title
    Arm 2: Booster at month 0
    Reporting group description
    		 Participants in this group received a booster vaccination at month 0 (baseline), immediately after enrolment

    Reporting group title
    Arm 3: Booster at month 2
    Reporting group description
    		 Participants in this group received a booster vaccination at month 2 after enrolment

    Reporting group title
    Arm 4: Booster at month 4
    Reporting group description
    		 Participants in this group received a booster vaccination at month 4 after enrolment.

    Reporting group title
    Arm 5: Booster at month 6
    Reporting group description
    		 Participants in this group received a booster vaccination at month 6 after enrolment

    Serious adverse events
    		 Arm 1: Control Arm 2: Booster at month 0 Arm 3: Booster at month 2 Arm 4: Booster at month 4 Arm 5: Booster at month 6
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 55 (1.82%)
    1 / 52 (1.92%)
    3 / 51 (5.88%)
    1 / 49 (2.04%)
    1 / 48 (2.08%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Surgical and medical procedures
    Leg amputation
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 52 (0.00%)
    1 / 51 (1.96%)
    0 / 49 (0.00%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal transplant
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 52 (0.00%)
    1 / 51 (1.96%)
    0 / 49 (0.00%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 52 (0.00%)
    1 / 51 (1.96%)
    0 / 49 (0.00%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
    1 / 49 (2.04%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Vestibular neuronitis
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
    0 / 49 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 52 (0.00%)
    0 / 51 (0.00%)
    0 / 49 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Orchitis
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 52 (1.92%)
    0 / 51 (0.00%)
    0 / 49 (0.00%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Arm 1: Control Arm 2: Booster at month 0 Arm 3: Booster at month 2 Arm 4: Booster at month 4 Arm 5: Booster at month 6
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    27 / 55 (49.09%)
    43 / 52 (82.69%)
    42 / 51 (82.35%)
    44 / 49 (89.80%)
    37 / 48 (77.08%)
    Nervous system disorders
    Headache
    Additional description: Non serious adverse event above 5% reported
         subjects affected / exposed
    2 / 55 (3.64%)
    13 / 52 (25.00%)
    10 / 51 (19.61%)
    9 / 49 (18.37%)
    5 / 48 (10.42%)
         occurrences all number
    2
    18
    11
    10
    5
    General disorders and administration site conditions
    Fatigue
    Additional description: Non serious adverse event above 5% reported
         subjects affected / exposed
    3 / 55 (5.45%)
    14 / 52 (26.92%)
    11 / 51 (21.57%)
    10 / 49 (20.41%)
    14 / 48 (29.17%)
         occurrences all number
    3
    23
    15
    15
    18
    Asthenia
    Additional description: Non serious adverse event above 5% reported
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 52 (1.92%)
    2 / 51 (3.92%)
    1 / 49 (2.04%)
    3 / 48 (6.25%)
         occurrences all number
    0
    1
    2
    2
    5
    Influenza like illness
    Additional description: Non serious adverse event above 5% reported
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 52 (0.00%)
    1 / 51 (1.96%)
    2 / 49 (4.08%)
    3 / 48 (6.25%)
         occurrences all number
    0
    0
    1
    2
    3
    Injection site discomfort
    Additional description: Non serious adverse event above 5% reported
         subjects affected / exposed
    0 / 55 (0.00%)
    20 / 52 (38.46%)
    27 / 51 (52.94%)
    27 / 49 (55.10%)
    19 / 48 (39.58%)
         occurrences all number
    0
    22
    27
    27
    21
    Injection site erythema
    Additional description: Non serious adverse event above 5% reported
         subjects affected / exposed
    0 / 55 (0.00%)
    5 / 52 (9.62%)
    5 / 51 (9.80%)
    9 / 49 (18.37%)
    4 / 48 (8.33%)
         occurrences all number
    0
    5
    5
    9
    4
    Injection site induration
    Additional description: Non serious adverse event above 5% reported
         subjects affected / exposed
    0 / 55 (0.00%)
    7 / 52 (13.46%)
    2 / 51 (3.92%)
    8 / 49 (16.33%)
    7 / 48 (14.58%)
         occurrences all number
    0
    9
    2
    8
    7
    Injection site pain
    Additional description: Non serious adverse event above 5 % reported
         subjects affected / exposed
    0 / 55 (0.00%)
    2 / 52 (3.85%)
    1 / 51 (1.96%)
    2 / 49 (4.08%)
    4 / 48 (8.33%)
         occurrences all number
    0
    2
    1
    2
    5
    Injection site pruritus
    Additional description: Non serious adverse event above 5% reported
         subjects affected / exposed
    0 / 55 (0.00%)
    3 / 52 (5.77%)
    2 / 51 (3.92%)
    6 / 49 (12.24%)
    5 / 48 (10.42%)
         occurrences all number
    0
    3
    2
    6
    5
    Injection site swelling
    Additional description: Non serious adverse event above 5% reported
         subjects affected / exposed
    0 / 55 (0.00%)
    8 / 52 (15.38%)
    7 / 51 (13.73%)
    10 / 49 (20.41%)
    10 / 48 (20.83%)
         occurrences all number
    0
    10
    7
    10
    10
    Malaise
    Additional description: Non serious adverse event above 5% reported
         subjects affected / exposed
    0 / 55 (0.00%)
    3 / 52 (5.77%)
    1 / 51 (1.96%)
    1 / 49 (2.04%)
    2 / 48 (4.17%)
         occurrences all number
    0
    3
    1
    1
    2
    Pyrexia
    Additional description: Non serious adverse event above 5% reported
         subjects affected / exposed
    2 / 55 (3.64%)
    1 / 52 (1.92%)
    5 / 51 (9.80%)
    4 / 49 (8.16%)
    3 / 48 (6.25%)
         occurrences all number
    2
    1
    5
    5
    3
    Chills
    Additional description: Non serious adverse events above 5% reported
         subjects affected / exposed
    0 / 55 (0.00%)
    4 / 52 (7.69%)
    1 / 51 (1.96%)
    2 / 49 (4.08%)
    2 / 48 (4.17%)
         occurrences all number
    0
    4
    1
    2
    2
    Blood and lymphatic system disorders
    Lymphadenopathy
    Additional description: Non serious adverse event above 5% reported
         subjects affected / exposed
    1 / 55 (1.82%)
    2 / 52 (3.85%)
    3 / 51 (5.88%)
    2 / 49 (4.08%)
    2 / 48 (4.17%)
         occurrences all number
    1
    3
    3
    2
    2
    Immune system disorders
    Seasonal allergy
    Additional description: Non serious adverse events above 5% reported
         subjects affected / exposed
    1 / 55 (1.82%)
    3 / 52 (5.77%)
    2 / 51 (3.92%)
    1 / 49 (2.04%)
    1 / 48 (2.08%)
         occurrences all number
    1
    3
    2
    1
    1
    Gastrointestinal disorders
    Diarrhoea
    Additional description: Non serious adverse event above 5% reported
         subjects affected / exposed
    1 / 55 (1.82%)
    5 / 52 (9.62%)
    1 / 51 (1.96%)
    3 / 49 (6.12%)
    1 / 48 (2.08%)
         occurrences all number
    1
    5
    1
    3
    1
    Nausea
    Additional description: Non serious adverse event above 5% reported
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 52 (0.00%)
    2 / 51 (3.92%)
    6 / 49 (12.24%)
    1 / 48 (2.08%)
         occurrences all number
    0
    0
    2
    7
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
    Additional description: Non serious adverse event above 5% reported
         subjects affected / exposed
    4 / 55 (7.27%)
    4 / 52 (7.69%)
    8 / 51 (15.69%)
    3 / 49 (6.12%)
    4 / 48 (8.33%)
         occurrences all number
    5
    4
    8
    3
    4
    Nasal congestion
    Additional description: Non serious adverse events above 5% reported
         subjects affected / exposed
    1 / 55 (1.82%)
    3 / 52 (5.77%)
    0 / 51 (0.00%)
    0 / 49 (0.00%)
    0 / 48 (0.00%)
         occurrences all number
    1
    3
    0
    0
    0
    Oropharyngeal pain
    Additional description: Non serious adverse events above 5% reported
         subjects affected / exposed
    2 / 55 (3.64%)
    9 / 52 (17.31%)
    7 / 51 (13.73%)
    6 / 49 (12.24%)
    3 / 48 (6.25%)
         occurrences all number
    2
    9
    7
    6
    3
    Rhinorrhoea
    Additional description: Non serious adverse events above 5% reported
         subjects affected / exposed
    0 / 55 (0.00%)
    2 / 52 (3.85%)
    5 / 51 (9.80%)
    2 / 49 (4.08%)
    2 / 48 (4.17%)
         occurrences all number
    0
    2
    5
    2
    2
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
    Additional description: Non serious adverse events above 5% reported
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 52 (1.92%)
    1 / 51 (1.96%)
    1 / 49 (2.04%)
    3 / 48 (6.25%)
         occurrences all number
    0
    2
    1
    1
    3
    Psychiatric disorders
    Insomnia
    Additional description: Non serious adverse event above 5% reported
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 52 (1.92%)
    1 / 51 (1.96%)
    3 / 49 (6.12%)
    2 / 48 (4.17%)
         occurrences all number
    0
    1
    1
    3
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
    Additional description: Non serious adverse event above 5% reported
         subjects affected / exposed
    0 / 55 (0.00%)
    4 / 52 (7.69%)
    3 / 51 (5.88%)
    5 / 49 (10.20%)
    1 / 48 (2.08%)
         occurrences all number
    0
    4
    4
    5
    1
    Joint swelling
    Additional description: Non serious adverse event above 5% reported
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 52 (0.00%)
    3 / 51 (5.88%)
    1 / 49 (2.04%)
    1 / 48 (2.08%)
         occurrences all number
    0
    0
    3
    1
    1
    Myalgia
    Additional description: Non serious adverse event above 5% reported
         subjects affected / exposed
    0 / 55 (0.00%)
    6 / 52 (11.54%)
    8 / 51 (15.69%)
    5 / 49 (10.20%)
    11 / 48 (22.92%)
         occurrences all number
    0
    6
    8
    5
    11
    Pain in extremity
         subjects affected / exposed
    0 / 55 (0.00%)
    6 / 52 (11.54%)
    1 / 51 (1.96%)
    1 / 49 (2.04%)
    3 / 48 (6.25%)
         occurrences all number
    0
    6
    1
    1
    3
    Infections and infestations
    Bronchitis
    Additional description: Non serious adverse event above 5% reported
         subjects affected / exposed
    3 / 55 (5.45%)
    0 / 52 (0.00%)
    1 / 51 (1.96%)
    2 / 49 (4.08%)
    1 / 48 (2.08%)
         occurrences all number
    3
    0
    1
    2
    1
    COVID-19
    Additional description: Non serious adverse events above 5% reported
         subjects affected / exposed
    8 / 55 (14.55%)
    8 / 52 (15.38%)
    5 / 51 (9.80%)
    5 / 49 (10.20%)
    7 / 48 (14.58%)
         occurrences all number
    8
    8
    5
    5
    7
    Nasopharyngitis
    Additional description: Non serious adverse events above 5% reported
         subjects affected / exposed
    5 / 55 (9.09%)
    12 / 52 (23.08%)
    6 / 51 (11.76%)
    5 / 49 (10.20%)
    7 / 48 (14.58%)
         occurrences all number
    5
    13
    6
    5
    10
    Pharyngitis
    Additional description: Non serious adverse event above 5% reported
         subjects affected / exposed
    1 / 55 (1.82%)
    3 / 52 (5.77%)
    0 / 51 (0.00%)
    0 / 49 (0.00%)
    0 / 48 (0.00%)
         occurrences all number
    1
    3
    0
    0
    0
    Sinusitis
    Additional description: Non serious adverse event above 5% reported
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 52 (0.00%)
    3 / 51 (5.88%)
    1 / 49 (2.04%)
    2 / 48 (4.17%)
         occurrences all number
    1
    0
    3
    1
    2
    Upper respiratory tract infection
    Additional description: Non serious adverse event above 5% reported
         subjects affected / exposed
    3 / 55 (5.45%)
    1 / 52 (1.92%)
    2 / 51 (3.92%)
    1 / 49 (2.04%)
    2 / 48 (4.17%)
         occurrences all number
    3
    1
    2
    1
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Dec 2021
    Version 2.0, dated 16-Dec-2021 and approved in Feb 2022. The first BOOSTAVAC study protocol was developed and approved during the last quarter of 2021, however, a protocol amendment was required soon after the first approval and prior to inclusion of any participant into the study, to adapt the study to the rapidly changing clinical and regulatory environment surrounding the pandemic, which included a change in vaccination guidelines to recommend a third dose vaccine. As such the protocol was amended from a 3rd to 4th dose booster vaccination.
    02 May 2022
    Version 3.0, dated 02-May-2022 and first approved in Jul 2022: Further adjustments to the study protocol were necessary in response to feedback from regulatory reviews across Europe
    26 Sep 2022
    Version 4.0, dated 26-Sep-2022 and first approved in Nov 2022: An expansion of the entry criteria was implemented to enable individuals to participate regardless of the number of prior vaccinations, provided that they had received at least three doses of mRNA COVID-19 vaccines.
    14 Sep 2023
    Version 5.0, dated 14-Sep-2023, first approved in Oct 2023: Addition of the new adapted Comirnaty vaccine targeting the Omicron XBB.1.5 subvariant, revised AEs and revised study timelines

    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.
    The study only included 255 participants (of originally planned size of 500) with statistical power reduced from 93% to 70%.
    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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