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    Clinical Trial Results:
    A MULTINATIONAL, PHASE 2, RANDOMISED, ADAPTIVE PROTOCOL TO EVALUATE IMMUNOGENICITY AND REACTOGENICITY OF DIFFERENT COVID-19 VACCINES ADMINISTRATION IN OLDER ADULTS (≥75) ALREADY VACCINATED AGAINST SARS-COV-2 (EU-COVAT-1 AGED)

    Summary
    EudraCT number
    		 2021-004526-29
    Trial protocol
    		 DE   NO   IE   ES   LT  
    Global end of trial date
    30 Nov 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Dec 2024
    First version publication date
    14 Dec 2024
    Other versions
    Summary report(s)
    		 EU-COVAT-1_AGED
    EU-COVAT-1_AGED
    EU-COVAT-1_AGED
    EU-COVAT-1_AGED
    EU-COVAT-1_AGED

    Trial information

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    Trial identification
    Sponsor protocol code
    uni-koeln-4602
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05160766
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Cologne
    Sponsor organisation address
    Albertus-Magnus-Platz, Cologne, Germany, 50923
    Public contact
    Project Manager, University Hospital Cologne, +49 22147885523, eucovat-1-aged@vaccelerate.eu
    Scientific contact
    Sponsor Representative, University Hospital Cologne, +49 22147885523, oliver.cornely@uk-koeln.de
    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
    30 Nov 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 Sep 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Nov 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To compare the immune response between treatment arms after a 3rd (Part A) or 4th (Part B) vaccination dose against SARS-CoV-2. Due to the extensive roll-out of COVID-19 booster campaigns throughout Europe and poor recruitment rate as a consequence, Part A of the trial (3rd COVID-19 vaccination) was closed to further enrolment as of 13 January 2022. Part B of the trial (4th COVID-19 vaccination) was introduced as of 21 January 2022. New COVID-19 vaccines targeting Omicron BA.1 and Omicron BA.4/BA.5 have been approved in September 2022 by the European Commission. Variant-adapted COVID-19 vaccines were rolled out in multiple countries as part of national booster campaigns. The EU-COVAT-1_AGED trial included BNT162b2 and mRNA-1273 as nonvariant adapated vaccines as IMP for booster vaccination. Recruitment was consequently prematurely terminated, thus all analyses should be considered as exploratory (pre-specified and post-hoc).
    Protection of trial subjects
    Protection measures of the subjects are summarised in the following, subjects were healthy volunteers with regard to the condition against they were vaccinated: a) An independent DMC was established to review efficacy and safety data, e.g. SAEs/SUSARs, and their impact on the benefit-risk assessment for the subjects. DMC gave recommendations on continuation, modification or early termination of the clinical trial considering particularly safety aspects, but also re-cruitment and potential superiority of specific treatment arms. b) Continuous sponsor assessment of SAEs, assuring an ongoing evaluation and medical review of the SAEs and to evaluate SAEs regarding their seriousness, causality and expectedness. c) An independent Medical Monitor was involved. Tasks of the Medical Monitor included periodic per subject and cumulative reviews of the accumulating safety data including a review of (S)AE, overdose and laboratory data (as applicable), medical review of specified clinical data to ensure completeness, consistency and medical sense, and review of medically related protocol deviations. The Medical Monitor war further involved in all correspondence addressed to the sponsor’s assessors in order to ensure a comprehensive medical surveillance by the Medical Monitor and immediate awareness of all SAEs including the SAE assessment and medical review information by the sponsor. d) SAE tracking tables which documented all received and processed SAEs (initial and follow-up SAE reports) were transmitted to the sponsor assessors, the Medical Monitor and the DMC members by safety management on a monthly basis.
    Background therapy
    		 Not applicable in a vaccination trial.
    Evidence for comparator
    		 The present vaccination trial is a head-to-head comparison of two anti SARS-CoV-2 vaccines which had received marketing authorisation during the COVID-19 pandemic. There was no control arm without vaccination.
    Actual start date of recruitment
    02 Nov 2021
    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: 50
    Country: Number of subjects enrolled
    Spain: 87
    Country: Number of subjects enrolled
    Germany: 132
    Country: Number of subjects enrolled
    Lithuania: 1
    Worldwide total number of subjects
    270
    EEA total number of subjects
    270
    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
    206
    85 years and over
    64

    Subject disposition

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    Recruitment
    Recruitment details
    		 Part A (3rd vaccination): n=53. First subject enrolled: 08 Nov 2021; last subject completed: 03 Jan 2023. One active trial site. Part B (4th vaccination): n=270. First subject enrolled: 16 Feb 2022; last subject completed: 13 Sep 2023. 9 active trial sites (4 countries). This report exclusively covers Part B. Part A results can be requested.

    Pre-assignment
    Screening details
    		 Not applicable in this trial.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 BNT162b2
    Arm description
    		 BNT162b2 (Comirnaty®) was administered as 2nd COVID-19 booster dose (4th vaccination in total). It contains 30 μg of tozinameran (0.3 mL after dilution) as approved for individuals ≥12 years by the European Commission.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    BNT162b2
    Investigational medicinal product code
    J07BX
    Other name
    Comirnaty®
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Dosage: 30 μg (0.3 mL after dilution) Administration details: Intramuscular injection

    Arm title
    		 mRNA-1273
    Arm description
    		 mRNA-1273 (Spikevax®) was administered as 2nd COVID-19 booster dose (4th vaccination in total). It contains 100 μg (0.5 mL after dilution).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    mRNA-1273
    Investigational medicinal product code
    J07BX03
    Other name
    Spikevax®
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Dosage: 100 μg (0.5 mL after dilution) Administration details: Intramuscular injection

    Number of subjects in period 1
    		BNT162b2 mRNA-1273
    Started
    135
    135
    Completed
    126
    123
    Not completed
    9
    12
         Adverse event, serious fatal
    2
    5
         Consent withdrawn by subject
    3
    2
         Physician decision
    -
    1
         Not showing up or showing up on the wrong date
    1
    1
         Subject's decision
    1
    -
         Lost to follow-up
    1
    2
         Too time-consuming
    -
    1
         Protocol deviation
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    BNT162b2
    Reporting group description
    		 BNT162b2 (Comirnaty®) was administered as 2nd COVID-19 booster dose (4th vaccination in total). It contains 30 μg of tozinameran (0.3 mL after dilution) as approved for individuals ≥12 years by the European Commission.

    Reporting group title
    mRNA-1273
    Reporting group description
    		 mRNA-1273 (Spikevax®) was administered as 2nd COVID-19 booster dose (4th vaccination in total). It contains 100 μg (0.5 mL after dilution).

    Reporting group values
    		 BNT162b2 mRNA-1273 Total
    Number of subjects
    		 135 135 270
    Age categorical
    Units: Subjects
        >=75-<85
    		 100 106 206
        85+
    		 35 29 64
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 80.99 ( 5.49 ) 81.09 ( 5.88 ) -
    Gender categorical
    Biological sex was differentiated by female and male.
    Units: Subjects
        Female
    		 67 68 135
        Male
    		 68 67 135

    End points

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    End points reporting groups
    Reporting group title
    BNT162b2
    Reporting group description
    		 BNT162b2 (Comirnaty®) was administered as 2nd COVID-19 booster dose (4th vaccination in total). It contains 30 μg of tozinameran (0.3 mL after dilution) as approved for individuals ≥12 years by the European Commission.

    Reporting group title
    mRNA-1273
    Reporting group description
    		 mRNA-1273 (Spikevax®) was administered as 2nd COVID-19 booster dose (4th vaccination in total). It contains 100 μg (0.5 mL after dilution).

    Primary: Antibody Titre Increase 14 Days After 4th Vaccination Dose

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    End point title
    		 Antibody Titre Increase 14 Days After 4th Vaccination Dose [1]
    End point description
    Rate of 2-fold antibody titre increase 14 days after 4th vaccination dose measured by qualitative enzyme-linked immunosorbent assay (Anti-RBD-ELISA) against wildtype virus. Because the trial was terminated before the initial target sample size was reached, only confidence intervals for the rates per group are reported. All analyses should be considered as exploratory (pre-specified and post-hoc) due to the premature termination. Descriptive analysis: In the BNT162b2 group 102/130 (78.5%) [97.5% CI: 69.2% - 86%] subjects showed a two-fold increase in anti-RBD IgG titres at 14 days after 4th dose compared to 116/133 (87.2%) [97.5% CI: 79.3% - 93%] subjects in the mRNA-1273 group. All primary analyses were performed on the mITT population set. All trial data (Part A and B) will be shared upon request as per FAIR principles.
    End point type
    Primary
    End point timeframe
    From Day 0 until Day 14
    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: Because the trial was terminated before the initial target sample size was reached, only confidence intervals for the rates per group are reported. All analyses should be considered as exploratory (pre-specified and post-hoc) due to the premature termination.
    End point values
    		 BNT162b2 mRNA-1273
    Number of subjects analysed
    130
    133
    Units: Count of participants
    102
    116
    No statistical analyses for this end point

    Secondary: Change in Neutralizing Antibody Titre Against Wild-type 14 Days After a 4th Vaccination Dose

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    End point title
    		 Change in Neutralizing Antibody Titre Against Wild-type 14 Days After a 4th Vaccination Dose
    End point description
    Change in neutralizing antibody titre (Virus Neutralisation Assay) against wild-type 14 days after a 4th vaccination dose, to be determined in a subgroup only. Number of subjects for whom the difference of neutralizing activity (Day 14 minus Day 0) could be calculated. For the descriptive statistics, only subjects with valid measurements at all timepoints have been considered.
    End point type
    Secondary
    End point timeframe
    From Day 0 until Day 14
    End point values
    		 BNT162b2 mRNA-1273
    Number of subjects analysed
    122
    120
    Units: Percentage
        arithmetic mean (standard deviation)
    37.33 ( 22.93 )
    41.45 ( 24.09 )
    Statistical analysis title
    		 ANCOVA
    Statistical analysis description
    For this analysis all subjects (n=262; BNT162b2 n= 129 and mRNA-1273 = 133) with valid values at baseline and Day 14 have been considered. No imputation of missing values.
    Comparison groups
    mRNA-1273 v BNT162b2
    Number of subjects included in analysis
    242
    Analysis specification
    Post-hoc
    Analysis type
    		 other
    P-value
    		 = 0.0101
    Method
    		 ANCOVA
    Parameter type
    		 Difference of means in percent
    Point estimate
    4.331
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.04
         upper limit
    		 7.621
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.671

    Secondary: Change in Neutralizing Antibody Titre Against Variants of Concern 14 Days After 4th Vaccination Dose

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    End point title
    		 Change in Neutralizing Antibody Titre Against Variants of Concern 14 Days After 4th Vaccination Dose
    End point description
    Change in neutralizing antibody titre (Virus Neutralisation Assay) against variants of concern 14 days after a 4th vaccination dose, to be determined in a subgroup only. The provided values refer to the variant "B.1.1.7 (alpha)". Besides for B.1.1.7 (alpha), all statistical tests described above were also conducted for the following variants of concern/interest: B.1.351 (beta), P.1 (gamma), P.2 (gamma), B.1.617, B.1.617.1 (kappa), AY.3 (delta), AY.4.2 (delta), B.1.617.3, B.1.526.1 (iota), BA.1 (omicron), BA.2 (omicron), BA.2+L452M (omicron), BA.2+L452R (omicron), BA.2.12.1 (omicron), BA.2.75 (omicron), BA.2.75.2 (omicron), BA.3 (omicron), BA.4 (omicron), BA.4.6 (omicron), BA.5 (omicron), BF.7 (omicron), BQ.1 (omicron), BQ.1.1 (omicron), and XBB.1 (omicron). For the descriptive statistics, only subjects with valid measurements at all timepoints have been considered. All trial results were published in an open-access journal. All trial data will be shared upon request.
    End point type
    Secondary
    End point timeframe
    From Day 0 until Day 14
    End point values
    		 BNT162b2 mRNA-1273
    Number of subjects analysed
    122
    120
    Units: difference of percentage (D14 minus D0)
        arithmetic mean (standard deviation)
    38.17 ( 21.74 )
    44.04 ( 23.94 )
    Statistical analysis title
    		 ANCOVA
    Statistical analysis description
    For this analysis all subjects (n=262; BNT162b2 n= 129 and mRNA-1273 = 133) with valid values at baseline and Day 14 have been considered. No imputation of missing values.
    Comparison groups
    mRNA-1273 v BNT162b2
    Number of subjects included in analysis
    242
    Analysis specification
    Post-hoc
    Analysis type
    		 other
    P-value
    		 = 0.00258
    Method
    		 ANCOVA
    Parameter type
    		 Difference of means in percent
    Point estimate
    6.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.41
         upper limit
    		 11.249
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.244

    Secondary: Antibody Titre Level at 12 Months After a 4th Vaccination Dose

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    End point title
    		 Antibody Titre Level at 12 Months After a 4th Vaccination Dose
    End point description
    Antibody titre level at 12 months after a 4th vaccination dose measured by a quantitative enzyme-linked immunosorbent assay (anti-RBD-ELISA assay). Subjects in whom a blood sampling was performed at Month 12.
    End point type
    Secondary
    End point timeframe
    From Day 0 until Month 12
    End point values
    		 BNT162b2 mRNA-1273
    Number of subjects analysed
    125
    121
    Units: IU/ml
        geometric mean (standard deviation)
    9961.92 ( 26292.23 )
    12024.3 ( 29129.18 )
    No statistical analyses for this end point

    Secondary: Neutralizing Antibody Titre Against Wild-type at 12 Months After a 4th Vaccination Dose

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    End point title
    		 Neutralizing Antibody Titre Against Wild-type at 12 Months After a 4th Vaccination Dose
    End point description
    Neutralizing antibody titre (Virus Neutralisation Assay) against wild-type SARS-CoV-2 at 12 months after a 4th vaccination dose, to be determined in a subgroup only.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    		 BNT162b2 mRNA-1273
    Number of subjects analysed
    123
    121
    Units: Percentage
        arithmetic mean (standard deviation)
    59.001 ( 30.67 )
    64.726 ( 31.205 )
    No statistical analyses for this end point

    Secondary: Neutralizing Antibody Titre Against Variants of Concern at 12 Months After a 4th Vaccination Dose

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    End point title
    		 Neutralizing Antibody Titre Against Variants of Concern at 12 Months After a 4th Vaccination Dose
    End point description
    Neutralizing antibody titre (Virus Neutralisation Assay) against variants of concern at 12 months after a 4th vaccination dose, to be determined in a subgroup only. Titres of neutralizing antibodies were reported as change in neutralization capacity. Provided values refer to the variant "B.1.1.7 (alpha)". For all other variants of concern/interest, please see the open-access publication.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    		 BNT162b2 mRNA-1273
    Number of subjects analysed
    122
    121
    Units: Percentage
        arithmetic mean (standard deviation)
    46.195 ( 31.1 )
    52.811 ( 33.279 )
    No statistical analyses for this end point

    Other pre-specified: Unsolicited AEs

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    End point title
    		 Unsolicited AEs
    End point description
    Unsolicited AEs until the end of trial
    End point type
    Other pre-specified
    End point timeframe
    From Day 0 until Month 12
    End point values
    		 BNT162b2 mRNA-1273
    Number of subjects analysed
    135
    135
    Units: Participants
    110
    112
    No statistical analyses for this end point

    Other pre-specified: Solicited AEs

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    End point title
    		 Solicited AEs
    End point description
    Solicited AEs for 7 days after a 4th vaccination dose.
    End point type
    Other pre-specified
    End point timeframe
    From Day 0 until Day 7
    End point values
    		 BNT162b2 mRNA-1273
    Number of subjects analysed
    135
    135
    Units: Participants
    76
    80
    No statistical analyses for this end point

    Other pre-specified: Rate of SAEs Grade ≥3

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    End point title
    		 Rate of SAEs Grade ≥3
    End point description
    Rate of serious adverse events (SAEs) Grade ≥3 according to the National Cancer Institute Common Toxicity Criteria up to three months after a 4th vaccination dose. Provided values refer to SAEs related to the IMP. All other trial data is available upon request.
    End point type
    Other pre-specified
    End point timeframe
    From Day 0 until Month 3
    End point values
    		 BNT162b2 mRNA-1273
    Number of subjects analysed
    135
    135
    Units: Participants
    1
    0
    No statistical analyses for this end point

    Other pre-specified: Change in Cellular Immune Response Measured by qPCR 14 Days After 4th Vaccination Dose

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    End point title
    		 Change in Cellular Immune Response Measured by qPCR 14 Days After 4th Vaccination Dose
    End point description
    Change in cellular immune response (CD4+ and CD8+ T cell response) measured by qPCR 14 days after 4th vaccination dose, to be determined in a subgroup only. Inclusion required completed visits at Day 0 and Day 14 with a sufficient number of aliquots as per CTP. Provided results are absolute values of the cellular immune response on Day 14 of tubes stimulated with peptides from spike (tube A). Samples were also stimulated with peptides from a virus membrane nucleoprotein (tube B) and with peptides from the Omicron variant (tube C). All trial results will be provided upon request.
    End point type
    Other pre-specified
    End point timeframe
    From Day 0 until Day 14
    End point values
    		 BNT162b2 mRNA-1273
    Number of subjects analysed
    79
    92
    Units: CT actine
        arithmetic mean (standard deviation)
    26.63 ( 1.58 )
    26.63 ( 1.59 )
    No statistical analyses for this end point

    Other pre-specified: Neutralizing Antibody Titre Against Newly Emerging Variants in Bio-banked Samples After 4th Vaccination Dose

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    End point title
    		 Neutralizing Antibody Titre Against Newly Emerging Variants in Bio-banked Samples After 4th Vaccination Dose
    End point description
    Neutralizing antibody titre (Virus Neutralisation Assay) against newly emerging variants in bio-banked samples after 4th vaccination dose, to be determined in a subgroup only. Provided values refer to the variant "XBB.1 (omicron)". For all other variants of interest, please see the open-access publication.
    End point type
    Other pre-specified
    End point timeframe
    Month 12
    End point values
    		 BNT162b2 mRNA-1273
    Number of subjects analysed
    123
    121
    Units: Percentage
        arithmetic mean (standard deviation)
    30.663 ( 31.374 )
    35.018 ( 32.202 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Day 0 until Month 12
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.1
    Reporting groups
    Reporting group title
    BNT162b2
    Reporting group description
    		 -

    Reporting group title
    mRNA-1273
    Reporting group description
    		 -

    Serious adverse events
    		 BNT162b2 mRNA-1273
    Total subjects affected by serious adverse events
         subjects affected / exposed
    21 / 135 (15.56%)
    22 / 135 (16.30%)
         number of deaths (all causes)
    2
    5
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial cancer
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningioma
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Plasmacytoma
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Vertebroplasty
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 135 (0.74%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 135 (0.74%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstructive sleep apnoea syndrome
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Concussion
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 135 (0.74%)
    3 / 135 (2.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 135 (0.00%)
    2 / 135 (1.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure congestive
         subjects affected / exposed
    1 / 135 (0.74%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 135 (0.74%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Sinus node dysfunction
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Brain stem stroke
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Dizziness
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 135 (0.00%)
    3 / 135 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo positional
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Amaurosis fugax
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glaucoma
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Visual impairment
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal disorder
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal sepsis
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    COVID-19
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea infectious
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 135 (1.48%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 135 (2.22%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 135 (0.74%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    2 / 135 (1.48%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 BNT162b2 mRNA-1273
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    103 / 135 (76.30%)
    110 / 135 (81.48%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    4 / 135 (2.96%)
    7 / 135 (5.19%)
         occurrences all number
    5
    7
    Headache
         subjects affected / exposed
    14 / 135 (10.37%)
    23 / 135 (17.04%)
         occurrences all number
    17
    27
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    14 / 135 (10.37%)
    16 / 135 (11.85%)
         occurrences all number
    14
    19
    Chills
         subjects affected / exposed
    6 / 135 (4.44%)
    8 / 135 (5.93%)
         occurrences all number
    6
    8
    Extensive swelling of vaccinated limb
         subjects affected / exposed
    1 / 135 (0.74%)
    4 / 135 (2.96%)
         occurrences all number
    1
    4
    Fatigue
         subjects affected / exposed
    31 / 135 (22.96%)
    51 / 135 (37.78%)
         occurrences all number
    34
    57
    Injection site erythema
         subjects affected / exposed
    8 / 135 (5.93%)
    20 / 135 (14.81%)
         occurrences all number
    8
    22
    Injection site pain
         subjects affected / exposed
    54 / 135 (40.00%)
    59 / 135 (43.70%)
         occurrences all number
    55
    62
    Injection site pruritus
         subjects affected / exposed
    9 / 135 (6.67%)
    9 / 135 (6.67%)
         occurrences all number
    9
    9
    Injection site swelling
         subjects affected / exposed
    10 / 135 (7.41%)
    15 / 135 (11.11%)
         occurrences all number
    10
    15
    Malaise
         subjects affected / exposed
    11 / 135 (8.15%)
    17 / 135 (12.59%)
         occurrences all number
    11
    18
    Pyrexia
         subjects affected / exposed
    0 / 135 (0.00%)
    3 / 135 (2.22%)
         occurrences all number
    0
    3
    Swelling face
         subjects affected / exposed
    0 / 135 (0.00%)
    3 / 135 (2.22%)
         occurrences all number
    0
    3
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    4 / 135 (2.96%)
    4 / 135 (2.96%)
         occurrences all number
    4
    4
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 135 (1.48%)
    6 / 135 (4.44%)
         occurrences all number
    2
    6
    Nausea
         subjects affected / exposed
    1 / 135 (0.74%)
    8 / 135 (5.93%)
         occurrences all number
    1
    9
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 135 (0.74%)
    3 / 135 (2.22%)
         occurrences all number
    1
    3
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    3 / 135 (2.22%)
    12 / 135 (8.89%)
         occurrences all number
    3
    14
    Night sweats
         subjects affected / exposed
    3 / 135 (2.22%)
    12 / 135 (8.89%)
         occurrences all number
    4
    13
    Pruritus
         subjects affected / exposed
    3 / 135 (2.22%)
    5 / 135 (3.70%)
         occurrences all number
    4
    6
    Rash
         subjects affected / exposed
    3 / 135 (2.22%)
    0 / 135 (0.00%)
         occurrences all number
    4
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    7 / 135 (5.19%)
    15 / 135 (11.11%)
         occurrences all number
    9
    17
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    6 / 135 (4.44%)
    8 / 135 (5.93%)
         occurrences all number
    6
    8
    Myalgia
         subjects affected / exposed
    7 / 135 (5.19%)
    11 / 135 (8.15%)
         occurrences all number
    8
    11
    Pain in extremity
         subjects affected / exposed
    34 / 135 (25.19%)
    40 / 135 (29.63%)
         occurrences all number
    35
    42
    Infections and infestations
    COVID-19
         subjects affected / exposed
    31 / 135 (22.96%)
    31 / 135 (22.96%)
         occurrences all number
    33
    33
    Nasopharyngitis
         subjects affected / exposed
    6 / 135 (4.44%)
    5 / 135 (3.70%)
         occurrences all number
    7
    5
    Urinary tract infection
         subjects affected / exposed
    3 / 135 (2.22%)
    3 / 135 (2.22%)
         occurrences all number
    4
    5
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    4 / 135 (2.96%)
    7 / 135 (5.19%)
         occurrences all number
    5
    8

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Dec 2021
    The main changes concerned the protocol (CTP V04) in which the visit schedule was simplified and the number of visits reduced. The revision of the visit schedule also included a designated process presentation for obtaining a GCP-compliant informed consent prior to the initiation of study-relevant measures.
    21 Jan 2022
    The main changes concerned the protocol (CTP V05) and the associated synopsis due to the introduction of a fourth instead of a third vaccination dose. In addition to changes to the content, the wording of the protocol was clarified in some passages. Editorial changes were also made.
    17 Aug 2022
    The main changes concerned the protocol (CTP V06) and the associated synopsis. In addition to a few content-related changes, the wording of the protocol has been the wording was clarified and editorial adjustments were made.

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

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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/36209129
    http://www.ncbi.nlm.nih.gov/pubmed/37919141
    http://www.ncbi.nlm.nih.gov/pubmed/38992789
    http://www.ncbi.nlm.nih.gov/pubmed/37919289
    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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