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    Clinical Trial Results:
    Characterization of humoral and cellular immunity for tick-borne encephalitis (TBE) vaccination in allogeneic blood and marrow graft recipients: a pilot study

    Summary
    EudraCT number
    		 2011-002928-41
    Trial protocol
    		 AT  
    Global end of trial date
    28 Oct 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Jan 2022
    First version publication date
    11 Jan 2022
    Other versions
    Summary report(s)
    		 Publication npj vaccines 2020
    Publication Vaccines 2021

    Trial information

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    Trial identification
    Sponsor protocol code
    Immunity_TBE
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01991067
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Medical University of Vienna
    Sponsor organisation address
    Währinger Gürtel 18-20, Vienna, Austria, 1090
    Public contact
    Christina Forstner, Med. Uni Wien, +43 1404004440, nicole.harrison@meduniwien.ac.at
    Scientific contact
    Christina Forstner, Med. Uni Wien, 4040044400 1404004440, nicole.harrison@meduniwien.ac.at
    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 Oct 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Oct 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Oct 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the humoral immunogenicity to a TBE vaccination in allogeneic blood and marrow graft (HSCT) recipients compared to healthy volunteers without previous TBE vaccination, by measuring the quantitative antibody levels using neutralization test (NT) and enzyme-linked immunosorbent assay test (ELISA)
    Protection of trial subjects
    Patients were vaccinated and blood draws were taken by professional staff. All patients were covered by insurance during the trial.
    Background therapy
    		 not applicable
    Evidence for comparator
    		 not applicable
    Actual start date of recruitment
    01 Jul 2014
    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
    Austria: 34
    Worldwide total number of subjects
    34
    EEA total number of subjects
    34
    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)
    34
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 In this prospective single-center open-label study, adult patients ≥18 years of age were screened 11 to 13 months after allogeneic HSCT at the Outpatient Clinic of the Bone Marrow Transplant Unit of the University Hospital of Vienna, Austria.

    Pre-assignment
    Screening details
    		 Between July 2014 and January 2018, 136 patients were assessed for eligibility and 117 were excluded for following reason: not meeting the inclusion criteria (n=39), declined to participate (n=56), other reasons (n=22). 19 Patients were included in the study and 15 age-matched healthy controls.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Patients
    Arm description
    		 Patients after allogeneic hematopoeitic stem cell transplantation
    Arm type
    		 Active comparator

    Investigational medicinal product name
    FSME Immun
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Injection
    Dosage and administration details
    FSME Immun® (each dose contains 2.4 µg of inactivated TBE virus strain Neudörfl) is applied intramuscularly (M. deltoideus)

    Arm title
    		 Healthy controls
    Arm description
    		 Healthy controls
    Arm type
    		 Active comparator

    Investigational medicinal product name
    FSME Immun
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Injection
    Dosage and administration details
    FSME Immun® (each dose contains 2.4 µg of inactivated TBE virus strain Neudörfl) is applied intramuscularly (M. deltoideus)

    Number of subjects in period 1
    		Patients Healthy controls
    Started
    19
    15
    Completed
    17
    15
    Not completed
    2
    0
         Lost to follow-up
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Patients
    Reporting group description
    		 Patients after allogeneic hematopoeitic stem cell transplantation

    Reporting group title
    Healthy controls
    Reporting group description
    		 Healthy controls

    Reporting group values
    		 Patients Healthy controls Total
    Number of subjects
    		 19 15 34
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 19 15 34
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 31 (22 to 61) 30 (21 to 60) -
    Gender categorical
    Units: Subjects
        Female
    		 8 6 14
        Male
    		 11 9 20
    Underlying disease
    Underlying disease of patients
    Units: Subjects
        acute myeloid leukemia
    		 13 0 13
        acute lymphoblastic leukemia
    		 3 0 3
        lymphoma
    		 2 0 2
        aplastic anemia
    		 1 0 1
        not applicable
    		 0 15 15
    Conditioning regimen
    Conditioning regimen used before hematopoietic stem cell transplantation
    Units: Subjects
        myeloablative regimen
    		 9 0 9
        non-myeloablative regimen
    		 10 0 10
        not applicable
    		 0 15 15

    End points

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    End points reporting groups
    Reporting group title
    Patients
    Reporting group description
    		 Patients after allogeneic hematopoeitic stem cell transplantation

    Reporting group title
    Healthy controls
    Reporting group description
    		 Healthy controls

    Primary: antibody response by neutralization assay

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    End point title
    		 antibody response by neutralization assay
    End point description
    The primary endpoint of this study was the antibody response after TBE-vaccination as measured by neutralization assay (NT) four weeks after the second vaccination. Antibody response was defined as a composite endpoint by a NT-titer of ≥10, which is considered as a surrogate marker for protection and at least a two-fold increase of titer from baseline (or titer above highest level of measurement).
    End point type
    Primary
    End point timeframe
    four weeks after second vaccination
    End point values
    		 Patients Healthy controls
    Number of subjects analysed
    17
    15
    Units: count
    6
    14
    Statistical analysis title
    		 antibody response by neutralization assay
    Statistical analysis description
    Antibody response measured by neutralization assay was compared between patients and controls using Fishers Exact test.
    Comparison groups
    Patients v Healthy controls
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.001
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Geometric mean titer

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    End point title
    		 Geometric mean titer
    End point description
    Geometric mean titers measured by neutralization assay were compared between patients and healthy controls after second vaccination.
    End point type
    Secondary
    End point timeframe
    after second vaccination
    End point values
    		 Patients Healthy controls
    Number of subjects analysed
    17
    15
    Units: titer
        geometric mean (confidence interval 95%)
    64.7 (28.1 to 149.4)
    58.5 (32.2 to 106.1)
    Statistical analysis title
    		 Geometric mean titer
    Statistical analysis description
    The geometric mean titer after second vaccination was compared between patients and controls using Wilcoxon test.
    Comparison groups
    Patients v Healthy controls
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 > 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: antibody response by ELISA

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    End point title
    		 antibody response by ELISA
    End point description
    The antibody response was measured by ELISA four weeks after second vaccination and defined by ELISA titer of >=220 Vienna Units and at least a two-fold increase of titer from baseline.
    End point type
    Secondary
    End point timeframe
    four weeks after second vaccination
    End point values
    		 Patients Healthy controls
    Number of subjects analysed
    17
    15
    Units: total
    9
    14
    Statistical analysis title
    		 antibody response by ELISA
    Statistical analysis description
    Antibody response measured by ELISA four weeks after second vaccination was compared between patients and controls by Fishers Exact test.
    Comparison groups
    Patients v Healthy controls
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.02
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Geometric mean fold change of titer

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    End point title
    		 Geometric mean fold change of titer
    End point description
    Geometric mean fold change of NT titer between baseline and four weeks after third vaccination was compared between HSCT patients and controls.
    End point type
    Secondary
    End point timeframe
    between baseline and four weeks after third vaccination
    End point values
    		 Patients Healthy controls
    Number of subjects analysed
    13
    10
    Units: fold change
        geometric mean (confidence interval 95%)
    3.9 (1.3 to 11.9)
    45.2 (17.5 to 117.0)
    Statistical analysis title
    		 Geometric mean fold change
    Statistical analysis description
    Geometric mean fold change of titers between baseline and after third vaccination comparing patients and controls.
    Comparison groups
    Patients v Healthy controls
    Number of subjects included in analysis
    23
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.01
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Lymyphocyte proliferation second vaccination

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    End point title
    		 Lymyphocyte proliferation second vaccination
    End point description
    Lymphocyte proliferation detected by thymidine incorporation assay measured one week after second vaccination comparing patients and controls.
    End point type
    Secondary
    End point timeframe
    one week after second vaccination
    End point values
    		 Patients Healthy controls
    Number of subjects analysed
    17
    8
    Units: SI
        median (full range (min-max))
    8.43 (0.67 to 76.56)
    8.3 (1.75 to 23.93)
    No statistical analyses for this end point

    Secondary: Lymyphocyte proliferation Baseline

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    End point title
    		 Lymyphocyte proliferation Baseline
    End point description
    Lymphocyte proliferation detected by thymidine incorporation assay measured at baseline comparing patients and controls.
    End point type
    Secondary
    End point timeframe
    at baseline before vaccination
    End point values
    		 Patients Healthy controls
    Number of subjects analysed
    17
    8
    Units: SI
        median (full range (min-max))
    4.15 (1.02 to 69.7)
    0.98 (0.61 to 2.37)
    No statistical analyses for this end point

    Secondary: Lymyphocyte proliferation third vaccination

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    End point title
    		 Lymyphocyte proliferation third vaccination
    End point description
    Lymphocyte proliferation detected by thymidine incorporation assay measured one week after third vaccination comparing patients and controls
    End point type
    Secondary
    End point timeframe
    one week after third vaccination
    End point values
    		 Patients Healthy controls
    Number of subjects analysed
    13
    5
    Units: SI
        median (full range (min-max))
    21.02 (0.84 to 109.3)
    12.99 (1.79 to 27.79)
    No statistical analyses for this end point

    Secondary: IL-13 at baseline

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    End point title
    		 IL-13 at baseline
    End point description
    Interleukin 13 was measured by Luminex at baseline and compared between patients and controls.
    End point type
    Secondary
    End point timeframe
    at baseline before vaccination
    End point values
    		 Patients Healthy controls
    Number of subjects analysed
    17
    8
    Units: fold induction
        median (full range (min-max))
    1 (0.96 to 98.93)
    0.61 (0.57 to 0.84)
    No statistical analyses for this end point

    Secondary: IL-13 after second vaccination

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    End point title
    		 IL-13 after second vaccination
    End point description
    Interleukin 13 was measured by Luminex one week after second vaccination and compared between patients and controls.
    End point type
    Secondary
    End point timeframe
    one week after second vaccination
    End point values
    		 Patients Healthy controls
    Number of subjects analysed
    17
    8
    Units: fold induction
        median (full range (min-max))
    5.61 (0.96 to 184.1)
    2.07 (0.6 to 5.89)
    No statistical analyses for this end point

    Secondary: IL-13 after third vaccination

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    End point title
    		 IL-13 after third vaccination
    End point description
    Interleukin 13 was measured by Luminex one week after third vaccination and compared between patients and controls.
    End point type
    Secondary
    End point timeframe
    one week after third vaccination
    End point values
    		 Patients Healthy controls
    Number of subjects analysed
    13
    5
    Units: SI
        median (full range (min-max))
    32.26 (0.53 to 153.83)
    3.41 (0.61 to 7.21)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    During the whole study period from 1st of July 2014 to 28th of October 2018
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18
    Reporting groups
    Reporting group title
    Patients
    Reporting group description
    		 Patients after allogeneic hematopoeitic stem cell transplantation

    Reporting group title
    Healthy controls
    Reporting group description
    		 Healthy controls

    Serious adverse events
    		 Patients Healthy controls
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 19 (21.05%)
    0 / 15 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Blood and lymphatic system disorders
    Relapse of acute myeloid leukemia
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Haematometra
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholezystolithiasis
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Influenza
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Patients Healthy controls
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 19 (78.95%)
    6 / 15 (40.00%)
    Cardiac disorders
    subjective tachycardia
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    headache
         subjects affected / exposed
    3 / 19 (15.79%)
    0 / 15 (0.00%)
         occurrences all number
    4
    0
    General disorders and administration site conditions
    shivering
         subjects affected / exposed
    2 / 19 (10.53%)
    1 / 15 (6.67%)
         occurrences all number
    2
    1
    fatigue
         subjects affected / exposed
    2 / 19 (10.53%)
    1 / 15 (6.67%)
         occurrences all number
    2
    1
    sweating
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    fever
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    cold-like symptoms
         subjects affected / exposed
    2 / 19 (10.53%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    Immune system disorders
    increase of Graft-versus-host-disease (skin exanthema)
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Increase of Graft-versus-host-disease (mucosal lesions)
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    nausea
         subjects affected / exposed
    2 / 19 (10.53%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    weight loss
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    local pressure pain
         subjects affected / exposed
    9 / 19 (47.37%)
    5 / 15 (33.33%)
         occurrences all number
    13
    7
    local swelling
         subjects affected / exposed
    2 / 19 (10.53%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    local redness
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    local induration
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    fever blister
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    skin exanthema
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Endocrine disorders
    swelling of parotid gland
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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/32728481
    http://www.ncbi.nlm.nih.gov/pubmed/34452033
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