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Humoral and Cellular Immunity for TBE Vaccination in Allogeneic HSCT Recipients

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ClinicalTrials.gov Identifier: NCT01991067
Recruitment Status : Completed
First Posted : November 25, 2013
Results First Posted : July 14, 2020
Last Update Posted : February 3, 2022
Sponsor:
Collaborator:
Austrian Science Fund (FWF)
Information provided by (Responsible Party):
Christina Forstner, MD, Medical University of Vienna

Brief Summary:
Patients undergoing allogeneic blood and marrow transplantation (HSCT) experience a prolonged period of dysfunctional immunity. Systematic reimmunization is necessary at appropriate time intervals following transplantation to re-establish immunity. Vaccination practices after HSCT remain varied and data sparse. Tick-borne encephalitis (TBE) is one of the most severe infections of the central nervous system caused by a tick-borne flavivirus. There is no specific treatment, and prevention with the vaccine is the only intervention available. To assess the efficacy of TBE vaccination in adult allogeneic HSCT recipients compared to an age-matched and sex-matched control group of healthy volunteers without previous TBE vaccination, a prospective open-label phase II pilot study on humoral and cellular immune responses after use of TBE vaccine (FSME Immun) will be performed. As primary end point the outcome of the neutralization test (NT) against TBE will be assessed in a total of 26 HSCT patients one year after HSCT and in 26 healthy volunteers, namely four weeks after the second vaccination. Therefore, the number of subjects with NT titres against TBE virus >10, assumed to be the threshold for antibody-mediated protection will be evaluated. As secondary endpoints, antibody concentrations of TBE enzyme-linked immunosorbent assay before and four weeks after the second and third vaccination and antibody concentrations of NT against TBE four weeks after primary immunization. To evaluate cellular immune responses, lymphocyte proliferations assays and cytokine detection assays will be performed. In a subgroup analysis, these secondary endpoints will be compared between healthy volunteers, HSCT patients without immunosuppressive treatment and HSCT patients receiving immunosuppressive agents. Additionally, immune reconstitution by analysis of peripheral blood lymphocyte subsets and serum immunoglobulin levels will be evaluated prior to vaccination, after twelve weeks and prior to the third vaccination in HSCT patients only.

Condition or disease Intervention/treatment Phase
Tick Borne Encephalitis Biological: TBE virus vaccine Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 34 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: Characterization of Humoral and Cellular Immunity for Tick-borne Encephalitis (TBE) Vaccination in Allogeneic Blood and Marrow Graft Recipients: a Pilot Study
Actual Study Start Date : July 2014
Actual Primary Completion Date : October 28, 2018
Actual Study Completion Date : October 28, 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: HSCT patients / TBE virus vaccine
Study population: patients who had undergone an allogeneic HSCT 11 to 13 months ago Eligible patients will receive at least two TBE vaccinations (study visit 1 - day 0, study visit 2 -1month after the first vaccination) with a total of two doses of the TBE vaccine FSME-IMMUN®. Whenever possible, the patients will receive complete primary vaccination with a third dose of TBE vaccine (study visit 9 - 9 to 12 months after the first vaccination).
Biological: TBE virus vaccine
TBE virus vaccine FSME Immun is used in both arms for the study population and the control group
Other Name: FSME Immun

Active Comparator: healthy volunteers / TBE virus vaccine
Clinical healthy volunteers will receive at least two TBE vaccinations (study visit 1 - day 0, study visit 2 -1month after the first vaccination) with a total of two doses of the TBE vaccine FSME IMMUN®. Whenever possible, the volunteers will receive complete primary vaccination with a third dose of TBE vaccine FSME IMMUN® (study visit 9 - 12 months after the first vaccination).
Biological: TBE virus vaccine
TBE virus vaccine FSME Immun is used in both arms for the study population and the control group
Other Name: FSME Immun




Primary Outcome Measures :
  1. Outcome of the Neutralization Test (Number of Subjects With Antibody Response Measured by Neutralization Assay) [ Time Frame: four weeks after the second vaccination ]
    The Primary endpoint of this study was the antibody Response after TBE-vaccination as measured by neutralization assay four weeks after second vaccination. Antibody response was defined as a Composite endpoint by a NT-titer of >=10, and at least a two-fold increase from baseline (or titer above the highest level of measurement


Secondary Outcome Measures :
  1. Antibody Response as Measured by TBE-ELISA After Second Vaccination [ Time Frame: comparison between baseline and four weeks after second vaccination ]
    The antibody response after TBE-vaccination four weeks after second vaccination was measured by ELISA defined by a ELISA titer of >=220 Vienna Units and at least a two-fold increase of titer from baseline

  2. Change of Antibody Concentration of NT Titer [ Time Frame: between baseline and four weeks after the third vaccination ]
    Geometric mean fold change of NT titer between baseline and four weeks after third vaccination was compared between HSCT patients and healthy controls

  3. Lymphocyte Proliferation as a Measure of Cellular Immune Response in the Study Population Versus the Control Group Prior Vaccination [ Time Frame: before vaccination ]
    Baseline data for lymphocyte proliferation was detected by thymidine incorporation assay after stimulation with albumin-free TBE Antigen. Data was standardized based on unstimulated controls of each participant. The stimulation index is given. The stimulation index is the ratio of the number of proliferating lymphocytes with thymidine incorporation in the presence of antigen to that in absence of antigen. A SI value equal or greater to 3.0 represents relevant lymphocyte proliferation, whereas a SI value <3.0 represents no relevant lymphocyte proliferation.

  4. Fold Induction in IL13 Cytokine Levels Before Vaccination (Baseline) in the Study Population Versus the Control Group [ Time Frame: before vaccination ]
    Determination of secreted IL13 cytokine levels iwas performed using the Luminex System at baseline. Data was standardized based on unstimulated controls of each patient. The fold induction in the presence of TBE antigen to that in absence is given.

  5. Lymphocyte Proliferation as a Measure of Cellular Immune Response in The Study Population Versus the Control Group After Second Vaccination [ Time Frame: 7 days after second vaccination ]
    Data for lymphocyte proliferation was detected by thymidine incorporation assay after stimulation with albumin-free TBE antigen 7 days after the second vaccination. Data was standardized based on unstimulated controls of each participant. The stimulation index is given. The stimulation index is the ratio of the number of proliferating lymphocytes with thymidine incorporation in the presence of antigen to that in absence of antigen. A SI value equal or greater to 3.0 represents relevant lymphocyte proliferation, whereas a SI value <3.0 represents no relevant lymphocyte proliferation.

  6. Lymphocyte Proliferation as a Measure of Celluar Immune Response in the Study Population Versus the Control Group After Third Vaccination [ Time Frame: 7 days after Third Vaccination ]
    Data for lymphocyte proliferation was detected by thymidine incorporation assay after stimulation with albumin-free TBE antigen 7 days after the third vaccination. Data was standardized based on unstimulated controls of each participant. The stimulation index is given. The stimulation index is the ratio of the number of proliferating lymphocytes with thymidine incorporation in the presence of antigen to that in absence of antigen. A SI value equal or greater to 3.0 represents relevant lymphocyte proliferation, whereas a SI value <3.0 represents no relevant lymphocyte proliferation.

  7. Fold Induction in IL13 Cytokine Levels in the Study Population Versus the Control Group After Second Vaccination [ Time Frame: 7 days after second vaccination ]
    Determination of secreted IL13 cytokine levels was performed using the Luminex System 7 days after second vaccination. Data was standardized based on unstimulated controls of each patient. The fold induction in the presence of TBE antigen to that in absence is given.

  8. Fold Induction in IL13 Cytokine Levels in the Study Population Versus the Control Group After Third Vaccination [ Time Frame: 7 days after third vaccination ]
    Determination of secreted IL13 cytokine levels was performed using the Luminex System 7 days after third vaccination. Data was standardized based on unstimulated controls of each patient. The fold induction in the presence of TBE antigen to that in absence is given.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Male and female subjects will be eligible for participation in this study if they:

    • Are ≥18 years on the day of screening
    • Had undergone an allogeneic HSCT 11 to 13 months ago (study population)
    • Are clinical healthy without previous TBE vaccination (control group)
    • Have an understanding of the study, agree to its provisions, and give written informed consent prior to study entry
    • If female and capable of bearing children - have a negative urine pregnancy test result at study entry and agree to employ adequate birth control measures for the duration of the study

Exclusion Criteria:

  • Subjects will be excluded from participation in this study if they:

    • Have received a TBE vaccination following HSCT
    • Suffer from extremely severe acute graft-versus host disease and therefore receive prednisone >0.5 mg/kg bodyweight as part of a combination therapy or a three agent immunosuppressive treatment (because in these HSCT patients any type of vaccination has to be postponed until immunosuppression is reduced to a double combination or prednisone <0.5 mg/kg bodyweight)
    • Suffer from or have a history of previous TBE virus infection or vaccination, previous dengue virus infection or vaccination against yellow fever or Japanese encephalitis
    • Have any acute febrile illness in the 2 weeks prior to or at the time of enrolment
    • Have a history of severe allergic reactions or anaphylaxis after vaccination
    • If female, are pregnant or lactating.
    • If belonging to the healthy control group, are immunosuppressed (suffer from or have a history of immune mediated diseases, long-term use of corticosteroids, hemodialysis, chronic renal insufficiency, liver cirrhosis Child-Pugh class C, hematooncological malignant disease, solid organ transplant, HSCT)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01991067


Locations
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Austria
Medical University of Vienna, Department of Medicine I, Division of Infectious Diseases and Tropical Medicine
Vienna, Austria, 1090
Sponsors and Collaborators
Medical University of Vienna
Austrian Science Fund (FWF)
Investigators
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Principal Investigator: Christina Forstner, MD Medical University of Vienna
  Study Documents (Full-Text)

Documents provided by Christina Forstner, MD, Medical University of Vienna:
Publications of Results:
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Responsible Party: Christina Forstner, MD, Associate Professor, PD, Medical University of Vienna
ClinicalTrials.gov Identifier: NCT01991067    
Other Study ID Numbers: EudraCT_2011-002928-41
First Posted: November 25, 2013    Key Record Dates
Results First Posted: July 14, 2020
Last Update Posted: February 3, 2022
Last Verified: January 2022
Keywords provided by Christina Forstner, MD, Medical University of Vienna:
Marrow transplant recipients
Additional relevant MeSH terms:
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Encephalitis, Tick-Borne
Encephalitis
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Encephalitis, Arbovirus
Encephalitis, Viral
Central Nervous System Viral Diseases
Central Nervous System Infections
Infections
Infectious Encephalitis
Arbovirus Infections
Vector Borne Diseases
Tick-Borne Diseases
Virus Diseases
RNA Virus Infections
Flavivirus Infections
Flaviviridae Infections