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Humoral and Cellular Immunity for TBE Vaccination in Allogeneic HSCT Recipients

Primary Purpose

Tick Borne Encephalitis

Status
Completed
Phase
Phase 2
Locations
Austria
Study Type
Interventional
Intervention
TBE virus vaccine
Sponsored by
Medical University of Vienna
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Tick Borne Encephalitis focused on measuring Marrow transplant recipients

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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)

Sites / Locations

  • Medical University of Vienna, Department of Medicine I, Division of Infectious Diseases and Tropical Medicine

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Active Comparator

Arm Label

HSCT patients / TBE virus vaccine

healthy volunteers / TBE virus vaccine

Arm Description

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).

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).

Outcomes

Primary Outcome Measures

Outcome of the Neutralization Test (Number of Subjects With Antibody Response Measured by Neutralization Assay)
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

Antibody Response as Measured by TBE-ELISA 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
Change of Antibody Concentration of NT Titer
Geometric mean fold change of NT titer between baseline and four weeks after third vaccination was compared between HSCT patients and healthy controls
Lymphocyte Proliferation as a Measure of Cellular Immune Response in the Study Population Versus the Control Group Prior 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.
Fold Induction in IL13 Cytokine Levels Before Vaccination (Baseline) in the Study Population Versus the Control Group
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.
Lymphocyte Proliferation as a Measure of Cellular Immune Response in The Study Population Versus the Control Group 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.
Lymphocyte Proliferation as a Measure of Celluar Immune Response in the Study Population Versus the Control Group 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.
Fold Induction in IL13 Cytokine Levels in the Study Population Versus the Control Group 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.
Fold Induction in IL13 Cytokine Levels in the Study Population Versus the Control Group 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.

Full Information

First Posted
November 6, 2013
Last Updated
January 27, 2022
Sponsor
Medical University of Vienna
Collaborators
Austrian Science Fund (FWF)
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1. Study Identification

Unique Protocol Identification Number
NCT01991067
Brief Title
Humoral and Cellular Immunity for TBE Vaccination in Allogeneic HSCT Recipients
Official Title
Characterization of Humoral and Cellular Immunity for Tick-borne Encephalitis (TBE) Vaccination in Allogeneic Blood and Marrow Graft Recipients: a Pilot Study
Study Type
Interventional

2. Study Status

Record Verification Date
January 2022
Overall Recruitment Status
Completed
Study Start Date
July 2014 (Actual)
Primary Completion Date
October 28, 2018 (Actual)
Study Completion Date
October 28, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Medical University of Vienna
Collaborators
Austrian Science Fund (FWF)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Tick Borne Encephalitis
Keywords
Marrow transplant recipients

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
34 (Actual)

8. Arms, Groups, and Interventions

Arm Title
HSCT patients / TBE virus vaccine
Arm Type
Active Comparator
Arm Description
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).
Arm Title
healthy volunteers / TBE virus vaccine
Arm Type
Active Comparator
Arm Description
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).
Intervention Type
Biological
Intervention Name(s)
TBE virus vaccine
Other Intervention Name(s)
FSME Immun
Intervention Description
TBE virus vaccine FSME Immun is used in both arms for the study population and the control group
Primary Outcome Measure Information:
Title
Outcome of the Neutralization Test (Number of Subjects With Antibody Response Measured by Neutralization Assay)
Description
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
Time Frame
four weeks after the second vaccination
Secondary Outcome Measure Information:
Title
Antibody Response as Measured by TBE-ELISA After Second Vaccination
Description
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
Time Frame
comparison between baseline and four weeks after second vaccination
Title
Change of Antibody Concentration of NT Titer
Description
Geometric mean fold change of NT titer between baseline and four weeks after third vaccination was compared between HSCT patients and healthy controls
Time Frame
between baseline and four weeks after the third vaccination
Title
Lymphocyte Proliferation as a Measure of Cellular Immune Response in the Study Population Versus the Control Group Prior Vaccination
Description
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.
Time Frame
before vaccination
Title
Fold Induction in IL13 Cytokine Levels Before Vaccination (Baseline) in the Study Population Versus the Control Group
Description
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.
Time Frame
before vaccination
Title
Lymphocyte Proliferation as a Measure of Cellular Immune Response in The Study Population Versus the Control Group After Second Vaccination
Description
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.
Time Frame
7 days after second vaccination
Title
Lymphocyte Proliferation as a Measure of Celluar Immune Response in the Study Population Versus the Control Group After Third Vaccination
Description
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.
Time Frame
7 days after Third Vaccination
Title
Fold Induction in IL13 Cytokine Levels in the Study Population Versus the Control Group After Second Vaccination
Description
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.
Time Frame
7 days after second vaccination
Title
Fold Induction in IL13 Cytokine Levels in the Study Population Versus the Control Group After Third Vaccination
Description
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.
Time Frame
7 days after third vaccination

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility 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)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Christina Forstner, MD
Organizational Affiliation
Medical University of Vienna
Official's Role
Principal Investigator
Facility Information:
Facility Name
Medical University of Vienna, Department of Medicine I, Division of Infectious Diseases and Tropical Medicine
City
Vienna
ZIP/Postal Code
1090
Country
Austria

12. IPD Sharing Statement

Citations:
PubMed Identifier
32728481
Citation
Harrison N, Grabmeier-Pfistershammer K, Graf A, Schwarzinger I, Aberle JH, Stiasny K, Greinix H, Rabitsch W, Kalhs P, Ramharter M, Burgmann H, Forstner C. Humoral immune response to tick-borne encephalitis vaccination in allogeneic blood and marrow graft recipients. NPJ Vaccines. 2020 Jul 24;5(1):67. doi: 10.1038/s41541-020-00215-1. eCollection 2020. Erratum In: NPJ Vaccines. 2020 Aug 31;5:79.
Results Reference
result
PubMed Identifier
34452033
Citation
Harrison N, Grabmeier-Pfistershammer K, Graf A, Trapin D, Tauber P, Aberle JH, Stiasny K, Schmidt R, Greinix H, Rabitsch W, Ramharter M, Burgmann H, Pickl WF, Bahrs C. Tick-Borne Encephalitis Specific Lymphocyte Response after Allogeneic Hematopoietic Stem Cell Transplantation Predicts Humoral Immunity after Vaccination. Vaccines (Basel). 2021 Aug 15;9(8):908. doi: 10.3390/vaccines9080908.
Results Reference
result

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Humoral and Cellular Immunity for TBE Vaccination in Allogeneic HSCT Recipients

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