Humoral and Cellular Immunity for TBE Vaccination in Allogeneic HSCT Recipients

Phase 2CompletedNCT01991067

Medical University of Vienna34 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

PREVENTION

Masking

Eligibility

Sex: ALLMin age: 18 YearsHealthy volunteers:

Medical Language ↔ Plain English

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)

Outcomes

Primary Outcomes

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

Time frame: four weeks after the second vaccination

Secondary Outcomes

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

Time frame: comparison between baseline and four weeks after second vaccination

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

Time frame: between baseline and four weeks after the third vaccination

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.

Time frame: before vaccination

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.

Time frame: before vaccination

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.

Time frame: 7 days after second vaccination

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.

Time frame: 7 days after Third Vaccination

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.

Time frame: 7 days after second vaccination

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.

Time frame: 7 days after third vaccination

Humoral and Cellular Immunity for TBE Vaccination in Allogeneic HSCT Recipients

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes