Tick Borne Encephalitis
Conditions
Keywords
Marrow transplant recipients
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.
Interventions
BIOLOGICALTBE virus vaccine
TBE virus vaccine FSME Immun is used in both arms for the study population and the control group
Sponsors
Austrian Science Fund (FWF)
Medical University of Vienna
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Outcome of the Neutralization Test (Number of Subjects With Antibody Response Measured by Neutralization Assay) | 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
| Measure | Time frame | Description |
|---|---|---|
| Change of Antibody Concentration of NT Titer | 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 |
| Lymphocyte Proliferation as a Measure of Cellular Immune Response in the Study Population Versus the Control Group Prior Vaccination | 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. |
| Fold Induction in IL13 Cytokine Levels Before Vaccination (Baseline) in the Study Population Versus the Control Group | 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. |
| Antibody Response as Measured by TBE-ELISA After Second Vaccination | 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 |
| Lymphocyte Proliferation as a Measure of Celluar Immune Response in the Study Population Versus the Control Group After Third Vaccination | 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. |
| Fold Induction in IL13 Cytokine Levels in the Study Population Versus the Control Group After Second Vaccination | 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. |
| Fold Induction in IL13 Cytokine Levels in the Study Population Versus the Control Group After Third Vaccination | 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. |
| Lymphocyte Proliferation as a Measure of Cellular Immune Response in The Study Population Versus the Control Group After Second Vaccination | 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. |
Countries
Austria
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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).
TBE virus vaccine: TBE virus vaccine FSME Immun is used in both arms for the study population and the control group | 19 |
| 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).
TBE virus vaccine: TBE virus vaccine FSME Immun is used in both arms for the study population and the control group | 15 |
| Total | 34 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 6 | 5 |
Baseline characteristics
| Characteristic | HSCT Patients / TBE Virus Vaccine | Healthy Volunteers / TBE Virus Vaccine | Total |
|---|---|---|---|
| Age, Continuous | 31 years | 30 years | 30.5 years |
| Body mass index | 26.9 kg/m^2 | 22.2 kg/m^2 | 24.2 kg/m^2 |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Region of Enrollment Austria | 19 participants | 15 participants | 34 participants |
| Sex: Female, Male Female | 8 Participants | 6 Participants | 14 Participants |
| Sex: Female, Male Male | 11 Participants | 9 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 19 | 0 / 15 |
| other Total, other adverse events | 15 / 19 | 6 / 15 |
| serious Total, serious adverse events | 4 / 19 | 0 / 15 |
Outcome results
Primary
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
Population: Patients who received two vaccinations were included in the analysis of the primary end point. Two patients were lost to follow-up after one vaccination and therefore not included in the analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| HSCT Patients / TBE Virus Vaccine | Outcome of the Neutralization Test (Number of Subjects With Antibody Response Measured by Neutralization Assay) | 6 Participants |
| Healthy Volunteers / TBE Virus Vaccine | Outcome of the Neutralization Test (Number of Subjects With Antibody Response Measured by Neutralization Assay) | 14 Participants |
Comparison: The calculation of the sample size was performed using nQuery 6.1. The primary endpoint was the outcome of the NT 4 weeks after the second vaccination. A Fisher exact tes was calculated to analyze the primary hypothesis on the difference in NT-titer response between patients and controlsp-value: <0.001Fisher Exact
Secondary
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
Population: Patients who received two vaccinations were included in the analysis of the primary end point. Two patients were lost to follow-up after one vaccination and therefore not included in the analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| HSCT Patients / TBE Virus Vaccine | Antibody Response as Measured by TBE-ELISA After Second Vaccination | 9 Participants |
| Healthy Volunteers / TBE Virus Vaccine | Antibody Response as Measured by TBE-ELISA After Second Vaccination | 14 Participants |
Comparison: A Fisher exact test was calculated to analyze antibody response by ELISA between patients and controls. To measure the Agreement between the NT and ELISA response, Cohens Kappa and the corresponding 95% confidence interval were calculatedp-value: 0.02Fisher Exact
Secondary
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
Population: Patients who received three vaccinations were included in the analysis. Two patients were lost to follow-up after first vaccination and four patients were lost to follow up after second vaccination therefore not included in the analysis. In the group of healthy volunteers 5 patients were lost to follow-up after second vaccination and therefore not included in the analysis
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| HSCT Patients / TBE Virus Vaccine | Change of Antibody Concentration of NT Titer | 3.9 Geometric mean fold change |
| Healthy Volunteers / TBE Virus Vaccine | Change of Antibody Concentration of NT Titer | 45.2 Geometric mean fold change |
Comparison: For titer values the geometric mean was calculated and the corresponding two-sided 95% confidence intervals were constructed by back-transfomration of the CI for the mean of the logarithmically transformed results.~To investigate the difference in absolute titer values and geometric mean fold changes between time point and Groups, Wilcoxon tests were performed.p-value: <0.01Wilcoxon (Mann-Whitney)
Secondary
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
Population: Patients who received two vaccinations were included in the analysis. Two patients were last of follow-up after one vaccination and therefore were not included in the analysis. For the group of healthy volunteers the measure of cellular immune response was optional and therefore only determined in 8 of 15 healthy volunteers.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| HSCT Patients / TBE Virus Vaccine | Fold Induction in IL13 Cytokine Levels Before Vaccination (Baseline) in the Study Population Versus the Control Group | 1.0 fold induction |
| Healthy Volunteers / TBE Virus Vaccine | Fold Induction in IL13 Cytokine Levels Before Vaccination (Baseline) in the Study Population Versus the Control Group | 0.61 fold induction |
Secondary
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
Population: Patients who received two vaccinations were included in the analysis. Two patients were last of follow-up after one vaccination and therefore were not included in the analysis. For the group of healthy volunteers the measure of cellular immune response was optional and therefore only determined in 8 of 15 healthy volunteers.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| HSCT Patients / TBE Virus Vaccine | Fold Induction in IL13 Cytokine Levels in the Study Population Versus the Control Group After Second Vaccination | 5.6 fold induction |
| Healthy Volunteers / TBE Virus Vaccine | Fold Induction in IL13 Cytokine Levels in the Study Population Versus the Control Group After Second Vaccination | 2.1 fold induction |
Secondary
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
Population: Patients who received three vaccinations were included in the analysis. Two patients were lost to follow-up after first vaccination and four patients were lost to follow-up after second vaccination therefore not included in the analysis. For the group of healthy volunteers the measure of cellular immune response was optional and therefore only determined in 5 of 15 healthy volunteers. In the group of healthy volunteers 5 patients were lost to follow-up after second vaccination.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| HSCT Patients / TBE Virus Vaccine | Fold Induction in IL13 Cytokine Levels in the Study Population Versus the Control Group After Third Vaccination | 32.3 fold induction |
| Healthy Volunteers / TBE Virus Vaccine | Fold Induction in IL13 Cytokine Levels in the Study Population Versus the Control Group After Third Vaccination | 3.4 fold induction |
Secondary
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
Population: Patients who received three vaccinations were included in the analysis. Two patients were lost to follow-up after first vaccination and four patients were lost to follow up after second vaccination therefore not included in the analysis. For the group of healthy volunteers the measure of cellular immune response was optional and therefore only determined in 5 of 15 healthy volunteers. In the group of healthy volunteers 5 patients were lost to follow-up after second vaccination.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| HSCT Patients / TBE Virus Vaccine | Lymphocyte Proliferation as a Measure of Celluar Immune Response in the Study Population Versus the Control Group After Third Vaccination | 21.0 stimulation index |
| Healthy Volunteers / TBE Virus Vaccine | Lymphocyte Proliferation as a Measure of Celluar Immune Response in the Study Population Versus the Control Group After Third Vaccination | 13.0 stimulation index |
Secondary
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
Population: Patients who received two vaccinations were included in the analysis. Two patients were lost to follow-up after vaccination and therefore not included in the analysis. For the group of healthy volunteers the measure of cellular immune response was optional and therefore only determined in 8 of 15 healthy volunteers.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| HSCT Patients / TBE Virus Vaccine | Lymphocyte Proliferation as a Measure of Cellular Immune Response in The Study Population Versus the Control Group After Second Vaccination | 8.4 stimulation index |
| Healthy Volunteers / TBE Virus Vaccine | Lymphocyte Proliferation as a Measure of Cellular Immune Response in The Study Population Versus the Control Group After Second Vaccination | 8.3 stimulation index |
Secondary
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
Population: Patients who received two vaccinations were included in the analysis. Two patients were lost to follow-up after vaccination and therefore not included in the analysis. For the group of healthy volunteers the measure of cellular immune response was optional and therefore only determined in 8 of 15 healthy volunteers.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| HSCT Patients / TBE Virus Vaccine | Lymphocyte Proliferation as a Measure of Cellular Immune Response in the Study Population Versus the Control Group Prior Vaccination | 4.2 stimulation index |
| Healthy Volunteers / TBE Virus Vaccine | Lymphocyte Proliferation as a Measure of Cellular Immune Response in the Study Population Versus the Control Group Prior Vaccination | 0.9 stimulation index |