Humoral and Cellular Immunity for TBE Vaccination in Allogeneic HSCT Recipients

• Sponsor: Medical University of Vienna (Other)
• Overall Status: Completed
• CT.gov ID: NCT01991067
• Collaborator: Austrian Science Fund (FWF) (Other)
• Enrollment: 34
• Location: 1
• Arms: 2
• Actual Duration (Months): 51.9
• Patients Per Site Per Month: 0.7

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Tick Borne Encephalitis	Biological: TBE virus vaccine	Phase 2

Study Design

• Study Type: Interventional
• 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: Jul 1, 2014
• Actual Primary Completion Date: Oct 28, 2018
• Actual Study Completion Date: Oct 28, 2018

Arms and Interventions

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 Names: 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 Names: FSME Immun

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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

2. 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

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	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

• Principal Investigator: Christina Forstner, MD, Medical University of Vienna

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Aug 24, 2015

More Information

Publications

None provided.

• 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: Nov 25, 2013
• Last Update Posted: Feb 3, 2022
• Last Verified: Jan 1, 2022

• Keywords provided by Christina Forstner, MD, Associate Professor, PD, Medical University of Vienna: Marrow transplant recipients
• Additional relevant MeSH terms: Encephalitis, Tick-Borne; Encephalitis

Study Results

Participant Flow

Arm/Group Title	HSCT Patients / TBE Virus Vaccine	Healthy Volunteers / TBE Virus Vaccine
Arm/Group 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). TBE virus vaccine: TBE virus vaccine FSME Immun is used in both arms for the study population and the control group	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
Period Title: Overall Study
STARTED	19	15
COMPLETED	13	10
NOT COMPLETED	6	5

Baseline Characteristics

Arm/Group Title	HSCT Patients / TBE Virus Vaccine	Healthy Volunteers / TBE Virus Vaccine	Total
Arm/Group 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). TBE virus vaccine: TBE virus vaccine FSME Immun is used in both arms for the study population and the control group	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	Total of all reporting groups
Overall Participants	19	15	34
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	31	30	30.5
Sex: Female, Male (Count of Participants)
Female	8 42.1%	6 40%	14 41.2%
Male	11 57.9%	9 60%	20 58.8%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (participants) [Number]
Austria	19 100%	15 100%	34 100%
Body mass index (kg/m^2) [Median (Full Range) ]
Median (Full Range) [kg/m^2]	26.9	22.2	24.2

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

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/Group Title	HSCT Patients / TBE Virus Vaccine	Healthy Volunteers / TBE Virus Vaccine
Arm/Group 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). TBE virus vaccine: TBE virus vaccine FSME Immun is used in both arms for the study population and the control group	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
Measure Participants	17	15
Count of Participants [Participants]	6 31.6%	14 93.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	HSCT Patients / TBE Virus Vaccine, Healthy Volunteers / TBE Virus Vaccine
	Comments	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 controls
	Type of Statistical Test	Other
	Comments	Furthermore, a multivariable logistic regression model was applied accounting for group as well as age, body mass index, and gender as possible influence factors.
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	The threshold for statistical significance was a p-value of <0.05.
	Method	Fisher Exact
	Comments

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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/Group Title	HSCT Patients / TBE Virus Vaccine	Healthy Volunteers / TBE Virus Vaccine
Arm/Group 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). TBE virus vaccine: TBE virus vaccine FSME Immun is used in both arms for the study population and the control group	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
Measure Participants	17	15
Count of Participants [Participants]	9 47.4%	14 93.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	HSCT Patients / TBE Virus Vaccine, Healthy Volunteers / TBE Virus Vaccine
	Comments	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 calculated
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.02
	Comments
	Method	Fisher Exact
	Comments

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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/Group Title	HSCT Patients / TBE Virus Vaccine	Healthy Volunteers / TBE Virus Vaccine
Arm/Group 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). TBE virus vaccine: TBE virus vaccine FSME Immun is used in both arms for the study population and the control group	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
Measure Participants	13	10
Geometric Mean (95% Confidence Interval) [Geometric mean fold change]	3.9	45.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	HSCT Patients / TBE Virus Vaccine, Healthy Volunteers / TBE Virus Vaccine
	Comments	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.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.01
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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/Group Title	HSCT Patients / TBE Virus Vaccine	Healthy Volunteers / TBE Virus Vaccine
Arm/Group 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). TBE virus vaccine: TBE virus vaccine FSME Immun is used in both arms for the study population and the control group	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
Measure Participants	17	8
Median (Full Range) [stimulation index]	4.2	0.9

5. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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/Group Title	HSCT Patients / TBE Virus Vaccine	Healthy Volunteers / TBE Virus Vaccine
Arm/Group 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). TBE virus vaccine: TBE virus vaccine FSME Immun is used in both arms for the study population and the control group	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
Measure Participants	17	8
Median (Full Range) [fold induction]	1.0	0.61

6. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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/Group Title	HSCT Patients / TBE Virus Vaccine	Healthy Volunteers / TBE Virus Vaccine
Arm/Group 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). TBE virus vaccine: TBE virus vaccine FSME Immun is used in both arms for the study population and the control group	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
Measure Participants	17	8
Median (Full Range) [stimulation index]	8.4	8.3

7. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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/Group Title	HSCT Patients / TBE Virus Vaccine	Healthy Volunteers / TBE Virus Vaccine
Arm/Group 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). TBE virus vaccine: TBE virus vaccine FSME Immun is used in both arms for the study population and the control group	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
Measure Participants	13	5
Median (Full Range) [stimulation index]	21.0	13.0

8. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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/Group Title	HSCT Patients / TBE Virus Vaccine	Healthy Volunteers / TBE Virus Vaccine
Arm/Group 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). TBE virus vaccine: TBE virus vaccine FSME Immun is used in both arms for the study population and the control group	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
Measure Participants	17	8
Median (Full Range) [fold induction]	5.6	2.1

9. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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/Group Title	HSCT Patients / TBE Virus Vaccine	Healthy Volunteers / TBE Virus Vaccine
Arm/Group 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). TBE virus vaccine: TBE virus vaccine FSME Immun is used in both arms for the study population and the control group	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
Measure Participants	13	5
Median (Full Range) [fold induction]	32.3	3.4

Adverse Events

Time Frame	Adverse events were collected during the whole study period from enrollment to four weeks after third vaccination (Day 298-393 corresponds to 4 weeks after third vaccination)
Arm/Group Title	HSCT Patients / TBE Virus Vaccine		Healthy Volunteers / TBE Virus Vaccine
Arm/Group 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). TBE virus vaccine: TBE virus vaccine FSME Immun is used in both arms for the study population and the control group		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
All Cause Mortality
	HSCT Patients / TBE Virus Vaccine		Healthy Volunteers / TBE Virus Vaccine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/19 (0%)		0/15 (0%)
Serious Adverse Events
	HSCT Patients / TBE Virus Vaccine		Healthy Volunteers / TBE Virus Vaccine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/19 (21.1%)		0/15 (0%)
Blood and lymphatic system disorders
acute myeloid leukemia	1/19 (5.3%)	1	0/15 (0%)	0
Hepatobiliary disorders
cholecystolithiasis	1/19 (5.3%)	1	0/15 (0%)	0
Infections and infestations
influenza	1/19 (5.3%)	1	0/15 (0%)	0
Reproductive system and breast disorders
haemometra	1/19 (5.3%)	1	0/15 (0%)	0
Other (Not Including Serious) Adverse Events
	HSCT Patients / TBE Virus Vaccine		Healthy Volunteers / TBE Virus Vaccine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/19 (78.9%)		6/15 (40%)
Cardiac disorders
subjective tachycardia	1/19 (5.3%)	1	0/15 (0%)	0
Endocrine disorders
swelling of parotid gland	0/19 (0%)	0	1/15 (6.7%)	1
Gastrointestinal disorders
nausea	2/19 (10.5%)	2	0/15 (0%)	0
weight loss	1/19 (5.3%)	1	0/15 (0%)	0
General disorders
shivering	2/19 (10.5%)	2	1/15 (6.7%)	1
fatigue	2/19 (10.5%)	2	1/15 (6.7%)	1
sweating	1/19 (5.3%)	1	0/15 (0%)	0
fever	1/19 (5.3%)	1	0/15 (0%)	0
cold-like symptoms	2/19 (10.5%)	2	0/15 (0%)	0
Immune system disorders
increase of Graft-versus-host-disease (skin exanthema)	1/19 (5.3%)	1	0/15 (0%)	0
increase of Graft-versus-host-disease (mucosal lesions)	1/19 (5.3%)	1	0/15 (0%)	0
Nervous system disorders
headache	3/19 (15.8%)	4	0/15 (0%)	0
Skin and subcutaneous tissue disorders
local pressure pain	9/19 (47.4%)	13	5/15 (33.3%)	7
local swelling	2/19 (10.5%)	2	0/15 (0%)	0
local redness	1/19 (5.3%)	1	0/15 (0%)	0
local induration	1/19 (5.3%)	1	0/15 (0%)	0
fever blister	1/19 (5.3%)	2	0/15 (0%)	0
skin exanthema	1/19 (5.3%)	1	0/15 (0%)	0

Limitations/Caveats

A limitation of this study might be the definition of response to vaccination. As the majority of HSCT patients had pre-existing antibodies, the concept of seroconversion was not applicable. Instead, a 2-fold rise in NT titer was used as outcome.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.