Trial Outcomes & Findings for Humoral and Cellular Immunity for TBE Vaccination in Allogeneic HSCT Recipients (NCT NCT01991067)

NCT ID: NCT01991067

Last Updated: 2022-02-03

Results Overview

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

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

34 participants

Primary outcome timeframe

four weeks after the second vaccination

Results posted on

2022-02-03

Participant Flow

Participant milestones

Participant milestones
Measure	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	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
Overall Study STARTED	19	15
Overall Study COMPLETED	13	10
Overall Study NOT COMPLETED	6	5

Reasons for withdrawal

Reasons for withdrawal
Measure	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	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
Overall Study Lost to Follow-up	6	5

Baseline Characteristics

Race and Ethnicity were not collected from any participant.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	HSCT Patients / TBE Virus Vaccine n=19 Participants 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	Healthy Volunteers / TBE Virus Vaccine n=15 Participants 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 n=34 Participants Total of all reporting groups
Age, Continuous	31 years n=19 Participants	30 years n=15 Participants	30.5 years n=34 Participants
Sex: Female, Male Female	8 Participants n=19 Participants	6 Participants n=15 Participants	14 Participants n=34 Participants
Sex: Female, Male Male	11 Participants n=19 Participants	9 Participants n=15 Participants	20 Participants n=34 Participants
Race and Ethnicity Not Collected	—	—	0 Participants Race and Ethnicity were not collected from any participant.
Region of Enrollment Austria	19 participants n=19 Participants	15 participants n=15 Participants	34 participants n=34 Participants
Body mass index	26.9 kg/m^2 n=19 Participants	22.2 kg/m^2 n=15 Participants	24.2 kg/m^2 n=34 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	HSCT Patients / TBE Virus Vaccine n=17 Participants 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	Healthy Volunteers / TBE Virus Vaccine n=15 Participants 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
Outcome of the Neutralization Test (Number of Subjects With Antibody Response Measured by Neutralization Assay)	6 Participants	14 Participants

SECONDARY outcome

Timeframe: 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

Outcome measures

Outcome measures
Measure	HSCT Patients / TBE Virus Vaccine n=17 Participants 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	Healthy Volunteers / TBE Virus Vaccine n=15 Participants 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
Antibody Response as Measured by TBE-ELISA After Second Vaccination	9 Participants	14 Participants

SECONDARY outcome

Timeframe: 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

Geometric mean fold change of NT titer between baseline and four weeks after third vaccination was compared between HSCT patients and healthy controls

Outcome measures

Outcome measures
Measure	HSCT Patients / TBE Virus Vaccine n=13 Participants 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	Healthy Volunteers / TBE Virus Vaccine n=10 Participants 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
Change of Antibody Concentration of NT Titer	3.9 Geometric mean fold change Interval 1.3 to 11.9	45.2 Geometric mean fold change Interval 17.5 to 117.0

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	HSCT Patients / TBE Virus Vaccine n=17 Participants 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	Healthy Volunteers / TBE Virus Vaccine n=8 Participants 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
Lymphocyte Proliferation as a Measure of Cellular Immune Response in the Study Population Versus the Control Group Prior Vaccination	4.2 stimulation index Interval 1.02 to 69.7	0.9 stimulation index Interval 0.61 to 2.37

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	HSCT Patients / TBE Virus Vaccine n=17 Participants 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	Healthy Volunteers / TBE Virus Vaccine n=8 Participants 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
Fold Induction in IL13 Cytokine Levels Before Vaccination (Baseline) in the Study Population Versus the Control Group	1.0 fold induction Interval 0.96 to 98.93	0.61 fold induction Interval 0.57 to 0.84

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	HSCT Patients / TBE Virus Vaccine n=17 Participants 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	Healthy Volunteers / TBE Virus Vaccine n=8 Participants 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
Lymphocyte Proliferation as a Measure of Cellular Immune Response in The Study Population Versus the Control Group After Second Vaccination	8.4 stimulation index Interval 0.7 to 76.6	8.3 stimulation index Interval 1.8 to 23.9

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	HSCT Patients / TBE Virus Vaccine n=13 Participants 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	Healthy Volunteers / TBE Virus Vaccine n=5 Participants 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
Lymphocyte Proliferation as a Measure of Celluar Immune Response in the Study Population Versus the Control Group After Third Vaccination	21.0 stimulation index Interval 0.8 to 109.3	13.0 stimulation index Interval 1.8 to 27.8

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	HSCT Patients / TBE Virus Vaccine n=17 Participants 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	Healthy Volunteers / TBE Virus Vaccine n=8 Participants 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
Fold Induction in IL13 Cytokine Levels in the Study Population Versus the Control Group After Second Vaccination	5.6 fold induction Interval 1.0 to 180.5	2.1 fold induction Interval 0.6 to 5.9

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	HSCT Patients / TBE Virus Vaccine n=13 Participants 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	Healthy Volunteers / TBE Virus Vaccine n=5 Participants 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
Fold Induction in IL13 Cytokine Levels in the Study Population Versus the Control Group After Third Vaccination	32.3 fold induction Interval 0.5 to 153.8	3.4 fold induction Interval 0.6 to 7.2

Adverse Events

HSCT Patients / TBE Virus Vaccine

Serious events: 4 serious events

Other events: 15 other events

Deaths: 0 deaths

Healthy Volunteers / TBE Virus Vaccine

Serious events: 0 serious events

Other events: 6 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	HSCT Patients / TBE Virus Vaccine n=19 participants at risk 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	Healthy Volunteers / TBE Virus Vaccine n=15 participants at risk 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
Hepatobiliary disorders cholecystolithiasis	5.3% 1/19 • Number of events 1 • 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)	0.00% 0/15 • 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)
Reproductive system and breast disorders haemometra	5.3% 1/19 • Number of events 1 • 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)	0.00% 0/15 • 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)
Infections and infestations influenza	5.3% 1/19 • Number of events 1 • 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)	0.00% 0/15 • 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)
Blood and lymphatic system disorders acute myeloid leukemia	5.3% 1/19 • Number of events 1 • 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)	0.00% 0/15 • 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)

Other adverse events

Additional Information

Assoc. Prof. Dr. Christina Bahrs

Medical University of Vienna, Department of Medicine I, Division of Infectious Diseases

Phone: +4314040044400

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	HSCT Patients / TBE Virus Vaccine n=19 participants at risk 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	Healthy Volunteers / TBE Virus Vaccine n=15 participants at risk 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
Skin and subcutaneous tissue disorders local pressure pain	47.4% 9/19 • Number of events 13 • 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)	33.3% 5/15 • Number of events 7 • 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)
Skin and subcutaneous tissue disorders local swelling	10.5% 2/19 • Number of events 2 • 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)	0.00% 0/15 • 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)
Skin and subcutaneous tissue disorders local redness	5.3% 1/19 • Number of events 1 • 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)	0.00% 0/15 • 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)
Skin and subcutaneous tissue disorders local induration	5.3% 1/19 • Number of events 1 • 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)	0.00% 0/15 • 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)
General disorders shivering	10.5% 2/19 • Number of events 2 • 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)	6.7% 1/15 • Number of events 1 • 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)
General disorders fatigue	10.5% 2/19 • Number of events 2 • 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)	6.7% 1/15 • Number of events 1 • 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)
Nervous system disorders headache	15.8% 3/19 • Number of events 4 • 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)	0.00% 0/15 • 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)
Gastrointestinal disorders nausea	10.5% 2/19 • Number of events 2 • 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)	0.00% 0/15 • 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)
General disorders sweating	5.3% 1/19 • Number of events 1 • 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)	0.00% 0/15 • 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)
General disorders fever	5.3% 1/19 • Number of events 1 • 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)	0.00% 0/15 • 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)
General disorders cold-like symptoms	10.5% 2/19 • Number of events 2 • 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)	0.00% 0/15 • 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)
Skin and subcutaneous tissue disorders fever blister	5.3% 1/19 • Number of events 2 • 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)	0.00% 0/15 • 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)
Immune system disorders increase of Graft-versus-host-disease (skin exanthema)	5.3% 1/19 • Number of events 1 • 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)	0.00% 0/15 • 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)
Immune system disorders increase of Graft-versus-host-disease (mucosal lesions)	5.3% 1/19 • Number of events 1 • 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)	0.00% 0/15 • 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)
Cardiac disorders subjective tachycardia	5.3% 1/19 • Number of events 1 • 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)	0.00% 0/15 • 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)
Gastrointestinal disorders weight loss	5.3% 1/19 • Number of events 1 • 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)	0.00% 0/15 • 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)
Skin and subcutaneous tissue disorders skin exanthema	5.3% 1/19 • Number of events 1 • 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)	0.00% 0/15 • 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)
Endocrine disorders swelling of parotid gland	0.00% 0/19 • 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)	6.7% 1/15 • Number of events 1 • 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)