Study to Evaluate the Immunogenicity, Safety, and Tolerability of a Tick-Borne Encephalitis (TBE) Vaccine in Healthy Japanese Participants 1 Year of Age and Older

Study Overview
=================
Brief Summary
-----------------
The main purpose of this study is to provide safety and immunogenicity data in Japanese participants.

Official Title
-----------------
A PHASE 3, SINGLE-ARM, OPEN-LABEL STUDY TO EVALUATE THE IMMUNOGENICITY, SAFETY, AND TOLERABILITY OF A TICK-BORNE ENCEPHALITIS VACCINE IN HEALTHY JAPANESE PARTICIPANTS 1 YEAR OF AGE AND OLDER

Conditions
-----------------
Tick-Borne Encephalitis

Intervention / Treatment
-----------------
* Biological: TBE vaccine 0.5 mL
* Biological: TBE vaccine 0.25 mL


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Japanese male or female participants ≥1 years old at Visit 1. Participants and/or a legally acceptable representative/parent/legal guardian are willing and able to comply with all scheduled visits, vaccination plan, and other study procedures including completion of the e-diary for 7 days for participants after each of 3 vaccinations. Participants and/or a legally acceptable representative/parent/legal guardian must be able to be contacted by telephone during study participation. Participants and/or a legally acceptable representative/parent/legal guardian are capable of giving signed informed consent. Exclusion Criteria: Major known congenital malformation or serious chronic disorder. Known history of TBEV infection. Known history of other flavivirus infection (eg, dengue fever, yellow fever, JEV, West Nile virus). Known history of infection with HIV, HCV, or HBV. Immunocompromised participants with known or suspected immunodeficiency. History of autoimmune disease or an active autoimmune disease requiring therapeutic intervention. Previous vaccination with any licensed or investigational TBE vaccine, or planned receipt of other flavivirus vaccines apart from JEV vaccine (eg, yellow fever, dengue fever) during the study. Administration of JEV vaccine is prohibited during participation.

Ages Eligible for Study
-----------------
Minimum Age: 1 Year

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ≥16 Years Old<br>TBE vaccine 0.5 mL (intramuscular injection). | Biological: TBE vaccine 0.5 mL<br>* TBE vaccine 0.5 mL (intramuscular injection).<br>|
| Experimental: 1 to <16 Years Old<br>TBE vaccine 0.25ｍL (intramuscular injection). | Biological: TBE vaccine 0.25 mL<br>* TBE vaccine 0.25 mL (intramuscular injection).<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Seropositive Participants at 4 Weeks After Dose 3 | Seropositivity rate based on the immune response was determined by neutralization test (NT). Participants who achieved tick-borne encephalitis virus (TBEV) NT titers >=1: 10 were considered as seropositive. Exact 2-sided 95% confidence interval (CI) based on the Clopper and Pearson method was presented. | 4 weeks after Dose 3 | 
| Percentage of Participants With Local Reactions (LR) Within 7 Days After Dose 1 | LR:participant or legally acceptable representative/parent/legal guardian using an electronic diary (e-diary). LR included redness, swelling and pain at injection site. Redness and swelling were measured using measuring device units. 1 measuring device unit =0.5 centimeter(cm). Redness and swelling were graded as: for participants >=12 years of age, mild(greater than[>] 2.0 to 5.0 cm), moderate(>5.0 to 10.0 cm) and severe (>10.0 cm); for participants less than (<)12 years of age, mild(>0 to 2.0 cm), moderate(>2.0 to7.0 cm) and severe(>7.0 cm). Pain at the injection site was graded as: for participants >2 years of age, mild(does not interfere with activity), moderate(interferes with activity) and severe(prevents daily activity); for participants less than or equal to (<=)2 years of age, mild(hurts if gently touched) moderate(hurts if gently touched with crying) and severe(causes limitation of limb movement). Exact 2-sided 95% CI based on the Clopper and Pearson method was presented. | Within 7 days after Dose 1 | 
| Percentage of Participants With Local Reactions Within 7 Days After Dose 2 | Local reactions were collected by participant or legally acceptable representative/parent/legal guardian using an e-diary. Local reactions included redness, swelling and pain at the injection site. Redness and swelling were measured using measuring device units. 1 measuring device unit =0.5 cm. Redness and swelling were graded as: for participants >=12 years of age, mild (> 2.0 to 5.0 cm), moderate (>5.0 to 10.0 cm) and severe (>10.0 cm); for participants <12 years of age, mild (>0 to 2.0 cm), moderate (>2.0 to 7.0 cm) and severe (>7.0 cm). Pain at the injection site was graded as: for participants >2 years of age, mild (does not interfere with activity), moderate (interferes with activity) and severe (prevents daily activity); for participants <=2 years of age, mild (hurts if gently touched) moderate (hurts if gently touched with crying) and severe (causes limitation of limb movement). Exact 2-sided 95% CI based on the Clopper and Pearson method was presented. | Within 7 days after Dose 2 | 
| Percentage of Participants With Local Reactions Within 7 Days After Dose 3 | Local reactions were collected by participant or legally acceptable representative/parent/legal guardian using an e-diary. Local reactions included redness, swelling and pain at the injection site. Redness and swelling were measured using measuring device units. 1 measuring device unit =0.5 cm. Redness and swelling were graded as: for participants >=12 years of age, mild (> 2.0 to 5.0 cm), moderate (>5.0 to 10.0 cm) and severe (>10.0 cm); for participants <12 years of age, mild (>0 to 2.0 cm), moderate (>2.0 to 7.0 cm) and severe (>7.0 cm). Pain at the injection site was graded as: for participants >2 years of age, mild (does not interfere with activity), moderate (interferes with activity) and severe (prevents daily activity); for participants <=2 years of age, mild (hurts if gently touched) moderate (hurts if gently touched with crying) and severe (causes limitation of limb movement). Exact 2-sided 95% CI based on the Clopper and Pearson method was presented. | Within 7 days after Dose 3 | 
| Percentage of Participants With Systemic Events (SE) Within 7 Days After Dose 1 | SE:participants or legally acceptable representative/parent/legal guardian using e-diary & included fever:temperature >=37.5 degree Celsius(C)&categorized as 37.5to38.4, 38.5 to 38.9,39.0 to 40.0,>40.0 degree C.Fatigue, headache, muscle pain, joint pain: mild(didn't interfere with activity), moderate(some interference with activity), severe(prevented daily activity). Vomiting: mild(1-2 times in 24 hours[hrs]), moderate(>2 times in 24hrs), severe(required intravenous hydration). Diarrhea: mild(2-3 loose stools in 24hrs), moderate(4-5 loose stools in 24hrs), severe(6 or more loose stools in 24hrs). Decreased appetite:mild(decreased interest in eating),moderate(decreased oral intake), severe(refusal to feed).Drowsiness: mild(Increased sleeping bouts),moderate(slightly subdued interfering with daily activity),severe(disabling not interested in usual daily activity).Irritability:mild(easily consolable), moderate(required increased attention),severe(inconsolable, crying can't be comforted). | Within 7 days after Dose 1 | 
| Percentage of Participants With Systemic Events Within 7 Days After Dose 2 | SE:participants or a legally acceptable representative/parent/legal guardian using e-diary and included fever:temperature >=37.5 degreeC & categorized as 37.5 to 38.4,38.5 to 38.9,39.0 to 40.0,>40.0 degreeC.Fatigue, headache, muscle pain, joint pain: mild(didn't interfere with activity),moderate(some interference with activity), severe(prevented daily activity). Vomiting: mild(1-2 times in 24 hours[hrs]), moderate(>2 times in 24hrs),severe(required intravenous hydration).Diarrhea: mild(2-3 loose stools in 24hrs), moderate(4-5 loose stools in 24hrs), severe(6 or more loose stools in 24hrs). Decreased appetite: mild(decreased interest in eating), moderate(decreased oral intake), severe(refusal to feed). Drowsiness: mild(Increased sleeping bouts), moderate(slightly subdued interfering with daily activity), severe(disabling not interested in usual daily activity).Irritability: mild(easily consolable), moderate(required increased attention),severe(inconsolable, crying can't be comforted). | Within 7 days after Dose 2 | 
| Percentage of Participants With Systemic Events Within 7 Days After Dose 3 | Systemic events collected by participant using e-diary and included fever defined as temperature >=37.5 degree C and categorized as 37.5 to 38.4, 38.5 to 38.9, 39.0 to 40.0, >40.0 degree C. Fatigue, headache, muscle pain, joint pain: mild(didn't interfere with activity), moderate(some interference with activity), severe(prevented daily activity). Vomiting: mild(1-2 times in 24 hours[hrs]), moderate(>2 times in 24hrs), severe(required intravenous hydration). Diarrhea: mild(2-3 loose stools in 24hrs), moderate(4-5 loose stools in 24hrs), severe(6 or more loose stools in 24hrs). Decreased appetite: mild(decreased interest in eating), moderate(decreased oral intake), severe(refusal to feed). Drowsiness: mild(Increased sleeping bouts), moderate(slightly subdued interfering with daily activity), severe(disabling not interested in usual daily activity). Irritability: mild(easily consolable), moderate(required increased attention), severe(inconsolable, crying can't be comforted). | Within 7 days after Dose 3 | 
| Percentage of Participants With Adverse Events (AEs) Within 1 Month After Dose 1 | An AE was defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether considered related to the study intervention. Exact 2-sided 95% CI based on the Clopper and Pearson method was presented. | Within 1 month after Dose 1 | 
| Percentage of Participants With Adverse Events (AEs) Within 1 Month After Dose 2 | An AE was defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether considered related to the study intervention. Exact 2-sided 95% CI based on the Clopper and Pearson method was presented. | Within 1 month after Dose 2 | 
| Percentage of Participants With Adverse Events (AEs) Within 1 Month After Dose 3 | An AE was defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether considered related to the study intervention. Exact 2-sided 95% CI based on the Clopper and Pearson method was presented. | Within 1 month after Dose 3 | 
| Percentage of Participants With Adverse Events (AEs) Within 1 Month After Any Dose | An AE was defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether considered related to the study intervention. Exact 2-sided 95% CI based on the Clopper and Pearson method was presented. | Within 1 month after any Dose | 
| Percentage of Participants With Serious Adverse Events (SAEs) Throughout the Study | An SAE was defined as any untoward medical occurrence that, at any dose that resulted in death; was life-threatening (immediate risk of death); required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent disability/incapacity (substantial disruption of the ability to conduct normal life functions); resulted in congenital anomaly/birth defect or that is considered to be an important medical event. Percentage of participants with SAEs and the exact 2-sided 95% CI based on the Clopper and Pearson method was presented. | From Day 1 up to end of study (up to approximately 13 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Seropositive Participants at 4 Weeks After Dose 2 | Seropositivity rate based on the immune response was determined by NT. Participants who achieved TBEV NT titers >=1: 10 were considered as seropositive. Exact 2-sided 95% CI based on the Clopper and Pearson method was presented. | 4 weeks after Dose 2 | 
| Geometric Mean Titers (GMTs) of TBEV Neutralizing Antibody Titers at 4 Weeks After Dose 2 and Dose 3 | GMTs and associated 2-sided 95% CIs were calculated as the mean of the assay results on the natural logarithmic scale based on Student's t distribution and then exponentiating the results. The lower limit of quantitation (LLOQ) value for NT was 5. Assay results below the LLOQ were set to 0.5 × LLOQ. | 4 weeks after Dose 2 and Dose 3 | 
| Geometric Mean Fold Rise (GMFR) of TBEV Neutralizing Antibody Titers at 4 Weeks After Dose 2 as Compared to Baseline | GMFRs and the corresponding 2-sided 95% CIs were calculated by exponentiating the mean logarithm of fold rises and the corresponding CIs (based on the Student t distribution). The LLOQ value for NT was 5. Assay results below the LLOQ were set to 0.5 × LLOQ. | From Baseline to 4 weeks after Dose 2 | 
| Geometric Mean Fold Rise (GMFR) of TBEV Neutralizing Antibody Titers at 4 Weeks After Dose 3 as Compared to Baseline | GMFRs and the corresponding 2-sided 95% CIs were calculated by exponentiating the mean logarithm of fold rises and the corresponding CIs (based on the Student t distribution). The LLOQ value for NT was 5. Assay results below the LLOQ were set to 0.5 × LLOQ. | From Baseline to 4 weeks after Dose 3 | 
| Geometric Mean Fold Rise (GMFR) of TBEV Neutralizing Antibody Titers at 4 Weeks After Dose 3 as Compared to 4 Weeks After Dose 2 | GMFRs and the corresponding 2-sided 95% CIs were calculated by exponentiating the mean logarithm of fold rises and the corresponding CIs (based on the Student t distribution). The LLOQ value for NT was 5. Assay results below the LLOQ were set to 0.5 × LLOQ. | From 4 weeks after Dose 2 to 4 weeks after Dose 3 | 
| Percentage of Participants With Neutralizing Antibody Titers >= Lower Limit of Quantification (LLOQ) | The LLOQ value for NT was 5. Assay results below the LLOQ were set to 0.5 × LLOQ. Percentage of participants with NT>=LLOQ and exact 2-sided 95% CI based on the Clopper and Pearson method was presented. | Before Dose 1, 4 weeks after Dose 2, Before Dose 3 and 4 weeks after Dose 3 |