A Randomized, Double-blind, Placebo-controlled Study on Immunogenicity and Safety of MVA-BN (IMVAMUNE™) Smallpox Vaccine in Healthy Subjects

Study Overview
=================
Brief Summary
-----------------
The primary objective of this study is to evaluate the immune response after a single vaccination of pre-immune subjects compared to two vaccinations in naive subjects. In addition the study further investigates the cardiac safety profile of MVA-BN® in a healthy population compared to placebo.

Detailed Description
-----------------
The study consists of 4 groups, which receive either MVA-BN once, MVA-BN two times, MVA-BN followed by placebo, or two administrations of placebo.

Official Title
-----------------
A Partially Randomized, Partially Double-blind, Placebo-controlled Phase II Non-inferiority Study to Evaluate Immunogenicity and Safety of One and Two Doses of MVA-BN® (IMVAMUNE™) Smallpox Vaccine in 18-55 Year Old Healthy Subjects

Conditions
-----------------
Smallpox

Intervention / Treatment
-----------------
* Biological: MVA-BN® (IMVAMUNE)
* Biological: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male and female subjects between 18 and 55 years of age. Women must have a negative serum pregnancy test at screening and a negative urine or serum pregnancy test within 24 hours prior to vaccination. Women of childbearing potential must have used an acceptable method of contraception for 30 days prior to the first vaccination, must agree to use an acceptable method of contraception during the study, and must not become pregnant for at least 28 days after the last vaccination. A woman is considered of childbearing potential unless post-menopausal or surgically sterilized. (Acceptable contraception methods are restricted to abstinence, barrier contraceptives, intrauterine contraceptive devices or licensed hormonal products.) Lab values without clinically significant findings Electrocardiogram (ECG) without abnormal findings (e.g. any kind of atrioventricular or intraventricular conditions or blocks such as complete left or right bundle branch block, AV-node block, QTc or PR prolongation, premature atrial contractions or other atrial arrhythmia, sustained ventricular arrhythmia, 2 premature ventricular contractions (PVC) in a row, ST elevation consistent with ischemia). Groups 1, 2 and 3 (All vaccinia-naïve subjects) additionally: No history of known or suspected previous smallpox vaccination. No detectable vaccinia scar. Group 4 (All previously vaccinated subjects) additionally: History of previous smallpox vaccination (documented and/or typical vaccinia scar). Most recent smallpox vaccination ≥ 5 years. Exclusion Criteria: Uncontrolled serious infection i.e. not responding to antimicrobial therapy. History of or active autoimmune disease. Persons with vitiligo or thyroid disease taking thyroid replacement are not excluded. Known or suspected impairment of immunologic function including, but not limited to, clinically significant liver disease; diabetes mellitus; moderate to severe kidney impairment. History of malignancy, other than squamous cell or basal cell skin cancer, unless there has been surgical excision that is considered to have achieved cure. Subjects with history of skin cancer at the vaccination site are excluded. History of coronary heart disease, myocardial infarction, angina, congestive heart failure, cardiomyopathy, stroke or transient ischemic attack, uncontrolled high blood pressure, or any other heart condition under the care of a doctor. History of an immediate family member (father, mother, brother, or sister) who died due to ischemic heart disease before age 50 years. Ten percent or greater risk of developing a myocardial infarction or coronary death within the next 10 years using the National Cholesterol Education Program's risk assessment tool. (http://hin.nhlbi.nih.gov/atpiii/calculator.asp?usertype=prof) NOTE: This criterion applies only to volunteers 20 years of age and older. History of anaphylaxis or severe allergic reaction. Immune modulatory therapy. History of any serious medical condition, which in the opinion of the investigator would compromise the safety of the subject. History or clinical manifestation of clinically significant and severe hematological, renal, hepatic, pulmonary, central nervous, cardiovascular or gastrointestinal disorders.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 55 Years

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

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

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

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GP 1: two x 1x10E08 TCID, MVA-BN® s.c., vaccinia naive<br>vaccinia naive subjects receiving two subcutanenous vaccinations with 0.5ml MVA-BN® IMVAMUNE (1x10E08 TCID) | Biological: MVA-BN® (IMVAMUNE)<br>* 1x 10E8_TCID50<br>|
| Experimental: GP 2: 1x10E08 TCID, MVA-BN®, 1x Placebo, s.c., vaccinia naive<br>vaccinica naive subjects receiving one vaccination with 0.5ml MVA-BN® IMVAMUNE(1x10E08 TCID), followed by one vaccination Placebo (0.5ml Tris Buffer) | Biological: MVA-BN® (IMVAMUNE)<br>* 1x 10E8_TCID50<br>Biological: Placebo<br>* Tris-Buffer<br>|
| Placebo Comparator: GP 3: two x Placebo, s.c., vaccinia naive<br>vaccinia naive subjects, receiving two subcutaneous vaccinations with Placebo (0.5ml Tris Buffer). | Biological: Placebo<br>* Tris-Buffer<br>|
| Experimental: GP 4: 1x10E08 TCID, MVA-BN®, s.c., vaccinia experienced<br>vaccinia experienced subjects, receiving one subcutaneous vaccination with 0.5ml MVA-BN® IMVAMUNE (1x10E08 TCID). | Biological: MVA-BN® (IMVAMUNE)<br>* 1x 10E8_TCID50<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Seroconversion by ELISA | Seroconversion rate based on vaccinia-specific Enzyme-linked Immunosorbent Assay (ELISA). Seroconversion is defined as the appearance of antibody titers ≥ detection limit (50) for initially seronegative subjects, or a doubling or more of the antibody titer compared to Baseline titer for initially seropositive subjects. Percentages based on number of subjects with data available. | 2 weeks following the last vaccination (Week 6 for Groups 1-3, Week 2 for Group 4) | 
| Number of Participants With ECG Changes | Occurrence of any specific or unspecific ECG change. Assessments at Screening (SCR), Visit 2 (Week 2) and Visit 4 (Week 6). | within 2 weeks after each vaccination | 
| Number of Cardiac Adverse Events (Adverse Events of Special Interest [AESI]) | Occurrence and relationship of any other cardiac symptom at any time during the study | within 32 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Seroconversion by ELISA | Seroconversion rate based on vaccinia-specific Enzyme-linked Immunosorbent Assay (ELISA). Seroconversion is defined as the appearance of antibody titers ≥ detection limit (50) for initially seronegative subjects, or a doubling or more of the antibody titer compared to Baseline titer for initially seropositive subjects. Percentages based on number of subjects with data available. | 4 weeks following the last vaccination (Week 8 for Groups 1-3, Week 4 for Group 4) | 
| Percentage of Participants With Seroconversion by PRNT | Seroconversion rate based on vaccinia-specific Plaque Reduction Neutralization Test (PRNT). Seroconversion is defined as the appearance of antibody titers ≥ detection limit (6) for initially seronegative subjects, or a doubling or more of the antibody titer compared to Baseline titer for initially seropositive subjects. Percentages based on number of subjects with data available. | 2 weeks following the last vaccination (Week 6 for Groups 1-3, Week 2 for Group 4) | 
| Percentage of Participants With Seroconversion by PRNT | Seroconversion rate based on vaccinia-specific Plaque Reduction Neutralization Test (PRNT). Seroconversion is defined as the appearance of antibody titers ≥ detection limit (6) for initially seronegative subjects, or a doubling or more of the antibody titer compared to Baseline titer for initially seropositive subjects. Percentages based on number of subjects with data available. | 4 weeks following the last vaccination (Week 8 for Groups 1-3, Week 4 for Group 4) | 
| Number of Participants With Related Serious Adverse Events | Number of participants with any serious adverse event possibly, probably or definitely related to the study vaccine at any time during the study | within 32 weeks | 
| Number of Participants With Solicited Local Adverse Events | Number of participants with solicited local AEs (pain, erythema, swelling and induration) within 8 days after any vaccination (vaccinations for Groups 1-3: Days 0 and 28; Group 4: Day 0). Percentages based on subjects with at least one completed diary card. | within 8 days after any vaccination | 
| Number of Participants With Solicited General Adverse Events | Number of participants with solicited systemic/general AEs (body temperature increased, headache, myalgia, nausea, and fatigue) within 8 days after any vaccination (vaccinations for Groups 1-3: Days 0 and 28; Group 4: Day 0). Percentages based on subjects with at least one completed diary card. | within 8 days after any vaccination | 
| Number of Participants With Related Grade>=3 Adverse Events | Number of participants with any Grade >=3 AE probably, possibly, or definitely related to the study vaccine within 4 weeks after any vaccination (vaccinations for Groups 1-3: Days 0 and 28; Group 4: Day 0). Pooled solicited (local and general) and unsolicited AEs. | within 4 weeks after any vaccination | 
| Number of Participants With Unsolicited Non-serious Adverse Events | Number of participants with non-serious unsolicited AEs within 4 weeks after any vaccination (vaccinations for Groups 1-3: Days 0 and 28; Group 4: Day 0). | within 4 weeks after any vaccination | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Smallpox, Vaccination, Prevention