An Open-Label Phase II Study to Evaluate Immunogenicity and Safety of a Single IMVAMUNE Booster Vaccination Two Years After the Last IMVAMUNE Vaccination in Former POX-MVA-005 Vaccinees

Study Overview
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Brief Summary
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The study was preformed to evaluate the persistence of antibodies following vaccination with MVA-BN and to assess the immunological memory response induced by a booster vaccination with MVA-BN in subjects two years after their participation in trial POX-MVA-005 (NCT00316524) in which they had received one or two doses of MVA-BN.

Official Title
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An Open-Label Phase II Study to Evaluate Immunogenicity and Safety of a Single IMVAMUNE Booster Vaccination Two Years After the Last IMVAMUNE Vaccination in Former POX-MVA-005 Vaccinees

Conditions
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Smallpox

Intervention / Treatment
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* Biological: IMVAMUNE
* Biological: IMVAMUNE
* Procedure: Blood Draw Only


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Groups 1 and 2 (first consenting 75 subjects in each group to be vaccinated) Male and female subjects having participated in Group 1 or 2 of the study POX-MVA-005 who completed the trial according to protocol. Women of childbearing potential 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 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 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.) Read, signed and dated informed consent document after being advised of the risks and benefits of the study in a language understood by the subject signed, and prior to performance of any study specific procedure. Troponin I within normal institutional limits. White blood cells ≥ 2,500/mm3 and <= 11,000/mm3. Absolute neutrophil count within normal limits. Negative urine glucose by dipstick or urinalysis. Hemoglobin within the laboratory reference ranges (unless the investigator considers the deviation to be not clinically significant). Platelets 100 - 440/nL. Adequate renal function defined as: Serum creatinine without clinically significant findings. Urine protein <= 30 mg/dL or none or trace proteinuria (by urinalysis or dip stick). Adequate hepatic function defined as: Total bilirubin <= 1.5 x upper limit of normal (ULN) in the absence of other evidence of significant liver disease (healthy subjects without clinical disease; Morbus Meulengracht can be included). AST (SGOT), ALT (SGPT), alkaline phosphatase without clinically significant findings. Electrocardiogram (ECG) without clinically relevant 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, two premature ventricular contractions (PVC) in a row, ST elevation consistent with ischemia). Group 4 (all subjects) and Groups 1 and 2 (subjects N > 75): blood draw only Male and female subjects having participated in the study POX-MVA-005 who completed the trial according to protocol. Read, signed and dated informed consent document after being advised of the risks and benefits of the blood draw in a language understood by the subject signed, and prior to performance of the blood draw. Exclusion Criteria: Groups 1 and 2 (first consenting 75 subjects in each group to be vaccinated) Participation in another study with a smallpox vaccine after the POX-MVA-005 study. Pregnant or breast-feeding women. Uncontrolled serious infection i.e. not responding to antimicrobial therapy. History of any serious medical condition, which in the opinion of the investigator would compromise the safety of the subject. 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 must not be vaccinated at the previous site of cancer. History or clinical manifestation of clinically significant and severe hematological, renal, hepatic, pulmonary, central nervous, cardiovascular or gastrointestinal disorders. Clinically significant mental disorder not adequately controlled by medical treatment. Any condition which might interfere with study objectives or would limit the subject's ability to complete the study or to be compliant in the opinion of the investigator. 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. Twenty 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). History of intravenous drug abuse. History of allergic disease or reactions likely to be exacerbated by any component of the vaccine, e.g. tris (hydroxymethyl)-amino methane, chicken embryo fibroblast proteins, aminoglycosides (gentamycin). History of any anaphylactic shock or severe allergic reaction requiring immediate treatment. Having received any vaccinations or planned vaccinations with a live vaccine within 30 days prior or after study vaccination. Having received any vaccinations or planned vaccinations with a killed vaccine within 14 days prior or after study vaccination. Chronic administration (defined as more than 14 days) of > 5 mg prednisone (or equivalent) per day or any other immune-modifying drugs during a period starting from three months prior to administration of the vaccine and ending at study conclusion (Visit 4). Post organ transplant subjects whether or not receiving chronic immunosuppressive therapy. Administration or planned administration of immunoglobulins and/or any blood products during a period starting from 3 months prior to administration of the vaccine and ending at study conclusion. Use of any investigational or non-registered drug or vaccine other than the study vaccine within 30 days preceding administration of the study vaccine, or planned administration of such a drug during the study period. Group 4 (all subjects) and Groups 1 and 2 (subjects N > 75): blood draw only Participation in another study with a smallpox vaccine after the POX-MVA-005 study. Any condition which might interfere with a blood draw.

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

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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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: Initially Vaccinia Naive, 2 dose primed, 1 booster dose<br>Group 1 Initially Vaccinia Naive Subjects 2 doses of MVA-BN in prior study (POX-MVA-005) 1 booster dose of MVA-BN (POX-MVA-023) IMVAMUNE: 1x 10E8_TCID50 | Biological: IMVAMUNE<br>* 1x 10E8_TCID50<br>|
| Experimental: Initially Vaccinia Naive, 1 dose primed, 1 booster dose<br>Group 2 Initially Vaccinia Naive Subjects 1 dose of MVA-BN and 1x Placebo in prior study (POX-MVA-005) 1 booster dose of MVA-BN (POX-MVA-023) IMVAMUNE: 1x 10E8_TCID50 | Biological: IMVAMUNE<br>* 1x 10E8_TCID50<br>|
| Other: Vaccinia Experienced, boosted, blood draw only<br>Group 4 Vaccinia Experienced 1 booster dose of MVA-BN in prior study (POX-MVA-005) Blood draw, Screening Visit only (POX-MVA-023) | Procedure: Blood Draw Only<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Individual Peak Booster Rate by ELISA (Percentage of Participants) | Booster rate based on vaccinia-specific Enzyme-linked Immunosorbent Assay (ELISA) is defined as the percentage of subjects with an appearance of antibody titers ≥ detection limit (50) for initially seronegative subjects, or an increase of the antibody titer compared to Baseline titer for initially seropositive subjects. Individual Peak booster rate is based on the maximum post-Baseline antibody titer within 4 weeks (measurements at Weeks 1, 2, and 4). Percentages based on number of subjects with data available. | within 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Booster Rate by ELISA (Percentage of Participants) | Booster rate based on vaccinia-specific Enzyme-linked Immunosorbent Assay (ELISA) is defined as the percentage of subjects with an appearance of antibody titers ≥ detection limit (50) for initially seronegative subjects, or an increase of the antibody titer compared to Baseline titer for initially seropositive subjects. Percentages based on number of subjects with data available. | within 26 weeks | 
| ELISA GMT | Geometric Mean Titers (GMT) based on vaccinia-specific Enzyme-linked Immunosorbent Assay (ELISA). Individual peak is defined as the maximum post-Baseline antibody titer within 4 weeks (measurements at Weeks 1, 2, and 4). Titers below the detection limit are included with a value of '1'. | within 26 weeks | 
| Booster Rate by PRNT (Percentage of Participants) | Booster rate based on vaccinia-specific Plaque Reduction Neutralization Test (PRNT) is defined as the percentage of subjects with an appearance of antibody titers ≥ detection limit (6) for initially seronegative subjects, or an increase of the antibody titer compared to Baseline titer for initially seropositive subjects. Individual Peak booster rate is based on the maximum post-Baseline antibody titer within 4 weeks (measurements at Weeks 1, 2, and 4). Percentages based on number of subjects with data available. | within 26 weeks | 
| PRNT GMT | Geometric Mean Titers (GMT) based on vaccinia-specific Plaque Reduction Neutralization Test (PRNT). Individual peak is defined as the maximum post-Baseline antibody titer within 4 weeks (measurements at Weeks 1, 2, and 4). Titers below the detection limit are included with a value of '1'. | within 26 weeks | 
| Correlation PRNT vs ELISA Titers | Pearson Correlation Coefficient between the log10 transformed PRNT titers and the log10 transformed ELISA titers | within 26 weeks | 
| Number of Participants With Related Serious Adverse Events | Number of participants with Serious Adverse Events (SAEs) probably, possibly or definitely related to the trial vaccine | within 26 weeks | 
| Number of Participants With Unsolicited Non-serious Adverse Events | Number of participants with any, grade >=3, and related non-serious unsolicited adverse events | within 29 days after any vaccination | 
| Number of Participants With Related Grade >= 3 Unsolicited Adverse Events | Number of participants with Grade >=3 Unsolicited Adverse Event probably, possibly, or definitely related to the study vaccine | within 29 days after vaccination | 
| Number of Participants With Solicited Local Adverse Events | Number of participants with and intensity of solicited local AEs (pain, erythema, swelling, induration, and pruritis). Percentages based on subjects with a completed diary card. | within 8 days after vaccination | 
| Number of Participants With Solicited General Adverse Events | Number of participants with solicited general AEs (body temperature increased, headache, myalgia, nausea, and fatigue): Intensity and relationship to vaccination. Percentages based on subjects with a completed diary card. | within 8 days after vaccination |