Combination Study With MVA BN and Dryvax

Study Overview
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Brief Summary
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The overall goals of this study are to expand the available data on the safety and immunogenicity of MVA-BN in vaccinia-naive adults and to determine the optimum dose of MVA-BN to induce immune responses and attenuate Dryvax take reactions. Participants will include 90 healthy volunteers, ages 18-32 years. Participants will be randomly assigned to 1 of 6 study groups (groups A-F). Participants will be involved in study related procedures for up to 2 years. During this time, volunteers will return periodically for blood draws to check immune responses.

Detailed Description
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The primary goal of this phase I trial is to expand the available data on the safety and immunogenicity of MVA-BN in vaccinia-naïve adults. The secondary goals of this vaccine trial are: to determine the optimum dose of MVA-BN, given twice, to induce an immune response and attenuate Dryvax® take reactions; and to compare the ability of 2 routes of administration of MVA-BN, subcutaneous and intramuscular, to induce an immune response at the highest tested dose. A total of 90 healthy adult volunteers ages 18-32 will participate in this study. The volunteers will be randomly assigned to 1 of 6 groups to be immunized with: MVA-BN (subcutaneously) at 1 of 3 dose levels and Dryvax® (per scarification); placebo (subcutaneously) and Dryvax® (per scarification); MVA-BN (subcutaneously) at the highest dose level and placebo scarification; or MVA-BN (intramuscularly) at the highest dose level and Dryvax® (per scarification). The study will last about 30 months. Each volunteer's participation will last 6 months for all treatment groups. Subjects randomized to treatment groups D and E will have follow-up for 2 years. During this time, volunteers will return periodically for blood draws to check immune responses. Subjects will require visits for dressing changes as needed post-Dryvax vaccination. Variables to be investigated include: adverse events and side effects to the vaccines, and immunogenicity testing including antibody and cellular responses to the vaccines.

Official Title
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A Phase I Clinical Trial to Evaluate the Safety and Immunogenicity of MVA-BN in a Dose Response Regimen Followed by Administration of Dryvax in Healthy Adult Volunteers

Conditions
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Smallpox

Intervention / Treatment
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* Biological: Live vaccinia virus vaccine
* Biological: MVA Smallpox Vaccine
* Biological: MVA Smallpox Vaccine
* Other: Placebo
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ages 18-32. Never received smallpox vaccination. Read, signed and dated informed consent document. Availability for follow-up for the planned duration of the study two years after first immunization. Acceptable medical history by screening evaluation and limited physical examination. For women, negative serum pregnancy test at screening and negative urine or serum pregnancy test within 24 hours prior to vaccination. If the volunteer is female and of child bearing potential, she agrees to use acceptable contraception, and not become pregnant for at least 56 days after the last vaccination. A woman is considered of child bearing potential unless post-menopausal or surgically sterilized. [Acceptable contraception methods are restricted to effective intrauterine devices (IUDs) or licensed hormonal products with use of method for a minimum of 30 days prior to vaccination.] Women who are not sexually active must agree to use one of the acceptable contraception methods if they are of childbearing potential. Negative ELISA for HIV. ALT<1.25 times institutional upper limit of normal. Negative hepatitis B surface antigen and negative antibody to hepatitis C virus. Negative urine glucose by dipstick or urinalysis. Adequate renal function defined as a serum creatinine less than or equal to 1.4mg/dL for males and less than or equal to 1.2mg/dL for females; urine protein < 30 mg/dL or none or trace proteinuria (by urinalysis or dipstick); and a calculated creatine clearance greater than or equal to 80 mL/min. based on the following formulas: Males [(140-age in years) X weight in kg]/(72 X serum creatinine) Females 0.85X[(140-age in years) X weight in kg]/(72 X serum creatinine) ECG without clinical significance (e.g., all kinds 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, or 2 premature ventricular contractions (PVC) in a row, or ST elevation consistent with ischemia) CBC: Hemoglobin >11g/dl; White blood cells greater than 2,500 and less than 11,000/cubic mm; Platelets greater than or equal to 140,000/cubic mm. Exclusion Criteria: History of immunodeficiency. Typical vaccinia scar. Known or suspected history of smallpox vaccination. Military service prior to 1989 or after January 2003. Known or suspected impairment of immunologic function including, but not limited to, clinically significant liver disease; diabetes mellitus; moderate to severe kidney impairment. Malignancy, including squamous cell skin cancer or basal cell skin cancer at vaccination site or history of skin cancer at the vaccination site. Active autoimmune disease. Persons with vitiligo or thyroid disease on thyroid replacement are not excluded. History of keloid formation. History of myocardial infarction, angina, congestive heart failure, cardiomyopathy, stroke or transient ischemic attack, or other heart condition under the care of a doctor. History of an immediate family member (father, mother, brother or sister) who has had onset of 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 for Estimating Your 10-Year Risk of Having a Heart Attack, located at the following URL: http://hin.nhlbi.nih.gov/atpiii/calculator.asp. NOTE: This criterion applies only to volunteers 20 years of age and older. Abnormal troponin I. Use of immunosuppressive medication. Corticosteroid nasal sprays are permissible. Persons who have used topical steroid can be enrolled after their therapy is completed. Medical or psychiatric condition or occupational responsibilities that preclude volunteer compliance with the protocol. Any history of illegal injection drug use. Receipt of inactivated vaccine 14 days prior to vaccination. Receipt of live attenuated vaccines within 30 days of vaccination. Use of experimental agents within 30 days prior to vaccination. Receipt of blood products or immunoglobulin in the 6 months prior to vaccination. Acute febrile illness (greater than or equal to 100.5 degrees F) on the day of vaccination. Pregnant or lactating women. Eczema of any degree or history of eczema. People with atopic dermatitis, Varicella zoster, chronic exfoliative skin disorders/conditions or any acute skin disorders of large magnitude, e.g., laceration requiring sutures, burn greater than 2x2 cm. Household contacts/sexual contacts with, or occupational exposure to (other than minimal contact), any of the following: Pregnant women; Children <12 months of age; People with or history of eczema; People with atopic dermatitis, Varicella zoster, chronic exfoliative skin disorders/conditions or any acute skin disorders of large magnitude, e.g., laceration requiring sutures, burn greater than 2x2 cm; People with immunodeficiency disease or use of immunosuppressive medications. Any condition that, in the opinion of the investigator, might interfere with study objectives. Known allergies to or any component of MVA or MVA-BN vaccine (e.g., tris(hydroxymethl)-amino methane, sodium chloride, sucrose, dextran, L-Glutamic acid monopotassium, chicken embryo fibroblast proteins, gentamycin). Known allergy to egg or aminoglycoside. Known allergies to any component of the Dryvax® vaccine (e.g. polymyxin B sulfate, dihydrostreptomycin sulfate, chlorotetracycline hydrochloride, neomycin sulfate). Known allergies to any known component of the Dryvax® diluent (i.e. glycerin and phenol). Known allergies to any known components of vaccinia immunoglobulin (VIG), i.e. thimerosal or previous allergic reaction to immunoglobulins. Known allergies to cidofovir or probenecid. Study personnel.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 32 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: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: E<br>Subject will receive an SC dose of MVA 1x10^8 on day 0 and day 28. On day 112 subjects will receive a dose of placebo by scarification. | Biological: MVA Smallpox Vaccine<br>* Imvamune/MVA-BN Groups A, B C and E will be administered subcutaneously: 2x10^7, 5x10^7, 1x10^8, 1x10^8, respectively, on days 0 and day 28.<br>Other: Placebo<br>* Group E will receive sterile saline placebo for injection via scarification on day 112.<br>|
| Active Comparator: D<br>Subject will receive a SC dose of placebo on day 0 and day 28. On day 112 subjects will receive a dose of Dryvax® by scarification. | Biological: Live vaccinia virus vaccine<br>* Dryvax®: 0.25 mL of vaccine will be administered by the standard route of scarification using a bifurcated needle on day 112 for Groups A, B, C, D and F.<br>Other: Placebo<br>* Group D will receive sterile saline placebo for injection subcutaneously on day 0 and day 28.<br>|
| Experimental: C<br>Subject will receive a SC dose of MVA 1x10^8 on day 0 and day 28. On day 112 subjects will receive a dose of Dryvax® by scarification. | Biological: Live vaccinia virus vaccine<br>* Dryvax®: 0.25 mL of vaccine will be administered by the standard route of scarification using a bifurcated needle on day 112 for Groups A, B, C, D and F.<br>Biological: MVA Smallpox Vaccine<br>* Imvamune/MVA-BN Groups A, B C and E will be administered subcutaneously: 2x10^7, 5x10^7, 1x10^8, 1x10^8, respectively, on days 0 and day 28.<br>|
| Experimental: B<br>Subjects will receive a SC dose of MVA 5x10^7 on day 0 and day 28. On day 112 subjects will receive a dose of Dryvax® by scarification. | Biological: Live vaccinia virus vaccine<br>* Dryvax®: 0.25 mL of vaccine will be administered by the standard route of scarification using a bifurcated needle on day 112 for Groups A, B, C, D and F.<br>Biological: MVA Smallpox Vaccine<br>* Imvamune/MVA-BN Groups A, B C and E will be administered subcutaneously: 2x10^7, 5x10^7, 1x10^8, 1x10^8, respectively, on days 0 and day 28.<br>|
| Experimental: A<br>Subjects will receive a SC dose of MVA 2x10^7 on day 0 and day 28. On day 112 subjects will receive a dose of Dryvax® by scarification. | Biological: Live vaccinia virus vaccine<br>* Dryvax®: 0.25 mL of vaccine will be administered by the standard route of scarification using a bifurcated needle on day 112 for Groups A, B, C, D and F.<br>Biological: MVA Smallpox Vaccine<br>* Imvamune/MVA-BN Groups A, B C and E will be administered subcutaneously: 2x10^7, 5x10^7, 1x10^8, 1x10^8, respectively, on days 0 and day 28.<br>|
| Experimental: F<br>Subject will receive an IM dose of MVA 1x10^8 on day 0 and day 28. On day 112 subjects will receive a dose of Dryvax® by scarification. | Biological: Live vaccinia virus vaccine<br>* Dryvax®: 0.25 mL of vaccine will be administered by the standard route of scarification using a bifurcated needle on day 112 for Groups A, B, C, D and F.<br>Biological: MVA Smallpox Vaccine<br>* Imvamune/MVA-BN 1x10^8 will be administered intramuscularly to Group F on day 0 and day 28.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events and side effects to the vaccines. |  | Reactogenicity will be evaluated for a 2-week period post-vaccination at each time point and for the duration of study. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immunogenicity testing of antibody and cellular responses to the vaccines. |  | Visit days 0, 14, 28, 42, 56, 112, 140, 182, 365, and 730. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Smallpox, vaccine