MVA Post-Event: Administration Timing and Boost Study

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate an investigational smallpox vaccine, called IMVAMUNE®, with respect to safety and immune (body's defense system) response. Participants will include healthy adults, age 18 or older born after 1971, who have not had smallpox vaccine before. Volunteers were originally assigned to 1 of 5 groups. In July 2007, a hold was placed on the Dryvax® groups and the study was modified. Volunteers, numbering 197, will be assigned by chance to one of 3 groups to be vaccinated twice with IMVAMUNE® vaccine or placebo (inactive substance) in Groups A and B, or to receive a single vaccination with IMVAMUNE® or placebo in Group F. Volunteers will complete a memory aid (diary) for 15 days following vaccination. Blood samples will be collected. Volunteers may participate for up to 425 days.

Detailed Description
-----------------
The study will evaluate the IMVAMUNE® smallpox vaccine with respect to safety and optimization of immune responses by different vaccination regimens in vaccinia-naïve adults. Study subjects must be age 18 and older and born after 1971. Originally, 215 subjects were planned to be randomly assigned to 1 of 5 groups to be immunized twice with IMVAMUNE® vaccine or placebo subcutaneously in Groups A and B, or Dryvax® or placebo by scarification in Group C or both IMVAMUNE® and Dryvax® or 2 placebos in Groups D and Group E. In July, 2007, enrollment was halted at the request of Center for Biologics Evaluation and Research (CBER). At that time, enrollment included zero subjects in Group A, 2 subjects in Group B, 8 subjects in Group C, 6 subjects in Group D, and 4 subjects in Group E. CBER placed an official hold on the enrollment into the Groups that would administer Dryvax®, i.e., Groups C, D and E. Subjects previously enrolled into Groups C, D, and E will be followed according to the protocol. The protocol has been modified as follows. One hundred and ninety-five subjects will be randomly assigned to 1 of 3 groups to be immunized twice with IMVAMUNE® vaccine or placebo subcutaneously in Groups A and B, or to receive a single immunization with IMVAMUNE® or placebo subcutaneously in Group F. (NOTE: A total of 197 subjects will be randomly assigned to Groups A, B, and F as 2 subjects were previously enrolled in Group B.) Group A will receive IMVAMUNE® vaccine or placebo on Days 0 and 7. Group B will receive IMVAMUNE® vaccine or placebo on Days 0 and 28. Group F will receive a single dose of IMVAMUNE® at Day 0. All subjects will complete a memory aid for 15 days following each vaccination. Groups C, D, and E will have the appropriate reactogenicity information collected until the vaccination lesion, if present is well dried. Adverse events will be collected for 28 days after each vaccination. Specimens will be collected for immunologic assays at the noted clinic visits, as well as 1 year post last vaccination. Serious adverse events will be collected throughout the study period. The primary safety objective is to evaluate the safety of IMVAMUNE® given as a single dose, IMVAMUNE® given in a 2 dose prime-boost regimen at Day 0 and 7 or Day 0 and 28, IMVAMUNE® followed by a boost with Dryvax®, and IMVAMUNE® given simultaneously with Dryvax®. The primary immunogenicity objective is to determine if the Geometric Mean Titer (GMT) of neutralizing antibody [using Modified Vaccinia Ankara (MVA) as the target antigen] among subjects receiving a regimen of 2 doses of IMVAMUNE® (1×10^8, Days 0 and 7, Group A) is non-inferior to that among subjects receiving 2 doses of IMVAMUNE® (1×10^8, Days 0 and 28, Group B) at Day 14 following the 2nd dose. The secondary immunogenicity objective is to determine if the GMT, as assessed by enzyme linked immunosorbent assay (ELISA) (using MVA as the target antigen), among subjects receiving a regimen of 2 doses of IMVAMUNE® (1×10^8, Days 0 and 7, Group A) is non-inferior to that among subjects receiving 2 doses of IMVAMUNE® (1×10^8, Days 0 and 28, Group B) at Day 14 following the 2nd dose. The tertiary immunogenicity objective is to characterize the kinetics, magnitude, and duration of cellular and humoral immune responses to IMVAMUNE® alone or IMVAMUNE® as a prime followed by a boost with IMVAMUNE® or Dryvax®, or Dryvax® alone.

Official Title
-----------------
Evaluation of IMVAMUNE® Smallpox Vaccine With Respect to Safety and Optimization of Immune Responses by Different Vaccination Regimens in Vaccinia-Naïve Adults

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

Intervention / Treatment
-----------------
* Drug: Placebo (subcutaneous)
* Drug: Placebo (scarification)
* Biological: Dryvax®
* Biological: IMVAMUNE®


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: At least 18 years of age and born after 1971 Never received smallpox vaccination Read, signed, and dated informed consent document Available for follow-up for the planned duration of the study (one year after last immunization) Acceptable medical history by screening evaluation and limited physical assessment If the subject is female and of childbearing potential, negative serum pregnancy test at screening and negative urine or serum pregnancy test within 24 hours prior to vaccination If the subject is female and of childbearing potential, she agrees to use acceptable contraception, and not become pregnant for the duration of the study A woman is considered of childbearing potential unless post-menopausal or surgically sterilized Acceptable contraception methods are restricted to effective devices (e.g., Intrauterine Devices (IUD)s, NuvaRing®) or licensed hormonal products with use of method for a minimum of 30 days prior to vaccination, and abstinence from sexual intercourse with men (vaginal penetration by a penis, coitus) Women who are not sexually active must agree to use one of the acceptable contraception methods if they are of childbearing potential Negative enzyme linked immunosorbent assay (ELISA) for human immunodeficiency virus (HIV) Alanine aminotransferase (ALT) <1.25 times institutional upper limit of normal Negative hepatitis B surface antigen and negative antibody to hepatitis C virus Negative urine glucose and urine protein <1 plus by dipstick or urinalysis Adequate renal function defined as a serum creatinine equal to or less than the institutional upper limit of normal by gender; and urine protein <30 mg/dL or trace proteinuria (by urinalysis or dip stick). Electrocardiogram (ECG) in absence of clinical significance (e.g., complete left or right bundle branch block, incomplete left bundle branch block or sustained ventricular arrythmia, or two premature ventricular contractions (PVC's) in a row, or sympathetic tonus (ST) elevation consistent with ischemia) Complete blood count (CBC): Hemoglobin equal to or above the lower limit of institutional normal; White blood cells greater than or equal to 3200 /mm^3 and equal to or below the upper limit of institutional normal Platelets equal to or above the lower limit of institutional normal Weight: greater than or equal to 110 pounds Exclusion Criteria: History of immunodeficiency Typical vaccinia scar Known or suspected history of smallpox vaccination Military service prior to 1991 or after January 2003 Known or suspected impairment of immunologic function including, but not limited to, clinically significant liver disease, diabetes mellitus, or moderate to severe kidney impairment Malignancy not including squamous cell skin cancer or basal cell skin cancer unless at the vaccination site or history of skin cancer at the vaccination site Active autoimmune disease Persons with vitiligo or thyroid disease (e.g., taking thyroid hormone replacement) are not excluded. History of myocardial infarction, angina, congestive heart failure, cardiomyopathy, stroke or transient ischemic attack, or other heart condition under the care of a doctor 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) NOTE that this criterion applies only to subjects 20 years of age and older AND only if at least one of the following apply: have smoked a cigarette in the past month, and/or have hypertension (defined as systolic blood pressure >140 mm Hg) or are on antihypertensive medication, and/or have a family history of coronary heart disease in male first-degree relative (father or brother) <55 years of age or a female first-degree relative (mother or sister) <65 years of age. Current use of immunosuppressive medication Corticosteroid nasal sprays are permissible Persons who are using a topical steroid can be enrolled after their therapy is completed Inhaled steroids for asthma are not permissible Medical or psychiatric condition or occupational responsibilities that preclude subject compliance with the protocol Any history of illegal injection drug use Receipt of inactivated vaccine 14 days prior to vaccination Receipt of live attenuated vaccine within 30 days prior to vaccination Use of experimental agent within 30 days prior to vaccination Receipt of blood products or immunoglobulin within six months prior to vaccination Donation of a unit of blood within 56 days prior to vaccination or for the duration of the study 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, chronic exfoliative skin disorders/conditions, current Varicella zoster, or any acute skin disorders of large magnitude, e.g., laceration requiring sutures, burn greater than 2×2 cm Any condition that, in the opinion of the investigator, might interfere with study objectives Known allergy to IMVAMUNE® vaccine Known allergy to egg or aminoglycoside Study personnel

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 38 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group C<br>Dryvax® vaccine or placebo on Day 0. This arm was discontinued from original protocol. Subjects already enrolled in this group will continue follow-up per protocol. | Drug: Placebo (scarification)<br>* Physiologic normal saline for injection.<br>Biological: Dryvax®<br>* Dryvax® Vaccinia Vaccine ( 10^5 [plaque forming units (pfu)/dose] given via scarification, titer 10^8 pfu per mL after reconstitution).<br>|
| Experimental: Group D<br>Standard dose IMVAMUNE® vaccine or placebo on Day 0 and Dryvax® vaccine or placebo on Day 7. This arm was discontinued from original protocol. Subjects already enrolled in this group will continue follow-up per protocol. | Drug: Placebo (subcutaneous)<br>* 0.9 percent (weight/volume) sodium chloride injection, United States Pharmacopeia [Sterile Saline Placebo (SSP)].<br>Drug: Placebo (scarification)<br>* Physiologic normal saline for injection.<br>Biological: Dryvax®<br>* Dryvax® Vaccinia Vaccine ( 10^5 [plaque forming units (pfu)/dose] given via scarification, titer 10^8 pfu per mL after reconstitution).<br>Biological: IMVAMUNE®<br>* IMVAMUNE® Vaccinia Vaccine delivered by subcutaneous (SC) route at titer 1X10^8 Tissue Culture Infections Dose50 per 0.5 mL dose.<br>|
| Experimental: Group E<br>Dryvax® vaccine and standard dose IMVAMUNE® vaccine or 2 placebos on Day 0. This arm was discontinued from original protocol. Subjects already enrolled in this group will continue follow-up per protocol. | Drug: Placebo (subcutaneous)<br>* 0.9 percent (weight/volume) sodium chloride injection, United States Pharmacopeia [Sterile Saline Placebo (SSP)].<br>Drug: Placebo (scarification)<br>* Physiologic normal saline for injection.<br>Biological: Dryvax®<br>* Dryvax® Vaccinia Vaccine ( 10^5 [plaque forming units (pfu)/dose] given via scarification, titer 10^8 pfu per mL after reconstitution).<br>Biological: IMVAMUNE®<br>* IMVAMUNE® Vaccinia Vaccine delivered by subcutaneous (SC) route at titer 1X10^8 Tissue Culture Infections Dose50 per 0.5 mL dose.<br>|
| Experimental: Group F<br>Standard dose IMVAMUNE® vaccine or placebo on Day 0. | Drug: Placebo (subcutaneous)<br>* 0.9 percent (weight/volume) sodium chloride injection, United States Pharmacopeia [Sterile Saline Placebo (SSP)].<br>Biological: IMVAMUNE®<br>* IMVAMUNE® Vaccinia Vaccine delivered by subcutaneous (SC) route at titer 1X10^8 Tissue Culture Infections Dose50 per 0.5 mL dose.<br>|
| Experimental: Group B<br>Standard dose IMVAMUNE® vaccine or placebo on Days 0 and 28. | Drug: Placebo (subcutaneous)<br>* 0.9 percent (weight/volume) sodium chloride injection, United States Pharmacopeia [Sterile Saline Placebo (SSP)].<br>Biological: IMVAMUNE®<br>* IMVAMUNE® Vaccinia Vaccine delivered by subcutaneous (SC) route at titer 1X10^8 Tissue Culture Infections Dose50 per 0.5 mL dose.<br>|
| Experimental: Group A<br>Standard dose IMVAMUNE® vaccine or placebo on Days 0 and 7. | Drug: Placebo (subcutaneous)<br>* 0.9 percent (weight/volume) sodium chloride injection, United States Pharmacopeia [Sterile Saline Placebo (SSP)].<br>Biological: IMVAMUNE®<br>* IMVAMUNE® Vaccinia Vaccine delivered by subcutaneous (SC) route at titer 1X10^8 Tissue Culture Infections Dose50 per 0.5 mL dose.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine whether the Geometric Mean Titer (GMT) of neutralizing antibody, among subjects receiving 2 doses of IMVAMUNE® (Days 0 and 7, Group A) is noninferior to that among subjects receiving 2 doses of IMVAMUNE® (Days 0 and 28, Group B). |  | At Day 14 following the 2nd dose of vaccine. | 
| Safety: adverse events and reactogenicity to the vaccine. |  | Duration of study. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Using enzyme linked immunosorbent assay results, determine whether the GMT among subjects receiving a 2 dose regimen of IMVAMUNE® (Days 0 and 7, Group A) is noninferior to that among subjects receiving 2 doses of IMVAMUNE® (Days 0 and 28, Group B). |  | At Day 14 following the 2nd dose of vaccine. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
smallpox, vaccine, IMVAMUNE®