High Dose IMVAMUNE® in Vaccinia-Naive Individuals

Study Overview
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Brief Summary
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The purpose of this research is to compare the ability of a new investigational smallpox vaccine called IMVAMUNE® to produce a strong immune response against smallpox disease if given as one single, higher dose compared with two lower doses given one month apart. Another purpose of the study is to see how quickly someone might be protected against smallpox. Volunteers will be vaccinia-naïve adults age 18 and older (born after 1971) divided into 2 groups. Volunteers in Group A will receive a high dose of vaccine given in 2 shots on day 0 followed by a placebo (inactive substance) shot on day 28. Group B will receive the standard dose of vaccine and placebo given in 2 shots on day 0 followed by a standard dose shot on Day 28. Study participation will include 10 planned study visits over approximately 7 months.

Detailed Description
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Despite the fact that the World Health Organization (WHO) officially declared smallpox to be eradicated, a new threat exists due to the potential use of variola virus as an agent for biological warfare and/or bio-terrorism. As a consequence, there is an urgent need for a safe and efficacious vaccine to protect the public against smallpox. To date, the majority of clinical studies with Modified Vaccinia Ankara (MVA) have studied a prime-boost vaccination regimen, with a dose of up to 1×10^8 tissue culture infectious dose 50 (TCID50) of MVA administered on Days 0 and 28. While this vaccination regimen induces a robust immune response that is protective in a variety of animal models and is appropriate for a pre-smallpox release scenario, in the event of a confirmed release of smallpox, a more rapid vaccination regimen that provides a protective immune response would be desirable. Ideally, at least short-term protection could be obtained with a single dose of vaccine. While a single dose of MVA at 1×10^8 TCID50, does induce an immune response in the majority of recipients, it is possible that a higher dose of MVA could provide a more rapid and/or stronger immune response relative to a single, standard 1×10^8 TCID50 dose of MVA. The goal of this study is to examine the kinetics and magnitude of the immune response of a single high dose of MVA (5×10^8 TCID50) relative to both a single and prime/boost regimen using the standard doses (1×10^8 TCID50) of MVA. This study will complement a current, ongoing study, DMID Protocol 06-0012, which is examining the immune response to compressed prime/boost dosing regimens of MVA administered at (1×10^8 TCID50). Upon the completion of these studies, clinical data will be generated which will inform policy makers about different options for post-event utilization of available smallpox vaccines. The study is designed as a randomized, non-placebo controlled, double blinded study containing two arms: Group A (N=45) will receive a single high dose of IMVAMUNE® (5x10^8 TCID50, consisting of two 0.5 mL injections) vaccine on Day 0 and a single saline placebo dose (single 0.5 mL injection) on Day 28 to match the two dose regimen of Group B. Group B (N=45) will receive a standard two dose regimen of IMVAMUNE® (1x10^8 TCID50) vaccine on Day 0 (consisting of 0.5 mL injection of vaccine and 0.5 mL injection of saline placebo) and Day 28 (single 0.5 mL injection of vaccine). Safety will be measured by assessment of adverse events for 28 days following the last vaccination (56 days following the initial vaccination for those subjects that fail to receive the second dose) and for serious adverse events at six months post the final vaccination, and reactogenicity to the vaccines for 15 days following each vaccination. Immunogenicity testing will include antibody testing [enzyme linked immunosorbent assay (ELISA) and plaque reduction neutralizing antibody titers (PRNT)] and cellular immune responses [(INF-gamma enzyme linked immunospot (ELISPOT)] following each vaccination and at six months post the final vaccination. In addition, ELISA responses, using MVA VR-1508 as the target antigen and PRNT using vaccinia WR (Western Reserve) as the target antigen will be explored. Participants will include 90 healthy, vaccinia-naïve adults, aged 18 and older (born after 1971). Study duration will be approximately 13 months (7 months/subject).

Official Title
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Comparison of Safety and Immunogenicity of a High Dose (5 x 10^8 TCID50) and a Standard Dose (1 x 10^8 TCID50) of IMVAMUNE® in Healthy Vaccinia-Naive Individuals

Conditions
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Variola Major (Smallpox)

Intervention / Treatment
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* Biological: IMVAMUNE® High Dose
* Drug: Placebo
* Biological: IMVAMUNE® Standard Dose


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Prior to initial vaccination: At least 18 years of age and born after 1971 Read, sign, and date informed consent document Available for follow-up for the planned duration of the study (six months 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 28 days following the last vaccination A woman is considered of childbearing potential unless post-menopausal (> 1 year) or surgically sterilized (tubal ligation, bilateral oophorectomy, or hysterectomy) Acceptable contraception methods are restricted to effective devices (IUDs, NuvaRing®) or licensed hormonal products with use of method for a minimum of 30 days prior to vaccination, abstinence from sexual intercourse with men (vaginal penetration by a penis, coitus), and monogamous relationship with a vasectomized partner. 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+ by dipstick or urinalysis Adequate renal function is defined as a serum creatinine not exceeding the institution's upper limit of normal. Electrocardiogram (ECG) in absence of clinical significance [e.g., complete left or right bundle branch block, incomplete left bundle branch block or sustained ventricular arrhythmia, or two premature ventricular contractions (PVC's) in a row, or sympathetic tonus (ST) elevation consistent with ischemia] The following blood parameters: Hemoglobin equal or above the lower limit of institutional normal (sex specific); White blood cells greater than 2,500 and less than 11,000/mm^3; Platelets greater than or equal to 140,000/mm^3 Weight greater than or equal to 110 pounds Inclusion Criteria that must be met prior to the second vaccination: Acceptable medical history ECG (obtained after Day 14 after first vaccination) in absence of clinical significance (e.g., complete left or right bundle branch block, incomplete left bundle branch block or sustained ventricular arrhythmia, or two PVC's in a row, or ST elevation consistent with ischemia) If the subject is female and of childbearing potential, 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 28 days following the last vaccination A woman is considered of childbearing potential unless post-menopausal or surgically sterilized Acceptable contraception methods are restricted to effective devices (IUDs, 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) Exclusion Criteria: Exclusion criteria that apply prior to the initial vaccination: History of immunodeficiency Typical vaccinia scar Known or suspected history of smallpox vaccination including Modified Vaccinia Ankara (MVA) alone or as a vector as well as other investigational smallpox vaccine 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 a. 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 Systolic blood pressure >/= 150 mmHg or diastolic blood pressure >/= 100 mmHg. 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: a. Have smoked a cigarette in the past month, and/or b. Have hypertension (defined as systolic blood pressure >140 mm Hg) or are on antihypertensive medication, and/or c. 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. High-dose steroid use for greater than 2 weeks duration within three months prior to vaccination and 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 or planned receipt of inactivated vaccine from 14 days prior to the first vaccination through 14 days post second vaccination Receipt or planned receipt of any other live attenuated vaccine within 30 days prior to the first vaccination through 30 days post second vaccination Use of any other experimental agent within 30 days prior to vaccination and for the duration of the study 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 prior to Visit 9 Acute febrile illness (greater than or equal to 100.5 degrees Fahrenheit) on the day of vaccination Pregnant or lactating women Eczema of any degree or history of eczema People with active atopic dermatitis, active 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 (including gentamicin) Study personnel Exclusion criteria that apply prior to the second vaccination: History of immunodeficiency 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 a. 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 Systolic blood pressure >/= 150 mmHg or diastolic blood pressure >/=100 mmHg High-dose steroid use for greater than 2 weeks duration within three months prior to vaccination and 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 or planned receipt of inactivated vaccine from 14 days prior to vaccination through 14 days post second vaccination Receipt or planned receipt of any other live attenuated vaccine from 30 days prior to vaccination through 30 days post second vaccination Use of any other experimental agent within 30 days prior to vaccination and for the duration of the study 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 prior to Visit 9 Acute febrile illness (greater than or equal to 100.4 degrees Fahrenheit) on the day of vaccination Pregnant or lactating women Eczema of any degree or history of eczema People with active atopic dermatitis, active 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 (including gentamicin)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 38 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: Group A: High Dose<br>Single high dose of IMVAMUNE® (5x10^8 TCID50, consisting of two 0.5 mL injections) vaccine on Day 0 and a single saline placebo dose (single 0.5 mL injection) on Day 28 to match the two dose regimen of Group B. | Biological: IMVAMUNE® High Dose<br>* IMVAMUNE® Vaccinia Vaccine, undiluted, delivered by subcutaneous route on Day 0 at high dose 5×10^8 TCID50 (5×10^8 TCID50 per 1.0 mL dose - administered as 2 x 0.5 mL.<br>Drug: Placebo<br>* 0.5 mL injection of saline placebo administered with vaccine on Day 0 (Group B) or single saline placebo dose (single 0.5 mL injection) on Day 28 (Group A).<br>|
| Active Comparator: Group B: Standard Dose<br>Standard two dose regimen of IMVAMUNE® (1x10^8 TCID50) vaccine on Day 0 (consisting of 0.5 mL injection of vaccine and 0.5 mL injection of saline placebo) and Day 28 (single 0.5 mL injection of vaccine). | Drug: Placebo<br>* 0.5 mL injection of saline placebo administered with vaccine on Day 0 (Group B) or single saline placebo dose (single 0.5 mL injection) on Day 28 (Group A).<br>Biological: IMVAMUNE® Standard Dose<br>* IMVAMUNE® Vaccinia Vaccine delivered by subcutaneous (SC) route on Day 0 and 28 at standard dose (diluted with saline by study pharmacist to (1×10^8 tissue culture infectious dose 50 [TCID50] per 0.5 mL dose)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety: serious and non-serious adverse events associated with vaccination. |  | Days 0-28 after last vaccination (56 days after initial vaccination for those subjects that fail to receive the second dose); serious adverse events collected throughout the study duration. | 
| Time to seroconversion after 1 standard dose of IMVAMUNE® (1x10^8 TCID50, Group B) as compared to that after 1 high dose of IMVAMUNE® (5x10^8 TCID50, Group A). |  | Days after first vaccination: 0, 4, 8, 14, 21 and 28. Days after second vaccination: 0, 14, 28 and 180. | 
| Safety: local and systemic reactogenicity. |  | Immediately following vaccination and in the 15 days following vaccination. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Geometric mean titer (GMT) after one standard dose of IMVAMUNE® (1x10^8 TCID50, Group B) as compared to one high dose of IMVAMUNE® (5x10^8 TCID50, Group A). |  | Days after first vaccination: 0, 4, 8, 14, 21 and 28. Days after second vaccination: 0, 14, 28 and 180. | 

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