A Non-inferiority Trial to Compare MVA-BN® Smallpox Vaccine to ACAM2000®
Condition: 18-42 Year Old Healthy Vaccinia-naïve Subjects
MeSH terms: Vaccinia; Smallpox
Intervention: MVA BN®; ACAM2000®
Intervention description: 0.5 ml MVA BN® with a nominal titer of 1x10E8 TCID50, administered as a subcutaneous injection; 0.0025 ml ACAM2000®, consisting of 2.5-12.5x10E5 plaque forming units of live vaccinia virus (VACV). Picked up with a bifurcated needle and administered by the percutaneous route (scarification) using 15 jabs of that bifurcated needle.
Intervention MeSH terms: Smallpox and monkeypox vaccine modified vaccinia ankara-bavarian nordic
Phase: Phase 3
Study type: Interventional
Primary purpose: Prevention
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Enrollment: 440.0
Sex: All
Minimum age: 18 Years
Maximum age: 42 Years
Healthy volunteers: Accepts Healthy Volunteers

Summary:

      To demonstrate the efficacy of MVA-BN® in terms of vaccinia-specific Plaque Reduction
      Neutralization Test (PRNT) antibody response and by showing that vaccination prior to
      administration of ACAM2000® results in an attenuated take.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Healthy male and female subjects, 18-42 years of age

          2. The subject has read, signed and dated the Informed Consent, having been advised of
             the risks and benefits of the trial in a language understood by the subject and prior
             to performance of any trial specific procedure

          3. Acceptable medical history by screening evaluation and physical examination

          4. BMI greater or eaqual than 18.5 and smaller than 35

          5. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test at
             Screening and a negative urine or serum pregnancy test within 24 hours prior to each
             vaccination

          6. WOCBP must have used an acceptable method of contraception for 28 days prior to the
             first vaccination, must agree to use an acceptable method of contraception during the
             trial, and must avoid becoming 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)

          7. Human Immunodeficiency Virus (HIV) antibody negative, hepatitis B surface antigen
             negative and negative antibody test to hepatitis C virus

          8. White blood cells greater or eaqual than 2500/mm3 and smaller than 11,000/mm3

          9. Hemoglobin within normal limits

         10. Platelets greater or eaqual than lower normal limits

         11. Adequate renal function defined as a calculated Creatinine Clearance (CrCl) greater
             than 60 ml/min as estimated by the Cockcroft-Gault equation

         12. Adequate hepatic function in the absence of other evidence of significant liver
             disease defined as:

               -  Total bilirubin greater than 1.5 x Upper Limit Normal (ULN)

               -  Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) greater than 1.5
                  x ULN

               -  Alkaline Phosphatase (Alk Phos) greater than 1.5 x ULN

         13. Troponin I smaller than 2 x ULN

         14. Electrocardiogram (ECG) without clinically significant findings, e.g. any kind of
             atrioventricular or intraventricular conditions or blocks such as complete left or
             right bundle branch block, atrioventricular node block, QTc or PR prolongation,
             premature atrial contractions or other atrial arrhythmia, sustained ventricular
             arrhythmia, two premature ventricular contractions in a row, ST elevation consistent
             with ischemia

        Exclusion Criteria:

          1. Pregnant or breast-feeding women

          2. Typical vaccinia scar

          3. Known or suspected history of smallpox vaccination defined as visible vaccination scar
             or documentation of smallpox vaccination or as reported by the subject

          4. History of vaccination with any poxvirus-based vaccine

          5. History of any serious medical condition, which in the opinion of the investigator
             would compromise the safety of the subject

          6. History of or active immunodeficiency or immunosuppression caused by acquired or
             congenital diseases or caused by ongoing treatments such as chronic (greater than 14
             days) high-dose corticosteroids (smaller than 5 mg prednisone [or equivalent] per day
             applied systemically, i.e. parenterally or orally), chronic or planned treatment with
             steroid eye drops or ointment at time of enrollment or radiation, or immunosuppressive
             drugs; low-dose corticosteroid topical products and nasal sprays used sporadically,
             i.e. pro re nata (according to circumstances) are permissible

          7. Having had radiation or X-ray treatment (not routine X-rays) within the last 3 months

          8. Post organ and bone-marrow transplant subjects whether or not receiving chronic
             immunosuppressive therapy

          9. Eye surgery within 4 weeks prior to trial vaccination

         10. History of or active autoimmune disease. Persons with vitiligo or thyroid disease
             taking thyroid hormone replacement are not excluded

         11. Uncontrolled serious infection, i.e. not responding to antimicrobial therapy

         12. History of malignancy, other than squamous cell or basal cell skin cancer, unless
             there has been surgical excision considered to have achieved cure. Subjects with
             history of skin cancer must not be vaccinated at the previous site of cancer

         13. History of keloid formation

         14. History or clinical manifestation of severe hematological, renal, hepatic, pulmonary,
             central nervous, cardiovascular or gastrointestinal disorders

         15. 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

         16. Chest pain (that is diagnosed as cardiac related) or trouble breathing on exertion

         17. 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: This criterion
             applies only to subjects 20 years of age and older

         18. History of an immediate family member (father, mother, brother, or sister) who has had
             onset of ischemic heart disease before the age of 50 years

         19. Clinically significant psychological disorder not adequately controlled by medical
             treatment

         20. Active or history of chronic alcohol abuse and/or intravenous and/or nasal drug abuse
             (within the past 6 months)

         21. History of anaphylaxis or any severe allergic reaction or serious adverse reaction to
             a vaccine

         22. Eczema of any degree or history of eczema

         23. People with active atopic dermatitis (AD) [characterized by pruritus, eczematous
             lesions, xerosis (dry skin), and lichenification (thickening of the skin and an
             increase in skin markings] or with a history of AD

         24. People with chronic exfoliative skin disorders/conditions

         25. People with active current Varicella zoster, Herpes zoster, impetigo, uncontrolled
             acne, Darier's disease or any acute skin disorders of large magnitude, e.g.,
             laceration requiring sutures

         26. People with a tattoo that covers the vaccination injection area (preventing assessment
             of the area and interfering with a vaccination site photograph)

         27. Having received any vaccinations or planned vaccinations with a live vaccine within 28
             days prior to or after trial vaccination

         28. Having received any vaccinations or planned vaccinations with a killed vaccine within
             14 days prior to or after trial vaccination

         29. Administration or planned administration of immunoglobulins and/or any blood products
             during a period starting from three months prior to administration of the vaccine and
             ending at trial conclusion

         30. Use of any investigational or non-registered drug or vaccine other than the trial
             vaccines within 28 days preceding the first dose of the trial vaccine or planned
             administration of such a drug /vaccine during the trial period

         31. Blood donation for the duration of the trial

         32. Acute disease (illness with or without a fever) at the time of enrollment

         33. Temperature ≥ 100.4°F (38.0°C) at the time of enrollment

         34. Known household contacts with, or occupational exposure (other than minimal contact)
             to any of the following:

               -  Pregnant women

               -  Children <12 months of age

               -  People with eczema or a history of eczema

               -  People with active AD or history of AD

               -  People with chronic exfoliative skin disorders/conditions

               -  People with active Varicella zoster, Herpes zoster, impetigo, uncontrolled acne,
                  Darier's disease or any acute skin disorders of large magnitude, e.g., laceration
                  requiring sutures, burn with areas greater than 2×2 cm

               -  People with active or recent immunodeficiency disease or use of immunosuppressive
                  medications, for example: have or take medication for HIV, AIDS, leukemia,
                  lymphoma, or chronic liver problem, have or take medication for Crohn's disease,
                  lupus, arthritis, or other immune disease; have had radiation or X-ray treatment
                  (not routine X-rays) within the last 3 months; have ever had a bone-marrow or
                  organ transplant (or take medication for that ); or have another problem that
                  requires steroids, prednisone or a cancer drug for treatment

               -  People having had eye surgery within the last 4 weeks

         35. Known allergy to MVA-BN® vaccine or any of its constituents, e.g.
             tris(hydroxymethyl)-amino methane, including known allergy to egg or aminoglycoside
             (gentamycin)

         36. Known allergies to ACAM2000® and its diluents including polymyxin B sulfate, neomycin
             sulfate, and phenol

         37. Known allergies to vaccinia immunoglobulin (VIG) including thimerosal or previous
             allergic reaction to immunoglobulins

         38. Known allergies to cidofovir, sulfa drugs, or probenecid

         39. Trial personnel