A Non-inferiority Trial to Compare MVA-BN® Smallpox Vaccine to ACAM2000®

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