A Study to Evaluate Safety and Immunogenicity of One and Two Doses of IMVAMUNE® Smallpox Vaccine in 56-80 Year Old Vaccinia-experienced Subjects

Inclusion Criteria: * Male and female subjects 56-70 years of age. If no safety concerns are identified upon review of the safety data from the first 30 subjects enrolled, the age range is extended up to 80 years. * Time since most current smallpox vaccination \> 10 years. * The subject has read, signed and dated the Informed Consent Form (ICF), successfully completed (at least 90% correct \[no more than 3 attempts allowed\]) the test of understanding and has signed the Health Insurance Portability and Accountability Act (HIPAA) authorization form. * Women must have a negative serum pregnancy test at screening and negative urine pregnancy test within 24 hours prior to vaccination. * Women of childbearing potential (WOCBP) must have used an acceptable method of contraception for 30 days prior to the first vaccination, must agree to use an acceptable method of contraception during the study and must not plan to become pregnant for at least 28 days after the last vaccination. (Acceptable contraception methods are restricted to abstinence, barrier contraceptives, intrauterine contraceptive devices or licensed hormonal products). * Weight: ≥ 100 pounds (45.5 kg) and ≤ 330 pounds (150 kg). * White blood cells ≥ 2500/mm3 and \< 11,000/mm3. * Absolute neutrophil count within normal limits. * Hemoglobin within normal limits. * Platelets within normal limits. * Adequate renal function defined as: 1. Urine protein ≤ +1 (by dip stick) 2. Serum creatinine within normal limits * Adequate hepatic function defined as: 1. Total bilirubin ≤ 1.5 x upper limit of normal (ULN) in the absence of other evidence of significant liver disease. 2. Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase ≤ 1.5 x ULN. * Cardiac troponin I \< 2 x ULN. * 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, AV node block, QTc or PR prolongation, sustained atrial arrhythmias, sustained ventricular arrhythmia, 2 premature ventricular contractions (PVC) in a row, ST elevation consistent with ischemia. Exclusion Criteria: * History of or active immunodeficiency or immuno-suppression caused by acquired or congenital diseases or caused by treatments such as chronic administration (\> 14 days) of systemic, i.e. parenteral or oral, corticosteroids (\> 5 mg prednisone \[or equivalent\] per day), radiation or immune-modifying drugs. * Periodic steroid injections, e.g. intraarticular, are not allowed within 30 days prior to the first vaccination and throughout the study until Visit 5 (V5). * Post organ transplant subjects whether or not receiving chronic immunosuppressive therapy. * Uncontrolled serious infection, i.e. not responding to antimicrobial therapy. * History of any serious medical condition, which in the opinion of the investigator would compromise the safety of the subject or prevent the subject from complying with study requirements. * History of or active autoimmune disease, e.g. Type I diabetes. Persons with vitiligo or thyroid disease taking thyroid hormone replacement are not excluded. * Skin cancer in the past six months. If treatment for skin cancer was successfully completed more than six months ago and the malignancy is considered to be cured, the subject may be enrolled. Subjects with history of skin cancer must not be vaccinated at the previous site of cancer. * Any other malignancy in the past five years. If treatment for cancer was successfully completed more than 5 years ago and the malignancy is considered to be cured, the subject may be enrolled. * Clinically significant hematological, renal, hepatic, pulmonary, central nervous, cardiovascular or gastrointestinal disorders which are not adequately controlled by medical treatment within the last 12 weeks before vaccination as judged by the site's Principal Investigator. * History of myocardial infarction, congestive heart failure with marked limitation of activity due to symptoms, e.g. walking short distances \[20 100 m\] (i.e. \> Grade II according to the New York Heart Association), cardiomyopathy and stroke or transient ischemic attack in the past two years. * Uncontrolled high blood pressure defined as systolic blood pressure ≥ 150 mm Hg and/or ≥ diastolic blood pressure ≥ 100 mm Hg within the last six months. * Subjects with active coronary heart disease manifested by angina, even if on medication. * 25 % 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 * Clinically significant mental disorder not adequately controlled by medical treatment. * History of chronic alcohol abuse (40 g/day, e.g. 3 glasses of beer or 2 glasses of wine for at least six months) and/or intravenous drug abuse (within the last six months). Subjects with a history of other substance and/or alcohol abuse are also excluded if - in the opinion of the investigator - the abuse could prevent the subject from complying with study requirements. * History of allergic disease or reactions likely to be exacerbated by IMVAMUNE® or any component of the vaccine, e.g. tris(hydroxymethyl)-amino methane, chicken embryo fibroblast proteins, aminoglycosides (gentamycin). * History of anaphylactic shock or any severe allergic reaction to a vaccine requiring immediate treatment. * Subjects undergoing treatment for tuberculosis infection or disease. * Having received any vaccinations or planned vaccinations with a live vaccine within 30 days prior to or after study vaccination. * Having received any vaccinations or planned vaccinations with a killed vaccine within 14 days prior to or after study vaccination. * Administration or planned administration of immuno-globulins and/or any blood products during a period starting from three months prior to administration of the vaccine and ending at study conclusion. * Use of any investigational or non-registered drug or vaccine other than the study vaccine within 30 days preceding the first dose of the study vaccine or planned administration of such a drug during the study period. * Temperature ≥ 100.4°F (38.0°C) at the time of enrollment. * Any condition which might interfere with study objectives or would limit the subject's ability to complete the study in the opinion of the investigator. * Study personnel.