Lyophilized IMVAMUNE® (1x10^8 TCID50) Versus Liquid IMVAMUNE® (1x10^8 TCID50) Administered Subcutaneously and a Lower Dose Liquid IMVAMUNE® (2x10^7 TCID50) Administered Intradermally

Inclusion Criteria: Inclusion criteria that must be met prior to the initial vaccination: * At least 18 years of age and born after 1971. * Read, signed, and dated informed consent document. * Available for follow-up for the planned duration of the study (6 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: 1. A woman is considered of childbearing potential unless post-menopausal (greater than or equal to 1 year) or surgically sterilized (tubal ligation, bilateral oophorectomy, or hysterectomy). 2. Acceptable contraception methods are restricted to effective devices \[intrauterine devices (IUD)s, NuvaRing®\] 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 plus 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 2 premature ventricular contraction's (PVC)'s in a row, or sympathetic tonus (ST) elevation consistent with ischemia). * The following blood parameters: 1. Hemoglobin equal or above the lower limit of institutional normal (sex-specific); 2. White blood cells greater than 2,500 and less than 11,000/mm\^3; 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. * 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: 1. A woman is considered of childbearing potential unless post-menopausal (greater than or equal to 1 year) or surgically sterilized (tubal ligation, bilateral oophorectomy, or hysterectomy). 2. 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. 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 greater than or equal to 150 mmHg or diastolic blood pressure greater than or equal to 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://hp2010.nhlbihin.net/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 1. Corticosteroid nasal sprays are permissible 2. Persons who are using a topical steroid can be enrolled after their therapy is completed 3. 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 and prior to Visit 6 * 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 * 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: * Continued inflammation (erythema and/or induration) graded as moderate or severe at the site of the initial 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 greater than or equal to 150 mmHg or diastolic blood pressure greater than or equal to 100 mmHg * High-dose steroid use for greater than 2 weeks duration within three months prior to vaccination and current use of immunosuppressive medication. 1. Corticosteroid nasal sprays are permissible 2. Persons who are using a topical steroid can be enrolled after their therapy is completed 3. 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 or planned receipt of inactivated vaccine from 14 days prior to vaccination through 14 days post second vaccination * Receipt of 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 and prior to Visit 6 * 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 * 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)