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)