Inclusion Criteria:

• Negative urine glucose by dipstick.
• Adequate renal function defined as a serum creatinine less than or equal to 1.5 mg/dL, urine protein < 100 mg/dL or trace or negative proteinuria by dipstick, and a calculated creatinine clearance > 55 ml/min based on the formulas in the manual of procedures.
• Hematocrit > 34% for females, >38% for males, platelets > 150,000/mm3, WBC > 2500/mm3 and < 11000/mm3.
• Typical vaccinia scar or validated documentation (e.g., military record, international travel certificate) of a smallpox vaccination, but not since 1989.
• Willing to sign informed consent.
• Availability for follow-up for the planned duration of the study at least 8 weeks after vaccination.
• Acceptable medical history by screening evaluation and brief clinical assessment.
• Negative urine or serum pregnancy test for women of childbearing potential.
• If the subject is female and of childbearing potential, she must use an acceptable contraception and not become pregnant for the duration of the study. (Acceptable contraception includes implants, injectables, combined oral contraceptives, effective intrauterine devices (IUDs), sexual abstinence, or a vasectomized partner).
• Negative ELISA for HIV or indeterminant Western blot or other assay confirming that the serostatus does not reflect HIV infection.
• ALT < 1.5 times institutional upper limit of normal.
• Negative hepatitis B surface antigen and negative antibody to hepatitis C virus.
• Age 32 to 70 years.

Exclusion Criteria:

• Any acute skin disorders of large magnitude, e.g., laceration requiring sutures, burn greater than 2x2 cm.
• Household contacts/sexual contacts with, or frequent and/or prolonged exposure to, any of the following: Pregnant women, children < 12 months of age, people with or history of eczema, people with chronic exfoliative skin disorders/conditions or any acute skin disorders of large magnitude, e.g., laceration requiring sutures, burn greater than 2x2 cm or people with immunodeficiency disease or use of immunosuppressive medications.
• Any condition that, in the opinion of the investigator, might interfere with study objectives.
• Known allergies to any component of the vaccine (e.g., polymyxin B sulfate, dihydrostreptomycin sulfate, chlortetracycline hydrochloride, neomycin sulfate).
• Known allergies to any known component of the diluent (i.e., glycerin and phenol).
• Known allergies to any known component of VIG, i.e., thimerosal or previous allergic reaction to immunoglobulins.
• Known allergies to cidofovir or probenecid.
• Live attenuated vaccines within 60 days of study.
• Use of investigational agents within 30 days prior to study.
• Receipt of blood products or immunoglobulin in the past 6 months.
• Acute febrile illness on the day of vaccination.
• Pregnant or lactating women.
• Eczema of any degree or history of eczema.
• History of chronic exfoliative skin disorders/conditions.
• Smallpox vaccination in 1990 or more recently.
• Inactivated vaccine 14 days prior to vaccination.
• History of immunodeficiency.
• Known or suspected impairment of immunologic function including, but not limited to, clinically significant liver disease, diabetes mellitus, moderate to severe kidney impairment.
• Malignancy, other than squamous cell or basal cell skin cancer.
• Active Autoimmune disease.
• Use of immunosuppressive medication.
• Medical or psychiatric condition or occupational responsibilites that preclude subject compliance with the protocol.
• History of "illegal" injection drug use.