This study will evaluate the safety and efficacy of both Dryvax® and the new cell-cultured vaccine (CCSV) in a comparative fashion. Across 3 cohorts, 150 vaccinia-naive volunteers will be randomly assigned to receive either CCSV (100 volunteers) or Dryvax® (50 volunteers) in a blinded fashion. Subjects will be followed closely for up to 6 months and a subgroup of volunteers will be followed up to 3 years in order to evaluate the duration of immunity following vaccination. Another cohort will enroll 100 vaccinia-experienced volunteers and randomly assign them to receive either CCSV (50 volunteers) or Dryvax® (50 volunteers) and a sub group will be followed up to 3 years. A fifth cohort will enroll 100 vaccinia-naive volunteers and randomly assign them to receive different dilutions of CCSV (1:1, 1:5, 1:25, and 1:50).

• Have never received smallpox vaccine or previously received an experimental smallpox vectored vaccine (for vaccinia-naive cohorts only)
• Have been previously vaccinated within the last 10 years (vaccinia-experienced cohort only)
• Must agree to have blood samples banked for future research testing
• Have not participated in any clinical trial using investigational product within past month
• No current or past history of exfoliative skin problems
• Not have regular contact with children under 3 years of age until scab at site of vaccination has fallen off (around 21 days or 3 weeks after vaccination)
• Do not have a positive test for HIV virus, hepatitis C virus, or hepatitis B surface antigen
• Are not a health care worker caring for newborns, patients that are immunocompromised or have skin that is adversely altered
• Will not engage in direct patient care until immunization scab falls off (around 21 days or 3 weeks after vaccination) if health care worker