The study will evaluate the IMVAMUNE® smallpox vaccine with respect to safety and optimization of immune responses by different vaccination regimens in vaccinia-naïve adults. Study subjects must be age 18 and older and born after 1971. Originally, 215 subjects were planned to be randomly assigned to 1 of 5 groups to be immunized twice with IMVAMUNE® vaccine or placebo subcutaneously in Groups A and B, or Dryvax® or placebo by scarification in Group C or both IMVAMUNE® and Dryvax® or 2 placebos in Groups D and Group E. In July, 2007, enrollment was halted at the request of Center for Biologics Evaluation and Research (CBER). At that time, enrollment included zero subjects in Group A, 2 subjects in Group B, 8 subjects in Group C, 6 subjects in Group D, and 4 subjects in Group E. CBER placed an official hold on the enrollment into the Groups that would administer Dryvax®, i.e., Groups C, D and E. Subjects previously enrolled into Groups C, D, and E will be followed according to the protocol. The protocol has been modified as follows. One hundred and ninety-five subjects will be randomly assigned to 1 of 3 groups to be immunized twice with IMVAMUNE® vaccine or placebo subcutaneously in Groups A and B, or to receive a single immunization with IMVAMUNE® or placebo subcutaneously in Group F. (NOTE: A total of 197 subjects will be randomly assigned to Groups A, B, and F as 2 subjects were previously enrolled in Group B.) Group A will receive IMVAMUNE® vaccine or placebo on Days 0 and 7. Group B will receive IMVAMUNE® vaccine or placebo on Days 0 and 28. Group F will receive a single dose of IMVAMUNE® at Day 0. All subjects will complete a memory aid for 15 days following each vaccination. Groups C, D, and E will have the appropriate reactogenicity information collected until the vaccination lesion, if present is well dried. Adverse events will be collected for 28 days after each vaccination. Specimens will be collected for immunologic assays at the noted clinic visits, as well as 1 year post last vaccination. Serious adverse events will be collected throughout the study period. The primary safety objective is to evaluate the safety of IMVAMUNE® given as a single dose, IMVAMUNE® given in a 2 dose prime-boost regimen at Day 0 and 7 or Day 0 and 28, IMVAMUNE® followed by a boost with Dryvax®, and IMVAMUNE® given simultaneously with Dryvax®. The primary immunogenicity objective is to determine if the Geometric Mean Titer (GMT) of neutralizing antibody [using Modified Vaccinia Ankara (MVA) as the target antigen] among subjects receiving a regimen of 2 doses of IMVAMUNE® (1×10^8, Days 0 and 7, Group A) is non-inferior to that among subjects receiving 2 doses of IMVAMUNE® (1×10^8, Days 0 and 28, Group B) at Day 14 following the 2nd dose. The secondary immunogenicity objective is to determine if the GMT, as assessed by enzyme linked immunosorbent assay (ELISA) (using MVA as the target antigen), among subjects receiving a regimen of 2 doses of IMVAMUNE® (1×10^8, Days 0 and 7, Group A) is non-inferior to that among subjects receiving 2 doses of IMVAMUNE® (1×10^8, Days 0 and 28, Group B) at Day 14 following the 2nd dose. The tertiary immunogenicity objective is to characterize the kinetics, magnitude, and duration of cellular and humoral immune responses to IMVAMUNE® alone or IMVAMUNE® as a prime followed by a boost with IMVAMUNE® or Dryvax®, or Dryvax® alone.