Modified Vaccinia virus Ankara (MVA) is a highly attenuated vaccinia virus that cannot replicate in human cells. It is expected to have a better safety profile than the traditional smallpox vaccines. The clinical trial design is phase I/II, randomized, placebo-controlled, double-blinded, schedule-finding studies of MVA in healthy adults who were vaccininated against smallpox more than 10 years ago. The hypothesis is that MVA will be safe in humans when administered by intramuscular (IM) injection and will result in an immune response comparable to that observed after Dryvax primary vaccination. Subjects were randomized to different immunization schedules with MVA or placebo. Each schedule includes a Dryvax challenge 12 weeks after completion of the primary vaccination schedule. Safety evaluations are performed on an ongoing basis throughout the study and immunogenicity samples are collected and frozen for batch testing by research laboratories. The Intramural Data and Safety Monitoring Board review interim safety data in June and December. The study was closed to accrual in June 2004 with 75 of the target 80 subjects enrolled.