Poxviruses are among prime candidates for generation of recombinant virus vaccines against infectious diseases and cancer. Poxvirus-based experimental vaccines have already proven to be efficient with regard to antigen delivery and the induction of antigen-specific immune responses in several animal models and first clinical trials (1–7). Live vector vaccines are designed to mimic microbial infections allowing for de novo synthesis of vaccine antigens that appear particularly suitable for presentation via MHC-I molecules. Vaccination with these live vaccines may elicit appropriate “danger” signals to the immune system, resulting in preferential recognition and presentation of recombinant (vaccine) antigens. Additional features of poxvirus vectors include the ability to accommodate large amounts of foreign DNA, high stability, and reasonable cost of manufacturing. However, vaccinia virus—the prototype live viral vaccine—can replicate in humans, and its imperfect safety record as a smallpox vaccine was a concern for its use as a vector in clinical applications. Therefore, most of the currently evaluated recombinant vaccines are based on vectors derived from highly attenuated vaccinia viruses such as modified vaccinia virus Ankara (MVA) (8), NYVAC (9) or avipoxviruses (10,11). These viruses all share the property of replication deficiency in mammalian cells that may have contributed to the already established clinical safety of these vectors (12–14). Importantly, even high dose inoculation of MVA was shown to be safe in immune-suppressed macaques, suggesting the safety of recombinant MVA vaccines in potentially immunocompromised individuals (15).