Recombinant modified vaccinia virus Ankara (rMVA). Many viruses have been investigated as potential recombinant vaccines. The successful worldwide eradication of smallpox via vaccination with live vaccinia virus highlighted vaccinia as a candidate for recombinant use. The recognition in recent years that non- replicating strains of poxvirus such as MVA and avipox vectors can be more immunogenic than traditional replicating vaccinia strains has enhanced the attractiveness of this approach. MVA (modified vaccinia virus Ankara) is a strain of vaccinia virus which has been passaged more than 570 times though avian cells, is replication incompetent in human cell lines and has a good safety record. It has been administered to more than 120,000 vaccinees as part of the smallpox eradication programme, with no adverse effects, despite the deliberate vaccination of high risk groups (Stickl, 1974; Mahnel, 1994). This safety in man is consistent with the avirulence of MVA in animal models. MVA has six major genomic deletions compared to the parental genome severely compromising its ability to replicate in mammalian cells (Meher, 1991). No replication has been documented in non- transformed mammalian cells. Viral replication is blocked late during infection of cells but importantly viral and recombinant protein synthesis is unimpaired even during this abortive infection. The viral genome has been proven to be stable through a large series of passages in chicken embryo fibroblasts. Replication-deficient recombinant MVA has been seen as an exceptionally safe viral vector. When tested in animal model studies recombinant MVAs have been shown to be avirulent, yet protectively immunogenic as vaccines against viral diseases and cancer. Recent studies in severely immuno-suppressed macaques have supported the view that MVA should be safe in immuno-compromised humans (Akira, 2001; Stittelaar, 2001). There is now safety data from a number of recombinant MVAs that are currently in Phase I/II trials in both the UK and Africa. Useful data on the safety and efficacy of various doses of a recombinant MVA vaccine comes from clinical trial data with a recombinant MVA expressing a number of CTL epitopes from Plasmodium falciparum pre-erythrocytic antigens fused to a complete pre-erythrocytic stage antigen, Thrombospondin Related Adhesion Protein (TRAP). To date MVA ME-TRAP has been administered to over 600 healthy volunteers (adults and children) in Oxford and Africa (The Gambia and Kenya) without any serious adverse events (Adrian Hill, unpublished, personal communication). Volunteers have received one to three doses of from 3 to 15 x 107 pfu per dose of intra-dermal vaccine at three-week intervals. All subjects have temporary local redness with typically a 5mm central red area with a paler pink surrounding area that ranges in size from about 1 -7cm in diameter and peaks at 48 hours post vaccination. At seven days post vaccination generally only the central red area remains. This fades over the next few weeks and is usually not apparent at 2 months after vaccination. The emerging safety profile of recombinant MVA vaccine is excellent and supported by data from clinical studies of three other MVA recombinants made in Oxford and currently in clinical studies using MVAs for HIV, HBV and melanoma. To date these vaccines have been administered to over 600 people with no serious adverse events (Hill; personal communication) 40 HIV positive individuals treated with highly active anti-retroviral therapy (HAART) have been vaccinated with at least 5 x 107 PFU MVA containing HIV antigens with no serious adverse events (Dorrell, unpublished data; Cosma et al 2003; Harrer et al, 2005). 7 HIV positive individuals have been vaccinated with MVA containing malaria antigens with no serious adverse events and no significant or sustained rise in viral load (Bejon at al, CID 2006, in press).