Analysis of DNA and recombinant viral vaccines against <i>P. falciparum</i> in malaria-naïve and malaria-exposed humans

The hypotheses under test were as follows. Firstly that sequential immunisation of humans with two candidate vaccines recombinant for the same malarial DNA sequence would be safe, would produce higher frequencies of antigen-specific T cells in peripheral blood and greater efficacy than repeated immunisation with one vaccine. Secondly that recombinant viral malaria immunization would be more immunogenic in malaria-exposed than malaria-naive individuals. The third hypothesis was contingent on the conduct of a field efficacy trial; liver-stage specific T cells induced by the regimen with greatest immunogenicity would provide protection against natural infection. Three delivery systems were evaluated - a circular plasmid DNA molecule (DNA), modified vaccinia virus Ankara (MVA) and fowlpox strain 9 (FP9); each recombinant for the multiple epitope - thrombospondin related anonymous (or adhesion) protein (ME-TRAP) P. falciparum DNA sequence. DNA ME-TRAP and MVA ME-TRAP were safe but poorly immunogenic when given alone in both UK and Gambian adults. Two doses of 1mg DNA ME-TRAP administered intramuscularly followed by one dose of 3 x 107 plaque forming units (pfu) MVA ME-TRAP administered intradermally induced higher effector T cell frequencies as measured by ex vivo γ-interferon ELISPOT (enzyme-linked immunospot) assay than three doses of either alone. A second MVA ME-TRAP immunisation did not increase immunogenicity above that after a single immunisation. At these doses the DNA/MVA regimen was more immunogenic in malaria-experienced Gambian adults than in malaria-naive British adults. Increasing the dose of DNA to 2mg and MVA to 1.5 x 108 pfu increased immunogenicity further. Two doses of FP9 ME-TRAP showed a trend towards to being less immunogenic than two doses of DNA ME-TRAP prior to a single MVA immunisation. The heterologous DNA/MVA regimen afforded protection manifested by delay in time to parasitaemia in a clinical challenge model in the UK. Therefore a randomised double-blind controlled trial was conducted in men aged 15 45 in The Gambia. This trial confirmed safety and high immunogenicity but there was 10.3% (95%CI -22% to +34%) efficacy for the time to infection primary endpoint. Potential reasons for failure of the intervention include an unfavourable CD4+/CD8+ T cell ratio, inadequate TRAP expression in infected hepatocytes, inadequate cross-reactivity and the duration or magnitude of the peak T cell immunogenicity