Phase 1 evaluation of 3 highly immunogenic prime-boost regimens, including a 12-month reboosting vaccination, for malaria vaccination in Gambian men

Abstract

Successful vaccination against intracellular pathogens, including liver-stage Plasmodium falciparum, will require induction of strong antigen-specific T lymphocyte responses. The multiple epitope (ME)-thrombospondin-related adhesion protein (TRAP) construct includes CD8(+) and CD4(+) T cell epitopes from pre-erythrocytic P. falciparum antigens fused in-frame to the entire pre-erythrocytic antigen TRAP. Three carriers for this construct--plasmid DNA and 2 recombinant nonreplicating poxviruses (modified vaccinia virus Ankara [MVA] and fowlpox strain 9 [FP9])--were administered at 3-week intervals in a heterologous prime-boost combination to 29 Gambian men aged 18-45 years. Doses of DNA ME-TRAP, MVA ME-TRAP, and FP9 ME-TRAP were 2 mg and 1.5x10(8) and 1x10(8) plaque-forming units, respectively. DNA ME-TRAP was injected intramuscularly; MVA ME-TRAP and FP9 ME-TRAP were injected intradermally. There were no clinically relevant laboratory abnormalities and no severe or serious adverse events related to vaccination. DNA/MVA and FP9/MVA regimens were the most potent inducers of circulating effector T cells seen to date in sub-Saharan Africa. Twelve months after the final vaccination, a single booster vaccination expanded the effector T cell pool to a similar or higher magnitude than that after the primary vaccinations. These results highlight optimized combination regimens with general relevance to the development of vaccines targeting intracellular pathogens.