Heterologous prime-boost immunisation with RTS,S/AS02A and the poxvirus MVA-CS was evaluated in 18 healthy malaria-naïve subjects in Oxford. Both priming with RTS,S and boosting MVA-CS, and the reverse, were found to be safe and well tolerated. T cell responses as measured by IFN-gamma ex vivo ELISPOT were induced, but the responses were low to moderate in both groups, with heterologous boosting yielding only small increments in T cell immunogenicity and no increased antibody response. Protection against 3D7 Plasmodium falciparum sporozoite challenge 4 weeks after the final vaccination was equal for both regimens at 33% (95% C.I. 4.3-77.7%), with one subject remaining fully protected on rechallenge at 5 months.