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Controlled human malaria infection in Kenyan adults: A safe model that could accelerate assessment of novel drugs and vaccines in malaria endemic populations Susanne Hodgson, Elizabeth Juma, Amina Salim, Charles Magiri, Domtila Kimani, Daniel Njenga, Alfred Muia, Andrew Cole, Caroline Ogwang, Peter Billingsley, Eric James, Kim Lee Sim, Thomas Rampling, Adrian Hill, Faith Osier, Simon Draper, Philip Bejon, Stephen Hoffman, Bernhards Ogutu, Kevin Marsh

A highly effective malaria vaccine is a major goal of global health research and will likely require a multi-stage product. Oxford researchers are developing the concept of a highly effective multi-stage P. falciparum vaccine to the point of proof-of-concept phase II testing in Europe, prior to trials in malaria-endemic areas. Remarkable recent advances in vaccine design for all four stages of the P. falciparum parasite’s life-cycle allow testing of a multi-stage multi-component vaccine for the first time, with strong chances of success. These advances are i) the availability of a new vectored prime-boost vaccination regime based on the chimpanzee adenovirus technology that has been found to induce exceptionally potent CD8+ T cell responses and high titre antibodies against multiple malaria antigens; ii) the development of an improved virus-like particle (VLP) version of the leading partially protective RTS,S sporozoite vaccine candidate, termed R21, that lacks the excess of HBsAg in RTS,S; iii) the identification, using a vector technology screen, of the blood-stage antigen RH5 as the first antigen to induce potent strain-transcending neutralization of blood-stage parasites in in vitro growth inhibition assays; and iv) the demonstration that antibodies against a mosquito-stage antigens that induce 100% transmission blocking against field isolates of P. falciparum in Africa are inducible by a new nanoparticle vaccine candidate. In parallel similar approaches using vectors and VLPs are underway to target the pre-erythrocytic stages of P. vivax, including the hypnozoite, and a phase I trial of the vivax blood-stage vaccine candidate, PvRII, is nearing completion. We are aiming to undertake phase I/II clinical trials to assess the P. falciparum pre-erythrocytic, blood-stage and mosquito-stage components individually, and then together, using state-of-the art immunomonitoring, key functional assays of vaccine-induced immunogenicity, and sporozoite and blood-stage parasite challenges to measure efficacy prior to field testing. An update on this programme will be presented. A viral vectored prime-boost regime has recently shown high efficacy against malaria infection in East Africa and the first combination trial of RTS,S/AS01 with these vectors has been completed. The prospects for achieving high efficacy with such combination approaches now appear very good.