Assessment of the safety, immunogenicity and efficacy of novel blood-stage malaria vaccines

Despite decades of research and the availability of effective medications, malaria remains a significant global health issue. The vast majority of infections are caused by two species: Plasmodium falciparum and Plasmodium vivax. There is currently no licensed malaria vaccine but an effective vaccine is widely considered necessary to maintain the progress towards eradication, particularly given the increasing issues of insecticide and antimalarial resistance developing. The manifestations of malaria disease are caused by the blood-stage of the parasite against which endemic populations, who are exposed to multiple episodes of malaria, develop some degree of natural immunity. It is therefore considered that vaccines against the blood-stage may mimic the immunity seen in these individuals. This thesis describes three early-phase clinical trials for blood-stage malaria vaccines, all carried out in healthy volunteers at the Jenner Institute in Oxford. The first of these was a Phase Ia trial of a novel P. vivax blood-stage vaccine, ChAd63/MVA PvDBP. This is the only blood-stage vivax vaccine to reach clinical trial and was safe and immunogenic, with functional activity of the antibodies induced by vaccination demonstrated in vitro. The second trial was a Phase I/IIa trial of a candidate P. falciparum vaccine, FMP2.1/AS01B. Vaccine efficacy was assessed by blood-stage controlled human malaria infection (CHMI) using a model developed for this trial. Although the vaccine did not demonstrate any efficacy, the CHMI model was highly reproducible. The final Phase Ia trial examined novel P. falciparum vaccines, ChAd63/MVA RH5. This is the first clinical trial in which purified IgG demonstrated inhibition of growth of P. falciparum in vitro in all strains tested. These studies have demonstrated the potential for developing an effective vaccine against blood stage vivax and falciparum malaria as well as the potential for using the CHMI model for proof-of-concept efficacy testing of novel malaria vaccines.