Pre-clinical development of a chemically synthetic anti-toxic vaccine against malaria

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Plasmodium falciparum malaria infects 5-10% of the global population (400 million clinical cases) and kills two million people annually1. As such it ranks along with HIV and TB as the most serious infectious disease of humanity. It is widely accepted that an efficacious vaccine is required to afford protection against malarial fatalities. The induction of broad-ranging sterilizing immunity is not considered a likely objective for anti-malarial vaccines. Instead, reduction in morbidity and mortality is the realistic aim of malaria vaccine strategies. Traditional approaches seek to provide this clinical protection indirectly, by killing the parasite or by reducing parasite multiplication. To this end, current anti-malarial vaccines candidates seek to confer on the host parasiticidal immune mechanisms, which have as their target antigenic proteins expressed on the surface of the different stages of the parasite. No malaria vaccine is yet on the market. There exist several potentially competitive leads in late-stage pre-clinical-early stage clinical development, particularly recombinant proteins. The US Navy MUSTDO-25 DNA vaccines are not living up to their promise. Most leading “vaccine candidates” are polymorphic alleles. There are significant prospects for vaccine-induced selection of breakthrough variants. Multiple alleles may also prove cost-prohibitive for vaccine development. The novelty and uniqueness of this approach have contributed to the acceptance of this study for publication by Nature. The aims of this proposal are four-fold: i) to further rationalize the target through chemical synthesis of intermediates and partial structures; (ii) to examine antigenicity and immunogenicity in large experimental mammals, and undertake epitope mapping of human anti-GPI IgG responses; (iii) to obtain preliminary safety data in these animals; and (iv) to undertake a vaccine trial in a simian malaria model. We envisage objectives (i)-(iii) will take 12 months. Objective (iv) will proceed in the six months thereafter.