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

恶性疟原虫疟疾感染全球5-10%的人口（4亿临床病例），每年造成200万人死亡1。因此，它与艾滋病毒和结核病一起沿着为人类最严重的传染病。人们普遍认为，需要一种有效的疫苗来提供保护，防止疟疾死亡。诱导广泛的杀菌免疫被认为不是抗疟疾疫苗的可能目标。相反，降低发病率和死亡率是疟疾疫苗战略的现实目标。传统方法试图通过杀死寄生虫或减少寄生虫繁殖来间接提供这种临床保护。为此，目前的抗疟疾候选疫苗寻求赋予宿主杀寄生虫免疫机制，其具有在寄生虫的不同阶段的表面上表达的靶抗原蛋白。目前市场上还没有疟疾疫苗。在后期临床前-早期临床开发中存在几种潜在的竞争性先导物，特别是重组蛋白。美国海军的MUSTDO-25 DNA疫苗并没有兑现他们的承诺。大多数主要的“候选疫苗”是多态等位基因。疫苗诱导的突破性变异选择具有重大前景。多个等位基因也可能证明疫苗开发的成本过高。这种方法的新奇和独特性有助于接受这项研究发表自然。该提案的目的有四个方面：（i）通过中间体和部分结构的化学合成进一步合理化靶标;（ii）检查大型实验哺乳动物中的抗原性和免疫原性，并进行人抗GPI IgG应答的表位作图;（iii）获得这些动物中的初步安全性数据;以及（iv）在猴疟疾模型中进行疫苗试验。我们预计第（i）至（iii）项目标需时12个月。目标㈣将在其后六个月内进行。

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.