Accelerating discovery of an efficacious Plasmodium vivax multivalent multi-stage vaccine

项目概要/摘要 间日疟原虫（Plasmodium vivax）是疟疾的第二大病因，也是疟疾在非洲以外最普遍的病因。 非洲据估计，全球间日疟负担的成本为每年14 - 40亿美元， 间日疟原虫比恶性疟原虫更有威胁。它主要在贫穷国家流行， 缺乏负担得起的保健，导致成年人丧失生产力。间日疟原虫复发感染 对消灭和根除疟疾构成了特殊挑战，因为它能够反复重新启动 血液阶段感染的催眠虫-休眠的寄生虫，可以持续在人类肝脏从数周 到子孢子感染数年后使问题恶化的是，间日疟原虫的传播发生在发病之前 临床症状和治疗选择，以清除复发的寄生虫在休眠期的肝脏是有限的。的 U 01项目的目标是通过验证一种最佳的 在红细胞前阶段中的间日疟原虫靶抗原的组合。我们的疫苗策略旨在验证 候选抗原一起可以有效地抑制子孢子感染和阻断肝脏阶段， 发展，包括血液阶段突破性感染。我们的策略利用我们新的体外功能 间日疟原虫肝脏发育阶段的实验研究。我们将追求结构疫苗学 方法，使用广泛中和结合抑制性抗血清和单克隆抗体，以确定和 表征最高价值的免疫原和疫苗递送方法，以设计多价疫苗， 预防和消灭间日疟。

Project Summary/Abstract Plasmodium vivax is the second leading cause of malaria and the most prevalent cause of malaria outside of Africa. The estimated cost of the global burden of vivax malaria is $1.4 - $4 billion per year and more people live at risk worldwide from P. vivax than P. falciparum. It is endemic mostly in poor countries where access to affordable health care is lacking, which leads to lost adult productivity. Relapse infections from P. vivax poses a special challenge to malaria elimination and eradication because of its ability to repeatedly restart blood-stage infections from hypnozoites – the dormant parasite that can persist in human livers from weeks to years after the sporozoite infection. Exacerbating the problem, P. vivax transmission occurs prior to onset of clinical signs and treatment options to clear relapsing parasites in the dormant liver stage are limited. The goal of this U01 project is to accelerate vivax malaria vaccine development by validation of an optimal combination of P. vivax target antigens in pre-erythrocytic stages. Our vaccine strategy seeks to validate candidate antigens that together can effectively inhibit sporozoite infection and block liver stage development, including blood stage breakthrough infection. Our strategy exploits our new in vitro functional assay for experimental studies of liver stage development of P. vivax. We will pursue a structural vaccinology approach, using broadly neutralizing binding inhibitory antisera and monoclonal antibodies to identify and characterize the highest value immunogens and vaccine delivery method to design a multivalent vaccine to prevent and eliminate vivax malaria.