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

项目摘要/摘要 间日疟原虫是疟疾的第二大原因，也是除 非洲。据估计，全球间日疟造成的损失为每年14-40亿美元， 在全球范围内生活在间日疟原虫而不是恶性疟原虫的危险中。它主要在贫穷国家流行，那里有机会获得 缺乏负担得起的医疗保健，这导致成年人生产力下降。间日疟原虫复发感染 对消除和根除疟疾构成特殊挑战，因为它有能力反复重新启动 由催眠虫引起的血液期感染-这种潜伏的寄生虫可以在人的肝脏中持续数周 到子孢子感染后数年。使问题雪上加霜的是，间日疟原虫在发病前传播 在肝脏休眠阶段清除复发寄生虫的临床体征和治疗选择有限。这个 这个U01项目的目标是通过验证最优的 间日疟原虫红细胞前期靶抗原的结合。我们的疫苗策略试图验证 共同有效抑制子孢子感染和阻断肝期的候选抗原 发展，包括血液期突破性感染。我们的策略利用了我们新的体外功能 间日疟原虫肝期发育的实验研究方法。我们将继续进行结构性疫苗接种 方法，使用广谱中和结合的抑制性抗血清和单抗来识别和 表征价值最高的免疫原和疫苗递送方法，以设计多价疫苗以 预防和消除间日疟。

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.