Development of a pre-erythrocytic P. vivax vaccine to prevent clinical relapse

摘要 超过30亿人面临感染由间日疟原虫（Pv）引起的疟疾的风险。Pv感染 与其他疟原虫物种不同的是，它发展出休眠的肝脏阶段形式，称为催眠虫。 催眠体可以在初次感染数月至数年后重新激活并引起血液期疟疾。是 据估计，近90%的活动性血液期Pv感染是由于复发感染，而不是原发性感染， 载体介导的感染。因此，休眠形式是PV传播的主要驱动力， 几乎所有的临床疾病负担。因此，减少或消除 催眠虫，从而减少复发感染，将对疾病负担和 传输速率。重要的是，模型表明，即使在没有 消灭免疫力，因为催眠虫只在一小部分感染的肝细胞中形成。 目前还没有临床上先进的疫苗来预防Pv感染或复发。发展努力 由于在实验室中使用Pv的固有困难，缺乏非CSP抗原， 缺乏模拟PV感染的生物学相关模型系统。我们的长期目标是 通过创建新型PvCSP疫苗和间日疟原虫/间日疟原虫来开发针对Pv的红细胞前疫苗。 恶性疟原虫遗传减毒寄生虫（GAP）疫苗，可以减少或预防复发感染。本 最后，我们制定了一个研究计划，解决了PV疫苗开发的所有主要障碍。 我们建议评估PvCSP疫苗对复发的有效性，并将研究新的非CSP疫苗。 最近被鉴定为表面蛋白质组的一部分的候选疫苗。我们将确定那些 可增强抗PvCSP介导的免疫力并减少或阻断催眠虫的形成。最后我们将 将PvCSP（和潜在的新型抗原）工程化到现有的PfGAP平台中， 评价重要的是，我们与泰国的玛希隆大学合作， 型子孢子。此外，我们建议在一个完全人性化的环境中进行我们的疫苗开发。 模型系统我们将在人源化免疫球蛋白小鼠中评估我们的疫苗， 复发感染的人源化肝小鼠模型，允许在此研究中更可靠地翻译结果。 为疫苗最终应用于临床而进行的研究。我们的最终目标是发展一个 接近临床准备的疫苗，有效减少或消除PV复发感染。

ABSTRACT More than 3 billion people are at risk for contracting malaria caused by Plasmodium vivax (Pv). Pv infection differs from other Plasmodium species in that it develops dormant liver stage forms called hypnozoites. Hypnozoites can reactivate and cause blood stage malaria months to years after primary infection. It is estimated that nearly 90% of active blood stage Pv infections are due to relapse infection and not primary vector-mediated infection. As such, the dormant form is a major driver of Pv transmission and accounts for nearly the entire clinical disease burden. Therefore, a vaccine that reduces or eliminates the formation of hypnozoites, and hence reduces relapse infection, would have a significant impact on both disease burden and transmission rates. Importantly, models suggest that this can be accomplished even in the absence of sterilizing immunity, because hypnozoites only form in a fraction of the infected hepatocytes. Currently there are no clinically advanced vaccines to prevent Pv infection or relapse. Development efforts have been hampered by the inherent difficulty of working with Pv in the lab, the lack of non-CSP antigens, and the lack of a biologically relevant model system that mimics Pv infection. Our long term goal is the development of a pre-erythrocytic vaccine against Pv by creating novel PvCSP vaccines and P. vivax/P. falciparum genetically attenuated parasite (GAP) vaccines that can reduce or prevent relapse infection. To this end, we put together a research program that addresses all the major roadblocks of Pv vaccine development. We propose to evaluate the efficacy of PvCSP vaccines against relapse, and will study novel, non-CSP vaccine candidates that were recently identified to be part of the surface proteome. We will identify those that can augment anti-PvCSP-mediated immunity and reduce or block the formation of hypnozoites. Finally, we will engineer PvCSP (and potentially novel antigens) into the existing PfGAP platform that is under clinical evaluation. Importantly, we have partnered with Mahidol University in Thailand to enable us to work with wild type Pv sporozoites. Additionally, we propose to conduct our vaccine development in a completely humanized model system. We will evaluate our vaccines in humanized immunoglobulin mice and test efficacy in humanized liver mouse models of relapse infection, allowing for a more reliable translation of results in this study toward the eventual deployment of the vaccine into the clinic. Our ultimate goal is the development of a near clinic-ready vaccine that is effective in reducing or eliminating Pv relapse infection.