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。光伏感染 与其他疟原虫物种的不同之处在于，它会形成休眠的肝期形式，称为催眠体。 催眠虫可在初次感染数月至数年后重新激活并导致血液期疟疾。它是 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感染 媒介传播的感染。因此，休眠状态是光伏传播的主要驱动力，并解释了 几乎整个临床疾病的负担。因此，一种减少或消除新城疫形成的疫苗 催眠药，从而减少复发感染，将对疾病负担和 传输率。重要的是，模型表明，即使在没有 杀菌免疫，因为催产素只在一小部分受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 在实验室使用光伏固有的困难，缺乏非CSP抗原，以及 缺乏模拟光伏感染的生物学相关模型系统。我们的长期目标是 通过创造新的PvCSP疫苗和间日疟原虫，开发一种针对PV的红细胞前疫苗。 恶性疟原虫基因减毒寄生虫(GAP)疫苗，可减少或防止复发感染。对这件事 最后，我们制定了一个研究计划，解决光伏疫苗开发的所有主要障碍。 我们建议评估PvCSP疫苗预防复发的效果，并将研究新的、非CSP的 最近被确认为表面蛋白质组一部分的候选疫苗。我们将确定哪些人 可增强抗PvCSP介导的免疫力，减少或阻断催眠体的形成。最后，我们会 将PvCSP(和潜在的新抗原)工程到正在临床的现有PfGAP平台 评估。重要的是，我们已经与泰国Mahidol大学合作，使我们能够与Wild合作 PV子孢子型。此外，我们建议在完全人性化的情况下进行疫苗开发 模型系统。我们将在人源化免疫球蛋白小鼠身上评估我们的疫苗，并在 人源化的小鼠肝脏复发感染模型，允许更可靠地转换这一结果 为最终将疫苗部署到临床进行研究。我们的最终目标是开发一种 接近临床准备就绪的疫苗，可有效减少或消除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.