Liver resident memory for malaria

摘要 我们的R01项目支持NIAID的使命，即通过专注于 红细胞前疟疾疫苗的开发。有效阻止疟原虫子孢子(SPZ)或肝脏的疫苗 这一阶段提供了对疟疾的全面保护，并将使根除努力成为可能。目前没有 FDA批准的用于人类的疟疾疫苗，尽管静脉注射减毒后重复给药 在多个1-2期临床试验中，SPZ已显示出对挑战的无菌保护。最近，CD8+T细胞 在肝脏中(肝脏常驻记忆T细胞或Trm细胞)已被确定为保护肝脏免受肝脏损害的关键细胞类型 处于感染阶段。因此，增加肝脏Trm细胞并易于临床使用的疫苗策略 这是急需的。这种疫苗可以增强CD8+T细胞免疫，并可能导致以T细胞为重点的疫苗 为流行和非流行地区的人提供持久、高质量的保护。我们的实验室已经研制出一种 增加肝脏Trm细胞并实现无菌保护的两剂疫苗。这种方法只需要单剂。 对SPZ的影响。该项目旨在为这种两剂疫苗的开发提供临床前支持。这个 华盛顿大学(UW)将与Sanaria Inc.的现有合作伙伴合作。在Aim 1中，我们将评估 关于拟议疫苗方案的生物学和技术问题，包括剂量依赖性、SPZ的效果 冷冻保存、佐剂效应、预先存在的抗体的干扰，以及多个DNA质粒的使用。在AIM 2，我们将调查接种疫苗后抗原传播的大小和程度，这一现象可能 加强对肝脏的保护。在目标3中，我们将在诺氏疟原虫非人类中评估初选和诱捕疫苗。 灵长类(NHP)免疫-挑战模型，并在恶性疟原虫NHP模型中演示Trm细胞靶向。 耐受性和毒理学终点将在NHP研究中获得，为未来的临床研究做准备。在……里面 总结，这个项目将优化和评估一种合理设计的两剂初级和陷阱疫苗，以获得完全 对肝脏疟原虫阶段的保护。

ABSTRACT Our R01 project supports NIAID’s mission to better understand, treat, and prevent infectious diseases by focusing on pre-erythrocytic malaria vaccine development. Vaccines that efficiently stop the Plasmodium sporozoite (spz) or liver stage provide complete protection against malarial disease and will enable eradication efforts. There are currently no FDA-approved malaria vaccines for use in humans although repeated dosing with intravenously-administered attenuated spz has shown sterile protection against challenge in multiple Phase 1-2 clinical trials. Recently, CD8+ T cells that reside in the liver (liver resident memory T cells or Trm cells) have been identified as key cell types in protection against liver stage infection. Vaccine strategies that increase liver Trm cells and can be readily adapted to clinical use are therefore critically needed. Such vaccines could bolster CD8+ T cell immunity and may result in T cell-focused vaccines that achieve durable, high-grade protection for persons in endemic and non-endemic regions. Our laboratory has developed a two-dose vaccine that increases liver Trm cells and achieves sterile protection. This approach requires only a single dose of spz. This project aims to provide pre-clinical support for development of this two-dose ‘prime-and-trap’ vaccine. The University of Washington (UW) will collaborate with established partners at Sanaria Inc. In Aim 1, we will evaluate biological and technical questions about the proposed vaccine regimen, including dose dependence, effects of spz cryopreservation, adjuvant effects, interference from pre-existing antibodies, and use of multiple DNA plasmids. In Aim 2, we will investigate the magnitude and degree of antigen spreading following vaccination, a phenomenon that could enhance protection in the liver. In Aim 3, we will evaluate the prime-and-trap vaccine in the P. knowlesi non-human primate (NHP) immunization-challenge model and demonstrate Trm cell targeting in a P. falciparum NHP model. Tolerability and toxicology endpoints will be obtained in NHP studies in preparation for future clinical studies. In summary, this project will optimize and assess a two-dose prime-and-trap vaccine rationally designed to elicit complete protection against the Plasmodium liver stage.