Development of an oral liver-targeted prime-and-trap malaria vaccine

摘要 我们的U 01项目支持NIAID的使命，以更好地了解，治疗和预防传染病， 重点是红细胞前期疟疾疫苗的研制。有效阻止疟原虫的疫苗 子孢子（SPZ）或肝脏阶段可以提供针对疟疾疾病完全保护， 根除工作。目前还没有FDA批准的用于人类的疟疾疫苗，尽管 静脉内给药的减毒SPZ的重复给药显示了对攻击的无菌保护 在多个1-2期临床试验中。最近，CD 8 + T细胞驻留在肝脏中，即肝脏驻留记忆， T细胞或TRM细胞已被鉴定为保护免受肝脏阶段感染的关键细胞类型。疫苗 因此，迫切需要增加肝脏TRM细胞并可容易地适应临床应用的策略。 这种疫苗可以增强CD 8 + T细胞免疫力，并可能导致T细胞聚焦疫苗， 为流行区和非流行区的人提供持久、高水平的保护。我们的实验室开发了 一种两剂疫苗，使用DNA引发剂，然后是减毒spz加强剂或“捕获剂量”， 增加肝脏TRM细胞并实现无菌保护。本项目旨在改进基于SPZ的诱捕 通过开发一种口服纳米颗粒诱捕疫苗。华盛顿大学将 与约翰霍普金斯大学合作，开发更容易制造，更容易交付， 更便宜的疫苗。在项目1中，我们将定义Pf抗原特异性TRM细胞的阈值， 使用DNA引发/子孢子捕获实现保护。在项目2中，我们将优化用于肝脏的纳米颗粒- 使用各种纳米颗粒组合物、尺寸 表面特性和配方策略。在项目3中，我们将评估优化的纳米颗粒， 在小鼠和非人灵长类动物中进行引发-陷阱疫苗接种的安全性、耐受性、免疫原性和 功效如果成功，该项目将提供一种优化的引发和口服陷阱疫苗， 引起对疟原虫肝脏阶段的完全保护。

ABSTRACT Our U01 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 can 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, namely 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 uses a DNA prime followed by an attenuated spz boost or ‘trapping dose’ that increases liver TRM cells and achieves sterile protection. This project aims to improve upon spz-based trapping by developing an orally-administered nanoparticle-based trapping vaccine. The University of Washington will collaborate with Johns Hopkins University to develop this more easily manufactured, more easily deliverable, and less expensive vaccine. In Project 1, we will define a threshold of Pf antigen-specific TRM cells needed to achieve protection using DNA prime/sporozoite trapping. In Project 2, we will optimize nanoparticles for liver- specific delivery and expression profile in hepatocytes using a variety of nanoparticle compositions, sizes, surface characteristics, and formulation strategies. In Project 3, we will evaluate the optimized nanoparticles in prime-and-trap vaccination in mice and non-human primates for safety, tolerability, immunogenicity, and efficacy. If successful, this project will deliver an optimized prime-and-oral trap vaccine rationally designed to elicit complete protection against the Plasmodium liver stage.