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

开发口服肝脏靶向引发和诱捕疟疾疫苗

• 批准号: 10308679
• 负责人: Sean C Murphy
• 金额: $ 84.49万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10308679
• 关键词: Antigens; Attenuated; Bile Acids; Bile fluid; Biocompatible Materials; Biology; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Cessation of life; Characteristics; Chemistry; Clinical; Communicable Diseases; Communities; Coupled; Culicidae; Cytotoxic T-Lymphocytes; DNA; DNA delivery; Data; Dependovirus; Development; Diabetes Mellitus; Disease; Doctor of Philosophy; Dose; Drug Delivery Systems; Engineering; Ensure; Enterohepatic Circulation; Erythrocytes; FDA approved; Formulation; Frequencies; Goals; Hepatocyte; Human; Immune signaling; Immunity; Immunology; Infection; Injections; Insulin; Insulin-Dependent Diabetes Mellitus; Intravenous; Knowledge; Laboratories; Lipids; Literature; Liver; Malaria; Malaria Diagnostic; Malaria Vaccines; Memory; Methods; Mission; Mus; National Institute of Allergy and Infectious Disease; Nucleic Acids; Oral; Parasites; Performance; Persons; Pharmacology; Phase I/II Clinical Trial; Plasmodium; Plasmodium vaccine; Polymers; Preclinical Testing; RNA; Radiation; Ramp; Regimen; Reporting; Research Personnel; Rhesus; Safety; Salivary Glands; Scientist; Shapes; Small Intestines; Sporozoites; Sterility; Surface; T memory cell; T-Lymphocyte; Testing; Therapeutic; Tissues; Universities; Vaccination; Vaccines; Viral; Washington; Work; base; booster vaccine; cell killing; cell type; first-in-human; gene gun; gene therapy; immunogenicity; improved; materials science; nanoparticle; next generation; nonhuman primate; novel; oral vaccine; plasmid DNA; prevent; rational design; recruit; success; therapeutic gene; vaccine development; vaccine distribution; vaccine strategy

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.

抽象的 我们的 U01 项目支持 NIAID 的使命，即通过以下方式更好地了解、治疗和预防传染病： 专注于红细胞前疟疾疫苗的开发，以有效阻止疟原虫。 子孢子 (spz) 或肝阶段可以提供针对疟疾疾病的全面保护，并使 尽管目前还没有FDA批准用于人类的疟疾疫苗。 静脉注射减毒 SPZ 重复给药已显示出针对攻击的无菌保护作用 最近在多个1-2期临床试验中，CD8+T细胞驻留在肝脏中，即肝脏驻留记忆。 T 细胞或 TRM 细胞已被确定为预防肝期疫苗感染的关键细胞类型。 因此，迫切需要增加肝脏 TRM 细胞并易于适应临床使用的策略。 此类疫苗可以增强 CD8+ T 细胞免疫，并可能产生以 T 细胞为重点的疫苗，从而实现 我们的实验室为流行区和非流行区的人员开发了持久、高等级的保护。 一种两剂疫苗，使用 DNA 引发剂，然后使用减毒 SPZ 加强剂或“捕获剂” 增加肝脏 TRM 细胞并实现无菌保护 该项目旨在改进基于 spz 的捕获。 华盛顿大学将开发一种口服纳米颗粒捕获疫苗。 与约翰霍普金斯大学合作开发这种更容易制造、更容易交付的产品， 在项目 1 中，我们将定义 Pf 抗原特异性 TRM 细胞的阈值。 在项目 2 中，我们将优化用于肝脏的纳米粒子。 使用各种纳米颗粒成分、尺寸、在肝细胞中的特异性递送和表达谱 在项目 3 中，我们将评估优化的纳米颗粒。 在小鼠和非人类灵长类动物中进行初免和诱捕疫苗接种，以确保安全性、耐受性、免疫原性和 如果成功，该项目将提供一种经过合理设计的优化初免和口服陷阱疫苗。 引起针对疟原虫肝脏阶段的完全保护。