Liver resident memory for malaria

疟疾的肝脏驻留记忆

• 批准号: 10054159
• 负责人: Sean C Murphy
• 金额: $ 79.79万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-11-23 至 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10054159
• 关键词: Adjuvant; Antibodies; Antigens; Attenuated; Biological; Biological Models; Blocking Antibodies; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Clinical; Clinical Research; Code; Collaborations; Communicable Diseases; Conduct Clinical Trials; Cryopreservation; Cytotoxic T-Lymphocytes; DNA; Data; Dependence; Development; Disease; Dose; Electroporation; Epitope spreading; Erythrocytes; FDA approved; Frequencies; Future; Glycolipids; Goals; Hepatocyte; Human; Immunity; Immunization; Infection; Intravenous; Laboratories; Liver; Logistics; Macaca mulatta; Malaria; Malaria Vaccines; Measures; Mediating; Memory; Mission; Modeling; Monkeys; Mus; National Institute of Allergy and Infectious Disease; Parasites; Persons; Phase I/II Clinical Trial; Plasmids; Plasmodium; Plasmodium falciparum; Preparation; Regimen; Rodent Model; Sporozoite vaccine; Sporozoites; Sterility; T cell response; T memory cell; T-Lymphocyte; Testing; Toxicology; Universities; Vaccination; Vaccine Design; Vaccines; Washington; Work; antigen-specific T cells; cell killing; cell type; circumsporozoite protein; design; gene gun; immunogenicity; improved; liver-specific protein; nonhuman primate; novel; novel vaccines; plasmid DNA; pre-clinical; preclinical study; prevent; protective efficacy; vaccine development; vaccine trial

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.

摘要 我们的R 01项目支持NIAID的使命，通过关注以下方面，更好地了解、治疗和预防传染病 红细胞前期疟疾疫苗的研制。有效阻止疟原虫子孢子（spz）或肝脏的疫苗 阶段提供针对疟疾疾病的完全保护，并将使根除工作成为可能。目前没有 FDA批准的用于人类的疟疾疫苗，尽管重复给予静脉内施用的减毒 SPZ已经在多个1-2期临床试验中显示出对攻击的无菌保护。最近，CD 8 + T细胞， 肝脏中的T细胞（肝脏驻留记忆T细胞或Trm细胞）已被确定为保护肝脏免受 阶段性感染。因此，增加肝Trm细胞并可容易地适应临床使用的疫苗策略是 急需的。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， 为地方病和非地方病地区的人提供持久、高水平的保护。我们的实验室开发了一种 两剂疫苗，增加肝脏Trm细胞，实现无菌保护。这种方法只需要一剂 关于SPZ该项目旨在为开发这种两剂“初免和诱捕”疫苗提供临床前支持。的 华盛顿大学（UW）将与Sanaria Inc.的合作伙伴合作。在目标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的影响 冷冻保存、佐剂作用、来自预先存在的抗体的干扰和多个DNA质粒的使用。在Aim中 2，我们将调查接种疫苗后抗原传播的幅度和程度， 加强对肝脏的保护。在目标3中，我们将在诺氏疟原虫非人中评价引发-诱捕疫苗。 在灵长类动物（NHP）免疫攻击模型中，证明了Trm细胞在恶性疟原虫NHP模型中的靶向。 将在NHP研究中获得耐受性和毒理学终点，为未来的临床研究做准备。在 总之，本项目将优化和评估一种合理设计的两剂引发-诱捕疫苗， 保护肝脏免受疟原虫感染。