Liver resident memory for malaria

疟疾的肝脏驻留记忆

• 批准号: 10515643
• 负责人: Sean C Murphy
• 金额: $ 59.57万
• 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 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10515643
• 关键词: Acceleration; Adjuvant; Antibodies; Antigens; Attenuated; Biological; Biological Models; Blocking Antibodies; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Clinical; Clinical Research; Clinical Trials; 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; Invaded; Laboratories; Licensing; Life Cycle Stages; Liver; Macaca mulatta; Malaria; Malaria Vaccines; Measures; Mediating; Memory; Mission; Modeling; Monkeys; Mus; National Institute of Allergy and Infectious Disease; Parasites; Persons; Phase; Plasmids; Plasmodium; Plasmodium falciparum; Preparation; Regimen; Rodent Model; Sporozoite vaccine; Sporozoites; Sterility; T cell response; T-Lymphocyte; Testing; Toxicology; Universities; Vaccination; Vaccine Design; Vaccines; Washington; Work; antigen-specific T cells; cell killing; cell type; circumsporozoite protein; gene gun; immunogenicity; improved; intravenous administration; liver-specific protein; nonhuman primate; novel; novel vaccines; plasmid DNA; pre-clinical; preclinical study; prevent; protective efficacy; rational design; tissue resident memory T cell; vaccine development; vaccine strategy; 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.

抽象的 我们的 R01 项目支持 NIAID 的使命，即通过专注于更好地了解、治疗和预防传染病 红细胞前疟疾疫苗的开发，可有效阻止疟原虫子孢子（spz）或肝脏。 阶段可提供针对疟疾疾病的全面保护，并将促成根除工作。 目前还没有。 FDA 批准的疟疾疫苗可用于人类，但需重复静脉注射减毒疫苗 最近，spz 在多项 1-2 期临床试验中显示出针对挑战的无菌保护作用。 肝脏中的（肝脏驻留记忆 T 细胞或 Trm 细胞）已被确定为预防肝脏损伤的关键细胞类型 因此，增加肝 Trm 细胞并易于适应临床使用的疫苗策略是必要的。 此类疫苗可以增强 CD8+ T 细胞免疫，并可能产生针对 T 细胞的疫苗。 为流行地区和非流行地区的人员提供持久、高等级的保护。 两剂疫苗可增加肝脏 Trm 细胞并实现无菌保护。这种方法仅需要单剂。 该项目旨在为这种两剂“初免和陷阱”疫苗的开发提供临床前支持。 华盛顿大学 (UW) 将与 Sanaria Inc. 的既定合作伙伴合作。在目标 1 中，我们将评估 有关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、佐剂效应、预先存在的抗体的干扰以及多种 DNA 质粒的使用。 2、我们将调查疫苗接种后抗原传播的幅度和程度，这种现象可能会 在目标 3 中，我们将评估诺氏疟原虫非人类体内的初免和诱捕疫苗。 灵长类动物 (NHP) 免疫挑战模型，并在恶性疟原虫 NHP 模型中展示 Trm 细胞靶向。 NHP 研究将获得耐受性和毒理学终点，为未来的临床研究做准备。 总之，该项目将优化和评估合理设计的两剂初发和诱捕疫苗，以引发完整的 预防疟原虫肝脏阶段。