Malaria vaccines modified with TLR agonist adjuvant

项目概要/摘要 疟疾疫苗的潜在功效已在人体实验中得到证实 用辐照的子孢子和生活在疟疾流行地区的自然感染个体进行免疫。一 靶向疟原虫红内期前和红内期阶段的亚单位疫苗数量 最近进行了I-III期临床试验。然而，瞬态和/或次优保护 这些亚单位疫苗候选物的功效强调了对更有效的佐剂的迫切需要， 刺激高水平体液和/或细胞免疫。TLR激动剂基于独特的病原体相关 分子模式（PAMPs）可以作为先天免疫应答的强刺激物， 对病毒、细菌和原生动物病原体的保护性适应性免疫。拟议的研究将 利用一种充分表征的TLR-5激动剂，鞭毛蛋白，其已用于开发TLR-5连接的候选物， 流感疫苗（目前正在临床试验中）和黄病毒疫苗，如西尼罗河病毒、日本脑炎 病毒和登革热病毒。用于设计、纯化和生产 有效的TLR激动剂修饰的病毒疫苗将用于开发恶性疟原虫疟疾疫苗， 鞭毛蛋白与全长环子孢子（CS）蛋白或CS的明确定义的功能性T和B细胞表位。 TLR 5激动剂修饰的CS将用作疫苗候选物以及模型抗原， 有助于阐明优化疟疾特异性体液和细胞免疫所需的关键参数， 免疫力将在转基因寄生虫模型中确定对抗子孢子攻击的保护效力 以及啮齿类动物疟疾模型。将探索免疫的替代途径，以开发鼻内 无针疫苗，如果成功，可以提供一种安全、成本效益高和易于管理的疟疾疫苗 在流行国家使用的疫苗。CS的研究将为未来的基本原理设计提供框架 多抗原疟疾疫苗可以靶向红细胞期和红细胞前期阶段， 寄生虫提供高度有效的疫苗为40%的世界人口目前面临疟疾的风险 感染

PROJECT SUMMARY/ABSTRACT The potential efficacy of malaria vaccines have been demonstrated experimentally in humans immunized with irradiated sporozoites and in naturally infected individuals living in malaria endemic areas. A number of subunit vaccines targeting the pre-erythrocytic and erythrocytic stages of the Plasmodium parasite have recently undergone Phase I - III clinical trials. However, the transient and / or suboptimal protective efficacy of these subunit vaccine candidates has emphasized the critical need for more potent adjuvants to stimulate high levels of humoral and/or cellular immunity. TLR agonists based on unique pathogen associated molecular patterns (PAMPs) can function as strong stimulators of innate immune responses that promote protective adaptive immunity against viral, bacterial and protozoan pathogens. The proposed studies will utilize a well characterized TLR 5 agonist, flagellin, which has been used to developTLR-5 linked candidate vaccines to influenza (currently in clinical trial) and flaviviruses such as West Nile virus, Japanese encephalitis virus, and Dengue virus by VaxInnate. The techniques used for the design, purification and production of potent TLR agonist modified viral vaccines will be utilized to develop a P. falciparum malaria vaccine by fusing flagellin to full-length circumsporozoite (CS) protein or to well-defined, functional T and B cell epitopes of CS. The TLR5 agonist modified CS will serve both as a vaccine candidate as well as a model antigen that will help elucidate the critical parameters required for optimization of malaria-specific humoral and cellular immunity. Protective efficacy against sporozoite challenge will be determined in the transgenic parasite model and in rodent malaria models. Alternative routes of immunization will be explored to develop an intranasal needle-free vaccine which, if successful, could provide a safe, cost effective and easily administered malaria vaccines for use in endemic countries. The studies on CS will provide the framework for future rationale design of multi-antigen malaria vaccines that can target both erythrocytic, as well as pre-erythrocytic, stages of the parasite to provide highly efficacious vaccines for the 40% of the world's population currently at risk of malaria infection.