Malaria vaccines modified with TLR agonist adjuvant

项目摘要/摘要 疟疾疫苗的潜在疗效已经在人类身上进行了实验证明。 用辐照的子孢子和生活在疟疾流行地区的自然感染者进行免疫。一个 针对疟原虫红细胞前期和红细胞阶段的亚单位疫苗的数量 最近进行了I-III期临床试验。然而，暂态和/或次优保护 这些候选亚单位疫苗的有效性强调了对更有效佐剂的迫切需要 激发高水平的体液和/或细胞免疫。基于相关独特病原体的TLR激动剂 分子模式(PAMP)可以作为天然免疫反应的强烈刺激因子，促进 针对病毒、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 利用一种特性良好的TLR5激动剂鞭毛蛋白，它已经被用来开发TLR5连接的候选分子 流感疫苗(目前正在临床试验中)和黄病毒，如西尼罗河病毒，日本脑炎 病毒，登革热病毒由VaxInative。用于设计、提纯和生产的技术 将利用有效的TLR激动剂修饰的病毒疫苗，通过融合开发恶性疟原虫疫苗 从鞭毛蛋白到全长环子孢子(CS)蛋白，或者到CS的T和B细胞表位。 TLR5激动剂修饰的CS既可以作为疫苗候选，也可以作为模型抗原 帮助阐明优化疟疾特异性体液和细胞所需的关键参数 豁免权。在转基因寄生虫模型中将确定对子孢子攻击的保护效果。 以及在啮齿动物疟疾模型中。将探索替代免疫途径，以发展鼻腔内免疫 无针头疫苗，如果成功，可以提供安全、成本效益高和易于管理的疟疾 在流行国家使用的疫苗。对CS的研究将为未来的理性设计提供框架 可以针对红细胞期和红细胞期的多抗原疟疾疫苗 寄生虫为目前有疟疾风险的40%的世界人口提供高效疫苗 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.