Protective immunity induced by P. yoelii genetically attenuated vaccines

描述（由申请人提供）：我们工作的长期目标是开发一种成功的抗疟疾疫苗。疟疾的负担，每年多达200万人死于恶性疟原虫感染，说明了这种疫苗的紧迫性。特别是，我们建议在此研究的免疫学基础，对红细胞前期阶段的寄生虫，诱导免疫与不同的遗传减毒寄生虫（GAP）在小鼠中的保护性免疫。了解保护性免疫的机制可以为合理设计和开发有效的疟疾疫苗提供基础。初步数据表明，LS寄生虫可能是保护性免疫的主要目标，LS蛋白也有助于诱导GAP疫苗诱导的保护性免疫。使用约氏疟原虫GAP（PyGAP）作为模型，我们证明了一种遗传缺陷寄生虫[Pyuis 4（-）]比另一种[Pyuis 3（-）]诱导更有效和更长的保护性免疫，并且用不同GAP免疫的小鼠识别不同的抗原。基于这些数据，我们假设不同GAP诱导的保护性免疫的变化可能涉及不同的免疫介质和免疫生物标志物和靶抗原的不同特征，这些免疫标志物和靶抗原区分保护性和非保护性，以及短期和长期免疫。在这个项目中，我们提出通过三个目标来测试我们的假设：在目标1中，我们将建立一个系统的保护性免疫模型，在三种不同的PyGAP和ESPZ免疫后，这些免疫代表了一系列保护性免疫-针对野生型约氏疟原虫子孢子攻击的完全持久、部分和短暂或非保护性免疫。然后，我们可以表征T细胞反应（幅度，表型和增殖）与不同的程度和持续时间的保护性免疫在不同的列车的小鼠。在目标2中，我们将确定与不同PyGAP诱导的差异保护性免疫相关的独特免疫生物标志物。目的3阐明PyGAP诱导的保护性CD 8 T细胞应答的效应机制。本研究的结果，更好地了解T细胞介导的免疫，识别针对疟疾感染的保护性免疫生物标志物，以及PyGAP疫苗诱导的保护性免疫的效应器机制，将对有效的亚单位疟疾疫苗的开发具有重要价值。

DESCRIPTION (provided by applicant): The long term goal of our work is to develop a successful anti-malaria vaccine. The burden of malaria, with up to two million deaths per year due to Plasmodium falciparum infection, illustrates the urgency for such a vaccine. In particular, we propose herein to study the immunological basis for the protective immunity against pre-erythrocytic stage parasites that is induced by immunizations with distinct genetically attenuated parasite (GAP) in mice. Understanding the mechanisms involved in protective immunity could then provide the foundation for rational design and development of an effective malaria vaccine. Preliminary data indicate that LS parasites may be the predominant targets of protective immunity and that LS proteins also contribute to the induction of protective immunity induced by GAP vaccines. Using P. yoelii GAPs (PyGAP) as model, we demonstrated that one genetically deficient parasite [Pyuis4(-)] induced more potent and prolonged protective immunity than another [Pyuis3(-)], and that mice immunized with different GAPs recognized different antigens. Based on these data, we hypothesize that the variation in protective immunities induced by different GAPs may involve different immune mediators and a divergent profile of immune biomarkers and target antigens that distinguish protective from non-protective, and short-lived from long-lived, immunity. In this project, we propose to test our hypothesis via three aims: In aim 1, we will establish a systematic model of protective immunity following three different PyGAPs and irr-spz immunization that represent a range of protective immunity - complete long-lasting, partial and short-lived, or non-protective immunity against wild type P. yoelii sporozoite challenge. We can then characterize T cell responses (magnitude, phenotypes and proliferation) associated with the different degrees and durations of protective immunity in different trains of mice. In Aim 2, we will determine the distinctive immune biomarkers that associate with differentially protective immunity induced by different PyGAPs. Aim 3 will delineate the effector mechanisms of protective CD8 T cell responses induced by PyGAP. The outcome of this study, a better understanding of the T cell-mediated immunity, identification of immune biomarkers of protection against malaria infection, and effector mechanisms of protective immunity induced by PyGAP vaccines, will be invaluable for development of an effective subunit malaria vaccine.