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。每年有多达200万人死于恶性疟原虫感染，疟疾造成的负担表明迫切需要这种疫苗。特别地，我们建议研究不同基因减毒疟原虫（GAP）免疫诱导小鼠对红细胞前期寄生虫产生保护性免疫的免疫学基础。了解保护性免疫所涉及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。以P. yoelii gap （PyGAP）为模型，我们证明了一种基因缺陷寄生虫[Pyuis4(-)]比另一种[Pyuis3(-)]诱导更有效和更持久的保护性免疫，并且用不同的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不同的免疫生物标志物和靶抗原，从而区分保护性免疫和非保护性免疫，以及短期免疫和长期免疫。在这个项目中，我们建议通过三个目标来验证我们的假设：在目标1中，我们将建立一个系统的保护性免疫模型，通过三种不同的PyGAPs和irr-spz免疫，代表一系列保护性免疫-完全持久的，部分和短暂的，或针对野生型约氏p.o elii孢子虫的非保护性免疫。然后，我们可以表征T细胞反应（大小，表型和增殖）与不同程度和持续时间的保护性免疫在不同的小鼠系。在Aim 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将描述PyGAP诱导的保护性CD8 T细胞反应的效应机制。这项研究的结果，更好地了解T细胞介导的免疫，鉴定抗疟疾感染的免疫生物标志物，以及PyGAP疫苗诱导的保护性免疫的效应机制，将对开发有效的亚单位疟疾疫苗具有宝贵的价值。

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. PUBLIC HEALTH RELEVANCE: Despite decades of research, there is still an urgent need for development of a successful anti-malaria vaccine. We have shown that Genetically Attenuated Parasites (GAP) can confer long term protective immunity against malaria. In the study proposed herein, we aim to elucidate and characterize, at the molecular and cellular levels, the mechanisms involved with such protective immunity. Results of this project will then provide the foundation for development of an effective anti-malaria vaccine.