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成功的抗疟疾疫苗。疟疾的负担每年导致多达 200 万人因恶性疟原虫感染而死亡，这说明了这种疫苗的紧迫性。特别是，我们在此建议研究针对红细胞前阶段寄生虫的保护性免疫的免疫学基础，该保护性免疫是通过在小鼠中用不同的遗传减毒寄生虫（GAP）免疫诱导的。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奠定基础。初步数据表明，LS 寄生虫可能是保护性免疫的主要目标，并且 LS 蛋白也有助于诱导 GAP 疫苗诱导的保护性免疫。使用 P. yoelii GAP (PyGAP) 作为模型，我们证明一种遗传缺陷寄生虫 [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 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以及区分保护性免疫和非保护性免疫以及区分短期免疫和长期免疫的免疫生物标志物和靶抗原的不同特征。在这个项目中，我们建议通过三个目标来检验我们的假设：在目标1中，我们将在三种不同的PyGAP和irr-spz免疫后建立一个系统的保护性免疫模型，这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长效、部分和短命或非保护性免疫。然后，我们可以表征不同小鼠组中与不同程度和持续时间的保护性免疫相关的 T 细胞反应（幅度、表型和增殖）。在目标 2 中，我们将确定与不同 PyGAP 诱导的差异性保护性免疫相关的独特免疫生物标志物。目标 3 将描述 PyGAP 诱导的保护性 CD8 T 细胞反应的效应机制。这项研究的结果是更好地了解 T 细胞介导的免疫、识别预防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，对于开发有效的亚单位疟疾疫苗将具有无价的价值。

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.