T cell immunity to Plasmodium sporozoite immunization

描述(申请人提供)：疟疾是一种破坏性疾病，对全球健康具有巨大的负面影响。对于经常接触受疟原虫感染蚊子的40%的人来说，一种有效的疟疾疫苗将是一个巨大的福音。尽管部分保护性疫苗(RTS，S)正处于第三阶段试验，但事实证明，诱导人类无菌肝期特异性免疫的亚单位疫苗很难开发。相比之下，30多年来，人们已经知道，通过蚊子叮咬提供的辐射减弱子孢子(RAS)免疫可以为人类提供无菌免疫。在小鼠身上的研究表明，T细胞，特别是CD8T细胞，与肝期疟原虫感染的灭菌免疫明显相关。重要的是，RAS免疫的人体临床试验正在进行中。此外，最近的许多努力都是针对开发基因减毒寄生虫(GAP)子孢子疫苗，这种疫苗可能具有更好的安全性，并提供比RAS更可靠的疫苗。GAP疫苗也进入了初步的人体临床试验。最后，最近的数据表明，在氯喹药物覆盖下感染子孢子也可以在小鼠和人类中产生实质性的保护性免疫。然而，目前尚不清楚哪种全子孢子免疫方案在产生保护性T细胞反应方面最有效。考虑到在发展中国家部署基于子孢子的疫苗所固有的障碍，临床前对最好的T细胞刺激疫苗的洞察可以为重点评估候选平台提供合理的基础，并大大加快有效疟疾疫苗的进展。正如我们最近在《公共科学图书馆·病原体》上发表的文章中所详细描述的那样，并在初步数据中强调，我们最近应用了我们实验室开发的替代激活标记方法，以跟踪近交系和近交系小鼠品系对RAS疫苗的总T细胞反应。我们现在建议使用这种方法来表征T细胞反应以及针对候选全寄生虫疫苗光谱的抗体反应，以便在临床前研究中识别最有效的疫苗。我们将通过以下特定目标来解决这一知识差距：特定目标1.比较RAS和GAP免疫的近交系和近交系宿主的总CD8 T细胞反应和保护性免疫。具体目的2：应用替代激活标记方法分析全子孢子免疫后CD4T细胞在抗疟疾保护中的作用。特异性目标3：研究近交系和近交系宿主在氯喹药物覆盖下对活子孢子感染的T细胞和抗体反应及保护性免疫。具体目标4：评估最佳全寄生虫疫苗通过翻译相关免疫途径诱导保护性T细胞和抗体反应的能力

DESCRIPTION (provided by applicant): Malaria is a devastating disease with enormous negative impact on global health. An efficacious vaccine for malaria would be a huge boon for the >40% of humanity with regular exposure to Plasmodium infected mosquitoes. Although a partially protective vaccine (RTS, S) is in phase III trials, subunit vaccines to induce sterilizing liver-stage specific immunity in humans have proven difficult to develop. In contrast, it has been known for over 30 years that radiation attenuated sporozoite (RAS) immunization delivered by mosquito bite can provide sterile immunity to humans. Studies in mice show clear relevance of T cells, particularly CD8 T cells, for sterilizing immunity to liver stage Plasmodium infection. Importantly, human clinical trials of immunization with RAS are underway. In addition, much recent effort has been directed at developing genetically attenuated parasite (GAP) sporozoite vaccines that may have better safety profiles and provide more reliability than RAS. GAP vaccines are also entering initial human clinical trials. Finally, recent data demonstrate that sporozoite infections under chloroquine drug cover can also generate substantial protective immunity in mice and humans. However, it is unknown which of these whole-sporozoite immunization regimens is most effective at generating protective T cell responses. Given the hurdles inherent in deploying a sporozoite based vaccine in the developing world, pre-clinical insight into the best T cell stimulating vaccines could provide a rational basis to focus evaluation of candidate platforms and substantially accelerate progress toward an efficacious malaria vaccine. As detailed in our recent publication in PLOS Pathogens and highlighted in the preliminary data, we recently applied a surrogate activation marker approach, developed in our laboratory, to track the total T cell response to RAS vaccination in inbred and outbred mouse strains. We now propose to use this approach to characterize the T cell response as well as antibody responses against the spectrum of candidate whole parasite vaccines in order to identify the most potent vaccines in preclinical studies. We will address this knowledge gap through the following specific aims: Specific Aim 1. Compare the total CD8 T cell response and protective immunity in RAS versus GAP immunized inbred and outbred hosts. Specific Aim 2: Apply a surrogate activation marker approach to dissect the role of CD4 T cells in antimalarial protection after whole-sporozoite immunization. Specific Aim 3: Characterize T cell and antibody responses and protective immunity to live sporozoite infection under chloroquine drug cover in inbred and outbred hosts. Specific Aim 4: Evaluate optimal whole-parasite vaccines for the ability to elicit protective T cell and antibody responses via translationally relevant routes of immunization