T cell immunity to Plasmodium sporozoite immunization

描述（由申请人提供）：疟疾是一种对全球健康产生巨大负面影响的毁灭性疾病。一种有效的疟疾疫苗对超过40%的经常接触疟原虫感染蚊子的人类来说将是一个巨大的布恩。尽管部分保护性疫苗（RTS，S）处于III期试验中，但已证明难以开发诱导人类肝脏阶段特异性免疫的亚单位疫苗。相比之下，30多年来已知通过蚊子叮咬递送的辐射减毒子孢子（RAS）免疫可以向人类提供无菌免疫。在小鼠中的研究表明，T细胞，特别是CD8 T细胞，与对肝期疟原虫感染的杀菌免疫有明显的相关性。重要的是，RAS免疫的人体临床试验正在进行中。此外，最近的许多努力已经针对开发遗传减毒寄生虫（GAP）子孢子疫苗，其可能具有比RAS更好的安全性并且提供更高的可靠性。GAP疫苗也正在进入初步的人体临床试验。最后，最近的数据表明，氯喹药物覆盖下的子孢子感染也可以在小鼠和人类中产生大量的保护性免疫。然而，这是未知的，这些全子孢子免疫接种方案是最有效的产生保护性T细胞反应。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，对最佳T细胞刺激疫苗的临床前洞察可以为集中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PLOS Pathogens上发表的文章中所详述的，并在初步数据中强调的那样，我们最近应用了我们实验室开发的替代激活标记方法，以跟踪近交系和远交系小鼠品系对RAS疫苗接种的总T细胞反应。我们现在建议使用这种方法来表征T细胞应答以及针对候选全寄生虫疫苗谱的抗体应答，以便在临床前研究中鉴定最有效的疫苗。我们将通过以下具体目标来解决这一知识差距：具体目标1。比较RAS与GAP免疫的近交和远交宿主中的总CD8 T细胞应答和保护性免疫。具体目标二：应用替代活化标记物方法来剖析CD4 T细胞在全子孢子免疫后抗疟保护中的作用。具体目标3：描述在氯喹药物覆盖下，近交和远交宿主对活子孢子感染的T细胞和抗体应答以及保护性免疫的特征。具体目标4：评价最佳全寄生虫疫苗通过免疫相关途径引发保护性T细胞和抗体应答的能力

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