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于经常接触感染了疟原虫的蚊子的40%的人类来说将是一个巨大的福音。尽管一种部分保护性疫苗（RTS， S）正处于III期试验中，但事实证明，很难开发出亚单位疫苗来诱导人类产生绝育性肝期特异性免疫。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毒孢子（RAS）免疫可以为人类提供无菌免疫。对小鼠的研究表明，T细胞，特别是CD8 T细胞，与肝脏期疟原虫感染的无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，最近的许多努力都是针对开发遗传减毒寄生虫（GAP）孢子子疫苗，这种疫苗可能比RAS具有更好的安全性和可靠性。GAP疫苗也正在进入初步人体临床试验阶段。最后，最近的数据表明，在氯喹药物覆盖下的孢子虫感染也可以在小鼠和人类中产生大量保护性免疫。然而，尚不清楚这些全孢子子免疫方案中哪一种在产生保护性T细胞反应方面最有效。鉴于在发展中国家部署基于孢子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重点评估候选平台提供合理的基础，并大大加快开发有效疟疾疫苗的进程。正如我们最近在PLOS Pathogens上发表的文章所详细介绍的那样，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，来跟踪近交系和近交系小鼠株对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细胞反应以及针对候选全寄生虫疫苗谱的抗体反应，以便在临床前研究中确定最有效的疫苗。我们将通过以下具体目标来解决这一知识差距：比较RAS与GAP免疫近交和远交宿主的总CD8 T细胞反应和保护性免疫。特异性目标2：应用替代激活标记方法分析CD4 T细胞在全孢子子免疫后抗疟疾保护中的作用。特异性目的3：表征近交和远交宿主在氯喹药物覆盖下对活孢子虫感染的T细胞和抗体反应和保护性免疫。特异性目标4：评估最佳全寄生虫疫苗通过翻译相关免疫途径引发保护性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