T cell immunity to Plasmodium sporozoite immunization

T细胞对疟原虫子孢子免疫的免疫

• 批准号: 8585021
• 负责人: John T Harty
• 金额: $ 59.95万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8585021
• 关键词: Address; Africa South of the Sahara; Antibodies; Antibody Formation; Antigens; Antimalarials; Attenuated; Bite; Blood; CD4 Positive T Lymphocytes; CD8B1 gene; Child; Chloroquine; Clinical Trials; Culicidae; Data; Disease; Down-Regulation; Drug Formulations; Epitopes; Evaluation; Exposure to; Genes; Goals; Health; Human; Humanities; Immunity; Immunization; Inbreeding; Infection; Kinetics; Knowledge; Laboratories; Life; Light; Liver; Malaria; Malaria Vaccines; Memory; Mouse Strains; Mus; Parasites; Pharmaceutical Preparations; Phase III Clinical Trials; Phenotype; Plasmodium; Publications; Radiation; Regimen; Role; Route; Safety; Specificity; Sporozoite vaccine; Sporozoites; Staging; Sterility; Subunit Vaccines; Surface; T cell response; T-Lymphocyte; Translations; Up-Regulation; Vaccination; Vaccines; base; design; global health; insight; irradiation; mortality; mouse model; next generation; novel strategies; pathogen; pre-clinical; preclinical study; vaccine candidate

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

描述（由申请人提供）：疟疾是一种毁灭性疾病，对全球健康有巨大的负面影响。有效的疟疾疫苗对于> 40％的人类来说是一个巨大的福音，并定期暴露于疟原虫感染的蚊子。尽管部分保护性疫苗（RTS，S）正在III期试验中，但事实证明，在人类中诱导肝脏阶段特异性免疫的亚基疫苗很难开发。相比之下，已有30多年的历史了，蚊子叮咬传递的散发孢子虫（RAS）免疫可以为人类提供无菌免疫。在小鼠中的研究表明，T细胞，特别是CD8 T细胞的明显相关性，以使对肝脏期疟原虫感染的免疫力进行消毒。重要的是，正在进行RAS免疫的人类临床试验。此外，最近的许多努力旨在开发遗传衰减的寄生虫（GAP）孢子岩疫苗，这些疫苗可能具有更好的安全性和比RAS更可靠性。 GAP疫苗还进入了初始人类临床试验。最后，最近的数据表明，氯喹覆盖下的孢子岩感染也可以在小鼠和人类中产生大量的保护性免疫。但是，尚不清楚这些全甲虫免疫方案中的哪一个最有效地产生了保护性T细胞反应。鉴于在发展中国家中部署基于孢子虫的疫苗的障碍，对最佳T细胞刺激疫苗的临时见解可以提供合理的基础，以关注候选平台的评估，并实质上将进展加速到有效的疟疾疫苗。正如我们最近在PLOS病原体上的出版物中所详述的，并在初步数据中突出显示，我们最近采用了一种在实验室中开发的替代激活标记方法，以跟踪T细胞对近育和近交小鼠菌株中RAS疫苗接种的总T细胞反应。现在，我们建议使用这种方法来表征T细胞反应以及针对候选整个寄生虫疫苗的抗体反应，以鉴定临床前研究中最有效的疫苗。我们将通过以下特定目的来解决这一知识差距：特定目标1。比较RAS中的总CD8 T细胞反应和保护性免疫与差距免疫的近交和近交宿主。具体目标2：应用替代激活标记方法在全孢子虫免疫后剖析CD4 T细胞在抗疟疾保护中的作用。特定目的3：表征T细胞和抗体反应和保护性免疫，可在近交和近交宿主中氯喹覆盖下生存的孢子岩感染。特定目的4：评估最佳的全寄生虫疫苗，以通过翻译相关的免疫途径引起保护性T细胞和抗体反应的能力