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，对全球健康产生巨大负面影响。对于经常接触疟原虫感染蚊子的超过 40% 的人类来说，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 III 期试验中，但事实证明，诱导人类绝育肝阶段特异性免疫的亚单位疫苗很难开发。相比之下，30 多年来人们就知道，通过蚊虫叮咬提供的辐射减毒子孢子 (RAS) 免疫可以为人类提供无菌免疫力。小鼠研究表明，T 细胞（尤其是 CD8 T 细胞）对于肝期疟原虫感染的免疫免疫具有明确的相关性。重要的是，RAS 免疫的人体临床试验正在进行中。此外，最近的许多努力都致力于开发遗传减毒寄生虫 (GAP) 子孢子疫苗，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。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力。然而，尚不清楚这些全子孢子免疫方案中哪一种对于产生保护性 T 细胞反应最有效。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，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 上发表的文章中详细介绍的以及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来跟踪近交和远交小鼠品系中对 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： 具体目标 1. 比较 RAS 与 GAP 免疫的近交和远交宿主的总 CD8 T 细胞反应和保护性免疫。具体目标 2：应用替代激活标记方法来剖析 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：表征近交和远交宿主在氯喹药物覆盖下对活子孢子感染的 T 细胞和抗体反应以及保护性免疫。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引发保护性 T 细胞和抗体反应的能力