Schistosome Vaccines

描述(由申请人提供)：本次R01重新提交的总体目标是开发针对日本血吸虫病的疫苗。血吸虫病是由三种主要的雌雄异体吸虫(扁虫)引起的，目前全世界有超过2.5亿人感染血吸虫病，每年导致153万人死亡。最近对全球血吸虫病负担的重新评估表明，实际的健康负担是世卫组织先前估计的4至30倍。这些巨大的数字突显了血吸虫病疫苗对全球人类健康的影响。虽然吡喹酮(PZQ)能有效治疗血吸虫病，但发病率反弹的快速再感染排除了仅基于化疗的有效控制，并证明了目前为这些寄生虫开发疫苗的努力是合理的。我们建议利用在我们之前的R-01资助研究中已经收集的血浆样本和寄生虫学数据，以确定与人类耐药性相关的新抗原。我们将使用一种完整的蛋白质组、差异筛选方法来识别抗药性但不敏感个体血浆中的抗体识别的寄生虫抗原。我们将使用抗体反应的高通量免疫图谱和在抵抗再感染的背景下分析这些反应来验证这些候选抗体。我们将通过评估居住在菲律宾莱特流行区的新登记的日本血吸虫感染者队列中的细胞免疫反应来延长这些候选病例的有效性。最后，将通过生物信息学、组织和阶段特异性免疫定位研究以及日本血吸虫感染水牛的超敏反应皮肤测试来向下选择候选者。在第4年和第5年的水牛疫苗试验中，将对其中四个候选疫苗的有效性和安全性(包括超敏反应)进行评估。这些研究的结果将是与人类对再感染的抵抗力相关的已验证抗原的清单。这些数据将为在啮齿动物和大型动物模型中进行额外的临床前安全性和有效性研究优先考虑抗原靶标提供强有力的基础。这些数据将进一步促进疫苗的合理开发，以限制再感染以及由此导致的人类发病率和死亡率。

DESCRIPTION (provided by applicant): The overall aim of this R01 resubmission is to develop vaccines against human schistosomiasis japonica. Schistosomiasis, caused by three principle species of dioecious trematodes (flatworms), currently infects over 250 million people world-wide and results in 1.53 million DALYs lost per annum. A recent reassessment of the global burden of schistosomiasis suggests that the actual health burden is 4 to 30 times greater than the previous WHO estimate. These tremendous figures underscore the impact a schistosomiasis vaccine would have on global human health. Although schistosomiasis is effectively treated with Praziquantel (PZQ), rapid reinfection with rebound morbidity precludes effective control based on chemotherapy alone and justifies current efforts to develop vaccines for these parasites. We propose to capitalize on plasma samples and parasitologic data already collected during our previous R-01 funded studies, to identify novel antigens associated with resistance in humans. We will use a whole proteome, differential screening method to identify parasite antigens that are recognized by antibodies in plasma of resistant but not susceptible individuals. We will validate these candidates using high throughput immune profiling of antibody responses and analysis of these responses in the context of resistance to reinfection. We will extend the validation of these candidates by assessment of cellular immune responses in a newly enrolled cohort of S. japonicum infected individuals living in an endemic area of Leyte, the Philippines. Finally, candidates will be down-selected by bioinformatics, tissue- and stage- specific immunolocalization studies, and skin testing for hypersensitivity in S. japonicum infected buffalo. Four of these down-selected candidates will be evaluated for efficacy and safety (including hypersensitivity) in buffalo vaccine trials in Yrs 4 and 5. The outcome of these studies will be a list of validated antigens associated with resistance to reinfection in humans. These data will provide a strong basis to prioritize antigenic targets for additional preclinical safety and efficacy studies in both rodents and large animal models. These data will further the rational development of vaccines that limit reinfection and consequent morbidity and mortality in humans.