Schistosome Vaccines

描述（由申请方提供）：本次R 01再提交的总体目标是开发抗人日本血吸虫病疫苗。由雌雄异株吸虫（扁形虫）的三种主要物种引起的血吸虫病目前在全世界感染超过2.5亿人，并且导致每年损失153万只DIFFERS。最近对全球血吸虫病负担的重新评估表明，实际健康负担比世卫组织先前的估计高出4至30倍。这些巨大的数字强调了血吸虫病疫苗对全球人类健康的影响。虽然血吸虫病是有效的治疗吡喹酮（PZQ），快速再感染与反弹的发病率排除了有效的控制基础上单独化疗，并证明目前的努力，为这些寄生虫的疫苗开发。我们建议利用我们以前的R-01资助的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。我们将使用一个完整的蛋白质组，差异筛选方法，以确定寄生虫抗原的抗体识别的血浆中的耐药，但不敏感的个人。我们将使用抗体应答的高通量免疫分析和在抵抗再感染的背景下分析这些应答来验证这些候选者。我们将通过评估一个新入组的S.日本血吸虫感染的个体生活在菲律宾莱特的流行区。最后，通过生物信息学、组织特异性和阶段特异性免疫定位研究以及皮肤过敏试验筛选候选人。日本血吸虫感染布法罗。在第4年和第5年的布法罗疫苗试验中，将评价这些下调选择的候选疫苗中的4种的有效性和安全性（包括超敏反应）。这些研究的结果将是一份与人类再感染抗性相关的经验证抗原的清单。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的抗原靶点优先级排序提供强有力的基础。这些数据将进一步合理开发疫苗，限制人类的再感染和随后的发病率和死亡率。

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.