Schistosome Vaccines

描述（由申请人提供）：本次R01再申请的总体目标是开发针对日本人血吸虫病的疫苗。血吸虫病由三种主要的雌雄异株吸虫（扁虫）引起，目前全世界有2.5亿多人感染，每年造成153万残疾调整生命年损失。最近对全球血吸虫病负担的重新评估表明，实际卫生负担比世卫组织以前的估计高出4至30倍。这些巨大的数字强调了血吸虫病疫苗将对全球人类健康产生的影响。尽管吡喹酮（PZQ）可以有效治疗血吸虫病，但快速再感染和反弹发病率阻碍了仅基于化疗的有效控制，这证明了目前开发这些寄生虫疫苗的努力是合理的。我们建议利用我们之前在R-01资助的研究中收集的血浆样本和寄生虫学数据来识别与人类耐药性相关的新抗原。我们将使用全蛋白质组，鉴别筛选方法，以确定寄生虫抗原，抗体在耐药而不是易感个体的血浆中识别。我们将利用抗体反应的高通量免疫谱分析和在再感染抵抗的背景下分析这些反应来验证这些候选药物。我们将通过评估菲律宾Leyte流行区新入组的日本血吸虫感染者的细胞免疫反应来延长这些候选药物的有效性。最后，候选人将通过生物信息学、组织和阶段特异性免疫定位研究和日本血吸虫感染水牛过敏皮肤试验来筛选。在4年级和5年级的水牛疫苗试验中，将对这些被淘汰的候选疫苗中的4种进行有效性和安全性（包括超敏反应）评估。这些研究的结果将是一份与人类抵抗再感染相关的经过验证的抗原清单。这些数据将为在啮齿类动物和大型动物模型中进行临床前安全性和有效性研究的抗原靶点优先排序提供强有力的基础。这些数据将进一步合理开发疫苗，以限制人类的再感染和由此引起的发病率和死亡率。

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.