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Schistosome Vaccines

血吸虫疫苗

基本信息

批准号：
8660282
负责人：
Jonathan D. Kurtis
金额：
$ 34.07万
依托单位：
RHODE ISLAND HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-05-10 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8660282
关键词：
Adult Aftercare Age Animal Model Antibodies Antibody Formation Antigens Area Bioinformatics Buffaloes Cattle Chronic Complementary DNA Coupled Data Development Enrollment Exons Expression Library Falciparum Malaria Funding Genomic DNA Health Human Hypersensitivity Hypersensitivity skin testing IgE Immune Immune response Immunity Individual Libraries Life Measures Mediating Methods Morbidity - disease rate Outcome Study Parasites Performance Phage Display Phase II Clinical Trials Philippines Plasma Platyhelminths Praziquantel Process Proteome Publishing Reliance Resistance Rodent Rodent Model Safety Sampling Schistosoma Schistosoma japonicum Schistosomiasis Schistosomiasis japonica Serological Signal Transduction Socioeconomic Status Staging Time Tissues Vaccine Antigen Vaccines Water base candidate validation chemotherapy cohort cytokine disability efficacy testing egg epidemiologic data follow-up health economics mortality novel novel vaccines preclinical efficacy preclinical safety public health relevance research study response safety testing screening sex vaccine candidate vaccine development vaccine efficacy volunteer

项目摘要

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.

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人类日本血吸虫病的疫苗。血吸虫病由雌雄异体吸虫（扁虫）的三种主要物种引起，目前感染全世界超过 2.5 亿人，每年导致 153 万伤残调整生命年损失。最近对全球血吸虫病负担的重新评估表明，实际的健康负担比世界卫生组织之前的估计高出 4 至 30 倍。这些巨大的数字凸显了血吸虫病疫苗对全球人类健康的影响。尽管吡喹酮（PZQ）可以有效治疗血吸虫病，但快速再感染和发病率反弹妨碍了仅基于化疗的有效控制，并且证明了目前为这些寄生虫开发疫苗的努力是合理的。我们建议利用我们之前 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差异筛选方法来鉴定耐药个体但非易感个体血浆中的抗体所识别的寄生虫抗原。我们将使用抗体反应的高通量免疫分析和在抗再感染的背景下分析这些反应来验证这些候选者。我们将通过评估新登记的生活在菲律宾莱特岛流行区的日本血吸虫感染者群体的细胞免疫反应来扩展对这些候选者的验证。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过敏皮肤测试来筛选候选者。其中四个被淘汰的候选药物将在第 4 年和第 5 年的水牛疫苗试验中评估其有效性和安全性（包括超敏反应）。这些研究的结果将是一系列与人类抗再感染相关的经过验证的抗原。这些数据将为啮齿类动物和大型动物模型中的额外临床前安全性和有效性研究的抗原靶点优先排序提供坚实的基础。这些数据将进一步促进疫苗的合理开发，以限制人类的再次感染以及随之而来的发病率和死亡率。