One Health Vaccine Development for Bovine and Human Schistosomiasis

一种针对牛和人类血吸虫病的健康疫苗的开发

基本信息

批准号：
10019231
负责人：
Jonathan D. Kurtis
金额：
$ 5.64万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-21 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10019231
关键词：
Adjuvant Adult Alhydrogel Animals Antibodies Antigens Area Autopsy Biochemical Body Weight Buffaloes Cattle Chemistry Child Data Dermis Development Disease Electron Microscopy Farming environment Feces Female Fibrosis Formulation Granulomatous Health Human IL17 gene IL4 gene IgE IgG1 IgG2 IgG4 Immune response Immunofluorescence Immunologic Immunologic Epidemiology Individual Infection Inflammation Interferon Type II Interleukin-1 beta Interleukin-10 Interleukin-13 Labor Forces Link Measures Microscopic Morbidity - disease rate Mus Outcome Output Parasites Paratropomyosin Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Phase Philippines Platyhelminths Praziquantel Prevalence Production Productivity Resistance Rice Rodent Rodent Model Safety Schistosoma Schistosoma japonicum Schistosoma mansoni Schistosomiasis Schistosomiasis japonica Serum Site TNF gene Testing Toxicology Vaccinated Vaccination Vaccines Water Buffalo Work anti-IgE base chemotherapy cohort cytokine efficacy trial egg experimental study follow-up health application health economics improved male novel phase 2 study phase II trial prevent primary outcome programs response screening secondary outcome transmission process vaccine development vaccine trial

项目摘要

The overall aim of this One Health application is to accelerate the development of paramyosin (rSj97) and a newly discovered antigen (rSj68) as vaccines against human and bovine schistosomiasis japonica. Schistosomiasis, caused by three principle species of dioecious trematodes (flatworms), currently infects over 250 million individuals, results in 1.53 million DALYs lost per annum 1, and contributes to poor health and economic stagnation in endemic areas 2. 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. Most importantly, Schistosoma japonicum is a zoonosis with domesticated water buffalo (the key labor force for rice farming) suffering from the disease, as well as constituting a critical reservoir for continuing transmission to humans. In our recent work, we show that buffalo residing in our field site in Leyte, the Philippines have a prevalence of infection of 97%- underscoring the importance of these species for transmission to humans. Paramyosin was originally identified as the parasite target of antibodies generated in mice protectively vaccinated with S. mansoni schistosomula or adult worm extract 3. Our group conducted the pivotal study linking paramyosin and protection in S. japonicum 4. In four independent experiments, vaccination of mice with biochemically purified paramyosin (Sj97) resulted in 62%-86% (all P < 0.001) reduction in worm burden following cercarial challenge. We have conducted extensive immuno-epidemiology studies of Sj97 in a treatment-reinfection cohort of 616 S. japonicum infected individuals 5. We demonstrate a 30 to 41% lower intensity of reinfection (all P < 0.05) after praziquantel treatment in individuals with high Th2/Th1 cytokine ratios measured in PBMCs stimulated with Sj97. In this same cohort, we recently demonstrated that individuals with IgE but not IgG4 responses to rSj97 had a 77% lower intensity of reinfection at 12 months compared to individuals with IgG4 but not IgE responses, even after adjusting for potential confounders (p=0.016) 6. We identified rSj68 using a novel differential screening approach to identify parasite antigens recognized by antibodies expressed by resistant, but not susceptible children 7. By immunofluorescence and immunogold electron microscopy, rSj68 localizes to the tegument and gastro-dermis of adult male and female worms. In a holoendemic site in the Philippines, individuals with high titer IgE anti-rSj68 had a 58% lower intensity of reinfection over 12 months of follow-up compared to individuals without these antibodies (n=616, P < 0.001). In the current application, we propose to accelerate the development of paramyosin and rSj68 as vaccines for human and bovine schistosomiasis by conducting safety and efficacy trials in water buffaloes. We will focus our studies on adjuvants that have already been tested and found safe in humans and animals, thus accelerating our development efforts toward a Phase I vaccination study in humans and Phase II studies in bovines. The deliverables of this program will be an adjuvant optimized, bivalent schistosome vaccine that is ready for human Phase I and bovine Phase II trials with safety data to support an FDA IND application. This vaccine would have a tremendous impact on One Health objectives, including: 1) improved animal health, 2) improved animal productivity, 3) improved farm output, 4) decreased transmission of schistsosomaisis to humans, and 5) improved human health due to both direct (human vaccination) and indirect (buffalo vaccination) effects.

该健康应用的总体目的是加速帕果素（RSJ97）的发育和新发现的抗原（RSJ68）作为针对人和牛血吸虫的疫苗。血吸虫病是由三种主要种类的二元型杂种（Flatems）引起的，目前超过2.5亿人感染了2.5亿人，每年损失153万达利，并导致了流行病地区的健康和经济停滞不良。目前为这些寄生虫开发疫苗的努力是合理的。最重要的是，japonicum是一种人畜共患病，伴有驯养的水牛（水稻养殖的关键劳动力），患有该疾病，并构成了继续向人类传播的关键储层。在我们最近的工作中，我们表明居住在莱特（Leyte）的野外地点的水牛，菲律宾的感染率为97％ - 强调了这些物种对传播人类的重要性。帕托质蛋白被确定为最初是用曼氏链球菌菌螺菌疫苗接种的小鼠中产生的抗体的寄生虫靶标，或成人蠕虫提取物3。我们的小组进行了尖刺菌素和保护链球菌4的关键研究。 0.001）在尾挑战后减轻蠕虫负担。 We have conducted extensive immuno-epidemiology studies of Sj97 in a treatment-reinfection cohort of 616 S. japonicum infected individuals 5. We demonstrate a 30 to 41% lower intensity of reinfection (all P < 0.05) after praziquantel treatment in individuals with high Th2/Th1 cytokine ratios measured in PBMCs stimulated with Sj97.在同一队列中，我们最近证明，与IgG4的个体相比，IgE但IgG4对RSJ97的响应的人在12个月时的重新感染强度降低了77％，即使调整了潜在的混杂因素，即使对潜在的混杂因素进行了调整，即使在使用新型的差异型蚂蚁识别出来的RESID群体中，也可以通过识别型号的抗体来识别出潜在的混杂因素（p = 0.016）。易感儿童7。通过免疫荧光和免疫元电子显微镜，RSJ68定位于成年雄性和女性蠕虫的Tegument和胃dermis。与没有这些抗体的个体相比，在菲律宾的全体学位中，在12个月的随访中，重新感染的强度降低了58％（n = 616，p <0.001）。在当前的应用中，我们建议通过在水牛中进行安全性和有效性试验来加快人和牛血吸虫病的丙糖苷和RSJ68作为疫苗的发展。我们将把研究重点放在已经在人类和动物中进行了测试和发现安全的佐剂上，从而加快了我们在人类和牛的II期研究中进行I期疫苗接种研究的开发工作。该程序的可交付成果将是一种辅助优化的二价螺旋体疫苗，可以使用安全数据进行人体I期和牛II期试验，以支持FDA IND应用。这种疫苗将对一个健康目标产生巨大影响，包括：1）改善动物健康，2）提高动物生产力，3）改善农场产量，4）降低了血吸虫病向人类的传播，5）由于直接（人类疫苗接种）和间接疫苗（Buffalo疫苗接种），改善了人类健康。