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

• 批准号: 10189672
• 负责人: Jonathan D. Kurtis
• 金额: $ 43.13万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-21 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10189672
• 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 evaluation; 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

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.

这一 One Health 应用的总体目标是加速副肌球蛋白 (rSj97) 和新发现的抗原 (rSj68) 的开发，作为针对人和牛日本血吸虫病的疫苗。 血吸虫病由雌雄异株吸虫（扁虫）的三种主要物种引起，目前感染超过 2.5 亿人，每年导致 153 万个伤残调整生命年 (DALY) 损失 1，并导致流行地区健康状况不佳和经济停滞 2。虽然吡喹酮 (PZQ) 可有效治疗血吸虫病，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和 证明目前为这些寄生虫开发疫苗的努力是合理的。最重要的是，日本血吸虫是一种人畜共患疾病，家养水牛（水稻种植的主要劳动力）患有这种疾病，也是继续向人类传播的重要宿主。在我们最近的工作中，我们发现生活在菲律宾莱特岛的水牛的感染率高达 97%，这强调了这些物种在向人类传播疾病方面的重要性。 副肌球蛋白最初被确定为用曼氏血吸虫或成虫提取物进行保护性疫苗接种的小鼠中产生的抗体的寄生虫靶点 3。我们的小组进行了将副肌球蛋白与日本血吸虫保护联系起来的关键研究 4。在四项独立实验中，用生化纯化的副肌球蛋白 (Sj97) 接种小鼠的结果为 62%-86%（所有 P < 0.001) 尾蚴攻击后蠕虫负担减少。我们在 616 名日本血吸虫感染个体的治疗-再感染队列中对 Sj97 进行了广泛的免疫流行病学研究。我们证明，在用 Sj97 刺激的 PBMC 中测量的高 Th2/Th1 细胞因子比率的个体中，吡喹酮治疗后，再感染强度降低了 30% 至 41%（所有 P < 0.05）。在同一队列中，我们最近证明，与有 IgG4 但没有 IgE 反应的个体相比，对 rSj97 有 IgE 但没有 IgG4 反应的个体在 12 个月时的再感染强度低 77%，即使在调整了潜在的混杂因素后也是如此 (p=0.016) 6。 易感儿童 7. 通过免疫荧光和免疫金电子显微镜观察，rSj68 定位于成年雄性和雌性线虫的皮膜和胃真皮。在菲律宾的一个大流行地区，与没有这些抗体的个体相比，具有高滴度 IgE 抗 rSj68 的个体在 12 个月的随访中再感染强度降低了 58% (n=616，P < 0.001)。 在目前的申请中，我们建议通过在水牛中进行安全性和有效性试验，加速副肌球蛋白和rSj68作为人和牛血吸虫病疫苗的开发。我们将把研究重点放在已经在人类和动物中进行测试并发现安全的佐剂上，从而加快我们的开发工作，以进行人类第一阶段疫苗研究和牛第二阶段研究。 该计划的交付成果将是一种佐剂优化的二价血吸虫疫苗，已准备好进行人类 I 期和牛 II 期试验，并提供支持 FDA IND 申请的安全数据。这种疫苗将对“同一个健康”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）提高农场产量，4）减少血吸虫病向人类的传播，以及5）由于直接（人类疫苗接种）和间接（水牛疫苗接种）效应而改善人类健康。