One Health Vaccine Development for Bovine and Human Schistosomiasis

One Health应用程序的总体目标是加快副肌球蛋白(RSj97)和一种新发现的抗原(RSj68)作为人和牛血吸虫病疫苗的开发。血吸虫病是由三种主要的雌雄异体吸虫(扁虫)引起的，目前感染了超过2.5亿人，每年导致153万人死亡1，并导致流行地区健康状况不佳和经济停滞2。尽管吡喹酮(PZQ)能有效治疗血吸虫病，但发病率反弹的快速再感染阻碍了仅基于化疗的有效控制，并证明了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病，家养水牛(水稻种植的关键劳动力)患有这种疾病，并构成持续传播给人类的关键水库。在我们最近的工作中，我们发现居住在我们菲律宾莱特市野外的水牛的感染率为97%--这突显了这些物种对人类传播的重要性。副肌球蛋白最初被确定为在保护性接种曼氏血吸虫血吸虫幼虫或成虫提取物3的小鼠中产生的抗体的寄生虫靶标。我们的团队在日本血吸虫中进行了将副肌球蛋白与保护联系起来的关键研究4。在四个独立的实验中，用生物化学纯化的副肌球蛋白(Sj97)接种小鼠后，尾蚴攻击后的蠕虫负担减少了62%-86%(均P&lt；0.001)。我们在616名日本血吸虫感染者的治疗-再感染队列中对Sj97进行了广泛的免疫流行病学研究5。我们证明，在用Sj97刺激的PBMC中检测到高Th2/Th1细胞因子比率的人，在吡喹酮治疗后再感染强度降低了30%至41%(均为P&lt；0.05)。在同一队列中，我们最近证明，即使在调整了潜在的混杂因素后，对rSj97有免疫球蛋白E而不是免疫球蛋白G4应答的个体在12个月时的再感染强度比对免疫球蛋白4有反应的个体低77%(p=0.016)6。我们使用一种新的差异筛选方法鉴定了rSj68，以识别耐药但不敏感的儿童表达的抗体识别的寄生虫抗原7。通过免疫荧光和免疫金电子显微镜，rSj68定位于成虫的雄虫和雌虫的被和胃真皮。在菲律宾的一个全流行区，在12个月的随访中，具有高滴度IgE抗rSj68抗体的个体的再感染强度比没有这些抗体的个体低58%(n=616，P&lt；0.001)。在目前的应用中，我们建议通过在水牛身上进行安全性和有效性试验，加快副肌球蛋白和rSj68作为人和牛血吸虫病疫苗的开发。我们将把我们的研究重点放在已经经过测试并在人和动物身上安全的佐剂上，从而加快我们在人类和牛身上进行第一阶段疫苗接种研究和第二阶段研究的发展努力。该计划的交付成果将是一种佐剂优化的双价血吸虫疫苗，可用于人类I期和牛II期试验，并具有支持FDA IND应用的安全数据。这种疫苗将对One Health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，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。

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.