Adjuvant and Dose Optimization of Paramyosin based Vaccines for Schistosmiasis

描述(由申请人提供)：本次R21重新提交的总体目标是优化和测试以副肌球蛋白为基础的抗日本血吸虫病疫苗的效力。这种疫苗的目标是减少动物疾病，减少血吸虫病向人类的传播。血吸虫病是由三种主要的雌雄异体吸虫(扁虫)引起的，目前感染超过2.5亿人，估计导致2%-15%的慢性残疾，并导致流行地区的健康状况不佳和经济停滞。虽然吡喹酮(PZQ)能有效治疗血吸虫病，但发病率反弹的快速再感染排除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。在感染人类的血吸虫物种中，日本血吸虫是独一无二的，它拥有大量的动物宿主，有助于人类传播，最近的两项研究表明，在流行地区用药物治疗或消灭水牛可以大大减少75%至93%的日本血吸虫向人类的传播。在我们最近的初步实验中，在Montanide ISA 206中用重组全长副肌球蛋白免疫水牛，与单独使用佐剂治疗的水牛相比，尾蚴攻击后水牛的平均蠕虫负担减少了52%。我们建议通过在水牛这一大型血吸虫病动物模型上进行安全性和有效性试验，加快副肌球蛋白作为人和牛血吸虫病疫苗的开发。一种成功的牛疫苗将：1)直接用于兽医，2)直接减少对人类的传播，3)作为非啮齿动物大动物模型，支持FDA IND申请，在人类身上启动副肌球蛋白疫苗的I/II阶段试验。

DESCRIPTION (provided by applicant): The overall aim of this R21 resubmission is to optimize and test the efficacy of a paramyosin based vaccine against bovine schistosomiasis japonica. The goal of this vaccine is to reduce animal disease and reduce transmission of schistosomiasis to humans. Schistosomiasis, caused by three principle species of dioecious trematodes (flatworms), currently infects over 250 million individuals, results in an estimated 2-15% chronic disability, and contributes to poor health and economic stagnation in endemic areas. 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. Amongst the species of schistosomes that infect humans, S. japonicum is unique in having significant animal reservoirs that contribute to human transmission and two recent studies have demonstrated that drug curing or eliminating water buffalos in endemic areas can profoundly reduce, by 75 to 93%, transmission of S. japonicum to humans. In our recent pilot experiments, vaccination of water buffalo with recombinant, full length paramyosin in Montanide ISA 206 resulted in 52% reduction in median worm burden after cercarial challenge compared to buffalo treated with adjuvant alone. We propose to accelerate the development of paramyosin as a vaccine for both human and bovine schistosomiasis by conducting safety and efficacy trials in water buffaloes, a large animal model of schistosomiasis. A successful bovine vaccine would: 1) have direct veterinary application, 2) directly reduce transmission to humans, and 3) serve as a non-rodent large animal model supporting an FDA IND application to initiate Phase I/II trials of a paramyosin based vaccine in humans.