Adjuvant and Dose Optimization of Paramyosin based Vaccines for Schistosmiasis

描述（由申请人提供）：本次R21再申报的总体目标是优化和测试一种基于副肌球蛋白的牛血吸虫病疫苗的有效性。这种疫苗的目标是减少动物疾病和减少血吸虫病向人类的传播。血吸虫病由三种主要的雌雄异株吸虫（扁虫）引起，目前感染超过2.5亿人，估计造成2-15%的慢性残疾，并在流行地区造成健康状况不佳和经济停滞。尽管吡喹酮（PZQ）可以有效治疗血吸虫病，但快速再感染和反弹发病率阻碍了仅基于化疗的有效控制，这证明了目前开发这些寄生虫疫苗的努力是合理的。在感染人类的血吸虫物种中，日本血吸虫的独特之处在于具有重要的动物宿主，有助于人类传播，最近的两项研究表明，在流行地区，药物治疗或消除水牛可大大减少日本血吸虫向人类的传播，减少75%至93%。在我们最近的试点实验中，与单独使用佐剂治疗的水牛相比，用重组的Montanide ISA 206全长副粘连蛋白接种水牛后，尾蚴攻击后的中位蠕虫负担减少了52%。我们建议通过在大型血吸虫动物模型水牛中进行安全性和有效性试验，加速副肌球蛋白作为人血吸虫病和牛血吸虫病疫苗的开发。一种成功的牛疫苗将：1)有直接的兽医应用，2)直接减少对人类的传播，3)作为非啮齿动物的大型动物模型，支持FDA IND申请启动基于副肌球蛋白的人类疫苗的I/II期试验。

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. PUBLIC HEALTH RELEVANCE: 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.