Schistosomiasis Vaccine Development and Morbidity throughout the Life Course

描述(由申请人提供)：本提案概述了在菲律宾蒙蒂卢帕市阿拉邦的热带医学研究所(RITM)建立热带医学研究中心(TMRC)的计划。该方案项目涉及血吸虫病的几个方面，血吸虫病是世卫组织确定的被忽视的热带疾病之一，总体目标是检查对日本血吸虫的保护性和适应不良免疫反应在整个生命过程中对人类感染和疾病的影响。该计划将有3个项目，每个项目都与国家血吸虫病控制计划相联系，以便通过TMRC获得的见解将对血吸虫病的控制产生立竿见影的影响。这3个项目是： 项目1将评估水牛接种rSj97疫苗对水牛和人类感染的影响。项目2，将审查母亲PZQ治疗对宫内免疫敏感化和儿童早期血吸虫相关发病率的影响。项目3将从我们正在进行的随机对照试验中检查母体PZQ治疗、异常的胶原蛋白代谢和母子二人组出生结果之间的相互作用。 除了这三个项目外，该TMRC还将通过与美国罗德岛医院国际卫生研究中心(CIHR-RIH)合作建立一个行政核心、免疫学复合核心和数据管理核心来扩大RITM的研究能力。 相关性：该计划将提供强有力的数据支持FDA对Sj97疫苗的IND，提供关于怀孕期间以吡喹酮治疗为目标的妇女的风险-收益分析，并突出日本血吸虫感染妇女中胶原蛋白代谢失调在调节不良妊娠结局中的机制。 项目1：血吸虫病疫苗开发 项目负责人(PL)：Jiz，M. (申请人提供的描述)：本项目1的总体目标是加速开发重组副肌球蛋白作为日本血吸虫病疫苗。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2.5亿人，每年导致153万人死亡，并导致流行地区健康状况不佳和经济停滞。虽然吡喹酮(PZQ)可以有效治疗血吸虫病，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。我们将评估副肌球蛋白(RSj97)的有效性和安全性，在我们的人体研究中，副肌球蛋白(RSj97)是保护Th2和IgE反应的目标，在水牛的疫苗试验中，水牛是血吸虫病的主要宿主。我们将在水牛的野外挑战实验中探索一系列疫苗佐剂。最后，我们将在水牛身上进行大规模的社区疫苗试验，以检验有效接种水牛疫苗将减少日本血吸虫病向人类传播的假设。这些研究的结果将是一种优化的、辅助性的、以副肌球蛋白为基础的牛日本血吸虫病疫苗，在大型动物模型中具有安全性和有效性的临床前数据。 相关性：血吸虫病疫苗的开发仍然是更好地控制这种慢性和衰弱疾病的一个有希望的途径。该TMRC项目将为部署牛疫苗提供坚实的基础，并将支持FDA IND申请进行后续的L/11期临床试验，以开发一种限制再感染以及随后的发病率和死亡率的人类疫苗。

DESCRIPTION (provided by applicant): The present proposal outlines the establishment of a Tropical Medicine Research Center (TMRC) in the Philippines at the Research Institute for Tropical Medicine (RITM) located in Alabang, Muntinlupa City. This program project addresses several aspects of schistosomiasis, one of WHO identified neglected tropical diseases, with the overall goals of examining the impact of protective and maladaptive immune responses to Schistosoma japonicum on human infection and disease throughout the life course. The program will have 3 projects, each are linked to the national control schistosomiasis control program in order that insights gained through this TMRC will have an immediate impact on the control of schistosomiasis . The 3 projects are: Project 1 will evaluate the impact of buffalo vaccination with rSj97 on buffalo and human infection. Project 2, will examine the impact of maternal PZQ treatment on the longevity of in utero immune sensitization and schistosome-related morbidity in early childhood. Project 3 will examine the interactions among maternal PZQ treatment, dysregulated collagen metabolism, and birth outcomes in maternal-child dyads from our ongoing RCT. In addition to the 3 projects, this TMRC will expand the research capacity of RITM through the establishment of an Administrative Core, Immunology Multiplex Core and Data Management Core in collaboration with the Center for International Health Research at Rhode Island Hospital (CIHR-RIH) in the US. RELEVANCE: This program will provide strong data in support of an FDA IND for the Sj97 vaccine, inform risk-benefit analysis with respect to targeting women for treatment with Praziquantel during pregnancy, and highlight mechanisms of dysregulated collagen metabolism in mediating poor pregnancy outcomes among Schistosoma japonicum-infected women. Project 1: Schistosomiasis Vaccine Development Project Leader (PL): Jiz, M. (Description as provided by applicant): The overall aim of this Project 1 is to accelerate the development of recombinant paramyosin as a vaccine against 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, and contributes to poor health and economic stagnation in endemic areas. Although schistosomiasis is effectively treated with praziquantel (PZQ), rapid re-infection with rebound morbidity precludes effective control based on chemotherapy alone and justifies current efforts to develop vaccines for these parasites. We will evaluate the efficacy and safety of paramyosin (rSj97), the target of protective Th2 and IgE responses in our human studies, in vaccine trials in water buffalo, a major bovine reservoir of schistosomiasis. We will explore a range of vaccine adjuvants in field-based challenge experiments in water buffalos. We will conclude with a large scale, community based vaccine trial in buffalo designed to test the hypothesis that effective vaccination of water buffalo will reduce the transmission of schistosomiasis japonica to humans. The outcome of these studies will be an optimized, adjuvanted, paramyosin-based vaccine for bovine schistosomiasis japonica with preclinical data on safety and efficacy in a large animal model. RELEVANCE: Vaccine development for schistosomiasis remains a promising avenue to better control this chronic and debilitating disease. This TMRC project will provide a strong basis to deploy a bovine vaccine and will support an FDA IND application for follow-on Phase l/ll clinical trials to develop a human vaccine that limits re-infection and consequent morbidity and mortality.