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廷卢帕市的热带医学研究所（RITM）建立热带医学研究中心（TMRC）。该计划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，其总体目标是研究日本血吸虫的保护性和适应不良免疫反应对人类整个生命过程中感染和疾病的影响。该计划将有3个项目，每个项目都与国家控制血吸虫病控制计划相关联，以便通过TMRC获得的见解将对血吸虫病的控制产生直接影响。这3个项目是： 项目1将评估布法罗接种rSj 97对布法罗和人感染的影响。项目2将研究母体PZQ治疗对宫内免疫致敏和幼儿期与染色体相关的发病率的影响。项目3将从我们正在进行的随机对照试验中研究母体PZQ治疗、胶原代谢失调和母婴配对的出生结局之间的相互作用。 除了这三个项目外，该TMRC还将通过与美国罗得岛医院国际卫生研究中心（CIHR-RIH）合作建立行政核心、免疫学多重核心和数据管理核心，扩大RITM的研究能力。 相关性：该项目将提供强有力的数据，支持Sj 97疫苗的FDA IND，为妊娠期吡喹酮治疗女性的风险-获益分析提供信息，并强调胶原代谢失调在介导日本血吸虫感染女性不良妊娠结局中的机制。 项目1：血吸虫病疫苗研制 项目负责人（PL）：Jiz，M. （申请人提供的描述）：本项目1的总体目标是加快日本血吸虫病重组副肌球蛋白疫苗的开发。由雌雄异株吸虫（扁形虫）的三种主要物种引起的血吸虫病目前感染了2.5亿多人，每年造成153万人死亡，并导致流行地区的健康状况不佳和经济停滞。虽然血吸虫病是有效的治疗吡喹酮（PZQ），快速再感染与反弹的发病率排除了有效的控制基础上单独化疗，并证明目前的努力，为这些寄生虫的疫苗。我们将在布法罗（血吸虫病的主要牛宿主）的疫苗试验中评估副肌球蛋白（rSj 97）的有效性和安全性，副肌球蛋白是我们人类研究中保护性Th 2和IgE应答的靶点。我们将在水牛的田间攻毒实验中探索一系列疫苗佐剂。最后，我们将在布法罗中进行一项大规模的、以社区为基础的疫苗试验，旨在检验布法罗的有效疫苗接种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个优化的，佐剂，副肌球蛋白为基础的疫苗，牛血吸虫病日本与临床前数据的安全性和有效性在一个大的动物模型。 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使人衰弱的疾病的一个有希望的途径。该TMRC项目将为部署牛疫苗提供强有力的基础，并将支持FDA IND申请，用于后续I/II期临床试验，以开发限制再感染和随后的发病率和死亡率的人用疫苗。

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.