Prophylactic Vaccines for Schistosomiasis

描述(申请人提供)：在许多发展中国家，血吸虫病仍然是人和动物的主要寄生虫感染。日本血吸虫流行于东南亚和中国地区，是一种人畜共患疾病，可感染水牛、牛等牲畜，也可感染人。血吸虫病的数学模型显示，水牛约占中国血吸虫病传播的80%，并预测40-45%的疫苗效果将显着减少中国血吸虫病的传播。将SjCTPI-Hsp70和SjC23-Hsp70 DNA疫苗与IL-12表达载体联合使用，在水牛体内进行了两次疫苗效力试验。结果表明，与pVAX质粒DNA免疫水牛相比，SjC23-Hsp70和SjCTPI-Hsp70疫苗在成虫负担、肝卵以及重要的粪便毛虫孵化率方面均降低了50%或更多。这一修订申请的目标是确定需要配方的哪些方面才能达到这种高水平的疫苗效力，然后修改疫苗配方和交付方式，以提高每种疫苗的效力。因此，将进行疫苗试验，以确认将Hsp70包括在质粒DNA构建物中可以增强疫苗效力，并确定是否也需要联合注射表达IL-12的质粒。接下来，我们将确定是否可以通过注射蛋白质抗原Boost而不是质粒DNA Boost来增强疫苗效力，我们将比较Boosting与可溶性重组SJC23和SjCTPI抗原以及这些结合到微珠上的抗原，以增强抗原提呈细胞的激活。然后，我们将确定联合接种两种疫苗的最佳形式是否比单独接种一种疫苗对水牛产生更大的效果。我们相信，拟议的研究将产生一种或多种预防疫苗，其效力水平将超过我们现有的50%，将在中国和东南亚其他地区使用，以减少血吸虫病的传播。目的1.确定SJC23和SjCTPI疫苗在水牛中的效力是否需要使用IL-12或Hsp70。目的2.确定蛋白质抗原佐剂，无论是可溶性的还是作为微珠结合物，是否能提高SJC23或SjCTPI疫苗在水牛中的效力？目的3.确定优化的SJC23和SjCTPI疫苗组合接种是否比单独接种其中一种疫苗对水牛产生更大的效果？

DESCRIPTION (provided by applicant): Schistosomiasis remains a major parasitic infection of man and animals in numerous developing countries. Schistosoma japonicum is found in southeast Asia and China and is a zoonotic disease, infecting water buffalo, cattle and other livestock as well as man. A mathematical model of schistosomiasis reveals that water buffalo account for approximately 80% of transmission in China and predicts that vaccines with 40-45% efficacy will significantly reduce transmission of schistosomiasis in China. We performed two vaccine efficacy trials in water buffalo using SjCTPI-Hsp70 and SjC23-Hsp70 plasmid DNA vaccines in combination with an IL-12 expressing plasmid. The results show that the SjC23-Hsp70 and SjCTPI-Hsp70 vaccines each induced efficacy of 50% or greater in reductions in adult worm burden, liver eggs and importantly in fecal miracidial hatching rates compared to pVAX plasmid DNA vaccinated buffalo. The goal of this revised application is to determine which aspects of the formulation are required for this high level of vaccine efficacy and then to modify vaccine formulation and delivery to enhance the efficacy of each of these vaccines. Thus vaccine trials will be performed to confirm that the inclusion of Hsp70 in the plasmid DNA constructs enhances vaccine efficacy and determine if co-administration of an IL-12 expressing plasmid is also required. We will next determine if vaccine efficacy can be enhanced by administration of a protein antigen boost instead of a plasmid DNA boost and we will compare boosting with soluble recombinant SJC23 and SjCTPI antigens as well as these antigens conjugated to micro-beads to enhance antigen presenting cell activation. We will then determine if co-administration of the optimal form of both vaccines induces greater efficacy in water buffalo than buffalo vaccinated with either single vaccine. We believe the proposed studies will give rise to one or more prophylactic vaccines with levels of efficacy greater than the 50% level we already have, that will be used in China and other regions of southeast Asia to reduce transmission of schistosomiasis. Aim 1. Determine if SJC23 and SjCTPI vaccine efficacy in water buffalo requires the use of IL-12 or Hsp70. Aim 2. Determine if a protein antigen boost, either soluble or as micro-bead conjugates increase efficacy of SJC23 or SjCTPI vaccines in water buffalo? Aim 3. Determine if vaccination with a combination of the optimized SJC23 and SjCTPI vaccines induce greater efficacy in water buffalo than when either vaccine is administered singly?