The focus of this program project is the identification and testing of vaccines for the prevention and treatment of Trypanosoma cruzi infection and Chagas' disease. Vaccine production with T. cruzi has recently become feasible due to the increased understanding of the disease process in T. cruzi infection, revelation of the effector mechanisms involved in control of the infection, the availability of excellent experimental models of the infection and disease, and the major advancements in vaccine discovery and delivery methods. In this Project, we will apply one of these advances in vaccine discovery, Expression Library Immunization or ELI, or the identification of new vaccine candidates in T. cruzi. ELI provides an unbiased method for screening potentially the entire genome of T. cruzi genes capable of generating immune protection to T. cruzi infection in mice. Eli also has the added advantage of using a cheap and efficient vaccine delivery method, genetic immunization, to both identify candidate vaccine molecules and test their vaccine potential in one step. In this Project we will generate a clonal genomic expression library from T. cruzi using a newly developed plasmid which selects for open reading frames in genomic DNA and provides for protein expression in both prokaryotic and eukaryotic systems. This library will then be screened for vaccine candidates by measuring the ability of pools of clones from the library to provide protection from lethal T. cruzi infection in mice. Protective pools of clones will be sequentially screened to eventually identify between 20 and 50 protective genes from the T. cruzi genome. In the final aim of this project, these protective clones will also be screened for the ability to protect mice from the development of Chagas' disease in the chronic phase of the infection. The vaccine candidates identified using ELI as well as those identified in Project 2 of this Program Project will be assembled into a multi- component vaccine in Project 3 and will also be tested in Project 4 to determine the level and type of immune responses that humans with T. cruzi infection have to these molecules.
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