Chagas disease, caused by persistent chronic infection with the tropical parasite Trypanosoma cruzi, remains a severe cause of morbidity and mortality in the South American poor population. There are no Chagas vaccines for human use available nor in human clinical vaccine trials. We have previously shown that T cells alone provide protection to normally susceptible BALB/c mice against lethal systemic parasite challenge. The availability of 'humanized' mice (i.e., HLA DR1/A2 dual transgenic mice) allows us to perform similar studies eliciting data more relevant to human Chagas vaccine development. The goals of our evolving studies are to: 1) identify sequences predicted to bind multiple HLA alleles within a) the highly conserved functional (enzymatically active) trans-sialidase (TS) gene family members, b) the larger subset of non-functional TS genes, and c) the total gene subset expressed during human infection, 2) verify that predicted epitopes are presented by MHC during human T. cruzi infection, 3) prepare several DNA vaccines encoding multiple class I and class II parasite epitopes, and 4) perform immunization/challenge experiments in HLA-DR1/A2 dual transgenic mice to determine whether these novel T cell-driven vaccines induce immunity protective against acute lethal challenges as well as against chronic inflammation and disease.