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Background:  Chagas cardiomyopathy is caused by  Trypanosoma cruzi  ( Tc ). Two antigenic candidates, TcG2 and TcG4, are recognized by antibodies in naturally infected dogs and humans; and these vaccine candidates provided protection from  Tc  infection in mice and dogs.  Trypanosoma rangeli  ( Tr ) is non-pathogenic to mammals and shown to elicit cross-reactive anti- Tc  antibodies. In this study, we investigated if fixed  Tr  (fTr) can further enhance the efficacy of the  TcG2/TcG4  DNA vaccine.   Methods and Results:  C57BL/6 mice were immunized with  TcG2/TcG4  DNA vaccine and fTr (delivered as an adjuvant or in prime-boost approach), and challenged with  Tc . Serology studies showed that fTr (±quil-A) elicited  Tc - and  Tr- reactive IgGs that otherwise were not stimulated by  TcG2/TcG4  vaccine only, and quil-A had suppressive effects on fTr-induced IgGs. After challenge infection,  TcG2/TcG4 -vaccinated mice exhibited potent expansion of antigen- and  Tc -specific IgGs that were not boosted by fTr±quil-A. Flow cytometry analysis showed that  TcG2/TcG4 -induced dendritic cells (DC) and macrophages (Mφ) responded to challenge infection by expression of markers of antigen uptake, processing, and presentation, and production of pro-inflammatory cytokines.  TcG2/TcG4 -induced CD4 + T cells acquired Th1 phenotype and expressed markers that orchestrate adaptive immunity. A fraction of vaccine-induced CD4 + T cells exhibited iTreg phenotype responsible for aversion of self-injurious immune responses. Further,  TcG2/TcG4 -vaccinated mice exhibited potent expansion of poly-functional CD8 + T cells with TNF-α/IFN-γ production and cytolytic phenotype post-infection. Subsequently, tissue parasites and pathology were hardly detectable in  TcG2/TcG4 -vaccinated/infected mice. Inclusion of fTr±quil-A had no clear additive effects in improving the  Tc -specific adaptive immunity and parasite control than was noted in mice vaccinated with  TcG2/TcG4  alone. Non-vaccinated mice lacked sufficient activation of Th1 CD4 + /CD8 + T cells, and exhibited >10-fold higher levels of tissue parasite burden than was noted in vaccinated/infected mice.   Conclusion:   TcG2/TcG4  vaccine elicits highly effective immunity, and inclusion of fTr is not required to improve the efficacy of DNA vaccine against acute  Tc  infection in mice.

frontiers in immunology

TcG2/TcG4 DNA Vaccine Induces Th1 Immunity Against Acute Trypanosoma cruzi Infection: Adjuvant and Antigenic Effects of Heterologous T. rangeli Booster Immunization