Can a DNA vaccine protect against Chagas disease? A systematic review of preclinical studies

Chagas disease, caused by Trypanosoma cruzi, remains a major neglected tropical disease with limited treatment options. DNA-based vaccination has been explored as a preventive strategy, but its overall efficacy and translational value remain uncertain. Despite encouraging preclinical findings, the evidence on DNA-based vaccines against T. cruzi remains heterogeneous and has not been systematically integrated across outcomes. A comprehensive review is therefore needed to contextualize the current knowledge and define the translational relevance of this platform. To systematically review preclinical in vivo evidence on the efficacy of DNA-based vaccination against T. cruzi, focusing on parasitological, immunological, histopathological, and cardiac outcomes. PubMed/MEDLINE, Scopus, Embase, and Web of Science were searched without date restrictions. Eligible studies were controlled in vivo experiments evaluating DNA vaccines against T. cruzi in animal models. Two reviewers performed study selection, data extraction, risk-of-bias (SYRCLE) and certainty of evidence (GRADE) assessment independently. Thirty preclinical studies were included. Murine models predominated, especially BALB/c, C57BL/6, and C3H/He mice, although canine studies added translational relevance. Naked plasmid DNA, Salmonella-delivered constructs, and adjuvanted DNA vaccines were the most common platforms. The principal antigens belonged to the trans-sialidase family and amastigote surface proteins. Overall, vaccination was associated with reduced parasitemia, improved survival in several murine models, Th1 immune responses characterized by increased IFN-γ, IgG2a, and CD8+ T-cell activation, as well as attenuation of inflammatory, histopathological, and cardiac damage. In canine models, vaccination also reduced parasite burden and myocardial inflammation, although protection remained incomplete. Confidence in the evidence was limited by substantial heterogeneity in animal background, antigen selection, parasite strain, inoculation route, dosing regimens, and follow-up duration. Frequent unclear risk of bias and incomplete reporting prevented meta-analysis and constrain causal inference. DNA-based vaccination against T. cruzi can induce Th1 immunity and reduce parasitological and tissue injury outcomes, but protection is often partial and rarely sterilizing.