mRNA-Tc-Vax vaccine induces T cell-dependent prophylactic and therapeutic protection against Trypanosoma cruzi

Chagas disease, a globally spreading neglected disease caused by Trypanosoma cruzi , presents a major therapeutic challenge, as current treatments are largely ineffective for the chronic phase where debilitating pathology develops. Therapeutic vaccines are a promising alternative to control chronic infection and its immunopathology. Here, we developed and evaluated mRNA-Tc-Vax, a novel LNP-formulated vaccine encoding an optimized version of a chimeric T. cruzi antigen. We assessed its potential in murine models using both prophylactic and therapeutic regimens, the latter alone and in combination with the parasiticidal drug Benznidazole (Bz). In naive mice, mRNA-Tc-Vax induced a robust CD8 ⁺ T cell response with high IFNγ expression and substantial polyfunctional CD8 ⁺ and CD4 ⁺ T cell populations. Adoptive transfer of these cells into non-vaccinated mice conferred strong protection against T. cruzi challenge, with improvements in all assessed parameters. Building on these promising findings, we evaluated the therapeutic efficacy of mRNA-Tc-Vax as both a monotherapy and in conjunction with a short Bz pretreatment in mice with chronic T. cruzi infection. The mRNA vaccine demonstrated potent immunogenicity, which was enhanced by prior Bz treatment. This combined approach generated a qualitatively superior immune response, characterized by a T cell rejuvenation profile, which stimulated a new population of effector cells with greater functional plasticity. This resulted in a modulation of the parasite-specific immune response, leading to a balanced Th1/Th2 profile. We also observed improvements in key disease markers, including electrocardiographic and histopathological findings, as well as a favorable shift in the serum TNF/IL-10 cytokine profile. These results highlight the ability of mRNA-Tc-Vax as an effective vaccine candidate for Chagas disease.