Calderon-Quintal, J. A.; Teh-Poot, C.; Piste, L. M. P.; Martinez-Vega, P. P.; Dzul-Huchim, V.; Torres-Acosta, F.; Waleckx, E.; Villanueva-Lizama, L. E.; Ortega-Lopez, J.; Herrera, C.; Dumonteil, E.; Cruz-Chan, J. V.

Background and Aims Chagas disease, caused by Trypanosoma cruzi, is a vector-borne parasitic disease, with dogs acting as a major domestic host of the parasite. An immunotherapeutic vaccine would be an excellent tool to treat infections and prevent chronic cardiac disease in this host. Building on previous pre-clinical studies, we performed here the first randomized field trial of a vaccine against T. cruzi among client-owned dogs with natural infections. Methods A total of 31 dogs with T. cruzi infection with diverse parasite strains were enrolled and received three doses of a vaccine composed of Tc24-C4 and TSA1-C4 recombinant proteins with MPLA (N=16) or saline control (N=15) and followed for up to six months to assess efficacy. Results Blood parasite burden and electrocardiographic (ECG) recordings as primary outcomes showed that therapeutic vaccination led to a significant decrease in parasite burden, prevented/stopped cardiac alterations and was safe. This clinical benefit was mediated by major changes in T cell activation and T cell receptor (TCR) repertoire, while antibody responses were minimally affected. In addition, vaccination also reprogrammed the ongoing trained immunity to reduce inflammation, suggesting a complex interplay between innate and T cells in its mechanism of action. Conclusions These results provide a strong support for the further development of a veterinary vaccine based on these antigens as well as a human therapeutic vaccine to prevent the progression of chronic cardiac disease from T. cruzi infection.