Randomized field trial of a therapeutic vaccine against Trypanosoma cruzi natural infection in dogs and correlates for efficacy
Background and AimsChagas 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. MethodsA 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. ResultsBlood 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. ConclusionsThese 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. Structured graphical abstractO_ST_ABSKey questionC_ST_ABSCan an immunotherapeutic vaccine against Trypanosoma cruzi control an ongoing infection and prevent the progression of chronic cardiac disease in naturally infected dogs? Key findingTherapeutic vaccination of chronically infected dogs led to a reduced blood parasite burden and prevented the progression of chronic cardiac disease (Primary outcomes). Correlates of vaccine efficacy included major changes in T cell repertoire/activation and changes in innate immunity to reduce inflammation. Take home messageImmunotherapeutic vaccination of dogs with natural infection with T. cruzi was safe and effective to control an ongoing infection with a broad diversity of parasite strains and prevented the progression of chronic cardiac disease. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=94 SRC="FIGDIR/small/653529v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@17ce572org.highwire.dtl.DTLVardef@bba649org.highwire.dtl.DTLVardef@1a20405org.highwire.dtl.DTLVardef@1b61c7e_HPS_FORMAT_FIGEXP M_FIG C_FIG Translational perspectiveCurrent drug treatments for Chagas disease have major limitations due to significant adverse effects and a limited efficacy as chronic cardiac disease develops. A veterinary vaccine for dogs, a major domestic host of the parasite, would help reduce domestic transmission and improve dog health, as well as provide support for the development of a human immunotherapeutic vaccine to prevent the progression of chronic Chagasic cardiomyopathy.