Treatment with low-dose bicistronic immunotherapy mitigates parasite persistence and improves serological and cardiac outcomes in adult mice infected with <i>Trypanosoma cruzi</i> : comparative analysis with benznidazole

) remains difficult to treat in adults, as benznidazole (BZN) has limited curable efficacy and notable adverse effects. This study evaluated a newly-designed immunotherapy without (BCV) and with RIG-I adjuvant (BCVR) in a mouse model of CD. Adult C57BL/6 mice were infected and treated with BCV/BCVR (0.5 mg/kg, two-doses, 21-days interval) or BZN (50 mg/kg for 6-weeks). Outcomes included parasite burden, biomarkers of inflammation, fibrosis, and heart disease, and left ventricular (LV) function. Infected/untreated mice developed high acute parasite burden, and persistence of proinflammatory, tissue damage, and clinical disease related biomarkers in circulation and cardiac tissue in chronic phase. Treatment with BCV, BCVR or BZN achieved >95% control of parasite burden. Tissue inflammatory infiltrate and peripheral biomarkers of inflammation, necrosis, and heart involvement were significantly reduced throughout the infection and disease by BCV, while BCVR- and BZN-mediated protection was more evident in chronic phase. Pro-fibrotic gene expression and cardiac hypertrophy were significantly blocked in CD mice post-treatment (BCV > BCVR = BZN). Morphological changes in the LV walls' thickness associated with compromised systolic and diastolic performance of the heart were abated by BCV/BCVR, while BZN moderately controlled the LV dysfunction in CD mice. We surmise that BCV/BCVR immunotherapies outperformed BZN in controlling the parasite persistence and ameliorating cardiac pathology and LV dysfunction that contribute to heart failure and death in CD. Overall, BCV and BCVR are promising alternatives to prevent and control CD morbidities that has not been uniformly feasible because of adverse effects of BZN in adults.