PROJECT SUMMARY Non-inferiority trial of a therapeutic vaccine against Chagas disease in naturally- infected rhesus macaques Chagas disease is a major vector borne parasitic disease cause by the protozoan parasite Trypanosoma cruzi, with over 6 million cases in the Americas. Chronic chagasic cardiomyopathy (CCC) is the most common and life-threathening manifestation of Chagas disease. There is a critical need to develop new treatments for Chagasic patients, and vaccines would represent a very cost-effective alternative to drug therapy. Preventive and therapeutic vaccines have shown promise in mouse and dog models, in particular with vaccines based on TSA-1 and Tc24 parasite antigens. Therefore, our long-term goal is to develop a human vaccine, to improve the prevention and control of Chagas disease, and we have established a first public-private consortium to reach this goal. The overall objective of the project is to evaluate the safety and efficacy of a therapeutic vaccine against T. cruzi in non-human primates by performing a non- inferiority trial in naturally infected rhesus macaques. Chagasic macaques will be randomly assigned to treatments based on (a) our therapeutic vaccine alone, (b) therapeutic vaccination plus subpatent benznidazole (BZN) treatment, for a non- inferiority comparison with (c) the standard BZN drug treatment (comparator arm). We will use blood parasitic load measured by qPCR, immediately (month 3) and 10 months after treatment as a primary efficacy outcome, as in several current clinical trials. We will test the hypothesis that therapeutic vaccination (alone or combined with BZN) is non- inferior to conventional BZN treatment, immediately and 10 months after treatment. We will also monitor cardiac function through electrocardiographic and echographic recordings as a secondary outcome, to test the hypothesis that cardiac function can be preserved by therapeutic vaccination. Finally, we will identify the immune correlates and biomarkers for disease progression and response to treatments by associating candidate molecules with cardiac function and parasite burden. Upon completion of these studies, we expect to identify a leading vaccine candidate for future clinical trials, which will lead to improved patient care and control of Chagas disease.