Biomarker-Based Test of Cure for Chagas Disease

Project Summary Chagas disease, caused by infection with the parasite Trypanosoma cruzi, is the most prevalent parasitic disease in the western hemisphere, infecting 8-11 million individuals and with over 70 million at risk. The infection is transmitted by an insect vector, but can also be acquired through blood transfusion, organ transplant, or congenitally. Following a brief acute phase, the parasite persists for years as a chronic, but often asymptomatic infection, which may progress to cardiomyopathy and other pathological conditions leading to severe morbidity and mortality. In the U.S., the prevalence of T. cruzi infection in immigrant populations has led to the implementation of blood screening assays to prevent transfusion transmission. Autochthonous transmission can be expected based on the gradual encroachment of the insect vector into the southernmost regions of the U.S. Treatment for Chagas disease currently relies on two drugs, benznidazole and nifurtimox. While these drugs are highly effective if used during the acute phase, their efficacy in the chronic phase varies significantly, decreasing with increasing duration of infection. Moreover, due to their known toxicity, both drugs are known to have frequent adverse effects, which intensify with patient age. Benznidazole has been approved by FDA only for use on children aged 2-12, while nifurtimox is not FDA-approved; both drugs can only be obtained in the U.S. from CDC for use outside the approved indication. Accordingly, a variety of efforts are underway to develop new drugs to treat Chagas disease, supported by public health organizations and pharmaceutical companies. However, a major limitation is the lack of a reliable, standardized and validated test of cure to measure the efficacy of Chagas drugs and to establish whether treatment has successfully eradicated an individual patient’s infection for purposes of clinical management. The aim of this project is the development of a test of cure for Chagas disease that will address these needs. Of the methodologies that have been evaluated for measuring drug effects on T. cruzi infection, serology and PCR have been the mainstays. A decrease in antibody titer to one or another T. cruzi antigen over a period of time following treatment has been used in various studies as a de factor test of cure, but the in-house assays used have not been standardized or validated and are not commercially available. PCR offers high positive predictive value, but its low negative predictive value excludes it as a methodology for a bona fide test of cure. Approach to assay development will be on the measurement of antibody response to a set of T. cruzi peptide antigens selected based on immunological characteristics. Assays will be developed first in ELISA and subsequently in point-of-care formats to address the needs of drug trials and individual patient management. Performance of the test-of-cure assays will be evaluated on available sets of well-characterized serum samples obtained at time intervals pre- and post-treatment from prior Chagas studies. In Phase II, broader validation studies will be carried out leading to introduction of the first commercially available test-of-cure for Chagas disease.Project Narrative This project addresses the critical need for a test of cure for Chagas disease which has emerged as a threat to public health and the blood supply both within the U.S. and internationally. Determining whether treatment of patients for Chagas disease with existing drugs or with new drugs under development has successfully eradicated the infection requires a test of cure, but no such test has been validated and made commercially available. In Phase I, we propose to develop a Chagas disease test of cure based on one or more well- characterized peptide antigens. In Phase II we will refine this assay into a manufactured product, carry out a validation study to support a 510(k) submission to FDA, and prepare for scale up and commercial launch of the assay.