Authors

I Almeida¹;  ¹ Department of Biological Sciences, The University of Texas at El Paso, Afghanistan

Discussion

Chagas disease (ChD) caused by Trypanosoma cruzi affects 6-8 million people worldwide. Chemotherapy is partially effective and toxic, and there is no preventive or therapeutic vaccine. T. cruzi has a surface coated by highly immunogenic mucins, which contain the immunodominant glycotope Gal(1,3)Gal(1,4)GlcNAc (Gal3LN) that induces abundant lytic anti-α-Gal antibodies. Here we evaluated the efficacy of the Gal3LN glycotope, covalently attached to the carrier protein human serum albumin (HSA), as potential vaccine in both murine and nonhuman primate models of ChD. First, the neoglycoprotein (NGP) Gal3LN-HSA was tested in the 1,3-galactosyltransferase-knockout (1,3-GalT-KO) mice, which akin to humans and Old-World nonhuman primates do not express linear -Gal glycotopes. 1,3-GalT-KO Mice vaccinated with Gal3LN-HSA were fully protected against lethal T. cruzi challenge by inducing a strong anti--Gal antibody-mediated humoral response and a balanced Th1/Th2-type cellular immunity. Furthermore, Gal3LN-HSA-vaccinated mice exhibited significant reduction (91.7-99.9%) in parasite load in all tissues analysed, cardiac inflammation, myocyte necrosis, and T-cell infiltration. Next, nonhuman primates (baboons) were immunized with NGP Gal3LN-HSA plus adjuvant (LMPLA), or LMPLA alone (control). Animals were subsequently challenged twice with T. cruzi metacyclic trypomastigotes (previously isolated from baboons) and humanely euthanized 14 weeks following the first parasite challenge. A strong anti--Gal Ab response, considerable reduction in cardiac parasite burden and inflammation, and protective Th1- and Th17-mediated response were observed in NGP24h+LMPLA-vaccinated baboons but not in control animals. Untargeted metabolomics identified overall cardiac correlates of vaccine protection and regiospecific alterations between cardiac ventricles. This is the first proof-of-concept study to demonstrate the efficacy of a prophylactic -Gal-based glycovaccine for experimental acute and chronic Chagas disease, in both mice and non-human primates.