A genome wide antigen-antibody screen identifies a yeast-based therapeutic vaccine candidate for Chagas disease

Abstract

Chagas disease is caused by Trypanosoma cruzi infection and results in decades-long, chronic, debilitating, and lethal disease. There is no vaccine available, largely due to the lack of vaccine targets. We generated a T. cruzi genome-wide library for yeast surface display and screened it with antibodies from Chagas disease patients to identify antigen-antibody interactions. We identified hundreds of T. cruzi antigens that are immunogenic in humans and mapped their antibody-binding sites at nucleotide resolution. Hundreds of immunogens were conserved across strains, divergent from human proteins, and expressed across all T. cruzi infectious forms, revealing potential vaccine targets. We vaccinated mice with a 63-amino-acid-long immunogenic region using recombinant protein (rIR1) or yeast surface expression (yIR1). yIR1 surpassed rIR1, reducing parasitemia in blood and muscle tissues in a prophylactic, acute-stage vaccination model, validating IR1 as an immunogen and yeast as a vaccine vehicle for Chagas disease. Notably, therapeutic vaccination of chronically infected mice with yIR1 cleared parasites from muscle tissues and was accompanied by the production of -IR1 antibodies and an increased proportion of CD8+ T cells, indicating that a vaccine for treating chronic Chagas disease may be feasible. The antigen-antibody screen revealed hundreds of immunogens for vaccine, diagnostic, and biomarker discovery, and uncovered yIR1 as a therapeutic vaccine candidate for Chagas disease. One Sentence SummaryA yeast-based therapeutic vaccine candidate for treating chronic Chagas disease