A therapeutic vaccine prototype induces protective immunity and reduces cardiac fibrosis in a mouse model of chronic Trypanosoma cruzi infection

Chagas disease, caused by the parasite Trypanosoma cruzi, develops into chronic Chagas' cardiomyopathy in similar to 30% of infected individuals, characterized by conduction disorders, arrhythmias, heart failure, and even sudden cardiac death. Current anti-parasitic treatments are plagued by significant side effects and poor efficacy in the chronic phase of disease; thus, there is a pressing need for new treatment options. A therapeutic vaccine could bolster the protective T(H)1-mediated immune response, thereby slowing or halting the progression of chronic Chagas' cardiomyopathy. Prior work in mice has demonstrated therapeutic efficacy of a Tc24 recombinant protein vaccine in the acute phase of Chagas disease. However, it is anticipated that humans will be vaccinated therapeutically when in the chronic phase of disease. This study investigates the therapeutic efficacy of a vaccine prototype containing recombinant protein Tc24, formulated with an emulsion containing the Toll-like receptor 4 agonist E6020 as an immunomodulatory adjuvant in a mouse model of chronic T. cruzi infection. Among outbred ICR mice vaccinated during chronic T. cruzi infection, there is a significant increase in the number of animals with undetectable systemic parasitemia (60% of vaccinated mice compared to 0% in the sham vaccine control group), and a two-fold reduction in cardiac fibrosis over the control group. The vaccinated mice produce a robust protective T(H)1-biased immune response to the vaccine, as demonstrated by a significant increase in antigen-specific IFN-production, the number of antigen-specific IFN-producing cells, and IgG2a antibody titers. Importantly, therapeutic vaccination significantly reduced cardiac fibrosis in chronically infected mice. This is a first study demonstrating therapeutic efficacy of the prototype Tc24 recombinant protein and E6020 stable emulsion vaccine against cardiac fibrosis in a mouse model of chronic T. cruzi infection. Author summary Chagas disease is a parasitic infection that can cause severe heart disease. Current treatments do not work well and have significant side effects. Because of this, the authors created a new vaccine prototype with the goal that it could be given to infected people to prevent Chagas-associated heart disease. The vaccine contains a manufactured protein identical to a protein in the parasite (called Tc24) as well as a component to help the body produce a protective immune response (a vaccine adjuvant called E6020). The vaccine would boost the body's natural immune response to the parasite infection, reducing the number of parasites in the body, and protecting the heart. Frequently, people are not diagnosed until later in the infection, because the early (or acute) stage of disease can be mistaken for a common cold. Because of this, it is important to test the vaccine when given in the later (or chronic) stage of infection. The authors tested the vaccine in a mouse model of chronic T. cruzi infection and found that the vaccinated mice had lower levels of parasites in their body and less damage to their hearts. This research shows promising value of a therapeutic vaccine to prevent Chagas-associated heart disease in a mouse model, with the hope that the same effect could be found in humans one day.