Abstract
Chagas disease, caused by the parasite Trypanosoma cruzi, develops into chronic Chagas’ cardiomyopathy in ~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 TH1-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 TH1-biased immune response to the vaccine, as demonstrated by a significant increase in antigen-specific IFNγ-production, the number of antigen-specific IFNγ-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.
Highlights
Chagas disease, caused by infection with the protozoan parasite Trypanosoma cruzi, is a leading neglected tropical disease globally [1], and the cause of Chagas’ cardiomyopathy, the most common form of non-ischemic cardiomyopathy in Latin America [2]
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
In order to evaluate the therapeutic efficacy of the prototype Tc24+E6020-stable emulsion (SE) vaccine in mice in the chronic stage of T. cruzi infection, we investigated cardiac pathology and persistence of systemic parasitemia post-vaccination
Summary
Chagas disease, caused by infection with the protozoan parasite Trypanosoma cruzi, is a leading neglected tropical disease globally [1], and the cause of Chagas’ cardiomyopathy, the most common form of non-ischemic cardiomyopathy in Latin America [2]. An estimated 7.2 million people are infected with Chagas disease, with 180,000 new cases occurring annually [3]. Chagas disease is responsible for over $7 billion in lost productivity and health care costs annually [4]. Chagas disease is characterized by two clinically distinct phases of disease: acute and chronic. Acute disease is most often a self-limiting febrile illness, up to 5% of cases develop severe disease including acute myocarditis, pericardial effusion, and meningoencephalitis, with an estimated 0.5% risk of mortality [5, 6]. 10–30 years after infection, 30% of patients develop chronic cardiomyopathy [2]
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