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

• Published in: PLoS neglected tropical diseases 2019-05, Vol.13 (5), p.e0007413-e0007413
• Main Authors: Barry, Meagan A, Versteeg, Leroy, Wang, Qian, Pollet, Jeroen, Zhan, Bin, Gusovsky, Fabian, Bottazzi, Maria Elena, Hotez, Peter J, Jones, Kathryn M
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Antibodies, Protozoan - immunology; Antigens; Biology; Biology and Life Sciences; Cardiomyopathy; Cardiovascular disease; Care and treatment; Chagas Cardiomyopathy - immunology; Chagas Cardiomyopathy - parasitology; Chagas Cardiomyopathy - pathology; Chagas Cardiomyopathy - prevention & control; Chagas disease; Chronic illnesses; Chronic infection; Complications and side effects; Conduction; Death; Defence mechanisms; Development and progression; Disease control; Disease Models, Animal; Effectiveness; Emulsions; Female; Fibrosis; Funding; Heart; Heart diseases; Heart failure; Humans; Immune response; Immune system; Immunity; Immunoglobulin G; Immunomodulation; Infections; Inflammation; Interferon-gamma - genetics; Interferon-gamma - immunology; Laboratory animals; Lymphocytes T; Medical research; Medicine; Medicine and Health Sciences; Mice; Mice, Inbred ICR; Mortality; Myocardial diseases; Myocardium - pathology; Parasitemia; Parasitemia - immunology; Parasitemia - parasitology; Parasitemia - pathology; Parasitemia - prevention & control; Parasites; Parasitic diseases; Pediatrics; Proteins; Prototypes; Protozoa; Protozoan Vaccines - administration & dosage; Protozoan Vaccines - immunology; Receptors; Recombinant proteins; Recombinants; Research and Analysis Methods; Side effects; Sudden cardiac death; Testing; Th1 Cells - immunology; TLR4 protein; Toll-like receptors; Tropical diseases; Trypanosoma cruzi; Trypanosoma cruzi - immunology; Trypanosoma cruzi - physiology; Vaccination; Vaccines; Vector-borne diseases; Virology; γ-Interferon
• ISSN: 1935-2735; 1935-2727; 1935-2735
• DOI: 10.1371/journal.pntd.0007413

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.