A Human Type 5 Adenovirus-Based Trypanosoma cruzi Therapeutic Vaccine Re-programs Immune Response and Reverses Chronic Cardiomyopathy

Abstract

Chagas disease (CD), caused by the protozoan Trypanosoma cruzi, is a prototypical neglected tropical disease. Specific immunity promotes acute phase survival. Nevertheless, one-third of CD patients develop chronic chagasic cardiomyopathy (CCC) associated with parasite persistence and immunological unbalance. Currently, the therapeutic management of patients only mitigates CCC symptoms. Therefore, a vaccine arises as an alternative to stimulate protective immunity and thereby prevent, delay progression and even reverse CCC. We examined this hypothesis by vaccinating mice with replication-defective human Type 5 recombinant adenoviruses (rAd) carrying sequences of amastigote surface protein-2 (rAdASP2) and trans-sialidase (rAdTS) T. cruzi antigens. For prophylactic vaccination, naïve C57BL/6 mice were immunized with rAdASP2+rAdTS (rAdVax) using a homologous prime/boost protocol before challenge with the Colombian strain. For therapeutic vaccination, rAdVax administration was initiated at 120 days post-infection (dpi), when mice were afflicted by CCC. Mice were analyzed for electrical abnormalities, immune response and cardiac parasitism and tissue damage. Prophylactic immunization with rAdVax induced antibodies and H-2Kb-restricted cytotoxic and interferon (IFN)γ-producing CD8+ T-cells, reduced acute heart parasitism and electrical abnormalities in the chronic phase. Therapeutic vaccination increased survival and reduced electrical abnormalities after the prime (analysis at 160 dpi) and the boost (analysis at 180 and 230 dpi). Post-therapy mice exhibited less heart injury and electrical abnormalities compared with pre-therapy mice. rAdVax therapeutic vaccination preserved specific IFNγ-mediated immunity but reduced the response to polyclonal stimuli (anti-CD3 plus anti-CD28), CD107a+ CD8+ T-cell frequency and plasma nitric oxide (NO) levels. Moreover, therapeutic rAdVax reshaped immunity in the heart tissue as reduced the number of perforin+ cells, preserved the number of IFNγ+ cells, increased the expression of IFNγ mRNA but reduced inducible NO synthase mRNA. Vaccine-based immunostimulation with rAd might offer a rational alternative for re-programming the immune response to preserve and, moreover, recover tissue injury in Chagas’ heart disease.

A therapeutic nanoparticle vaccine againstTrypanosoma cruziin a BALB/c mouse model of Chagas disease

“…Ultimately, Tc24 may be combined with other T. cruzi antigens, such as TSA1, TcG2, and TcG4 to increase vaccine efficacy. 22,24,29,30,58 Additionally, this vaccine could potentially be tested in combination with reduced dose chemotherapy. 15 If the vaccine provides a dose-sparing effect on the chemotherapeutic agents, the side effect profile could be minimized while increasing efficacy though multiple parasite killing mechanisms.…”

“…23,27 In particular, production of IFNg is critical for control of T. cruzi infection, unlike IL-4, a T H 2-associated cytokine. 23,[28][29][30] Nanoparticles have been shown to increase antigen uptake by antigen-presenting cells 31 and enhance the T H 1-mediated CD8 C T cell response [32][33][34] through increased MHC I antigen presentation. 35 Nanoparticles can also serve as a depot for antigen, 36 allowing prolonged stimulation of the T H 1 pathway.…”

Inhibitory Receptor Expression on CD8+ T Cells Is Linked to Functional Responses against Trypanosoma cruzi Antigens in Chronic Chagasic Patients

“…Altering these progressive changes in CD8 + T cell function could improve the prognosis of chronic chagasic myocarditis. Indeed, the results of studies using mouse models have suggested that the application of genetic vaccination with recombinant adenoviruses can reprogram this deleterious immune response and attenuate chronic chagasic myocarditis (98).…”

Coadministration of cruzipain and GM-CSF DNAs, a new immunotherapeutic vaccine againstTrypanosoma cruziinfection

“…3 and 6). Recently, Pereira et al 44 have highlighted the importance of reprogramming the immune response to preserve and recover tissue injury in Chagas heart disease induced by parasite infection.…”