Abstract
In this study, we evaluated the long-term efficacy of a two-component subunit vaccine against Trypanosoma cruzi infection. C57BL/6 mice were immunized with TcG2/TcG4 vaccine delivered by a DNA-prime/Protein-boost (D/P) approach and challenged with T. cruzi at 120 or 180 days post-vaccination (dpv). We examined whether vaccine-primed T cell immunity was capable of rapid expansion and intercepting the infecting T. cruzi. Our data showed that D/P vaccine elicited CD4+ (30-38%) and CD8+ (22-42%) T cells maintained an effector phenotype up to 180 dpv, and were capable of responding to antigenic stimulus or challenge infection by a rapid expansion (CD8>CD4) with type 1 cytokine (IFNγ+ and TFNα+) production and cytolytic T lymphocyte (CTL) activity. Subsequently, challenge infection at 120 or 180 dpv, resulted in 2-3-fold lower parasite burden in vaccinated mice than was noted in unvaccinated/infected mice. Co-delivery of IL-12- and GMCSF-encoding expression plasmids provided no significant benefits in enhancing the anti-parasite efficacy of the vaccine-induced T cell immunity. Booster immunization (bi) with recombinant TcG2/TcG4 proteins 3-months after primary vaccine enhanced the protective efficacy, evidenced by an enhanced expansion (1.2-2.8-fold increase) of parasite-specific, type 1 CD4+ and CD8+ T cells and a potent CTL response capable of providing significantly improved (3-4.5-fold) control of infecting T. cruzi. Further, CD8+T cells in vaccinated/bi mice were predominantly of central memory phenotype, and capable of responding to challenge infection 4-6-months post bi by a rapid expansion to a poly-functional effector phenotype, and providing a 1.5-2.3-fold reduction in tissue parasite replication. We conclude that the TcG2/TcG4 D/P vaccine provided long-term anti-T. cruzi T cell immunity, and bi would be an effective strategy to maintain or enhance the vaccine-induced protective immunity against T. cruzi infection and Chagas disease.
Highlights
Chagas disease is prevalent in almost all Latin American countries, including Mexico and Central America [1]
Based upon several studies we have conducted, we believe that TcG2 and TcG4 candidate antigens that are highly conserved in T. cruzi, expressed in clinically relevant forms of the parasite, and recognized by both B and T cell responses in multiple hosts, are an excellent choice for subunit vaccine development
We demonstrate that the delivery of TcG2 and TcG4 as a DNA-prime/protein-boost vaccine provided long-term protection from challenge infection, and this protection was associated with elicitation of long-lived CD8+ effector T cells
Summary
Chagas disease is prevalent in almost all Latin American countries, including Mexico and Central America [1]. Several studies, including our published reports (reviewed in [7]), testing the efficacy of subunit vaccines have resulted in findings that vaccine-induced immunity can provide a reduction in tissue parasite burden associated with variable degrees of control of acute or chronic disease symptoms. The vaccine mediated control of infection and disease in experimental studies generally resembled that noted in 60–70% of the chagasic patients that remained seropositive and maintained residual parasites for their entire lives, but did not develop a clinically symptomatic form of the disease [2]. It is ethically appropriate to consider a satisfactory vaccination goal to reduce the frequency and severity of clinical disease by decreasing the extent of persistent parasite burden; and continuing efforts towards developing a vaccine against T. cruzi infection and Chagas disease are economically justifiable
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