title: A Two-Component DNA-Prime/Protein-Boost Vaccination Strategy for Eliciting Long-Term, Protective T Cell Immunity against Trypanosoma cruzi.
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.
authors.affiliation: Department of Microbiology and Immunology, School of Medicine, University of Texas Medical Branch (UTMB), Galveston, Texas, United States of America.
authors.forename: Shivali
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Department of Microbiology and Immunology, School of Medicine, University of Texas Medical Branch (UTMB), Galveston, Texas, United States of America; Department of Pathology, School of Medicine, University of Texas Medical Branch (UTMB), Galveston, Texas, United States of America; Institute for Human Infections and Immunity and the Sealy Center for Vaccine Development, University of Texas Medical Branch (UTMB), Galveston, Texas, United States of America.
authors.forename: Nisha J
authors.initials: NJ
authors.lastname: Garg
mesh_terms: D000818:Animals; D014355:Chagas Disease / Q000276:immunology* / Q000473:pathology; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D016054:DNA, Protozoan / Q000235:genetics* / Q000276:immunology; D007117:Immunization, Secondary / Q000379:methods*; D008213:Lymphocyte Activation / Q000276:immunology; D008810:Mice, Inbred C57BL; D010957:Plasmids / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D014349:Trypanosoma cruzi / Q000276:immunology*; D014611:Vaccination / Q000379:methods; D019444:Vaccines, DNA / Q000276:immunology
chemical_list: D016207:Cytokines; D016054:DNA, Protozoan; D019444:Vaccines, DNA