title: Efficacy of a trans-sialidase-ISCOMATRIX subunit vaccine candidate to protect against experimental Chagas disease.
abstract: Recombinant protein vaccines are safe but elicit low immunological responses. The new generation of adjuvants is currently reversing this situation. Here, a new antigen-adjuvant combination for protection against experimental Chagas disease was assessed. The antigen used in the formulation was a glycosylated mutant inactive trans-sialidase (mTS) that was previously proven to be highly protective against Trypanosoma cruzi infection; here, we show that it can be produced in large quantities and high quality using Pichia pastoris. The adjuvant used in the formulation was ISCOMATRIX (IMX), which was found to be effective and safe in human clinical trials of vaccines designed to control other intracellular infections. Fifteen days after the third immunization, mice immunized with mTS-IMX showed a TS-specific IgG response with titers >10(6) and high avidity, an increased IgG2a/IgG1 ratio, significant delayed-type hypersensitivity (DTH) reactivity, a balanced production of IFN-γ and IL-10 by splenocytes and a strong IFN-γ secretion by CD8(+) T lymphocytes. When these mice where challenged with 1000 trypomastigotes of T. cruzi, all mTS-IMX immunized mice survived, whereas mice immunized with mTS alone, IMX or PBS exhibited high mortality. Remarkably, during acute infection, when the parasitemia is highest in this infection model (day 21), mTS-IMX immunized mice had ∼50 times less parasitemia than non-immunized mice. At this moment and also in the chronic phase, 100 days after infection, tissue presented ∼4.5 times lower parasite load and associated inflammatory infiltrate and lesions. These results indicate that protection against Chagas disease can be achieved by a protein antigen-adjuvant mTS formulation that is compatible with human medicine. Therefore, the current formulation is a highly promising T. cruzi vaccine candidate to be tested in clinical trials.
authors.affiliation: Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Argentina.
authors.forename: Iván Alejandro
authors.initials: IA
authors.lastname: Bontempi
authors.affiliation: Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Argentina.
authors.forename: Miguel Hernán
authors.initials: MH
authors.lastname: Vicco
authors.affiliation: Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Argentina.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Cabrera
authors.affiliation: IDICER-CONICET and Instituto de Inmunología, Facultad de Ciencias Médicas, Universidad Nacional de Rosario, Argentina.
authors.forename: Silvina Raquel
authors.initials: SR
authors.lastname: Villar
authors.affiliation: IDICER-CONICET and Instituto de Inmunología, Facultad de Ciencias Médicas, Universidad Nacional de Rosario, Argentina.
authors.forename: Florencia Belén
authors.initials: FB
authors.lastname: González
authors.affiliation: IDICER-CONICET and Instituto de Inmunología, Facultad de Ciencias Médicas, Universidad Nacional de Rosario, Argentina.
authors.forename: Eduardo Angel
authors.initials: EA
authors.lastname: Roggero
authors.affiliation: Medical Biotechnology Unit, Inflammation Research Center, VIB, Ghent, Belgium; Department of Biochemistry and Microbiology, Ghent University, Belgium.
authors.forename: Paul
authors.initials: P
authors.lastname: Ameloot
authors.affiliation: Medical Biotechnology Unit, Inflammation Research Center, VIB, Ghent, Belgium; Department of Biochemistry and Microbiology, Ghent University, Belgium.
authors.forename: Nico
authors.initials: N
authors.lastname: Callewaert
authors.affiliation: IDICER-CONICET and Instituto de Inmunología, Facultad de Ciencias Médicas, Universidad Nacional de Rosario, Argentina.
authors.forename: Ana Rosa
authors.initials: AR
authors.lastname: Pérez
authors.affiliation: Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Argentina. Electronic address: imarcipr@gmail.com.
authors.forename: Iván Sergio
authors.initials: IS
authors.lastname: Marcipar
mesh_terms: D000276:Adjuvants, Immunologic; D000818:Animals; D000913:Antibodies, Protozoan / Q000276:immunology; D000915:Antibody Affinity / Q000276:immunology; D000953:Antigens, Protozoan / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D014355:Chagas Disease / Q000276:immunology* / Q000517:prevention & control; D002784:Cholesterol / Q000276:immunology*; D004338:Drug Combinations; D005260:Female; D006023:Glycoproteins / Q000276:immunology*; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009439:Neuraminidase / Q000276:immunology*; D010743:Phospholipids / Q000276:immunology*; D016052:Protozoan Vaccines / Q000276:immunology; D012503:Saponins / Q000276:immunology*; D014349:Trypanosoma cruzi / Q000276:immunology*; D014611:Vaccination; D022223:Vaccines, Subunit / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D004338:Drug Combinations; D006023:Glycoproteins; C493786:ISCOMATRIX; D007074:Immunoglobulin G; D010743:Phospholipids; D016052:Protozoan Vaccines; D012503:Saponins; D022223:Vaccines, Subunit; D007371:Interferon-gamma; D002784:Cholesterol; C069715:trans-sialidase; D009439:Neuraminidase
keywords: ISCOM; Trans-sialidase; Trypanosoma cruzi; Vaccine