DNA-launched RNA replicon as a novel vaccine platform against Trypanosoma cruzi infection

DELFINO MARIA ALICIA; TRINITARIO, SEBASTIÁN NICOLÁS; DZVONIK POLINA; CARDOSO LADANBURU ALEJANDRO; CERNY, NATACHA; MALCHIODI, EMILIO LUIS; TARLETON RICK L; BIVONA, AUGUSTO E.; SANCHEZ ALBERTI ANDRES

Breckenridge, CO

Simposio; Progress in Vaccine Development for Infectious Diseases; 2022

Keystone simposia

Chagas disease is a potentially life-threatening illness caused by the protozoan intracellular parasite Trypanosoma cruzi. About 6 million people worldwide are estimated to be infected. Currently there is no vaccine and treatment is limited to the acute phase.Nucleic acid-based vaccines are strong type I response inducers, effective to control intracellular pathogens infection. Here, we developed a DNA-launched RNA replicon encoding Traspain, a chimeric T.cruzi antigen (DREP-Tp) and assessed its immunogenicity in a murine model.Semliki Forest virus based DREP was constructed employing a quality by design approach, applying DNA assembly tools. Its identity was confirmed by sequencing and restriction analysis. Antigen expression was detected by Western blot in transfected cells. To evaluate its immunogenicity, groups of C3H female mice were vaccinated by the intramuscular route with 3 doses of either 10 ug, 100 ug or 250 ug of naked DREP-Tp. Placebo group received PBS and a reference group was immunized with 3 doses of 10 ug of recombinant Traspain combined with 50 ug of cyclic-di-AMP adjuvant (Tp-CDA).Higher specific antibody titers were detected in Tp-CDA vs DREP-Tp groups (IgG titers: 64834 vs <400). The latter, conversely, showed an increased expansion of epitope-specific CD8+ T cells at endpoint (%CD8+CD44highTEWETGQI+ 1.16 vs 2.37, Tp-CDA and DREP-Tp 250ug respectively). Memory phenotype of this subset at early time-point showed a predominance of effector vs central and effector memory T cells in DREP-Tp groups compared to Tp-CDA. CD4+ IL-17+ T cells were detected in lymph nodes from all vaccinated mice [(0.96*; 0.97*; 0.86*; 0.69 vs 0.28%, DREP-Tp 10ug, 100ug, 250ug and Tp-CDA respectively vs placebo (*p<0.05)]. Increased proliferation of spleen cells was observed in higher doses of DREP-Tp groups vs placebo (PI: 6.5-11.6-14.3 vs 6).Future experiments will be focused on the evaluation of DREP-Tp efficacy as an anti-T.cruzi vaccine in the murine model. In conclusion, this work highlights the utility of the SFV-DREP platform as a tool to assess immunogenicity of novel T. cruzi antigens.