Sting agonist and antigen design as a vaccine model to combat parasitic chronic infections

SANCHEZ ALBERTI ANDRES; BIVONA AUGUSTO; CERNY NATACHA; CAZORLA SILVIA INÉS; CARDOSO LANDABURU ALEJANDRO; SCHULZE KAI; WEIßMANN STEFAN; GUZMAN CARLOS ; MALCHIODI EMILIO LUIS

Seattle

Simposio; Keystone Symposium. The Modes of Action of Vaccine Adjuvants (S1); 2014

T. cruzi is an obligatory intracellular parasite recognized by WHO as a neglected tropical disease, which affects 12 million people in Latin America. After 100 years of its discovery, there are still no effective vaccines to prevent or treat the infection. In this work we employed rational design of the immunogen based in the three dimensional structure, in order to present a multivalent display of key parasitic cytotoxic T lymphocyte (CTL) and antibody targets as well as to omit known immune evasion associated sequences. In search for novel components to increase the levels of CTL response, we have employed cyclic di nucleotides (CDNs) ? 3?5?-c-di-AMP (a STING agonist) with recombinant (r) Protein or DNA-prime + rProtein-boost ? in vaccination protocols by the intranasal route. With these strategies, we have been able to obtain not only an excellent humoral immune response that blocked in-vitro infection (60% vs. preimmune serum) but also a robust cell mediated immunity. Regarding the rProtein/c-di-AMP protocol, we determined the profile of the immune response by ELISPOT assay resulting in a balance TH1/TH17 profile for immunized groups vs controls. In addition, we observed an expansion of pathogen specific CD8 T lymphocytes comparing with the control group (%TEWETGQI+ CD8+ T cells 2.2 vs. 0.2 p<0.01). This result, highlight the capacity of the c-di-AMP to trigger in-vivo cross presentation. Moreover, we compared the performance of this adjuvant with CpG for boosting the immune response triggered by a mucosal DNA prime with attenuated Salmonella AroA as DNA delivery system. We observed a balanced TH1/TH17 profile for c-di-AMP comparing with CpG TH1 profile [(IFNγ: 1370 vs. 706?. IL-17: 280 vs. 25?. IL-2: 228 vs. 240. IL-4: 32 vs.15) SFU/106 cells for each adjuvant ?p<0,01]. In addition, CDNs boost resulted in enhanced systemic CD8 T response, not only in the percentage of specific cells (1-0.5-0.07) for c-di-AMP, CpG, and control respectively, but also in its functionality. Finally, vaccinated animals show a decrease in parasitemia, lower weight loss and higher survival. In conclusion, STING agonists represent a promising tool for vaccines against T. cruzi.