DNA vaccine for prevention and treatment of Trypanosoma cruzi infection.

CAZORLA SI, MATOS MN, RAMIREZ CV, CERNY N, FRANK FM, MALCHIODI EL.

Facultad de Farmacia y Bioquímica

Simposio; Advances in Biomedical Sciences. An International Symposium of the International Master in Biomedical Sciences.; 2008

Facultad de Farmacia y Bioquímica

Chemotherapy of Chagas’ disease has limited efficacy and is not innocuous, added to the fact that neither reliable nor safe vaccine for prevention or treatment of the disease is so far available. Moreover, immune therapeutic or prophylactic interventions directed to control T. Cruzi infection and parasitemia would prevent or arrest the development of Chagas’ disease. Our main goal is the development of vaccine prototypes able to augment the anti-T. Cruzi immune response without exacerbating tissue inflamation. We performed different treatments given prophylactically before infection or therapeutically after infection. For this purpose we cloned in prokariotic and eukariotic vectors, different proteins that were crucial for T.cruzi life-cycle. Some of them were: Cruzipain (a major lysosomal cysteine proteinase), Tc52 (a glutathione S-trasnferases), Tc24 (trypomastigote excretory-secretory) and Complement regulartory protein (CRP). We show results in which we explored the ability of cruzipain(Cz)-DNA immunization as a prophylaxis or therapy strategies. In our novel approach of immunoprofylaxis vaccine, orally administered Salmonella was used as a Cz-DNA delivery system (SCz) to ensure strong activation of innate immunity and efficient stimulation of both local and systemic anti-T. cruzi responses. Attempts were also carried out to further improve the efficacy of this vaccine: 1-coadministation with bacteria containing a granulocyte-macrophage colony-stimulating factor encoding plasmid (SGM-CSF); 2- prime-boost protocols in which mice primed with SCz were subsequently boosted with recombinant Cz (rCz) coadministered with different adjuvants. The complexity of the parasite life cycle, the expression of developmentally regulated proteins in different morphological stages, and the multifaceted manifestations of Chagas’ disease caused by different T. cruzi strains render critical the identification of multiple antigenic targets. The proposed studies are expected to provide the basis for the design of multicomponent vaccine, including natural, recombinant or/and DNA-based anti-T.cruzi vaccine, which may ultimately be used not only to protect humans at risk of infection, but also may alleviate or prevent the pathogenic responses characteristic of chronic Chagas’ disease by reducing or perhaps eliminating tissue parasites from infected patients.