Evaluación preclínica de antígenos candidatos a vacuna frente a la leishmaniasis visceral humana

Resumen

Leishmaniasis is a vector borne neglected tropical disease transmitted by females of genus Phlebotomus and Lutzomya. With an annual incidence of 1.5 million cases, the most severe clinical form, visceral leishmaniasis (VL) is producing between 20,000 and 40,000 deaths per year. There is no vaccine against human visceral leishmaniasis, although it is considered that it would be the best cost-effectiveness measure for disease control. In order to find an effective vaccine against human VL, in this thesis work, we have studied the suitability of 4 Leishmania antigens as vaccine candidates: LACK, KMP-11, and the two chimeric proteins Leish-F3 and Leish-F3+). We have evaluated the presence of T-cell epitopes in these proteins and the type of immune response that they were able to induce in PBMCs of individuals with immunological memory against L. infantum. In addition, the efficacy of 11 different vaccine formulations against L. infantum infection has been evaluated in the hamster model. Two of them were DNA vaccines with the LACK antigen as an immunogen. The remaining nine formulations, were multiprotein vaccines, in which the Leishmania antigens KMP-11 and Leish-F3 or KMP-11 and Leish-F3+ were combined with the vector salivary protein LJL-143. The antigens were combined or not with the adjuvant GLA-SE, and included or not in virosomes as antigen delivery system. We found that the Leishmania antigens had T-cell epitopes, and that they induced the specific secretion of cytokines characteristic of the Th1 type response involved in disease control as shown by numerous works. Regarding to efficacy trials carry out in hamster model, the two DNA vaccines were found to be protective against L. infantum infection. In the case of multiprotein vaccines, the inclusion of the virosomes and the adjuvant in the final formulation made the combination of the KMP-11 (5μg), Leish-F3+ (5μg) and LJL-143 (1μg) antigens was significantly effective against infection. In summary, the two DNA-LACK vaccines evaluated generated protection in the hamster model, suggesting that they are exceptional vaccine candidates to study in clinical trials; as well as the multiprotein vaccine composed of KMP-11 (5 μg), Leish-F3 + (5 μg) and LJL- 143 (1 μg) formulated in virosomes in combination with GLA-SE. These results about efficacy of multiprotein vaccines have been taken into account to begin clinical phase studies in humans in the framework of the FP7European project “Mulevaclin”.