Vaccine development for vector-borne pathogens may be accelerated through the use of relevant challenge models, as has been the case for
malaria. Because of the demonstrated
biological importance of vector-derived molecules in establishing natural
infections, incorporating natural challenge models into
vaccine development strategies may increase the accuracy of predicting efficacy under field conditions. Until recently, however, there was no natural challenge model available for the evaluation of
vaccine candidates against
visceral leishmaniasis. We previously demonstrated that a candidate
vaccine against
visceral leishmaniasis containing the
antigen LEISH-F3 could provide protection in preclinical models and induce potent T-cell responses in human volunteers. In the present study, we describe a next generation candidate, LEISH-F3+, generated by adding a third
antigen to the LEISH-F3 di-fusion
protein. The rationale for adding a third component, derived from
cysteine protease (CPB), was based on previously demonstrated protection achieved with this
antigen, as well as on recognition by human T cells from individuals with
latent infection. Prophylactic immunization with LEISH-F3+formulated with
glucopyranosyl lipid A adjuvant in stable
emulsion significantly reduced both Leishmania infantum and L. donovani burdens in needle challenge mouse models of
infection. Importantly, the data obtained in these
infection models were validated by the ability of LEISH-F3+/
glucopyranosyl lipid A adjuvant in stable
emulsion to induce significant protection in hamsters, a model of both
infection and disease, following challenge by L. donovani-infected Lutzomyia longipalpis sand flies, a natural vector. This is an important demonstration of
vaccine protection against
visceral leishmaniasis using a natural challenge model.