A defined subunit vaccine that protects against vector-borne visceral leishmaniasis

Abstract

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.

Integrative genomic, proteomic and phenotypic studies of Leishmania donovani strains revealed genetic features associated with virulence and antimony-resistance

“…However, leishmaniasis remains to be one of the povertyrelated diseases in underprivileged countries and regions [1,2,8]. No vaccines are currently available for clinical use to prevent the infection and reinfection by Leishmania species, although progress has been made in this field [9][10][11]. Chemotherapy is still the first-line option for the treatment and elimination of Leishmania infection and related diseases [12,13].…”

Cytokine Effect of TLR3, TLR4, and TLR7 Agonists Alone or Associated withLeishmania infantumAntigen on Blood from Dogs

“…Recently, several studies have evaluated the use of TLR4a as adjuvant during Leishmania infection. Particularly, a vaccine antigen formulated with the TLR4a Glucopyranosyl lipid adjuvant in stable emulsion (GLA-SE) proved to induce antigen-specific responses that protected mice against Leishmania donovani infection and also demonstrated that prophylactic mouse immunization resulted in a marked reduction of the parasite spleen burden together with induction of memory CD4+ T lymphocytes enhancing IFN- γ , TNF- α , and IL-2 production [ 49 ]. Moreover, an innovative virus-like particles (VLP) vaccine loaded with sand fly saliva antigen plus Leishmania antigens and GLA-SE as adjuvant improved both cellular and humoral immune responses in a murine model and also in human peripheral blood mononuclear cells (PBMCs) [ 50 ].…”

Vaccines for Human Leishmaniasis: Where Do We Stand and What Is Still Missing?

“…However some argue that to use a single antigen, or a peptide as vaccine, may be less than optimal, considering that there will be a limitation in terms of epitope diversity. To answer to this, some propose the use of defined polyantigen vaccines (fusion proteins or mixed recombinants), also rationale based, as a way to generate "first-generation-like" second-generation vaccines, increasing epitope diversity and consequently in theory enhancing recognition by human T cells (Table 1) that is going through the pre-clinical phase of the vaccine development pipeline, with promising results, either alone [99] or in combination with KMP-11 and the vector-derived antigen LJL-143, within a virosomal formulation [96].…”

“…[55,85,86,[96][97][98][99][100][101]. Some of these candidates are among the second-generation vaccines that went further in the vaccine pipeline.…”