Short-term protection conferred by Leishvacin® against experimental Leishmania amazonensis infection in C57BL/6 mice

Abstract

To date, there is no vaccine available against human leishmaniasis. Although some vaccination protocols can induce immunity in murine models, they fail to induce protection in humans. The reasons for that remain unclear. The aim of the present study was to characterize the changes in the pattern of the immune response during subcutaneous vaccination with Leishvacin® in mice. We also investigated whether IFN-γ and nitric oxide synthase are indispensable for the protection elicited by the vaccine. C57BL/6 WT vaccinated mice showed smaller lesions and fewer numbers of parasites in footpads until 8 weeks post-infection. Up to this time, they produced higher levels of IFN-γ, IL-2, IL-4, IL-17A and IL-10 and higher specific antibody response than control non-vaccinated mice. Moreover, we showed that IFN-γ, most likely by induction of iNOS expression, is essential for immunity. However, after 12 weeks of infection, we observed loss of difference in lesion size and parasite burden between the groups. Loss of resistance was associated with the disappearance of differences in cytokine patterns between vaccinated and control mice, but not of antibody response, which remained different until a later time of infection. The reversal of resistance to L. amazonensis could not be explained by upregulation of regulatory cytokines. Our data point to a subversion of the host immune response by L. amazonensis even when a protective response was previously induced.

The role of TLR9 on Leishmania amazonensis infection and its influence on intranasal LaAg vaccine efficacy

“…We demonstrated the partial involvement of TLR9 in LaAg vaccine in the lesion control and parasite load (Figs 10 and 11). Although some studies investigate the profile of the immune response during vaccination against leishmaniasis, this is mainly focused on IFN-γ and iNOS [49], and few studies investigate the participation of receptors, specially TLR9, in vaccination mechanisms against leishmaniasis. From what we know at present, this is the first report that associates the importance of TLR9 receptor in LaAg vaccine efficacy against leishmaniasis.…”

Th1-Th2 Cross-Regulation Controls Early Leishmania Infection in the Skin by Modulating the Size of the Permissive Monocytic Host Cell Reservoir

“…We have previously argued the importance of the early response to Leishmania in subsequent infection outcome and vaccine efficacy (Hohman and Peters, 2019). The dual role played by IFNg may explain why vaccination strategies that induce highly polarized Th1-IFN-g-mediated immunity against phagosomal pathogens do not necessarily induce protection, potentially due to enhanced and counter-productive recruitment of permissive monocytic host cells and/or IL-10 production (Carneiro et al, 2014;Darrah et al, 2019;Peters et al, 2012).…”

Cutaneous Leishmaniasis Vaccination: A Matter of Quality

“…One previous study designed to evaluate the quality of the Th1 response induced by L. amazonensis and L. braziliensis promastigotes extracts in PBMC from healed CL patients demonstrated that L. amazonensis response is associated with a low contribution of multifunctional T cells and a high number of IFN-γ single-positive effector cells, while L. braziliensis induces a Th1 response with high proportion of multifunctional T cells and low proportion of IFN-γ single-positive cells ( 39 ). As IFN-γ single-positive CD4+ T cells are short-lived, this can offer a possible explanation for the contrasting results observed in prophylaxis and immunotherapy studies with L. amazonensis whole-cell extract vaccine (Leishvacin ® ) ( 40 , 56 – 58 ). The substantial amount of IFN-γ single-positive effector CD4+ T cells induced by this antigen may not be sufficient to induce long-term and good-quality protection against infection, but could be effective when a rapid and transient Th1 response is needed, as in the case of immunotherapeutic interventions.…”