Abstract
Visceral leishmaniasis is a neglected tropical disease affecting 12 million people annually. Even in the second decade of the 21st century, it has remained without an effective vaccine for human use. In the current study, we designed three multiepitope vaccine candidates by the selection of multiple IFN-γ inducing MHC-I and MHC-II binder T-cell specific epitopes from three previously identified antigen genes of Leishmania donovani from our lab by an immuno-informatic approach using IFNepitope, the Immune Epitope Database (IEDB) T cell epitope identification tools, NET-MHC-1, and NET MHC-2 webservers. We tested the protective potential of these three multiepitope proteins as a vaccine in a hamster model of visceral leishmaniasis. The immunization data revealed that the vaccine candidates induced a very high level of Th1 biased protective immune response in-vivo in a hamster model of experimental visceral leishmaniasis, with one of the candidates inducing a near-sterile immunity. The vaccinated animals displayed highly activated monocyte macrophages with the capability of clearing intracellular parasites due to increased respiratory burst. Additionally, these proteins induced activation of polyfunctional T cells secreting INF-γ, TNF-α, and IL-2 in an ex-vivo stimulation of human peripheral blood mononuclear cells, further supporting the protective nature of the designed candidates.
Highlights
We identified T cell epitopes using three different web servers, Immune Epitope Database (IEDB) T cell epitope identification tools for major histocompatibility complex (MHC)-I and MHC-II, NET MHC1 [50,51], NET MHC-2
The second construct of 36 kDa mass was based on MHC-I (CTL) specific to the IFN-γ inducing epitope as predicted by the IFNepitope and Propred1 results
visceral leishmaniasis (VL) has remained without a protective vaccine probably due to the lack of a candidate that could generate a predominant Th1 polarized response while keeping the immunosuppressive responses to a minimum
Summary
Has remained without any vaccine formulation approved for human use. The development of a vaccine for kala-azar has manifested itself into an immunological challenge of its own [1]. VL is a systemic infection of the reticuloendothelial system with macrophages being the primary host, if left untreated, the condition becomes perilous. The immunology of the disease is centered around the Th1 cytokine axis [4]. In the natural course of infection, there is a polyclonal hypergammaglobulinemia with non-specific antibody response along with the elevated levels of immunosuppressive cytokines like IL-10 and TGF-β, whereas recovering patients develop elevated levels of IFN-γ and TNF-α [5,6]. Acute infection in recovered patients results in lifelong immunity, which indicates that an effective vaccine is possible [7]
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