Protective efficacy of conserved Leishmania hypothetical proteins against visceral leishmaniasis
Led by Prof Myron Christodoulides (University of Southampton, UK), with Assoc Prof Eduardo Coelho (Federal Unversity of Minas Gerais, Brazil)
The parasite Leishmania infantum causes the disease Visceral Leishmaniasis (VL) with ~700,000 – 1 million new cases and 50,000 deaths reported annually. The parasite is transmitted by a sandfly vector and the highest rates of leishmaniasis are reported in Brazil, India and from other low-middle-income countries on the Indian/African continents. In Brazil, VL disproportionately affects the poorest in society, especially those who live in remote areas with low incomes and poor access to health programs. Dogs act as a parasite reservoir in Brazil for transmission to humans and thus, VL is of veterinary importance also, as the dog population in Brazil alone numbers ~20-30 million.
There are NO vaccines for human VL and this project is collaboration between Brazilian and UK research groups with expertise in parasitology, vaccine development and immunology, with the aim to develop a novel experimental VL vaccine. We have already identified four components (proteins) of the parasite that could potentially go into a vaccine, and for this application we propose to discover the important parts of these proteins (the ‘epitopes’) that can stimulate human blood cells in the laboratory to produce the specific type of response that is needed for protection against infection. We will then combine these ‘epitopes’ to produce a chimera vaccine, which we will then produce in the laboratory by genetic engineering. We will also produce large amounts of this chimera vaccine for studies aimed at defining its structure. Importantly, we will test the chimera vaccine to see if it protects mice from L. infantum infection.
Finally, the desired measures of success for our project of i) chimera vaccine development and ii) demonstrable protection in laboratory animals against parasite infection, could then be used as a springboard for eventual phase I testing in humans and dogs living in areas with endemic disease.
The team had already identified four components (proteins) of the parasite that could potentially go into a vaccine, and for this application they went further and discovered the important parts of these proteins (the ‘epitopes’) that could stimulate human blood cells in the laboratory to produce the specific type of response that is needed for protection against infection. This response is believed to be mediated by human T cells, and thus the team identified the important T cell epitopes from these proteins. The team then combined these ‘T cell epitopes’ to produce a vaccine called ChimeraT, which they then synthesised in the laboratory by genetic engineering. They then mixed ChimeraT with a detergent saponin and also incorporated it into artificial membranes called liposomes, to make two vaccines – ChimeraT/Saponin and ChimeraT/Liposome. These vaccines were injected into mice and the team studied the immune response following vaccination and also following infection. The key outcomes of their animal studies was that the vaccines stimulated a specific T cell response that protected the mice from infection with live parasites. Furthermore, ChimeraT/Liposome vaccine was the preferred choice of the two vaccines, as liposomes are non-toxic and safe for human vaccines.
Thus, the project led to the development of ChimeraT/Liposome vaccine, and the outputs from the project will form the basis for further investigations into the potential of this vaccine for preventing leishmaniasis in both human and dogs.
Daniela P Lage et al. Liposomal Formulation of ChimeraT, a Multiple T-Cell Epitope-Containing Recombinant Protein, Is a Candidate Vaccine for Human Visceral Leishmaniasis. Vaccines 2020 8(2), 289
Daniela P Lage et al. A candidate vaccine for human visceral leishmaniasis based on a specific T cell epitope-containing chimeric protein protects mice against Leishmania infantum infection. Npj Vaccines 2020 5, 75
Papers also citing VALIDATE, as the supported post-docs contributed to these studies:
Martins VT et al. Preclinical Assessment of the Immunogenicity of Experimental Leishmania Vaccines. Methods Mol Biol. 2022;2410:481-502. doi: 10.1007/978-1-0716-1884-4_25. PMID: 34914064
Machado AS et al. In Silico Design of Recombinant Chimera T Cell Peptide Epitope Vaccines for Visceral Leishmaniasis. Methods Mol Biol. 2022;2410:463-480. doi: 10.1007/978-1-0716-1884-4_24. PMID: 34914063
Galvani NC et al. Sensitive and specific serodiagnosis of tegumentary leishmaniasis using a new chimeric protein based on specific B-cell epitopes of Leishmania antigenic proteins. Microb Pathog. 2022 Jan;162:105341. doi: 10.1016/j.micpath.2021.105341. Epub 2021 Dec 6. PMID: 34883228
Galvani NC et al. ChimLeish, a new recombinant chimeric protein evaluated as a diagnostic and prognostic marker for visceral leishmaniasis and human immunodeficiency virus coinfection. Parasitol Res. 2021 Dec;120(12):4037-4047. doi: 10.1007/s00436-021-07342-1. Epub 2021 Oct 19. PMID: 34664113 Free PMC article.
Santos TTO et al. Potential of recombinant LiHyQ, a novel Leishmania infantum protein, for the diagnosis of canine visceral leishmaniasis and as a diagnostic and prognostic marker for human leishmaniasis and human immunodeficiency virus co-infection: A preliminary study. Acta Trop. 2021 Dec;224:106126. doi: 10.1016/j.actatropica.2021.106126. Epub 2021 Sep 16. PMID: 34537185