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Engineering a vector-based pan-Leishmania vaccine for humans: proof of principle

Leishmaniasis is a spectrum of diseases transmitted by sand fly vectors that deposit Leishmania spp. parasites in the host skin during blood feeding. Currently, available treatment options are limited, associated with high toxicity and emerging resistance. Even though a vaccine for human leishmanias...

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Autores principales: Cecílio, Pedro, Oristian, James, Meneses, Claudio, Serafim, Tiago D., Valenzuela, Jesus G., Cordeiro da Silva, Anabela, Oliveira, Fabiano
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596519/
https://www.ncbi.nlm.nih.gov/pubmed/33122717
http://dx.doi.org/10.1038/s41598-020-75410-0
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author Cecílio, Pedro
Oristian, James
Meneses, Claudio
Serafim, Tiago D.
Valenzuela, Jesus G.
Cordeiro da Silva, Anabela
Oliveira, Fabiano
author_facet Cecílio, Pedro
Oristian, James
Meneses, Claudio
Serafim, Tiago D.
Valenzuela, Jesus G.
Cordeiro da Silva, Anabela
Oliveira, Fabiano
author_sort Cecílio, Pedro
collection PubMed
description Leishmaniasis is a spectrum of diseases transmitted by sand fly vectors that deposit Leishmania spp. parasites in the host skin during blood feeding. Currently, available treatment options are limited, associated with high toxicity and emerging resistance. Even though a vaccine for human leishmaniasis is considered an achievable goal, to date we still do not have one available, a consequence (amongst other factors) of a lack of pre-clinical to clinical translatability. Pre-exposure to uninfected sand fly bites or immunization with defined sand fly salivary proteins was shown to negatively impact infection. Still, cross-protection reports are rare and dependent on the phylogenetic proximity of the sand fly species, meaning that the applicability of a sand fly saliva-based vaccine will be limited to a defined geography, one parasite species and one form of leishmaniasis. As a proof of principle of a future vector saliva-based pan-Leishmania vaccine, we engineered through a reverse vaccinology approach that maximizes translation to humans, a fusion protein consisting of immunogenic portions of PdSP15 and LJL143, sand fly salivary proteins demonstrated as potential vaccine candidates against cutaneous and visceral leishmaniasis, respectively. The in silico analysis was validated ex vivo, through T cell proliferation experiments, proving that the fusion protein (administered as a DNA vaccine) maintained the immunogenicity of both PdSP15 and LJL143. Additionally, while no significant effect was detected in the context of L. major transmission by P. duboscqi, this DNA vaccine was defined as partially protective, in the context of L. major transmission by L. longipalpis sand flies. Importantly, a high IFNγ response alone was not enough to confer protection, that mainly correlated with low T cell mediated Leishmania-specific IL-4 and IL-10 responses, and consequently with high pro/anti-inflammatory cytokine ratios. Overall our immunogenicity data suggests that to design a potentially safe vector-based pan-Leishmania vaccine, without geographic restrictions and against all forms of leishmaniasis is an achievable goal. This is why we propose our approach as a proof-of principle, perhaps not only applicable to the anti-Leishmania vector-based vaccines’ field, but also to other branches of knowledge that require the design of multi-epitope T cell vaccines with a higher potential for translation.
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spelling pubmed-75965192020-10-30 Engineering a vector-based pan-Leishmania vaccine for humans: proof of principle Cecílio, Pedro Oristian, James Meneses, Claudio Serafim, Tiago D. Valenzuela, Jesus G. Cordeiro da Silva, Anabela Oliveira, Fabiano Sci Rep Article Leishmaniasis is a spectrum of diseases transmitted by sand fly vectors that deposit Leishmania spp. parasites in the host skin during blood feeding. Currently, available treatment options are limited, associated with high toxicity and emerging resistance. Even though a vaccine for human leishmaniasis is considered an achievable goal, to date we still do not have one available, a consequence (amongst other factors) of a lack of pre-clinical to clinical translatability. Pre-exposure to uninfected sand fly bites or immunization with defined sand fly salivary proteins was shown to negatively impact infection. Still, cross-protection reports are rare and dependent on the phylogenetic proximity of the sand fly species, meaning that the applicability of a sand fly saliva-based vaccine will be limited to a defined geography, one parasite species and one form of leishmaniasis. As a proof of principle of a future vector saliva-based pan-Leishmania vaccine, we engineered through a reverse vaccinology approach that maximizes translation to humans, a fusion protein consisting of immunogenic portions of PdSP15 and LJL143, sand fly salivary proteins demonstrated as potential vaccine candidates against cutaneous and visceral leishmaniasis, respectively. The in silico analysis was validated ex vivo, through T cell proliferation experiments, proving that the fusion protein (administered as a DNA vaccine) maintained the immunogenicity of both PdSP15 and LJL143. Additionally, while no significant effect was detected in the context of L. major transmission by P. duboscqi, this DNA vaccine was defined as partially protective, in the context of L. major transmission by L. longipalpis sand flies. Importantly, a high IFNγ response alone was not enough to confer protection, that mainly correlated with low T cell mediated Leishmania-specific IL-4 and IL-10 responses, and consequently with high pro/anti-inflammatory cytokine ratios. Overall our immunogenicity data suggests that to design a potentially safe vector-based pan-Leishmania vaccine, without geographic restrictions and against all forms of leishmaniasis is an achievable goal. This is why we propose our approach as a proof-of principle, perhaps not only applicable to the anti-Leishmania vector-based vaccines’ field, but also to other branches of knowledge that require the design of multi-epitope T cell vaccines with a higher potential for translation. Nature Publishing Group UK 2020-10-29 /pmc/articles/PMC7596519/ /pubmed/33122717 http://dx.doi.org/10.1038/s41598-020-75410-0 Text en © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2020 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Cecílio, Pedro
Oristian, James
Meneses, Claudio
Serafim, Tiago D.
Valenzuela, Jesus G.
Cordeiro da Silva, Anabela
Oliveira, Fabiano
Engineering a vector-based pan-Leishmania vaccine for humans: proof of principle
title Engineering a vector-based pan-Leishmania vaccine for humans: proof of principle
title_full Engineering a vector-based pan-Leishmania vaccine for humans: proof of principle
title_fullStr Engineering a vector-based pan-Leishmania vaccine for humans: proof of principle
title_full_unstemmed Engineering a vector-based pan-Leishmania vaccine for humans: proof of principle
title_short Engineering a vector-based pan-Leishmania vaccine for humans: proof of principle
title_sort engineering a vector-based pan-leishmania vaccine for humans: proof of principle
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596519/
https://www.ncbi.nlm.nih.gov/pubmed/33122717
http://dx.doi.org/10.1038/s41598-020-75410-0
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