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

Abstract 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 le...

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Autores principales:	Pedro Cecílio, James Oristian, Claudio Meneses, Tiago D. Serafim, Jesus G. Valenzuela, Anabela Cordeiro da Silva, Fabiano Oliveira
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ebd49ccaad9d4970afc0c598e51f5cf8
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spelling	oai:doaj.org-article:ebd49ccaad9d4970afc0c598e51f5cf82021-12-02T15:09:56ZEngineering a vector-based pan-Leishmania vaccine for humans: proof of principle10.1038/s41598-020-75410-02045-2322https://doaj.org/article/ebd49ccaad9d4970afc0c598e51f5cf82020-10-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-75410-0https://doaj.org/toc/2045-2322Abstract 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.Pedro CecílioJames OristianClaudio MenesesTiago D. SerafimJesus G. ValenzuelaAnabela Cordeiro da SilvaFabiano OliveiraNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-20 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Pedro Cecílio James Oristian Claudio Meneses Tiago D. Serafim Jesus G. Valenzuela Anabela Cordeiro da Silva Fabiano Oliveira Engineering a vector-based pan-Leishmania vaccine for humans: proof of principle
description	Abstract 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.
format	article
author	Pedro Cecílio James Oristian Claudio Meneses Tiago D. Serafim Jesus G. Valenzuela Anabela Cordeiro da Silva Fabiano Oliveira
author_facet	Pedro Cecílio James Oristian Claudio Meneses Tiago D. Serafim Jesus G. Valenzuela Anabela Cordeiro da Silva Fabiano Oliveira
author_sort	Pedro Cecílio
title	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_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_sort	engineering a vector-based pan-leishmania vaccine for humans: proof of principle
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/ebd49ccaad9d4970afc0c598e51f5cf8
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Engineering a vector-based pan-Leishmania vaccine for humans: proof of principle

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