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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\u00a0phylogenetic 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-<jats:italic>Leishmania<\/jats:italic> 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 <jats:italic>L. major<\/jats:italic> transmission by <jats:italic>P. duboscqi<\/jats:italic>, this DNA vaccine was defined as partially protective, in the context of <jats:italic>L. major<\/jats:italic> transmission by <jats:italic>L. longipalpis<\/jats:italic> sand flies. Importantly, a high IFN\u03b3 response alone was not enough to confer protection, that mainly correlated with low T cell mediated <jats:italic>Leishmania<\/jats:italic>-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-<jats:italic>Leishmania<\/jats:italic> 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-<jats:italic>Leishmania<\/jats:italic> vector-based vaccines\u2019 field, but also to other branches of knowledge that require the design of multi-epitope T cell vaccines with a higher potential for translation.<\/jats:p>","DOI":"10.1038\/s41598-020-75410-0","type":"journal-article","created":{"date-parts":[[2020,10,29]],"date-time":"2020-10-29T11:02:54Z","timestamp":1603969374000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Engineering a vector-based pan-Leishmania vaccine for humans: proof of principle"],"prefix":"10.1038","volume":"10","author":[{"given":"Pedro","family":"Cec\u00edlio","sequence":"first","affiliation":[]},{"given":"James","family":"Oristian","sequence":"additional","affiliation":[]},{"given":"Claudio","family":"Meneses","sequence":"additional","affiliation":[]},{"given":"Tiago D.","family":"Serafim","sequence":"additional","affiliation":[]},{"given":"Jesus G.","family":"Valenzuela","sequence":"additional","affiliation":[]},{"given":"Anabela","family":"Cordeiro da Silva","sequence":"additional","affiliation":[]},{"given":"Fabiano","family":"Oliveira","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2020,10,29]]},"reference":[{"key":"75410_CR1","doi-asserted-by":"publisher","first-page":"e0004349","DOI":"10.1371\/journal.pntd.0004349","volume":"10","author":"M Akhoundi","year":"2016","unstructured":"Akhoundi, M. et al. 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