Abstract
Visceral Leishmaniasis (VL), a potentially fatal disease is caused by Leishmania donovani parasites with no vaccine available. Here we produced a dermotropic live attenuated centrin gene deleted Leishmania major (LmCen−/−) vaccine under Good Laboratory Practices and demonstrated that a single intradermal injection confers robust and durable protection against lethal VL transmitted naturally via bites of L. donovani-infected sand flies and prevents mortality. Surprisingly, immunogenicity characteristics of LmCen−/− parasites revealed activation of common immune pathways like L. major wild type parasites. Spleen cells from LmCen−/− immunized and L. donovani challenged hamsters produced significantly higher Th1-associated cytokines including IFN-γ, TNF-α, and reduced expression of the anti-inflammatory cytokines like IL-10, IL-21, compared to non-immunized challenged animals. PBMCs, isolated from healthy people from non-endemic region, upon LmCen−/− infection also induced more IFN-γ compared to IL-10, consistent with our immunogenicity data in LmCen−/− immunized hamsters. This study demonstrates that the LmCen−/− parasites are safe and efficacious against VL and is a strong candidate vaccine to be tested in a human clinical trial.
Highlights
Visceral Leishmaniasis (VL), a potentially fatal disease is caused by Leishmania donovani parasites with no vaccine available
Hamsters were injected intradermally with either LmCen−/− promastigotes or wild-type L. major (LmWT) and monitored for lesion development up to 7 weeks (49 days) post injection and parasite loads were determined at the study end point by using serial dilution method
Hamsters injected with L. major wildtype (LmWT) parasites, developed ear lesions within 15 days of parasite injection that progressively increased in size (Fig. 1a, b)
Summary
Visceral Leishmaniasis (VL), a potentially fatal disease is caused by Leishmania donovani parasites with no vaccine available. We produced a dermotropic live attenuated centrin gene deleted Leishmania major (LmCen−/−) vaccine under Good Laboratory Practices and demonstrated that a single intradermal injection confers robust and durable protection against lethal VL transmitted naturally via bites of L. donovani-infected sand flies and prevents mortality. Disease progression is associated with a dominant Th2 type as well as IL10 mediated response[7] This Th1/Th2 dichotomy is clear in cutaneous leishmaniasis, it is not well defined in visceral leishmaniasis[7,8]. Among the several vaccination strategies attempted against leishmaniasis, infection with low dose of live wild-type Leishmania promastigotes (leishmanization), was the only successful immunization strategy for CL in humans[13,14,15].
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