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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.

Preclinical validation of a live attenuated dermotropic Leishmania vaccine against vector transmitted fatal visceral leishmaniasis