Leish-111f, a Recombinant Polyprotein Vaccine That Protects against Visceral Leishmaniasis by Elicitation of CD4+T Cells

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Abstract
TheLeishmania-derived recombinant polyprotein Leish-111f or its three component proteins, thiol-specific antioxidant (TSA),Leishmania majorstress-inducible protein 1 (LmSTI1), andLeishmaniaelongation initiation factor (LeIF), have previously been demonstrated to be efficacious against cutaneous or mucosal leishmaniasis in mice, nonhuman primates, and humans. In this study we demonstrate that Leish-111f is also a vaccine antigen candidate against visceral leishmaniasis (VL) caused byLeishmania infantum. We evaluated the immune response and protection induced by Leish-111f formulated with monophosphoryl lipid A in a stable emulsion (Leish-111f+MPL-SE) and demonstrated that mice developed strong humoral and T-cell responses to the vaccine antigen. Analysis of the cellular immune responses of immunized, uninfected mice demonstrated that the vaccine induced a significant increase in CD4+T cells producing gamma interferon, interleukin 2, and tumor necrosis factor cytokines, indicating a Th1-type immune response. Experimental infection of immunized mice and hamsters demonstrated that Leish-111f+MPL-SE induced significant protection againstL. infantuminfection, with reductions in parasite loads of 99.6%, a level of protection greater than that reported for other vaccine candidates in animal models of VL. Taken together, our results suggest that this vaccine represents a good candidate for use against severalLeishmaniaspecies. The Leish-111f+MPL-SE product we report here is the first defined vaccine for leishmaniasis in human clinical trials and has completed phase 1 and 2 safety and immunogenicity testing in normal, healthy human subjects.

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