Leish-111f, a Recombinant Polyprotein Vaccine that Protects against Visceral Leishmaniasis by the elicitation of CD4+ T cells

Infectious Disease Research Institute, 1124 Columbia St., Suite 400, Seattle WA 98104, USA

^* To whom correspondence should be addressed. Email: sreed{at}idri.org.

	Abstract

The Leishmania-derived recombinant polyprotein Leish-111f, or its three component proteins, thiol-specific antioxidant (TSA), Leishmania major stress-inducible protein 1 (LmSTI1), and Leishmania elongation initiation factor (LeIF) have previously been demonstrated to be efficacious against cutaneous or mucosal leishmaniasis in mice, non-human primates, and humans. In this study we demonstrate that Leish-111f is also a vaccine antigen candidate against visceral leishmaniasis caused by Leishmania infantum. We evaluated the immune response and protection induced by Leish-111f formulated with MPL®-SE (Leish-111f+MPL-SE vaccine) 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 IFN-, IL-2 and TNF cytokines, indicating a Th1-type immune response. Experimental infection of immunized mice and hamsters demonstrated that Leish-111f + MPL®-SE induced significant protection against L. infantum infection with reductions in parasite loads of 99.6%, a level of protection greater than has been 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 several Leishmania species. 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.