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

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, nonhuman primates, and humans. In this study we demonstrate that Leish-111f is also a vaccine antigen candidate against visceral leishmaniasis (VL) caused by Leishmania 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 against L. infantum infection, 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 several Leishmania species. The Leish111f؉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.

Ubiquitin Conjugation of Open Reading Frame F DNA Vaccine Leads to Enhanced Cell-Mediated Immune Response and Induces Protection against Both Antimony-Susceptible and -Resistant Strains ofLeishmania donovani

“…Current data suggest that protection to Leishmania infection requires the effective activation of several cell populations, including DC, Ag-specific CD4 ϩ and CD8 ϩ T cells, and macrophages (8,51,60). Resistance to leishmaniasis has been associated with a predominant IL-12 and IFN-␥ production from the Ag-specific CD4 ϩ Th lymphocyte population termed as Th1 immune response (61,62).…”

Current diagnosis and treatment of cutaneous and mucocutaneous leishmaniasis

“…Recombinant Leishmania antigen has been identified as a candidate for immunotherapy. Leish111f, formulated in monophosphoryl lipid A with a squalene oil emulsion [112], was used to treat refractory ML with promising results [113]. Immunotherapy associated with antimonials could be an alternative for the treatment of leishmaniasis, including HIV-Leishmania coinfection, PKDL and chronic refractory tegumentary leishmaniasis [114].…”

Safety and skin delayed-type hypersensitivity response in vervet monkeys immunized with Leishmania donovani sonicate antigen delivered with adjuvants

“…Although immunization with AlBCG+Ag and MISA 720 induced comparable and significantly higher DTH and Th1 cytokine responses compared with the MPLA+Ag immunization, the association of BCG with adverse skin reaction may preclude it from future evaluation for possible use in the development of a safe vaccine in humans. Monophosphoryl lipid A has been indicated as an adjuvant with desirable results in vaccination studies against murine leishmaniasis (COLER et al, 2007). In the present study, the failure of the MPLA+Ag immunized group to induce a higher DTH reaction than the Ag alone group may be a factor in the MPLA formulation.…”

“…In the present study, the failure of the MPLA+Ag immunized group to induce a higher DTH reaction than the Ag alone group may be a factor in the MPLA formulation. COLER et al (2007) used the oil based MPL-ES (MPL-A in stable emulsion) while our current study used MPL-A based on aqueous formulation. Furthermore the MPLA used in this study, a natural product, is a heterogeneous mixture, which may affect its effectiveness (COLER et al, 2009).…”