From mouse to man: safety, immunogenicity and efficacy of a candidate leishmaniasis vaccine LEISH‐F3+GLA‐SE

Abstract

Key antigens of Leishmania species identified in the context of host responses in Leishmania-exposed individuals from disease-endemic areas were prioritized for the development of a subunit vaccine against visceral leishmaniasis (VL), the most deadly form of leishmaniasis. Two Leishmania proteins—nucleoside hydrolase and a sterol 24-c-methyltransferase, each of which are protective in animal models of VL when properly adjuvanted— were produced as a single recombinant fusion protein NS (LEISH-F3) for ease of antigen production and broad coverage of a heterogeneous major histocompatibility complex population. When formulated with glucopyranosyl lipid A-stable oil-in-water nanoemulsion (GLA-SE), a Toll-like receptor 4 TH1 (T helper 1) promoting nanoemulsion adjuvant, the LEISH-F3 polyprotein induced potent protection against both L. donovani and L. infantum in mice, measured as significant reductions in liver parasite burdens. A robust immune response to each component of the vaccine with polyfunctional CD4 TH1 cell responses characterized by production of antigen-specific interferon-γ, tumor necrosis factor and interleukin-2 (IL-2), and low levels of IL-5 and IL-10 was induced in immunized mice. We also demonstrate that CD4 T cells, but not CD8 T cells, are sufficient for protection against L. donovani infection in immunized mice. Based on the sum of preclinical data, we prepared GMP materials and performed a phase 1 clinical study with LEISH-F3+GLA-SE in healthy, uninfected adults in the United States. The vaccine candidate was shown to be safe and induced a strong antigen-specific immune response, as evidenced by cytokine and immunoglobulin subclass data. These data provide a strong rationale for additional trials in Leishmania-endemic countries in populations vulnerable to VL.

Vaccination with poly(D,L-lactide-co-glycolide) nanoparticles loaded with soluble <em>Leishmania</em> antigens and modified with a TNF&alpha;-mimicking peptide or monophosphoryl lipid A confers protection against experimental visceral leishmaniasis

“…These vaccines are safer than live vaccines, but they lack strong immunogenicity and thus require the use of an adjuvant. 32 Therefore, microparticulate and nanoparticulate formulations are currently considered as the ideal vaccine delivery systems. Although several antigens have been tested for vaccine development, soluble leishmanial antigens are still part of vaccine development research due to their proven immunogenicity, as already mentioned.…”

Recovery of antigen-specific T cell responses from dogs infected with Leishmania (L.) infantum by use of vaccine associated TLR-agonist adjuvant

“…150 µL of diluted whole blood was plated into 96 well plates. Vaccine antigens L111f [15] and NS [37] were added to wells at a final concentration of 1 µg/mL (Fig. 1).…”

Optimizing Immunization Strategies for the Induction of Antigen-Specific CD4 and CD8 T Cell Responses for Protection against Intracellular Parasites

“…donovani infection (18, 19). Defined subunit vaccines involving recombinant proteins typically generate robust antigen-specific Th1 responses but do not appear to induce CD8 T cells (18, 20, 21). …”