Open AccessFrom mouse to man: safety, immunogenicity and efficacy of a candidate leishmaniasis vaccine LEISH‐F3+GLA‐SE
Author(s) -
Coler Rhea N,
Duthie Malcolm S,
Hofmeyer Kimberly A,
Guderian Jeffery,
Jayashankar Lakshmi,
Vergara Julie,
Rolf Tom,
Misquith Ayesha,
Laurance John D,
Raman Vanitha S,
Bailor H Remy,
Cauwelaert Natasha Dubois,
Reed Steven J,
Vallur Aarthy,
Favila Michelle,
Orr Mark T,
Ashman Jill,
Ghosh Prakash,
Mondal Dinesh,
Reed Steven G
Publication year - 2015
Publication title -
clinical and translational immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.321
H-Index - 34
ISSN - 2050-0068
DOI - 10.1038/cti.2015.6
Subject(s) - visceral leishmaniasis , adjuvant , immune system , antigen , biology , immunogenicity , leishmania , immunology , leishmania donovani , leishmania infantum , virology , leishmaniasis , context (archaeology) , parasite hosting , paleontology , world wide web , computer science
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 T H 1 (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 T H 1 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.