title: 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.
authors.affiliation: Infectious Disease Research Institute , Seattle, WA, USA.
authors.forename: Rhea N
authors.initials: RN
authors.lastname: Coler
authors.affiliation: Infectious Disease Research Institute , Seattle, WA, USA.
authors.forename: Malcolm S
authors.initials: MS
authors.lastname: Duthie
authors.affiliation: Infectious Disease Research Institute , Seattle, WA, USA.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Hofmeyer
authors.affiliation: Infectious Disease Research Institute , Seattle, WA, USA.
authors.forename: Jeffery
authors.initials: J
authors.lastname: Guderian
authors.affiliation: Infectious Disease Research Institute , Seattle, WA, USA.
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Jayashankar
authors.affiliation: Infectious Disease Research Institute , Seattle, WA, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Vergara
authors.affiliation: Infectious Disease Research Institute , Seattle, WA, USA.
authors.forename: Tom
authors.initials: T
authors.lastname: Rolf
authors.affiliation: Infectious Disease Research Institute , Seattle, WA, USA.
authors.forename: Ayesha
authors.initials: A
authors.lastname: Misquith
authors.affiliation: Infectious Disease Research Institute , Seattle, WA, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Laurance
authors.affiliation: Infectious Disease Research Institute , Seattle, WA, USA.
authors.forename: Vanitha S
authors.initials: VS
authors.lastname: Raman
authors.affiliation: Infectious Disease Research Institute , Seattle, WA, USA.
authors.forename: H Remy
authors.initials: HR
authors.lastname: Bailor
authors.affiliation: Infectious Disease Research Institute , Seattle, WA, USA.
authors.forename: Natasha Dubois
authors.initials: ND
authors.lastname: Cauwelaert
authors.affiliation: Infectious Disease Research Institute , Seattle, WA, USA.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Reed
authors.affiliation: Infectious Disease Research Institute , Seattle, WA, USA.
authors.forename: Aarthy
authors.initials: A
authors.lastname: Vallur
authors.affiliation: Infectious Disease Research Institute , Seattle, WA, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Favila
authors.affiliation: Infectious Disease Research Institute , Seattle, WA, USA.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Orr
authors.affiliation: Infectious Disease Research Institute , Seattle, WA, USA.
authors.forename: Jill
authors.initials: J
authors.lastname: Ashman
authors.affiliation: International Center for Diarrhoeal Diseases Research, Centre for Nutrition and Food Security, Parasitology Laboratory , Dhaka, Bangladesh.
authors.forename: Prakash
authors.initials: P
authors.lastname: Ghosh
authors.affiliation: International Center for Diarrhoeal Diseases Research, Centre for Nutrition and Food Security, Parasitology Laboratory , Dhaka, Bangladesh.
authors.forename: Dinesh
authors.initials: D
authors.lastname: Mondal
authors.affiliation: Infectious Disease Research Institute , Seattle, WA, USA.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Reed