| Autor: |
Coler RN; Infectious Disease Research Institute , Seattle, WA, USA., Duthie MS; Infectious Disease Research Institute , Seattle, WA, USA., Hofmeyer KA; Infectious Disease Research Institute , Seattle, WA, USA., Guderian J; Infectious Disease Research Institute , Seattle, WA, USA., Jayashankar L; Infectious Disease Research Institute , Seattle, WA, USA., Vergara J; Infectious Disease Research Institute , Seattle, WA, USA., Rolf T; Infectious Disease Research Institute , Seattle, WA, USA., Misquith A; Infectious Disease Research Institute , Seattle, WA, USA., Laurance JD; Infectious Disease Research Institute , Seattle, WA, USA., Raman VS; Infectious Disease Research Institute , Seattle, WA, USA., Bailor HR; Infectious Disease Research Institute , Seattle, WA, USA., Cauwelaert ND; Infectious Disease Research Institute , Seattle, WA, USA., Reed SJ; Infectious Disease Research Institute , Seattle, WA, USA., Vallur A; Infectious Disease Research Institute , Seattle, WA, USA., Favila M; Infectious Disease Research Institute , Seattle, WA, USA., Orr MT; Infectious Disease Research Institute , Seattle, WA, USA., Ashman J; Infectious Disease Research Institute , Seattle, WA, USA., Ghosh P; International Center for Diarrhoeal Diseases Research, Centre for Nutrition and Food Security, Parasitology Laboratory , Dhaka, Bangladesh., Mondal D; International Center for Diarrhoeal Diseases Research, Centre for Nutrition and Food Security, Parasitology Laboratory , Dhaka, Bangladesh., Reed SG; Infectious Disease Research Institute , Seattle, WA, USA. |
| Abstrakt: |
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. |
Plný text