title: Evaluation of recombinant Leishmania polyprotein plus glucopyranosyl lipid A stable emulsion vaccines against sand fly-transmitted Leishmania major in C57BL/6 mice.
abstract: Numerous experimental Leishmania vaccines have been developed to prevent the visceral and cutaneous forms of Leishmaniasis, which occur after exposure to the bite of an infected sand fly, yet only one is under evaluation in humans. KSAC and L110f, recombinant Leishmania polyproteins delivered in a stable emulsion (SE) with the TLR4 agonists monophosphoryl lipid A or glucopyranosyl lipid A (GLA) have shown protection in animal models. KSAC+GLA-SE protected against cutaneous disease following sand fly transmission of Leishmania major in susceptible BALB/c mice. Similar polyprotein adjuvant combinations are the vaccine candidates most likely to see clinical evaluation. We assessed immunity generated by KSAC or L110f vaccination with GLA-SE following challenge with L. major by needle or infected sand fly bite in resistant C57BL/6 mice. Polyprotein-vaccinated mice had a 60-fold increase in CD4(+)IFN-γ(+) T cell numbers versus control animals at 2 wk post-needle inoculation of L. major, and this correlated with a 100-fold reduction in parasite load. Immunity did not, however, reach levels observed in mice with a healed primary infection. Following challenge by infected sand fly bite, polyprotein-vaccinated animals had comparable parasite loads, greater numbers of neutrophils at the challenge site, and reduced CD4(+)IFN-γ(+)/IL-17(+) ratios versus nonvaccinated controls. In contrast, healed animals had significantly reduced parasite loads and higher CD4(+)IFN-γ(+)/IL-17(+) ratios. These observations demonstrate that vaccine-induced protection against needle challenge does not necessarily translate to protection following challenge by infected sand fly bite.
authors.affiliation: Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. NPeters@niaid.nih.gov
authors.forename: Nathan C
authors.initials: NC
authors.lastname: Peters
authors.forename: Sylvie
authors.initials: S
authors.lastname: Bertholet
authors.forename: Phillip G
authors.initials: PG
authors.lastname: Lawyer
authors.forename: Melanie
authors.initials: M
authors.lastname: Charmoy
authors.forename: Audrey
authors.initials: A
authors.lastname: Romano
authors.forename: Flavia L
authors.initials: FL
authors.lastname: Ribeiro-Gomes
authors.forename: Lisa W
authors.initials: LW
authors.lastname: Stamper
authors.forename: David L
authors.initials: DL
authors.lastname: Sacks
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D004195:Disease Models, Animal; D004655:Emulsions; D007371:Interferon-gamma / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology; D018320:Leishmania major / Q000235:genetics / Q000276:immunology*; D054332:Leishmaniasis Vaccines / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D016773:Leishmaniasis, Cutaneous / Q000235:genetics / Q000276:immunology / Q000517:prevention & control* / Q000635:transmission; D008050:Lipid A / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D015800:Protozoan Proteins / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D011576:Psychodidae; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology / Q000494:pharmacology
chemical_list: D000276:Adjuvants, Immunologic; D004655:Emulsions; D020381:Interleukin-17; D054332:Leishmaniasis Vaccines; D008050:Lipid A; D015800:Protozoan Proteins; D011994:Recombinant Proteins; D007371:Interferon-gamma; C048436:monophosphoryl lipid A