title: Protective efficacy of a tandemly linked, multi-subunit recombinant leishmanial vaccine (Leish-111f) formulated in MPL adjuvant.
abstract: Three immunodominant leishmanial antigens (TSA, LmSTI1 and LeIF) previously identified in the context of host response to infection in infected donors and BALB/c mice, as well as their ability to elicit at least partial protection against Leishmania major infection in the BALB/c mouse model, were selected for inclusion into a subunit based vaccine. This is based on the premise that an effective vaccine against leishmaniasis (a complex parasitic infection) would require a multivalent cocktail of several antigens containing a broader range of protective epitopes that would cover a wide range of MHC types in a heterogeneous population. For practical considerations of vaccine development, we report on the generation of a single recombinant polyprotein comprising the sequences of all three open reading frames genetically linked in tandem. The resulting molecule, Leish-111f, comprises an open reading frame that codes for a 111kDa polypeptide. Evaluation of the immunogenicity and protective efficacy of Leish-111f formulated with IL-12 revealed that the immune responses to the individual components were maintained and as well, rLeish-111f protected BALB/c mice against L. major infection to a magnitude equal or superior to those seen with any of the individual components of the vaccine construct or SLA, a soluble Leishmania lysate. But because rIL-12 is expensive and difficult to manufacture and its efficacy and safety as an adjuvant for human use is questionable, we screened for other adjuvants that could potentially substitute for IL-12. We report that monophosphoryl lipid A (MPL) plus squalene (MPL-SE) formulated with rLeish-111f elicited protective immunity against L. major infection. The demonstrated feasibility to manufacture a single recombinant vaccine comprising multiple protective open reading frames and the potential use of MPL-SE as a substitute for IL-12, takes us closer to the realization of an affordable and safe Leishmania vaccine.
authors.affiliation: Corixa Corporation, 1124 Columbia Street, Suite 200, Seattle, WA 98104, USA. skeiky@corixa.com
authors.forename: Yasir A W
authors.initials: YA
authors.lastname: Skeiky
authors.forename: Rhea N
authors.initials: RN
authors.lastname: Coler
authors.forename: Mark
authors.initials: M
authors.lastname: Brannon
authors.forename: Erika
authors.initials: E
authors.lastname: Stromberg
authors.forename: Kay
authors.initials: K
authors.lastname: Greeson
authors.forename: R Thomas
authors.initials: RT
authors.lastname: Crane
authors.forename: John R
authors.initials: JR
authors.lastname: Webb
authors.forename: Antonio
authors.initials: A
authors.lastname: Campos-Neto
authors.forename: Steven G
authors.initials: SG
authors.lastname: Reed
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000595:Amino Acid Sequence; D000818:Animals; D000913:Antibodies, Protozoan / Q000097:blood; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016054:DNA, Protozoan / Q000235:genetics; D005260:Female; D006801:Humans; D018320:Leishmania major / Q000235:genetics / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000276:immunology / Q000517:prevention & control*; D008050:Lipid A / Q000008:administration & dosage / Q000031:analogs & derivatives*; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D016366:Open Reading Frames; D016052:Protozoan Vaccines / Q000008:administration & dosage* / Q000235:genetics; D013185:Squalene / Q000008:administration & dosage; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000235:genetics
chemical_list: D000276:Adjuvants, Immunologic; D000913:Antibodies, Protozoan; D016054:DNA, Protozoan; D008050:Lipid A; D016052:Protozoan Vaccines; D014614:Vaccines, Synthetic; D013185:Squalene; C048436:monophosphoryl lipid A