title: From genome to vaccines for leishmaniasis: screening 100 novel vaccine candidates against murine Leishmania major infection.
abstract: The genomic sequence of Leishmania major provides a rich source of vaccine candidates. One hundred randomly selected amastigote-expressed genes were screened as DNA vaccines, and efficacy determined following high-dose L. major footpad challenge in BALB/c mice. Fourteen protective novel vaccine candidates were identified; seven vaccines exacerbated disease. There were no differences in the number of predicted MHC H-2d class I or II epitopes mapping to protective versus exacerbatory antigens. A proportion of both protective (7/14; 50%) and exacerbatory (4/7; 57%) proteins showed short (8- to 18-mer) 100% amino acid sequence identities to human, mouse or gut flora proteins. A high proportion of these (4/7 protective; 3/4 exacerbatory) showed full or partial overlap with RANKPEP-predicted H-2d classes I and II epitopes. Our data suggest, therefore, that there may be little difference between antigens/epitopes that drive regulatory versus effector CD4 T cell populations. The best novel protective antigen was an amastin-like gene that maps to a 17-gene tandem array on Leishmania chromosome 8 and is closely related to 37 other amastin-like genes. Two ribosomal proteins, a V-ATPase subunit, and a dynein light chain orthologue were the only other protective genes with putative functions.
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 2XY, UK.
authors.forename: Carmel B
authors.initials: CB
authors.lastname: Stober
authors.forename: Uta G
authors.initials: UG
authors.lastname: Lange
authors.forename: Mark T M
authors.initials: MT
authors.lastname: Roberts
authors.forename: Brian
authors.initials: B
authors.lastname: Gilmartin
authors.forename: Richard
authors.initials: R
authors.lastname: Francis
authors.forename: Renata
authors.initials: R
authors.lastname: Almeida
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Peacock
authors.forename: Sharon
authors.initials: S
authors.lastname: McCann
authors.forename: Jenefer M
authors.initials: JM
authors.lastname: Blackwell
mesh_terms: D000818:Animals; D000953:Antigens, Protozoan / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D016054:DNA, Protozoan / Q000008:administration & dosage / Q000276:immunology; D004195:Disease Models, Animal; D018503:Genome, Protozoan; D018320:Leishmania major / Q000737:chemistry* / Q000235:genetics* / Q000276:immunology; D007896:Leishmaniasis / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D015800:Protozoan Proteins / Q000008:administration & dosage / Q000235:genetics; D016052:Protozoan Vaccines / Q000008:administration & dosage* / Q000235:genetics; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000235:genetics
chemical_list: D000953:Antigens, Protozoan; D016054:DNA, Protozoan; D015800:Protozoan Proteins; D016052:Protozoan Vaccines; D014614:Vaccines, Synthetic