From genome to vaccines for leishmaniasis: screening 100 novel vaccine candidates against murine Leishmania major infection.
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.
Stober
Carmel B
CB
Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 2XY, UK.
Lange
Uta G
UG
Roberts
Mark T M
MT
Gilmartin
Brian
B
Francis
Richard
R
Almeida
Renata
R
Peacock
Christopher S
CS
McCann
Sharon
S
Blackwell
Jenefer M
JM
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
D000953:Antigens, Protozoan; D016054:DNA, Protozoan; D015800:Protozoan Proteins; D016052:Protozoan Vaccines; D014614:Vaccines, Synthetic