title: Alteration of epitope recognition pattern in Ag85B and ESAT-6 has a profound influence on vaccine-induced protection against Mycobacterium tuberculosis.
abstract: To analyze the effect of vaccine delivery systems on antigen recognition and vaccine efficacy, we compared immune responses in mice immunized either with an adenovirus vector expressing a fusion of Ag85B and ESAT-6 or with the recombinant fusion protein in a liposomal adjuvant. Both vaccines induced high levels of antigen-specific IFN-gamma production. The adjuvanted protein vaccine induced primarily a CD4 T cell response directed to the epitope Ag85B(241-255) and gave efficient protection against subsequent Mycobacterium tuberculosis infection. In contrast, the adenoviral construct induced a strong CD8 response predominantly targeted to the epitope ESAT-6(15-29) and no significant protection against infection. Vaccination with the protein vaccine resulted in highly accelerated recall of Ag85B(241-255)-specific T cells immediately post M. tuberculosis challenge whereas the ESAT-6(15-29) epitope was barely recognized during infection. Delivery of the viral construct in cationic liposomes switched the immune response to a protective one dominated by CD4 T cells targeted to the Ag85B(241-255) epitope. These data demonstrate that the nature of the T cell response to a vaccine antigen is more important than its magnitude with respect to protective efficacy and that vaccine-mediated changes in immunodominance can result in T cell responses of limited relevance during the natural infection.
authors.affiliation: Department of Infectious Disease Immunology, Statens Serum Institut, Copenhagen, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bennekov
authors.forename: Jes
authors.initials: J
authors.lastname: Dietrich
authors.forename: Ida
authors.initials: I
authors.lastname: Rosenkrands
authors.forename: Anette
authors.initials: A
authors.lastname: Stryhn
authors.forename: T Mark
authors.initials: TM
authors.lastname: Doherty
authors.forename: Peter
authors.initials: P
authors.lastname: Andersen
mesh_terms: D000217:Acyltransferases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000256:Adenoviridae / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000942:Antigens, Bacterial / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D018604:Epitope Mapping; D005260:Female; D007156:Immunologic Memory / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000276:immunology*; D014376:Tuberculosis / Q000276:immunology / Q000517:prevention & control*; D032581:Tuberculosis Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D022223:Vaccines, Subunit / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C093276:ESAT-6 protein, Mycobacterium tuberculosis; D032581:Tuberculosis Vaccines; D022223:Vaccines, Subunit; D014614:Vaccines, Synthetic; D000217:Acyltransferases; C121433:antigen 85B, Mycobacterium tuberculosis