title: Tuberculosis vaccine with high predicted population coverage and compatibility with modern diagnostics.
abstract: A central goal in vaccine research is the identification of relevant antigens. The Mycobacterium tuberculosis chromosome encodes 23 early secretory antigenic target (ESAT-6) family members that mostly are localized as gene pairs. In proximity to five of the gene pairs are ESX secretion systems involved in the secretion of the ESAT-6 family proteins. Here, we performed a detailed and systematic investigation of the vaccine potential of five possible Esx dimer substrates, one for each of the five ESX systems. On the basis of gene transcription during infection, immunogenicity, and protective capacity in a mouse aerosol challenge model, we identified the ESX dimer substrates EsxD-EsxC, ExsG-EsxH, and ExsW-EsxV as the most promising vaccine candidates and combined them in a fusion protein, H65. Vaccination with H65 gave protection at the level of bacillus Calmette-Guérin, and the fusion protein exhibited high predicted population coverage in high endemic regions. H65 thus constitutes a promising vaccine candidate devoid of antigen 85 and fully compatible with current ESAT-6 and culture filtrate protein 10-based diagnostics.
authors.affiliation: Department of Infectious Disease Immunology, Statens Serum Institut, DK 2300 Copenhagen, Denmark.
authors.forename: Niels Peter H
authors.initials: NP
authors.lastname: Knudsen
authors.forename: Sara
authors.initials: S
authors.lastname: Nørskov-Lauritsen
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Dolganov
authors.forename: Gary K
authors.initials: GK
authors.lastname: Schoolnik
authors.forename: Thomas
authors.initials: T
authors.lastname: Lindenstrøm
authors.forename: Peter
authors.initials: P
authors.lastname: Andersen
authors.forename: Else Marie
authors.initials: EM
authors.lastname: Agger
authors.forename: Claus
authors.initials: C
authors.lastname: Aagaard
mesh_terms: D000483:Alleles; D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology; D001500:BCG Vaccine / Q000276:immunology; D001426:Bacterial Proteins / Q000276:immunology; D015704:CD4 Antigens / Q000378:metabolism; D003114:Colony-Forming Units Assay; D000939:Epitopes / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D015967:Gene Expression Regulation, Viral; D006680:HLA Antigens / Q000378:metabolism; D006801:Humans; D051379:Mice; D009163:Mycobacterium bovis / Q000276:immunology; D009169:Mycobacterium tuberculosis / Q000276:immunology; D010802:Phylogeny; D055503:Protein Multimerization; D013601:T-Lymphocytes / Q000276:immunology; D014376:Tuberculosis / Q000276:immunology / Q000517:prevention & control*; D032581:Tuberculosis Vaccines / Q000276:immunology*
chemical_list: D000942:Antigens, Bacterial; D001500:BCG Vaccine; D001426:Bacterial Proteins; D015704:CD4 Antigens; D000939:Epitopes; D006680:HLA Antigens; D032581:Tuberculosis Vaccines
keywords: T-cell immunology; gene expression; tuberculosis