title: Analysis of host responses to Mycobacterium tuberculosis antigens in a multi-site study of subjects with different TB and HIV infection states in sub-Saharan Africa.
abstract: BACKGROUND
  Tuberculosis (TB) remains a global health threat with 9 million new cases and 1.4 million deaths per year. In order to develop a protective vaccine, we need to define the antigens expressed by Mycobacterium tuberculosis (Mtb), which are relevant to protective immunity in high-endemic areas.
  
  
  METHODS
  We analysed responses to 23 Mtb antigens in a total of 1247 subjects with different HIV and TB status across 5 geographically diverse sites in Africa (South Africa, The Gambia, Ethiopia, Malawi and Uganda). We used a 7-day whole blood assay followed by IFN-γ ELISA on the supernatants. Antigens included PPD, ESAT-6 and Ag85B (dominant antigens) together with novel resuscitation-promoting factors (rpf), reactivation proteins, latency (Mtb DosR regulon-encoded) antigens, starvation-induced antigens and secreted antigens.
  
  
  RESULTS
  There was variation between sites in responses to the antigens, presumably due to underlying genetic and environmental differences. When results from all sites were combined, HIV- subjects with active TB showed significantly lower responses compared to both TST(-) and TST(+) contacts to latency antigens (Rv0569, Rv1733, Rv1735, Rv1737) and the rpf Rv0867; whilst responses to ESAT-6/CFP-10 fusion protein (EC), PPD, Rv2029, TB10.3, and TB10.4 were significantly higher in TST(+) contacts (LTBI) compared to TB and TST(-) contacts fewer differences were seen in subjects with HIV co-infection, with responses to the mitogen PHA significantly lower in subjects with active TB compared to those with LTBI and no difference with any antigen.
  
  
  CONCLUSIONS
  Our multi-site study design for testing novel Mtb antigens revealed promising antigens for future vaccine development. The IFN-γ ELISA is a cheap and useful tool for screening potential antigenicity in subjects with different ethnic backgrounds and across a spectrum of TB and HIV infection states. Analysis of cytokines other than IFN-γ is currently on-going to determine correlates of protection, which may be useful for vaccine efficacy trials.
authors.affiliation: Vaccinology Theme, Medical Research Council Unit, Fajara, The Gambia.
authors.forename: Jayne S
authors.initials: JS
authors.lastname: Sutherland
authors.forename: Maeve K
authors.initials: MK
authors.lastname: Lalor
authors.forename: Gillian F
authors.initials: GF
authors.lastname: Black
authors.forename: Lyn R
authors.initials: LR
authors.lastname: Ambrose
authors.forename: Andre G
authors.initials: AG
authors.lastname: Loxton
authors.forename: Novel N
authors.initials: NN
authors.lastname: Chegou
authors.forename: Desta
authors.initials: D
authors.lastname: Kassa
authors.forename: Adane
authors.initials: A
authors.lastname: Mihret
authors.forename: Rawleigh
authors.initials: R
authors.lastname: Howe
authors.forename: Harriet
authors.initials: H
authors.lastname: Mayanja-Kizza
authors.forename: Marie P
authors.initials: MP
authors.lastname: Gomez
authors.forename: Simon
authors.initials: S
authors.lastname: Donkor
authors.forename: Kees
authors.initials: K
authors.lastname: Franken
authors.forename: Willem
authors.initials: W
authors.lastname: Hanekom
authors.forename: Michel R
authors.initials: MR
authors.lastname: Klein
authors.forename: Shreemanta K
authors.initials: SK
authors.lastname: Parida
authors.forename: W Henry
authors.initials: WH
authors.lastname: Boom
authors.forename: Bonnie A
authors.initials: BA
authors.lastname: Thiel
authors.forename: Amelia C
authors.initials: AC
authors.lastname: Crampin
authors.forename: Martin
authors.initials: M
authors.lastname: Ota
authors.forename: Gerhard
authors.initials: G
authors.lastname: Walzl
authors.forename: Tom H M
authors.initials: TH
authors.lastname: Ottenhoff
authors.forename: Hazel M
authors.initials: HM
authors.lastname: Dockrell
authors.forename: Stefan H E
authors.initials: SH
authors.lastname: Kaufmann
mesh_terms: D000328:Adult; D017954:Africa South of the Sahara / Q000453:epidemiology; D000942:Antigens, Bacterial / Q000276:immunology*; D018791:CD4 Lymphocyte Count; D016000:Cluster Analysis; D060085:Coinfection; D005260:Female; D015658:HIV Infections / Q000453:epidemiology*; D006801:Humans; D007371:Interferon-gamma / Q000097:blood; D008297:Male; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D014376:Tuberculosis / Q000453:epidemiology* / Q000276:immunology*; D055815:Young Adult
chemical_list: D000942:Antigens, Bacterial; D007371:Interferon-gamma
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