PLoS ONE (Jan 2013)

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.

  • Jayne S Sutherland,
  • Maeve K Lalor,
  • Gillian F Black,
  • Lyn R Ambrose,
  • Andre G Loxton,
  • Novel N Chegou,
  • Desta Kassa,
  • Adane Mihret,
  • Rawleigh Howe,
  • Harriet Mayanja-Kizza,
  • Marie P Gomez,
  • Simon Donkor,
  • Kees Franken,
  • Willem Hanekom,
  • Michel R Klein,
  • Shreemanta K Parida,
  • W Henry Boom,
  • Bonnie A Thiel,
  • Amelia C Crampin,
  • Martin Ota,
  • Gerhard Walzl,
  • Tom H M Ottenhoff,
  • Hazel M Dockrell,
  • Stefan H E Kaufmann,
  • GCGH Biomarkers for TB consortium

DOI
https://doi.org/10.1371/journal.pone.0074080
Journal volume & issue
Vol. 8, no. 9
p. e74080

Abstract

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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.