Analysis of host responses to secreted, latent and reactivation Mycobacterium tuberculosis antigens in a multi-site study of subjects with different TB and HIV infection states in sub-Saharan Africa

Sutherland, Jayne S. ; Lalor, Maeve K. ; Black, Gillian F. ; Ambrose, Lyn R. ; Loxton, Andre G. ; Chegou, Novel N. ; Kassa, Desta ; Mihret, Adane ; Howe, Rawleigh ; Mayanja-Kizza, Harriet ; Gomez, Marie P. ; Donkor, Simon ; Franken, Kees ; Boom, W. Henry ; Thiel, Bonnie A. ; Crampin, Amelia C. ; Hanekom, Willem ; Klein, Michel R. ; Parida, Shreemanta K. ; Ota, Martin ; Walzl, Gerhard ; Ottenhoff, Tom H. M. ; Dockrell, Hazel M. ; Kaufmann, Stefan H. E. (2013-09-10)

CITATION: Sutherland, J. S. et al. 2013. Analysis of host responses to secreted, latent and reactivation Mycobacterium tuberculosis antigens in a multi-site study of subjects with different TB and HIV infection states in sub-Saharan Africa. PLoS ONE, 8(9): e74080, doi:10.1371/journal.pone.0074080.

The original publication is available at http://journals.plos.org/plosone

Article

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.

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