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

• DOI: 10.1371/journal.pone.0074080
• Publication Date: 2013-09-11T05:24:30Z
• Authors: 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-K...; 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. Kauf...
• Keywords: Adult; Male; 0301 basic medicine; Science; HIV Infections; Interferon-gamma; Young Adult; 03 medical and health sciences; Journal Article; Bacterial/immunology; Cluster Analysis; Humans; Tuberculosis; Antigens; Africa South of the Sahara; Antigens, Bacterial; Coinfection; Research Support, Non-U.S. Gov't; Q; R; Mycobacterium tuberculosis; Middle Aged; Africa South of the Sahara/epidemiology; CD4 Lymphocyte Count; 3. Good health; HIV Infections/epidemiology; Tuberculosis/epidemiology; Medicine; Female; Mycobacterium tuberculosis/immunology; Interferon-gamma/blood; Research Article

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.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.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.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.