LIS Latent TB infection phase 1 and 2 2009

1 Tuberculosis (TB) has been declared a global emergency by WHO and remains a major public health problem worldwide, with more than 8 million new cases and over 2 million deaths each year. It has been estimated that one third of the global population is latently infected with Mycobacterium tuberculosis (Mtb). Ordinarily only 5-10% of latently infected people will develop TB disease, but co-infection with HIV has been shown to dramatically increase the annual risk of developing TB, especially in sub-Saharan Africa. Despite years of effort there are currently no reliable biomarkers for identifying protective immunity against tuberculosis disease or for progression to disease, or for predicting response to intervention. This proposed study, to be undertaken at Karonga Prevention Study (KPS), will investigate immune responses to Mtb in subjects with and without active TB disease, latent TB infection and HIV infection over a period of two years. Peripheral blood samples will be collected for antigen-specific immunoassays and RNA and serum will be stored for future analyses of hosbiomarkers of disease and protection. This study will be part of a multi-centre study involving other laboratories in Africa (Uganda, Ethiopia, Gambia, and South Africa), Europe (UK, Germany, Netherlands and Denmark) and USA. The results of this study will allow insights into the mechanisms of protection and TB disease progression and will enable the definition of immune correlates and host markers of disease that will aid the development of TB vaccines that will be effective in an African setting.

2, Latent infection with M.tuberculosis (M.tb) may not always be life-long in the absence of intervention and some individuals may be able resolve infection. Understanding these natural pathways and recognising the individual host characteristics that affect these processes are key to development of vaccines capable of protecting individuals from active tuberculosis life-long and understanding whether elimination of TB can ever be achieved given the long standing nature of infection. Studying this requires life-time cohorts of infected individuals which is a rare opportunity presented by the Karonga Programme with its detailed databases of individuals tuberculin skin tested (TST) decades ago , and ability to reliably trace and identify people in the community. Pilot work on a group of individuals with very high TST reactivity in the 1980s has shown exciting results, with some individual showing exaggerated immune responses consistent with active protection and others displaying a phenotype suggesting that spontaneous resolution has taken place. We proposed to extend this work, by including other groups of individuals with known TST histories to act as appropriate controls to convincingly demonstrate the differences between individuals who can successfully control or clear infection and those who develop disease. Cohorts of individuals will be traced and a sample of each will be bled for immunological and gene expression profiling.