Title: Understanding Immunity to Tuberculosis using the TB case-contact research platform (TBCC)
Funder: Medical Research Council

Abstract: Importance of the research: Tuberculosis (TB) remains a daunting global health problem with over 9 million new cases and 1.4 million deaths each year. We urgently require new vaccines, diagnostics and treatment regimes but to achieve this we need a better understanding of the interaction between the underlying pathogen (Mycobacterium tuberculosis) and the host response to the pathogen. This can be determined using the spectrum of infection/disease states that are available to us through the TB case-contact (TBCC) platform. Our central research paradigm is that dynamic changes in host immune responses that take place during encounters with invading pathogens and during interventions such as treatment or vaccination, will allow us to reveal causal relationships with biomarkers. The MRC TB case-contact platform has been running since 2001 and has encompassed epidemiological, clinical, genetic, microbiological and immunological aspects of tuberculosis with over 80 peer-reviewed publications. Aims of the TBCC: Our aims are to analyse the host and pathogen at different stages of infection and disease that will inform on rational development of novel vaccines and diagnostics. Study design: Following diagnosis of TB, patients are consented and recruited to the TBCC platform. Subsequently, field workers visit their household to recruit and consent family members (average 10 per household). Sputum samples from index cases are studied for bacterial load, drug-resistance, strain of infection and follow-up for treatment response. At the same time, blood and other body fluids are analysed for host immune responses to TB antigens. Household contacts are tested to determine presence of latent infection (90% of infected people remain asymptomatic throughout life) and are monitored for 2 years to determine any changes in infection/disease states. Blood samples from exposed but apparently uninfected household contacts are analysed to determine what factors contribute to protective immunity to TB. Clinical and diagnostic studies: Our well established platform has allowed us to perform novel vaccine trials, multi-site biomarker studies; TB transmission studies; molecular typing of bacteria; implementation of new diagnostic tests such as the GeneXpert; host genetics and many more. The adult TBCC platform has also enabled the development of a pediatric TB program through Prof. Kampmann’s MRC Program Grant. Importantly, we have generated a unique and well-characterized bank of samples for future studies such as host genetics and ‘omics research and also mycobacterial strains and transmission data. Translational research and public health benefits: Our major translational focus is on development of new diagnostic tests for adult and pediatric TB. We have 2 patents in this regard for development of point-of-care tests. All our research has a public health focus with potential to impact on policy and practice. Importantly, we have long-standing collaborations with leaders in the TB field: the Bill and Melinda Gates funded Grand Challenges project established us as a major player in multi-site consortiums, which are essential for development of next generation diagnostics and vaccines.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: INFECTION