A lung-oriented controlled human infection model using live BCG to evaluate tuberculosis immunopathogenicity and vaccine efficacy (TB-CHIM). Tuberculosis (TB) is one of the deadliest diseases known to man. It has killed over 1 billion people in the last 2 centuries and is currently the biggest infectious disease killer globally. In 2016 there were over 10 million newly diagnosed TB cases and 1.7 million people died (worldwide 3 people die from TB every minute!). In some parts of the world, like Sub-Saharan Africa, the disease is out of control.   TB most commonly affects the lungs and is transmitted through the inhalation of cough droplets, which enter the host's lung and eventually reach the air sacs (alveoli) where the infection takes root. However, if someone inhales TB bacteria it does not necessarily mean that they will develop active TB disease. In most people (~90 to 95%), the immune system is able to either kill or contain the bacteria before they develop disease. However, in ~5-10% of people, the bacteria multiply leading to TB disease.    The immune system is complex with many interacting components. However, how these components work together in the lung to kill the bacteria and prevent disease development is poorly understood. Thus, it remains unclear why some people get the disease while others are protected. This is mainly because most research, up to now, involved animal models and cells from the human blood compartment, which poorly approximate what happens in the human lung. However, several lines of evidence now suggest that a type of white blood cell called a memory T-cell, if "trained", can rapidly recognise and kill the TB bacteria. New research also suggests that antibodies, once thought to have no role in protection, can interact with other cells to kill TB bacteria. We aim to investigate these specific components and how they can protect against development of disease in the human lung. This will give us clues how to design protective interventions against TB.  The best way to eradicate TB is by developing an effective vaccine. Yet the current vaccine used in many countries, BCG, only protects against TB in children and offers little protection in adults, especially in countries where TB is common. About 20 new vaccines are being evaluated but the development process is very long (10 to 15 years) and expensive (about  £800 million from start to finish) and most vaccines will fail in the late stages of human testing. Thus, we need a new efficient and more affordable approach, involving small numbers of patients, to choose the best vaccines to move to larger human studies. Another unresolved issue is how best to administer the vaccine. Traditionally, vaccines are given by injection in the skin but inhaling it directly into the lungs may better activate the protective responses against airborne infections like TB.  Our proposed study will attempt to address these unmet needs and unresolved questions by directly infecting the lungs of different groups of test participants (each group showing a different level of susceptibility against TB) with a live weakened strain of TB (called BCG) and examining the immune response before and after infection. This is called a controlled human infection model (CHIM). Such a model more accurately reflects how a person is naturally infected with TB. CHIM has been used in the past to develop vaccines for other disease such as cholera and malaria with great success. We have recently completed a study funded by the Gates Foundation and SA-MRC using a similar model where we have infected the lungs of healthy persons with BCG and a mixture of different proteins from TB bacteria (called PPD) and examined the immune response in the lungs after 3 days. We have established the safety of this CHIM in close to 100 participants. We now need to leverage these gains by using this model to now interrogate which specific aspects of the immune system are protective, refine the system to finalise a model that can be used to triage new vaccine candidates, and to determine the best route by which to administer new vaccines. The Global Challenges Research Fund (GCRF) supports cutting-edge research to address challenges faced by developing countries. The fund addresses the UN sustainable development goals. It aims to maximise the impact of research and innovation to improve lives and opportunity in the developing world.