GL08

1:The University of Oxford

In 2023, more than 10 million people developed TB and more than one million died from this disease. A universally and highly effective vaccine would be game-changing for global TB control. The only licensed vaccine against TB, an attenuated strain of Mycobacterium bovis, Bacille Calmette Guerin (BCG) is more than 100 years old. Whilst BCG is effective at preventing disseminated disease in childhood, the efficacy against pulmonary disease is highly variable and very low in TB high burden countries. However to date only one of 4 candidate vaccines evaluated in human efficacy trials has shown any significant efficacy.

Mycobacterium is a complex intracellular pathogen which is adept at evading and subverting host immunity. The uncertain predictive value of preclinical animal models and the lack of validated correlates of protection mean that vaccine R&D is difficult and high risk for investment. In vaccine R&D for other complex pathogens, controlled human infection models have been invaluable in de-risking vaccine R&D in small scale studies prior to committing to large field efficacy studies. It would not be ethical to deliberately infect people with Mycobacterium tuberculosis, however attenuated M.bovis BCG may be an acceptable surrogate challenge agent. We have established a skin and aerosol BCG human challenge model and validated both models against a BCG vaccine effect in the UK. These models can also be utilised to define the immunobiology of infection in humans. Data from recent studies will be shown.