Epidemiological insights to inform the development and implementation of new vaccines against tuberculosis

<p class="MsoNormal">Tuberculosis (TB), caused by <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>), remains the leading infectious cause of death worldwide. It spreads through the air from people with active pulmonary TB. <i>Mtb </i>infection refers to a state where the bacteria are present in the body but inactive, causing no symptoms and not being contagious. However, in about 5–10%of infected individuals, the bacteria causes disease, particularly when the immune system is compromised.<br/>Tests used to detect TB infection, such as the tuberculin skin test or interferon-gamma release assays, only indicate whether exposure to <i>Mtb</i> has occurred. They do not distinguish between active, latent, or cleared infection, complicating both clinical decision-making and vaccine evaluation.<br/>The BCG vaccine, developed over a century ago, provides protection against severe forms of TB in young children, but offers limited protection against pulmonary TB in adolescents and adults. Although several new vaccine candidates are under development, only a few have progressed to late-stage clinical trials.<br/>This thesis examines, how BCG vaccination effectiveness differ across settings, how TB infection is defined and how this translates into disease. It addresses the diagnostic challenges related to TB infection, the consequences for clinical trial design, and the need to tailor vaccine implementation strategies to local TB epidemiology. The goal is to inform the development of TB vaccines that are not only scientifically effective but also feasible and equitable in diverse populations.