Antibodies in tuberculosis: functional capacity as key determinant

The human immune system employs both innate and adaptive mechanisms to control pathogens, with antibodies playing a pivotal role in immune memory and defense, in particular against viral infections. In tuberculosis, antibody titers have long been used to assess immune responses, but their presence alone fails to predict protective efficacy. Recent studies highlight that antibody functionality is critical for effective immune activity. Despite widespread detection of <i>Mycobacterium tuberculosis</i> (Mtb)-reactive antibodies in individuals with active disease, <i>Mtb</i> infection, and even in healthy controls, their potential to control <i>Mtb</i> growth is variable and only detected in a proportion of individuals. This perspective emphasizes the need for robust functional assessment of antibodies to better understand their role in mycobacterial control and inform vaccine development. Notably, antibodies binding to purified protein derivative of <i>Mtb</i>, a mixture of degraded antigens from <i>Mtb</i> cultures, are widespread but not universally functional, underscoring the importance of Fc characteristics and epitope specificity. Initial high-throughput screening using phagocytosis and direct mycobacterial binding assays is an active indicator of antibody function. By refining and combining existing assays, as recommended in this perspective, we can better characterize antibody contributions, particularly their immunomodulatory potential, toward improved control of <i>Mtb</i>. Albeit antibodies may not be essential in natural protection, functional antibodies induced by vaccination may be of added value and contribute to host protection.