BCG at 100: The Paradox of an Indispensable Vaccine.

Bacille Calmette-Guerin (BCG) vaccine, in use for over a century, occupies a paradoxical position in global health. It protects infants against disseminated tuberculosis (TB) with 60-80% efficacy and reduces all-cause infant mortality through non-specific effects mediated by trained immunity. Yet it provides limited and variable protection against pulmonary TB in adolescents and adults who drive transmission. A tuberculin survey from western Uttar Pradesh documented an annual risk of TB infection of 3.5-4.1%, nearly 50 times the national target, in a predominantly BCG-vaccinated child population. This perspective addresses four fundamental questions: Has BCG become redundant for its original purpose? Can it be improved? Is it more efficacious for non-TB indications? And is it currently indispensable? The pipeline is reviewed from a pediatric prism, identifying preferred candidates for each age group. MTBVAC leads as the most promising infant BCG replacement candidate while M72/AS01E is a frontrunner for adolescents and adults.