Reinfection as a central constraint on tuberculosis vaccine development

Tuberculosis (TB) vaccine development is hindered by the absence of validated correlates of protection, the low proportion of infected individuals who progress to disease, and the pervasive impact of reinfection in endemic settings. Although several candidates have advanced clinically, only M72/AS01E has demonstrated prevention of disease in adults. These limitations underscore the need to reassess both vaccine objectives and preclinical evaluation strategies. Epidemiological, immunological, and experimental evidence indicates that natural Mycobacterium tuberculosis infection can provide substantial protection against disease progression in immunocompetent adults through lung-localized adaptive immunity. However, this protection is anatomically restricted and initially eroded by repeated endogenous reinfection. In high-transmission environments, repeated exposures simultaneously increase bacillary burden while boosting host immune responses, thereby reducing the incremental benefit of vaccination. An in silico multiple consecutive infection (MCI) model predicted that successive infections would produce a cumulative rise in pulmonary bacillary load reaching a plateau, together with an exponential decline in BCG efficacy. This prediction was subsequently validated experimentally in the C3HeB/FeJ murine model, which develops neutrophil-rich, liquefaction-prone lesions resembling human active TB. Repeated daily infections reproduced the anticipated increase in bacillary burden but paradoxically reduced the proportion of neutrophilic exudative lesions, reflecting modulation of inflammatory pathology. Under MCI conditions, BCG conferred only marginal additional protection compared with single infection. Collectively, these findings identify reinfection as a central biological constraint on prophylactic TB vaccines and support incorporating MCI models into preclinical pipelines to enhance predictive value and prioritize prevention of disease.