Reinfection as a central constraint on tuberculosis vaccine development

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.