Tuberculosis (TB) is a leading cause of death worldwide despite the availability of effective
chemotherapy for over 60 years. Although Mycobacterium bovis bacillus Calmette-Guérin (BCG) vaccination protects against active TB disease in some populations, its efficacy is suboptimal. Development of an effective TB
vaccine is a top global priority that has been hampered by an incomplete understanding of protective immunity to TB. Thus far, preventing TB disease, rather than
infection, has been the primary target for
vaccine development. Several areas of research highlight the importance of including preinfection
vaccines in the development pipeline. First, epidemiology and mathematical modeling studies indicate that a preinfection
vaccine would have a high population-level impact for control of TB disease. Second, immunology studies support the rationale for targeting prevention of
infection, with evidence that host responses may be more effective during acute
infection than during
chronic infection. Third, natural history studies indicate that resistance to TB
infection occurs in a small percentage of the population. Fourth, case-control studies of BCG indicate that it may provide protection from
infection. Fifth, prevention-of-
infection trials would have smaller sample sizes and a shorter duration than disease prevention trials and would enable opportunities to search for correlates of immunity as well as serve as a criterion for selecting a
vaccine product for testing in a larger TB disease prevention trial. Together, these points support expanding the focus of TB
vaccine development efforts to include prevention of
infection as a primary goal along with
vaccines or other interventions that reduce the rate of transmission and reactivation.