Significance: It is not known whether natural immunity to TB exists or whether antibodies play an important role in immunity against infection by Mycobacterium tuberculosis (Mtb), the causative agent of TB. Here, we identify that a significant minority of healthcare workers who are exposed to high doses of Mtb make protective antibodies against infection as measured in both mouse infection and in vitro models. Some of these individuals had no prior evidence of latent TB infection, suggesting that they may represent a subset of “restrictors” who can control infection by Mtb. These results have important implications in the rational development of both protective and therapeutic vaccines against TB.

Are antibodies important for protection against tuberculosis? The jury has been out for more than 100 years. B cell depletion in experimental Mycobacterium tuberculosis infection failed to identify a major role for these cells in immunity to tuberculosis. However, recent identification of naturally occurring antibodies in humans that are protective during M. tuberculosis infection has reignited the debate. Here, we discuss the evidence for a protective role for antibodies in tuberculosis and consider the feasibility of designing novel tuberculosis vaccines targeting humoral immunity.

Bacillus Calmette-Guérin (BCG) is the only licensed vaccine against tuberculosis (TB). However, BCG has variable efficacy and cannot completely prevent TB infection and transmission. Therefore, the worldwide prevalence of TB calls for urgent development of a more effective TB vaccine. In the absence of other approved vaccines, it is also necessary to improve the efficacy of BCG itself. Intravenous (IV) BCG administration and BCG revaccination strategies have recently shown promising results for clinical usage. Therefore, it is necessary for us to revisit the BCG vaccination strategies and summarize the current research updates related to BCG vaccination. This literature review provides an updated overview and perspectives of the immunization strategies against TB using BCG, which may inspire the following research on TB vaccine development.