Immunological mechanistic action of intravenous BCG-mediated protection against tuberculosis.

The Bacillus Calmette-Guérin (BCG) vaccine, the only licensed vaccine against tuberculosis (TB), has played a crucial role in mitigating severe manifestations of the disease, particularly in children. However, its effectiveness against pulmonary TB in adults remains variable, largely due to its limited ability to elicit a sustained antigen-specific TH1 immune response and to generate long-lived tissue-resident memory T cells (TRM) within the lungs. Consequently, innovative strategies that address these immunological shortcomings are needed to enhance BCG immunogenicity and efficacy against pulmonary TB. Recent studies on intravenous (IV)-BCG have emerged as a promising alternative, achieving near-sterilizing immunity in preclinical models such as nonhuman primates by strengthening pulmonary defenses against Mycobacterium tuberculosis (Mtb). This review examines how IV-BCG enhances BCG efficacy through a synergistic network of immunological factors, including trained immunity, effector TH1 cells, lung TRM, inducible bronchus-associated lymphoid tissue (iBALT), and antibody responses. Systemic delivery of IV-BCG induces durable trained immunity, primes robust TH1 and TRM responses in the lungs, may foster iBALT formation for localized protection, and enhances antibody production to reinforce humoral defenses. Drawing on data from preclinical studies, this review highlights how these components interconnect to sustain long-lasting pulmonary protection and offers insights into optimizing BCG-based TB vaccines.