The dual legacy of BCG: a century of tuberculosis prevention and the evolving pursuit of trained immunity-based therapies.

内容摘要

The Bacillus Calmette-Guérin (BCG) vaccine, a live-attenuated derivative of Mycobacterium bovis, has long been central to global tuberculosis prevention. Although it protects well against severe childhood TB, its efficacy against adult pulmonary TB is variable. At the same time, epidemiological and clinical observations suggest that BCG may reduce all-cause mortality and protect against infections beyond TB. Randomised trials have reported lower neonatal all-cause mortality and fewer sepsis-related deaths, supporting the idea of broader immunological benefits. These heterologous effects are proposed to be derived from trained immunity, a form of functional reprogramming of innate immune cells driven by epigenetic and metabolic changes. In some settings, BCG may also induce trained tolerance, leading to a more suppressive immune state, based mainly on animal and in vitro evidence. Clinically, intravesical BCG is an established local immunotherapy for non-muscle-invasive bladder cancer, with current evidence and emerging data suggesting that its effects may extend beyond the bladder through systemic immune training. However, repurposing BCG for other cancers, non-oncological autoimmune diseases, and respiratory tract infections remains established in experimental animal models but is represented with mixed efficacy accompanied by inconclusiveness in human trials and mostly in preclinical or early-phase evidence. Major barriers to translation include strain variability, lack of standardised dosing, uncertain durability, and unresolved long-term safety concerns. Future progress will depend on engineered BCG derivatives, improved delivery systems, rational combination therapies, and well-designed controlled clinical trials.Methodology: Literature was identified through searches of PubMed, Google Scholar, and the Cochrane Library, from database inception to 2026, with a primary focus on studies published between 2011 and 2026. The Bacillus Calmette-Guérin (BCG) vaccine was developed over a century ago, in 1921, to combat tuberculosis. Beyond its primary role, researchers are uncovering its capacity for “trained immunity” a form of innate immune memory. This process involves the functional reprogramming of the body’s natural defenses, which may allow them to respond to a diverse spectrum of pathogens and diseases.Clinical observations have established that BCG administration may reduce neonatal mortality from non-specific infections, such as sepsis, by enhancing the underlying immune reprogramming and granulopoiesis. This broad-spectrum immunomodulation remains investigational and preclinical for oncological applications with mixed and negative results. While BCG is already a foundational immunotherapy for non-muscle-invasive bladder cancer, emerging evidence suggests it possesses epigenetic reprogramming potential that may work to some extent in fighting respiratory tract infections and to some extent slow down progression of autoimmune conditions, including type 1 diabetes and multiple sclerosis, with mixed/biased outcomes.However, the transition from successful preclinical models to widespread clinical use requires addressing several complex variables. These include the nuances of strain variability, standardized dosing protocols, and the long-term systemic safety of these therapies. The future of BCG-based vaccines lies in the development of engineered derivatives and novel delivery mechanisms designed to optimize this “trained” response.For patients and advocates, this research represents a noble pursuit: repurposing the BCG vaccine by overcoming translational challenges and by bridging a century of vaccine history with modern epigenetic science, we can enter a new era of multi-targeted disease prevention and treatment.Methodology: Literature searches were conducted in PubMed, Google Scholar, and the Cochrane Library, with additional screening of relevant reviews and reference lists from independent journals and reputable scientific websites, from database inception to 2026, to identify English-language articles, with a primary focus on recent developments from 2011 to 2026. while integrating a few from foundational records of earlier years. Search terms included combinations of “Bacillus Calmette-Guérin,” “BCG,” “trained immunity,” “innate immune memory,” “heterologous effects,” “epigenetic reprogramming,” “metabolic reprogramming,” “histone modification,” “lactylation,” “tolerance,” and disease-specific terms such as “tuberculosis,” “bladder cancer,” “autoimmunity,” and “viral infection,” chosen to capture the major biological mechanisms, clinical applications, and conflicting or context-dependent outcomes of BCG-induced immune modulation.