The Bacillus Calmette-Guérin (BCG) strain is a live, weakened bacterium derived from Mycobacterium bovis, a species closely related to the one that causes human tuberculosis. BCG is not a pathogen itself but an attenuated version used primarily as the world’s most widely administered vaccine against tuberculosis. The strain’s importance stems from its ability to stimulate a powerful, broad-spectrum immune response.
The Development of BCG
The history of the BCG strain began in the early 20th century through the dedicated work of French scientists Albert Calmette and Camille Guérin at the Pasteur Institute in Lille. They sought to create a safe, live vaccine against tuberculosis by working with Mycobacterium bovis, the bacterium responsible for bovine tuberculosis.
This weakening was achieved by serially subculturing the strain approximately 230 times over a period of 13 years, from 1908 to 1921. The scientists grew the bacterium on a specialized medium containing ox bile, a stressful environment that forced the microbes to adapt and lose their disease-causing capabilities. This rigorous and lengthy laboratory passage resulted in genetic changes, most notably the loss of the Region of Difference 1 (RD1), a significant genomic segment that codes for a protein secretion system involved in virulence. The resulting attenuated strain, now unable to cause disease, was first administered to a human infant in 1921.
Primary Role as a TB Vaccine
The BCG vaccine’s primary function is to provide protection against tuberculosis, particularly the severe, disseminated forms such as miliary TB and tuberculous meningitis in young children. As a live-attenuated vaccine, it must be taken up by specialized immune cells, like macrophages and dendritic cells, which then process the bacterial components. These cells subsequently present the antigens to T-cells, leading to the activation of both CD4+ and CD8+ T lymphocytes.
This activation creates an adaptive immune memory that allows the body to mount a rapid and specific response if it later encounters the virulent Mycobacterium tuberculosis. While BCG is highly effective at preventing severe childhood disease, its efficacy against adult pulmonary tuberculosis varies widely, ranging from 0% to 80% depending on geographical location and environmental factors. This variability is often attributed to pre-exposure to non-tuberculous mycobacteria in the environment, which can interfere with the vaccine’s ability to prime the immune system.
Why BCG Strains Are Not Identical
The current BCG vaccine is a collection of genetically distinct substrains, a direct consequence of its long history of independent cultivation. After the original strain was distributed from the Pasteur Institute, different laboratories around the world continued to culture and propagate it under varying conditions. This process of prolonged, independent passage in different media and facilities led to further spontaneous genetic mutations and losses, including the deletion of additional Regions of Difference (RDs).
These subtle genetic variations result in measurable differences in the characteristics of the major substrains, which include lineages like Danish (Copenhagen), Pasteur, Tokyo, and Russia. For example, the Danish strain is often cited in studies as being highly immunogenic. Other strains may have slightly different profiles in terms of the magnitude of T-cell response they elicit, their tendency to cause localized side effects, and even their efficacy rates in clinical trials. These genotypic and phenotypic differences mean that a BCG vaccine produced in one country may not be identical in its biological effects to one produced elsewhere.
BCG’s Unexpected Immunotherapy Role
Beyond its application as a vaccine against tuberculosis, the BCG strain has found application as an immunotherapy for non-muscle-invasive bladder cancer. This treatment involves directly instilling a suspension of the live bacteria into the bladder, where it initiates a potent, localized inflammatory response. The BCG bacteria attach to the bladder wall’s urothelial cells, often facilitated by a protein called fibronectin, which allows the microbe to be internalized by the cells.
This localized “infection” acts as a powerful immune stimulant, recruiting a large number of immune cells, including macrophages, T lymphocytes, and natural killer cells, to the bladder lining. The resulting immune cascade targets and destroys the cancerous cells through mechanisms that include the release of cytotoxic molecules. In this context, BCG is not acting as a pathogen-specific vaccine but as a general, non-specific immune adjuvant, leveraging its strong immunogenicity to provoke a targeted anti-tumor reaction. This application is considered the gold standard for treating this specific type of bladder cancer.