BCG Vaccine

Introduction

Fig. 1. Image of a dendritic cell after ingesting a small amount of the BCG vaccine. Image: Institute for Animal Health http://www.bbsrc.ac.uk/news/health/2012/120126-pr-how-to-make-better-vaccines.aspx

Bacille Calmette Guerin (BCG) is the most common vaccine administered to combat tuberculosis disease in the world. (1) The vaccine contains a weakened live strain of Mycobacterium bovis, which is present in cows and shares a common ancestor with the human tubercule bacillus Mycobacterium tuberculosis (2). Similar to other vaccines, BCG creates the formation of antibodies from the harmless strain of Myobacterium bovis to help prevent tuberculosis, and the vaccine usually leaves a skin lesion or a scar (1). The efficacy of BCG vaccine varies from 0-80% depending on age, the type of BCG vaccine, and the population (1). Although BCG remains as the primary vaccine against tuberculosis, it has only produced variable amounts of success. Many factors, including recent findings that distinct BCG strains have very different biochemical characteristics due to mutations, have further complicated the issue (1). Researchers are currently searching for a more effective way to treat tuberculosis disease, but none has been found to date (1).

Origin

The origin of the Bacile Calmette Guerin virus began when Albert Calmette and Camille Guerin started working on Mycobacterium bovis in 1908. After the stain was attenuated 230 times over thirteen years, BCG was used as a vaccine to treat tuberculosis (1). The strain went through many unknown genetic changes as it became less virulent in animals. After the original success of the vaccine, it was distributed all around the world. However, as the vaccine underwent distribution, the newly distributed strains underwent distinct genetic changes (1). BCG strains continued to change as individual countries altered the strain to fit their own needs (3). Currently, there are seven strands that are administered throughout the world, but they differ in gene sequences and protein production (3).

Tuberculosis Function

Tuberculosis is almost always contracted through the air when the respiratory system ingests the bacteria Mycobacterium Tuberculosis. Once the bacteria enter the organism, Mycobacterium tuberculosis becomes implanted in alveoli and is usually ingested by nearby macrophages, although it can also be ingested by alveolar epithelial type II pneumocytes (4). When the bacteria enter the macrophage it is phagocytosed by macrophage mannose and occupies an endocytic vacuole called the phagosome (4). After the Mycobacterium tuberculosis becomes assimilated in the phagosome, it must avoid death from the macrophage’s phagolysosome. Mycobacterium tuberculosis has many mechanisms to combat this problem, which include stopping phagosome-lysosome fusion and recruiting RAB proteins to prevent phagosomal maturation and catalyze endosome trafficking (4). If the bacteria continue to grow in the lung, it can have varying effects depending on the strength of the organism’s immune system. Latent tuberculosis occurs when the organism has a strong immune system; in which case the infection cannot progress and remains dormant. However, if an organism has a weak immune system, the granulomatous focal lesions that prohibit the spread of bacteria liquefy and allow Mycobacterium tuberculosis to replicate and spread throughout the lungs (4). It is for this reason that other factors that slow the immune system such as HIV, sickness, and aging can bolster the effectiveness of Mycobacterium tuberculosis. Eventually, uncontrolled growth of Mycobacterium tuberculosis can lead to lung damage and eventually suffocation and death because of an organism’s lack of oxygen (4).

BCG'S response to Tuberculosis

BCG, like most vaccines, stimulates antibodies and creates a resistance without damaging the organism. The BCG vaccine recruits CD 4 and CD 8 T cells as a response to protective mycobacterial antigens (5). After recruiting these cells, the new cells are exposed to the macrophage product interleukin 12 which calls for T cell to secrete interferon y (6). When Mycobacterium tuberculosis enters the cell, interferon y reduces the pH in the phagosomal membrane and produces superoxide and nitric oxide, which can destroy Mycobacterium Tuberculosis (6).

Structural and Functional Differences of Mycobacterium tuberculosis and BCG

The M. Bovis strain of the BCG vaccine is similar to Mycobacterium tuberculosis, but there are some structural and functional differences between the two strains. Recent genetic sequencing has shown that the BCG vaccine and Mycobacterium tuberculosis have three distinct genomic regions (2). The first genomic difference, named RD 3, is a 9.3-kb genomic segment that is absent in BCG compared to virulent M. Bovis and Mycobacterium tuberculosis (2). However, the researchers concluded that the absence of RD3 occurred during the derivation of BCG and that RD3 did not make Mycobacterium tuberculosis virulent. A similar conclusion was made for the genomic segment RD2, which also disappeared from the BCG strain after it had already been used as a vaccine. However, the researchers discovered through two dimensional gel electrophoresis that RD1, a 9.5-kb DNA segment absent in BCG, could have significant implications as to why BCG is not virulent for humans. RD1 was found to repress at least ten proteins involved the in the regulation of multiple genetic loci which suggests that it is likely that a regulatory mutation is responsible for the lack of virulence in BCG (2). Some researchers now hypothesize that the absence of RD1 calls for BCG-derived antigens to the vacuolar pathway to antigen presentation (5). Additionally, another study injected mice with a mutated M. Bovis and Mycobacterium tuberculosis strain that did not contain RD1 and found more ways in which the presence of BCG differentiates itself from Mycobacterium tuberculosis. The mutant mice could not cause cytolysis of pneumocytes compared to their infected counterparts (7). They found that RD1 codes for the protein ESAT 6, which mediates cytolysis of the infected cell and tissue invasiveness (7). Since BCG lacks RD1, cytolysis does not occur and the organism can remain unharmed.

References

1. 2. 3. 4. 5. 6. 7.

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Image of a dendritic cell after ingesting a small amount of the BCG vaccine. Image: Institute for Animal Health http://www.bbsrc.ac.uk/news/health/2012/120126-pr-how-to-make-better-vaccines.aspx

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Edited by Scott Treiman, student of Joan Slonczewski for BIOL 116 Information in Living Systems, 2013, Kenyon College.