Genetic issues in BCG Vaccination

Genetic issues in BCG Vaccination

Sam Stew1 and Hui-Qi Qu2

1 University of Texas at Austin, School of Biological Sciences;

2 University of Texas Health Science Center Houston, School of Public Health

1.  BCG Vaccinations

BCG, or Bacillus Calmette-Guérin, is a vaccine used to protect against serious tuberculosis (TB) in early childhood. It is routinely given to children in regions of the world where TB is endemic, and it is estimated that about 100 million children are vaccinated with BCG each year. This is done to protect them from developing disseminated forms of TB, such as miliary or meningitis TB, which is often fatal. The vaccine contains attenuated, or weakened, Mycobacterium bovis (M. bovis), which is related to M. tuberculosis, the bacterium that causes tuberculosis. The body will recognize the BCG as an offending microbe and mount an immune response against it. Since BCG and M. tuberculosis are related, the immune response generated will be efficacious to prevent future systemic infections of M. tuberculosis in children.

Generally, the vaccine is very safe and usually causes only minor skin irritations at the site of the injection. In rare cases the vaccine can lead to disseminated infection of the vaccine, in which the BCG bacilli is able to spread throughout the body and cause a systemic infection. The incidence of the BCG vaccine causing this disease is very rare. According to Sadeghi-Shanbestari et al 2009, disseminated BCG infection occurs in 0.1 to 4.3 per one million children vaccinated, and is fatal in 50 to 71% of those cases.

2. Disputes

Since disseminated BCG infection is such a serious disease, and it tends to strike children shortly after being vaccinated with BCG, some parents may doubt the BCG vaccine because they are concerned that it is unsafe or that it could possibly cause their child to become ill, and there is no evidence that it will protect their children in later years. The quality of the BCG vaccine causing the disease may be doubted.  In fact, the quality of the vaccine is not the problem unless many children who receive the same batch of vaccine develop side effects or illness. The importance of this vaccine to protect children from the fatal disseminated TB should not be neglected.

3. Reason for disseminated BCG Infection

Actually, the cause of disseminated BCG infection has been found to be due to a mutation in one of the specific genes that encode proteins involved in the immune response to mycobacterial infection. Other names used in conjunction with disseminated BCG infection are Mendelian Susceptibility to Mycobacterial Diseases (MSMD) or Famial Atypical Mycobacteriosis (FAM).  Only newborn children with a causative mutation will become ill with disseminated BCG infection after they have been vaccinated. These genes known of harboring such mutations include IFNGR1, IFNGR2, STAT1, IL12B, IL12RB1, and IKBKG. An individual with normally functioning genes will not become ill since the BCG infection will be under full control and localized by the effective immune response.

4. Uses of this Knowledge

This knowledge can be used to detect these mutations in the future siblings of the children who have been diagnosed with BCG infection. Family members, especially newborns, should be screened for these mutations, and if found to have these mutations or MSMD/FAM then the BCG vaccine can be avoided. Furthermore, individuals with MSMD/FAM mutations are more susceptible to tuberculosis and therefore should be treated prophylactically when they have the chance of being exposed to TB bacilli. A common problem is the need of a newborn screening process to detect mutations in the families with MSMD/FAM cases. This presents a unique challenge since most of the nations that use the BCG vaccine are developing or don’t have the public health research infrastructure that is necessary to carry out the molecular diagnosis. Further research to develop convenient diagnostic kits for the mutation detection will help control this disease.

5. Future work on this subject

At this point there are approximately half of the patients whose BCG infections have idiopathic origins. It is hypothesized that these cases are caused by mutations that have not yet been identified, and so the further study of patients with BCG infection will be necessary to discover these mutations. Knowledge is power. The more we know about genes involved in the immune response, the more likely we will be able to control this disease. Finding new genes involved in BCG infection will increase our knowledge on host immunity against mycobacterial infection. This knowledge is critical for better control of the stubborn tuberculosis that is harming people’s health in developing countries.

* Sam Stew is a student at the University of Texas at Austin who is interested in how human genetics plays a role in microbial infection and cancer; Hui-Qi Qu’s group is aiming to dissect the molecular mechanisms of tuberculosis from an integrated approach of genetics, functional genomics, and environment. Correspondence to: