There is probably no vaccine in wide use that has been the subject of as much scrutiny and controversy as the tuberculosis vaccine commonly referred to as Bacillus Calmette-Guerin (BCG) [ 1 ]. It is one of the oldest vaccines available and has been widely adopted worldwide except for the USA and the Netherlands. The estimated efficacy rates have varied widely in different studies ranging from broad protection of more than 80 % to no efficacy at all.  

Tuberculosis has caused disease in human for many millennia with cases being noted in mummies from the age of the Pharaohs in Egypt. It is likely responsible for the majority of deaths in the USA and Europe in recorded history. During the tenth century it was responsible for 400 in every 100,000 deaths. With improving living conditions, sanitation, and social advances came a decrease in the incidence and mortality in the industrialized world.

The disease is caused by the pathogen Mycobacterium tuberculosis first described by Koch in 1882. Tuberculosis is acquired through the respiratory tract and from there can enter a latent stage or progress to active disease. The majority of patients infected initially are asymptomatic, entering a latent stage where the immune system keeps the disease in check. For most individuals infected with tuberculosis, the average lifetime risk of reactivation disease is roughly 10 %. Should disease become active, tuberculosis most commonly causes disease in the lungs but has the potential to disseminate to virtually any organ [ 1 ]. The time between primary infection and reactivation can span anywhere from weeks to years which is one of the more challenging aspects of conducting trials for a vaccine. It is a highly infectious disease with 25–50 % of close contacts becoming infected when exposed to an active case.

The live attenuated oral BCG vaccine was first given to infants in Paris in 1921 and has undergone substantial changes since then. The attenuated Mycobacterium bovis strain was first used by French scientists Calmette and Guerin where they studied a strain of M. bovis causing tuberculous mastitis in cows. They painstakingly cultured a strain every 3 weeks over the course of 13 years leading to a non-pathogenic and phenotypically different bacteria. BCG has been part of the expanded program for immunization of the WHO since the 1970s and has been administered some four billion times with relatively few significant side effects. Only recently has it been noted that administration of BCG can result in active infection in patients with advanced immune suppression such as those with HIV. Recommendations have changed as to not include such patients in current immunization schedules.

The extent of efficacy of this vaccine seems to depend on prior exposure to Mycobacteria which itself is a function of age. Trials on efficacy have widely varied with some trials demonstrating great protection against pulmonary tuberculosis and others showing virtually no protection at all [ 2 ]. In a meta-analysis performed in 2012, investigators found that in children who were school aged with negative prior tuberculin testing a relative risk of 0.26 was achieved and a relative risk of 0.41 was achieved in neonates. This effect seems to disappear in adolescent trials although some protection was observed in adult trials. Factors that may explain this decrease in protection during the teenage years include the fact that the immune system may not be mature enough when first administered to confer long-lasting immunity, and co-infection with certain helminthic and viral pathogens which could depress immunity (the extreme of this being HIV). The greatest efficacy of the tuberculous vaccine seems to be in decreasing disseminated disease and meningitis in children where protection can be as high as 80 % [ 3 ]. The effect of BCG on immunity seems to be greatest during the first 10–15 years after administration with no significant increased protection noted in adolescents and adults.

The BCG vaccine is currently administered to newborns in countries that have adopted the vaccine in the form of one intradermal injection. The dose of vaccine varies by age and formulation. The official WHO recommendation is to receive a single intradermal vaccine dose.

References
-------------

[1]. Plotkin SA, Orenstein WA, Offit PA (eds) Vaccines, 6th edn

[2]. Trunz BB, Fine PEM, Dye C (2006) Effect of BCG vaccination on childhood tuberculous meningitis and miliary tuberculosis worldwide: a meta-analysis and assessment of cost- effectiveness. Lancet 367:1173–1180

[3]. Rodriques LC, Diwan VK, Wheeler JG (1993) Protective effect of BCG against tuberculous meningitis and miliary tuberculosis: a meta-analysis. Int J Epidemiol 22:1154–1158