Bacillus Calmette-Guérin (BCG)

Bacillus Calmette-Guérin (BCG) is a live attenuated vaccine derived from a strain of Mycobacterium bovis, primarily used for the prevention of tuberculosis (TB). Developed in the early 20th century, the BCG vaccine remains one of the oldest and most widely administered vaccines in the world. Beyond its role in tuberculosis control, it also has therapeutic applications in bladder cancer and potential immunomodulatory effects in other diseases.

Historical Background and Development

The BCG vaccine was developed by two French scientists, Albert Calmette and Camille Guérin, at the Pasteur Institute in Lille. Beginning in 1908, they sought to attenuate the virulence of Mycobacterium bovis, a pathogen closely related to Mycobacterium tuberculosis, by repeated subculturing on a bile–potato medium. After 230 serial passages over 13 years, they produced a strain that was non-virulent in animals but retained immunogenic properties.
The first human administration of BCG took place in 1921 in Paris, marking the beginning of its use in TB prevention. Following successful trials, the vaccine was adopted internationally through the efforts of the League of Nations Health Committee. By the mid-20th century, it had become a key component of global tuberculosis control programmes under the World Health Organization (WHO).

Composition and Characteristics

The BCG vaccine contains live attenuated Mycobacterium bovis bacteria that have lost their ability to cause disease but still stimulate an immune response. Unlike many modern vaccines, BCG does not contain adjuvants or preservatives and must be stored under refrigeration to maintain viability.
There are several BCG substrains in use worldwide, resulting from genetic divergence during propagation in different laboratories. Common strains include:

• BCG Pasteur (France)
• BCG Danish 1331 (Denmark)
• BCG Tokyo 172 (Japan)
• BCG Moreau (Brazil)
• BCG Russia (Moscow strain)

Although all provide protective immunity, minor differences in genetic composition and antigenic expression can affect immunogenicity and side-effect profiles.

Mechanism of Action

The BCG vaccine works by stimulating the cell-mediated immune response — crucial in defending against mycobacterial infections. Following intradermal administration, the attenuated bacilli are taken up by macrophages and dendritic cells, which present antigens to T lymphocytes. This triggers the activation of CD4+ and CD8+ T cells, leading to the production of cytokines such as interferon-gamma (IFN-γ) and tumour necrosis factor-alpha (TNF-α).
These immune mediators enhance macrophage killing of intracellular Mycobacterium tuberculosis and establish long-term immune memory. The vaccine thereby primes the immune system to recognise and respond rapidly to future TB exposure.
Interestingly, BCG also exerts non-specific or heterologous effects, boosting innate immune responses against other pathogens — a phenomenon known as trained immunity. This has led to research into its potential protective role against viral and non-mycobacterial infections.

Administration and Dosage

BCG is administered intradermally, typically into the upper arm (deltoid region). It is usually given as a single dose at birth or soon after in countries with a high prevalence of tuberculosis.
Dosage guidelines:

• Infants (<1 year): 0.05 mL of vaccine
• Children (>1 year) and adults: 0.1 mL of vaccine

The site of injection often develops a small papule that may ulcerate and heal over several weeks, leaving a characteristic scar. Revaccination is not generally recommended, as evidence suggests limited additional benefit.

Efficacy and Protection

The protective efficacy of BCG varies widely between populations and regions — ranging from 0% to 80% — due to factors such as genetic variation, environmental mycobacteria exposure, and differences in vaccine strain or administration technique.
However, BCG is highly effective in preventing severe forms of childhood tuberculosis, including:

• Miliary TB (disseminated disease)
• TB meningitis (infection of the central nervous system)

Its effectiveness against pulmonary TB in adults is more variable and generally lower, contributing to continued research into next-generation TB vaccines.

Safety and Adverse Effects

The BCG vaccine is generally safe, with a strong safety record over decades of global use. However, as it is a live vaccine, some local and systemic reactions may occur:

• Local reactions: Pain, redness, or mild ulceration at the injection site (a normal immune response).
• Regional lymphadenitis: Swelling of nearby lymph nodes, occasionally suppurative.
• Disseminated BCG infection: Rare but serious complication, usually in immunocompromised individuals (e.g., HIV-infected infants).
• Keloid formation: In some individuals, hypertrophic scarring may develop at the site.

The vaccine is contraindicated in:

• Individuals with immunodeficiency disorders (including HIV-positive infants).
• Pregnant women, due to theoretical risks of foetal infection.

Role in Global Tuberculosis Control

The World Health Organization (WHO) recommends routine BCG vaccination in all countries with a high incidence of tuberculosis, particularly to protect infants and young children. It forms part of the Expanded Programme on Immunization (EPI), typically administered at birth alongside other vaccines.
In low-incidence countries (e.g., the United Kingdom, the Netherlands, and the United States), BCG vaccination is reserved for high-risk groups such as:

• Healthcare workers exposed to TB patients.
• Travellers to TB-endemic regions.
• Infants and children in close contact with active TB cases.

Despite its limitations, BCG remains the only available vaccine against tuberculosis, pending the development of newer candidates like M72/AS01E and VPM1002.

Use in Bladder Cancer Therapy

Beyond infectious disease prevention, BCG has a well-established role in oncology. Since the 1970s, it has been used as intravesical therapy for non–muscle-invasive bladder cancer (NMIBC).
When instilled directly into the bladder, BCG triggers a robust local immune response involving cytokine release, recruitment of immune cells, and destruction of tumour cells. This treatment significantly reduces tumour recurrence and progression rates and remains a first-line therapy for NMIBC worldwide.

Emerging and Experimental Applications

Recent studies have explored the broader immunological effects of BCG beyond tuberculosis and cancer, including:

• Diabetes prevention: Trials such as the FAIR and BCG Trial for Type 1 Diabetes investigate its potential in modulating autoimmune responses.
• COVID-19 research: Preliminary studies examined whether BCG’s trained immunity could reduce susceptibility or severity, though results remain inconclusive.
• Allergy and inflammatory disease modulation: BCG may influence immune tolerance mechanisms, warranting further investigation.

These findings highlight the vaccine’s complex and potentially far-reaching impact on human immunity.

Challenges and Future Directions

Despite its success, several challenges remain:

• Variable efficacy: The reasons behind regional differences in protection are still being investigated.
• Duration of immunity: Protection tends to wane after 10–15 years.
• HIV co-infection: The risk of disseminated infection limits use in populations with high HIV prevalence.

Global research efforts are focused on developing new-generation TB vaccines, either as improved replacements or boosters for BCG. Promising candidates include recombinant BCG strains, subunit vaccines, and viral vector–based formulations.

Significance

The Bacillus Calmette-Guérin vaccine stands as a landmark achievement in medical history. It has saved millions of lives by preventing severe tuberculosis in children and continues to play a vital role in public health. Its versatility — spanning infectious disease prevention, cancer therapy, and immune modulation — underscores its enduring scientific and clinical importance.