Introduction

Tuberculosis (TB), caused by Mycobacterium tuberculosis, is a global public health challenge. Despite significant advances in medicine, TB remains one of the leading infectious causes of morbidity and mortality worldwide. Among the various interventions to control TB, vaccination has been a cornerstone. The Bacillus Calmette-Guérin (BCG) vaccine, first introduced in 1921, is the only licensed vaccine currently available for TB prevention.

The BCG vaccine has played a crucial role in reducing the incidence of severe forms of TB in children, such as meningitis and miliary TB. However, its variable efficacy against pulmonary TB in adults, the most infectious and common form of the disease, continues to drive research into improved TB vaccines. This document provides a detailed exploration of the BCG vaccine, including its history, biology, administration, efficacy, limitations, and future prospects in TB vaccination strategies.


History of the BCG Vaccine

Development

  • The BCG vaccine was developed by French scientists Albert Calmette and Camille Guérin at the Pasteur Institute.
  • Between 1908 and 1921, they attenuated a strain of Mycobacterium bovis by repeated subculturing in a bile-glycerin medium.
  • The resulting strain, named Bacillus Calmette-Guérin, was found to be non-virulent but retained its ability to induce an immune response against M. tuberculosis.

Global Rollout

  • The first human trials were conducted in 1921.
  • The BCG vaccine was adopted by various countries during the mid-20th century as part of TB control programs.
  • It is now one of the most widely used vaccines, with over 100 million doses administered annually.

Biology of the BCG Vaccine

Composition

The BCG vaccine is a live attenuated strain of Mycobacterium bovis. It retains some genetic and antigenic similarities to M. tuberculosis, enabling it to elicit a protective immune response.

Mechanism of Action

  • Cell-Mediated Immunity: The vaccine stimulates the immune system, particularly T-helper 1 (Th1) cells, to produce cytokines such as interferon-gamma (IFN-γ), which activate macrophages to kill intracellular bacteria.
  • Memory T Cells: It generates a pool of memory T cells that can rapidly respond to subsequent exposure to M. tuberculosis.

Administration

  • The BCG vaccine is administered intradermally, usually in the upper arm.
  • The recommended dose varies depending on the age and immunization schedule, with newborns typically receiving 0.05–0.1 mL.

Efficacy of the BCG Vaccine

Protection Against Severe TB in Children

  • The BCG vaccine is highly effective (70–80%) in preventing severe forms of TB, such as meningitis and miliary TB, in children.
  • Its efficacy is greatest when administered at birth or shortly after.

Variable Efficacy Against Pulmonary TB

  • The vaccine’s efficacy in preventing pulmonary TB, particularly in adults, varies widely (0–80%) across studies and populations.
  • Factors influencing variability include:
    • Geographic Location: Higher efficacy in non-tropical regions.
    • Exposure to Environmental Mycobacteria: Prior exposure can reduce the effectiveness of the vaccine.
    • Genetic Variability: Differences in host genetics and immune responses.

Duration of Protection

  • Protection wanes over time and is generally not effective beyond 10–20 years after vaccination.
  • Booster doses are not typically recommended due to limited evidence of added benefit.

Limitations of the BCG Vaccine

  1. Variable Efficacy:
    • Inconsistent protection against pulmonary TB in adults is a major limitation.
  2. Interference with Diagnostic Tests:
    • The BCG vaccine can cause false-positive results in the tuberculin skin test (TST), complicating TB diagnosis.
  3. Safety Concerns in Immunocompromised Individuals:
    • Live vaccines, including BCG, are contraindicated in individuals with HIV/AIDS or other forms of immunosuppression due to the risk of disseminated BCG infection.
  4. Limited Impact on Transmission:
    • Because the vaccine is less effective against pulmonary TB, it has limited ability to reduce transmission in high-burden settings.

Global Use and Policies

Universal Immunization

  • The WHO recommends universal BCG vaccination in countries with high TB prevalence to protect children from severe forms of TB.
  • In low-burden countries, BCG vaccination is not part of routine immunization but may be offered to high-risk groups.

Vaccination Coverage

  • Over 150 countries include BCG vaccination in their national immunization programs.
  • Coverage rates exceed 85% globally, with the highest coverage in regions with endemic TB.

Contraindications

  • BCG vaccination is contraindicated in:
    • Infants with symptomatic HIV infection.
    • Individuals with known immunodeficiency.
    • People with active TB or a history of severe allergic reactions to the vaccine.

Adverse Reactions

  1. Local Reactions:
    • Pain, swelling, and ulceration at the injection site are common and typically resolve without treatment.
  2. BCG Lymphadenitis:
    • Enlargement of regional lymph nodes, sometimes requiring aspiration or surgical intervention.
  3. Disseminated BCG Infection:
    • A rare but serious complication in immunocompromised individuals.

BCG and TB Diagnosis

The BCG vaccine can interfere with the interpretation of the tuberculin skin test (TST), as both the vaccine and infection induce a delayed-type hypersensitivity reaction.

  • TST False Positives:
    • Common in vaccinated individuals, particularly if vaccinated recently or multiple times.
  • IGRA Tests:
    • Interferon-gamma release assays (IGRAs) are preferred for TB diagnosis in BCG-vaccinated individuals, as they are unaffected by prior vaccination.

New and Improved TB Vaccines

The limitations of the BCG vaccine have spurred efforts to develop new vaccines with greater efficacy, especially against pulmonary TB.

Types of TB Vaccines in Development

  1. Subunit Vaccines:
    • Contain specific antigens from M. tuberculosis to elicit a targeted immune response.
    • Examples: M72/AS01E, ID93 + GLA-SE.
  2. Recombinant BCG Vaccines:
    • Genetically modified strains of BCG with enhanced immunogenicity.
    • Example: VPM1002.
  3. Live Attenuated Vaccines:
    • Modified strains of M. tuberculosis with reduced virulence.
  4. Viral Vector Vaccines:
    • Use viruses as delivery systems for TB antigens.
    • Example: MVA85A.
  5. Therapeutic Vaccines:
    • Aimed at boosting the immune response in individuals with latent or active TB.

Promising Candidates

  • M72/AS01E:
    • Demonstrated 50% efficacy in preventing active TB in a Phase 2b trial.
  • VPM1002:
    • A recombinant BCG vaccine showing promise in clinical trials.

BCG and Non-Tuberculosis Applications

Protection Against Non-TB Diseases

  • The BCG vaccine has demonstrated non-specific benefits, including protection against other respiratory infections and sepsis in neonates.
  • This phenomenon, termed “trained immunity,” involves enhanced innate immune responses.

BCG in Cancer Therapy

  • BCG is used as an intravesical therapy for non-muscle-invasive bladder cancer.
  • It stimulates a local immune response, reducing the risk of recurrence.

BCG and COVID-19

  • Studies during the COVID-19 pandemic explored whether BCG vaccination provides cross-protection against SARS-CoV-2. While some data suggested reduced mortality in BCG-vaccinated populations, more research is needed.

The Future of TB Vaccination

Challenges

  1. Complex Pathogenesis:
    • The ability of M. tuberculosis to evade the immune system complicates vaccine design.
  2. Funding and Resources:
    • Limited funding for TB vaccine research compared to other diseases.
  3. Clinical Trials:
    • Long and expensive trials are required to demonstrate efficacy against TB, given its slow progression and latency.

Opportunities

  • Advances in immunology, genomics, and vaccine technology offer hope for more effective vaccines.
  • Collaborative initiatives like the TB Vaccine Initiative (TBVI) and Aeras aim to accelerate vaccine development.

Conclusion

The BCG vaccine has been a cornerstone of TB prevention for over a century, particularly in protecting children from severe forms of the disease. However, its limited efficacy against pulmonary TB and inability to curb transmission highlight the urgent need for new vaccines. Continued investment in TB vaccine research and global collaboration are critical to achieving the WHO’s End TB Strategy and ultimately eradicating this ancient disease.

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Last Update: January 26, 2025