Tuberculosis (TB) remains a major global health challenge. In 2021, an estimated 10.6 million people developed TB, with 1.6 million deaths, a concerning increase from previous years. Vaccines have historically been, and continue to be, powerful tools in public health efforts against pathogens like Mycobacterium tuberculosis, the bacterium responsible for TB.
The BCG Vaccine
The Bacille Calmette-Guérin (BCG) vaccine was first administered to humans in 1921. It is derived from an attenuated, or weakened, live strain of Mycobacterium bovis, a bacterium related to Mycobacterium tuberculosis. The vaccine is administered via intradermal injection, into the upper layer of the skin.
BCG stimulates the immune system to recognize and respond to components of Mycobacterium tuberculosis. This involves innate and adaptive immune responses, including the production of T helper 1 (Th1) cytokines like interferon-gamma (IFN-γ). The vaccine’s mechanism also involves “trained immunity,” referring to long-lasting changes in innate immune cells that enhance their response to subsequent infections.
Despite widespread use, with over 100 million newborns vaccinated globally each year, BCG exhibits variable efficacy. It offers strong protection against severe forms of TB in infants and young children, such as TB meningitis (TB affecting the brain) and disseminated TB (TB spread throughout the body), with an average efficacy of 86%. However, its protection against pulmonary TB in adolescents and adults, the most common and transmissible form, is limited and inconsistent, especially in high-burden areas.
The reasons for this variable efficacy are not fully understood, but hypotheses include genetic differences among vaccine strains, variations in study methodologies, and the influence of environmental mycobacteria exposure. BCG has a favorable safety profile, with severe side effects occurring rarely, approximately one per one million doses in immunocompetent individuals. Common side effects include a mild local reaction at the injection site, which may involve a shallow ulcer, and minor regional lymph node swelling. Disseminated BCG infection can occur in immunocompromised individuals, so it is not recommended for those with conditions like HIV/AIDS.
Developing New Tuberculosis Vaccines
The limitations of the BCG vaccine, particularly its inconsistent protection against pulmonary TB in adults, underscore the need for new and improved TB vaccines. Current research and development efforts are exploring various approaches to overcome these challenges. One approach involves booster vaccines, given after BCG vaccination to enhance and prolong the protective immune response, especially in adolescents and adults.
Pre-exposure prophylactic vaccines are another strategy. These vaccines aim to prevent Mycobacterium tuberculosis infection or disease in individuals not yet exposed to the bacterium. This includes vaccines designed to replace BCG for initial immunization or to provide protection where BCG’s efficacy is low.
A third category, therapeutic vaccines, are intended for individuals already infected with Mycobacterium tuberculosis. They aim to prevent progression from latent infection to active disease, or to improve outcomes for those with active TB undergoing drug treatment. These vaccines could potentially shorten treatment regimens or prevent recurrence after standard therapy.
Developing new TB vaccines presents scientific challenges. The complex nature of Mycobacterium tuberculosis and its interactions with the human immune system are not fully understood, making it difficult to identify the precise immune responses needed for effective protection.
Vaccines are also needed that are effective across diverse populations, including those with HIV, and at various disease stages. Despite these obstacles, over 22 TB vaccine candidates are currently in various stages of clinical trials. Promising candidates include M72/AS01E, which demonstrated 50% protection against TB disease in a Phase IIb trial among individuals with latent TB infection. Another candidate, MTBVAC, is a live attenuated Mycobacterium tuberculosis vaccine currently undergoing Phase IIb/III clinical trials for prevention in adolescents and adults with latent TB infection.
Global Vaccination Efforts
Tuberculosis vaccination is an integral part of global disease control strategies. The World Health Organization (WHO) recommends that in countries with a high incidence of TB, a single dose of the BCG vaccine be provided to all infants at or soon after birth as part of national immunization schedules. This approach aims to protect the most vulnerable population against severe forms of the disease. In 2020, 154 countries reported BCG vaccination as a standard part of their childhood immunization programs, with over 95% coverage in 53 nations.
Implementing global vaccination programs faces logistical and equitable access challenges. Many communities in developing countries lack reliable infrastructure, making vaccine delivery difficult. Ensuring vaccines are kept at appropriate temperatures throughout transport and delivery is also a considerable hurdle. International organizations like the WHO play a guiding role, establishing preferred product characteristics for new TB vaccines and launching initiatives to accelerate their development and equitable access.
Vaccination is a component within a strategy to combat TB. This approach also includes early diagnosis, effective treatment, and prevention measures, such as contact tracing and infection control. The WHO’s End TB Strategy aims for a 95% reduction in TB mortality and a 90% reduction in incidence worldwide by 2035, and new, more effective vaccines are considered necessary to achieve these ambitious targets.