Tuberculosis (TB), caused by the bacterium Mycobacterium tuberculosis, remains one of the leading infectious causes of death worldwide, despite being preventable and curable. An estimated 10.7 million people fell ill with TB in 2024, resulting in 1.23 million deaths. One-quarter of the global population is thought to have latent TB infection (LTBI). The World Health Organization has set targets to drastically reduce TB incidence and mortality. These goals cannot be met without a more effective tool for prevention, particularly one that protects adults.
Understanding the Existing BCG Vaccine
The Bacille Calmette-Guérin (BCG) vaccine is the only licensed vaccine against tuberculosis. It is a live-attenuated vaccine derived from Mycobacterium bovis, and it has been in use for nearly a century. The vaccine is primarily administered to infants in countries where TB is common, and it offers significant protection against severe, disseminated forms of TB in young children, such as miliary TB and tuberculous meningitis.
The protective effect of the vaccine, however, is highly variable against the most common form of the disease: pulmonary TB in adolescents and adults. Studies have shown that protection from BCG can wane as children grow older, offering no protection to adults in some high-burden settings. The efficacy against adult pulmonary disease can range widely, with some trials showing negligible effect.
One significant factor contributing to this variable and low efficacy is environmental exposure to non-tuberculous mycobacteria (NTM). These environmental organisms share antigens with M. tuberculosis and are common in tropical regions. Exposure to NTM may improperly prime the immune system, which interferes with the BCG vaccine’s ability to generate specific immunity against TB.
This lack of reliable, long-lasting protection against pulmonary TB in adults means that the BCG vaccine cannot interrupt the transmission of the disease effectively. A new vaccine is needed to break the cycle of infection and achieve global elimination targets. The development of drug-resistant strains of TB, such as multidrug-resistant TB (MDR-TB), further highlights the need for a preventive solution beyond current treatments.
Identifying High-Risk Groups for Vaccination
Individuals residing in areas with a high TB incidence, particularly in Asia and Africa, are a primary target group for a new vaccine. This includes people who frequently travel or immigrate from these high-burden countries.
Certain co-morbidities significantly increase the risk of developing active TB disease once infected. People living with HIV are at a higher risk, as are those with diabetes, severe kidney disease, or head and neck cancer. Individuals receiving immunosuppressive therapies, such as specialized treatments for rheumatoid arthritis or organ transplant recipients, are also vulnerable.
Healthcare workers (HCWs) represent another high-risk group due to occupational exposure in clinical settings. HCWs in high-incidence settings, especially those dealing with drug-resistant TB, face a constant threat of infection. An effective adult vaccine would also be valuable for the one-quarter of the global population already living with latent TB infection (LTBI). For these individuals, a new vaccine could act as a booster or therapeutic agent to prevent the latent infection from reactivating into active disease.
Developing New Adult TB Vaccines
The current pipeline for next-generation TB vaccines is focused on two strategic goals: prevention and therapy. Preventative vaccines aim to protect adolescents and adults who are not yet infected with M. tuberculosis or to boost the waning protection of the original BCG vaccine. Therapeutic vaccines are designed to be administered to people already infected with LTBI or as an adjunct to antibiotic treatment for active TB, helping to shorten the duration of drug therapy or prevent relapse.
One of the most promising candidates is M72/AS01E, a subunit vaccine that has demonstrated significant efficacy in clinical trials. M72/AS01E uses a fusion protein, M72, derived from two M. tuberculosis antigens, combined with the AS01E adjuvant. In a Phase IIb trial, M72/AS01E showed an overall efficacy of 50% over three years in preventing the progression to active pulmonary TB in HIV-negative adults who already had latent infection.
The success of M72/AS01E highlights the shift toward subunit vaccines, which use specific mycobacterial proteins to elicit a targeted immune response. Other candidates include modified whole-cell vaccines and recombinant BCG strains, like VPM1002, which are being developed to improve on the original BCG’s performance. The development process is lengthy, requiring large-scale Phase III trials to confirm long-term safety and efficacy data before a new vaccine can be approved and deployed globally.