Tuberculosis (TB), caused by the rod-shaped bacterium Mycobacterium tuberculosis (Mtb), remains one of the world’s deadliest infectious diseases. In 2022, TB was the second leading cause of death globally, with an estimated 10.6 million people falling ill worldwide. The disease primarily affects the lungs (pulmonary TB), and its aerosol transmission makes it highly contagious. Despite decades of effort, an effective vaccine capable of preventing pulmonary TB in adults has yet to be developed.
The Paradox of the BCG Vaccine
The Bacille Calmette–Guérin (BCG) vaccine is the only licensed vaccine against TB and has been in use for nearly a century. BCG is an attenuated, or weakened, strain of Mycobacterium bovis and is administered globally, primarily to infants in countries where TB is common. The vaccine is effective at providing protection against the most severe, disseminated forms of the disease in young children, such as tuberculous meningitis and miliary TB.
However, the protective efficacy of BCG against adult pulmonary TB is highly variable, often ranging from 0% to 80% depending on the population and geographical region. This limited and inconsistent protection in adolescents and adults is the central challenge.
The current vaccine, therefore, fails to solve the main problem of controlling the global epidemic, underscoring the urgent need for a new generation of TB vaccines.
Mtb’s Unique Biological Defenses
The pathogen possesses intrinsic biological properties that allow it to resist immune destruction and persist within the host. The Mtb cell wall is encased in a thick, waxy layer rich in mycolic acids, which acts as a protective barrier. This lipid-heavy coat shields the bacteria from the host’s immune enzymes and makes it resistant to many standard antibiotics.
Once inhaled, Mtb is quickly engulfed by alveolar macrophages, which are immune cells designed to destroy invading microbes. Instead of being killed, the bacteria actively prevent the normal maturation of the phagosome, the internal compartment where it resides. Mtb achieves this by inhibiting the fusion of the phagosome with the lysosome, the cell’s digestive organelle, thereby avoiding the highly acidic and enzyme-rich environment that would normally break it down.
This ability to survive and multiply inside the macrophage allows Mtb to establish a persistent, long-term infection known as latency. The immune system responds by walling off the infected macrophages and other immune cells, forming a structured lesion called a granuloma. Within this granuloma, the bacteria can remain dormant for decades, only to reactivate later if the host’s immune system weakens.
The Necessity of Cellular Immunity
Traditional vaccines typically work by inducing a robust antibody-based, or humoral, immune response. However, because Mtb survives and hides inside host cells, antibodies are largely ineffective as they cannot reach the intracellular bacteria. Clearing Mtb infection requires a T-cell mediated, or cellular, immune response.
Specifically, the vaccine must induce effector T-cells, primarily CD4+ and CD8+ T-cells, that can recognize Mtb antigens and migrate deep into the lung tissue. These T-cells are responsible for producing signaling molecules like interferon-gamma (IFN-\(\gamma\)), which is necessary to activate the infected macrophages and enable them to finally kill the Mtb within. A major immunological hurdle is that Mtb actively delays the onset of this adaptive T-cell response, allowing the bacteria a critical window to establish a foothold and begin multiplying before the immune system can react effectively.
The challenge is designing a vaccine that can consistently generate these specific, long-lasting T-cells and ensure they are rapidly deployed to the site of infection. The cells must exhibit a particular quality of function, capable of overcoming the pathogen’s immune-evasion tactics.
Hurdles in Clinical Development and Testing
The scientific complexity is compounded by significant practical challenges in the development and testing of new TB vaccines. The long and unpredictable latency period of Mtb infection means that human efficacy trials are lengthy and extremely expensive. Trials must follow vaccinated individuals for several years to determine if a candidate vaccine truly prevents the progression to active disease.
A major impediment is the lack of reliable “correlates of protection,” which are measurable biological markers that could predict vaccine efficacy without waiting for years for active disease to develop. Without these validated biomarkers, vaccine testing remains an empirical process, forcing researchers to rely on costly and protracted field trials to prove a vaccine works. Conducting large-scale trials in the diverse, high-burden endemic regions presents substantial logistical and ethical complexities.