Tuberculosis is one of the oldest known human diseases and still remains a global health problem today despite significant medical advancements. TB primarily attacks the lungs but can also affect other parts of the body. If not treated properly, TB disease can be fatal. The World Health Organization (WHO) has declared tuberculosis a global health emergency. Continued research is critical to developing better diagnostics, treatments, and a more effective vaccine to ultimately end this epidemic.
Mycobacterium tuberculosis is the bacteria that causes tuberculosis in humans. It is spread through the air from one person to another when people who are sick with pulmonary or laryngeal TB expel bacteria by coughing, sneezing or spitting. Only people who are actively sick are infectious. It is estimated that one-third of the world’s population is infected with the bacteria that causes TB but have latent TB, meaning they are infected but do not have active TB disease and cannot spread it. Latent TB is not infectious. Five to ten percent of latent infections will progress to active TB disease which, if left untreated, kills more than half of its victims.
TB disproportionately affects poorer nations and marginalized populations. Over 95% of TB deaths occur in developing countries. It is one of the top ten causes of death and the leading cause of a single infectious agent (above HIV/AIDS). In 2020, an estimated 10 million people fell ill with TB worldwide and 1.5 million died from the disease (including 214 000 people with HIV). India, Indonesia, China, the Philippines, and Pakistan reported the highest numbers of cases. Areas with high HIV prevalence, poverty and malnutrition are most severely impacted. Contributing factors for TB include overcrowding that enables easy spread, poor nutrition, lack of access to quality healthcare, and social determinants like homelessness or incarceration.
Diagnosing TB can be challenging. Currently, diagnosis relies on microscopic examination of body fluids or tissues for the presence of TB bacteria. This is called direct smear microscopy. The TB bacteria are sometimes difficult to detect under the microscope, especially in people with extra pulmonary or smear negative pulmonary TB. Culturing TB bacteria is the gold standard for diagnosis but can take 1-6 weeks for results. New diagnostics are urgently needed to overcome these limitations and enable rapid testing at the point-of-care. Several promising technologies are in development including blood-based tests, urine-based tests, molecular assays that can detect TB in all forms and drug resistance, and tests that can provide a diagnosis in hours instead of weeks. Diagnostics that enable automated, nonspecialized testing outside of laboratories could facilitate earlier diagnosis especially in resource-limited settings.
The current standard treatment for drug-susceptible TB is a 6 month regimen consisting of isoniazid, rifampicin, pyrazinamide and ethambutol given for 2 months followed by isoniazid and rifampicin for 4 months. Non-adherence to treatment and improper or incomplete treatment can lead to the development of drug-resistant TB. Multidrug-resistant TB (MDR-TB) is TB that does not respond to at least isoniazid and rifampicin, the two most powerful anti-TB drugs. Treating MDR-TB requires using second-line drugs that are less effective, have more adverse effects and are much more expensive. Extensively drug-resistant TB (XDR-TB) is a rarer form of TB that is resistant to isoniazid and rifampicin along with any fluoroquinolone and at least one of three injectable second-line drugs. Treatment for XDR-TB and other pre-XDR and XXDR forms takes 2 years or more and has poor treatment success rates. Novel antimicrobial regimens for both drug-susceptible and drug-resistant TB are urgently required, especially oral formulations that can be given for shorter durations to improve adherence and reduce transmission.
Several candidate vaccines in clinical trials are being evaluated to replace or improve upon Bacille Calmette-Guérin (BCG), the only currently approved vaccine for TB. BCG provides effective protection against severe childhood forms of TB such as TB meningitis and miliary disease, however its efficacy in preventing pulmonary TB in adolescents and adults is highly variable, ranging from 0% to 80%. Developing a more effective vaccine capable of preventing pulmonary TB in all age groups is crucial for global TB control and elimination. Vaccines that boost or improve on the efficacy of BCG are being evaluated such as: VPM1002, rBCG30 and MTBVAC. Whole-cell vaccines using inactivated or live-attenuated forms of M. tuberculosis with or without protein subunits are also promising approaches potentially capable of conferring protection against latent TB infection and reactivation. Advancing vaccine candidates through late-stage efficacy trials is urgently needed.
Tuberculosis research continues to be vital in the fight against this ancient yet evolving disease threat. Developing point-of-care diagnostics, novel drug regimens for all TB forms including drug-resistant cases, and improving vaccines all have the potential for major impacts on reducing the global health and economic burden of TB. Sustained investment and research collaborations across the public and private sectors will be key to accelerate progress towards ending the tuberculosis epidemic.