The Persistent Threat of Tuberculosis

Throughout the last three years, while the world was primarily focused on Covid-19, tuberculosis (TB) continued to pose a significant threat to public health globally. Fortunately, advancements are on the horizon with the development of a new vaccine, the first in more than a hundred years.

Tuberculosis has plagued humanity for centuries, dating back to ancient Egyptian mummies, and remains a formidable adversary. Alarmingly, it currently impacts approximately 10.6 million individuals worldwide, resulting in nearly 1.6 million fatalities in 2021 alone. This makes TB the second deadliest infectious disease globally, surpassed only by Covid-19, which claimed over 3.5 million lives that same year.

Similar to Covid-19, tuberculosis spreads through the air and primarily targets the respiratory system. However, unlike Covid, it is caused by a bacterium known as Mycobacterium tuberculosis, which specifically infects the lower respiratory tract, including the trachea, bronchi, and lungs.

Symptoms of TB are often nonspecific and may include fever, chest pain, persistent cough, fatigue, and loss of appetite. These symptoms can range from mild to severe, with advanced stages potentially causing bloody coughs and swollen lymph nodes. If left untreated, TB can become fatal in approximately 70% of cases within a decade of diagnosis.

Despite the severity of the disease, not everyone infected with M. tuberculosis will become ill. In fact, around 85% to 95% of those infected remain asymptomatic, a condition referred to as latent TB. During this stage, individuals are not contagious as their immune system actively fights off the bacteria.

The immune response is led by alveolar macrophages—immune cells located in the lungs that engulf and attempt to eradicate the bacteria. These cells call for additional immune support, and once the reinforcements arrive, they either eliminate the bacteria or create a granuloma, a collection of immune cells that aims to contain the infection. Granulomas are common in many diseases but are especially characteristic of pulmonary tuberculosis.

At this containment stage, granulomas may calcify, and individuals can remain symptom-free for years or even decades. However, this does not guarantee that the infection is fully controlled.

If granulomas fail to completely eradicate the bacteria, they can become sites for bacterial growth. M. tuberculosis produces proteins and lipids that hinder the immune cells' ability to destroy it, effectively transforming granulomas into reservoirs for the bacteria. Over time, these granulomas may deteriorate, releasing bacteria into the lungs and leading to tuberculous bronchopneumonia.

As the infection progresses, the bacteria wreak havoc in the lungs, leading to the onset of active TB, where patients exhibit symptoms and can infect others. Although TB is not highly contagious, an infected individual can transmit the disease to one to three people during the course of their illness.

Diagnosis typically involves rapid molecular tests or culturing the bacteria from sputum samples, along with chest X-rays to identify lesions linked to tuberculosis. This comprehensive approach allows for identifying M. tuberculosis and initiating treatment.

Currently, there are four primary antibiotics used to treat TB, which are administered in combination over a six-month period, boasting a success rate exceeding 85%.

Yet, the battle against tuberculosis is far from over. TB can also affect other organs, including the skin, lymph nodes, nervous system, and bones, leading to extrapulmonary tuberculosis, which complicates diagnosis and treatment. Such cases constitute nearly 16% of all TB instances and are particularly prevalent among immunocompromised individuals and children.

Moreover, the lengthy six-month treatment can be daunting for those in low-income regions with limited healthcare access, contributing to higher TB rates in these areas due to treatment interruptions and relapses. The global rise in antibiotic resistance poses another significant challenge, with drug-resistant strains accounting for 3.6% of total TB cases in 2021—over a quarter of cases in India.

Preventing the spread of TB remains an uphill battle. While at-risk individuals may receive preventive antibiotics, vaccination stands as the strongest defense against the disease.

The history of TB dates back to 1882 when German physician Robert Koch identified the causative agent, Mycobacterium tuberculosis. It wasn't until nearly forty years later that scientists Albert Calmette and Camille Guérin developed the Bacillus Calmette-Guérin (BCG) vaccine, derived from a weakened strain of M. bovis. This vaccine is still in use today.

BCG is administered to newborns within six months of birth, reducing the risk of severe forms of TB by 85% in children and by 50% for pulmonary TB. However, its effectiveness diminishes significantly when administered to adults.

Excitingly, a new TB vaccine is set to enter a Phase 3 clinical trial in 2024, developed by GlaxoSmithKline (GSK). This trial, anticipated to enroll nearly 26,000 participants across Africa and Southeast Asia, aims to evaluate the efficacy of the M72 vaccine, which incorporates engineered proteins from M. tuberculosis. Previous trials demonstrated a 54% effectiveness in preventing pulmonary TB, potentially halving mortality rates.

Backed by funding from the Gates Foundation and the Wellcome Trust, which will contribute $550 million towards development, hopes are high for the approval of this new vaccine in 2024, marking a century since the introduction of BCG.

The first video, "Bio303 Lecture 1: The Global Burden of Infection and an Old Enemy, Malaria," delves into the historical context and current challenges of infectious diseases, including tuberculosis.

The second video, "Tuberculosis: The Enemy Within (1950)," provides a historical perspective on tuberculosis, illustrating its long-standing impact on health systems.

In conclusion, as we await the potential breakthrough in TB vaccination, the ongoing challenges of this ancient disease remind us of the importance of continued research and public health initiatives to combat tuberculosis effectively.