Tuberculosis: The Never-Ending Epidemic

Introduction

Tuberculosis (TB) remains the world’s leading infectious killer and a major driver of antimicrobial resistance. Nearly one-quarter of the global population is infected with Mycobacterium tuberculosis (Mtb), and an estimated 5–10% of those infected will develop active TB disease during their lifetime—imposing a profound health and economic burden worldwide. In 2023 alone, approximately 1.8 million people developed TB, leading to 1.25 million deaths despite decades of global control efforts.

Between 2015 and 2023, global TB incidence and mortality rates declined by only 8.3% and 23%, respectively falling short of the World Health Organization (WHO) “End TB Strategy” milestones of a 50% reduction in incidence and 75% reduction in deaths by 2025.

Advancing the Fight: Current Tools and Strategies to Control TB

While the WHO envisions TB elimination by 2035, achieving this goal will require transformative progress in the following:

Diagnosis

Despite remarkable scientific progress, many diagnostic approaches for TB remain rooted in the past. The Ziehl–Neelsen stain, developed in 1882, continues to be used in many parts of the world despite its limited sensitivity and inability to prevent transmission through early detection. Similarly, the Mantoux tuberculin skin test, introduced in the 1920s, is still employed to detect latent TB infection, even though far more accurate and rapid tools are now available. A major breakthrough came in 2010 with the introduction of the Xpert MTB/RIF assay (Cepheid Inc., Sunnyvale, CA, USA), the first WHO-endorsed, fully automated molecular test providing rapid diagnosis and rifampicin resistance detection. Its successor, Xpert Ultra (2017), offered further improvements in sensitivity and accuracy. Yet, according to the WHO Global Tuberculosis Report, only about 50% of TB cases worldwide are diagnosed using WHO-recommended molecular methods. The proportion of bacteriologically confirmed cases has also plateaued at roughly 60% between 2015 and 2023, underscoring persistent challenges in culturing Mtb in routine practice. Meanwhile, traditional skin testing has been complemented—and in many contexts surpassed—by interferon-gamma release assays (IGRAs) such as T-SPOT (Oxford Immunotec, Abingdon, UK) and QuantiFERON (Qiagen, Hilden, Germany), which provide greater specificity for Mtb infection. However, the long-held assumption that immunological reactivity equals latent TB is increasingly being challenged. Emerging evidence suggests that Mtb infection exists along a dynamic continuum, rather than a simple “latent versus active” dichotomy. 

Treatment

In recent years, TB treatment has undergone remarkable transformation, particularly for multidrug-resistant (MDR) and extensively drug-resistant (XDR) forms. Historically, TB therapy depended on lengthy and toxic regimens with limited efficacy, but innovative drug combinations are rapidly reshaping the therapeutic landscape. Landmark trials such as Nix-TB and ZeNix have demonstrated that a 6-month, all-oral regimen comprising bedaquiline, pretomanid, and linezolid (BPaL) can achieve superior outcomes compared to traditional, prolonged MDR-TB regimens—substantially improving cure rates while reducing both toxicity and treatment duration. Encouragingly, evidence is also emerging that shorter regimens may be effective for rifampicin-sensitive TB. Studies such as the TB-PRACTECAL, SimpliTB, and SHINE trials (the latter conducted in children) have shown that fluoroquinolone-based or optimized 4-month regimens can match the efficacy of standard 6-month therapy, offering the prospect of shorter, more manageable treatment courses for many patients. The TB drug development pipeline is now more robust than ever, with several promising candidates under evaluation through global collaborations such as the UNITE4TB initiative, which focuses on novel drug classes and mechanisms—including agents targeting ethionamide activation and cell-wall synthesis pathways. However, emerging resistance to newer drugs, particularly bedaquiline, is a growing concern. This underscores a persistent challenge in TB control: Mtb continues to develop resistance faster than the pace at which new antimycobacterial agents are brought into clinical use—highlighting the urgent need for sustained innovation, stewardship, and global access strategies.

Vaccines

The persistent inequities in access to diagnostic tools and effective treatments, compounded by the ongoing challenges of malnutrition, poverty, and broader social determinants of health, continue to hinder global progress toward tuberculosis (TB) elimination. Moreover, the rapidly evolving resistance to existing anti-TB drugs threatens to undermine recent therapeutic advances and further complicates disease management, particularly in low- and middle-income settings. At the same time, the growing understanding of TB pathogenesis and immune responses underscores an urgent need to reorient efforts toward prevention. Strengthening **preventive strategies—particularly through the development and equitable deployment of effective vaccines—**remains essential to achieving lasting control and eventual eradication of TB worldwide.

Vaccines for TB

The bacillus Calmette–Guérin (BCG) vaccine, introduced in the 1920s, remains the only widely used vaccine for TB. While BCG provides strong protection against severe childhood manifestations of the disease—such as TB meningitis and disseminated TB—its efficacy against pulmonary TB, the most prevalent and transmissible form in adults, is notably limited. The variable and often inconsistent performance of BCG, particularly in high-burden settings, highlights the urgent need for next-generation vaccines capable of providing broader, more durable, and reliable protection across all age groups and geographic regions.

A novel TB vaccine must have the potential to reduce TB incidence, prevent the progression from latent infection to active disease, and curb the transmission of drug-resistant strains, making it a critical component of global TB control strategies, especially the WHO End TB goal.

Significant progress has been achieved in TB vaccine research over the past decade, driven by the ambitious global goal of licensing at least one new vaccine within the next five years. As of August 2024, a total of 15 vaccine candidates were in clinical development, each targeting different components of the immune response to Mtb. Of these, four are in Phase I, five in Phase II, and six in Phase III clinical trials (see Table 1), reflecting a dynamic and increasingly mature vaccine pipeline that brings renewed optimism for the future of TB prevention.

Conclusions

New TB vaccines represent the cornerstone of global efforts to eliminate this devastating disease. Although the timeline for a fully effective vaccine remains uncertain, the remarkable progress achieved in recent years offers renewed optimism and momentum. With sustained research investment, increased funding, and stronger international collaboration, next-generation TB vaccines have the potential to dramatically reduce disease incidence, curb the rise of drug resistance, and bring the world closer to achieving the World Health Organization’s (WHO) End TB Strategy and long-term elimination goals.

Public–private partnerships, such as the Global Vaccine Alliance (Gavi), the Bill & Melinda Gates Foundation, and the Stop TB Partnership, play a crucial role in accelerating research and ensuring equitable access to new vaccines in resource-limited settings. At the same time, countries with high TB burdens are increasingly investing in TB research, while collaborations between pharmaceutical companies, academic institutions, and international organizations are expediting vaccine development. Together, these combined efforts aim to overcome the scientific, financial, and logistical barriers that have long impeded progress—bringing the goal of impactful, accessible TB vaccines closer to reality.

For the millions currently affected by TB—and the billions at risk of infection—the promise of a new vaccine represents more than scientific progress; it symbolizes hope for a healthier and more equitable future. However, the success of these scientific breakthroughs will depend on our collective ability to ensure that global health equity remains central to TB vaccine research and delivery. Without deliberate efforts to guarantee affordable access and equitable distribution, particularly in low- and middle-income countries where the TB burden is greatest, advances in research and clinical development will have limited real-world impact.

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