The Ancient Scourge That Refused to Surrender
In the annals of medical history, few diseases have cast as long and persistent a shadow as tuberculosis. For over a century, while scientists celebrated victory after victory against other infectious diseases, TB remained the stubborn enemy that refused to surrender. The global health community fought this ancient scourge with the same single weapon—the BCG vaccine—first developed in 1921, while tuberculosis continued its relentless march through vulnerable populations, particularly in low-and middle-income countries, adapting and surviving while medical science struggled to keep pace.
The numbers tell a sobering story that stretches across generations. TB has claimed more lives than any other infectious disease in human history, with an estimated 1.3 million deaths in 2022 alone and recent WHO reports indicating over 10.8 million new cases in 2023. Yet, these dry statistics barely capture the human toll—the children left orphaned, the families plunged into poverty, the communities devastated by a disease that preys disproportionately on the most vulnerable. The COVID-19 pandemic further exacerbated this crisis, disrupting TB detection and treatment programs worldwide and reversing years of hard-won progress.
Then, in 2024, a transformative development emerged from research laboratories across Africa and Asia—a potential new vaccine called M72/AS01E that demonstrated remarkable efficacy in cutting active TB risk in large-scale trials. This breakthrough represents more than just another medical advance. It stands as a testament to decades of stalled efforts, renewed commitment, and scientific perseverance against a disease that many in wealthier nations had forgotten, yet which continues to devastate communities worldwide.
For the first time since 1921, when the Bacille Calmette-Guérin (BCG) vaccine was first administered, we stand on the brink of having a new tool to protect against one of humanity’s oldest killers. The story of this vaccine development reads like a medical thriller—filled with dead ends, tantalizing clues, scientific rivalries, and ultimately, a breakthrough that could transform global health. It’s a story that spans continents, from research laboratories in Europe to clinical trial sites in South Africa, from the boardrooms of global health organizations to the rural clinics where TB remains a daily reality.
Understanding the Enemy: The Complex Biology of Tuberculosis
To truly appreciate the significance of this breakthrough, we must first understand the enemy in all its complexity. Tuberculosis is caused by the bacterium Mycobacterium tuberculosis, a cunning pathogen that has evolved alongside humans for thousands of years. Unlike many microbes that cause immediate illness, TB bacteria can linger in the body for years, even decades, waiting for an opportunity to strike. The bacteria primarily attack the lungs, creating lesions that can destroy lung tissue, but they can also travel to other organs, including the brain, bones, and kidneys, demonstrating remarkable adaptability.
The transmission of TB is deceptively simple—it spreads through the air when an infected person coughs, sneezes, or even speaks, releasing microscopic droplets containing the bacteria. This airborne transmission makes it particularly dangerous in crowded living conditions, healthcare settings, and communities with limited access to medical care. An estimated one-quarter of the world’s population lives with a latent TB infection, meaning they carry the bacteria without showing symptoms. Among these, 5-10% will develop active TB disease during their lifetime, typically when their immune systems become compromised by other illnesses, malnutrition, or aging.
The fight against TB has been hampered by several formidable challenges that have made it one of the most difficult infectious diseases to eradicate:
Drug-resistant strains represent perhaps the most alarming development in the TB landscape. The emergence of multi-drug resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) has created versions of the disease that are difficult and sometimes impossible to treat with conventional antibiotics. These strains develop when treatment is interrupted or when patients receive inadequate drug regimens, allowing the hardiest bacteria to survive and multiply. Treating drug-resistant TB requires lengthy, expensive, and often toxic drug regimens that can last up to two years and cause severe side effects including hearing loss, kidney damage, and psychiatric symptoms.
Poverty and social determinants create a vicious cycle with tuberculosis that has proven incredibly difficult to break. TB disproportionately affects the most vulnerable populations—those living in poverty, with limited access to healthcare, or compromised by malnutrition. Crowded housing, inadequate ventilation, and poor nutrition all increase the risk of transmission and progression from latent infection to active disease. Meanwhile, the disease itself deepens poverty, as affected individuals face catastrophic healthcare costs and lost income during prolonged treatment. The stigma associated with TB can lead to social isolation, job loss, and delayed diagnosis and treatment, creating a downward spiral that affects entire communities.
Diagnostic limitations have plagued TB control efforts for decades, creating a persistent barrier to effective control. Accurate, rapid diagnosis remains challenging in resource-limited settings, allowing undetected cases to continue spreading the disease. Traditional diagnostic methods like smear microscopy have poor sensitivity, while more advanced molecular tests remain expensive and difficult to implement in remote areas. The COVID-19 pandemic demonstrated how quickly modern science can develop and deploy diagnostic tests when sufficient resources are allocated—a stark contrast to the decades of inadequate investment in TB diagnostics that has hampered progress.
The vaccine gap created by the limitations of the BCG vaccine has left a massive protection gap, particularly among adolescents and adults who account for most TB transmission. This single limitation has arguably been the most significant barrier to TB control, creating a situation where we vaccinate children but leave them vulnerable as they enter the age groups most likely to contract and spread the disease. This fundamental flaw in our defense strategy has allowed TB to persist despite decades of control efforts.
The Century-Old Vaccine That Couldn’t Finish the Job
The story of the BCG vaccine begins in the early 20th century, when French bacteriologists Albert Calmette and Camille Guérin began their pioneering work at the Pasteur Institute in Lille. Starting in 1908, they patiently cultivated a strain of bovine tuberculosis bacteria, subculturing it 230 times over 13 years until it lost its virulence while maintaining its ability to stimulate protective immunity. The result was the Bacille Calmette-Guérin vaccine, first administered to a newborn infant in Paris on July 18, 1921. The child’s mother had died of tuberculosis shortly after delivery, and the infant’s grandmother who was caring for him was also suffering from the disease. Despite this heavy exposure, the child never developed TB, marking the beginning of a new era in TB prevention.
BCG quickly became one of the most widely used vaccines in history, distributed across the globe as the primary defense against tuberculosis. For a hundred years, it has served as our sole defense against TB, with most people living today having never known a world with an alternative TB vaccine. The vaccine is particularly effective at preventing severe forms of TB in children, including TB meningitis and miliary TB (widespread infection throughout the body). This protection has undoubtedly saved countless young lives, particularly in regions where TB remains endemic, and represents one of the great success stories of early 20th-century medicine.
However, BCG’s protection comes with significant limitations that have hampered global TB control efforts for decades and ultimately prevented the eradication of this disease. The vaccine’s effectiveness wanes over time, offering little to no protection against pulmonary TB in adolescents and adults—the very group responsible for most TB transmission. Imagine a shield that protects children but disappears just when they enter the ages when they’re most likely to contract and spread the disease. This fundamental limitation has meant that despite widespread BCG vaccination, TB continues to spread through communities, finding ready hosts among adolescents and adults who believe they’re protected but aren’t.
The reasons behind BCG’s variable effectiveness have puzzled scientists for decades, leading to numerous research initiatives aimed at understanding this phenomenon:
Genetic variations in BCG strains used in different parts of the world may account for some differences in effectiveness. The original BCG strain has given rise to numerous daughter strains as laboratories around the world maintained their own cultures, creating a patchwork of slightly different vaccines across different regions. These strains have acquired different genetic mutations over time, potentially affecting their protective efficacy and creating inconsistent results across different populations and geographic areas.
Environmental factors including exposure to non-tuberculous mycobacteria in soil and water may provide some natural immunity in certain regions, potentially masking or interfering with BCG’s protection. This might explain why BCG shows higher efficacy in northern latitudes compared to tropical regions, where exposure to environmental mycobacteria is more common and may either block BCG’s action or provide some cross-protection that makes BCG’s additional benefit less noticeable.
Immune response differences between individuals and populations may influence how effectively BCG stimulates lasting protection. Some researchers suggest that the timing of vaccination, nutritional status, or genetic factors affecting immune function might determine whether BCG provides long-term protection, creating a complex interplay between the vaccine, the host, and environmental factors that we are only beginning to understand.
Bavesh Kana, one of South Africa’s leading TB researchers, puts it bluntly: “Because TB has primarily been a disease of the poor, there has been insufficient investment in the development of new vaccines over the past century.” The rapid development of COVID-19 vaccines demonstrated what’s possible with sufficient resources and political will—a stark contrast to the decades of neglected TB research that allowed this preventable disease to continue claiming millions of lives.
The Long Road to a New TB Vaccine
The quest for a new TB vaccine has been marked by both frustration and determination, a scientific odyssey spanning multiple decades and involving researchers across the globe. For years, scientists struggled to understand the complex immune response needed to fight TB effectively, confronting a pathogen that has evolved sophisticated mechanisms to evade human immunity. The bacteria can persist in the body for years without causing disease, and the immune system’s ability to control or clear the infection varies widely between individuals, creating a challenging landscape for vaccine development.
The early years of TB vaccine research were characterized by slow progress and limited funding, with TB often described as the “neglected epidemic” despite its massive global burden. While diseases like polio, measles, and hepatitis attracted significant research investment and public attention, TB—despite killing more people than all these diseases combined—remained in the shadows, its victims primarily poor and politically marginalized. The turning point came in the 1990s, when the World Health Organization declared TB a global emergency and recognized the growing threat of drug-resistant strains, sounding an alarm that finally began to attract serious attention and resources.
This declaration helped catalyze renewed interest and investment in TB vaccine development, leading to the emergence of a diverse research landscape with several promising approaches, each with distinct advantages and challenges:
Subunit vaccines use specific proteins from the TB bacterium to stimulate an immune response without using the whole bacterium, offering a targeted approach to immunity. These vaccines typically focus on antigens—molecules that the immune system recognizes—that are critical to the bacteria’s survival or virulence. The advantage of this approach is safety, as there’s no risk of causing infection from the vaccine itself, but the challenge lies in selecting the right antigens and combining them with effective adjuvants (immune-boosting compounds) to stimulate strong, lasting protection against a complex pathogen.
Viral vector vaccines employ modified viruses to deliver TB antigens into the body, leveraging viral infection mechanisms to stimulate immunity. These vaccines use harmless viruses as delivery vehicles, engineering them to carry genes that instruct human cells to produce TB antigens, thereby training the immune system to recognize the real pathogen. This approach can stimulate strong cellular immune responses—critical for fighting TB—and the technology gained prominence during the COVID-19 pandemic with vaccines like AstraZeneca’s, but researchers had been exploring its potential for TB for years before the coronavirus emerged.
Whole cell vaccines use killed or weakened whole TB bacteria, presenting the immune system with a broad array of antigens rather than selected components. Some approaches use killed TB bacteria themselves, while others use related mycobacteria that don’t cause disease in humans but share enough characteristics to provide cross-protection. These vaccines aim to present a broader array of antigens to the immune system, potentially stimulating more comprehensive protection, though they may carry higher risks of side effects compared to more targeted approaches.
BCG boosters are designed to enhance or extend the protection offered by the original BCG vaccine, building on existing immunity rather than starting from scratch. The concept is simple: give BCG early in life as usual, then administer a booster vaccine later in childhood or adolescence to renew and strengthen the immune response. This approach acknowledges BCG’s partial success while addressing its key limitation—waning immunity—and could potentially be easier to implement than completely new vaccination strategies.
Throughout the early 2000s, various candidates entered clinical trials, but none progressed beyond phase 2 studies, highlighting the immense scientific challenges of TB vaccine development. The scientific challenges were immense, compounded by limited funding and the complexity of the disease, with researchers lacking reliable biomarkers to predict which vaccine approaches would work. This meant each candidate required lengthy and expensive clinical trials involving thousands of participants followed for years, creating a high barrier to progress that few candidates could overcome.
The turning point came when global health organizations recognized that achieving the World Health Organization’s End TB Strategy targets—a 95% reduction in TB mortality and a 90% reduction in TB incidence by 2035—would be impossible without a more effective vaccine. This realization sparked increased investment and coordination in TB vaccine research, setting the stage for the breakthroughs that would follow and creating the conditions for a candidate like M72/AS01E to emerge from the pack.
The Breakthrough Candidate: M72/AS01E
Amid these challenges, one candidate began to show exceptional promise, emerging from the laboratories of pharmaceutical company GSK after years of meticulous research and development. The M72/AS01E vaccine represents a novel approach to TB protection, combining cutting-edge vaccine science with insights from decades of TB immunology research to create a potentially transformative tool in the fight against this ancient disease.
Unlike BCG, which contains live bacteria, M72/AS01E is a subunit vaccine composed of a fusion protein derived from two Mycobacterium tuberculosis antigens (MTB32A and MTB39A) combined with GSK’s proprietary AS01E adjuvant system. This combination is crucial—the antigens provide the specific targets for the immune system, while the adjuvant supercharges the immune response, creating stronger and longer-lasting protection than either component could achieve alone, representing a sophisticated approach to vaccine design.
The selection of these particular antigens wasn’t accidental but resulted from years of careful research into TB immunology. Researchers identified MTB32A and MTB39A as proteins that the immune system of people with latent TB infection recognizes strongly, suggesting they might be important in controlling the disease and therefore ideal targets for a vaccine. By combining these two antigens, the vaccine aims to stimulate a broad immune response targeting multiple aspects of the bacteria, reducing the likelihood that the pathogen could evolve to evade immunity by changing a single antigen.
The AS01E adjuvant system represents a technological marvel in itself, reflecting decades of research into how to optimize immune responses to vaccines. Adjuvants have been called the “secret ingredients” of vaccines—components that enhance and shape the immune response to make vaccination more effective. AS01E contains two immune-stimulating compounds plus a liposome delivery system that helps present the antigens to the immune system in the most effective way possible, creating a powerful immune-stimulating environment. This particular adjuvant system had previously shown success in GSK’s malaria vaccine and shingles vaccine, providing confidence in its safety and effectiveness and demonstrating how advances in one area of vaccinology can benefit others.
The scientific journey toward this candidate reached a pivotal moment in 2019, when results from a phase 2b trial conducted in Kenya, South Africa, and Zambia demonstrated unprecedented efficacy that electrified the TB research community. The trial enrolled 3,573 HIV-negative adults aged 18-50 with latent TB infection—exactly the population that BCG fails to protect and that accounts for much of TB transmission globally. Participants received two doses of either M72/AS01E or a placebo, one month apart, in a carefully designed study that would ultimately provide the proof-of-concept that the field had been seeking for decades.
The results, published in the New England Journal of Medicine, marked a watershed moment in TB research that many had feared might never come. Over approximately three years of follow-up, the vaccine showed 54% efficacy in preventing active pulmonary TB disease, a level of protection that had never been demonstrated before in adults. Among participants who received the vaccine, there were 10 cases of active TB, compared to 22 cases in the placebo group, providing clear evidence that preventing the progression from latent to active TB was achievable. The World Health Organization described this result as “an important scientific breakthrough,” noting it was “unprecedented in decades of TB vaccine research in terms of clinical significance and strength of evidence” and represented a turning point in the struggle against tuberculosis.
Table: M72/AS01E Phase 2b Trial Results
| Parameter | Vaccine Group | Placebo Group | Efficacy |
|---|---|---|---|
| Number of participants | 1,786 | 1,787 | – |
| TB cases | 10 | 22 | 54.0% |
| Incidence per 100 person-years | 0.3 | 0.6 | – |
| Severe adverse events | 5.5% | 5.5% | Similar rate |
| Local injection site reactions | 68% | 22% | More common with vaccine |
| Systemic reactions | 45% | 25% | More common with vaccine |
The safety profile of the vaccine proved generally acceptable, with most adverse events being mild to moderate and resolving quickly, addressing concerns about whether a vaccine powerful enough to protect against TB would be tolerable. Injection site pain, fatigue, muscle aches, and headache were more common in the vaccine group, but severe adverse events occurred at similar rates in both groups, suggesting that the vaccine did not cause serious safety concerns. This safety profile compared favorably to other adult vaccines and represented a crucial milestone in the vaccine’s development, clearing a major hurdle on the path to potential widespread use.
While the phase 2b trial focused on HIV-negative adults with latent TB infection, the vaccine’s potential extends much further, offering hope for multiple at-risk populations. As Dr. Alemnew Dagnew, who leads the clinical development of the current Phase 3 trial, notes, “If we think about the population level, the impact is going to be huge.” The vaccine could potentially protect other vulnerable groups, including people living with HIV, children, and healthcare workers in high-TB settings, potentially transforming the landscape of TB prevention across multiple demographics.
From Promise to Practice: The Accelerated Phase 3 Trial
Building on the promising phase 2b results, the Bill & Melinda Gates Medical Research Institute (Gates MRI), which licensed the vaccine candidate from GSK, launched a large-scale phase 3 trial in March 2024, marking the beginning of the final stage of clinical evaluation. The scope and pace of this trial signal a new commitment to accelerating TB vaccine development and reflect lessons learned from the rapid vaccine development during the COVID-19 pandemic, demonstrating that when the world prioritizes a health threat, timelines that once seemed impossible can become reality.
The phase 3 trial represents one of the most ambitious clinical research projects in the history of TB research, requiring unprecedented coordination and resources. Its design reflects both scientific rigor and practical considerations for eventual vaccine deployment, ensuring that if successful, the vaccine could be quickly evaluated and made available to those who need it most:
Unprecedented speed characterizes the trial’s timeline, running a year ahead of schedule and demonstrating a new urgency in TB research. Within just one year of initiation, 90% of the planned 20,000 participants had been recruited—a remarkable achievement for a TB vaccine trial that would have been unthinkable just a decade ago. This acceleration stems from careful planning, efficient regulatory processes, and strong community engagement at trial sites, showing what’s possible when sufficient resources and commitment are brought to bear against a neglected disease.
Diverse participants make this trial particularly comprehensive and increase the likelihood that its results will be applicable across different populations. The inclusion criteria encompass people with and without latent TB infection, as well as people living with HIV—a group for whom TB is a leading cause of death and who have historically been excluded from many clinical trials. This broad inclusion will help researchers understand how the vaccine works across different populations and immune statuses, providing crucial information for how to deploy the vaccine if it proves effective.
Global collaboration forms the backbone of the trial, spanning up to 60 sites across seven countries in Africa and Southeast Asia, including South Africa, Zambia, Malawi, Mozambique, Kenya, Indonesia, and Vietnam. This geographical diversity ensures the trial will generate data relevant to multiple regions heavily burdened by TB, reflecting the global nature of the TB epidemic and the need for solutions that work across different genetic backgrounds and circulating TB strains.
Substantial funding from Wellcome and the Bill & Melinda Gates Foundation—approximately $550 million—provides the resources necessary for a trial of this scale and duration, addressing the chronic underfunding that has plagued TB research for decades. This level of investment marks a significant shift in the prioritization of TB vaccine research and sends a powerful message that the global health community is serious about developing new tools to combat this ancient disease.
The trial employs a double-blind, placebo-controlled design—the gold standard in clinical research that ensures the highest quality data. Neither participants nor investigators know who receives the vaccine or placebo, ensuring that assessments of potential TB cases remain objective and not influenced by knowledge of who received the active product. Participants will be followed for up to five years, monitoring for safety and efficacy, with the trial designed to stop once 110 people have developed pulmonary TB—providing sufficient data to analyze the vaccine’s efficacy with statistical confidence and determine whether it truly represents the breakthrough the world has been waiting for.
Table: M72/AS01E Phase 3 Trial Overview
| Trial Aspect | Details |
|---|---|
| Start Date | March 2024 |
| Participant Goal | 20,000 people |
| Age Range | 15-44 years |
| Trial Sites | Up to 60 across 7 countries |
| Key Populations | People with latent TB, uninfected people, people living with HIV |
| Estimated Completion | Within 5 years |
| Primary Outcome | Prevention of pulmonary TB disease |
| Secondary Outcomes | Safety, efficacy in subgroups, prevention of infection |
| Follow-up Period | Up to 5 years |
The implementation of such a large trial involves enormous logistical complexity that extends far beyond the scientific challenges, requiring solutions to practical problems across multiple countries and health systems. From maintaining cold chain storage for vaccines to ensuring proper training for healthcare workers at all sites, from navigating different regulatory requirements in each country to building community trust and engagement—the challenges are immense and multifaceted. Yet the successful recruitment to date suggests these challenges are being met effectively, demonstrating that global health research can overcome even the most daunting practical obstacles when properly resourced and coordinated.
Dr. Dagnew reflects on the personal significance of leading this trial, connecting the scientific endeavor to the human reality of TB: “One of the most common health conditions that I used to manage was TB, so I have seen the devastating impact of TB on patients, their families and also the communities.” He notes that TB disproportionately affects people of poor socioeconomic status, creating a vicious cycle where illness leads to lost income, which in turn deepens poverty, a pattern he has witnessed firsthand. A vaccine, he believes, could be “a gift to the community that I came from,” representing not just a scientific achievement but a tool for social justice and health equity.
More Than a Vaccine: The Potential Global Impact
The potential impact of an effective new TB vaccine extends far beyond individual protection, potentially transforming the entire landscape of global TB control and creating ripple effects across societies and economies. Mathematical models developed by the World Health Organization and other research groups suggest that widely deployed TB vaccines could have effects that ripple through communities, health systems, and economies for decades to come, fundamentally altering the trajectory of this ancient disease.
According to WHO estimates, over 25 years, a vaccine with 50% efficacy for protecting adolescents and adults could have staggering impacts that justify the massive investment in TB vaccine research: 8.5 million lives saved, 76 million new TB cases prevented, and $41.5 billion saved for TB-affected households who would otherwise face catastrophic costs. These numbers represent more than statistical abstractions—they translate to children who won’t lose parents, workers who won’t lose income, and communities freed from the shadow of a devastating disease that has limited human potential for millennia.
The economic argument for vaccine investment is compelling and extends far beyond the direct savings on TB treatment, encompassing broader economic benefits that benefit entire societies. The WHO estimates that for every $1 spent on new TB vaccines, there’s a return of $7-14 in economic benefits, including reduced treatment costs and minimized productivity loss from TB-related illness, with some models projecting up to $474 billion in total economic benefits by 2050. This return on investment compares favorably with many other public health interventions and represents a strong economic case for governments and international funders to prioritize TB vaccine development and deployment.
Perhaps equally important is the potential impact on drug-resistant TB, which represents one of the most serious threats to global health security. By reducing transmission and preventing the need for antibiotics, an effective vaccine could play a crucial role in curbing antimicrobial resistance—one of the greatest emerging threats to global health that could render many modern medical procedures unsafe. Drug-resistant TB currently requires treatment regimens that are lengthier, more expensive, and more toxic than those for drug-sensitive TB, creating a heavy burden on healthcare systems and causing tremendous suffering for patients. A vaccine that prevents TB cases, including drug-resistant cases, could significantly reduce the burden on healthcare systems and slow the development of further resistance, protecting the effectiveness of our antibiotic arsenal for future generations.
The introduction of a new TB vaccine would also have important effects on global health equity, addressing one of the most striking health disparities between rich and poor nations. TB disproportionately affects the world’s poorest and most marginalized communities, contributing to cycles of poverty and limited opportunity that span generations. An effective vaccine could help break these cycles, reducing the economic impact of TB on households and freeing up resources for education, economic development, and other health needs, creating a virtuous cycle of improved health and economic well-being in the communities that need it most.
The potential benefits extend beyond traditional health metrics to encompass broader social and systemic improvements:
Mental health improvements could result from reducing the stigma and anxiety associated with TB diagnosis and treatment, which often carries significant social consequences. The current long treatment regimens often cause significant psychological distress for patients and their families, which would be avoided through prevention, improving quality of life beyond just physical health.
Healthcare system strengthening would likely accompany vaccine rollout, as successful vaccination programs require robust delivery systems, trained healthcare workers, and improved surveillance—all of which benefit other health programs and create infrastructure that can be leveraged for other health priorities, creating positive spillover effects across the health system.
Research and development momentum would be generated by a successful vaccine, demonstrating that complex global health challenges can be overcome with sufficient investment and scientific commitment. This could stimulate increased investment in vaccines for other neglected diseases that primarily affect the poor, creating a legacy of innovation that extends far beyond TB alone and potentially transforming the landscape of global health research.
For Dr. Dagnew, the mission is personal and connects the scientific endeavor to the human stories behind the statistics: “One of the most common health conditions that I used to manage was TB, so I have seen the devastating impact of TB on patients, their families and also the communities.” He notes that TB disproportionately affects people of poor socioeconomic status, creating a vicious cycle where illness leads to lost income, which in turn deepens poverty, a pattern he has witnessed throughout his career. A vaccine, he believes, could be “a gift to the community that I came from,” representing not just a scientific achievement but a tool for restoring dignity, opportunity, and hope to communities that have borne the burden of this disease for too long.
The Road Ahead: Challenges of Delivery and the Future Pipeline
While the M72/AS01E candidate shows tremendous promise and has reached an advanced stage of clinical evaluation, significant challenges remain before it can become widely available to those who need it most. The path from successful clinical trial to global vaccination program is long and complex, requiring careful planning, substantial resources, and continued commitment from multiple stakeholders across the global health landscape.
If the phase 3 trial confirms its safety and efficacy—a outcome that is hopeful but not guaranteed—the vaccine must still undergo rigorous regulatory approval processes in multiple countries, each with its own requirements and timelines. This process involves submitting detailed data on manufacturing, quality control, safety, and efficacy to regulatory agencies like the U.S. Food and Drug Administration, the European Medicines Agency, and national regulatory authorities in TB-endemic countries, creating a complex web of reviews and approvals that must be navigated successfully. Each agency has its own requirements and timelines, potentially creating delays in availability in some regions and highlighting the need for coordinated regulatory approaches to speed access in high-burden countries.
Manufacturing must be scaled up to produce millions of doses annually, requiring significant investment in production facilities and quality control systems to ensure consistent quality and supply. The complex nature of the vaccine—combining recombinant proteins with a sophisticated adjuvant system—presents manufacturing challenges that must be addressed while maintaining consistent quality and potency, requiring advanced manufacturing capabilities that may need to be established in regions where the vaccine will be used. This scale-up must begin even before final trial results are available to avoid delays if the vaccine proves effective, requiring calculated risk-taking from manufacturers and funders.
Delivery strategies must be developed to ensure the vaccine reaches those who need it most, particularly in resource-limited settings where health systems are often fragile and underfunded. Unlike childhood vaccines that can be integrated into existing immunization programs, an adolescent/adult TB vaccine would require new delivery approaches that reach different age groups. Potential strategies include school-based vaccination programs, integration with other health services (such as HIV care or reproductive health services), or stand-alone vaccination campaigns, each with its own advantages and challenges that must be carefully considered in different contexts.
The experience from other vaccine introductions suggests that equitable distribution will be crucial—particularly in low- and middle-income countries that bear the highest TB burden but have the most limited resources for health. Global partnerships will be essential, involving organizations like Gavi (the Vaccine Alliance), the Stop TB Partnership, The Global Fund, and national governments, who must coordinate funding, procurement, and delivery to ensure the vaccine reaches all who could benefit, not just those in countries with stronger health systems or greater purchasing power.
Funding for vaccine introduction represents another critical challenge that must be addressed through sustained advocacy and resource mobilization. While the clinical trial is generously funded, the resources needed for manufacturing scale-up, regulatory approvals, and delivery systems in multiple countries will require additional investment from both public and private sources. Advocacy will be needed to ensure that governments and international funders prioritize TB vaccine introduction alongside other health priorities, making the case that investment in TB prevention is both a moral imperative and a smart economic decision.
Meanwhile, the TB vaccine pipeline continues to grow and diversify, providing multiple shots on goal and ensuring that even if one candidate encounters obstacles, others may succeed. As of late 2024, there were at least 16 TB vaccine candidates in clinical development—four in phase I, five in phase II, and six in phase III trials—demonstrating remarkable progress in a field that was once considered stagnant. This robust pipeline suggests that even if one candidate encounters obstacles, others may succeed, and the diversity of approaches—including whole cell vaccines, viral vectors, and other subunit vaccines—increases the likelihood that at least one will prove safe and effective, while also providing potential options for different populations or uses.
In 2023, WHO’s Director-General established a TB Vaccine Accelerator Council to facilitate the development, testing, authorization, and use of new TB vaccines, drawing lessons from the rapid response to the COVID-19 pandemic that showed how quickly vaccine development can proceed when properly prioritized. The Council aims to address funding gaps, identify market solutions to incentivize TB vaccine development, and ensure equitable access once vaccines are available, creating a coordinated global effort to accelerate the end of TB through vaccination.
A Future Free of TB?
The development of a new TB vaccine after a century of waiting represents more than just scientific progress—it signifies a renewal of global commitment to defeating a disease that has plagued humanity for millennia and a belief that health equity is achievable. As we stand at this potential turning point, it’s worth reflecting on how far we’ve come and how far we still have to go, acknowledging both the remarkable progress and the significant challenges that remain.
The story of the M72/AS01E vaccine candidate is still being written, with its final chapter yet to be determined by the results of the ongoing phase 3 trial and the global community’s response to those results. Its final chapter will be determined by the results of the ongoing phase 3 trial, and later, by our collective ability to ensure that if it proves effective, it reaches everyone who could benefit, regardless of where they live or their economic circumstances. The scientific journey—from basic research on TB immunology to large-scale clinical trials—demonstrates what’s possible when persistence, collaboration, and scientific ingenuity converge, offering a model for addressing other global health challenges that have seemed intractable.
What’s clear is that after 100 years of relying on a single vaccine with limited effectiveness, we may finally be on the cusp of having new tools to transform TB from a global threat into a manageable disease that no longer claims millions of lives each year. For the millions affected by TB and those at risk, the promise of a new vaccine offers not only hope but the prospect of a brighter, healthier future worldwide, where children can grow up without fear of this disease and communities can thrive without the shadow of TB limiting their potential.
As Dr. Dagnew reflects on his work and its broader significance: “It’s going to motivate not only those of us who are working on this vaccine, but the whole TB research community.” Indeed, this breakthrough has already energized a field that has long struggled for attention and resources, proving that even the most stubborn health challenges can be overcome with persistence, collaboration, and scientific ingenuity, and inspiring a new generation of researchers to tackle the world’s most pressing health problems.
The fight against tuberculosis has been one of the longest chapters in the history of medicine, spanning centuries of suffering and scientific struggle. With new tools on the horizon, we may finally be approaching its conclusion—a world where no one suffers from this ancient disease, where children grow up without fear of TB, and where the considerable resources currently devoted to TB control can be redirected to other pressing health needs. That future is not yet here, but for the first time in a century, it appears within reach, offering the promise of turning the page on one of humanity’s oldest and deadliest enemies.
