Tuberculosis and us — we go way back. Way, way back: Biomolecular evidence suggests that the bacterium responsible, Mycobacterium tuberculosis or an ancestor, might have hitched its wagon to humanity’s star more than 70,000 ago, before humans set foot off the African continent.
Others argue for a timeline that’s less ancient but plenty elderly. Archeologists have found skeletal remains from the Neolithic period, 8,000 to 10,000 years ago, that show classic traces of TB. This microbe spans the globe (and for that we can blame seals, not Columbus).
Despite our ancient relationship, it’s only been about 150 years (since German scientist Robert Koch identified M. tb in 1882) that we’ve been able to do much to combat TB. Milk pasteurization, strict quarantining protocols, public investment in mass detection and access to antibiotics helped make TB seem a dim memory in places like the United States.
But TB is very much still with us: Each year it kills more people than any other infectious disease. More than 2 billion people are currently infected and the World Health Organization estimates that in 2024 alone, 10.7 million people fell ill from TB and 1.23 million died of it. After a long downward trend since the U.S. committed to eliminating TB in 1989, the incidence in the U.S. is rising. The U.S. Centers for Disease Control and Prevention reported over 10,000 cases in 2024, a nearly 8% increase over 2023. This reflects a global trend, triggered by the damage to health systems, diagnosis and treatment caused by the COVID-19 pandemic.
But today, World TB Day, Fred Hutch Cancer Center scientists are optimistic. Several promising vaccines are in late-phase clinical trials and recently developed preclinical models of TB disease point toward new avenues for treating it. Our understanding of the bacterium and our responses to it are deepening every day.
“It’s a very exciting time to be in TB science because our understanding of TB is changing rapidly,” said Fred Hutch biostatistician Paul Edlefsen, PhD, a principal staff scientist in the Gilbert Lab who helps design and analyze clinical trials and preclinical studies as a member of the HIV Vaccine Trials Unit (HVTN) and the Immune Mechanisms of Protection Against Mycobacterium tuberculosis Centers (IMPAc-TB) Program.
These rapid changes are driving a surge in TB vaccine candidates and opening up potential new treatment paradigms.
Fred Hutch has long-standing expertise in immunology, clinical trial design and analysis, and clinical trial implementation, all of which are being directed toward tackling TB. Fred Hutch investigators in the HVTN and other trial networks are working to understand how our immune system responds to M. tb and to vaccines, and what characterizes a protective response. They are helping design and analyze the trials as well as the preclinical studies that are revealing more about the basic biology of infection and immune response.
“TB is not a disease of the past. It's not a disease of someplace else,” said Fred Hutch and University of Washington infectious disease physician Adrienne Shapiro, MD, PhD, who works to develop, test and implement TB and HIV prevention strategies as the associate medical director of the Seattle Vaccines Trial Unit (VTU). “It is a disease that affects us [in the U.S.] and in Seattle.”
“The way I frame it, almost all TB in the world could be prevented,” said Shapiro, an assistant professor in Fred Hutch’s Vaccine and Infectious Disease Division (VIDD), who also treats patients, including people with TB, at Seattle’s Harborview Medical Center. “Every person with TB disease represents a missed opportunity for preventing TB.”
M. tb is generally spread through the air via respiratory droplets expelled by coughing or sneezing, and needs sustained, close contact. Once inhaled, the bacterium gets eaten by white blood cells called macrophages, but they are often unable to digest and kill it off. And so it lingers.
The lungs are the microbe’s avenue into our bodies, but once inside, “It can go anywhere and do anything,” Shapiro said.
It can break our bones, render us infertile and swell our brains. There’s TB of the lymphatic system, the central nervous system and of the bones and joints (Pott’s disease), just to start with. When TB travels to the lymph nodes in the neck and bursts them, it’s called scrofula.
“It’s a very challenging pathogen to fight,” said HVTN Executive Director Jim Kublin, MD, MPH, pointing to the microbe’s more than 4,000 genes, which contribute to its ability to divert protective immune responses away. Kublin is a principal staff scientist in VIDD’s Immunology and Vaccine Development Program and medical director of the Seattle Malaria Trials Center.
The very slow-growing M. tb can lurk without apparent symptoms for years and may never progress. An initial immune response triggers the formation of granulomas, in which immune cells dogpile the bacteria to wall off the infection. Most people never progress to TB disease, but about 5% to 10% do. In these cases, the immune response can no longer keep the bug quashed.
People with TB disease struggle with lingering coughs, lose their appetites, waste away and experience night sweats, fevers, fatigue and chills. Uncontrolled granulomas can cause permanent tissue damage or lung scarring so severe it is lethal.
“Because there’s a latent phase where you can have TB infection but not show any signs of illness — and really, potentially never show any sign of it — there are a lot of challenges with knowing if you have the infection or not, knowing if you're at risk for progression to disease or not,” Shapiro said.
She sees at least one patient with TB disease every time she works in the clinic, she said.
“In Washington state, we know our TB,” said Shapiro, who has been interested in working to help those affected by TB since she was about 14. (Shapiro discovered that TB was not merely a disease of pallid 19th century poets while researching a report for her freshman-year science class.) “If there was any place in the country where I’d want to be, if I had TB, it’s here.”
And even so, only about half the people at risk for a TB infection in Washington state get screened, she said. Of people with a positive TB test, fewer than 50% get on preventative treatment. These missed opportunities dog TB treatment around the world; many people present so late in the course of their disease that drugs can no longer help them.
Because we do have cures. We have an antibiotic cocktail, colloquially dubbed RIPE, that can cure TB disease and antibiotics that can cure latent TB and completely prevent progression.
What weakens the immune system and enables M. tb to thrive? In a word, poverty.
The World Health Organization lists five main contributing factors: malnourishment, smoking, diabetes, alcohol use disorders and HIV.
“Globally, if we just gave people food, we would dramatically reduce the risk of TB disease,” Shapiro said, citing the RATIONS trial, which showed that providing food supplementation to people with TB and their household members could reduce incidence of TB disease by 40%. Adequate food reduced mortality from TB disease by up to 50%.
Sometimes the factors that encourage TB progression arise from negligence, and sometimes from design: TB flares in prisons, and remains high in some Native Alaskan and First Nations communities, a legacy of the residential and boarding school systems that crammed children together while denying them adequate nutrition or medical care.
Poverty also stands in the way of antibiotic access: in many places, the drugs are inconsistently available or only available at clinics far away from home. Each course of antibiotics takes six to nine months to complete, and patients are required to visit the clinic every day — no matter how far — for each new dose. A one-dose vaccine would be much easier to access and administer than current treatments and diagnostics, scientists said.
It’s an exciting time for TB vaccines: six are vaccines being tested for efficacy and effectiveness in Phase 3 clinical trials, eight are being evaluated for efficacy and safety in Phase 2 trials, and another four are in (or moving into) Phase 1 trials that assess safety and immunogenicity. More candidates are in preclinical testing.
The experimental vaccine strategies run the gamut from killed/inactivated mycobacteria, protein-based vaccines, or attenuated (weakened) live mycobacteria.
But wait, why so many? We already have one vaccine (Bacillus Calmette-Guérin, or BCG, an attenuated form of M. bovis) that’s been around for over 100 years.
“BCG is very effective at preventing severe disseminated TB in small children under the age of five,” Shapiro said. “It is not effective at preventing pulmonary [lung] TB or lymph node TB or brain TB in adults, and we know that because pretty much every adult who has pulmonary TB in the world had BCG as a child.”
For reasons we don’t understand, protection from the BCG vaccine wanes with age and boosting is not particularly effective.
“There’s a huge need for vaccines that prevent infection or prevent infection from progressing to disease,” Shapiro said. “Twenty-four percent of the world’s population has been infected, at some point in their life, with TB.”
The WHO estimates that an effective adult TB vaccine could save between 4 and 8 million lives by 2050. The HVTN has committed resources to ending TB because the disease is so closely linked to HIV in areas where HIV is highly prevalent, forming what’s known as a syndemic.
Kublin has been arguing in favor of investing the time, money and effort into researching prevention strategies for HIV-syndemic diseases like TB and malaria for more than a decade.
“When you look at these pathogens independently, you’re missing an opportunity,” he said. “Not only is there a syndemic on the pathogen side, but there’s synergy on the investigation and operations side.”
During the last re-competition cycle for the National Institutes of Health grant that supports the HVTN, “there was a growing appreciation that the machinery that's been developed to study and develop HIV vaccines was going be really useful for developing any vaccine,” said biostatistician Andrew Fiore-Gartland, PhD, a principal staff scientist in VIDD’s Gilbert Lab and co-director of VIDD’s Gates Foundation-funded Vaccine and Immunology Statistical Center (VISC).
“We have the statistical and data management tool. … we can do that really well. And we've got the HVTN labs with state-of-the-art assays set up to study antibodies and T cells against HIV — why not adapt them for TB?” he said.
Now, the globe-spanning network supports several novel vaccine candidates, ranging from first-in-human trials to late-stage Phase 2 and 3 trials. The network previously dug into the protective immune responses elicited by BCG revaccination and two novel subunit vaccines and are now working to understand the immune correlates of protection from blood samples provided by volunteers in the study that were protected by BCG.
Currently under evaluation (in collaboration with the AIDS Clinical Trials Group, or ACTG) is MTBVAC, a hobbled version of M. tb, genetically tweaked to remove some key virulence genes. MTBVAC trials have reached Phase 3 in infants and Phase 2 in adults and adolescents.
“It’s been attenuated to replace BCG at birth in infants and the idea is that it's a little bit safer and a little more like M. tb, so it will elicit better immune responses and maybe have better efficacy,” Fiore-Gartland said. “Now we're testing it as a booster vaccine that could be given to adults.”
The trials of MTBVAC in adults and adolescents are assessing safety and immunogenicity in people with and without HIV.
“We’ve been working on these studies to try to build the evidence that these vaccines are safe and they're immunogenic in people living with HIV so that when they get to Phase 3 trials and we find out that they work, they can immediately be licensed for people with HIV,” Fiore-Gartland said.
MTBVAC is being evaluated in South Africa, and other TB vaccines are being tested elsewhere in southern Africa and in Peru. TB vaccines need to be tested not only where TB incidence is highest, but must also assess immune responses in the right population: people already vaccinated with BCG or already infected with M. tb.
Another promising vaccine candidate is M72/AS01. This is what’s known as a subunit vaccine; rather than including the whole bacterium it uses subunits of key proteins and an adjuvant from the same family of immune stimulators already in the shingles-preventing Shingrix vaccine. In a Phase 2 trial, M72 showed 50% efficacy in preventing progression to TB disease and is now being tested in a massive, 20,000-person Phase 3 trial funded by the Gates Foundation and Wellcome.
Also under way is a Phase 2A trial evaluating ID93 + GLA-SE, which mixes four recombinant M. tb proteins with immune-stimulating molecules. A temperature-stable form of ID93 + GLA-SE is also being tested. This will be tested in people with TB disease undergoing treatment, to see if the vaccine can improve outcomes.
Immunologist Erica Andersen-Nissen, PhD, a principal staff scientist in the McElrath Lab, heads the Cape Town Lab where HIV and TB vaccine trial participants’ immune responses are evaluated. A deeper understanding of how our bodies are responding helps scientists improve vaccine design and assess how to determine if a candidate is more likely to be protective.
Andersen-Nissen and her team examine immune responses induced by new vaccines under testing, with a focus on immune cells called T cells. T cells help kill off infected cells and so are critical to the successful immune responses to pathogens like HIV and M. tb, which get inside target cells.
In the trial testing BCG revaccination in teenagers, she and her team measured various T-cell populations and relevant cytokines, immune molecules that help orchestrate immune responses. They use leading-edge tests to examine what the T cells (which used highly specialized receptors to find their targets), recognize. Melding experimental assays and statistics, the inter-continental team found that certain populations of “helper” T cells (which support the activity of immune cells that kill infected cells and those that produce protective antibodies) changed after BCG vaccination.
“There are a lot of great South African powerhouse research labs that do amazing work here,” Andersen-Nissen said. “We bring the analysis of clinical trial samples piece.”
They have their work cut out for them: M. tb isn’t the only mycobacterium that people are exposed to and produce immune responses to. It can be hard to distinguish immune responses to pathogenic M. tb from those induced by mycobacteria present everywhere in our environment. Their work points to polyfunctional CD4 T cells (helper T cells that produce several cytokines) and what are known as donor-unrestricted T cells (which may be important for effective immunity against mycobacteria) as important players in protective TB vaccine responses.
The Cape Town team hands these analyses over to Fiore-Gartland’s team of biostatisticians. They crunch the numbers, seeking to define important biological signatures.
“We seek to characterize something called correlates of protection,” he said. “Especially in vaccines where there’s partial efficacy, our goal is to understand which participants were protected, which weren’t, and to compare their immune responses after vaccination to try to understand what immune responses correlated with protection.”
VISC statisticians are currently evaluating data from two prior trials, including from the trial that test BCG revaccination in teenagers. Scientists measured whether revaccination could help prevent teenagers from sustained conversion of their IGRA test (a proxy for TB infection) from negative to positive. The vaccine was 45% effective in preventing sustained conversion.
These insights, which can be used to make future vaccines more effective, build on a methodological framework created for HIV vaccine trials and further honed for COVID-19 vaccine trials. But the methods aren’t plug-and-play; with TB, Fiore-Gartland and his team must develop new approaches to assess vaccine-induced immune responses in people who have already reacted to M. tb infection or BCG vaccination. This is different than HIV vaccine trials or the first COVID-19 vaccine trials, which enroll unexposed trial participants.
Andersen-Nissen’s team is generating immune data from the Phase 2b trial of M72, which VISC statisticians are evaluating.
“If we can identify protective immune responses made by M72, that could help us figure out which other vaccines to prioritize for further clinical development,” Fiore-Gartland said.
Lamar Fleming, BS, a staff scientist in the McElrath Lab, is gearing up to do a single-cell analysis.
“It’s going to be one of the biggest single-cell studies ever done,” Andersen-Nissen said. “The fact that we get to do it on case-control samples has the promise to yield a lot more granular detail and maybe some mechanistic potential insights about why this vaccine might work.”
It will still be at least five years before the first TB vaccine is deployed, Shapiro said. But that’s a close enough horizon that WHO is telling countries to start developing implementation plans now. Shapiro does vaccine acceptability research, including for potential TB vaccines.
“With TB, it’s been hundreds of years, and we finally have a vaccine. What can we do in the next five years, before the product is ready to go, to ensure there is a strong rollout strategy?” she said. “Fortunately, most of the work that’s been done suggests that in communities hit hardest by TB, there’s a lot of enthusiasm.”Kublin and his collaborators, including Andersen-Nissen, Fiore-Gartland and Chetan Sheshadri, MD, at UW, are also exploring the use of challenge studies, in which human volunteers are infected and then treated, for TB vaccine work. Also called a controlled human infection model (CHIM), this strategy can be utilized for diseases where effective treatments are available.
Kublin has previously used BCG as a proxy for TB in a skin challenge model and is wrapping up analysis of a challenge model combining BCG and the TB drug rifampin. Now, with collaborators at Harvard University, Kublin is gearing up to develop an even more ambitious challenge model, using a strain of M. tb that incorporates kill switches into the bacteria itself. Without drugs like tetracycline or doxycycline, the bacterium “undergoes suicide,” Kublin said.
This model would better mimic natural infection, while providing several layers of safety (the kills switches, plus effective TB drugs as backups). The collaborators are doing the preclinical work needed to advance the engineered M. tb into a translational study, which Kublin estimates to be at least two years away.
“This avenue of research could really help advance both vaccine and drug studies against TB,” he said.
Biostatistician Edlefsen works on TB primarily through IMPAc-TB, which aims to elucidate essential, protective immune responses against M. tb. He also helps train the next generation of TB biostatisticians through the African Tuberculosis Biostatistics Training Program at Stellenbosch University in South Africa.
VTU Associate Medical Director Dr. Adrienne Shapiro
Edlefsen leads the design and analysis of clinical trials and helps scientists grapple with the mountains of data generated by today’s assays that can give scientists big-picture views on the DNA, RNA and proteins within single cells. This supports both vaccine research and more foundational research into the biology of our responses to M. tb.
In one collaboration, Edlefsen and his colleagues are exploring why BCG vaccination protects against more than just M. tb infection. They’re comparing the immune responses of infants vaccinated with BCG at birth to those vaccinated about three months later.
“We can see some of what BCG is doing, and it seems to be changing the way the immune system reacts to everything,” Edlefsen said.
He is also working with a team that’s using preclinical models to better understand the intricacies of granuloma formation and immune damage in TB disease. These and similar studies generate what’s known as “high-dimensional data” (an in-depth survey of all the genes and RNA molecules in individual cells is very information-rich), which Edlefsen helps non-bioinformaticians sift through and make sense of.
“We have to collect all these data, but right now you can’t just put it into a computer and press a button and understand what’s going on,” he said. “We need to thoughtfully analyze the data in iterations so that we can ask scientific questions and answer them. That’s my MO in helping people design studies.”
Edlefsen is using large language models to develop methods that will help scientists predict the course of disease using, for example, transcripts from a single cell or a blood sample taken at one point in time.
“Ultimately, you want to be able to look at the blood and say what you think is going to happen in the lungs,” he said. “And to do that, you need data, you need to sample the blood and sample the lungs and you need some way to connect them.”
“One of the big challenges we have is that our diagnostic tests to identify TB are not very good,” Shapiro said. “There is a giant diagnostic gap for the ‘missing millions,’ where we estimate that there are about 10 million cases of TB disease per year. And of those, only about 7 million are ever identified, diagnosed, notified to TB programs, and started on treatment.”
Currently available diagnostic tests miss about of a third of the cases of TB disease. Each test has its limitations and can be hard to access.
The most reliable test for TB disease is the sputum test, in which sputum (phlegm) coughed up from deep in the lungs is examined for TB DNA. (Culturing M. tb is the gold standard, but can take weeks.) But this test requires specialized equipment. Patients’ lungs must first be irritated with a saline spray to induce the necessary deep cough. It’s more likely to be negative in children or early on. People with long-standing TB disease may be too weak to produce the sputum.
Chest X-rays — also not available everywhere — can show evidence of TB even if the sputum test is negative. TB outside the lungs is even harder to detect (Shapiro estimates that infectious disease physicians will only find the bacterium about 50% of the time).
Fred Hutch file photos
But scientists are working toward better options.
Shapiro was part of a committee that reviewed the evidence for a new TB tongue swab test, based on research from UW. Based on Shapiro and her colleagues’ recommendation, the WHO endorsed the approach earlier this month. The tongue swab test will help identify people with signs of TB who need additional diagnostics.
“It's hugely advantageous to both the vaccine enterprise and other TB prevention strategies, and also for people living with HIV, to be able to offer more, easier diagnostics that increase the reach and increase the yield of who has access to TB diagnostics,” Shapiro said.
Fred Hutch researchers are also working toward TB biomarkers that could form the basis of an easy-to-administer test to help find people at high risk of disease, Fiore-Gartland said. The work grew out of a COVID-19 Prevention Network trial that Kublin led in South Africa. The trial tested mRNA SARS-CoV-2 vaccines in people who had already had COVID-19, and examined different boosters in people with co-morbidities and people living with HIV.
“We were looking at the data, and we realized how many people in this study were developing TB — and we weren’t even looking for it,” Fiore-Gartland said.
The study had been designed to look at COVID-19, but the burden of TB couldn’t be ignored: “There were over 19 deaths from TB and zero deaths from COVID,” Kublin said.
The team asked for an NIH supplement grant to support a TB sub-study. They were able to bring back 6,000 participants (about half of the original trial) and perform X-ray and sputum tests. The idea was to diagnose people and get them on treatment regimens, Fiore-Gartland said, but also to leverage the samples collected during the original trial to work toward better biomarkers for TB.
Astoundingly, the researchers saw that up to 80% of cases of TB disease were not associated with symptoms. The insight that so many people are living with asymptomatic TB is prompting a major shift in our understanding of the course of TB infection, Edlefsen said.
Now, Fiore-Gartland’s team is working to understand the differences between people who were TB negative, positive but asymptomatic, positive with TB symptoms, and people who may be negative by sputum tests but whose X-rays show signs of TB.
“If you came up with a biomarker that could be measured at the point of care, and you could say, ‘Hey, this person is at high risk for TB disease, we should bring them into the clinic and do the full workup,’ that would be transformational,” Fiore-Gartland said.
Many pieces of evidence from across the TB field highlight that much of the debilitating damage experienced during TB disease comes from the immune system, not the bacterium, Edlefsen noted. Vaccines work in part by shifting the immune system away from this damaging approach.
As deadly as TB disease is, some people do recover — but may have lifelong complications from the scarring. Edlefsen is working on projects that that use preclinical animal models to understand how granulomas with necrotizing centers (the kind that decimate the lungs) form, and how to disrupt them. It may come down to impeding neutrophils, a type of white blood cell.
“It seems like we may have stumbled on a therapeutic intervention,” he said. “If we could disrupt the neutrophil recruitment while we’re treating people for their tuberculosis, they might heal better.”
In preclinical models, this strategy allows animals to heal from TB with much less scarring.
“If this could translate to people, it would have more impact, frankly, than any other thing that I have done,” Edlefsen said.
For too long, the size of our investment in strategies to better prevent or treat TB did not reflect its impact on humanity. But that is changing.
“In the last five years, there’s been a real shift,” said Fiore-Gartland, pointing to unprecedented levels of investment, including from the NIH and the Gates Foundation. “There’s definitely momentum.”
Sabrina Richards, a senior editor and writer at Fred Hutch Cancer Center, has written about scientific research and the environment for The Scientist and OnEarth Magazine. She has a PhD in immunology from the University of Washington, an MA in journalism and an advanced certificate from the Science, Health and Environmental Reporting Program at New York University. Reach her at srichar2@fredhutch.org.
Are you interested in reprinting or republishing this story? Be our guest! We want to help connect people with the information they need. We just ask that you link back to the original article, preserve the author’s byline and refrain from making edits that alter the original context. Questions? Email us at communications@fredhutch.org
Every dollar counts. Please support lifesaving research today.
For the Media