tuberculosis
Findings in Tuberculosis Immunity Point Toward New Approaches to Treatment and Prevention
Posted on by Dr. Monica M. Bertagnolli
Tuberculosis, caused by the bacteria Mycobacterium tuberculosis (Mtb), took 1.3 million lives in 2022, making it the second leading infectious killer around the world after COVID-19, according to the World Health Organization. Current TB treatments require months of daily medicine, and certain cases of TB are becoming increasingly difficult to treat because of drug resistance. While TB case counts had been steadily decreasing before the COVID-19 pandemic, there’s been an uptick in the last couple of years.
Although a TB vaccine exists and offers some protection to young children, the vaccine, known as BCG, has not effectively prevented TB in adults. Developing more protective and longer lasting TB vaccines remains an urgent priority for NIH. As part of this effort, NIH’s Immune Mechanisms of Protection Against Mycobacterium tuberculosis Centers (IMPAc-TB) are working to learn more about how we can harness our immune systems to mount the best protection against Mtb. And I’m happy to share some encouraging results now reported in the journal PLoS Pathogens, which show progress in understanding TB immunity and suggest additional strategies to fight this deadly bacterial infection in the future.1
Most vaccines work by stimulating our immune systems to produce antibodies that target a specific pathogen. The antibodies work to protect us from getting sick if we are ever exposed to that pathogen in the future. However, the body’s more immediate but less specific response against infection, called the innate immune system, serves as the first line of defense. The innate immune system includes cells known as macrophages that gobble up and destroy pathogens while helping to launch inflammatory responses that help you fight an infection.
In the case of TB, here’s how it works: If you were to inhale Mtb bacteria into your lungs, macrophages in tiny air sacs called alveoli would be the first to encounter it. When these alveolar macrophages meet Mtb for the first time, they don’t mount a strong attack against them. In fact, Mtb can infect these immune macrophages to produce more bacteria for a week or more.
What this intriguing new study led by Alissa Rothchild at the University of Massachusetts Amherst and colleagues from Seattle Children’s Research Institute suggests is that vaccines could target this innate immune response to change the way macrophages in the lungs respond and bolster overall defenses. How would it work? While scientists are just beginning to understand it, it turns out that the adaptive immune system isn’t the only part of our immune system that’s capable of adapting. The innate immune system also can undergo long-term changes, or remodeling, based on its experiences. In the new study, the researchers wanted to explore the various ways alveolar macrophages could respond to Mtb.
In search of ways to do it, the study’s first author, Dat Mai at Seattle Children’s Research Institute, conducted studies in mice. The first group of mice received the BCG vaccine. In the second model, the researchers put Mtb into the ears of mice to cause a persistent but contained infection in their lymph nodes. They’d earlier shown that this contained Mtb infection affords animals some protection against subsequent Mtb infections. A third group of mice—the control group—did not receive any intervention. Weeks later, all three groups of mice were exposed to aerosol Mtb infection under controlled conditions. The researchers then sorted infected macrophages from their lungs for further study.
Alveolar macrophages from the first two sets of mice showed a strong inflammatory response to subsequent Mtb exposure. However, those responses differed: The macrophages from vaccinated mice turned on one type of inflammatory program, while macrophages from mice exposed to the bacteria itself turned on another type. Further study showed that the different exposure scenarios led to other discernable differences in the macrophages that now warrant further study.
The findings show that macrophages can respond significantly differently to the same exposure based on what has happened in the past. They complement earlier findings that BCG vaccination can also lead to long-term effects on other subsets of innate immune cells, including myeloid cells from bone marrow.2,3 The researchers suggest there may be ways to take advantage of such changes to devise new strategies for preventing or treating TB by strengthening not just the adaptive immune response but the innate immune response as well.
As part of the IMPAc-TB Center led by Kevin Urdahl at Seattle Children’s Research Institute, the researchers are now working with Gerhard Walzl and Nelita du Plessis at Stellenbosch University in South Africa to compare the responses in mice to those in human alveolar macrophages collected from individuals across the spectrum of TB disease. As they and others continue to learn more about TB immunity, the hope is to apply these insights toward the development of new vaccines that could combat this disease more effectively and ultimately save lives.
References:
[1] Mai D, et al. Exposure to Mycobacterium remodels alveolar macrophages and the early innate response to Mycobacterium tuberculosis infection. PLoS Pathogens. DOI: 10.1371/journal.ppat.1011871. (2024).
[2] Kaufmann E, et al. BCG Educates Hematopoietic Stem Cells to Generate Protective Innate Immunity against Tuberculosis. Cell. DOI: 10.1016/j.cell.2017.12.031 (2018).
[3] Lange C, et al. 100 years of Mycobacterium bovis bacille Calmette-Guérin. Lancet Infectious Diseases. DOI: 10.1016/S1473-3099(21)00403-5. (2022).
NIH Support: National Institute of Allergy and Infectious Diseases
Tuberculosis: An Ancient Disease in Need of Modern Scientific Tools
Posted on by Anthony S. Fauci, M.D., National Institute of Allergy and Infectious Diseases
Although COVID-19 has dominated our attention for the past two years, tuberculosis (TB), an ancient scourge, remains a dominating infectious disease globally, with an estimated 10 million new cases and more than 1.3 million deaths in 2020. TB disproportionately afflicts the poor and has long been the leading cause of death in people living with HIV.
Unfortunately, during the global COVID-19 pandemic, recent gains in TB control have been stalled or reversed. We’ve seen a massive drop in new TB diagnoses, reflecting poor access to care and an uptick in deaths in 2020 [1].
We are fighting TB with an armory of old weapons inferior to those we have for COVID-19. The Bacillus Calmette–Guérin (BCG) vaccine, the world’s only licensed TB vaccine, has been in use for more than 100 years. While BCG is somewhat effective at preventing TB meningitis in children, it provides more limited durable protection against pulmonary TB in children and adults. More effective vaccination strategies to prevent infection and disease, decrease relapse rates, and shorten durations of treatment are desperately needed to reduce the terrible global burden of TB.
In this regard, over the past five years, several exciting research advances have generated new optimism in the field of TB vaccinology. Non-human primate studies conducted at my National Institute of Allergy and Infectious Diseases’ (NIAID) Vaccine Research Center and other NIAID-funded laboratories have demonstrated that effective immunity against infection is achievable and that administering BCG intravenously, rather than under the skin as it currently is given, is highly protective [2].
Results from a phase 2 trial testing BCG revaccination in adolescents at high risk of TB infection suggested this approach could help prevent TB [3]. In addition, a phase 2 trial of an experimental TB vaccine based on the recombinant protein M72 and an immune-priming adjuvant, AS01, also showed promise in preventing active TB disease in latently infected adults [4].
Both candidates are now moving on to phase 3 efficacy trials. The encouraging results of these trials, combined with nine other candidates currently in phase 2 or 3 studies [5], offer new hope that improved vaccines may be on the horizon. The NIAID is working with a team of other funders and investigators to analyze the correlates of protection from these studies to inform future TB vaccine development.
Even with these exciting developments, it is critical to accelerate our efforts to enhance and diversify the TB vaccine pipeline by addressing persistent basic and translational research gaps. To this end, NIAID has several new programs. The Immune Protection Against Mtb Centers are taking a multidisciplinary approach to integrate animal and human data to gain a comprehensive understanding of the immune responses required to prevent TB infection and disease.
This spring, NIAID will fund awards under the Innovation for TB Vaccine Discovery program that will focus on the discovery and early evaluation of novel TB vaccine candidates with the goal of diversifying the TB vaccine pipeline. Later this year, the Advancing Vaccine Adjuvant Research for TB program will systematically assess combinations of TB immunogens and adjuvants. Finally, NIAID’s well-established clinical trials networks are planning two new clinical trials of TB vaccine candidates.
As we look to the future, we must apply the lessons learned in the development of the COVID-19 vaccines to longstanding public health challenges such as TB. COVID-19 vaccine development was hugely successful due to the use of novel vaccine platforms, structure-based vaccine design, community engagement for rapid clinical trial enrollment, real-time data sharing with key stakeholders, and innovative trial designs.
However, critical gaps remain in our armamentarium. These include the harnessing the immunology of the tissues that line the respiratory tract to design vaccines more adept at blocking initial infection and transmission, employing thermostable formulations and novel delivery systems for resource-limited settings, and crafting effective messaging around vaccines for different populations.
As we work to develop better ways to prevent, diagnose, and treat TB, we will do well to remember the great public health icon, Paul Farmer, who tragically passed away earlier this year at a much too young age. Paul witnessed firsthand the devastating consequences of TB and its drug resistant forms in Haiti, Peru, and other parts of the world.
In addition to leading efforts to improve how TB is treated, Paul provided direct patient care in underserved communities and demanded that the world do more to meet their needs. As we honor Paul’s legacy, let us accelerate our efforts to find better tools to fight TB and other diseases of global health importance that exact a disproportionate toll among the poor and underserved.
References:
[1] Global tuberculosis report 2021. WHO. October 14, 2021.
[2] Prevention of tuberculosis in macaques after intravenous BCG immunization. Darrah PA, Zeppa JJ, Maiello P, Hackney JA, Wadsworth MH,. Hughes TK, Pokkali S, Swanson PA, Grant NL, Rodgers MA, Kamath M, Causgrove CM, Laddy DJ, Bonavia A, Casimiro D, Lin PL, Klein E, White AG, Scanga CA, Shalek AK, Roederer M, Flynn JL, and Seder RA. Nature. 2020 Jan 1; 577: 95–102.
[3] Prevention of M. tuberculosis Infection with H4:IC31 vaccine or BCG revaccination. Nemes E, Geldenhuys H, Rozot V, Rutkowski KT, Ratangee F,Bilek N., Mabwe S, Makhethe L, Erasmus M, Toefy A, Mulenga H, Hanekom WA, et al. N Engl J Med 2018; 379:138-149.
[4] Final analysis of a trial of M72/AS01E vaccine to prevent tuberculosis. Tait DR, Hatherill M, Van Der Meeren O, Ginsberg AM, Van Brakel E, Salaun B, Scriba TJ, Akite EJ, Ayles HM, et al.
[5] Pipeline Report 2021: Tuberculosis Vaccines. TAG. October 2021.
Links:
Tuberculosis (National Institute of Allergy and Infectious Diseases/NIH)
NIAID Strategic Plan for Tuberculosis Research
Immune Mechanisms of Protection Against Mycobacterium tuberculosis Centers (IMPAc-TB) (NIAID)
Partners in Health (Boston, MA)
[Note: Acting NIH Director Lawrence Tabak has asked the heads of NIH’s Institutes and Centers (ICs) to contribute occasional guest posts to the blog to highlight some of the interesting science that they support and conduct. This is the seventh in the series of NIH IC guest posts that will run until a new permanent NIH director is in place.]
Creative Minds: Lessons from Halfway Around the Globe
Posted on by Dr. Francis Collins
Caption: Duncan Maru (right) and Community Health Director Ashma Baruwal (left) evaluating a patient in rural Nepal.
Credit: Allison Shelley
A decade ago, as a medical student doing volunteer work at a hospital in India’s capital of New Delhi, Duncan Maru saw a young patient who changed the course of his career: a 12-year-old boy in a coma caused by advanced tuberculosis (TB). Although the child had been experiencing TB symptoms for four months, he was simply given routine antibiotics and didn’t receive the right drugs until his parents traveled hundreds of miles at considerable expense to bring him to a major hospital. After five weeks of intensive treatment, the boy regained consciousness and he was able to walk and talk again.
That’s quite an inspiring story. But it’s also a story that haunted Maru because he knew that if this boy had access to good primary care at the local level, his condition probably never would have become so critical. Determined to help other children and families in similar situations, Maru has gone on to dedicate himself to developing innovative ways of providing high-quality, low-cost health care in developing areas of the world. His “lab” for testing these efforts? The South Asian nation of Nepal—specifically, the poverty-stricken, rural district of Achham, which is located several hundred miles west of the national capital of Kathmandu.
LabTV: Curious About Tuberculosis
Posted on by Dr. Francis Collins
One reason that I decided to share these LabTV profiles is that they put a human face on the amazingly wide range of NIH-supported research being undertaken every day in labs across the country. So far, we’ve met young scientists pursuing basic, translational, and clinical research related to the immune system, cancer, Alzheimer’s disease, and the brain’s natural aging process. Today, we head to Boston to visit a researcher who has set her sights on a major infectious disease challenge: tuberculosis, or TB.
Bree Aldridge, PhD, an assistant professor at Tufts University School of Medicine in Boston, runs a lab that’s combining microbiology and bioengineering in an effort to streamline treatment for TB, which leads to more than 2 million deaths worldwide every year [1]. Right now, people infected with Mycobacterium tuberculosis—the microbe that causes TB—must take a combination of drugs for anywhere from six to nine months. When I was exposed to TB as a medical resident, I had to take a drug for a whole year. These lengthy regimens raise the risk that people will stop taking the drugs prematurely or that an opportunistic strain of M. tuberculosis will grow resistant to the therapy. By gaining a better basic understanding of both M. tuberculosis and the cells it infects, Aldridge and her colleagues hope to design therapies that will fight TB with greater speed and efficiency.
New Weapon Targets Ancient Foe
Posted on by Dr. Francis Collins
Colorized scanning electron micrograph of Mycobacterium tuberculosis. Source: Clifton E. Barry III, Ph.D., NIAID, NIH.
Tuberculosis is an ancient scourge that has evolved in lockstep with humans for more than ten millennia. It infected residents of ancient Egypt; remnants of Mycobacterium tuberculosis, the deadly bacterium that ravages the lungs and other organs of its victims, have been found in Egyptian mummies dating back 3,000 years. It is considered one of the world’s deadliest diseases.
I’ve had my own experience with TB. As a medical resident in the intensive care unit in North Carolina in 1977, I was exposed to the bacterium during emergency care of a young migrant worker who arrived at our hospital in extremis from internal bleeding. Only after the hemorrhaging was stopped did we discover his advanced tuberculosis. But I’m happy to say we treated him successfully with a battery of drugs, and he walked out of the hospital. My own TB skin test tested positive a few months later, and so I had to take a year’s worth of therapy with isoniazid to wipe out those little microbial invaders. That was all it took.
For the most part, TB cases have been reduced to a trickle in the Western world—thanks to antibiotics—and relegated to the history books with descriptions of ‘consumption’ in nineteen-century England and tales of jail-like sanatoria where those consumptives were quarantined and often died.
