Category: Respiratory Diseases

To Beat Lung Fibrosis, Researchers Turn to Body’s own Healing Powers

Photo by Robina Weermeijer on Unsplash

The most common type of lung fibrosis is idiopathic – of unknown cause. Researchers are urgently trying to find ways to prevent or slow idiopathic pulmonary fibrosis (IPF) and related lung conditions, which can cause worsening shortness of breath, dry cough, and extreme fatigue. Average survival following diagnosis of IPF is just three to five years, and the disease has no cure.

A recent U-M study from a team led by Sean Fortier, MD and Marc Peters-Golden, MD at University of Michigan Medical School uncovers a pathway used during normal wound healing that has the potential to reverse IPF. They published their research in the Journal of Clinical Investigation.

Using a mouse model, they simulated IPF by administering bleomycin, a chemotherapy agent that causes cell injury and confirmed that the resulting lung scarring resolved itself over the span of about six weeks.

Because of this, “studying fibrosis is kind of tough,” said Fortier. “If we’re going to give experimental drugs to try and resolve fibrosis, we have to do it before it resolves on its own.

Otherwise, we will not be able to tell if the resolution was the action of the drug or natural repair mechanisms of the body.”

However, he said, “there’s actually a lot to learn about how the mouse gets better on its own. If we can learn the molecular mechanisms by which this occurs, we may uncover new targets for IPF.”

The process by which lung injury either leads to healing or fibrosis relies in part on what happens to fibroblasts – cells which forms connective tissue.

During injury or illness, fibroblasts are activated, becoming myofibroblasts that form scar tissue by secreting collagen. When the job is done, these fibroblasts must be deactivated, or de-differentiated, to go back to their quiet state or undergo programmed cell death and be cleared.

“This is the major distinction between normal wound healing and fibrosis – the persistence of activated myofibroblasts,” explained Fortier. That deactivation is controlled by molecular brakes. The study examined one of these brakes, called MKP1 – which the team found was expressed at lower levels in fibroblasts from patients with IPF.

By genetically eliminating MKP1 in fibroblasts of mice after establishing lung injury, the team saw that fibrosis continued uncontrolled.

“Instead of at day 63, seeing that nice resolution, you still see fibrosis,” said Fortier.

“We argued by contradiction: when you knock out this brake, fibrosis that would otherwise naturally disappear, persists and therefore MKP1 is necessary for spontaneous resolution of fibrosis.”

They performed several additional studies using CRISPR techniques to demonstrate how MKP1 applies the brakes, mainly by deactivating the enzyme p38α, which is implicated in a cell’s reaction to stress.

Furthermore, they demonstrated that neither of the two current FDA approved drugs for lung fibrosis, pirfenidone and nintedanib, are able to turn off myofibroblasts.

“That’s totally in keeping with the fact that they do slow the progression, but they don’t halt or reverse disease,” said Fortier.

Fortier hopes the discovery that this pathway reverses fibrosis leads to exploration of additional brakes on fibrosis.

“So much work on fibrosis has focused on how we can prevent it, but when a patient presents to my clinic with a dry cough, shortness of breath, and low oxygen as a result of underlying IPF, the scarring is already present. Of course, we’d love a way to prevent the scarring from getting worse, but the Holy Grail is to reverse it.”

Source: Michigan Medicine – University of Michigan

Large Study Finds Antibiotics are Ineffective for Most Lower Respiratory Tract Infections

Photo by Robina Weermeijer on Unsplash

Use of antibiotics provided no measurable impact on the severity or duration of coughs, even if a bacterial infection was present, finds a large prospective study of people seeking care for lower-respiratory tract infections. The study by researchers at Georgetown University Medical Center and colleagues appeared in the Journal of General Internal Medicine.

“Upper-respiratory tract infections usually include the common cold, sore throat, sinus infections and ear infections and have well established ways to determine if antibiotics should be given,” says the study’s lead author, Dan Merenstein, MD, professor of family medicine. “Lower-respiratory tract infections tend to have the potential to be more dangerous, since about 3% to 5% of these patients have pneumonia. But not everyone has easy access at an initial visit to an X-ray, which may be the reason clinicians still give antibiotics without any other evidence of a bacterial infection. Plus, patients have come to expect antibiotics for a cough, even if it doesn’t help. Basic symptom-relieving medications plus time brings a resolution to most people’s infections.”

The antibiotics prescribed in this study for lower-tract infections were all appropriate, commonly used antibiotics to treat bacterial infections. But the researchers’ analysis showed that of the 29% of people given an antibiotic during their initial medical visit, there was no effect on the duration or overall severity of cough compared to those who didn’t receive an antibiotic.

“Physicians know, but probably overestimate, the percentage of lower-tract infections that are bacterial; they also likely overestimate their ability to distinguish viral from bacterial infections,” says Mark H. Ebell, MD, MS, a study author and professor in the College of Public Health at the University of Georgia. “In our analysis, 29% of people were prescribed an antibiotic, while only 7% were given an antiviral. But most patients do not need antivirals, as there exist only two respiratory viruses where we have medications to treat them: influenza and SARS-CoV-2. There are none for all of the other viruses.”

To determine if there was an actual bacterial or viral infection present, beyond the self-reported symptoms of a cough, the investigators confirmed the presence of pathogens with advanced lab tests to look for microbiologic results classified as only bacteria, only viruses, both virus and bacteria, or no organism detected. Very importantly, for those with a confirmed bacterial infection, the length of time until illness resolution was the same for those receiving an antibiotic versus those not receiving one –about 17 days.

Overuse of antibiotics can result in dizziness, nausea, diarrhoea and rash, along with about a 4% chance of serious adverse effects including anaphylaxis, which is a severe, life-threatening allergic reaction; Stevens-Johnson syndrome, a rare, serious disorder of the skin and mucous membranes; and Clostridioides difficile-associated diarrhoea. The World Health Organization considers antibiotic resistance to be a major an emerging threat.

“We know that cough can be an indicator of a serious problem. It is the most common illness-related reason for an ambulatory care visit, accounting for nearly 3 million outpatient visits and more than 4 million emergency department visits annually,” says Merenstein. “Serious cough symptoms and how to treat them properly needs to be studied more, perhaps in a randomized clinical trial, as this study was observational and there haven’t been any randomized trials looking at this issue since about 2012.”

Source: Georgetown University School of Medicine

Landmark Study Supports Use of Cystic Fibrosis Drug in Infants from Four Weeks of Age

Photo by William Fortunato on Pexels

A cystic fibrosis drug targeting the basic defect that causes the condition has been shown to be safe and effective in newborns aged four weeks and above, new research involving RCSI University of Medicine and Health Sciences and Children’s Health Ireland has found.

The finding is described as a “huge moment” for cystic fibrosis by one of the lead researchers. The study included the first baby in the world with cystic fibrosis to be diagnosed from birth and enrolled directly onto a trial of this sort.

The drug, ivacaftor (Kalydeko), is the first drug designed to treat the basic defect in cystic fibrosis. It was originally approved for adults, then sequentially over several years for older and younger children. Currently, it is approved for babies aged four months and older, however, this new research suggests that it is safe and effective for babies as young as four weeks of age.

Cystic fibrosis experts predict that the earlier treatments can begin, the more likely that progression of the condition can be slowed down or halted in children, and this is the focus of several international research studies led by RCSI and Children’s Health Ireland. The findings of this study could pave the way for eligible newborns to start treatment on the medicine at the time of diagnosis (typically at newborn screening) rather than having to wait until they are four months old.

“This is a huge moment in cystic fibrosis,” said Paul McNally, Associate Professor of Paediatrics at RCSI and Consultant in Respiratory Medicine at CHI. McNally is one of the authors of the new study which was published in the Journal of Cystic Fibrosis.

“Over the years ivacaftor, or Kalydeko, has been put through clinical trials in younger and younger children. Now, through this study, it has been shown to be safe and effective all the way down to four weeks of age,” he said.

“This is an important development because almost all children are diagnosed through newborn screening at around this time. The availability of a treatment that targets the underlying cause of the disease in newborns and can be started immediately at diagnosis will provide a huge sense of reassurance and hope for families.”

Cystic fibrosis is an inherited disease that mainly affects the lungs and digestive system. Ireland has the highest incidence of the condition in the world: approximately 1400 children and adults in Ireland live with the condition and more than 30 new cases of cystic fibrosis are diagnosed here each year, typically around four weeks of age through the newborn screening programme.

In recent years, new medicines have emerged that target the basic defect that causes cystic fibrosis. Ivacaftor (Kalydeko) is one such treatment. It targets a genetic change seen in around 4% of people with cystic fibrosis worldwide, and around 10% in Ireland.

Siblings Kara (aged 5) and Isaac Moss (aged 2) both participated in the study through Children’s Health Ireland. Kara was part of an earlier phase of the study that paved the approval of the drug in older infants and led to the latest trial that Isaac took part in.

Isaac was the first baby with cystic fibrosis in the world to be diagnosed from birth and enrolled directly onto a trial of these ground-breaking treatments.

“Both Kara and Isaac are doing really well and remarkably are not experiencing any of the typical symptoms of cystic fibrosis at the moment,” said their mother Debbie.

“Research studies like this one are so important to ensuring that children get access to the right treatments as early as possible. With the right medications, they can enjoy a healthy childhood and look forward to a brighter future”

Ivacaftor is manufactured by pharmaceutical company Vertex Pharmaceuticals, who are currently applying to the European Medicines Agency for an extension to the marketing authorization for Ivacaftor down to one month of age.

The study involved researchers from RCSI, Children’s Health Ireland, the U.S. and the UK.

Source: RCSI

Limiting the Damage from an Asthma Attack could Halt the Disease

Credit: Pixabay CC0

Scientists at King’s College London have discovered that the features of asthma attacks, a disease usually treated as being inflammatory, in fact stem from constriction of airways, making breathing difficult. The new study, published in Science, shows for the first time that many features of an asthma attack – inflammation, mucus secretion, and damage to the airway barrier that prevents infections – result from this mechanical constriction in a mouse model.

The findings suggest that blocking a process that normally causes epithelial cell death could prevent the damage, inflammation, and mucus that result from an asthma attack.

Professor Jody Rosenblatt from King’s College London said: “Our discovery is the culmination of more than ten years work. As cell biologists who watch processes, we could see that the physical constriction of an asthma attack causes widespread destruction of the airway barrier. Without this barrier, asthma sufferers are far more likely to get long-term inflammation, wound healing, and infections that cause more attacks. By understanding this fundamental mechanism, we are now in a better position to prevent all these events.”

Asthma symptoms include wheezing, coughing, feeling breathlessness and a tight chest. Triggers such as pollen or dust can make asthma symptoms worse and can lead to a life-threatening asthma attack.

Despite the disease commonality, the causes of asthma are still not understood. Current medications treat the consequences of an asthma attack by opening the airways, calming inflammation, and breaking up the sticky mucus which clogs the airway, which help control asthma, but do not prevent it.

The answer to stopping asthma symptoms may lie in cell extrusion, a process the researchers discovered that drives most epithelial cell death. Scientists used mouse lung models and human airway tissue to discover that when the airways contract, known as bronchoconstriction, the epithelial cells that line the airway get squeezed out to later die.

Because bronchoconstriction causes so many cell extrusions, it damages the airway barrier which causes inflammation and excess mucus.

In previous studies, the scientists found that the chemical compound gadolinium can block extrusion. In this study, they found it could work in mice to prevent the excess extrusion that causes damage and inflammation after an asthma attack. The authors note that gadolinium has not been tested in humans and has not been deemed to be safe or efficacious.

Professor Rosenblatt said: “This constriction and destruction of the airways causes the post-attack inflammation and excess mucus secretion that makes it difficult for people with asthma to breathe.

“Current therapies do not prevent this destruction – an inhaler such as Albuterol opens the airways, which is critical to breathing but, dishearteningly, we found it does not prevent the damage and the symptoms that follow an attack. Fortunately, we found that we can use an inexpensive compound, gadolinium which is frequently used for MRI imaging, to stop the airway damage in mice models as well as the ensuing inflammation and mucus secretion. Preventing this damage could then prevent the build-up of musculature that cause future attacks.”

Professor Chris Brightling from the University of Leicester and one of the co-authors of the study said: “In the last decade there has been tremendous progress in therapies for asthma particularly directed towards airway inflammation. However, there remains ongoing symptoms and attacks in many people with asthma. This study identifies a new process known as epithelial extrusion whereby damage to the lining of the airway occurs as a consequence of mechanical constriction and can drive many of the key features of asthma. Better understanding of this process is likely to lead to new therapies for asthma.”

The discovery of the mechanics behind cell extrusion could underlie other inflammatory diseases that also feature constriction such as cramping of the gut and inflammatory bowel disease.

Source: King’s College London

What we can Learn about TB at the Autopsy Table

Credit: Scientific Animations CC4.0

By Tiyese Jeranji for Spotlight

In addition to shedding light on what people actually die of, autopsies can also play an important role in helping us to better understand disease. Tiyese Jeranji unpacks tuberculosis-related autopsy research in the Western Cape and delves into some of the fascinating complexities of this branch of TB research.

Figuring out how many people in South Africa die every year of tuberculosis (TB) is not straight-forward. On the one hand, Stats SA’s frequent mortality reports put the number at under 30 000, on the other hand, the World Health Organization (WHO) estimates that it is over 50 000.

While this may at first glance seem like a large discrepancy, there is a simple explanation. The Stats SA figures are based on what is written on death notifications, and these notifications very often do not tell the full story of what a person died of. The WHO estimate, is derived using mathematical modelling that triangulates estimates based on several data sources.

Looking at the numbers from studies that determine the cause of death (or what people actually died of) is one of the ways we know that relying on death notifications result in an undercount of TB deaths. Such autopsy studies have consistently found that many people had undiagnosed TB at the time of death and that the undiagnosed TB was often the actual cause of death.

One review study published in the journal AIDS concluded that “in resource-limited settings, TB accounts for approximately 40% of facility-based HIV/AIDS-related adult deaths” and that “almost half of this disease remains undiagnosed at the time of death”. According to WHO figures, of the estimated 280 000 people who fell ill with TB in South Africa in 2022, over 65 000 were not diagnosed.

Importance of autopsy research

Dr Muhammad Osman, Academic Portfolio Lead and Senior Lecturer: Public Health at the University of Greenwich, tells Spotlight that it is important to do TB autopsy studies because it enables us to identify TB that was not diagnosed during life – and this helps us understand the true burden of the disease.

Osman says identifying TB at autopsies has significant benefits. He says by overlaying health seeking behaviour (how people visit clinics), we can identify missed opportunities for TB screening and design interventions to improve screening for TB. “We could trace family contacts of the deceased and offer TB screening and prevention. This is not taking place at present,” he says.

Osman and his colleagues published a paper in the International Journal of Infectious diseases in 2021  looking at TB in people with sudden unexpected death (SUD) in Cape Town. They found that active TB was identified at post-mortems in 6.2% of the 770 cases they studied. More strikingly, in around 92% of those cases the TB had not been diagnosed while the person was alive.

Osman says that these days there is an increasing awareness of undiagnosed and untreated TB. He points out that new interventions to improve TB testing and diagnosis have been implemented such as targeted universal testing — an approach by which people who do not have any TB symptoms, but who are considered to be at high risk of TB, are routinely offered TB tests.

He says these days healthcare worker risk is considered more carefully and he stresses the importance of protecting forensic and pathology teams. (Forensics focuses on determining the cause and manner of death while  pathology  is the study and diagnosis of disease through examination of tissue, cells, autopsies, and so on.)

Closing the gaps

Osman says their study also identified a gap between the pathology services and access to routine health service records. “We thought that this is an essential gap to close – the forensic/pathology services need access to routine health service. For a limited number of these deaths we were able to match their records to the public health clinic and hospital records – and many of them had contact with the health services in the six months before death,” he says.

“If forensic pathologists are given full access to the health records, they would know the timing of previous TB and the treatment outcomes of those episodes. The lung changes seen with TB are different in the case of active TB and healed/recovered TB. There are well documented macroscopic (what’s is seen by the examination) and microscopic (seen through histology and microbiology) findings,” says Osman.

A complex disease

The study of TB is complicated by the fact that TB can occur at several stages on a continuum and can impact several different parts of the body.

Professor Threnesan Naidoo, research pathologist at the African Health Research Institute (AHRI), tells Spotlight that when people think of TB, they usually think of the person who’s been coughing for a few months, loss of weight, loss of appetite, having night sweats, and maybe coughing up some blood. “But there’s a journey to that point and then generally beyond that point, and clinically, there’s a continuum of the disease. We refer to it as latent disease, subclinical, active and then healed TB,” he says. It is an area in which things are changing fast – a paper published in the Lancet medical journal last week proposed dividing TB into five stages.

Naidoo says autopsies provide an opportunity to study TB at different stages (latent, subclinical, active, healed) especially when someone with TB dies of another cause. He says they  can encounter people at any stage along the TB continuum because at any point someone could be shot, stabbed, or involved in a motor vehicle accident. “You (pathologist) have a unique opportunity to study the effect of TB on cells and tissue physically under a microscope and not through imaging (x-ray),” Naidoo says.

Autopsies also presents the opportunity to look at TB disease not only in the lung, but also the brain, thyroid gland, kidney or urinary system since TB has the capacity to spread everywhere, explains Naidoo.

“Autopsy gives you the opportunity to study TB everywhere,” he says. “Clinically (when someone is alive), you don’t  go about investigating the entire body. Neither is it practical nor feasible or safe. But [with an] autopsy you’re examining the entire body anyway. We study TB in totality,” he says.

How it is done

The standard manner of doing an autopsy involves a thorough examination of the body. Naidoo explains that the process starts with an external examination to document injuries, marks, and other physical characteristics that are visible. The internal examination involves dissecting organs, tissues, and body cavities to identify any abnormalities or signs of disease. Samples may be taken for further analysis, such as toxicology tests, histological examination, or TB research.

Any findings from the samples, Naidoo notes, must be interpreted taking into account changes that occur in a dead body. “[In] the living, you know, it’s a living person and they’re able to do things and you’re able to see things on imaging (X-Ray), but in the dead you have to account for the fact that the person has now demised and certain changes occur after death.”

Autopsy study at UCT

An ongoing study at the University of Cape Town is exploring the role of lymph nodes in the spread or containment of TB disease by looking at tissue of the deceased.

Much TB research so far have been done on animals and not on humans, points out Dr Virginie Rozot, research officer at the South African TB Vaccine Initiative (SATVI) and co-principal investigator of the UCT study. “We have great non-human primate and great mice studies that try to underline the mechanism of the  disease progression. However, animal models are not a true reflection of what happens in humans.

“For the longest time in these human studies, most studies have been done in the blood and what is happening in the blood has been taken to correlate with what is happening in the lung.”

In short, autopsies allow researchers to look directly at lung, brain and other tissue in a way that simply isn’t feasible in living people.

“So the only way you can actually access tissues is to do post mortem studies. Post mortem studies have been happening since the beginning of last century. And they were like fantastic studies, but the tools were not the same as we have today.  I think that should come back to the front of the scene of research because then you can ask all the questions we’ve been trying to answer on what is happening in the tissue by looking into the blood,” she says. “Autopsy allows us to study the exact part we want to study not just the blood.”

Collecting samples

In collaboration with the Western Cape Forensic Pathology Service, UCT has created  a postmortem sample collection platform to help with TB research. By leveraging the Inquest Act of 1959, which states that people that die of unnatural causes  must undergo a medico-legal investigation to determine the cause of death, Rozot and her team come in to conduct a post-mortem to get their samples. They aim to do the post-mortem in less than 24 hours after death.

Since starting this study about eight months ago, they have done 125 autopsies , with a consent rate of 64%. “I think our consent rate is incredible. We are still putting together our findings to determine how many cases of TB we have found so far by looking at autopsies,” says Rozot.

Representative samples

Dr Laura Taylor, forensic pathologist at the Western Cape Forensic Pathology Services, says the bodies that they look at, in line with the Inquest Act relating to unnatural deaths, are representative of people in South Africa. “However, they are not exactly representative of the entire South African population because there are certain socio economic groups that are more likely to die of unnatural deaths due to increased prevalence of trauma and violence in their communities,” she says.

Because there is no central database, Taylor couldn’t say how many cases of TB they find among the deceased. “[T]here are autopsy records or reports which are written for each case, but there is no central database for TB specifically detected [through] autopsy,” she says.

Forensic autopsy and other diseases

Rozot and Naidoo share the view that, if done well, TB autopsy studies can help shed light on other diseases.

The value of this information is that people dying with or from TB will also have any of  the other conditions such as hypertension, HIV, and diabetes, Naidoo says.

“You can work out all those variables… [people] don’t just come with diabetes, the diabetes changes the face of TB, HIV changes the face of TB and TB changes the face of those diseases as well. So, the complexity of it becomes something that we need to pay attention to, and look at all the common variables, like the association of TB and HIV is a big one. So studies might look at HIV infection and how it may affect TB and vice versa. Same with diabetes, hypertension, any of the other non-communicable diseases as well,” he concludes.

Republished from Spotlight under a Creative Commons licence.

Source: Spotlight

New Enzymatic Cocktail can Kill Tuberculosis-causing Mycobacteria

Mycobacterium tuberculosis drug susceptibility test. Photo by CDC on Unsplash

With resistance to chemical antibiotics on the rise, the world needs entirely new forms of antibiotics. A new study published in Microbiology Spectrum, a journal of the American Society for Microbiology, shows that an enzymatic cocktail can kill a variety of mycobacterial species of bacteria, including those that cause tuberculosis. The research was carried out by scientists at Colorado State University and Endolytix Technologies.

“We have a mycobacterial drug that works for Nontuberculous Mycobacteria and M. tuberculosis that is biological, not phage therapy, and not small molecule antibiotics,” said Jason Holder, Ph.D., a study coauthor and Founder and Chief Science Officer at Endolytix Technology.

“Mycobacterial infections are particularly hard to treat due to poor efficacy with standard of care drugs that are used in multidrug regimens resulting in significant toxicities and treatments lasting 6 months to years. This is often followed up by reemergence of the bacterial infection after a year of testing negative.”

In the new proof of principle study, the researchers took a biological approach instead of a chemical one to develop a cocktail of enzymes that attack the cell envelope of mycobacteria.

The cocktail of enzymes contains highly specific biochemical catalysts that target and degrade the mycobacteria cell envelope that is essential for mycobacterial viability.

To increase efficacy, the researchers delivered the enzymatic drug inside of host macrophages where mycobacteria grow. In laboratory experiments, the drug was effective against M. tuberculosis and Nontuberculous Mycobacteria (NTMs), both lethal pulmonary lung diseases (PD). TB kills roughly 1.5 million people per year.

“We characterised the mechanism of bactericide as through shredding of the bacterial cells into fragments,” Holder said.

“We’ve shown we can design and develop biological antibiotics and deliver them to the sites of infection through liposomal encapsulation. By combining drug delivery science with enzymes that lyse bacteria, we hope to open up treatment options in diseases such as NTM pulmonary disease, tuberculosis pulmonary disease and others.”

According to study coauthor Richard Slayden, PhD, a professor in the Department of Microbiology, Immunology and Pathology at Colorado State University, the new therapy complements current standard-of-care drugs and does not have many of the drug-drug interactions that are problematic with many anti-mycobacterial drugs in use. “Endolytix enzymes work powerfully with standard-of-care antibiotics to kill bacteria with lower drug concentrations,” Holder said. “This has the potential to reduce the significant toxicities associated with multi-drug regimens that are the standard for mycobacterial infections and hopefully lead to more rapid cures.”

Source: American Society for Microbiology

Massive TB Vaccine Trial Kicks off in SA – it could be the First TB Vaccine in over a Century

A massive and long-awaited study of an experimental tuberculosis vaccine has kicked off in South Africa. Marcus Low reports.

Photo by National Cancer Institute

By Marcus Low for Spotlight

The first jabs in a much-anticipated clinical trial of an experimental tuberculosis (TB) vaccine have been administered at a clinical trial site at the University of the Witwatersrand in Johannesburg. Up to 20 000 people are anticipated to take part in the study, according to study sponsor, the Bill and Melinda Gates Medical Research Institute (Gates MRI).

The study will be conducted at 60 different sites in South Africa, Zambia, Malawi, Mozambique, Kenya, Indonesia, and Vietnam. The researchers estimate that between 50% and 60% of the study participants will be in South Africa.

The experimental vaccine called M72/AS01E (M72 for short) made waves in 2018 and 2019  when it was found to be around 50% effective at preventing people with latent TB infection from falling ill with TB over a three-year period in a phase 2b clinical trial. In June 2023, it was announced that, after some delays, $550 million in funding had been secured for a phase 3 study of the vaccine. Medicines or vaccines are typically only registered and brought to market after being shown to be safe and effective in large, phase 3 clinical trials.

While most cases of TB can be cured using a combination of four antibiotics for four or six months, TB rates are declining relatively slowly and it is widely thought that an effective vaccine would help bring TB rates down much more quickly. The World Health Organization estimates that at the level of protection seen in the phase 2b trial, the vaccine could potentially save 8.5 million lives and prevent 76 million people from falling ill with TB over a 25-year period. The one TB vaccine we already have, called bacille Calmette-Guerin (BCG), is over a century old and only provides limited protection against severe illness for children and no protection for adolescents or adults.

“Reaching Phase 3 with an urgently needed TB vaccine candidate is an important moment for South Africans because it demonstrates that there is a strong local and global commitment to fight a disease that remains distressingly common in our communities,” said Dr Lee Fairlie,  national principal investigator for the trial in South Africa, in a media statement released by Gates MRI.

“South Africa also has considerable experience with TB- and vaccine-related clinical trials and a strong track record for protecting patient safety and generating high quality data essential for regulatory approvals.”

Fairlie is also the Director of Maternal and Child Health at the Wits Reproductive Health and HIV Institute at Wits University.

The initial response from TB activists was positive.

“TB Proof (a South African TB advocacy group) is delighted that the M72 phase 3 trial has been launched,” the organisation’s Ruvandhi Nathavitharana and Ingrid Schoeman told Spotlight.  “Having an effective TB vaccine is critical for TB elimination efforts.”

While he said it is good to finally see the phase 3 trial of M72 get underway, Mike Frick, TB co-director at Treatment Action Group, a New York-based TB advocacy organisation, went on to say:

“The fact that we had to wait so long between phase II and phase III says everything one needs to know about the headwinds – financial, political, commercial – that TB research is up against.”

How the study will work

Half of the up to 20 000 study participants will receive the M72 jab and the other half a placebo. The vaccine is administered as two intramuscular injections given a month apart. After being jabbed, study participants, all aged 15 to 44, will be followed for four years from the date of the first study participant being enrolled to see if they fall ill with TB.

“The plan is to complete enrolment in 2 years,” Fairlie and Alemnew Dagnew, clinical lead for the trial, told Spotlight in response to written questions. They explained that the actual duration of the trial will depend on how long it takes for 110 people in the study to fall ill with TB. According to the Gates MRI statement, the study is expected to take around five years to complete.

According to Fairlie and Dagnew, the majority of study participants (around 18 000 people) will be people who are HIV negative and who have latent TB infection – that is to say people who have TB bacteria in their lungs, but who are not ill with TB. Latent TB infection is thought to be very common in South Africa and only around 10% of people with latent infection ever fall ill with TB. In the study, latent infection will be tested for using a type of test called an IGRA (Interferon-Gamma Release Assay).

Around 1000 HIV negative people with no TB infection will also be recruited to the study. This is being done to make sure the vaccine is safe and effective in this group of people – while latent infection will be tested for in the study, in the real world such testing may not always be feasible prior to vaccination.

It is anticipated that 1000 of the 20 000 study participants will be people living with HIV. Establishing how well the vaccine works in people living with HIV is important since around 13% of people in South Africa are living with HIV and HIV substantially increases the risk of falling ill with TB. The main phase 2b study of M72 did not include people living with HIV although another phase 2 study looked specifically at the safety and immunogenicity of M72 in people living with HIV – according to Fairlie and Dagnew, “that trial “was completed and supported the inclusion of such participants in a phase 3 trial”.

Smaller than previously thought

When funding for the phase 3 trial was announced last year, it was estimated that 26 000 people would participate in the study. That number has now been revised down to 20 000.

“As a result of ongoing discussions between the institute and our funders, the decision was taken to review the study protocol with the intent of simplifying the study given its size and complexity.  This will not affect the safety of the trial. It is common to continue to refine a protocol. We found a way to expedite the study that would potentially allow us to offer the public health impact of this vaccine to those in need sooner. All partners, including the trial funders, are fully aligned to the protocol refinements,” Fairlie and Dagnew explained to Spotlight.

“Some assumptions used to inform the design of the first protocol were deemed overly conservative, so the clinical team used slightly less conservative assumptions on vaccine efficacy and TB incidence rate, thus allowing for a reduction in the number of participants in the trial, while still retaining the primary goal of confirming the safety and efficacy of the M72/AS01-E-4 vaccine for prevention of TB, guided by the final results of the phase 2b study completed several years ago.”

Planning for access

The development of M72 has taken a somewhat unusual path – with the pharmaceutical company GSK leading development up to the end of phase 2b and then largely passing the baton to Gates MRI with the conclusion of a licensing deal in 2020. GSK has come in for some criticism for not moving more quickly after the initial publication of the phase 2b results in 2018. A ProPublica article published last year suggested that the development of M72 slowed because GSK were focussing on more profitable vaccines.

According to the Gates MRI statement, GSK continues to provide technical assistance to the Gates MRI, supplies the adjuvant component of the vaccine for the phase 3 trial, and will provide the adjuvant post licensure should the trial be successful. An adjuvant is an agent included in the vaccine that improves the immune response elicited by the vaccine – in the case of M72/AS01E the AS01E refers to the adjuvant made by GSK.

This ongoing dependence on a single company for the adjuvant has some activists worried. “We are concerned about reports that scaling this vaccine may be difficult due to limited availability of the vaccine adjuvant. Access for everyone who needs it should be part of the early phases of the research process – not an afterthought,” said Nathavitharana and Schoeman.

“The press release announcing the study’s start in several places refers to the ‘complexity’ of ‘developing and ensuring access’ to a new vaccine. Part of the unspoken complexity here is the opaque licensing deal GSK and Gates MRI signed in 2020 in which GSK gave rights to develop and commercialise M72 to Gates MRI while retaining control over the AS01E adjuvant,” Frick told Spotlight. “There are legitimate concerns that the fine print of this arrangement could work against equitable access, but terms of the licence remain unknown to the public.”

When asked about supply concerns, Gates MRI told Spotlight:  “Gates MRI collaboration with GSK includes provisions to ensure there is sufficient supply of adjuvant for the clinical development and first adoption in low-income countries with high TB burden, at an affordable price, should the vaccine candidate be successful in phase 3 trials and approved for use. For broader implementation, GSK has committed to working with its partners to ensure there is sufficient supply.”

Disclosure: The Gates MRI is a non-profit subsidiary of the Bill and Melinda Gates Foundation. Spotlight receives funding from the Bill and Melinda Gates Foundation. Spotlight is editorially independent and a member of the South African Press Council.

Republished from Spotlight under a Creative Commons licence.

Source: Spotlight

Harnessing Technology to Improve Tuberculosis Outcomes

Dr Phathokuhle Zondi, Clinical Lead: Unu Health

Few realise the extent of the global burden of tuberculosis (TB) or know how many people still succumb to this disease every year. The Centres for Disease Control in the United States estimates that two billion people – a quarter of the world’s population – may be infected with TB, with 10.6 million becoming ill each year. Although TB is preventable and treatable, around 3 500 people lose their lives to it every day, making up an annual mortality rate of 1.3 million people. This means that TB ranks third to only COVID-19 and HIV/Aids as the world’s most deadly infectious disease. 

These statistics are alarming and demand immediate attention from all sectors of society. It is crucial to recognise the potential of technology and digital platforms in revolutionising treatment outcomes. By harnessing the power of innovation, we can transform the way in which TB is diagnosed, treated and managed, ultimately saving lives and reducing the burden of this disease.

Equally as sobering is the fact that around 30 percent of people who become ill with TB are missed by healthcare screenings and do not get the care they need, leading to poor outcomes and an increased spread of the disease, especially in remote, rural and underserved communities. People infected with TB do not necessarily become ill but can pass on the bacteria that causes the infection to between ten and fifteen other people through coughing, sneezing or the transfer of saliva. Approximately 10% of those infected go on to develop an active form of disease at some time in their lives.

TB in South Africa

In South Africa, the first-ever National Tuberculosis Prevalence Survey, published in 2018, found that the country is one of 30 countries with the highest prevalence of TB in the world. When adjusted for population size, it is often ranked as the country with the highest prevalence in the word.

The power of digital healthcare has the potential to change this scenario radically. The greatest challenges we face are the low rate of diagnosis and poor access to – and compliance with – treatment. That’s where digital platforms have such a significant role to play.

How digital can make a difference

Digital health platforms have the potential to revolutionise the fight against TB by improving early detection, enhancing treatment adherence and strengthening healthcare delivery systems. Through the integration of mobile applications, telemedicine, artificial intelligence (AI) and big data analytics, we can address the key challenges of TB diagnosis, treatment access and patient support.

Firstly, digital tools enable early detection and diagnosis of TB cases. Advanced imaging techniques, supported by AI algorithms, can swiftly identify TB-related abnormalities in medical images, facilitating prompt intervention and preventing the progression of the disease. Predictive analytics can also forecast TB outbreaks and hotspot areas, enabling healthcare authorities to take proactive measures to contain the spread of the disease.

Secondly, digital health platforms facilitate remote consultations and monitoring, which is particularly beneficial for patients in remote or underserved areas. By providing timely medical intervention and personalised support, these platforms promote treatment adherence and improve patient outcomes.

Thirdly, mobile health applications empower patients to actively participate in their care management. Through features such as medication reminders, digital health checks and access to educational resources, individuals can adhere to treatment protocols better, ultimately contributing to improved health outcomes.

In addition, digital health platforms streamline healthcare delivery by facilitating data interoperability and real-time monitoring of TB trends. Innovative technologies such as TB Check, the free service application of the South African National Department of Health, are revolutionising TB testing as they are being used to determine the risk of contracting TB and to provide guidelines on how to access testing and treatment.

Further, applications such as One Impact, a comprehensive digital health platform, connects individuals with TB support groups, provides access to TB services and enables the reporting of difficulties in accessing care. By leveraging such platforms, national TB programmes can gain valuable insights into the needs and concerns of affected communities, leading to more responsive and effective service delivery.

TB is treatable and curable, especially when patients are diagnosed early, have access to the medication they need and can be carefully monitored throughout their treatment programme.

As we observe World TB Day on 24 March, it is encouraging to know that the integration of digital health platforms provides immense promise in transforming TB outcomes. To realise this potential, collaboration among governments, healthcare providers, technology companies and civil society organisations is essential. By prioritising investment in innovative solutions and leveraging digital technologies, we can accelerate progress towards the elimination of TB and save countless lives. It is time to harness the power of technology to combat TB and create a healthier, TB-free world for all.

New TB Drug Shows Promise, but Experimental Vaccine Disappoints

By Elri Voigt for Spotlight

Tuberculosis bacteria. Credit: CDC

While three new tuberculosis (TB) medicines have been registered in South Africa over the last decade, TB treatment still comes with several side effects and requires taking multiple different medicines, typically for six or more months. The search for better TB medicines got a boost last week with the presentation of promising findings from a study conducted in South Africa on an experimental drug called quabodepistat. Elri Voigt reports on this and other TB studies presented at a conference in Denver, Colorado.

Arguably, the biggest TB news at the Conference on Retroviruses and Opportunistic Infections (CROI) this year was that the experimental new TB drug quabodepistat performed well in a phase 2b/c clinical trial. This means the drug can now proceed to a pivotal phase 3 trial (medicines are typically approved by regulators only after positive results in phase 3 trials).

The interim study results presented at CROI indicated that quabodepistat in combination with bedaquiline and delamanid and given for four months to people with drug susceptible TB is safe and efficacious, when compared to the six-month standard of care regimen. The standard of care regimen, currently used in South Africa’s public sector, consists of the drugs rifampicin, isoniazid, ethambutol, and pyrazinamide.

Participants were split into four study arms to either receive 10mg, 30mg or 90mg of quabodepistat (along with delamanid and bedaquline) once a day for four months or the standard of care regimen for six months. In the quabodepistat arms, a total of 98 study participants completed treatment, compared to 19 in the standard of care arm.

Taken together, 96% of participants in the quabodepistat arms had sputum culture conversion compared to 91% in the standard of care arm. Sputum culture conversion means TB was no longer detected in sputum samples that people coughed up when those samples were grown in the lab.

The study was conducted at several sites in South Africa and was funded by the Japanese pharmaceutical company Otsuka.

‘Furthest along’

Lindsay McKenna, the TB Project Co-Director at Treatment Action Group (TAG – a New York-based NGO), explained to Spotlight that quabodepistat is a new drug with a new mechanism of action for inhibiting TB’s cell wall synthesis. Essentially, this means that the drug interferes with the TB bacteria’s cell wall structure.

While there are a few new drugs that work the same way, quabodepistat is the furthest along.

“It’s the first in a new class of TB drugs to reach this stage since bedaquiline and delamanid were in phase 2b over ten years ago,” McKenna said.

There is however still some way to go before we will know if quabodepistat is bound for wider use than just in clinical trials. “We need to see data on clinical outcomes first,” McKenna told Spotlight, adding that quabodepistat is also being assessed in another ongoing phase 2b/c clinical trial.

“Remember that we have only seen sputum culture conversion results. Follow up is ongoing and so we will learn more when we see the proportion of participants with favorable outcomes (for example relapse free cure) 12 months post randomisation,” she said. “In the meantime, I think Otsuka should immediately begin working to start up a pre-approval access programme to enable people with unmet needs to access quabodepistat.”

Safety signals

Dr Simbarashe Takuva, Associate Director of Clinical Development at Otsuka Novel Products GmbH (an affiliate of Otsuka), who presented the results on behalf of the study team, said that overall, the quabodepistat regimen was well tolerated and considered safe.

In terms of side effects, the adverse events reported were generally described as mild or moderate, but there were some concerning signals. Grade 3 adverse events stood at 15% in the quabodepistat 10mg arm, 12% in the 30mg arm, 11% in the 90mg arm and 5% in the standard of care arm. Grade 3 adverse events are typically serious enough to prevent someone from working.

Takuva said that there were no serious adverse events (which we understand to mean grade 4/life threatening adverse events) related to the study drugs. There were also no treatment discontinuations related to the drugs. There was a single death in the study, a 25-year-old man who had met all study eligibility criteria but got sicker during the study. The study drugs were halted and standard of care drugs were given instead but the participant later died in hospital.

The researchers also looked for signs that quabodepistat might adversely affect the liver and the heart, but no safety signals related to the drugs were seen in either the liver (hepatoxicity) or the heart (cardiotoxicity).

“The data presented didn’t raise concerns about any treatment related cardio- or hepatotoxicity signals, however, it was a relatively small study, and the inclusion criteria were conservative,” McKenna commented on these findings.

One snag is that the results presented at CROI did not provide a clear answer regarding which of the three quabodepistat dosages in the study is preferable. Based on the clinical data, Takuva said it is difficult to determine which dose is best to use. He did however point out that additional work is being done looking at Pharmacokinetic and Pharmacodynamic data  which will hopefully help provide more information on the ideal dose.

“Follow up on this study is ongoing. We await the final results of our phase 2 trial toward the end of the year,” he told Spotlight.

No study participants with HIV

One big limitation of these results is that the study did not enroll any people living with HIV. According to Takuva, the study had a strict exclusion criterion for the CD4 count of enrolling anyone living with HIV. A person’s CD4 count is a measure of the state of one’s immune system – higher counts are better.

Initially, the CD4 count cut off for the study was set at above 500 cells/mm3, then was amended to 350 cells/mm3 and finally it was dropped to above 250 cells/mm3 but by that time it was too late to enroll anyone living with HIV.

“The interim results are encouraging. However, I was really surprised and disappointed that they weren’t able to enroll any people living with HIV in the trial,” McKenna told Spotlight.

When asked about this, Takuva told Spotlight that the protocol did include the provision to recruit people living with HIV, but it was not feasible to include any. However, people living with HIV will be considered as important to include in any phase 3 trials going forward.

“As with all studies, we need to balance patient safety and the goal of the study outcome. In this instance, despite our best efforts, recruitment of people living with HIV was not feasible, though as we consider the possibility of a phase 3 trial, people living with HIV will remain a population that we consider important to include as far as possible in the phase 3 trial,” he said.

Treating DR-TB in people living with HIV

In contrast to the lack of people with HIV in the quabodepistat study, research was also presented at CROI looking specifically at how people living with HIV did in the landmark endTB trial. Other results from endTB were previously reported and the trial is widely considered one of a hand full of key trials transforming the treatment of drug-resistant forms of TB. The researchers found that two nine-month regimens studied in endTB did particularly well in people living with HIV. Such findings are of particular importance in a country like South Africa where many people who fall ill with TB are also living with HIV. (For those interested in the details, the two regimens were bedaquiline/linezolid/moxifloxacin/pyrazinamide and bedaquiline/clofazimine/linezolid/levofloxacin/pyrazinamide)

Some disappointments

Mycobacterium tuberculosis drug susceptibility test. Photo by CDC on Unsplash

In a disappointing development, researchers presenting at CROI reported that a study testing a three-month regimen for the treatment of drug-susceptible TB was stopped early after an interim review found the regimen had poor efficacy compared to the six-month standard of care. The regimen contained the drugs clofazimine and rifapentine, among others. It means that for now the shortest regimen for treating drug-susceptible TB validated in a clinical trial remains a four-month regimen containing the medicines rifapentine and moxifloxacin, among others. That four-month regimen is not yet in wide use, even though findings confirming its safety and efficacy were reported in 2020.

We also received some bad news on an experimental TB vaccine called H56:IC31. The idea of H56:IC31 was to vaccinate people who were just cured of TB to prevent the TB from coming back – people whose TB is deemed to be cured are known to have an increased risk of falling ill with TB again. Despite promising signs in earlier studies, the vaccine failed to reduce TB recurrence in a phase 2 clinical trial of over 800 people. Much of this study was conducted at sites in South Africa.

TB treatment’s impact on mental and physical health

Another interesting study conducted in South Africa and presented at CROI looked at the changes in mental and physical health that people ill with TB experience before and after treatment. It found that the quality of life and physical fitness of participants was reduced at the start of TB treatment but did improve by the end of TB treatment.

The researchers looked at 200 study participants split between South Africa, Zambia, Malawi, Mozambique and Zimbabwe. Their mental and physical health was assessed when they started TB treatment through a standardised short form quality of life survey, depression assessed through a patient health questionnaire and their physical health was tested using a six-minute walk test. Participants were assessed again when treatment was completed, and data was compared to see what changed between the start and end of TB treatment.

Overall, participant’s physical quality of life increased by 39% by the end of TB treatment, mental quality of life increased by 19%, ability to do a six-minute walk increased by 15% and depression scores decreased by 26%.

Long-acting therapies for TB

Long-acting therapies have been making waves for some time in HIV treatment and a long-acting injection and ring are currently being offered in pilot projects in South Africa. Two studies of long-acting therapies in mice presented at CROI show that there is at least some movement in this area as well when it comes to TB. Such long-acting therapies have particular potential for TB preventive therapy – with for example what is now a three-month course of pills being administered as a single long-acting injection.

One study found that a long-acting injectable form of the drug rifapentine had similar efficacy to a one-month course of preventive therapy in pill form, while another had similarly promising findings for an injection using a long-acting formulation of a diarylquinoline (a class of TB drugs that include bedaquiline). It is anticipated these early proof of concept mouse studies will be followed by studies in humans.

Republished from Spotlight under a Creative Commons licence.

Source: Spotlight

Scientists Discover Macrophages on Standby in the Pleural Cavity

Credit: Scientific Animations CC4.0

Scientists have long thought of the pleural cavity merely as a cushion from external damage. Turns out, it also houses macrophages that rush into the lungs during flu infections.

“We were surprised to find them in the lungs because nobody has seen this before, that these cells go into the lung when there’s an infection,” said UC Riverside virologist Juliet Morrison, who led the discovery team.

A paper published in the Proceedings of the National Academy of Sciences details how during an influenza infection, macrophages leave the exterior cavity and cross into the lungs where they decrease inflammation and reduce levels of disease.

“This study shows it’s not just what happens in the lung that matters, but also what’s outside of the lung. Cell types not normally connected to the lung can have outsized impacts on lung disease and health,” Morrison said.

There are three main cavities in the body: one around the heart, the abdominal cavity, and the pleural cavity surrounding the lungs.

“Because it contains fluid, it prevents the lungs from collapsing. However, people have not thought much about the pleural cavity being a whole organ within itself. This research may change that perception,” Morrison said.

Initially, the researchers set out to understand the more general question of what types of cells are present in the lungs during flu infections. They took existing data on lung-related genes from studies of mice that either died from the flu or survived. They then mined the data using an algorithm to predict cell types that change in the lungs during infections.

“We took big data and broke it down to assign which potential immune cells are in the lung tissues. That’s where I got a hint that maybe we had a previously unknown external source of cells in the lung,” Morrison said.

Next, using a laser-based technique, the team tracked macrophages going into the lungs of mice, and observed what happened if they took these cells out of the equation.

“When you take them out of the mouse you see more disease and more lung inflammation,” Morrison said.

Morrison says she hopes this study will encourage other scientists to reevaluate data sets from older studies.

“Our approach was to take information already out there and put it to new use, and we were able to see something new,” she said.

Moving forward, the research team is hoping to determine which proteins “tell” the macrophages to move into the lungs. Once the protein signals have been identified, it may be possible to create drugs that boost either the number of macrophages, or their activity.

The strategy of boosting human defences to infection, rather than developing another antiviral to which viruses could become resistant, could offer people a flu treatment that would be more effective for much longer.

“If we can boost what resolves infection in us, we probably have a better shot. We’re less likely to have resistance. The immune system is so complicated, but it’s our best bet in the long run to work with what we have rather than chase viruses that continue to escape our therapeutics,” Morrison said.