A first-of-its-kind clinical trial has launched in the UK, which could cut years from the search for treatments that work for people with Alzheimer’s disease.
The national trial is called AD-SMART (Alzheimer’s disease Systematic Multi-arm Adaptive Randomised Trial). It is led by the UK Dementia Research Institute (UK DRI) and Alzheimer’s Research UK (ARUK), in partnership with the National Institute for Health and Care Research, the Medical Research Council (MRC) and Health Data Research UK, with ongoing UK government funding.
It will test multiple drugs simultaneously, starting with two repurposed medicines already used to treat type 2 diabetes and attention deficit hyperactivity disorder. Groups of participants will each begin treatment with a different drug. The study will examine whether these medicines can lessen symptoms such as memory and thinking problems, and help people maintain their quality of life as the disease progresses. Testing drugs that are already approved to treat other conditions and known to be safe means that, if successful, treatments can reach people living with Alzheimer’s much faster than a medicine developed from scratch. As well as repurposed drugs, the trial is designed to test new potential treatments coming through the research pipeline.
Heather Ransome, 67, from the Isle of Wight, was diagnosed with Alzheimer’s in 2024. She said: “Before my diagnosis, my partner and I were going on lots of cruises and coach holidays, enjoying retirement together. We still enjoy life, but I’m worried about my condition getting worse. I’m not the sort of person who gets upset, but being told you have Alzheimer’s is quite upsetting. There weren’t many treatment options available, and the one drug I was offered has been around for many years. Getting involved with AD-SMART has given me some hope for the future. It’s not too taxing, just some extra tablets to take every day. I don’t know whether I’m being given the active treatment, but if it helps me, or helps others in future, that feels positive. I would encourage anyone who thinks they might be eligible to sign up and speak to the team.”
The Prime Minister Andy Burnham said: “I know how it feels to lose a loved one to dementia and have seen first-hand the devastating impact this illness has on families. That’s why I’m proud to see this trial being launched in the UK, so that cutting edge treatments can reach patients here as soon as possible. I have made dementia research a national priority. I want Britain to be the leading nation, making the breakthroughs that change people’s lives.”
AD-SMART is a multi-arm, multi-stage platform trial. Several drugs are tested at the same time, and the results compared with one group of participants taking a dummy drug (placebo). This means more people receive an active treatment than would in a traditional trial. Results are checked at regular stages throughout the trial and any drug that isn’t showing benefit can be dropped quickly, with new drugs added in its place. Overall, this means fewer participants end up receiving ineffective drugs. Testing several drugs against one shared placebo group means that compared with a traditional trial, the time to evaluate treatments can be more than halved, which also reduces costs.
The trial is being delivered by a team at Imperial College London, the UCL Innovative Clinical Trials Unit and the MRC Centre of Research Excellence in Clinical Trial Innovation (UCL), the University of Oxford, and Dementias Platform UK. Leading Alzheimer’s experts from across the UK will be providing support.
Chief Investigator, Dr Paresh Malhotra, Group Leader at the UK Dementia Research Institute (UK DRI) Centre for Care Research and Technology at Imperial College London, said: “For too long, Alzheimer’s research has moved at the pace of one drug, one trial, one answer, sometimes taking a decade or more before we know if we’ve found something that works. We are applying advances from cancer and other conditions to accelerate testing of treatments for people with Alzheimer’s disease. The way AD-SMART is set up means we’re testing several treatments at the same time, and those that don’t show promise can be quickly stopped. Then we can start testing something else. That’s the best way to get effective treatments to patients as quickly as we can.”
The first trial participants have been recruited at Cambridgeshire and Peterborough NHS Foundation Trust and Surrey and Borders Partnership NHS Foundation Trust. Sites based at Imperial College Healthcare NHS Trust, Edinburgh and Southampton are also now open. Up to 20 NHS sites are expected to open across the UK over the next 12 to 18 months and more than 30 are planned overall. Researchers aim to recruit 1,200 participants across the UK to test these first two drugs. They expect to finish evaluating the first drugs in 2030, in around four years’ time. During this initial four-year period, the team expect additional drugs to be added into the trial for testing.
AD-SMART is the first trial of this kind for people living with Alzheimer’s, but the model has already proven itself in the UK. MND-SMART, a similar platform trial for motor neuron disease, also led by the UK DRI, concluded that its first drugs tested were ineffective in just over three years. This process would normally take at least eight years. The trial has now moved on to testing other promising drugs.
MRC Executive Chair Dr Patrick Chinnery said: “Innovative clinical trials like AD-SMART are crucial to accelerating progress in health research, generating robust evidence at pace and supporting faster translation of research into patient benefit. This is particularly important in dementia and Alzheimer’s disease research, where there is an urgent clinical need for new therapeutic options. This UK DRI-led trial draws on expertise across the MRC’s institutes, the MRC Centre of Research Excellence in Clinical Trial Innovation, and the Dementia Trials Accelerator, which speeds up recruitment into clinical trials, to evaluate promising interventions more rapidly, and hopefully bring new treatment options to the people who need them.”
Science Minister, Chris McDonald MP said: “Dementia has a devastating impact on millions of people, both for those living with the illness and for their friends and families. There is still so much we need to learn about how this disease works so we can then find the best ways to treat it, but this programme can help us bridge the gap. AD-SMART will help to uncover potential new treatments faster by exploring how existing drugs might be used to treat dementia, giving hope that we might be able to find ways to improve patients’ quality of life in the future.”
Cancer drug entered clinical trials based on a false mechanism, exposing risks and costs of testing drugs without knowing their true target.
Photo by National Cancer Institute on Unsplash
A cancer drug currently being tested in patients may have entered clinical trials based on an incorrect understanding of how it works, according to a new study led by the University of Sydney in collaboration with Goethe University, Oxford University and the Institute of Cancer Research, London.
Published in Nature Chemical Biology, the study found the experimental drug zavondemstat and a closely related research compound, QC6352 – developed to treat cancers such as colorectal, pancreatic and prostate cancer – do not primarily target KDM4, a family of proteins which can help cancer cells grow and spread when it becomes overactive. Instead, both compounds largely work by blocking DHODH, an enzyme cancer cells rely on to produce the molecules needed for rapid growth.
Lead author Professor Lenka Munoz from the University of Sydney School of Medical Sciences and Charles Perkins Centre said: “We can think of DHODH as a machine producing bricks needed to build new DNA. If you switch off the machine, the cell starts running out of bricks and can no longer efficiently copy its DNA and keep dividing.”
These findings could affect the interpretation of previous studies around the world that used the research compound (QC6352) to investigate the biology of the cancer protein and may have implications for the ongoing clinical development of the zavondemstat drug.
The discovery emerged from research investigating whether zavondemstat and QC6352 could be repurposed for glioblastoma, the most common and aggressive form of brain cancer.
“We tested these compounds to investigate whether they could potentially be repurposed for glioblastoma treatment,” Professor Munoz said.
“When we tested other KDM4 inhibitors, we found they did not reproduce the anti-cancer effects observed with QC6352.
“If blocking KDM4 was driving those effects, we would have expected the other inhibitors to behave similarly. Instead, the results suggested QC6352 was acting through a different mechanism.”
“Our study shows this is not just a historical problem but one still happening today. Greater rigour is needed to ensure we understand exactly how potential treatments work before they move into clinical testing.”
Professor Lenka Munoz Charles Perkins Centre
Using patient-derived glioblastoma stem cells, tumour models and a series of genetic, mechanistic and molecular experiments, the researchers traced the compounds’ response to DHODH rather than KDM4.
“Researchers around the world have used QC6352 as a leading tool to study KDM4 biology, while the related drug zavondemstat progressed into clinical trials based on the same understanding,” Professor Munoz said.
“Our study found much of the anti-cancer activity of these compounds is driven by blocking DHODH rather than KDM4.”
Study highlights broader issue facing cancer drug development
Professor Munoz said the findings highlight a broader challenge in cancer drug development.
“Getting a drug’s mechanism wrong can lead to poorly designed clinical trials, inappropriate patient selection and years of research focused on the wrong biological target,” she said.
“There are well-known examples of cancer drugs advancing through large clinical trials before researchers realised they were not working through the mechanism originally proposed.
“Our study shows this is not just a historical problem but one still happening today. Greater rigour is needed to ensure we understand exactly how potential treatments work before they move into clinical testing.
“Establishing a drug’s true mechanism early can protect patients, prevent wasted research effort and help ensure what limited funding we have is directed towards genuinely promising treatments.”
The findings also point to DHODH inhibition as a potential new avenue for glioblastoma treatment. Several drugs targeting DHODH are already being investigated for other cancers, raising the possibility they could eventually be tested in patients with brain cancer.
Beyond identifying the drug’s true target, the researchers developed new compounds that inhibit KDM4 without affecting DHODH, which could help scientists study the role of KDM4 more accurately in future cancer research.
A new report in the New England Journal of Medicine by researchers at Baylor College of Medicine, Texas Children’s Hospital and Seattle Children’s describes a complete regression of hepatoblastoma, the most common paediatric liver cancer, in a 3-year-old treated with a novel immunotherapy. The patient is enrolled in the CARE study (NCT04715191), a first-in-human, Phase 1 trial evaluating glypican-3-specific chimeric antigen receptor (GPC3-CAR) T cells armed with interleukin-15 and -21 (IL15 and IL21).
The child initially presented with a large primary liver tumour and metastases in the lungs. Prior to enrolment in the CARE study, the patient was treated with three lines of chemotherapy and underwent complete resection of the primary liver tumour and two lung metastases. His cancer was no longer responsive to chemotherapy, and a new lung metastasis recurred after surgery when he was enrolled on the CARE study.
The immunotherapy was engineered from the patient’s own cells at the Good Manufacturing Practices laboratories at the Center for Cell and Gene Therapy using two vectors: one encoding the second-generation GPC3-CAR and the second encoding IL15, IL21 and the inducible caspase 9 safety switch, which Center for Cell and Gene Therapy investigators previously showed controlled CAR T expansion.
Two infusions were administered eight weeks apart in the outpatient setting. A partial response was observed after the first infusion, and imaging showed complete resolution of the metastatic disease after the second infusion. No dose-limiting toxicities or cytokine release syndrome occurred. Complete regression continues one year after treatment.
“This case demonstrates that a durable complete response in a chemotherapy-resistant solid tumour can be achieved entirely in the outpatient setting without systemic toxicity,” said first author Dr David Steffin, associate chief of cellular therapy and bone marrow transplant at Texas Children’s and associate professor of paediatrics – haematology and oncology in the Center for Cell and Gene Therapy at Baylor.
“This study provides evidence that these novel CAR T cells may be a safe and effective modality for hepatoblastoma and highlights the need for further assessment in patients with GPC3+ solid tumors,” said corresponding author Dr Andras Heczey, principal investigator at Seattle Children’s and professor of pediatrics in hematology-oncology at the University of Washington School of Medicine. Heczey was at Baylor and Texas Children’s at the time of research.
Modern medicine prides itself on being a universal science, built on evidence from clinical trials.
But there’s a bias in medical research. While Africa accounts for roughly 25% of the global disease burden and 19% of the global population, the continent’s people are largely invisible in some clinical trials.
The scale of the erasure is revealed in a landmark study of 2,472 randomised controlled trials globally published between 2019 and 2024.
I led this team of researchers, who scrutinised the world’s most influential medical publications to quantify African representation. They included the New England Journal of Medicine, The Lancet, the Journal of the American Medical Association, Nature Medicine, and the British Medical Journal. There were also three leading cardiovascular journals in the study: Circulation, the European Heart Journal and the Journal of the American College of Cardiology.
I am a physician-scientist working at the intersection of cardiometabolic epidemiology and biomedical data science. I also focus on large-scale population studies in Africa and data-driven cardiovascular prevention.
Randomised controlled trials are a cornerstone of evidence-based medicine. Introduced in the mid-20th century, they rigorously evaluate the safety and effectiveness of treatments by randomly assigning participants to different groups. This is done to minimise bias. Trials like these have been central to major medical breakthroughs, from cardiovascular therapies to vaccines. They continue to guide clinical decisions and the development of new treatments worldwide.
What we discovered
Our findings show a profound imbalance in the global clinical research landscape. Across the five most prestigious general medical journals, only 3.9% of trials were conducted exclusively in Africa. In cardiovascular health, the numbers drop to a statistical whisper. Of the major trials published in leading cardiology journals, just two studies (0.6%) were conducted solely on African soil.
This is a crisis of scientific accuracy. When clinical trials exclude African populations, they produce evidence that lacks “external validity”. This refers to how well the results of a study can be generalised beyond the participants. It asks whether findings from a clinical trial will still hold true when applied to different populations, settings, or real-world conditions.
Without that validity, doctors are essentially conducting unmonitored experiments on millions of patients every day.
Modern medicine cannot claim to be universal if entire populations remain invisible in the evidence base. Biology, health systems and disease patterns are not identical across the world.
The gap and why it matters
Many treatments used across the continent are based on evidence generated in non-African populations, raising concerns about their applicability.
Moreover, most Africa-based trials still focus on infectious diseases, despite the rising burden of non-communicable diseases such as cardiovascular disease.
Emerging evidence shows that genetics, environment and diet can radically alter how a body responds to a drug. It therefore makes no medical sense that an entire continent is left out of the trial net.
There’s also evidence showing that certain treatments have different safety profiles in Black patients. Diabetes and gout are just two examples. So are certain common blood pressure medications, such as angiotensin-converting enzyme (ACE) inhibitors. Research shows that they carry a three- to four-fold higher risk of severe, life-threatening side effects in people of African descent compared to other populations.
When clinical trials exclude populations, doctors are forced to extrapolate findings from one population and apply them to another.
The study also highlights a dangerous lag between global research funding and the evolving reality of African health. The new data show that nearly 76% of trials conducted exclusively in Africa focused on infectious diseases. But the continent is undergoing a massive epidemiological shift. Non-communicable diseases – heart disease, stroke, and diabetes – now account for about 38% of all deaths in many African nations.
The middle class in Africa has tripled to 300 million people from roughly 100 million people in the early 2000s. More people are now living long enough with lifestyles that increase the risk of chronic conditions such as heart disease, diabetes, and hypertension. Consequently, there is a growing need and market for long-term treatments that manage these diseases, rather than short-term therapies for infections. Yet cardiovascular trials continue to be discouraged.
Even within the continent, the data show deep “black holes” of information. South Africa accounted for over 62% of all trials conducted on the continent. Central Africa, a region that’s home to more than 180 million people, was virtually non-existent in the global research record. It contributed less than 3% of the continent’s limited trial output. Possible reasons include South Africa’s decades of cumulative investment, seen in stronger academic hubs, research governance, experienced trial units, and more established sponsor relationships. Other regions face barriers like fewer resourced research institutions, less access to trial platforms, and sometimes language and publication issues that can reduce visibility in top-tier journals.
The inequity extends into the hierarchy of science itself. Even when African sites are included in large, multicontinental trials, they are often relegated to the role of “recruitment hubs” rather than scientific partners. Our study found that African scientists led only 3.6% of multicontinental trials that included an African site.
Towards a new era of African science
Africa should not simply be a location where studies are conducted.
It must be a place where research is conceived, led and interpreted. The current model creates a cycle of external dependence where international institutions manage the funding and the data. This leaves local research systems fragile and unable to translate evidence into national policy.
There is need for “ring-fenced” funding for African-led research, the development of regional trial networks, and a mandate for medical journals to report on the diversity of trial populations.
There are signs of a rising momentum. Organisations like Alliance for Medical Research in Africa are working to equip a new generation of African investigators. Africa must create a research ecosystem that is too important for the global community to ignore.
If you’re a black, 34-year-old South African woman living with HIV, antiretroviral (ARV) treatment options have likely been limited to tenofovir disoproxil fumarate (TDF), lamivudine (3TC) and the ‘gold standard’ dolutegravir (DTG).
Now, another once-a-day, three-drug regimen has been found to be as effective as DTG in supressing HIV viral load.
Not only is the once daily regimen of tenofovir disoproxil fumarate (TDF), lamivudine (3TC) and doravirine non-inferior to DTG, it is associated with significantly less weight gain and has a better lipid profile than the combination favoured and recommended as first-line in many countries, and increasingly in low-and-middle income countries.
These were the end point findings of the South African Opti-DOR study presented at the 2026 International AIDS Society Conference on HIV Science on 31 July and published in the Journal of the American Medical Association (JAMA).
Dr Joana Woods, Senior Research Clinician at Ezintsha at the University of the Witwatersrand (Wits) and lead author, says:“The findings are important because although second-generation ARVs such as dolutegravir and bictegravir are highly effective HIV medicines, they have been consistently associated with substantial weight gain and new onset obesity, particularly among women and black populations and especially when combined with TAF. This has raised concern about long-term cardiometabolic risk, including diabetes and cardiovascular disease.”
In primary healthcare, prevention is better than having to deal with long term consequences. This is why in a country like South Africa with widespread HIV and NCDs, managing weight gain in people living with HIV is critical to their health.
“So if you can start an ARV that’s not going to cause as much weight gain, or not cause weight gain at all, or have an alternative, that would be first prize. And that’s the premise of this study,” says Woods.
About the OPTI-DOR Study
The Africa Health Research Institute (AHRI) ran the rural arm of the Opti-DOR study at the AHRI-Somkhele site in rural northern KwaZulu-Natal province.
“By including participants from both rural KwaZulu-Natal and urban Gauteng, we can be confident that these findings are relevant to people living with HIV in different communities across South Africa,” says Professor Limakatso Lebina, Principal Investigator at the rural AHRI-Somkhele study and Director of Science at AHRI.
The AHRI site enrolled 178 participants between December 2023 and March 2025, with the Johannesburg site enrolling the rest, for a total of 600.
Participants were randomised in a 1:1 ratio to receive either oral daily doravirine (TDF/3TC/DOR) or dolutegravir (TAF/FTC/DTG).
Weight gain differed significantly between the two study groups. Median weight gain at week 48 was 3.0 kg with doravirine (TDF/3TC/DOR) compared with 5.0 kg with dolutegravir (TAF/FTC/DTG).
Increases in total body fat percentage were also significantly lower with doravirine (TDF/3TC/DOR) at 1.5%, versus 2.2%.
“These results add some clarity to a challenge that has frustrated both doctors and patients for years: how to treat HIV effectively without causing significant weight gain,” says Lebina. “For many patients, especially black women who are disproportionately affected by treatment-associated weight gain, this could be a game changer. It offers an important new treatment option that supports long-term health while maintaining excellent HIV control.”
Non-inferior yet drug resistance potential
Woods emphasises that the efficacy of doravirine is dependent on patients’ absolute adherence to taking it. If doravirine is taken properly, HIV viral load will be suppressed. However, failure to adhere can cause drug resistance.
“Doravirine is non-inferior to dolutegravir in the sense that if you take the drug properly, you will suppress it [HIV viral load]. If you don’t take it properly, you will likely become resistant. That unfortunately is one of the downsides of using doravirine.”
In the Opti-DOR clinical trial, seven patients developed resistance to the drug. These participants were then switched over to dolutegravir and successfully suppressed again.
Woods emphasises that doravirine is unlikely to be a replacement for DTG: “It is not a replacement. It has to be targeted to patients who are at risk of gaining more weight – and complications thereof.”
Despite drug resistance, the data prove that doravirine is not inferior to dolutegravir and that it causes less weight gain.
Research into action
Doravarine is already an available and registered drug.
The researchers have alerted the South African National Department of Health and the South African Health Products Regulatory Authority.
“Imagine you’re a diabetic and you only have access to one drug? It’s the same thing with HIV. Yes, the drug they have at the moment is really top of the tops, but it doesn’t suit everybody. You have to have options. Until we can cure HIV, you’ve got to make it as easy as possible for people to take their treatment. That’s what it comes down to.”
Key findings of the Opti-DOR study at week 48
Doravirine [TDF/3TC/DOR] was non-inferior to dolutegravir [TAF/FTC/DTG] for viral suppression.
Viral suppression was achieved by 89.0% of participants on doravirine [TDF/3TC/DOR] and 90.7% on dolutegravir [TAF/ FTC/DTG].
Median weight gain was significantly lower with doravirine [TDF/3TC/DOR]: 3.0 kg versus 5.0 kg.
Total body fat percentage increased less with doravirine [TDF/3TC/DOR]: 1.5% versus 2.2%.
Lipid changes favoured doravirine [TDF/3TC/DOR].
Glycaemic measures and blood pressure were similar between arms.
No emergent integrase inhibitor resistance was observed.
Bone mineral density declined more with doravirine [TDF/3TC/DOR].
Serious adverse events and major laboratory abnormalities were infrequent across and similar between both groups, and not considered treatment related.
Australian hospitals will lead a first-in-human clinical trial of a new investigational genetic therapy that aims to lower cholesterol in people at increased risk of cardiovascular disease. The Victorian Heart Hospital, operated by Monash Health in partnership with Monash University, will be the first clinical trial site globally to begin testing the investigational therapy STX-1150, developed by Scribe Therapeutics.
The therapy is designed to reduce LDL (‘bad’) cholesterol by targeting a gene in the liver called PCSK9, a well-established regulator of cholesterol levels and cardiovascular risk. Elevated LDL cholesterol is a major cause of atherosclerotic cardiovascular disease, including heart attacks and strokes.
STX-1150 uses a next-generation CRISPR-based approach known as epigenetic silencing. Delivered as a one-time infusion, the therapy is designed to reduce cholesterol levels for an extended period without permanently altering a person’s DNA.
Principal Investigator of the study Professor Stephen Nicholls, Director of the Victorian Heart Hospital and Victorian Heart Institute, and Professor of Cardiology at Monash University, said the trial represented another major step forward in developing more durable approaches to cardiovascular prevention.
‘The best way to treat heart disease, the leading cause of death globally, is to prevent it,’ Professor Nicholls said.
‘While existing cholesterol-lowering therapies are highly effective, many people still struggle to maintain long-term treatment due to cost, access, side effects, or the burden of ongoing medication.’
‘This new investigational therapy is designed to provide sustained cholesterol reduction following a single treatment, which could significantly change how we manage cardiovascular risk in the future. This represents the new frontier of cardiovascular medicine.’
‘It is incredibly exciting that Victorians and Australians will again play a leading role in the development of next-generation genetic therapies for heart disease.’
The Phase 1 study will assess the safety, tolerability and biological effects of STX-1150 in adults with elevated LDL cholesterol who are at increased cardiovascular risk.
The trial plans to enrol up to 64 participants across sites in Australia and New Zealand, with participants monitored for one year following treatment.
The study follows regulatory clearance from Australia’s Therapeutic Goods Administration and builds on growing international interest in genetic approaches to cardiovascular disease prevention.
About the study
The Phase 1 trial will evaluate STX-1150 in adults with elevated LDL cholesterol and increased cardiovascular risk.
The study is designed as an open-label, single ascending dose trial followed by a dose expansion phase.
Up to 64 participants are planned to be enrolled across Australia and New Zealand.
The Victorian Heart Hospital will serve as the initial clinical trial site.
Participants will be followed for one year after treatment.
Two new vaccines to prevent tuberculosis (TB) are safe for use in adults and children, but they do not offer protection against all forms of TB, finds a large trial from India published by The BMJ.
TB remains a major global public health concern. In 2023, an estimated 10.8 million people worldwide were reported to have TB and the rate of new cases increased by 4.6% between 2020 and 2020, highlighting the growing scale of the problem. BCG is currently the only licensed vaccine against TB. Yet although it is effective against severe forms of TB in young children, it does not offer protection for adolescents and adults.
To address this gap, researchers in India conducted a large trial to evaluate whether two new TB vaccines (VPM1002 and Immuvac) can protect against all forms of tuberculosis (pulmonary and extrapulmonary), prevent latent (dormant) infection, and generate an immune response against the TB bacterium.
The study enrolled 12 717 household contacts (aged 6 years and older) of recently diagnosed TB patients across 18 sites in six Indian states between July 2019 and December 2020.
Participants were randomly allocated to receive a first dose of either VPM1002, Immuvac, or a placebo (4 239 in each group) and were followed up for 38 months. A second dose was administered to 11,829 participants one month later. A total of 12 295 participants (96.7% of those enrolled) completed 38 months of follow-up.
While neither vaccine offered general protection against TB or prevented latent TB infection, both demonstrated an ability to prevent the progression to active TB in those who developed latent TB.
The researchers found that although both vaccines did not show effectiveness against all TB and pulmonary TB (PTB), one of the vaccines, VPM1002 showed effectiveness (50.4%) against extrapulmonary TB (EPTB) across all age groups, including those aged 36-60 years (79.5%). These findings suggest a potentially significant public health benefit, because extrapulmonary TB, which affects organs beyond the lungs, is often associated with a higher risk of mortality than pulmonary TB.
A promising key finding was the protection seen against TB in children, whereby VPM1002 provided protection against all TB, PTB and EPTB in the 6 to under 14 year age group, while Immuvac provided protection against EPTB only in the 6 to under 10 year age group.
However, neither vaccine protected children and adults who were underweight. This suggests that nutritional support may be needed along with vaccination, especially for younger children, report the authors.
Both vaccines were found to be safe and induced an immune response.
The researchers acknowledge that the covid-19 pandemic affected the study, leading to the exclusion of some participants who missed the second dose and sometimes delayed follow-ups. Furthermore, the findings may not apply in other countries or ethnicities.
Nevertheless, this was a large, well-designed study that reflects a real world scenario because it included both children and adults, regardless of pre-existing conditions like diabetes and risk factors, as reported by authors. Further research on commonly targeted high-risk groups for TB could be undertaken, they conclude.
Current clinical guidelines stress that lower LDL cholesterol levels significantly reduce the risk of major cardiac events. Essential strategies for treatment include heart-healthy lifestyle changes and pharmacological interventions using statins, ezetimibe, and PCSK9 inhibitors. Early intervention is vital, as the cumulative exposure to high cholesterol over time – often termed “LDL years” – determines the onset of vascular disease. But a major question has remained as to whether more aggressive lip-lowering targets is worth the potential side effects such as kidney damage.
Now, a new clinical trial published in NEJM provides evidence that an intensive target of less than 55mg/dL is superior for preventing secondary complications. In the Ez-PAVE trial, researchers in South Korea investigated whether this more intensive provided better protection than the conventional goal of less than 70mg/dL. The study found that patients in the intensive group experienced a significant reduction in cardiovascular events over a three-year period. The researchers conclude that their findings support stricter lipid-lowering guidelines, which can safely and effectively improve long-term patient outcomes.
An international, randomised, double‑blind, placebo‑controlled phase 3 study, the largest of its kind for mpox, found that tecovirimat did not improve clinical outcomes for adults with clade II mpox compared with placebo, while demonstrating a similar safety profile. Results of the STOMP/A5418 trial, published in the New England Journal of Medicine underscore both the urgent need for alternative therapeutics and the critical importance of randomised trials during public health emergencies.
This Phase 3 study randomised 412 participants (344 with laboratory‑confirmed mpox), to receive either tecovirimat or a matching placebo for 14 days. Randomisation was stratified by early versus later symptom onset and by the presence of severe pain. Participants had active skin or mucosal lesions and self‑reported daily symptoms, pain scores, and lesion status through Day 29, with confirmatory clinical assessments at scheduled visits. Biospecimens, including lesion swabs, oral and rectal swabs, and blood samples, were collected at multiple time points to assess viral DNA clearance. The primary endpoint was time to clinical resolution of all lesions, and key secondary endpoints included pain reduction, complete lesion healing, and virologic response.
Conducted across seven countries at 49 sites, the phase 3 study showed that tecovirimat did not shorten the time to lesion resolution, reduce pain, or speed viral clearance compared with placebo. These results align with interim findings released in December 2024, which led the trial’s independent Data and Safety Monitoring Board to halt further enrolment due to statistical futility.
“In the midst of a global public health emergency, the ACTG team rapidly conducted this randomized controlled trial to deliver a clear answer for patients and clinicians,” said William A. Fischer II, MD, associate professor of pulmonary and critical care medicine at the UNC School of Medicine, and director of emerging pathogens research at the UNC Institute for Global Health and Infectious Diseases. “These findings advance our understanding of mpox and help the field refocus efforts on identifying safe, effective and accessible treatment strategies, particularly for people at highest risk of severe disease.”
Although the trial did not demonstrate efficacy, tecovirimat demonstrated a favourable safety profile, with no major safety concerns identified – an important confirmation as thousands of patients worldwide have already received the drug under expanded access protocols.
“The STOMP trial provides essential evidence at a critical time and demonstrates why randomized controlled trials are an indispensable part of outbreak response,” said Joe Eron, MD, chief of infectious diseases and chair of the ACTG network. “But now we must keep going to find safe and effective treatment for people as this virus continues to circulate globally.”
The study’s conclusions are expected to influence clinical practice and public health guidance worldwide. With mpox still causing outbreaks in multiple regions, researchers emphasise that developing and evaluating new antiviral candidates remains a top priority.
Dr Sheetal Kassim, the site lead for the Desmond Tutu Health Foundation’s clinical trial site at Groote Schuur Hospital. (Photo: Nasief Manie/Spotlight)
By Elri Voigt
A cutting-edge, South African-led HIV vaccine trial built on decades of research recently kicked off in Cape Town. Spotlight unpacks what exactly is being studied, and how the resilience, tenacity and urgency of a group of dedicated South African researchers made it possible.
Antiretroviral medicines can suppress HIV in the body and keep people healthy, but we do not yet have a viable cure for HIV or an effective vaccine. It is not for lack of trying. For decades now, researchers across the globe have been working hard to develop a vaccine against HIV. While there have been several major disappointments along the way with vaccines failing in large studies, a new clinical trial in South Africa might soon find vital answers that could reinvigorate the field.
The study was originally set to start in 2025, but researchers had to pivot and find new funders when the United States abruptly terminated much of its international research funding. After some scrambling, a stripped-down version of the study has now started. Rather than being cowed by having to delay, and reduce the size of the study, it seems that forging ahead without US support have sparked a pervasive sense of optimism.
“It feels like the most coherent, involved clinical trial I’ve ever been involved in – so that’s why I’m so excited. I feel like it’s going to lead to big things because it’s bringing so many people with it,” says Professor Penny Moore, a leading virologist who is heading up the laboratory work for the study.
That optimism is tangible at the clinical trial site in the Old Main Building at Groote Schuur Hospital in Cape Town. During our visit, one can’t help noticing how the Desmond Tutu Health Foundation’s signature rainbow logo and colourful walls and furniture breaks through the dark hospital corridors and ancient elevators.
The colourful waiting room at the Desmond Tutu Health Foundation’s clinical research site at Groote Schuur Hospital where a South African led HIV vaccine trial is taking place. (Photo: Nasief Manie/Spotlight)
Like the sugar coating on a Smartie
In the clinical trial, called BRILLIANT 011, researchers are testing two immunogens, says Dr Sheetal Kassim. She is the site lead for the Desmond Tutu Health Foundation’s clinical trial site at Groote Schuur Hospital and Principal Investigator for the trial. An immunogen is an engineered agent designed in a laboratory, she explains, to cause a specific immune response. The aim of this trial, Kassim says, is to see if these two immunogens are able to trigger the development of cells that have the potential to later become special immune cells called broadly neutralising antibodies.
Once HIV is in someone’s body, it is able to stick around mainly by taking over immune cells called CD4 cells. It evades the immune system by constantly mutating so the antibodies sent to find it don’t recognise it. Eventually the infected CD4 cells burst and die, but HIV keeps replicating, weakening the immune system.
Broadly neutralising antibodies are special antibodies that can recognise and fight a range of different HIV strains, no matter how much it has mutated, says Moore.
HIV is covered in something called glycans that make it hard for antibodies to reach it, she explains. Think of these glycans as the hard sugar coating around a Smartie. A broadly neutralising antibody can recognise the parts of the virus that won’t change when it mutates. This allows the broadly neutralising antibody to be able to reach through that hard outer coating, bind to the virus and destroy it.
Two immunogens, given at the same time
In late January, the researchers enrolled the first of an expected 20 healthy participants, who do not have HIV, and are at a low risk for getting HIV. By mid-February, seven participants had received their first shots.
It is a phase one study, which is to say it is still very early days. A phase one trial looks at the safety of a drug or vaccine in a small number of individuals, while a phase two trial looks at safety in slightly larger groups and gives some early indication of efficacy. A phase three trial is much larger and looks mainly at efficacy.
The researchers are testing the immunogenicity – essentially the ability to elicit an immune response against HIV – and safety of the two immunogens in humans for the first time. A special adjuvant – known as SMNP – is being added to the agents to enhance their effect.
The hope is that the study results will help identify a potential vaccine candidate to test in future, larger studies, says Kassim. “We’re not going to come out of this study and say we have a vaccine that can prevent or cure HIV,” she says. “But we will have information on these immunogens that will help us in the future.”
It has already been shown that the two immunogens can target the type of antibody cells that have the potential to become broadly neutralising antibodies and essentially switch them on. Think of it as a talent finding agency, says Kassim, that can find the next “star” that can become an important broadly neutralising antibody.
The two shots are injected into the muscle of the arm on three separate visits, she says. The first is given after a rigorous health screening. The second is given one month later and the final dose is given three months later. Doing it this way, primes the immune system with the first shots and then the doses that follow boost the initial effects.
Putting ‘the puzzle pieces together’
Research studies like this one is still in the “experimental medicine” phase, Professor Linda-Gail Bekker, CEO of the Desmond Tutu Health Foundation, tells Spotlight. She says results from this study will help “put the puzzle pieces together” to get a clearer picture of which immunogens should eventually be tested in a phase three efficacy trial.
The trial is novel because of the use of two immunogens instead of one. Professor Glenda Gray, Chief Scientific Officer at the South African Medical Research Council (SAMRC), refers to it as an “ambitious and aggressive approach”. She tells Spotlight that usually researchers follow a sequential pattern, testing one immunogen, then another and eventually testing them together. The problem with this is that if they don’t work together, you’ve lost up to five years of research.
“We also have this philosophy of ‘failing fast’,” Gray says. “[I]nstead of wasting money and time and effort, we need to know whether our strategy is going to work or not in the beginning.”
A proudly South Africa trial
Beyond the cutting-edge science, it’s clear that what makes this trial so unique is the people involved.
Bekker describes the trial as “proudly South African”. She says: “It’s just terrific that we’re doing this end-to-end. We’re involving the community, the recruiters are people from the country, the people who are taking the blood are people from the country, the people who are doing the laboratory science are from the country, and we’re doing it for people in our country.”
Moore adds: “We’ve got so many people in the background working on these trials at the clinical sites and here in my lab…There’s this huge mass of people all working together on this trial.”
BRILLIANT 011 is one of 22 trials currently running at the Groote Schuur Hospital site, Henriette Kyepa the Unit Manager for the site, tells Spotlight. The doors open at 07:00 and the last participant leaves by 15:00, and since at least 40 participants are being seen each day, she describes the goings on as “bustling”.
The hospital has an illustrious medical history, with the first human heart transplant having been performed in the Old Main building – the Christiaan Barnard Heart Museum is just a few floors down. The Desmond Tutu Foundation’s research site has been operating at the hospital for more than 10 years.
During a tour of the unit, Spotlight was led through a waiting area, pharmacy, and two nursing areas – where patient’s vitals are checked and data captured. Staff manning the different stations were busy, but friendly and took requests for photographs in their stride. There are four doctors’ rooms and a procedure room, equipped with things like a crash cart in case anyone has a bad reaction to a drug or device that’s being tested. The site also includes private counselling rooms and a purple, gender inclusive bathroom. Down the hall, there is a hospital ward and a small laboratory, which is shared with the University of Cape Town Clinical Research Unit, for patients that need timed blood draws for studies where drug levels are being monitored.
But before they come to the site, the first point of contact for many potential trial participants – for BRILLIANT 011 and other studies – are the community recruiters. This is a team of three outreach workers led by Amelia Mfiki, who is the community liaison officer for the Desmond Tutu Health Foundation and lead recruiter. Their job is to keep the local communities updated on what the site is doing, get their feedback and to find participants who fit the eligibility criteria for different studies.
If someone is interested in a study, Mfiki explains, they are sent to the site for an information session, where the trial, eligibility criteria and the commitment required to participate is clearly unpacked. If they meet the criteria and want to participate, they go through a further informed consent process and screening. With a big smile, she tells Spotlight there has been a lot of requests for information about the BRILLIANT 011 trial.
Once enrolled, clinical trial participants will spend a lot of time with the nursing staff. Among them is Viwe Soko, a senior nurse who says “making people smile” is part of his job.
How they’ll test if it works
The BRILLIANT 011 trial participants will need to come back roughly two weeks after each jab to have white blood cells – which contain the cells that can become broadly neutralising antibodies – extracted from their blood through a process called leukapheresis. This is how the researchers are looking for those “star” antibodies that have the potential to become broadly neutralising antibodies.
Basically, the leukapheresis machine draws a participant’s blood and runs it through a centrifuge that separates the white blood cells from all the other cells in the blood, explains Moore. The white blood cells are collected into a sterile blood bag, while the rest of the blood goes back into the participant. (Here’s a useful video showing how it works).
Hundreds of millions of white blood cells are collected each time a participant goes through this process, according to Moore. “The reason we need a crazy number [of cells] is because the responses that we’re looking for are rare as hen’s teeth,” she says.
The cells are then processed in the laboratory at Groote Schuur Hospital and sorted into different tubes containing 20, 50 and 100 million cells respectively, frozen, and then sent more than 1 000 km away to Moore’s laboratory at Wits University in Johannesburg.
Once there, the thawed antibodies are run through a special machine called a flow cytometer, which is able to spit out individual cells of interest via an ultra-thin stream. The cells are mixed with a dye to make them easy to spot, says Moore. Then a laser and computer, under the supervision of a highly trained scientist sorts the cells to isolate the types of antibodies they’re interested in.
These precursors of the broadly neutralising antibodies are “structurally weird”, said Moore, some of them have really long “arms” that can reach through HIV’s hard outer coating, or really short “arms” to get close to it.
At the end of the process, there might be 100 relevant cells which then go through a process called next generation sequencing. The researchers are looking for two specific genetic signatures that will show that the right antibody was produced. Moore likens this to a cell that has “a purple head and an orange arm” and is extremely rare. Once they find all the cells with these signatures, they count them.
At its core, Moore says, they’ll know the immunogens have worked if they find more “cells with purple heads and orange arms” than has been seen in other vaccine trials that only used one immunogen.
“I think this is some of the most important work I’ll ever do,” Moore says. “It feels like 20 years of basic science has finally paid off.”
She has been monitoring the antibody responses for the CAPRISA 002 cohort for the last two decades. It is within this cohort, that a handful of women living with HIV who had naturally produced broadly neutralising antibodies were discovered and since studied. This is part of the foundation on which the BRILLIANT 011 trial has been built.
Because of all the lab work and specialised equipment required, this kind of study is expensive to run. For the study period, it costs about R1 million for each participant to be in the trial, according to Gray. This trial has a budget of R25 million, the bulk of which has been supplied by the Gates Foundation. Some emergency funding from the SAMRC was used to make up the rest.
‘Nobody gets the urgency’ like South Africa
This amount is a far cry from the five-year USAID grant worth over $45 million, that was originally awarded to the BRILLIANT Consortium in 2023. This ambitious African-led Consortium, led by Gray and run out of the SAMRC, had big plans for HIV vaccine research and capacity development across Sub-Saharan Africa. As Spotlight previously reported, the Consortium planned to conduct three HIV vaccine trials, about one a year, and develop laboratory capacity for this kind of research across the African continent.
In the end, they only had the USAID grant for a year, just enough time to set everything up for BRILLIANT 001, a much flashier version of the trial that is currently running. It was set to take place at sites in Uganda, Kenya, Zimbabwe, South Africa and Nigeria, and recruit 60 participants, according to Gray.
“We were actually due to start it [BRILLIANT 001] in February of 2025. And then it was stopped,” Bekker says. “And so, we went through the five stages of grief and finally got to the point of acceptance. And with acceptance came a real sort of verve to try and find alternative funding.”
Essentially, the researchers were racing against the clock on multiple fronts.
The immunogens, which had been donated by labs in the Netherlands and the United States were already in the country and had expiration dates that meant the study could not be delayed indefinitely (in the end the study would start in time for this to no longer to be a concern).
But more importantly there was the roughly eight million people living with HIV in the country.
“I think nobody gets the urgency like a South African,” Bekker says. “It’s very real in our lives that this virus continues to devastate [and] change the lives of people we love and serve and work with. So that sense of urgency is very real within us.”
The team wrote up a new funding proposal and study protocol, which Bekker describes as a much lighter version, “pared down to the absolute bones”. They presented this to the Gates Foundation, which agreed to provide funding for this leaner version, and the team pushed to get everything else in place.
Gray weighs in on how, just as the process was taking off again and the protocol had been submitted to the South African Health Products Regulatory Authority (SAHPRA), which has to review and approve all clinical trials conducted in the country, the adjuvant they had planned to use was recalled by the manufacturer. Luckily, they had had some warning this might happen and had a protocol using another adjuvant ready to go. And just a year after the original trial was meant to start, they were able to kick off BRILLIANT 011.
“No one works in these timelines,” says Gray, adding that part of the reason they were able to pull this off was because of how well the team works together. “Everyone puts in more than their pound of flesh, they work incredibly hard…everyone believes in the kind of programme that we’re trying to put together,” she adds.
‘I want to help my community’
Participants for the 011 trial are reimbursed for their time and travel using a SAHPRA approved model. However, Kassim says there appears to be a more altruistic motive among participants, with some sharing sentiments like: “I want to help people. I want to help my community.”
Bekker notes a similar theme that’s held true over the last two decades of HIV vaccine research. “It’s incredibly encouraging, but it’s also incredibly humbling that, in a country like ours, where people have so many other challenges, that they could … [have] an entirely altruistic motivation, that they are digging deep within themselves and saying: ‘I’m motivated because I want to see an end to the suffering’.”
“If we truly want to bring this epidemic to an end and eliminate transmission, we will need a vaccine,” says Bekker. “And imagine, a world where you could get your vaccination, at age 10 or even younger, and then not have to think about HIV ever again.”
Disclosure: The Gates Foundation is mentioned in this article. Spotlight receives funding from the Gates Foundation but is editorially independent – an independence that the editors guard jealously. Spotlight is a member of the South African Press Council.
