Tag: 24/5/23

Categories : VaccinesTags :

Smallpox Vaccine Offers Protection Against Mpox

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Smallpox vaccines offer continuing cross-reactive immunity to mpox (previously known as monkeypox), researchers from Karolinska Institutet in Sweden report in a study published in the scientific journal Cell Host & Microbe. The smallpox vaccine had been administered in Sweden from the early 19th century until it was discontinued in 1976 with the eradication of the disease.

During last year’s mpox outbreak, the virus spread for the first time outside Africa, causing over 85 000 cases of the disease to date. Men who have sex with men account for the most infections, with a marked skew towards the young.

The virus that causes mpox is what is known as an orthopoxvirus and is very similar to the virus that caused smallpox until the mid-1970s when it was finally eradicated. South Africa stopped its smallpox vaccinations in 1982.

Since there were data indicating that the old smallpox vaccine could protect against mpox, the researchers at Karolinska Institutet wondered if the individuals who were vaccinated decades ago against the former would have some protection against the latter owing to a remaining memory response.

“Our study shows that this is the case, which implies that the memory cells are very long-lived and that they can recognise closely related viruses such as the mpox virus and provide overlapping, or cross-reactive immunity,” says the study’s corresponding author Marcus Buggert, docent and researcher at the Center for Infectious Medicine, Karolinska Institutet.

By analysing the T-cell immune response in 105 healthy blood donors, the researchers were able to show that individuals born before 1976 had a significantly stronger immune response against both viral types. The researchers also analysed the immune response in 22 men with a recent mpox infection and showed that they also exhibited a strong immune response to the virus, which may provide future immunity.

The current study was too small to judge how much protection previous smallpox vaccination provides, but Dr Buggert refers to a recently published British observational study examining the effect of a smallpox vaccine given to risk-group males in 2022.

“This study shows that smallpox vaccine can provide about 80% protection against mpox,” he says.

Source: Karolinska Institutet

Categories : Ageing NeurologyTags :

Instead of Dying, Motor Neurons Just Lose Connectivity with Age

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Source: CC0

A new study published in the Journal of Clinical Investigation Insight offers a blueprint to help scientists prevent and reverse motor deficits that occur in old age. Their findings showed that loss of connectivity of motor neurons in the spinal cord – not the death of those neurons, as was previously thought – is what impairs voluntary movements during aging.

As humans age, tasks that require coordinated motor skills, such as navigating stairs or writing a letter, become increasingly difficult to perform. Reduced mobility caused by aging is strongly associated with adverse health outcomes and a diminished quality of life.

Researchers at Brown University led by Gregorio Valdez, an associate professor of molecular biology, cell biology and biochemistry, discovered that motor neurons start to have fewer synapses.

“This is an important fundamental discovery because it tells us that treatments are possible to prevent and reverse motor deficits that occur as we age,” said Valdez, who is affiliated with both the Center for Translational Neuroscience and the Center for Alzheimer’s Disease Research at the Carney Institute and Brown’s Center on the Biology of Aging. “The primary hardware, motor neurons, are spared by aging. If we can figure out how to keep synapses from degenerating, or mimic their actions using pharmacological interventions, we may be able to treat motor issues in the elderly that often lead to injuries due to falls.”

For the study, researchers examined spinal motor neurons in three species, including humans, rhesus monkeys and mice.

“These findings revealed that, as individuals age, motor neurons lose many of the connections that direct their function,” said Ryan Castro, first author of the study, who earned a PhD in neuroscience from Brown in 2022.    

Because of their critical function, Valdez said, the loss of either motor neurons or their synapses would impair voluntary movements. 

The number and size of motor neurons do not significantly change during aging, the researchers discovered. However, they undergo other processes that contribute to aging.

“Aging causes motor neurons to engage in self-destructive behaviour,” Valdez said. “While motor neurons do not die in old age, they progressively increase expression of molecules that cause degeneration of their own synapses and cause glial cells to attack neurons, and that increases inflammation.” 

Some of these aging-related genes and pathways are also found altered in motor neurons affected with amyotrophic lateral sclerosis (ALS).

The researchers now plan to pursue studies to target molecular mechanisms they found altered in motor neurons that could be responsible for the loss of their own synapses with advancing age.  

Source: Brown University

Categories : HIVTags :

Khayelitsha Trial Shows Single-dose Dolutegravir May Suffice in HIV-associated Tuberculosis

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Tuberculosis bacteria. Credit: CDC

In the RADIANT-TB randomised controlled trial carried out in Khayelitsha, researchers found that tuberculosis (TB) patients with HIV taking a double dose of dolutegravir had similar viral suppression to those taking a single dose plus placebo. The findings, published in The Lancet HIV, suggest that a only once-daily dolutegravir is feasible in patients with HIV-associated tuberculosis.

WHO’s preferred first-line antiretroviral therapy (ART) regimen for adults and adolescents with HIV is dolutegravir, combined with tenofovir and lamivudine or emtricitabine. A disadvantage of dolutegravir is substantial drug–drug interaction with rifampicin, which is important as tuberculosis is the most common cause of hospitalisation and mortality among people living with HIV.

The drug–drug interaction between rifampicin and dolutegravir can be overcome by supplemental dolutegravir dosing, but is a challenge in resource-constrained settings. The researchers sought to investigate whether virological outcomes with standard-dose dolutegravir-based ART are acceptable in people with HIV on rifampicin-based antituberculosis therapy.

RADIANT-TB was a phase 2b, randomised, double-blind, non-comparative, placebo-controlled trial in Khayelitsha, Cape Town, South Africa. Participants were aged over 18 years, with plasma HIV-1 RNA >1000 copies/mL, CD4 count > 100 cells/μL, ART-naive or first-line ART interrupted, and on rifampicin-based antituberculosis therapy for less than three months. Participants were assigned (1:1) to receive either tenofovir disoproxil fumarate, lamivudine, and dolutegravir plus supplemental 50mg dolutegravir 12h later or the same drugs but with placebo in place of the supplemental dolutegravir. Participants received standard antituberculosis therapy (rifampicin, isoniazid, pyrazinamide, and ethambutol for the first two months followed by isoniazid and rifampicin for four months). The primary outcome was the proportion of participants with virological suppression (HIV-1 RNA <50 copies/mL) at week 24 analysed in the modified intention-to-treat population.

No treatment-related dolutegravir resistance emerged in the trial, and though not significant, an increase in insomnia was noted in the supplemental dolutegravir arm. In terms of future research, it is questionable whether a phase 3 trial would be needed given the significant time required for a policy change. Limitations included the study not being powered to compare efficacy.

The authors concluded, “Our findings suggest that twice-daily dolutegravir dosing might be unnecessary in people with HIV-associated tuberculosis. More evidence, from cohort studies or possibly a phase 3 trial, might be necessary to change policy on the need for a supplemental dolutegravir dose with rifampicin-based antituberculosis therapy.”

Categories : COVID PaediatricsTags :

Study Points to Direct Link Between COVID and Type 1 Diabetes in Children

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A study that used data for 1.1 million children in Bavaria found that SARS-CoV-2 infection was linked to an increased risk of a diagnosis of type 1 diabetes. The findings, which are published in JAMA, also point to a direct effect of COVID on the development of type 1 diabetes.

Different studies have documented an increased incidence of type 1 diabetes during the COVID pandemic. However, none of the studies distinguishes between children with and without SARS-CoV-2 infection.

Researchers at Helmholtz Munich and TU Dresden, in cooperation with the Kassenärztliche Vereinigung Bayern (KVB) used a database to make an analysis of the temporal relationship between a COVID diagnosis and the diagnosis of type 1 diabetes. Amongst the analysed children without type 1 diabetes diagnosis before the start of the pandemic, 16.6% had a diagnosis of COVID between January 2020 and December 2021.

SARS-CoV-2 infection associated with an increased risk of type 1 diabetes in children

The researchers’ initial findings were consistent with data from Germany and other countries: the incidence rate of type 1 diabetes in children between the ages of two and 12 years was around 50% higher in the years 2020 to 2021 as compared to the incidence rate in 2018 to 2019. Important and novel, they found that the development of type 1 diabetes in 2020 to 2021 was higher in the children with COVID. The likelihood to develop type 1 diabetes was increased by 57% in children who had a confirmed SARS-CoV-2 infection compared to non-infected children. The increase in type 1 diabetes incidence occurred in the same quarter as the COVID diagnosis and also in later quarters.

The new data point to a direct effect of SARS-CoV-2 infection on the development of type 1 diabetes

“We are cautious in our interpretation, but the findings suggest that the virus could either promote initiation of the underlying autoimmunity in type 1 diabetes or accelerate the progression of the disease in children with existing autoimmunity,” says Ezio Bonifacio, last author of the study. Further studies will be needed, to elucidate the exact mechanism driving the increased incidence of type 1 diabetes during the COVID pandemic in young children.

Further studies planned

The team of researchers also has access to cohorts of prospectively followed children from the Global Platform for the Prevention of Autoimmune Diabetes (GPPAD) and the Fr1da Study. “We want to look into these cohorts to see whether the development of islet autoantibodies and/or type 1 diabetes was increased in the children after SARS-CoV-2 infection,” says Anette-Gabriele Ziegler, Director of the Helmholtz Munich Institute of Diabetes Research and GPPAD researcher. The findings of these studies will help to determine whether vaccination against COVID should be considered in children at risk for type 1 diabetes.

Source: TU Dresden

Categories : Diseases, Syndromes and Conditions New Compounds and TreatmentsTags :

FDA Approves First Drug Designed to Treat Indolent Systemic Mastocytosis

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Systemic mastocytosis (SM) is a rare haematologic disorder that can lead to a range of debilitating symptoms across multiple organ systems and a significant impact on patients’ quality of life, and now the first medicine has been approved to specifically treat the most common form of the disease. On Monday 22 May, the US Food and Drug Administration (FDA) approved AYVAKIT® (avapritinib) to treat indolent systemic mastocytosis (ISM) in adults.

ISM represents the vast majority of SM cases, and AYVAKIT is now available for adults with ISM at the recommended dose of 25mg once daily. AYVAKIT was designed to potently and selectively inhibit KIT D816V, the primary underlying driver of the disease. AYVAKIT has been FDA approved for the treatment of advanced SM since June 2021.

“After decades of caring for people with indolent systemic mastocytosis, I have seen firsthand its profound impact on patients’ underlying mast cell burden, symptoms, physical and mental health, and ability to work and participate in daily activities,” said investigator Cem Akin, MD, PhD, Professor of Medicine at the University of Michigan. “Despite the use of multiple supportive care treatments, a considerable number of patients with indolent systemic mastocytosis continue to experience a substantial disease burden. AYVAKIT advances the treatment of indolent systemic mastocytosis by targeting KIT D816V, the primary underlying cause of the disease, and establishes a new standard of care for a broad population of patients with this disorder. AYVAKIT delivered statistically significant and consistent clinical improvements in the PIONEER trial, and based on these practice-changing data, I feel a tremendous sense of hope for the future for all those affected by the disease.”

The approval of AYVAKIT in ISM is based on data from the double-blind, placebo-controlled PIONEER trial – the largest study ever conducted for this disease – in which patients received AYVAKIT 25mg once daily plus best supportive care (AYVAKIT) or placebo plus best supportive care (placebo). AYVAKIT demonstrated significant improvements versus placebo in the primary and all key secondary endpoints, including overall symptoms and measures of mast cell burden.

AYVAKIT was well-tolerated with a favourable safety profile compared to placebo, and most adverse reactions were mild to moderate in severity. The most common adverse reactions for AYVAKIT (≥10%) were eye oedema, dizziness, peripheral oedema and flushing. Serious adverse reactions and discontinuations due to adverse reactions occurred in less than 1% of patients.

Detailed results from the PIONEER trial, including open-label extension study data showing the clinical benefits of AYVAKIT through 48 weeks of treatment, were presented in February 2023 at the American Academy of Allergy, Asthma & Immunology (AAAAI) Annual Meeting.

Source: Blueprint Medicines