Tag: 30/7/21

Intranasal Administration of AstraZeneca Vaccine Reduces Viral Shedding

A multi-institutional team of researchers has found that administering the AstraZeneca COVID vaccine intranasally to infected hamsters and monkeys reduced viral loads in nasal swabs, suggesting reduced shedding.

The group describes the testing they conducted with COVID-infected animals and the possible implications of their work, in their paper published in the journal Science Translational Medicine.

Another COVID surge is occurring in a number of countries where vaccinations are readily available, likely due to the arrival of new variants and wide resistance to the vaccinations. Breakthrough infections have been reported in vaccinated individuals. These has resulted in renewed calls for mask-wearing, even in vaccinated individuals. This is because it is not yet clear if vaccinated people can infect other people, even if they have no symptoms. In this new effort, the researchers suggest that adding intranasal inoculation to vaccination efforts might help.

Currently, the vast majority of vaccines developed and in use are intramuscular, given via shots in the arm. Recently, a team at the University of Alabama noted that an intranasal administration of COVID vaccines would seem to make more sense, since COVID is a disease of the nose, throat and lungs. In this new study, the researchers have given an already existing COVID vaccine intranasally to test animals with COVID to see what would happen.

They found that intranasal administration of the AstraZeneca vaccine to infected hamsters and monkeys led to lowered viral loads on nasal swabs, indicating that intranasal administration reduces viral shedding and thereby transmissibility of the virus.

Unfortunately, prior research has also shown that vaccines given intranasally confer immunity for a shorter period of time than intramuscular vaccination. Thus, as the team in Alabama noted, the best approach might turn out to be a combination of a shot in the arm along with a puff of mist up the nose to confer both short-term and long-term protection.

Source: MedicalXpress

Journal information: Neeltje van Doremalen et al, Intranasal ChAdOx1 nCoV-19/AZD1222 vaccination reduces viral shedding after SARS-CoV-2 D614G challenge in preclinical models, Science Translational Medicine (2021). DOI: 10.1126/scitranslmed.abh0755

Over 100 Fast-tracked Drugs Not Confirmed Effective

Of 253 drugs approved via the FDA’s accelerated approval pathway, clinical effectiveness has been confirmed in 112, according to a new investigation by The BMJ.

Clinical reporter Elisabeth Mahase found that, as of the end of last year, 24 of those 112 drugs have been on the market for more than 5 years, and some have been on the market for more than 2 decades — often with a high price tag, according to.

Though the accelerated approval pathway allows drugs onto the market before efficacy has been established, the manufacturer has to perform confirmatory trials or else the approval will be rescinded.

However, Mahase noted that only 16 drugs authorised through the accelerated approval pathway have been withdrawn since its creation in 1992 . Most of those were shown to lack efficacy, but in some cases, confirmatory trials were simply never done. Celecoxib (Celebrex), for example, was given accelerated approval in 1999 for the treatment of familial adenomatous polyposis, a genetic disorder that carries a high risk of bowel cancer if untreated, remained on the market for about 12 years before the FDA asked Pfizer to voluntarily withdraw it for this specific indication because efficacy trials were never completed.

The BMJ asked the manufacturers of 24 drugs that have been on the market for more than 5 years if they had conducted phase IV trials. Six drugs had been withdrawn, approved, or postponed. Of the remaining 18 drugs, relevant trial information was provided for a third. Four manufacturers of those six drugs were recruiting participants, and two reported talking to the FDA about final trial design. Eleven companies representing 12 drugs did not respond.

FDA response

“We are committed to ensuring the integrity of the accelerated approval program, which is designed to bring safe and effective drugs to patients with unmet medical needs as quickly as possible,” an FDA spokesperson said in a statement provided to MedPage Today. “The program allows the FDA to approve a drug or biologic product intended to treat a serious or life-threatening condition based on an outcome that can be measured earlier than survival that demonstrates a meaningful advantage over available therapies.”

The FDA could choose to initiate proceedings to withdraw a drug’s approval should post-marketing trials show no benefit or not be performed in time, added the spokesperson.

“Because the FDA continues to use this pathway to accelerate access to drugs for serious and life-threatening diseases for which there is an unmet medical need, at any point in time there will be drugs that are not converted because the confirmatory trials are ongoing,” the spokesperson said.

“Despite the pathway’s good intentions to accelerate ‘the availability of drugs that treat serious diseases,’ experts are concerned that it is now being exploited, to the detriment of patients — who may be given a drug that offers little benefit and possible harm — and of taxpayers,” she continued.

Fixing the accelerated approval pathway

Concerns about the accelerated approval pathway include a lack of threats from the FDA to withdraw a drug should confirmatory trials not be done, the agency’s use of indirect (or surrogate) measures of clinical benefit in some cases, and the potential for drug manufacturers to take advantage of the pathway when it comes to actual measures of safety and effectiveness, Mahase wrote.

Nevertheless, experts still agree that the accelerated approval pathway is of benefit, she noted. Suggested changes to the pathway include planning or starting confirmatory trials as part of the approval as well as closer examination of surrogate measures.

A recent example is Biogen’s controversial Alzheimer’s disease treatment aducanumab (Aduhelm) received FDA approval via the process last month, which was based on the surrogate endpoint of reduction of amyloid-beta plaque in the brain.

The drug has attracted criticism since its recent fast-track approval, with critics pointing out that the drug has not been proven effective and its $56 000 annual price is unreasonable.

Source: MedPage Today

Journal information: Mahase E “FDA allows drugs without proven clinical benefit to languish for years on accelerated pathway” BMJ 2021; DOI: 10.1136/bmj.n1898.

ACE Inhibitors Reduce Immune Defence against Bacteria

Neutrophil interacting with two pink-colored, rod shaped, multidrug-resistant (MDR), Klebsiella pneumoniae
Neutrophil interacting with two pink-colored, rod shaped, multidrug-resistant (MDR), Klebsiella pneumoniae. Photo by CDC on Unsplash

Scientists have found evidence suggesting that giving patients ACE inhibitors reduces the ability of their immune system to resist bacterial infections.  the group describes testing of multiple ACE inhibitors in mice and human cells.

ACE inhibitors are typically given to patients with hypertension, and some instances to people with heart failure, kidney disease or diabetes. The drugs relaxes the walls of arteries, veins and capillaries, reducing blood pressure. Some prior studies had shown that the drugs also help the immune system by boosting neutrophils, which are produced to fight bacteria. In this new study, published in the journal Science Translational Medicine, the researchers have found the opposite to be true.

In order to see the effects of ACE inhibitors on the immune system, researchers at Cedars-Sinai Medical Center administered different brands of ACE inhibitor such as Zestril and Altace, to mice and then tested their ability to resist bacterial infections. Compared to untreated mice, those with the ACE inhibitors had greater difficulty in recovering from bacterial infections such as staph.

Seven human patients who were taking an ACE inhibitor volunteered blood samples to measure their immune response. The researchers found that the neutrophils were unable to produce the molecules needed to fight off bacteria. They were also found to be in vitro ineffective against bacteria.

The researchers also tested another drug used to treat hypertension, an angiotensin II receptor drug, Cozaar. These drugs work by preventing arterial walls from constricting, which reduces blood pressure. They found no evidence of a negative impact on immunity. They did not test beta-blockers, which work by preventing adrenergic receptors from being stimulated, reducing cardiac action.

The researchers concluded that administering ACE inhibitors to patients puts them at an increased risk of bacterial infections, noting that doctors may want to try alternative drugs to treat their patients.

Source: MedicalXpress

Journal information: Duo-Yao Cao et al, An ACE inhibitor reduces bactericidal activity of human neutrophils in vitro and impairs mouse neutrophil activity in vivo, Science Translational Medicine (2021). DOI: 10.1126/scitranslmed.abj2138

Lambda Variant Might Be The Most Dangerous Yet

Source: CDC

The evolutionary traits of the Lambda variant, giving it both greater transmissibility and immune escape abilities make it possibly the most dangerous variant so far, according to a new study published on the bioRxiv preprint server.

Mutations present in the Spike (S) protein seen in many variants of concern (VOCs) and variants of interest (VOI) allow them to be resistant to the neutralising antibodies (NAbs) from COVID vaccination or infection.

The Lambda variant is predominantly spreading in South American countries. According to the Global Initiative on Sharing All Influenza Data (GISAID) database, the Lambda variant has been reported in 26 countries worldwide. Chile, despite its vaccination rate of 60% saw a surge in COVID cases due to the Lambda variant, due to its immune escape capability.

Lambda variant’s evolutionary traits

In this study, which is awaiting peer review as a preprint, the researchers reported that insertion of the N246-253RSYLTPGD mutation in the NTD of the Lambda S protein is associated with the increased virulence. This mutation is responsible for the rapid spread of the Lambda variant in the Southern American countries.

The authors of this study have indicated two of the critical virological features of the Lambda variant, namely, a) resistance to viral-induced immune responses due to the RSYLTPGD246- 253N, L452Q, and F490S mutations and b) enhancement in transmissibility due to the T76I and L452Q mutations.

This study found that the Lambda S is more resistant to the vaccine-induced antisera compared to the Lambda+N246-253RSYLTPGD S derivative. Another key finding is that RSYLTPGD246-253N mutation overlaps with a component of the NTD “supersite” indicating that it is the immunodominant site. Mutation of this site has therefore enabled the Lambda variant to escape immunity conferred by COVID vaccination.

The comparative study between the parental D614G S strain and the Lambda variant has shown significantly higher infectivity in the latter viral strain.

This study confirms other studies’ finding of increased infectivity of the Lambda, Delta and Epsilon variants is due to the L452Q/R mutation. However, higher infectivity does not guarantee a rapid spread, as seen with the Epsilon variant which failed to spread in the human population despite high infectivity.

This caused the to WHO drop it from the VOC/VOI classification on July 6, 2021. In order to understand if a variant would infect a large number of people, it is essential to determine if it has increased viral infectivity and evasion from the immune response. This study revealed that the Lambda variant possesses both these virological features.

Source: News-Medical.Net

Journal information: “SARS-CoV-2 Lambda variant exhibits higher infectivity and immune resistance,” Izumi Kimura, et al., bioRxiv, 2021.07.28.454085; doi: https://doi.org/10.1101/2021.07.28.454085

Foetal Brain Development Mapped in Great Detail

Image source: Pixabay

Researchers at Karolinska Institute have charted a highly detailed molecular atlas of the foetal development of the brain.

The study, published in Nature, made use of single-cell technology which was performed on mice. In this way, researchers have identified almost 800 different cells that are active during foetal development – far more than previously known.

“Brain development is well described and the main cell types are known. What is new about our atlas is the high resolution and detail,” said Sten Linnarsson, head of research and professor at the Department of Medical Biochemistry and Biophysics, Karolinska Institutet.

In their work, the researchers followed the brain development of the mice from day seven, when the brain is just forming, to the end of pregnancy on day 18.

Using single-cell technology, they were able to identify the detailed composition of the brain during foetal development: what cell types exist, how many cells of each type, and how this changes at the various stages of development.

The researchers also studied gene activity in each individual cell, classifying cells according to these activity patterns.

Creating a molecular atlas

The result is a molecular atlas that accurately illustrates how all cells in the brain develop from the early embryo. The atlas shows, for example, the way early neural stem cells first increase and then decrease in number, being replaced by transitional forms in several waves that eventually mature into ready-made neurons.

The researchers also demonstrated how early stem cell lines branch much like a family tree, giving rise to several different types of mature cells. The next step is mapping out atlases of the human brain, both in adults and during foetal development.

“Atlases like this are of great importance for research into the brain, both to understand brain function and its diseases. Cells are the body’s basic building blocks and the body’s diseases are always expressed in specific cells. Genes that cause serious diseases are found in all of the body’s cells, but they cause disease only in specific cells in the brain,” said Prof Linnarsson.

Source: Karolinska Institute

Journal information: “Molecular Architecture of the Developing Mouse Brain”, Gioele La Manno, et al. Nature, online 28 July 2021, doi:10.1038/s41586-021-03775-x.

Boy Walks With Help of A Robotic Exoskeleton his Father Designed

Photo by Rachel Kuo on Unsplash

Though it’s not quite as fantastic as Iron Man’s super-powered exoskeleton, a robotic exoskeleton designed by his father’s company helps 16 year old Oscar Constanza to walk. Oscar has a genetic neurological condition that means his nerves do not send enough signals to his legs.

Fastened to his shoulders, chest, waist, knees and feet, the exoskeleton enables Oscar to walk across the room and turn around. The exoskeleton is a voice-operated robot, responding to the user’s verbal commands, rather than other designs which respond to user movements or nerve signals.

“Before, I needed someone to help me walk … this makes me feel independent,” said Oscar.

His father Jean-Louis Constanza is one of the co-founders of the company that makes the exoskeleton, which is called Atalante.

“One day Oscar said to me: ‘dad, you’re a robotic engineer, why don’t you make a robot that would allow us to walk?’” his father recounted
“Ten years from now, there will be no, or far fewer, wheelchairs,” he said.

Exoskeletons are being produced around the world, with a wide variety of applications including, the military, industrial work and in healthcare to help nurses move and position patients. During the COVID pandemic, they have even been evaluated for use in the physically taxing task of prone positioning of COVID patients in ICU wards. Some, like Wandercraft’s model, are designed to help people with mobility problems to walk.

Since most are still quite heavy, manufacturers are competing to make them as light and usable as possible.

Wandercraft’s Atalante exoskeleton, which is an outer frame that supports but also simulates the movement of the wearer’s body, has been sold to dozens of hospitals in France, Luxembourg and the United States, with a unit price of about $176 000, said Constanza. The Atalante exoskeleton is currently aimed at use in physical rehabilitation in stroke and spinal cord injury patients.

At the moment, it cannot be bought by private individuals for everyday use – but the Wandercraft engineers are working on this as the design would need to be much lighter.

Source: New York Post