LIVE BLOG: R&D response to COVID-19 pandemic (archived)

A study on the role of microscopic particles in transmitting COVID-19 suggests pollen is nothing to sneeze at, according to researchers who have investigated how pollen facilitates the spread of viruses like SARS-CoV-2.

The study was sparked when the researchers noticed a correlation between COVID-19 infection rates and pollen concentrations on the US National Allergy Map.

They used computational methods for analysing fluid dynamics to mimic pollen movement from a willow tree, showing airborne pollen grains contribute to the spread of airborne viruses, especially in crowded environments.

Trees can release up to 1,500 grains per cubic metre into the air, depending on the time of year and the weather. Each pollen grain can carry hundreds of virus particles at a time.

"To our knowledge, this is the first time we show through modelling and simulation how airborne pollen micrograins are transported in a light breeze, contributing to airborne virus transmission in crowds outdoors," the researchers said.

The researchers started by modelling the pollen production of their computational willow tree. They then simulated outdoor gatherings of 10 or 100 people, some of them shedding COVID-19 particles, and subjected them to 10,000 pollen grains.

Tuning the model to the temperature, wind speed and humidity of a typical spring day in the US, the pollen passed through the crowd in less than one minute. The researchers say that could significantly affect the virus load carried along by the breeze and increase the risk of infection.

Given this, the two metres often cited for COVID-19 social distancing might not be adequate for those at risk for the disease to be protected in crowded areas with high pollen levels.

Researchers from the German Centre for Infection Research at Charité-Universitätsmedizin Berlin and the University of Bonn who have investigated how SARS-CoV-2 reprogrammes the metabolism of human cells, have identified four substances which inhibit SARS-CoV-2 replication in host cells.

These are: spermine and spermidine, substances naturally found in the body; MK-2206, an experimental cancer drug; and niclosamide, which is used to treat tapeworm.

Charité is now conducting a trial to assess if niclosamide is effective against COVID-19 in humans.

The team of researchers, led by Marcel Müller of Charité's Institute of Virology, and Nils Gassen of the Psychiatry and Psychotherapy Clinic at the University Hospital Bonn, found SARS-CoV-2 slows down the cell's own recycling mechanism, a process known as autophagy, through which cells dispose of damaged materials and waste products, whilst recycling reusable products into new cellular structures.

"In our study, we were able to show that at the same time as using the cell's building blocks for its own benefit, SARS-CoV-2 deceives the cell by simulating a nutrient-rich status, thereby slowing cellular recycling,” Gassen said.

The same reprogramming strategy is also used by the MERS coronavirus, whose autophagy-inhibiting action the researchers elucidated more than a year ago.

When results suggested autophagy pathways might be a potential target for COVID-19 therapies, the researchers tested whether substances which induce cellular recycling also block replication of SARS-CoV-2 inside infected cells.

The four potential drugs they discovered include spermidine, an autophagy-enhancing metabolite which is produced in all human cells and by bacteria in the human gut. It occurs naturally in foods such as wheat germ, soya, mushrooms, and mature cheese. When the researchers added spermidine to cells infected with SARS-CoV-2, there was an 85% reduction in the number of virus particles produced.

Similar results were produced by spermine, which also occurs naturally in the body. This was found to reduce viral replication by more than 90% in human lung cells and in a human gut model.

The third substance to prove effective against SARS-CoV-2, MK-2206, is currently in clinical trials against a range of different cancers. In the COVID-19 study, the drug reduced production of SARS-CoV-2 virus by approximately 90%.

The most pronounced antiviral effect was associated with niclosamide, which reduced production of SARS-CoV-2 particles by more than 99 percent. "Niclosamide showed the strongest effect in our cell culture-based experiments. What is more, it has been licensed for use against tapeworm infections in humans for a very long time and is well tolerated at potentially relevant doses,” said Müller.

"Out of the four new candidate substances, we consider it to be the most promising one. This is why we are now conducting a clinical trial at Charité to test whether niclosamide might also have a positive effect on people with COVID-19,” Muller said. “[This] shows how quickly findings from basic research can reach patients if research and clinical practice are closely interlinked and work together in an efficient manner."

COVID-19 patients are suffering from cognitive and other problems as long as two months after being discharged from hospital, with many experiencing deficits in memory, spatial awareness and information processing, according to a study conducted in Italy.

One in five patients reported post-traumatic stress disorder (PTSD), with 16% having symptoms of depression.

The study involved testing neurocognitive abilities and taking MRI brain scans of patients two months after COVID-19 symptoms had cleared. More than 50% of patients experienced cognitive disturbances; 16% had problems with memory, flexible thinking and information processing; 6% experienced difficulties judging depth and seeing contrast; and 25% manifested a combination of all these symptoms.

Cognitive and psychopathological problems were much worse in younger people, with the majority of patients aged under 50 demonstrating issues with these executive functions.

Across the whole sample, greater severity of COVID-19 acute respiratory symptoms during hospital admission was associated with low executive function performance subsequently.

Ten months post-COVID-19, the cohort showed a reduction of cognitive disturbances, from 53% to 36%, but a PTSD and depressive symptoms persisted.

Massimo Filippi of the Scientific Institute and University Vita-Salute San Raffaele, Milan, who led the research, said, "Our study has confirmed significant cognitive and behavioural problems are associated with COVID-19 and persist several months after remission of the disease. A particularly alarming finding is the changes to executive function we found, which can make it difficult for people to concentrate, plan, think flexibly and remember things. These symptoms affected three in four younger patients who were of a working age."

Larger studies and longer-term follow up are both needed, but this study suggests that COVID-19 is associated with significant cognitive and psychopathological problems. Patients should be followed-up and treated to ensure they are given adequate support to help alleviate these symptoms.

The research was presented at European Academy of Neurology meeting in Vienna on Monday.

A team led by researchers at Newcastle University has successfully derived a model of the cells found in the lungs, which they say can be used to replicate how COVID-19 infects the airways.

This paves the way for broader studies of viral lung infections, using a cost-effective system that can easily be manufactured on a large scale.

The researchers used induced pluripotent stem cells to generate airway epithelial cells, culturing them on a polyester membrane to allow formation of a single layer, and then exposing them to an air/liquid interface that induce the cells to differentiate into a stratified epithelial model.

While previous research has shown blood clotting is a significant cause of death in patients with COVID-19, it was not known why this happens.

Now, scientists have analysed blood samples from patients with COVID-19 treated in intensive care at a hospital in Dublin, finding the balance between a molecule that causes clotting, called von Willebrand Factor (VWF), and another molecule, ADAMTS13 that regulates it, are severely disrupted.

The discovery could lead to targeted therapies to prevent this from happening, the researchers say.

When compared to control groups, the blood of COVID-19 patients had higher levels of the pro-clotting VWF and lower levels of the anti-clotting ADAMTS13. Furthermore, the researchers identified other changes in proteins that caused the reduction of ADAMTS13.

"Our research helps provide insights into the mechanisms that cause severe blood clots in patients with COVID-19, which is critical to developing more effective treatments," said one of the researchers, Jamie O'Sullivan, of the Irish Centre for Vascular Biology in Dublin.

"While more research is needed to determine whether targets aimed at correcting the levels of ADAMTS13 and VWF may be a successful therapeutic intervention, it is important that we continue to develop therapies for patients with COVID-19,” O’Sullivan said. “COVID-19 vaccines will continue to be unavailable to many people throughout the world, and it is important that we provide effective treatments to them, and to those with breakthrough infections.”

The COVID-19 vaccine under development by German biotech CureVac is only 47% effective in preventing infections of the SARS-CoV-2 virus, according to an interim analysis of the phase III trial involving 40,000 volunteers.

The company said the failure to meet the pre-specified target for effectiveness was a result of a high number of variants of the virus circulating in the areas where the trial took place. While the vaccine, CVnCoV was designed against the original wild type of the virus that emerged in Wuhan, China, volunteers in the study were infected with a least 13 different variants.

A total of 57% of the infections were caused by the variants of concern, which have also been having an impact on the effectiveness of the approved vaccines.

Curevac said CVnCoV had a good safety profile and the trial will go through to the final analysis.

The interim analysis involved 134 cases of COVID-19 infection. Of these, the DNA of 124 viruses was sequenced and only one case was caused by the original Wuhan strain.

“We will continue the study,” said Franz-Werner Haas, CEO of Curevac. “The final efficacy may change.”  

With the World Health Organisation warning the Delta variant of the Sars-CoV-2 virus first detected in India is poised to take hold in Europe, there is positive news, indicating vaccines remain effective.

A new analysis by Public Health England (PHE) shows two doses of either Pfizer/BioNTech’s or Astrazeneca’s COVID-19 vaccines are preventing people infected with the Delta variant becoming seriously ill and needing to be admitted to hospital.

According to the date the Pfizer/BioNTech vaccine is 96% effective against hospitalisation after two doses, while the AstraZeneca vaccine is 92% effective against hospitalisation after two doses.

These are comparable with vaccine effectiveness against hospitalisation from the Alpha variant that first emerged in Kent in December and rapidly spread around Europe.

Further work remains underway to establish the level of protection the vaccines provide against mortality from the Delta variant.

The analysis included 14,019 cases of the Delta variant, 166 of whom were hospitalised, between 12 April and 4 June, looking at emergency hospital admissions in England.

PHE has previously published analysis showing that one dose is 17% less effective at preventing symptomatic illness from the Delta variant, compared to Alpha, underlining the importance of ensuring people are fully vaccinated.

A team of researchers at the Freiburg University Medical Centre has shown a severe inflammatory response can develop in the central nervous system of COVID-19 patients, involving different immune cells around the vascular system and in the brain tissue.

“Even though there was already evidence of central nervous system involvement in COVID-19, the extent of inflammation in the brain surprised us," said Henrike Salié co-author of the research published in the journal Immunity.

Notably, the researchers detected structures called microglial nodules that are not found in healthy brains. 

Using a novel measurement method, the researchers were able to image different cell types, including virus-infected cells, and to view spatial interactions of cells, in previously unseen detail.

"Until now, the inflammatory pattern in COVID-19 was poorly understood. Even compared to other inflammatory brain diseases, the inflammatory responses triggered by COVID-19 are unique and indicate a severe disturbance of the brain's immune response,” said Marco Prinz, medical director at the Institute of Neuropathology.

“In particular, the essential defence cells of the brain, microglial cells, are [very] strongly activated,” Prinz said. There was also pronounced neuroinflammation in the brain stem.

The immune changes are easiest to pick up in small blood vessels in the brain where the ACE2 receptor by which the virus enters human cells is expressed. Here, the virus was directly detectable. The researchers suggest that the immune system responds to these infected cells, sparking inflammation that then spreads to the nerve tissue, causing symptoms.

It is possible that early immunomodulatory or immunosuppressive treatment could reduce inflammation, they say.

After COVID-19 was officially declared a pandemic by the World Health Organisation (WHO), the peak in total number of clinical trials investigating therapies for the virus was 445, in April 2020.

There has since been a steady decrease in new clinical trials in every month, apart from December 2020 and March 2021, according to market research firm GlobalData.

There has been a divergence between therapies and vaccines, with the number of COVID-19 vaccines trials continuing to increase throughout the pandemic. The number peaked in March 2021 at 89 trials.

At the beginning of the pandemic there was a surge in trials of potential therapeutics in the scramble to find treatments for the infection. But once vaccines began to be approved, trials of therapies began to decline.

“The upward trend for vaccine COVID-19 clinical trials is expected to continue due to the same approved vaccines [being] tested against new variants of the virus,” said Scotty Chung-Siu, senior analyst at GlobalData. “On the other hand, the decrease in therapeutic COVID-19 clinical trials may be due to the increase in availability of vaccines, as well as the negative data in clinical trials from some therapeutics.”

The European Commission is making a push to expand access to COVID-19 vaccines in low and middle income incomes countries, whilst resisting the call to over-ride patents other countries, including the US, have called for.

In a speech to the European Parliament, setting out the position she will put to the G7 meeting taking place in the UK this coming weekend, Commission president Ursula von der Leyen said, “I want to be very clear: I think intellectual property has to be protected because it is the idea behind the breakthrough, and it retains the incentives for innovation in research and development.”

Rather than compulsory licensing, as called for by the World Trade Organisation (WTO), von der Leyen said voluntary licences are the most effective way to support local production of vaccines.

But she said, there is a “big however”. In a global emergency like this, “If voluntary licencing fails, compulsory licensing has to be, and is, the legitimate tool to scale up production,” von der Leyen said.

As von der Leyen noted, vaccine production requires not only patents but highly trained staff. “These are very complicated biological processes. They require know-how, they require technology, they require skilled personnel and, of course, infrastructure,” she said.

Simply waiving intellectual property rights will not increase production. “It is actually by collaboration and, if need be, compulsory licensing that you enhance technology transfer,” von der Leyen said.

But patents should not stand in the way, which is why Europe had started an initiative in WTO to simplify compulsory licensing, said von der Leyen.

In addition, the EU has committed €1 billion to help set up vaccine manufacturing hubs in Africa. The G7 meeting will provide a good opportunity to reaffirm the EU’s commitments “and to go even further,” von der Leyen said.