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

Cambridge University researchers have identified 200 approved drugs they predict will work against COVID-19, of which only 40 are currently being tested in COVID-19 clinical trials.

Using a combination of computational biology and machine learning, the researchers created a comprehensive map of the proteins that are involved in SARS-CoV-2 infection – ranging from proteins that help the virus enter the host cell, to those generated as a consequence of infection.

By examining this network using artificial intelligence (AI) approaches, they were able to identify key proteins involved in infection, as well as biological pathways that might be targeted by drugs.

Based on this, the team used computer modelling to carry out a virtual screen of almost 2,000 approved drugs and identified 200 approved products that could be effective against COVID-19. Forty of these drugs are in clinical trials, which the researchers argue supports the approach they have taken.

When the researchers tested a subset of those drugs implicated in viral replication, they found that two in particular - an antimalarial drug and a type of medicine used to treat rheumatoid arthritis - were able to inhibit the virus, providing initial validation of the data-driven approach.

Tony Kouzarides who led the study, said, "By looking across the board at the thousands of proteins that play some role in SARS-CoV-2 infection - whether actively or as a consequence of infections - we've been able to create a network uncovering the relationship between these proteins.

"We then used the latest machine learning and computer modelling techniques to identify 200 approved drugs that might help us treat COVID-19. Of these, 160 had not been linked to this infection before."

Of particular note were sulfasalazine, used to treat conditions such as rheumatoid arthritis and Crohn's disease, and proguanil, an antimalarial drug.

The study has provided unexpected information about the mechanisms underlying COVID-19 and pointed at drugs that might be repurposed for either treating or preventing infection. While the researchers took a data-driven approach, allowing AI to interrogate datasets, they validated the findings in the laboratory, confirming the power of this approach.

Researchers at the Francis Crick Institute, London and Dundee University have screened thousands of drugs, identifying a range of compounds with antiviral effects they say could be developed into treatments for COVID-19.

This would fill a big gap in the treatment of COVID-19, with very few drugs that can be used in the community to reduce symptoms and speed up recovery time. Therapies that act directly on the virus are especially needed by groups where the vaccines are less effective, for example, people with impaired immune systems.

In a series of seven papers, published in the Biochemical Journal, the scientists identified 15 compounds which inhibit the growth of SARS-CoV-2 by blocking different enzymes involved in its replication.

The researchers developed and ran tests for around 5,000 molecules to see if any blocked the function of any of seven SARS-CoV-2 enzymes. They then validated potential inhibitors against SARS-CoV-2 in the lab, to see if they slowed viral growth. The team found at least one inhibitor for each of the seven enzymes.

Three of the molecules identified are existing drugs used to treat other diseases. Lomeguatrib is used in melanoma and has few side-effects, suramin is a treatment for African sleeping sickness and river blindness and trifluperidol is used for mania and schizophrenia. As there is existing safety data on these drugs, it may be possible to more quickly develop them into SARS-CoV-2 antivirals.

John Diffley, lead author of the papers and associate research director at the Crick, said, "We've developed a chemical toolbox of information about potential new COVID-19 drugs. We hope this attracts attention from scientists with the drug development and clinical expertise needed to test these further."

The 15 molecules were also tested in combination with remdesivir, an antiviral being used to treat patients with COVID-19. Four of these, all which target the SARS-CoV-2 enzyme Nsp14 mRNA Cap methyltransferase, were found to improve the effectiveness of remdesivir in lab tests.

The scientists now plan to see if any pairs of the 15 molecules they identified inhibit the virus more than when they are used alone.

Targeting enzymes involved in virus replication could also help prepare for future viral pandemics, Diffley said. “Proteins on the outside of viruses evolve rapidly, but within different classes of viruses are well conserved proteins that change very little with time.”

German biotech announced results from the final analysis of its 40,000 subject international phase III study of its COVID-19 vaccine, CVnCoV, showing it was 48% effective at preventing infections.

That is lower than other vaccines that have been approved, but the company is stressing the trial was conducted in a different context, with 15 viral variants circulating within the study population at the time of final analysis.

In addition, there was a tougher endpoint than for other vaccines, which were assessed mostly on their ability to prevent serious disease and hospitalisation. Curevac on the other hand, assessed the ability of CVnCov to prevent COVID-19 disease of any severity, including single non-respiratory mild symptoms.

Significant protection was demonstrated among participants in the age group of 18 to 60, with an efficacy of 53% against disease of any severity, and across all 15 identified variants. At the same time, protection against moderate to severe disease was calculated to be 77%. In the same age group, CVnCoV provided 100% protection against hospitalization or death.

In participants above 60 years, who represented 9% of the analysed cases, the available data did not enable a statistically significant determination of efficacy. The data confirm the favourable safety profile of CVnCoV in all age groups. The data have been communicated to the European Medicines Agency.

“In this final analysis, CVnCoV demonstrates a strong public health value in fully protecting study participants in the age group of 18 to 60 against hospitalization or death and 77% against moderate and severe disease – an efficacy profile, which we believe will be an important contribution to help manage the COVID-19 pandemic and the dynamic variant spread,” said Franz-Werner Haas, CEO of CureVac.

“In the current context of an increasingly diverse environment of COVID-19 variants, and with very little residual prevalence of the original strain, we are confident that the HERALD study offers clinically relevant data regarding the effect of emerging variants on vaccine efficacy.”

In total, 228 COVID-19 cases, 83 in people who received two doses of vaccines versus 145 in the placebo arm, were assessed in the final analysis. In the 18 to 60 age group vaccine efficacy against different variants ranged from approximately 42% to up to 67%.

New research suggests that coronavirus infection alters the biomechanical properties of red and white blood cells, in some cases for months, and that this is a possible explanation for some symptoms of Long-COVID.

Scientists at the Max-Planck-Zentrum für Physik und Medizin in Erlangen were able to show for the first time that COVID-19 significantly changes the size and stiffness of red and white blood cells. They point to the shortness of breath, fatigue and headaches that some patients experience six months or more after being infected and suggest these are all phenomena in which the blood cells and their altered physical properties play a key role.

"We were able to detect clear and long-lasting changes in the cells, both during an acute infection and even afterwards," said co-author of the research, Jochen Guck.

The biophysicists examined more than four million blood cells, from 17 patients who were acutely ill with COVID-19, 14 people who had recovered and 24 healthy people as a control.

They found the size and deformability of red blood cells from patients with the disease were markedly different from those of healthy people. The damage to these cells could explain the increased risk of blood clots in hospitalised COVID-19 patients and long running symptoms afterwards.

Some of the changes observed persisted up to seven months after an acute infection.

The concentration of droplets in aerosols generated by blowing into woodwind and brass instruments was lower than in those produced when speaking and singing, and no different from a person breathing, according to new research by scientists at Bristol University.

The findings could help in developing a roadmap for lifting COVID-19 restrictions in the performing arts, which have been more or less shut down since the start of the pandemic.

The study looked at the amount of aerosols and droplets generated when playing woodwind and brass instruments compared with breathing, and speaking and singing. The work was carried out in an environment with no background aerosol particles to complicate measurement interpretation, with nine musicians playing 13 woodwind and brass instruments.

The research team found aerosols generated while playing the instruments were similar to that produced by breathing, based on several musicians playing the flute and piccolo, and measurements across a range of instruments including clarinet, trumpet, trombone, and tuba. Aerosol concentrations generated while instrument playing were lower than those associated with singing at high volume.

Large droplets were not observed during instrument playing, but were seen during singing and coughing. Together the findings indicate that playing woodwind and brass instruments generates fewer aerosols than vocalising at high volume.

Jonathan Reid, director of the Bristol Aerosol Research Centre, said the study confirms that the risks of transmission of SARS-CoV-2 are likely to be elevated during vocalisation at loud volume in poorly ventilated spaces.” By comparison, playing wind instruments, like breathing, generates fewer particles that could carry the virus than speaking or singing," he said.

As the COVID-19 vaccines rollout in Europe prevents acute cases of infection, reducing hospitalisation and deaths, attention is turning to trying to prepare for the next stage of the pandemic, which will be in understanding and treating Long-COVID symptoms.

New research from Aarhus University, Aarhus University Hospital and Regional Hospital West Jutland, shows that even patients who experienced mild COVID-19 infections may have persistent symptoms.

In particular, 30% of participants in the study experienced a significantly long-lasting reduced sense of taste and smell.

The same was true for long-term shortness of breath, although in the case of this symptom relatively few people were affected.

While the vast majority of people who fall ill with COVID-19 experience mild symptoms and get over the disease in two to three weeks, emerging evidence indicates some symptoms – some of which are serious - may persist.

In the largest study yet, involving more than half a million people in England, 5.8% of participants had one or more symptoms following COVID-19 that persisted for 12 weeks or more. This would translate to two million-plus affected people for the population of England as a whole.

To date, most studies have looked at long term effects in people who were sick enough to be admitted to hospital. Community data are starting to put a new complexion on Long-COVID, both in terms of the disease burden and the stress it will put on health services.

In the Danish study, researchers compared symptoms every day, for up to 90 days, in 210 healthcare workers who had tested positive for COVID-19, and 630 with a negative test. Each day, participants received a questionnaire on whether they had experienced one of the following symptoms within the last 24 hours: coughing, sore throat, headaches, fever, muscle pain, shortness of breath and reduced sense of taste and smell.

"We saw that the prevalence of a longer-lasting reduced taste and smell is significantly increased in patients with mild COVID-19 disease who did not require hospitalisation. This pattern is also seen for shortness of breath, but far fewer people were affected," says Henrik Kolstad, an author of the study.

Thirty per cent of those who had tested positive reported a reduced sense of taste and smell for the full ninety days. At the beginning of the project, shortness of breath was reported by twenty per cent of those who had tested positive. That fell to 5% after thirty days, but did not fall as low as in participants who had tested negative.

Coughing, sore throat, headaches, muscle pain and fever were more common among those who tested positive than those who tested negative over the first few days, but had stopped by day 30.

Heart attacks that occurred during the COVID-19 pandemic were more likely to result in heart failure compared with heart attacks one year earlier, according to research presented this week at the European Society of Cardiology in Sophia Antipolis, France.

"Heart attack patients waited an average of 14 hours to get help during the pandemic, with some delaying for nearly two days. That compares to a delay of six hours in the previous year," said study author Ali Aldujeli of the Lithuanian University of Health Sciences, Kaunas. "This gap may have been one contributor to the higher incidence of subsequent heart failure."

Fast treatment of heart attacks is essential to restore the flow of oxygen-rich blood to the heart muscle. A longer duration of oxygen deprivation is associated with a greater area of damaged muscle and a reduction in pumping function.

The retrospective, multicentre study covered six out of ten regions in Lithuania, with a total of 269 heart attack patients evaluated in the retrospective study. There was a 34.0% decline in heart attack admissions during the early phase of the pandemic compared to the same period in 2019. Patients waited significantly longer before presenting to hospital during the pandemic compared to 2019 (a median of 858 versus 386 minutes, respectively).

Aldujeli said the decline in admissions and delays in seeking treatment may be partly attributed to the extensive media coverage which “amplified patients' fear of contracting COVID-19” and “precluded them from seeking timely medical care.”

Outcomes differed according to type of heart attack, and that may have been influenced by new pandemic-specific protocols that were implemented to prevent spread of the virus, Aldujeli said. "Our findings suggest that all heart attacks during a pandemic should be treated urgently with staff using personal protective equipment. More balanced media coverage is also needed so that patients do not wait to seek help in medical emergencies."

The EU strategy on COVID-19 therapeutics has delivered its first outcome, with the announcement of the first portfolio of five drugs, which could be made available to treat patients across the EU.

Four of these are monoclonal antibodies currently under rolling review by the European Medicines Agency, the other is an approved  immunosuppressant, for which the label could be extended to include treatment of COVID-19 patients.

Commissioner for health Stella Kyriakides, said, “Today we are taking the first step towards a broad portfolio of therapeutics to treat COVID-19. Whilst vaccination is progressing at increasing speed, the virus will not disappear and patients will need safe and effective treatments to reduce the burden of COVID-19.”

The five drugs that have been selected are at an advanced stage of development and could be approved by October 2021, the target set under the strategy.

Overall, the Commission will draw up a portfolio of at least 10 potential COVID-19 drugs by October, building on the work of a newly-established expert group on COVID-19 virus variants.  The selection process will be objective and science based, with selection criteria agreed with the member states.

CEOs of global biotechnology companies and associations from across Europe and the US have hit out against the waiver of intellectual property rights proposed in the World Trade Organisation, saying it will be ineffective and counterproductive in addressing the pandemic.

Intellectual property rights are not responsible for the imbalance in COVID vaccine supplies between higher and lower income countries, and the waiver will create a long, contentious global negotiation that will not address the crisis, they say. Rather, it will foster more “vaccine nationalism,” and exacerbate shortages in an already strained global supply chain.

“It would divert limited resources from companies that are focused on maximising current global partnerships, while maintaining quality and patient safety,” the CEOs say.

The waiver would also send a signal to the biotech sector and investors to avoid taking the risks involved in developing vaccines, diagnostics and treatments in future public health emergencies, the CEOs said.

“Intellectual property is the foundation of our sector. It is responsible for creating the global biotech network that responded so quickly to the COVID crisis in the first place. It is what gives investors the confidence to fund companies with long time horizons and high risks.”

Intellectual property rights gave companies the assurance that they could quickly pivot during the early days of the pandemic, and to move into COVID projects.

Based on these efforts, current estimates are that existing global vaccine manufacturers will produce more than 11 billion doses of COVID vaccines in 2021, and significantly more in the first part of 2022. “We are committed to working with other global stakeholders to see that these doses get to those that most need them, wherever they may be,” the CEOs say.

Strategically rearranging the seats of orchestra musicians and altering the airflow in concert venues could dramatically reduce concentrations of COVID-19-spreading aerosols that accumulate on stage during performances, according to a new simulation-based study.

Performing artists’ careers and livelihoods across the piece have been greatly impacted by the pandemic, with many unable to practice their craft. However, few studies have investigated exactly how the virus might be transmitted in this context, including in large spaces such as concert hall stages.

To better understand how wind instruments might contribute to the spread of infectious aerosols during on-stage performances, researchers at the University of Utah used information about the flow rates of different instruments to simulate airflow and the spread of fine aerosols for two Utah concert venues, the Abravanel Hall and Capitol Theatre.

The researchers assessed possible COVID-19 exposure and risk of infection for musicians on stage (not audience members) and simulated how rearranging the players, altering airflow patterns in the venue by opening doors, or adding structural enhancements to redirect airflow, could better protect the performers.

For Abravanel Hall they found emissions accumulation could be reduced by placing non-wind instruments (piano and percussion) at the centre of the stage, situating bassoons, which project aerosols high into the air, near the doors, and arranging other instruments close to air vents.

Since there was little airflow around musicians in the Capitol Theatre and nothing to recirculate air, the researchers modelled the construction of an airflow passageway over the back doors, showing that created stronger airflow behind the performers.