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

G7 health ministers committed to a new international agreement designed to make it easier and quicker to share results from vaccine and therapeutic trials to tackle COVID-19 and prevent future health threats.

The Therapeutics and Vaccines Clinical Trials charter will help deliver high quality, reliable and comparable evidence from international clinical trials, to speed up access to approved treatments and vaccines.

During the COVID-19 pandemic some of the rapidly organised clinical trials played a critical role in informing public health and clinical decisions, but many other studies were inadequate in size, design and how they were conducted, failing to generate reliable evidence.

More effective international collaboration on trials would have made better use of scarce resources and may have saved lives. An assessment by the US Food and Drug Administration suggests only about a quarter of enrolled patients contributed to adequately powered and well controlled trials.

While vaccine development has been faster in the pandemic than ever before, improvements can be made. For example, the use of different laboratory testing methods and reagents meant it was often not possible to compare immune responses directly; a lack of pre-agreed processes was a barrier to the cross-border movement of materials; and there was no overall coordination of trial testing methodology.

The G7 charter pledges to avoid the proliferation of trials that do not contribute valid evidence, prioritising support for randomised controlled trials. This will be taken this forward through national healthcare and research systems, with ministers agreeing to promote communication and coordination between them.

To avoid unnecessary duplication in future the G7 will coordinate emergency and preparedness research agendas, for example, sharing vaccines and therapeutics national research agendas and sharing information on ongoing and planned trials.

A team led by researchers at Newcastle University has demonstrated that the gene HLA-DR1 is found three times more often in people who have a confirmed COVID-19 infection but don’t have any symptoms, suggesting the gene confers some level of protection from severe infection.

HLA-DR1 is known to be involved in the body’s immune response to infections and the researchers believe this is the first clear evidence of inbuilt genetic resistance to the worst effects of COVID-19.

Carlos Echevarria from the Translational and Clinical Research Institute at Newcastle University who is a respiratory consultant at Newcastle Hospital said, "This is an important finding as it may explain why some people catch COVID but don't get sick.”

It could lead to a genetic test to help in prioritising those most at risk when designing vaccination programmes. Knowing who has this natural genetic resistance would also be important for other control measures.

"At a population level, this is important for us to know because when we have lots of people who are resistant, so they catch COVID but don't show symptoms, then they risk spreading the virus while asymptomatic," Echevarria said.

The study used samples from 49 patients with severe COVID-19 who had been hospitalised with respiratory failure, samples from an asymptomatic group of 69 hospital workers who had tested positive, and a historic control group.

Daily crime counts before and after COVID-19 restrictions were implemented in major metropolitan areas such as Barcelona and London show that while stringency of lockdowns varied considerably from city to city, most types of crime fell significantly.

Overall, stricter lockdowns led to greater declines in crime, but even cities with voluntary "recommendations" instead of restrictions, such as Malmo and Stockholm in Sweden, saw drops in daily rates of theft, according to the study led by researchers at the universities of Cambridge and Utrecht.

Across 27 cities worldwide, daily assaults fell by an average of 35%, robberies involving violence or intimidation almost halved, falling an average of 46%, and other types of theft, from pick pocketing to shoplifting, fell an average of 47%.

Theft of vehicles fell by an average of 39% over the study sites. Researchers found that tougher restrictions on use of buses and trains during lockdowns was linked to greater falls in vehicle theft - suggesting that negotiating cities via public transport is often a prerequisite for stealing a car.

In Barcelona there were massive falls in the number of assaults (84% drop) and robberies (80% drop). Thefts reported to police in the city declined from an average of 385 per day, to just 38 per day under lockdown.

London saw less pronounced, but still significant falls in some crime, with daily robberies dropping by 60%, theft by 44% and burglaries by 29%.

"City living has been dramatically curtailed by COVID-19, and crime is a big part of city life," said Manuel Eisner, director of the Violence Research Centre at Cambridge University, who is senior author of the study published in Nature Human Behaviour.

"No drinkers spilling into the streets after nights out at bars and pubs. No days spent in shops and cafés, or at the racetrack or football match. Some cities even introduced curfews. It choked the opportunism that fuels so much urban crime,” said Eisner.

The one exception was the number of murders committed, with a fall of just 14% on average across all cities in the study. Criminologist Amy Nivette, assistant professor at Utrecht University said, "In many societies, a significant proportion of murders are committed in the home. The restrictions on urban mobility may have little effect on domestic murders.”

Falls in crime resulting from COVID-19 stay-at-home orders tended to be sharp but short-lived, with a maximum drop occurring around two to five weeks after implementation, followed by a gradual return to previous levels.

"The measures taken by governments across the world to control COVID-19 provided a series of natural experiments, with major changes in routines, daily encounters and use of public space over entire populations,” Eisner said. "The pandemic has been devastating, but there are also opportunities to better understand social processes, including those involved in causing city-wide crime levels."

The largest analysis to date shows that unnecessary use of antibiotics to treat patients with serious COVID-19 could be fuelling bacterial resistance.

The research found that antibiotic use was very high in hospitalised COVID-19 patients in the UK during the first wave of the pandemic, despite confirmed bacterial infections being uncommon.

Of 46,000 patients in the study, 85% received one or more antibiotics when in hospital, while 37% of patients were prescribed antibiotics prior to admission. In the event, only 1,017 of the patients had a confirmed bacterial infection.

The researchers believe the high level of antibiotic use in the UK is likely to be replicated elsewhere, meaning the COVID-19 pandemic could undermine international efforts to preserve the effectiveness of antimicrobial drugs.

The overuse of antibiotics during the first wave, in February to May 2020, is attributed to the fact that there was little knowledge of COVID-19 and how to treat it. Other viral respiratory infections, notably influenza, are strongly associated with bacterial co-infections, leading clinicians to treat COVID-19 patients with antibiotics on a just-in-case basis.

Currently, national and international COVID-19 guidelines vary in their recommendations on such empirical antibiotic use. UK guidelines have now been updated to advise against antibiotics in COVID-19, without specific evidence of bacterial infection.

In the UK study, very few patients had bacterial co-infections when first admitted to hospital, and the few infections that did occur began more than 48 hours after admission.

These secondary infections were not specific to COVID-19, but more in keeping with the usual run of hospital-acquired infections, particularly those typically seen in intensive care units.

“Until now, a detailed understanding of the nature of bacterial co-infections identified in patients with COVID-19, and the frequency and types of antibiotics these patients have been prescribed has been lacking,” said Antonia Ho of Glasgow University’s Centre for Virus Research, who led the study.

“This study demonstrates the very high antibiotic use we see in hospitalised COVID-19 patients may not be necessary, indeed it may contribute to antimicrobial resistance,” she said

Some COVID-19 patients will require antibiotics, mostly for secondary infections which develop after admission to hospital, but not all COVID-19 patients should be prescribed antibiotics. “The bugs we identified are similar to those found in patients with hospital-acquired infection, and not specific to COVID-19,” Ho said.

The World Health Organisation has come up with a new naming system for key variants of SARS-CoV-2 virus that it says are easier to say and remember.

Rather than a single letter followed by a string of numbers, as in B.1.1.7, also known as the Kent variant; the South African variant B.1.351; the Indian variant, B.1.617; and the Brazil variant P1, WHO recommends using letters of the Greek alphabet.

The Kent variant becomes alpha, South African delta, Brazilian gamma and the Indian variant delta.

These labels were chosen after wide consultation and a review of many potential naming systems. WHO convened partners from around the world including experts who are part of existing naming systems, nomenclature and virus taxonomic experts, researchers and national authorities.

WHO will assign labels for viral variants that are designated as variants of interest or variants of concern, because it is thought they could be more transmissible and/or more virulent.

The labels do not replace the existing scientific names, which convey important scientific information and will continue to be used in research. But while they have their advantages, WHO says these scientific names can be difficult to say and recall, and are prone to misreporting.

As a result, people often resort to calling variants by the places where they are first detected. That is “stigmatising and discriminatory” WHO said. To avoid this and to simplify public communications, WHO encourages adoption of the new labels.

The European Centre for Disease Prevention and Control (ECDC) adopted a technical report on COVID-19 vaccination of adolescents, setting out key elements to take into account when considering whether or not to vaccinate this age group.

This follows a European Medicines Agency decision last week that the Pfizer/BioNTech vaccine is safe for use in 12 – 15 year olds.

ECDC is now following up with “practical evidence based considerations” to support member states that are considering expanding national vaccination programmes to adolescents, said health commissioner Stella Kyriakides. 

Such vaccinations should be considered in the broader context of the COVID-19 vaccination strategy for the whole population, ECDC says.

The vaccination of adolescents at high risk of severe COVID-19 should be considered a priority, as with other age groups.

The design and implementation of adolescent vaccination is a national responsibility, and member states are now in a position to start using the vaccine for 12-15 year olds should they decide to do so, the Commission said.

Researchers from Aarhus University have developed electronic support stockings and tested them on COVID-19 patients at Copenhagen University Hospitals, showing the stockings significantly counteracted the loss of muscle mass typically seen in people who are confined to bed.

The Aarhus researchers developed a biocompatible electrode for electrical muscle stimulation that was 3D-printed onto the medical support stockings. These were tested on consenting patients who were in hospital with COVID-19 infection in the winter 2020/2021.

The participants , who were hospitalised for five to seven days wore a support stocking on each leg, only one of which had the printed electrodes, meaning patients acted as their own control.

Participants' thigh muscles were electrically stimulated for 30 minutes, twice a day, at an individually adapted intensity.

"The study demonstrated that these patients lost approximately 10% of their muscle mass after just five to six days of hospitalisation,” said Charlotte Suetta, chief physician and lead investigator in the clinical trial. “However, with this new technology we've been able to counteract the loss,” Suetta said.

Muscle loss is a serious problem for hospitalised patients, especially those that need intensive care and are on ventilators for long periods. Recovering from muscle loss after several weeks of total inactivity may take months or years, and some people never recover fully.

While there is nothing new about electrical stimulation of muscles, there are several disadvantages with existing products including difficulties in getting electrodes on and off, and skin irritation in the stimulated areas.

"Our invention is much easier to use because the electrodes are an integral part of the textile," said Shweta Agarwala, an expert in printed electronics.

The electrodes have three ultra-thin, flexible layers, and these can be printed directly onto different types of material, making it possible to stimulate the muscles through the stocking with minimal irritation. “Since the electrodes are an integral part of the stockings, they can also tolerate hospital cleaning processes,” Agarwala said.

To date, Aarhus University has printed almost 600 support stockings for medical use. It is likely the stockings can be used for a far larger group than just COVID-19 patients, including bedridden patients in general, as well as in rehabilitation and for wheelchair users.

A new pandemic sciences centre is being set up at Oxford University to build on global research collaborations developed over the past 40 years, with the aim of ensuring that the world is better equipped to prepare for, identify, and counter future pandemic threats.

The university is now looking to raise over £500 million to invest in this centre 

The centre, which will include a number of core institutes, will also harness the collaborations that have developed in record time across national borders between academia, industry and public health bodies, during the current coronavirus pandemic.  

The pandemic has demonstrated the contributions research universities can make to pandemic preparedness, said Louise Richardson, Oxford’s vice chancellor. “We are building on decades of medical research on infectious disease and data science, we have longstanding international partnerships and we have the ability to act and to adapt quickly.”

Within the university, the centre will draw together academics and experts including from infectious diseases, vaccinology, immunology, structural biology, diagnostics, drug discovery, clinical trials, data science, public health, and social and political sciences.

The inaugural director of the centre will be Peter Horby, professor of emerging infectious diseases, who is leader of the UK-wide Recovery clinical trial, which has tested a number of  different drugs in the treatment of COVID-19 infections. The Recovery trial demonstrated the steroid dexamethasone is an effective treatment for severe disease, while showing the malaria drug hydroxychloroquine is not.

“The COVID-19 pandemic has shown us that spectacular advances are possible through an alliance of science, the public sector and industry – creating digital disease control tools, diagnostic tests, and life-saving treatments and vaccines at unprecedented speed,” Horby said. “But it should not take a pandemic to make this happen. This level of innovation and multi-sectoral collaboration must be applied, day in and day out, to prevent another catastrophe like COVID-19.”

GlaxoSmithKline and its US partner Vir Biotechnology said the US. Food and Drug Administration (FDA) has granted an emergency use authorisation (EUA) for sotrovimab, an antibody drug for treating mild to moderate COVID-19 in adults and children aged 12 and older, who are at high risk for progression to severe COVID-19, including hospitalisation or death.

The latest analysis of clinical trial data showed sotrovimab resulted in an 85% reduction in all-cause hospitalisations or death, while in vitro studies show it retains activity against all known variants of concern, including the variant of the virus from India

The EUA was granted to sotrovimab based on an interim analysis of efficacy and safety data from the phase III trial in high risk adult outpatients, which was stopped early by an independent data monitoring committee in March 2021 because of the evidence of profound clinical efficacy.

Sotrovimab targets a conserved part of the viral spike protein that is less likely to mutate over time. The EUA submission also included data from in vitro studies, which demonstrated that sotrovimab maintains activity against all known circulating variants of concern, including the variants from Brazil (P.1), California (B.1.427/B.1.429), India (B.1.617), New York (B.1.526), South Africa (B.1.351) and the UK (B.1.1.7).

On 21 May 2021, the European Medicines Agency issued a positive scientific opinion for sotrovimab, and the agency has started a rolling review of data on the drug that will continue until enough evidence is available to support the filing of a formal marketing authorisation application.

Sanofi and GlaxoSmithKline plc said they started enrolment in a phase III clinical study to assess the safety, efficacy and immunogenicity of their COVID-19 vaccine.

The study will include more than 35,000 volunteers aged 18 and older from several countries, including the US, Asia, Africa and Latin America.

If the phase III is positive, the vaccine could be approved in Q4 2021. Manufacturing will begin in the coming weeks to enable rapid access to the vaccine should regulators approve.

The primary endpoint of the study is the prevention of symptomatic COVID-19 in people who have not previously been exposed to the infection, with secondary endpoints being the prevention of severe COVID-19 disease and prevention of asymptomatic infection.

In a two-stage approach, the study will initially investigate the efficacy of a vaccine formulation targeting the original virus that emerged in Wuhan, China, while a second stage will evaluate a second formulation targeting the South African variant. Recent evidence indicates antibodies created against this variant may provide broad cross-protection against other more transmissible variants. 

The design of the phase III study also allows evaluation of the efficacy of the vaccine against a variety of circulating variants.

Following encouraging interim results from the recent phase II study, the companies will also begin clinical studies in the coming weeks to assess the ability of their vaccine to generate a strong booster response regardless of the initial vaccine received.

“We have adapted our vaccine development strategy based on forward-looking considerations as the virus continues to evolve, as well as anticipating what may be needed in a post-pandemic setting,” said Thomas Triomphe, head of Sanofi Pasteur. “This trial is testament to the urgency and agility in our approach to help overcome the ongoing impact of this pandemic.”

The phase III study follows the interim phase II results which showed that the COVID-19 vaccine candidate achieved high rates of neutralising antibody responses in all adult age groups,

This trial has received funding from the US Biomedical Advanced Research and Development Authority.