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

A UK clinical trial has found that interrupting the treatment of people on long-term immune supressing drugs for two weeks after a COVID-19 booster vaccination, doubles their antibody response to the vaccine.

The trial has implications for people on immune-supressing drugs, who are among the millions of clinically vulnerable patients advised to shield during the pandemic.

The study was planned to recruit 560 patients but recruitment was stopped early when interim results from the first 254 participants showed a clear result.

Methotrexate is the most commonly used immune-suppressing drug, with around 1.3 million people in the UK prescribed it for inflammatory diseases such as rheumatoid arthritis, and skin conditions such as psoriasis. Many of them were advised to shield during the first phase of the COVID-19 pandemic, because while methotrexate is effective at controlling these conditions it reduces the body’s ability to fight infections and the ability to generate a robust response to vaccines, including those against COVID-19.

The trial evaluated temporarily stopping, versus continuing methotrexate treatment immediately after a third booster dose of COVID-19 vaccine.

After 4 weeks and 12 weeks, levels of antibodies against the viral spike protein were more than two-fold higher in the group where methotrexate was suspended for two-weeks following vaccination, compared to the group who continued use.

There was a short-term increase in risk of flare-up of inflammatory conditions. However, most could be self-managed and there was no adverse impact on quality of life.

The European Medicines Agency (EMA) is recommending approval of French biotech Valneva’s inactivated whole-virus COVID-19 vaccine for use in primary vaccination in people from 18 to 50 years of age.

Although late to the party, there is hope that the more traditional format of the vaccine will persuade people who did not want to be vaccinated with the earlier novel vaccines using mRNA and viral vectors as delivery vehicles, to overcome their reservations.

Thomas Lingelbach, CEO of Valneva said, “We hope that the European Commission and its member states will recognise the potential advantages of an inactivated vaccine and make a meaningful order, since we have clear evidence that Europeans are seeking a more traditional vaccine technology. Our aim is to further support public health in Europe by providing a new option for the 15% of Europeans over 18 who are not yet vaccinated.”

On May 16 the Commission cancelled its advance purchase agreement with Valneva, citing its right to do so if the vaccine was not approved by 30 April 2022. At that point Lingelbach said, “The European Commission decision is regrettable especially as we continue to receive messages from Europeans who are looking for a more traditional vaccine solution. We have started a dialogue with member states who are interested in our inactivated approach.”

The EMA nod follows conditional marketing authorisation in the UK which was granted in April 2022, emergency use authorisation granted in the United Arab Emirates in May 2022 and in Bahrain in March.  

The vaccine, VLA2001, consists of inactivated whole virus particles of SARS-CoV-2 with high S-protein density, in combination with two adjuvants, alum and CpG 1018. The adjuvant combination has consistently induced higher antibody levels in preclinical experiments than alum-only formulations. VLA2001’s manufacturing process includes chemical inactivation to preserve the native structure of the S-protein.

The largest study to date of Long COVID symptoms in children aged 0-14 years confirms that children who have received a COVID-19 diagnosis can experience symptoms lasting at least two months.

The study used national level sampling of children in Denmark and matched COVID-19 positive cases, with a control group of children with no prior history of a COVID-19 infection.

“The overall aim of our study was to determine the prevalence of long-lasting symptoms in children and infants, alongside quality of life, and absence from school or day care,” said Selina Kikkenborg Berg of Copenhagen University Hospital. While children with a positive COVID-19 diagnosis are more likely to experience long-lasting effects, the pandemic has affected every aspect of all young people’s lives. Further research into the long-term consequences of the pandemic on all children will be important going forwards,” Berg said.

Most previous studies of Long COVID in young people have focussed on adolescents, with infants and toddlers seldom represented.

The most commonly reported symptoms among children 0-3 years old were mood swings, rashes, and stomach aches. Among 4-11 years old the most commonly reported symptoms were mood swings, trouble remembering or concentrating, and rashes, and among 12-14 years old, fatigue, mood swings, and trouble remembering or concentrating.

Children diagnosed with COVID-19 in all age groups were more likely to experience at least one symptom for two months or longer than the control group.

The types of non-specific symptoms associated with long COVID are often experienced by otherwise healthy children; headache, mood swings, abdominal pain, and fatigue are all symptoms of common ailments. However, this study revealed that children with a positive COVID-19 diagnosis were more likely to experience long-lasting symptoms than children who had never had a positive diagnosis.

“The opportunity to undertake such research is rapidly closing as the vast majority of children have now had a COVID-19 infection, for example 58% of children in Denmark had lab confirmed infection between December 2021 and February 2022,” said Berg. Knowledge of long-term symptom burden in SARS-CoV-2 positive children is essential to guide diagnosis and care.

Researchers have demonstrated how airborne diseases such as COVID-19 spread along the length of a train carriage and shown there is no ‘safest spot’ for passengers to minimise the risk of transmission.

The researchers from Cambridge University and Imperial College London developed a mathematical model to help predict the risk of disease transmission in a train carriage and found that in the absence of ventilation systems that draw in fresh air, the risk is the same along the entire length of the carriage.

The model, which was validated with a controlled experiment in a real train carriage, also showed masks are more effective than social distancing at reducing transmission, especially in trains that are not ventilated with fresh air.

The researchers say the results highlight how important it to improve train ventilation systems.

“In order to improve ventilation systems, it’s important to understand how airborne diseases spread in certain scenarios, but most models are very basic and can’t make good predictions,” said researcher Rick de Kreij. “Most simple models assume the air is fully mixed, but that’s not how it works in real life.”

Many different factors can affect the risk of transmission in a train, including whether the people in the train are vaccinated, whether they’re wearing masks, how crowded it is. “Any of these factors can change the risk level, which is why we look at relative risk, not absolute risk. It’s a toolbox that we hope will give people an idea of the types of risk for an airborne disease on public transport,” de Kreij said.

The SARS-CoV-2 Omicron sublineages BA.2.12.1, BA.4 and BA.5 that are currently causing most COVID-19 infections, exhibit higher transmissibility than their predecessor, BA.2.

In investigating the reason for this, scientists in China made structural comparisons of the Spike protein by which the virus locks onto the human ACE2 receptor and enters the host cell. They showed that BA.2.12.1 and BA.4/BA.5 have comparable ACE2-binding affinities to BA.2.

However, it was also shown that BA.2.12.1 and BA.4/BA.5 are more able to evade neutralising antibodies in blood samples from people who had received three doses of COVID-19 vaccine, and more significantly, in the blood of people who had been infected with the earlier BA.1 Omicron variant after receiving three doses of vaccine.

In the paper published in Nature, the researchers say their results indicate that Omicron may have evolved mutations to evade the immunity elicited by BA.1 infection. That suggests vaccine boosters designed against BA.1 may not achieve broad-spectrum protection against newer Omicron variants, they say.

An analysis by researchers at King’s College London of data from ZOE, a smartphone app that has been gathering information on COVID symptoms from the general public since the start of the pandemic, has found Long COVID is less likely after infection with the Omicron variant than the Delta variant.

Long COVID is defined in UK guidelines as having new or ongoing symptoms four weeks or more after the start of disease. Symptoms include fatigue, shortness of breath, loss of concentration and joint pain. These can adversely affect day-to-day activities, and in some cases can be severely debilitating.

The odds of experiencing Long COVID were between 20-50% less with Omicron than Delta, depending on age and time since vaccination.

The study identified 56,003 UK adult cases first testing positive between 20 December 2021 and 9 March 2022, when Omicron was the dominant strain. Researchers compared these cases to 41,361 cases first testing positive between 1 June 2021 and 27 November 2021 when the Delta variant was dominant.

The analysis shows 4.4% of Omicron cases were Long COVID, compared to 10.8% of Delta cases. 

However, the absolute number of people experiencing Long COVID was in fact higher in the Omicron period, because of the vast numbers of people infected with Omicron from December 2021 to February 2022.

The UK Office of National Statistics estimated the number of people with Long COVID increased from 1.3 million in January 2022 to 2 million as of 1 May 2022.

International regulators have issued a report outlining what they have learned from the high level of international collaboration in pooling and analysing data that was spurred by the pandemic, and which allowed them to rapidly generate real world evidence of the safety and effectiveness of the vaccines and antivirals approved to prevent and treat COVID-19.

In particular, the report, issued under the auspices of the International Coalition of Medicines Regulatory Authorities, focusses on the importance of sharing data for vaccines surveillance; research on the safety of drugs and vaccines in pregnancy; and the building of international cohorts of patients to increase the statistical power of observational studies.

The contributors to the report represent more than 28 drugs regulatory authorities as well as experts from the World Health Organisation.

The report acknowledges the importance of sharing of data, experience and tools, and says there is broad agreement that rapid generation of evidence as a result of active interactions between regulators, researchers and academia is crucial for regulatory decision-making in case of a new pandemic or other public health crises.

In the case of COVID-19 and its effects on pregnant women and their babies, data was gathered from around the world, the first time where such an exhaustive collaborative collection of data on this special population had been achieved. It was shown that performing studies based on the same protocol with some adaptations to the local databases made it possible to conduct extremely strong studies in relatively short time periods.

The report also identifies opportunities for strengthening international collaboration beyond the pandemic, and highlighted that a state of readiness is essential.

An US/UK research collaboration has identified genetic factors that lead some healthy adults with the COVID-19 infection become seriously ill, whilst others have few symptoms.

While it is known that age, body mass index and pre-existing health problems account for some of the disparities in severity of infection, genetics also plays a significant role.

Using machine learning, the researchers identified more than 1,000 genes linked to the development of severe COVID-19 and which particularly affect the function of white blood cells called natural killer cells.

This is said to be one of the first studies to link coronavirus-associated genes to specific biological functions.

“During the research we discovered the genetic architecture underlying coronavirus infection, and found that these 1,000 genes account for three quarters of the genetic drivers for severe COVID-19,” said Johnathan Cooper-Knock, lecturer in the Department of Neuroscience at Sheffield University.  “This is significant in understanding why some people have had more severe symptoms of Covid-19 than others.”

The researchers used several large data sets to unpack the genetics behind severe COVID-19. The first, containing sequence data from healthy human lung tissue was used to track gene expression in 19 different types of lung cells, including epithelial cells that line the respiratory tract and which are the first defence against infection.

That was cross referenced against the COVID-19 Host Genetics Initiative, one of the largest genetic studies of critically ill coronavirus patients, to look for mutations that might indicate someone is at a higher risk for severe COVID-19.

By layering the mutations onto the cell-specific genomes of healthy cells the researchers pinpointed which genes were dysfunctioning and within which cell-types. They found that severe COVID-19 is largely associated with a weakened response from two immune cells, natural killer cells and T cells.

Cooper-Knock said, “We found that in people with severe coronavirus infection, critical genes in NK cells are expressed less, so there’s a less robust immune response. The cell isn’t doing what it’s supposed to do.”

The findings lay the foundation for a genetic test to predict who is at an increased risk for severe COVID-19.

Trials of NK cell infusions for severe COVID-19 are now underway.

The European Medicines Agency has started a rolling review for a version of the Pfizer/BioNTech COVID-19 vaccine that has been designed to provide better protection against variants of SARS-CoV-2.

The review will initially focus on manufacturing of the vaccine, and as there is progress in the development of the adapted vaccine, EMA will look at data on the immune response to the vaccine and its efficacy against Omicron variants.

Details about the adapted vaccine, for example whether it will specifically target one or more SARS-CoV-2 variants or subvariants, are not yet defined.

French researchers have found two broadly neutralising antibodies that have the potential to provide long-acting immunity against COVID-19 in immunocompromised people.

The antibodies were effective against all SARS-CoV-2 variants of concern tested and could be used alone or in an antibody cocktail to diminish the risk of infection.

The researchers at the Institut Pasteur, Université Paris Cité, and INSERM examined 102 SARS-CoV-2 spike monoclonal antibodies cloned from blood cells of patients who recovered from COVID-19. They found two antibodies, labelled Cv2.1169 and Cv2.3194, that were the only ones to neutralise all SARS-CoV-2 variants, including Omicron BA.1 and BA.2 subtypes.

The two antibodies also were fully active against Alpha, Beta, Gamma, and Delta variants. A modified version of the Cv2.1169 antibody was also effective at treating SARS-CoV-2 infection in mice and hamsters.

“The broadly neutralising antibodies we described were more efficient in vitro than many anti–SARS-CoV-2 monoclonals previously approved by the FDA for treatment or prevention,” said Hugo Mouquet, head of the Laboratory of Humoral Immunology at the Institut Pasteur, who led the study. “Therefore, we are pretty confident that they represent premium candidates for pre-exposure prophylaxis in immunocompromised patients.”

Previous research has shown that SARS-CoV-2 spike-specific monoclonal antibodies play a key role in providing in vivo protection, however, immunocompromised people still lack effective immunity against SARS-CoV-2 infection.

The first molecule being developed based on the new research, SPK001 is expected to start clinical trials shortly.

The research has its roots in a task force launched by the Institut Pasteur in the early days of the COVID-19 pandemic.

Notably, one of the two broadly neutralizing antibodies, Cv2.1169, is an immunoglobulin A that is produced by B cells in the respiratory tract, and can be crucial in the early response to respiratory pathogens like SARS-CoV-2.