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

Researchers at the University of British Columbia faculty of medicine have conducted the world’s first molecular-level structural analysis of the Omicron variant spike protein by which the virus gets access to human cells.

The Omicron variant has an unprecedented 37 mutations on its spike protein - three to five times more than previous variants. 

The near single atom resolution analysis, published in the journal Science, reveals how the heavily mutated Omicron variant attaches to and infects human cells. 

Understanding the molecular structure of the viral spike protein will inform the development of more effective therapies against Omicron and related variants in the future, said Sriram Subramaniam, professor in the department of biochemistry and molecular biology and lead author of the paper. “By analysing the mechanisms by which the virus infects human cells, we can develop better treatments that disrupt that process and neutralise the virus,” he said.

The structural analysis revealed that several mutations create new salt bridges (bonds between oppositely charged proteins) and hydrogen bonds between the spike protein and the ACE2 receptor on human cells. The researchers say these new bonds appear to increase the binding affinity, creating stronger attachments between the virus and human cells. However, another mutation was shown to decrease the strength of these attachments.

“Overall, the findings show that Omicron has greater binding affinity than the original virus, with levels more comparable to what we see with the Delta variant,” said Subramaniam. “It is remarkable that the Omicron variant evolved to retain its ability to bind with human cells despite such extensive mutations.”

In other experiments, the researchers showed the Omicron spike protein has an increased ability to evade antibody drugs. In contrast to previous variants, Omicron showed measurable evasion from all six monoclonal antibodies tested, with complete escape from five. The variant also displayed increased evasion of antibodies in blood samples from vaccinated individuals and unvaccinated COVID-19 patients. 

The US Food and Drug Administration has revised the authorisations for two monoclonal antibody drugs bamlanivimab and etesevimab (administered together) and REGEN-COV (casirivimab and imdevimab) to limit their use to only when a patient is not infected by the Omicron variant that is now causing most infections worldwide.

The move comes on the heels of data showing these treatments are highly unlikely to be active against Omicron.

Current monoclonal antibodies are designed to neutralise SARS-CoV-2 by binding to the spike protein seen in the original variant of the virus that emerged in Wuhan. The mutations in the Omicron variant means this mechanism of action is no longer effective.

Valneva announced results from an initial laboratory study demonstrating that antibodies induced by three doses of its whole virus, inactivated COVID-19 vaccine candidate, VLA2001, neutralise the Omicron variant.

Blood samples from 30 participants in the phase I/II trial of VLA2001-201 were used in a pseudovirus assay to analyse neutralisation of the original Wuhan variant of SARS-CoV-2, as well as the Delta and Omicron variants.

All 30 samples presented neutralising antibodies against the ancestral virus and Delta variant, and 26 samples (87%) presented neutralising antibodies against the Omicron variant. The mean reduction of neutralisation relative to the ancestral virus was 2.7-fold for Delta and 16.7-fold for Omicron.

Juan Carlos Jaramillo, chief medical officer of Valneva, said, “We are extremely pleased with these results, which confirm the potential for broad-spectrum protection of our inactivated, adjuvanted whole virus vaccine and its ability to address currently circulating variants of concern.

“We continue to believe that VLA2001 could be an important component of the fight against COVID-19, and Valneva remains fully committed to bringing VLA2001 to people who need it as soon as we can,” he said.

Valneva is continuing to provide data to the European Medicines Agency, the UK Medicines and Healthcare products Regulatory Agency, and the National Health Regulatory Authority in Bahrain, as part of the rolling submissions process for initial approval of VLA2001. The company continues to expect to complete these submissions in time to receive potential regulatory approvals in the first quarter of 2022.

Valneva announced in November 2021 that the European Commission signed an agreement for the company to supply up to 60 million doses of VLA2001 over two years – including 24.3 million doses in 2022. Delivery of the vaccine in Europe is currently expected to begin in April 2022, subject to approval by the EMA.

Policies to tackle COVID-19 are more likely to get broad public support if they are proposed by experts or by politicians from cross-party coalitions, rather than from politicians from a single ruling party, according to a new study of seven countries.  

Public behaviour and support for measures such as facemasks or social distancing have been crucial in tackling the worldwide pandemic.  Yet, it has also been difficult to secure and maintain that support, and to avoid debates getting polarised. 

The research found that polarisation emerges when policies are associated with opposing political parties and politicians, but that people have a high level of confidence that science experts will act in the public’s best interest. 

The COVID pandemic provided a unique opportunity to study this issue.  It was a new threat and one that was experienced simultaneously across the world, allowing for international comparisons. 

The research team included colleagues from the UK, US, Sweden, Israel, Austria, Italy and Singapore and involved 13,000 participants in 7 countries:  UK, US, Brazil, Israel, Italy, Sweden and South Korea.  These countries display a range of different political systems and parties in government and varying experiences of COVID and responses to it.  

In each country, participants were asked first about their overall political views, using a measure called affective polarisation: their feelings towards liberal and conservative politicians and towards experts.  

They were then asked to give their views on two COVID policies.  Both involved restrictions, but one emphasised more stringent public health measures to keep case numbers down, while the other involved fewer restrictions for economic recovery.    

Respondents in all countries supported policies proposed by experts and bipartisan coalitions, more than those proposed by either liberal or conservative elites.

A comparative study conducted at the Spallanzani Institute in Rome, the leading Italian research institute for infectious diseases, by a joint Italian-Russian team of researchers has shown that the Sputnik V coronavirus vaccine induces more than two times higher levels of virus neutralising antibodies to the Omicron variant than two doses of Pfizer/BioNTech vaccine.

The study was conducted on comparable blood samples from individuals dosed with Sputnik V and Pfizer’s vaccines.

Among all samples, 74.2% of Sputnik V-vaccinated blood samples were able to neutralise Omicron, compared to 56.9% of samples from Pfizer-vaccinated people.

The data support the results of a recent laboratory study by the Gamaleya Centre in Moscow, where Sputnik V was developed, also demonstrating that Sputnik V induces robust neutralising antibody response to Omicron variant.

Sputnik V is currently approved in 71 countries with a total population of over 4 billion people. Its safety and efficacy have been demonstrated in more than 30 studies and real-world data publications from more than 10 countries.

A research team led by virologist Stephan Ludwig, at the Institute of Virology, University of Münster, has demonstrated that a drug targeting RNA viruses has the dual action of preventing replication of SARS-CoV-2 in human cells and of blocking the exaggerated immune response seen in severe cases of COVID-19.

The data, published in Cellular and Molecular Life Sciences, provided the basis for approval to conduct an ongoing phase II clinical trial.

“In the results we have published, we have been able for the first time to show such a dual action for an anti-COVID 19 agent,” Ludwig said.

The drug in question, Zapnometinib, originally under development as an anti-flu medication, was shown to be effective in a variety of cell culture models, including showing activity against all tested variants of SARS-CoV-2. That implies it will have broad applicability against any emerging variants in the future. Animal testing to confirm this is currently underway, as the clinical trial progresses.

Zapnometinib, which is being developed by German biotech Atriva Therapeutics, inhibits the Raf/MEK/ERK signalling pathway that is involved in the replication of many RNA viruses, including flu, hantavirus, respiratory syncytial virus and also coronaviruses.

“Positive results from the still ongoing clinical study in humans might already lead to an emergency approval this year for a new, broadly effective COVID-19 medication,” said Ludwig.

In April 2021 Atriva was awarded €11.4 million by the German Federal Ministry of Education and Research (BMBF) to finance the phase II study. The funding was part of a €50 million BMBF programme for COVID-19 therapies, awarded to eight companies.

An international metastudy led by researchers at Karolinska Institutet has identified a specific gene variant that protects against severe COVID-19 infection.

The researchers homed in on the variant by studying people of different ancestries, which they say highlights the importance of conducting clinical trials that include people of diverse descent.

Previous studies, mainly involving people of European ancestry, found individuals carrying a particular segment of DNA that encodes for genes in the immune system, have a 20% lower risk of developing a severe COVID-19 infection.

This region of DNA is, however, packed with numerous genetic variants, which makes it challenging to pinpoint the one that could potentially serve as a drug target to develop treatments for severe COVID-19 infection.

A small piece of this DNA region is the same in people of both African and European ancestries, leading the researchers to look for individuals of predominantly African ancestry who had the same protection against COVID-19 as those of European ancestry and enabling them to identify the gene variant of interest.

The analysis included 2,787 hospitalised COVID-19 patients of African ancestry in the US and 130,997 people in a control group from six cohort studies. Eighty percent of individuals of African ancestry carried the protective variant. The outcome was compared with a previous metastudy of individuals of European heritage.

The COVID-19 pandemic has spurred considerable collaboration among researchers in different parts of the world, which has made it possible to study genetic risk factors in a wider diversity of individuals than previously. Even so, the majority of all clinical research is still being done on individuals of predominantly European descent.

“This study shows how important it is to include individuals of different ancestries. If we had only studied one group, we would not have been successful in identifying the gene variant in this case,” said Hugo Zeberg, assistant professor in the department of Neuroscience at Karolinska Institutet, co-author of the research published in Nature Genetics.

A genetic risk factor that influences whether an individual is likely to experience a loss of smell or taste as symptoms of COVID-19 has been discovered by the US consumer genetic testing company 23and Me.

Loss of smell or taste are recognised symptoms of COVID-19 but not all individuals infected with SARS-CoV-2 experience them, and the mechanisms responsible are unclear.

Adam Auton and colleagues performed a genome-wide association study using online survey data collected from 69,841 (63% female; 37% male) research participants aged over 18 years, living in the US and the UK. They found that a set of variants located near the two genes, UGT2A1 and UGT2A2, increased the likelihood that an individual will experience a loss of smell or taste following SARS-CoV-2 infection by 11%.

Both genes encode enzymes that are expressed in cells that line the inside of the nose and are involved in eliminating odorants that bind to receptors involved in smell detection.

This discovery provides clues into the biological mechanisms that underlie COVID-19-related loss of smell or taste, the researchers say. The details are published in Nature Genetics.

A study led by Exeter University and published in the International Journal of Infectious Disease has found that 13% of people who test PCR positive for SARS-CoV-2 still exhibited clinically-relevant levels of virus after 10 days.

The researchers used a new test that can detect if virus is still active, meaning people might still be infectious. Some people in the study retained clinically relevant levels of virus for up to 68 days. The researchers say the new test they used should be applied in settings where people are vulnerable, to stop the spread of COVID-19.

Conventional PCR works by testing for the presence of viral fragments. While it is possible to tell if someone has recently had the virus, it does not detect whether it is still active. The new test gives a positive result only when the virus is active and potentially capable of onward transmission.

The test was applied to samples from 176 people in Exeter who had tested positive on standard PCR tests. The data shows that at five days, 30% still exhibited clinically-relevant levels of potentially active virus.

Merlin Davies, of Exeter University Medical School, said, “In some settings, such as people returning to care homes after illness, continuing to be infectious after ten days could pose a serious public health risk. We may need to ensure people in those settings have a negative active virus test to ensure people are no longer infectious. We now want to conduct larger trials to investigate this further.”

Positive results from a preliminary analysis of an ongoing safety and immunogenicity trial of AstraZeneca’s vaccine given as a third dose booster, show there is an increased immune response to Beta, Delta, Alpha and Gamma SARS-CoV-2 variants, while a separate analysis of samples from the trial showed increased antibody response to the Omicron variant.

The results were observed among individuals previously vaccinated with either the AstraZeneca vaccine, or Pfizer or Moderna’s mRNA vaccines.

A separate phase IV trial showed that a third dose of the AstraZeneca vaccine substantially increased antibody levels following primary vaccination with CoronaVac, which is manufactured by the Chinese company Sinovac Biotech.

Astrazeneca said these data add to the growing body of evidence supporting the use of its vaccine as a third dose booster, irrespective of the primary vaccination received. 

Mene Pangalos, executive vice president of biopharmaceuticals R&D at AstraZeneca, said the vaccine has already protected hundreds of millions of people from COVID-19 and these data show that it has an important role to play as a booster, including when used after other vaccines. “We will continue to progress regulatory submissions around the world for its use as a third dose booster,” he said.