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

Researchers from the University of Helsinki and KU Leuven who investigated the arrival and spread of SARS-CoV-2 in Finland in 2020 found a total of 42 independent virus lineages reached the country in spring 2020. Most of these came from Italy, Austria and Spain, but only a handful caused large chains of transmission.

“Four of these lineages caused two-thirds of the entire epidemic in Finland in spring 2020, while a single virus lineage from Spain led to a major transmission chain that covered one-third of the epidemic in the country,” said Ravi Kant of the Department of Virology at Helsinki University.

In the early stages of the pandemic, one of the biggest problems in monitoring the chains of transmission was the genetic similarity of the virus everywhere in the world – there were very few differences in the viral genome between individual countries and chains of transmission.

Philippe Lemey, a specialist in evolutionary and computational virology at KU Leuven, developed an analysis technique that combines data on human mobility at individual and population levels with the sequence analysis of the viral genome, and this was used to analyse SARS-CoV-2 sequencing data from Finland.

This showed that Austria, Spain and Italy, the countries in Europe that had the earliest infection spikes, starting in February 2020, were the most significant sources of coronavirus spreading to Finland.

“Our results show that only a small share of infections is transmitted further, indicating that if travel restrictions and quarantines, testing, tracing and isolation schemes, or other border control measures are deployed early enough, they can delay the development of cases of infection into widespread transmission chains in society. However, these measures will only be effective if combined with other preventive measures, and if the viral strains to be prevented have not already spread,” said Olli Vapalahti, professor in the Department of Virology at Helsinki University.

Questions remain about the ongoing evolution of the virus. Originally, SARS-CoV-2 spread to humans as a zoonotic disease, most likely from bats.

“The circulation of the virus in a new host species requires numerous changes: for instance, the virus must adjust its surface proteins to make them attach more effectively to the cells of the host. In addition, the virus must overcome the host’s innate defences,” said Tarja Sironen, associate professor at Helsinki University. “In fact, the rapid transmission of coronavirus between people in large human populations has produced complex genetic diversity in the virus. At the moment, one of the most central questions in related research is how these different changes alter the biological characteristics of the virus, and what kind of changes in selection pressure is guiding the virus towards in the future.”

The first SARS-CoV-2 case was diagnosed in Finland on 29 January 2020 in a tourist who arrived from Wuhan, China. However, at this point the infection was not transmitted to others in Finland, and the first wave of the epidemic in Finland did not begin until the end of February 2020, peaking in early May and ending by early June.

A comparison of respiratory vaccine delivery systems carried out by scientists at McMaster University, Canada has confirmed that inhaled aerosol vaccines provide far better protection and stronger immunity than nasal sprays.

While nasal sprays reach primarily the nose and throat, inhaled aerosols bypass the nasal passage and deliver vaccine droplets deep in the airway, where they can induce a broad protective immune response, the researchers say.

Infections in the upper respiratory tract tend to be non-severe. In the context of infections caused by viruses like influenza or SARS-CoV-2, it tends to be when the virus gets deep into the lung that it causes severe illness, said Matthew Miller, a co-author of the study, who is a specialist in viral pandemics.

“The immune response you generate when you deliver the vaccine deep into the lung is much stronger than when you only deposit that material in the nose and throat because of the anatomy and nature of the tissue and the immune cells that are available to respond are very different,” Miller said.

The study for the first time provides strong preclinical evidence to support the development of inhaled aerosol delivery over nasal spray for human vaccination against respiratory infections including COVID-19, the researchers say.

More than 6.3 million have people died during the COVID-19 pandemic, and respiratory infections remain a significant cause of illness and death throughout the world, driving an urgent and renewed worldwide effort to develop vaccines that can be delivered directly to the mucous lining of the respiratory tract.

Scientists at McMaster, who have developed an inhaled form of a COVID-19 vaccine, believe this deep-delivery method offers the best defence against the current and future pandemics.

A phase I clinical trial is currently under way to evaluate the inhaled aerosol vaccine in healthy adults who had previously received two or three doses of an injected COVID mRNA vaccine.

Previous research by the McMaster team has shown that in addition to being needle-free and painless, an inhaled vaccine is so efficient at targeting the lungs and upper airways that it can achieve maximum protection with a much smaller dose than injected vaccines.

Two clinical trials of Sanofi’s next-generation COVID-19 booster vaccine have shown it increases neutralising antibodies above baseline against multiple variants of concern in adults who have already been vaccinated with mRNA COVID-19 vaccines.

In particular, the vaccine generated a 40-fold increase in neutralising antibodies against Omicron BA.1 and BA.2.

The second study demonstrated that following primary vaccination with two doses of Pfizer-BioNTech’s vaccine, the Sanofi-GlaxoSmithKline next-generation booster candidate generated a higher immune response than Pfizer-BioNTech’s booster or the Sanofi-GSK first-generation booster. The proportion of participants with at least a 10-fold increase in neutralising antibody levels between day 0 and day 15 was 76.1% for the Sanofi-GSK next-generation booster, versus 63.2% for the Pfizer BioNTech booster, and 55.3% for the Sanofi-GSK first-generation parent booster candidate

“COVID-19 keeps evolving and the combination of emergence of variants and waning immunity is likely to lead to the need for additional booster shots, at least in some populations,” said Thomas Triomphe, executive vice president of Sanofi Vaccines. “Seeing the cross-neutralisation data from the [second] study, we believe this next-generation booster could have an important role to play for public health vaccination campaigns. We look forward to submitting these data to global regulatory authorities.”

 Sanofi said the data supporting its next-generation booster vaccine will be submitted to regulators in the upcoming weeks, with the aim of making it available later this year.

Moderna has announced new clinical data on its COVID-19 booster vaccine candidate, mRNA-1273.214, which is designed to be effective against the Omicron variant, showing a single dose met all pre-specified endpoints.

That included superior neutralising antibody response against Omicron, currently the cause of most infections, one month after administration, when compared to the original mRNA-1273 vaccine, which was designed to protect against the original variant from Wuhan, China.

The booster dose of mRNA-1273.214 was generally well-tolerated, with side effects comparable to a booster dose of mRNA-1273.

"The preliminary data analysis on mRNA-1273.214 […] is the second demonstration of superiority of our bivalent booster platform against variants of concern,” said Stéphane Bancel, CEO of Moderna. "We anticipate more durable protection against variants of concern with mRNA-1273.214, making it our lead candidate for a fall 2022 booster. We are submitting our preliminary data and analysis to regulators with the hope that the Omicron-containing bivalent booster will be available in the late summer.”

Neutralising antibody levels with mRNA-1273.214 were also significantly higher against all other variants of concern - Alpha, Beta, Gamma and Delta.

The European Medicines Agency’s medicines shortages steering group has adopted the list of critical drugs for the COVID-19 public health emergency, meaning their supply and demand will be closely monitored to identify and manage potential or actual shortages.

Given the current stage of the pandemic, the published list contains all the EU-approved vaccines and therapeutics.

Companies marketing the products on the list, which was approved on 7 June, are required to regularly update EMA about potential or actual shortages and available stocks, forecasts of supply and demand.

To ensure stocks are sufficient, member states will be providing regular reports on estimated demand at a national level, enabling EMA to recommend and coordinate appropriate EU-level actions to the European Commission and EU member states.

The medicines shortages group was set up in response to EMA being given greater responsibility for crisis preparedness for public health emergencies, and to coordinate urgent action on the supply of drugs within the EU.

IDAlert, a Horizon Europe project kicking off at the start of June, aims to tackle the emergence and transmission of pathogens from animals to humans, developing novel indicators, early warning systems and tools for decision-makers, and by investigating adaptation and mitigation strategies make Europe more resilient to emerging health threats.

As the planet heats up due to climate change, outbreaks of zoonotic diseases that spread from animals to humans are on the rise. Warmer temperatures, more variable rainfall, and the loss of biodiversity, influence the survival and spread of zoonotic pathogens, and the reproduction and geographic location of their vectors, such as mosquitoes or ticks.

Past and recent health crises, including the COVID-19 pandemic, have shown there is a need for stronger and more inclusive preparedness and responsiveness to epidemic-prone pathogens at the EU and global level. To address this, IDAlert will develop a range of decision support tools and systems to enable decision makers to react sooner.

Amongst these will be climate and health indicators for viruses circulating among wild birds and mosquitoes, and monitoring mechanisms to improve surveillance, early warning, and response systems.

IDAlert will also assess the costs, effectiveness, benefits and viability of adaptation measures and strategies to improve the climate resilience of health systems in Europe.

Finally, the project will look at socioeconomic aspects, investigating the emergence, transmission, and spread of zoonotic pathogens and how policy can help reduce their impacts.

The tools and methods developed in the project will be validated in key hotspot sites in Spain, the Netherlands, Greece, Sweden, and Bangladesh, all of which are experiencing rapid urban transformation and climate-induced disease threats.

IDAlert - Infectious Disease decision support tools and Alert systems to build climate Resilience to emerging health Threats - is a five year project involving 19 organisations from Sweden, Germany, France, Spain, Greece, The Netherlands, Italy, UK, and Bangladesh.

Spanish researchers have found that babies born to mothers who were infected with COVID-19 while pregnant show greater difficulties in relaxing and adapting their bodies when they are being held, compared to infants from non-infected mothers. This is especially the case when infection happened late in pregnancy.

In addition, infants whose mothers had COVID-19 tend to show greater difficulty in controlling head and shoulder movements, suggesting a possible COVID-19 effect on motor function.

The data were presented at the European Congress of Psychiatry held from 4 – 7 June in Budapest.

The results come from an initial evaluation of the Spanish COGESTCOV-19 project, which followed the course of pregnancy and baby development in mothers infected with COVID-19. The data relate to pregnancy and post-natal assessment at 6 weeks after birth, but the project will continue to see if there are longer-term effects. The group will monitor infant language and motor development between 18 and 42 months old.

The initial evaluation compared babies born to 21 COVID positive pregnant women and their babies, with 21 healthy controls at the Marqués de Valdecilla University Hospital in Santander, Spain.  The mothers underwent a series of tests during and after pregnancy.

The post-natal tests included the Neonatal Behavioural Assessment Scale, which measures a baby’s movement and behaviour.

One of the researchers, Águeda Castro Quintas from the University of Barcelona Network Centre for Biomedical Research in Mental Health) said, “We found that certain elements of the NBAS measurement were changed in 6-week-old infants who had been exposed to the SARS-COV-2 virus. Effectively they react slightly differently to being held or cuddled.”

The researchers note that these are preliminary result, but this is part of a project following a larger sample of 100 mothers and their babies. They have also been monitored during pregnancy, and after birth. It is also planned to compare these mothers and babies with data from another similar project, which is looking at the effect of stress and genetics on a child’s neurodevelopment.

Project leader Rosa Ayesa Arriola said, “This is the right moment to establish international collaborations that would permit us to assess long-term neurodevelopment in children born during the COVID-19 pandemic. Research in this field is vital in understanding and preventing possible neurological problems and mental health vulnerabilities in those children in the coming years.”

Long-term exposure to air pollution is linked to a greater risk of severe COVID-19, according to new research presented at the annual meeting of the European Society of Anaesthesiology and Intensive Care in Milan, Italy, 4-6 June.

The study by German researchers found that people living in counties with higher levels of the pollutant nitrogen dioxide (NO2) were more likely to need to be admitted to intensive care and mechanical ventilation if they had COVID-19.

Long-term exposure to NO2 that is released into the atmosphere when fossil fuels are burned, can have harmful effects on the lungs.  This includes damage to the endothelial cells, which play a key role in oxygen transfer from inhaled air to the blood.

Although the links between air pollution and COVID-19 have previously been demonstrated by researchers in Spain, Mexico, Canada and other countries, few of these studies have focused on severity of disease or taken into account population density, underlying health conditions and other factors which affect the impact of the disease.

Susanne Koch, of the Department of Anaesthesiology & Intensive Care, Charité – Universitätsmedizin Berlin and colleagues explored the impact of long-term air pollution on the need for ICU treatment and mechanical ventilation of COVID-19 patients.

Air pollution data from 2010 to 2019 was used to calculate the long-term annual mean level of NO2 for each county in Germany. The highest level was in Frankfurt and the lowest level in Suhl, a small county in Thuringia. 

The German Interdisciplinary Association for Intensive Care and Emergency Medicine registry, set up to monitor ICU capacity during the pandemic, was used to provide information on how many COVID-19 patients in each hospital needed ICU treatment and mechanical ventilation.

The study found that there was a greater need for ICU treatment and mechanical ventilation of COVID-19 patients in counties with higher long-term annual mean NO2 levels.

On average, 28 ICU beds and 19 ventilators were needed for COVID-19 patients in each of the ten counties with the lowest long-term NO2 exposure, during the month studied. This compares to an average of 144 ICU beds and 102 ventilators in the ten counties with the highest long-term NO2 exposure.

While the results do not prove causation, there is a potential biological explanation for them.

ACE-2, the protein that the COVID-19 virus binds to when entering our cells, has many key roles in the body, including helping down-regulate the activities of angiotensin II, a protein which increases inflammation. 

When the SARS-CoV-2 virus binds to ACE-2, however, these brakes are removed.  Air pollution also releases the brakes and so the combination of COVID-19 and long-term air pollution exposure could lead to more severe inflammation and more severe COVID-19.

“Long-term exposure to NO2 long before the pandemic may have made people more vulnerable to more severe COVID-19 disease,” Koch said. “Exposure to ambient air pollution can contribute a range of other conditions, including heart attacks, strokes, asthma and lung cancer and will continue to harm health long after the COVID-19 pandemic ends.”

Researchers from the Zoonosis Science Centre at Uppsala University have identified a new coronavirus in a study of approximately 260 bank voles caught around Grimsö in Örebro County. The data show the virus is well established in Sweden’s red-backed voles.

“Between 2015 and 2017, we consistently found what we have called the ‘Grimsö Virus’ in 3.4% of these voles, which would suggest that the virus is widespread and common in Sweden’s bank voles,” said Åke Lundkvist, professor in virology and head of the Zoonosis Science Centre.

Researchers at the centre map zoonotic viruses to increase the understanding of the interaction between viruses and host animals. Unlike the SARS-CoV and MERS coronaviruses that originate in bats, some seasonal coronaviruses appear to have spread to humans from rodents like rats, mice and voles.

In recent years, there has been a dramatic increase in the number of infectious diseases that can be linked to small mammals like rodents, and research around the ecology of these host animals is an essential component in the work to prevent future outbreaks.

The bank vole (Myodes glareolus) is one of Europe’s most common rodents. Previous studies have found several coronaviruses circulating amongst these animals in countries including the UK, Poland, France and Germany.

“We still do not know what potential threats the Grimsö Virus may pose to public health. However, based on our observations and previous coronaviruses identified among bank voles, there is good reason to continue monitoring the coronavirus amongst wild rodents,” said Lundkvist

One of the first studies to document the impact of COVID-19 on already existing viruses in Australia has shown the pandemic was responsible for creating a huge change in the incidence and genetics of Respiratory Syncytial Virus (RSV) in the country.

RSV is a common virus that generally causes mild, cold like symptoms but the infection can be serious for infants and older adults.

The researchers say the pandemic disrupted the seasonal pattern of RSV, which is one of the regular ‘winter viruses’. For the first time on record, in 2020 there was no winter RSV epidemic, which is attributed to COVID-19 travel restrictions and infection control measures.

However, RSV was one of the first of the key respiratory pathogens to re-emerge after COVID-19.

The researchers genetically sequenced major outbreaks of RSV occurring out of season over the summer of 2020-21 on both sides of the country. These outbreaks coincided with the easing of COVID-19 control measures.

They found there had been a major collapse in RSV strains known before COVID-19, and the emergence of new RSV strains. These new strains dominated each outbreak in Western Australia, New South Wales and the Australian Capital Territory.

The researchers then tracked the seeding of viruses from each outbreak into Victoria, which led to another major RSV outbreak.

“Our genetic studies showed that most of the previous RSV strains had gone ‘extinct’ and that for each outbreak only a single genetic lineage had survived all the lockdowns,” said lead researcher John-Sebastian Eden, senior research fellow at the University of Sydney Institute for Infectious Diseases.

The study raises important questions as to how rapid spread and evolution of RSV could inform the re-emergence of other viruses including influenza.

“The constellation of flu strains circulating pre and post-COVID-19 has also changed a lot, leading to challenges in how we choose the composition and timing of our annual vaccines. For example, the flu season in Australia has kicked off much earlier than in previous years.” said Eden.

There is currently no approved RSV vaccine, but it is a major focus for vaccine and therapeutic development.

“We need to be vigilant – some viruses may have all but disappeared, but will likely rebound in the near future, possibly at unusual times and with stronger impact,” Eden said. “We need to be prepared for large outbreaks of RSV outside of normal seasonal periods.”

Before COVID-19, two major RSV subtypes, A and B, co-circulated at similar levels.

During late 2020 to early 2021 during the outbreak periods, this changed dramatically. The RSV-A subtype was found to be the dominant strain – making up more than 95% of cases in all the states. The RSV-B had all but disappeared.