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

In the current wave of COVID-19 there is a particularly high risk of reinfection by the newer Omicron variant of SARS-CoV-2.

To uncover the reason behind this, a team from the Centre for Emerging Viral Diseases of the University of Geneva and Geneva University Hospital analysed the antibody neutralisation capacity of 120 people infected with the original SARS-CoV-2 strain, or with one of its Alpha, Beta, Gamma, Delta, Zeta or Omicron (sub-variant BA.1) variants.

They found that unlike its predecessors, Omicron appears to be able to evade the antibodies generated by other variants. In people who have been vaccinated the neutralisation capacity is also reduced, but it remains far superior to natural immunity alone.

This could explain why Omicron is responsible for a net increase in vaccine break-through infections, but not serious disease and hospitalisation.

Isabella Eckerle, professor in the faculty of Medicine who led this work said, “Since the beginning of 2020, we have collected samples of the original virus and all its variants that appeared in Switzerland, even the rarest ones such as Gamma or Zeta. This makes it a comprehensive collection of samples from individuals with different infection backgrounds, collected according to an identical protocol.”

The research team took blood samples from 120 volunteers previously infected with one of the different variants, unvaccinated, or vaccinated and infected, either before or after vaccination. The aim was to determine how well antibodies generated during the first infection were able to neutralise the different variants of SARS-CoV-2.

“Omicron proved to be the most effective at evading pre-existing natural immunity, as well as, to a lesser extent, that induced by vaccination”, said Benjamin Meyer, researcher at the Centre for Vaccinology. Antibody levels against ancestral SARS-CoV-2 in vaccinated people are roughly 10 times higher than in people who have only developed post-infection immunity. Moreover, the combination of the two seems to maintain even higher and broader reactive antibody levels.

“Thus, Omicron can evade existing immunity and cause an infection, but hospitalisation and death due to COVID-19, even with Omicron, is still reduced after vaccination,” Meyer said.

Nevertheless, SARS-CoV-2 retains an astonishing ability to mutate, and the rate of mutation appears to be accelerating. “Vigilance is still required, especially as the epidemiological curves have been rising sharply since the appearance of BA.5, the most recent Omicron sub-variant,” said Eckerle.

Infection with the "old" Omicron subvariants BA.1 and BA.2 is providing little protection against the SARS-CoV-2 subvariants BA.2.12.1 and BA.4, and the BA.5 subvariant that is causing a “summer wave” of COVID-19 cases in Germany and elsewhere in Europe, according to German researchers.

The Omicron subvariants BA.1 and BA.2 of the SARS-CoV-2 virus dominated the COVID-19 pandemic in early 2022, but in many countries these are now outcompeted by emerging subvariants BA.2.12.1, BA.4 and BA.5, with BA.5 being responsible for the current uptick of cases in Germany.

However, at present it is unclear whether these three new Omicron subvariants have acquired biological traits that allow for more efficient transmission, or whether they are less efficiently blocked by antibodies compared to the old Omicron subvariants BA.1 and BA.2.

A study by researchers at the German Primate Centre (DPZ) - Leibniz Institute for Primate Research together with colleagues from Hannover Medical School and Friedrich-Alexander-University Erlangen-Nürnberg shows that the Omicron subvariants BA.2.12.1, and especially BA.4 and BA.5 are less inhibited than their predecessors BA.1 and BA.2, by antibodies generated after vaccination or infection.

The researchers also showed that most of the approved therapeutic antibody drugs for treating COVID-19, either do not inhibit BA.2.12.1, BA.4 and BA.5 at all, or only do so with reduced potency.

The researchers found that of ten therapeutic antibodies studied only two were able to at least partially inhibit BA.2.12.1, BA.4, and BA.5 and that only Eli Lilly’s monoclonal antibody bebtelovimab efficiently blocked infection by all Omicron subvariants.

“These results confirm a trend that we have already seen in previous studies: Omicron subvariants are not appreciably inhibited by most therapeutic antibodies and the few antibodies that inhibit frequently do so in a subvariant-specific fashion. Therefore, it is important to develop new antibodies in order be prepared for future subvariants,“ said Prerna Arora, first author of the study.

In terms of the ongoing effectiveness of vaccines or previous infection in protecting against the new subvariants, antibodies from unvaccinated individuals who were infected with Omicron subvariants BA.1 or BA.2 in spring 2022 neutralised BA.2.12.1 with similar efficiency, but were much less potent against BA.4 and BA.5.

 Antibodies induced by three doses of Pfizer/BioNTech’s vaccine blocked all Omicron subvariants, but inhibition was less efficient as compared to earlier SARS-CoV-2 variants, and inhibition of BA.2.12.1, BA.4, and BA.5 was less efficient compared to BA.1 and BA.2.

Similar results were obtained for antibodies induced by vaccination plus breakthrough infection. Although this so-called hybrid immunity conferred overall higher neutralising activity against all variants tested, inhibition of BA.2.12.1, BA.4 and BA.5 was significantly reduced.

“BA.2.12.1 and particularly BA.4 and BA.5 are antibody evasion variants. Vaccination will still protect against severe disease induced by these variants, but protection might be somewhat less efficient as that measured for previously circulating variants,” said Markus Hoffmann, senior author of the study.

Future studies will investigate whether BA.2.12.1, BA.4 and BA.5 are not only less efficiently inhibited by antibodies but also better at infecting lung cells. If this is the case, then an uptick in hospitalisations might be the consequence, although this has so far not been observed in South Africa, where BA.4 and BA.5 were first detected.

The European Medicines Agency and other regulators from around the world met to review the emerging evidence of reduction in the effectiveness of COVID-19 vaccines against the new Omicron BA.4 and BA.5 subvariants of SARS-CoV-2 and to discuss how vaccines could be adapted.

The meeting focused on identifying key principles to support changes to COVID-19 vaccines to better match Omicron variants of concern, and on ensuring global regulatory alignment.

The currently authorised COVID-19 vaccines continue to offer protection against severe disease, hospitalisation and death, but the regulators recognised that the continuous evolution of SARS-CoV-2 reduces the protection offered by the approved vaccines against infection and mild disease.

Although the Omicron BA.4 and BA.5 subvariants are dominant in many parts of the world, experience has shown that new variants may emerge rapidly and could replace those currently circulating very quickly, making it tricky to decide what targets updated vaccines should be aimed at.

Preliminary data indicate that adapted mRNA vaccines which incorporate an Omicron variant strain, can increase and extend protection, when used as a booster.

There is also emerging data showing a bivalent mRNA vaccine designed against both the original virus that emerged in Wuhan, China and against an Omicron strain, may provide some advantages in widening the immune response. EMA said such bivalent vaccines could be considered initially for use as boosters, but there is not enough data as yet to support their use for primary vaccination.

Vaccines which include other variants, for example the Beta variant, could also be considered for use as boosters if there is enough clinical trial data to demonstrate they neutralise Omicron and other variants of concern.

The regulators also highlighted the importance of planning effectiveness studies with adapted vaccines to determine the level of protection conferred from infection, hospitalisation and death in real-life conditions.

While obesity was flagged as a risk factor for more serious disease in the early stages of the COVID-19 pandemic, it was not known if two doses of vaccine are as effective against severe disease in people who are underweight, overweight or obese.

As a result of obesity being identified as a risk factor for severe COVID-19 early in the pandemic, the UK vaccine programme in 2021 gave priority to calling people with a body mass index of over 40 for vaccination.

But while the evidence was they were at risk of more severe disease, little was known about the effectiveness of COVID-19 vaccines for overweight and obese people.

Now a UK study involving more than nine million people has shown that while vaccinated people who are underweight or overweight are better protected than counterparts who have not been vaccinated, they are at greater risk of hospitalisation and death compared to vaccinated people of healthy weight.

Characteristics such as age, sex, smoking status, and social deprivation were accounted for in the analyses.

The study provides some of the first indicators as to the effectiveness of COVID-19 vaccines across body mass index (BMI) categories. 

“Our findings provide further evidence that COVID-19 vaccines save lives for people of all sizes,” said lead author, Carmen Piernas of Oxford University’s department of primary care health sciences. The results provide reassurance to people living with obesity that vaccination substantially lowers their risk of severe illness if they are infected with COVID-19, she said.

Piernas and colleagues searched anonymised health records from more than 12 million patients across 1,738 GP practices in England. Of these, patients who were over 18 years old, had BMI data, and had not previously been infected with SARS-CoV-2 were included in the study.

Of over nine million people included in the study, 566,461 tested positive for SARS-CoV-2 during the study period, from 8 December 2020 - the date the first vaccine was given in the UK - to 17 November 2021. Of these, 32,808 were admitted to hospital and 14,389 died.

The proportion of people who had had no doses of any COVID-19 vaccine at the end of the study were 23.3% of the healthy weight group (817,741 of 3,509,231 people); 32.6% of the underweight group (104,488 of 320,737 people); 16.8% of the overweight group (513,570 of 3,062,925 people) and 14.2% of the obese group (322,890 of 2,278,649 people).

The risk of severe disease in vaccinated versus non-vaccinated people was compared at least 14 days after a second dose. The researchers found that being vaccinated offered high protection across all BMI groups, but that the effect was slightly lower in underweight people.

For all groups other than people who were underweight, being vaccinated meant they were around 70% less likely to be hospitalised than unvaccinated people. In addition, these groups were also around two-thirds less likely to die than their unvaccinated counterparts two weeks after a second dose.

Looking only at vaccinated people, even though vaccination helped reduce the number of severe COVID-19 cases, there was a significantly higher risk of severe disease for people who were underweight, overweight or obese, compared to people with a healthy BMI, following two doses of vaccine.

For example, a BMI of 17 was linked to a 50% increase in risk of hospitalisation compared with a healthy BMI of 23, and a very high BMI of 44 had three times the risk of hospitalisation compared with a healthy BMI. This is similar to the increased risk of severe COVID-19 outcomes shown prior to the vaccination programme.

“The cause of the increased risk among people with obesity is unknown,” Piernas said. “We suspect that these findings may be explained, in part, by an altered immune response in heavier weight individuals, but that is just speculation at this point. The reduced effectiveness of COVID-19 vaccines among people with a low BMI may also reflect a reduced immune response due to frailty or other conditions associated with low body weight.”

While obesity was flagged as a risk factor for more serious disease in the early stages of the COVID-19 pandemic, it was not known if two doses of vaccine are as effective against severe disease in people who are underweight, overweight or obese.

As a result of obesity being identified as a risk factor for severe COVID-19 early in the pandemic, the UK vaccine programme in 2021 gave priority to calling people with a body mass index of over 40 for vaccination.

But while the evidence was they were at risk of more severe disease, little was known about the effectiveness of COVID-19 vaccines for overweight and obese people.

Now a UK study involving more than nine million people has shown that while vaccinated people who are underweight or overweight are better protected than counterparts who have not been vaccinated, they are at greater risk of hospitalisation and death compared to vaccinated people of healthy weight.

Characteristics such as age, sex, smoking status, and social deprivation were accounted for in the analyses.

The study provides some of the first indicators as to the effectiveness of COVID-19 vaccines across body mass index (BMI) categories. 

“Our findings provide further evidence that COVID-19 vaccines save lives for people of all sizes,” said lead author, Carmen Piernas of Oxford University’s department of primary care health sciences. The results provide reassurance to people living with obesity that vaccination substantially lowers their risk of severe illness if they are infected with COVID-19, she said.

Piernas and colleagues searched anonymised health records from more than 12 million patients across 1,738 GP practices in England. Of these, patients who were over 18 years old, had BMI data, and had not previously been infected with SARS-CoV-2 were included in the study.

Of over nine million people included in the study, 566,461 tested positive for SARS-CoV-2 during the study period, from 8 December 2020 - the date the first vaccine was given in the UK - to 17 November 2021. Of these, 32,808 were admitted to hospital and 14,389 died.

The proportion of people who had had no doses of any COVID-19 vaccine at the end of the study were 23.3% of the healthy weight group (817,741 of 3,509,231 people); 32.6% of the underweight group (104,488 of 320,737 people); 16.8% of the overweight group (513,570 of 3,062,925 people) and 14.2% of the obese group (322,890 of 2,278,649 people).

The risk of severe disease in vaccinated versus non-vaccinated people was compared at least 14 days after a second dose. The researchers found that being vaccinated offered high protection across all BMI groups, but that the effect was slightly lower in underweight people.

For all groups other than people who were underweight, being vaccinated meant they were around 70% less likely to be hospitalised than unvaccinated people. In addition, these groups were also around two-thirds less likely to die than their unvaccinated counterparts two weeks after a second dose.

Looking only at vaccinated people, even though vaccination helped reduce the number of severe COVID-19 cases, there was a significantly higher risk of severe disease for people who were underweight, overweight or obese, compared to people with a healthy BMI, following two doses of vaccine.

For example, a BMI of 17 was linked to a 50% increase in risk of hospitalisation compared with a healthy BMI of 23, and a very high BMI of 44 had three times the risk of hospitalisation compared with a healthy BMI. This is similar to the increased risk of severe COVID-19 outcomes shown prior to the vaccination programme.

“The cause of the increased risk among people with obesity is unknown,” Piernas said. “We suspect that these findings may be explained, in part, by an altered immune response in heavier weight individuals, but that is just speculation at this point. The reduced effectiveness of COVID-19 vaccines among people with a low BMI may also reflect a reduced immune response due to frailty or other conditions associated with low body weight.”

When SARS-CoV-2 is airborne after infected people cough or sneeze, the virus can lose up to 90% of its potency within 20 minutes, according to the first study to investigate the decrease in infectivity of the virus in aerosol particles over periods from seconds to a few minutes.

Scientists from Bristol University looked see how the survival and infectivity of airborne SARS-CoV-2 inhalable particles is affected by environmental conditions such as relative humidity and temperature. Relative humidity measures how much moisture there is in the air compared to how much there could be at that temperature. Ideal indoor levels are between 40% to 60%.

The researchers generated airborne particles and examined how temperature and humidity drive changes in infectivity at timescales from five seconds to 20 minutes. The same experiment was carried out comparing four different SARS-CoV-2 variants.

There was a significant fall in infectivity within the first ten minutes of aerosol particle generation that was strongly dependent on the environmental relative humidity, but not temperature, across the different SARS-CoV-2 variants.

A 50% decrease in airborne infectivity occurred at low relative humidity (of less than 50%) within ten seconds of aerosol generation. This happens because the airborne particles dry out and rapidly lose moisture, forming solid particles.

At high relative humidity, the loss in infectivity following aerosolisation was more gradual, with a steady loss of infectivity of 50% within the first five minutes and 90% within twenty minutes.

Jonathan Reid, professor of physical chemistry said, “We know that aerosol particles, exhaled when infected individuals breathe, speak or cough, can transmit viruses. Understanding the mechanisms that influence the survival of pathogens while airborne is a further piece of the jigsaw puzzle in understanding the spread of diseases such as COVID-19.”

While COVID-19 is categorised as a respiratory disease, it has harmful effects far beyond the lungs. Now, Japanese researchers have identified a gene that mediates the effects of SARS-CoV-2 infection on blood sugar metabolism and shown the virus can cause metabolic problems, including diabetes, by interfering with insulin signalling.

The researchers hypothesised that SARS-CoV-2 was impacting insulin signalling and causing problems with blood sugar regulation. To test this, they analysed datasets of gene expression from patients, as well as in vivo and in vitro models, looking for genes that were noticeably over- or under-expressed.

“The results were striking,” said Iichiro Shimomura, senior author of the study. Infection with SARS-CoV-2 affected the expression of insulin signalling pathway components in the lung, liver, adipose tissue, and pancreatic cells. These changes were attributed in part to activation of the interferon regulatory factor 1 gene (IRF1).

Further investigation showed that IRF1 expression is elevated in older patients, men, obese individuals, and patients with diabetes. The combined effects of older age, male sex, obesity and diabetes with SARS-CoV-2 means that the expression of IRF1 occurs at an increased rate, which may explain why these patients are more vulnerable to COVID-19.

In addition, patients who were critically ill with COVID-19 had higher IRF1 expression and lower insulin signalling pathway genes in their blood, compared to noncritical patients.

Given the devastating impact that COVID-19 can have on multiple organ systems, treatment strategies that could decrease the effect of the disease on blood sugar metabolism could be vitally important. By identifying patients at greater risk of experiencing these effects and intervening to decrease IRF1 activation, some of the severe consequences of COVID-19 could be avoided in susceptible populations, the researchers say.

There is no evidence to support the use of ivermectin for treating or preventing COVID-19 infection, according to a meta-analysis of 11 trials involving 3,409 people.

The drug, which is used to treat parasites such as scabies in humans, was screened in 2020 for activity against COVID-19. Laboratory tests suggested a weak effect on SARS-CoV-2 virus in a test-tube, but the dose required for humans would need to be so large it was dismissed as an option.

However, a number of small trials suddenly appeared in the literature, suggesting large effects on mortality. This caused an explosion of interest, with some groups lobbying for it to be used worldwide. Shortly after, several of these studies were shown to be fabricated; others had serious data errors and were poorly conducted.

In the light of these fake and poorly conducted studies, the new review reappraised eligible studies specifically in relation to research integrity. The authors only included randomised controlled trials that were registered in advance in registries meeting the WHO guidelines for clinical trial registration.

The researchers also investigated whether the studies had adequate ethics approval and if the results were plausible.

Overall, the review found no evidence to support the use of ivermectin for treating or preventing COVID-19 infection.

New research has shown the original SARS-CoV-2 viral strain was able to latch on to sugars called sialic acids found on the surface of human cells, a function that later strains did not retain.

This function in the early strain raises the possibility that this is how the virus first transferred from animals to humans. Subsequent variants do not have the ability to latch onto sialic acid and instead rely on receptors on their spikes proteins to attach to ACE2 receptors on human cells.

“Two of the ongoing mysteries of the coronavirus pandemic are the mechanisms behind viral transmission and the origins of the zoonotic leap,” said researcher Ben Davis of the Rosalind Franklin Institute at  Oxford University. “There is evidence that some influenza viruses can grab sialic acid on the surface of human host cells, and this has been seen in Middle Eastern Respiratory Syndrome (MERS), which is a coronavirus. Although SARS-CoV-2 variants of concern had not shown this mechanism, our research finds that the viral strain that emerged in early 2020 could use this as a way of getting into human cells.”

The binding mechanism is found on the end of the N-terminal domain, a part of the virus that evolves rapidly. The domain has previously been implicated in sialic acid binding but until the researchers at the Rosalind Franklin Institute applied high-resolution precision imaging and analysis this was unproven.

As to why the virus has discarded the sugar binding feature as it has evolved into new variants, Davis suggests it may be necessary for the initial zoonotic leap into humans from animals but can then be hidden until it is required again, particularly if the function is broadly detrimental to the virus’s mission of replication and infection within humans.

The finding correlates with evidence from the first wave in Italy. The Italian Genomics Consortium saw a correlation between severity of COVID-19 illness and genetics, as patients with a particular gene mutation that affects the type of sialic acid on cells were underrepresented in intensive care units. This suggested the virus was finding it easier to infect some genotypes compared to others.

“With our ultra-high precision imaging and new method of analysis we can see a previously unknown structure at the very end of the SARS-CoV-2 spike,” said James Naismith, director of the Rosalind Franklin Institute. “The amazing thing is that our finding correlates with what the Italian researchers noted in the first wave, suggesting that this was a key role in early infection.

A new mathematical modelling study has estimated COVID-19 vaccines reduced the potential global death toll during the pandemic by more than half in the year following their implementation, with 19.8 million out of a potential 31.4 million deaths prevented worldwide, according to estimates based on excess deaths from 185 countries.

The study estimates a further 599,300 lives could have been saved if the World Health Organisation’s target of vaccinating 40% of the population in each country with two or more doses by the end of 2021 had been met.

“Our findings offer the most complete assessment to date of the remarkable global impact that vaccination has had on the COVID-19 pandemic,” said Oliver Watson, lead author of the study, from Imperial College London.

Of the deaths estimated to have been prevented in the first year after vaccines were introduced, almost 7.5 million deaths were prevented in countries covered by the COVID-19 Vaccine Access initiative (COVAX), set up because it was clear early on that global vaccine equity would be the only way out of the pandemic.

“Our findings show that millions of lives have likely been saved by making vaccines available to people everywhere, regardless of their wealth,” said Watson. “However, more could have been done. If the targets set out by the WHO had been achieved, we estimate that roughly 1 in 5 of the estimated lives lost due to COVID-19 in low-income countries could have been prevented.”

Since the first COVID-19 vaccine was administered outside of a clinical trial setting on 8 December 2020, almost two thirds of the world’s population has received at least one dose of a COVID-19 vaccine. Despite the speed of the vaccine roll-out worldwide, more than 3.5 million COVID-19 deaths have been reported since the first vaccine was administered in December 2020.

“Quantifying the impact that vaccination has made globally is challenging because access to vaccines varies between countries, as does our understanding of which COVID-19 variants have been circulating, with very limited genetic sequence data available for many countries,” said Gregory Barnsley, co-first author of the study. “It is also not possible to directly measure how many deaths would have occurred without vaccinations. Mathematical modelling offers a useful tool for assessing alternative scenarios, which we can’t directly observe in real life.”

More than three quarters, or 15.5 million of deaths averted were due to the direct protection against severe symptoms provided by vaccination, leading to lower mortality rates. The remaining 4.3 million averted deaths were estimated to have been prevented by indirect protection from reduced transmission of the virus in the population and reduced burden on healthcare systems, thereby improving access to medical care for those most in need.

Vaccine impact changed over time and in different areas of the world as the pandemic progressed, the study found. In the first half of 2021, the greatest number of deaths averted by vaccination was seen in lower middle-income countries, resulting from the significant epidemic wave in India as the Delta variant emerged. This subsequently shifted to the greatest impact being concentrated in higher income countries in the second half of 2021, as restrictions on travel and social mixing were eased in some areas, leading to greater virus transmission.

Overall, the number of estimated deaths prevented per person was greatest in high income countries, reflecting the earlier and wider roll out of vaccination campaigns in these areas, with 66 deaths prevented per 10,000 people in high-income countries vs 2.711 deaths prevented per 10,000 people in low-income countries.

For the 83 countries included in the analysis that are covered by the COVAX commitment to affordable vaccines, an estimated 7.4 million deaths were averted out of a potential 17.9 million.