The coronavirus pandemic is disrupting universities and research institutes across the world. But the same institutions are also working very hard to find out how the disease can be stopped and its effects mitigated.
Follow this live blog for the latest updates on how the crisis is impacting research and innovation, and what governments, funders, companies, universities, associations and scientists are doing to stop or cope with the pandemic.
Despite all the controversy - and the accusation that SARS-CoV-2 escaped from the Wuhan Institute of Virology - the origin of the virus and how it was transferred into the human population remains unknown.
Now, scientists at Institut Pasteur have identified coronaviruses that are genetically similar to SARS-CoV-2, within bat populations in northern Laos. Their research, published as an accelerated preview in Nature suggests that these novel bat coronaviruses may have the potential for infecting humans.
Lead author Marc Eloit and colleagues tested 645 bats, belonging to 6 families and 46 species, living in limestone caves in northern Laos.
They found three viruses that they considered to be closely related to SARS-CoV-2, with the genetic sequences encoding the ACE2 binding regions by which SARS-CoV-2 enters human host cells similar to that of SARS-CoV-2.
These bat viruses were able to bind to human ACE2 receptors more efficiently than the original Wuhan SARS-CoV-2 strain isolated from humans. One of these viruses was also shown to replicate within human cell lines, but was inhibited by antibodies that neutralise SARS-CoV-2.
The findings support the hypothesis that SARS-CoV-2 could have originated from bats living in the limestone caves of Southeast Asia and southern China.
This is the first time that SARS-CoV-2 progenitor bat viruses genetically close to SARS-CoV-2 and able to enter human cells through the ACE2 pathway have been identified. The ACE2 receptor binding domains of these viruses differ from that of SARS-CoV-2 by only one or two residues at the interface with ACE2.
“Our findings therefore indicate that bat-borne SARS-CoV-2-like viruses potentially infectious for humans circulate in [bats] in the Indochinese peninsula,” the researchers conclude.
Among the casualties of the COVID-19 pandemic, one that has not been highlighted to date is biomedical research not directly related to the pandemic and SARS-CoV-2.
The extent of the impact on other fields of research is seen in a new analysis carried out by researchers at the IMT School for Advanced Studies in Lucca, Italy. They looked at papers that appeared on the PubMed search engine for published research between the beginning of 2018 and the end of 2020, showing that COVID-19 profoundly affected and shifted priorities in the biomedical field.
While publications related to all the aspects of the pandemic skyrocketed, publications, clinical trials, and grants in subjects not directly related to COVID-19 decreased by up to 25% compared to the pre-COVID era, a phenomenon referred to as the ‘Covidisation’ of research.
To conduct their analysis, Massimo Riccaboni, professor of economics at the IMT School, and Luca Verginer, now a post-doc at the ETH Zürich, analysed more than 34 million biomedical citations on PubMed, developing an index of keywords related to COVID-19. One example is anosmia, loss of the sense of smell, which quickly emerged as a major symptom of infection.
In the first three months of the pandemic, the number of scientific papers about COVID-19 was five times higher than the number of articles on H1N1 swine influenza. The term betacoronavirus skyrocketed from 2019 to 2020, while alphacoronavirus - a different genus from SARS-CoV-2 - did not experience any growth.
Medical terms not related to COVID-19 appeared less and less frequently in the scientific literature, with a fall of between 10 – 13% in the number of papers, and in their impact factor of almost 20%.
Another effect emerged from the analysis, with grants assigned in the 2018 pre-COVID era, diverted to support COVID-19 related research, as seen from the number of publications linked to those grants.
The Italian researchers did not coin the term ‘Covidisation’ of research, but their analysis reveals the magnitude and proportions of this shift for the first time. “The overall picture that emerges is that there has been a profound realignment of priorities and research efforts, with the entirety of medicine focused on COVID-19,” said Riccaboni.
“While this effort and the mobilisation of the scientific community brought us vaccines, this shift in fact also displaced biomedical research in the fields not related to COVID-19, bringing other undesired consequences,” he said.
This phenomenon adds to other negative impacts of COVID-19 on research, such as the record number of studies suspended, the toll on women and early-career scientists, and the questionable quality of methods and data gathered in fast-tracked, small scale clinical trials.
A pilot study suggests that many of the symptoms connected to long COVID could be linked to the effect of the virus on the vagus nerve.
One of the most important multi-functional nerves in the body, the vagus nerve extends from the brain to the torso and into the heart, lungs and intestines, as well as several muscles, including those involved in swallowing.
It is responsible for a wide variety of functions including controlling heart rate, speech, the gag reflex, moving food through the intestines, sweating, and many others.
The researchers propose SARS-CoV-2-mediated vagus nerve dysfunction could explain long COVID symptoms, including dysphonia (persistent voice problems), dysphagia (difficulty in swallowing), dizziness, tachycardia (abnormally high heart rate), low blood pressure and diarrhoea.
This is based on morphological and functional evaluation of the vagus nerve in cohort of long COVID patients with symptoms that are known to be related to its dysfunction.
In 22 patients in the study, the most frequent vagus nerve damage-related symptoms were diarrhoea, tachycardia, dizziness, dysphagia, dysphonia, and low blood pressure. Almost all had at least three vagus nerve dysfunction-related symptoms.
In this pilot evaluation, most long COVID subjects with vagus nerve dysfunction symptoms had a range of significant, clinically-relevant, structural and/or functional alterations in their vagus nerve, including nerve thickening, trouble swallowing, and symptoms of impaired breathing, the researchers said. “Our findings so far thus point at vagus nerve dysfunction as a central pathophysiological feature of long COVID.”
A number of existing strains of SARS-CoV-2, and possible future variants that could arise, have the potential to escape the immune system’s cytotoxic T cell response in some of the population, according to a computational modelling study conducted by Antonio Martín-Galiano and colleagues at the Carlos III Health Institute in Madrid.
The T cell response is encoded by HLA (human leukocyte antigen) genes which show the greatest diversity of any genes in humans. As a result, different individuals have different HLAs that lock onto SARS-CoV-2 based on the motifs of different epitopes on the surface of the virus.
The thousands of different HLA types in the human population and the thousands of epitopes on SARS-CoV-2, make it difficult to directly evaluate the immune response of every human HLA to every viral variant by in vitro screening.
Instead, using bioinformatics techniques, the researchers first determined the full set of epitopes from the original reference strain of SARS-CoV-2 from Wuhan, China.
They found 1,222 epitopes of SARS-CoV-2 were associated with the 12 major HLA subtypes that cover around 90% of the human population. That means at least 9 out of every 10 people can launch a T cell response to COVID-19 based on these 1,222 epitopes.
However, SARS-CoV-2 has gathered thousands of mutations since it was first characterized late in 2019. The researchers computationally analysed whether any of almost 118,000 different SARS-CoV-2 isolates from around the world had mutations in the epitopes seen on the Wuhan strain. They showed 47% of the epitopes were mutated in at least one isolate.
In some cases, existing virus isolates had mutations in multiple epitope regions. However, these cumulative mutations never affected more than 15% of epitopes for any given HLA type.
The distribution of different HLA types varies by geography and when susceptible HLAs were cross-referenced with the geographic origin of their respective escape isolates, it was shown they co-existed in some geographical regions, including sub-Saharan Africa and East and Southeast Asia. That suggests there is potential genetic pressure on the T cell response in these areas.
“The accumulation of these changes in independent isolates is still too low to threaten the global human population,” the researchers said. But they added, “Our protocol has identified mutations that may be relevant for specific populations and warrant deeper surveillance.”
In addition, Martín-Galiano notes that “unnoticed SARS-CoV-2 mutations” might in future “threaten the cytotoxic T response” in some populations.
In the popular understanding, mutations of the SARS-CoV-2 virus are associated with the emergence of virus variants that are more contagious and pathogenic than their predecessors.
However, a new study shows that virus mutations often work in the opposite direction.
Virology researchers at the University of Gothenburg’s Sahlgrenska Academy have mapped mutation patterns in the SARS-CoV-2 and shown that a naturally occurring human enzyme ADAR1 (adenosine deaminases acting on RNA), can cause mutations that impairs the virus’ ability to replicate.
ADAR1 in the membrane of human cells can induce mutations in nucleotides that form the building blocks in the RNA of the virus.
“Our study shows that there is an inverse relationship between the viral load and the extent to which ADAR1 has mutated the virus. We also found that ADAR1-induced mutations are the most common type of SARS-CoV-2 mutation,” said virologist Johan Ringlander.
In particular, the scientists noted that individual patients are often infected with more than one variant of the virus. When mutations in relatively rare virus variants were investigated, it was found that a common mutation induced by ADAR1, in which one nucleotide, guanosine, replaces another, adenosine, significantly worsened the reproductive ability of SARS-CoV-2.
Analyses of more than 200,000 virus strains from patients who were ill with COVID-19 showed that mutations caused by ADAR1 were mainly circulating in summer 2020, when transmission and mortality rates were low in Europe. When transmission and mortality rates were higher, virus variants with ADAR1-induced mutations were uncommon, probably because they were outcompeted by more infectious virus strains.
The results clarify how human host cells can generate mutated virus variants. “Mutations can make a virus more infectious, but in most cases the mutations we’ve studied make the virus weaker; instead of spreading, it’s removed from infected cells. These findings suggest that ADAR1 serves as a protective mechanism used by the body to limit viral infections,” Ringlander said.
“When SARS-CoV-2 multiplies in the airways, inflammation occurs. Its effects include activation of ADAR1, which in turn reduces the likelihood of the virus infecting other cells, said lead author Michael Kann, professor of clinical virology at Sahlgrenska Academy. “We’re currently investigating whether this protective mechanism may be important in other viral infections as well,” Kann said.
The first research definition of what is meant by Long-COVID in children and young people has been formally agreed, following a UK government-funded study to map the symptoms.
The definition sets out what should be measured; the next stage of the research project is to reach consensus on how to make these measurements.
The definition will be important in providing an internationally agreed standard that can be used to measure outcomes in clinical trials of potential treatments. Currently, the lack of such agreement means that data collection is inconsistent, making it hard to assess efficacy.
The definition in children and teenagers closely complements that proposed by the World Health Organisation for Long COVID in adults, and if widely adopted, will substantially help strengthen the evidence base on this debilitating condition, say the researchers.
The slew of definitions currently used, all of which differ in number, type, and duration of symptoms has contributed to the very wide reported variations in the estimated prevalence of Long COVID in children of 1% to 51%.
A consistently applied definition of Long COVID will enable researchers to reliably compare and evaluate studies on prevalence, disease course, and outcomes, providing a more accurate picture on the true impact of the condition.
Consensus was reached among a representative panel of 120 international experts skilled in health service delivery (47), research (50), and lived experience (23).
The research definition of Long COVID in children and young people is as follows:
- A condition in which a child or young person has symptoms (at least one of which is a physical symptom) that:
- Have continued or developed after a diagnosis of COVID-19 (confirmed with one or more positive COVID tests)
- Impact their physical, mental or social wellbeing
- Are interfering with some aspect of daily living (eg, school, work, home or relationships) and
- Persist for a minimum duration of 12 weeks after initial testing for COVID-19 (even if symptoms have waxed and waned over that period)
These translate into, “Post-COVID-19 condition occurs in young people with a history of confirmed SARS CoV-2 infection, with at least one persisting physical symptom for a minimum duration of 12 weeks after initial testing that cannot be explained by an alternative diagnosis. The symptoms have an impact on everyday functioning, may continue or develop after COVID-19 infection, and may fluctuate or relapse over time.”
The study has been accepted by the journal Archives of Disease in Childhood, but is yet to be published.
Scientists at Ludwig-Maximilians-Universitaet in Munich, Helmholtz Munich, and Technical University of Munich have shown that the immune system is capable of neutralising the Omicron variant of SARS-CoV-2 after three exposures to the spike protein of the virus.
In a paper in Nature Medicine, they show this level of exposure leads to production of a high quantity of high quality neutralising antibodies that have high affinity for the spike protein.
This was the case in people who had received three doses of vaccine, people who had recovered from COVID-19 and then had two vaccinations, and to double-vaccinated people who then had a breakthrough infection.
The longitudinal study involved 171 participants who are members of staff at the University Hospital, who have been regularly tested for COVID-19. The researchers identified individuals who had contracted SARS-CoV-2 during the first wave of the pandemic in spring 2020, and compared them to a second group of people who had not been infected. Subsequently, both groups were vaccinated and monitored for almost two years. The cohort included 98 people who had a natural infection and 73 who had not.
The longitudinal study made it possible to follow how the immune response evolves over time against the virus and after vaccination. It was shown that the ability of the immune system to neutralise the virus correlates only weakly with the amount of neutralising antibodies. Rather, the critical factor was how effectively these antibodies bind to the virus and block infection.
Omicron exhibited the most pronounced evasion from neutralising antibodies compared to all other viral variants tested and three separate exposures to the spike protein are needed to build up high-level neutralising activity against this newest variant of concern.
SARS-CoV-2 infection has little effect on some people, while others develop life-threatening COVID-19 symptoms. But although it is known that severe disease is marked by strong activation of the immune system, it is not known exactly why symptoms and disease severity vary so significantly.
A team of German scientists has now discovered that a hallmark of severe COVID-19 is damage to the endothelial cells that line the blood vessels.
By studying 25 patients with severe COVID-19 and 17 recovered patients in the intensive care unit, the scientists were able to prove that the severity of disease is linked to disruption of the endothelial barrier and to identify seven proteins in blood that are biomarkers of a severe form of COVID-19.
They also showed that recovery was dependent on the regeneration of damaged endothelial cells.
In addition to enabling patients to be triaged according to their risk of severe disease, the biomarkers are potential targets for COVID-19 therapies.
The team now wants to investigate which elements of the immune system lead to damage to the endothelium and if there are indicators of which patients will suffer from Long-COVID.
The level of protection COVID-19 vaccines provide against infection quickly wanes, though they continue to protect against severe disease, according to a nationwide, registry-based study performed by researchers at Umeå University, Sweden, published in The Lancet.
“The bad news is that the protection against infection seems to be diminished by seven months after the second dose of vaccine,” says Peter Nordström, professor of geriatric medicine at Umeå University. “The good news, however, is that the protection against a severe infection that leads to hospitalisation or death seems to be better maintained.”
The study included almost 1.7 million individuals, with the results then confirmed in an even larger population of almost 4 million individuals. It showed protection against infection of any severity waned progressively following the peak of protection, which occurred a month after the second dose.
Protection against severe disease was 89% after one month and 64% from four months and onwards during follow-up of nine months. There was some evidence to suggest a lower level of protection in the oldest individuals.
Anna Nordström, adjunct professor in public health at Umeå University and co-author of the study said a key strength of the study is the long follow-up and it was done in a real-world setting based on the total population of Sweden. “This increases the possibility to generalise the results to other countries with similar population structure as in Sweden,” she said.
The world’s first human challenge study in which healthy volunteers were deliberately infected with the SARS-CoV-2 virus in controlled conditions has shown this is safe.
That sets the scene for other human challenge studies to be used in efficacy studies of vaccines, antiviral drugs and diagnostics, according Open Orphan, the Dublin-based contract research organisation that ran the trial.
The aim was to find the lowest dose of nasally administered SARS-CoV-2 that reliably caused a low level infection, enabling the testing of drugs and vaccines.
Among the 18 of 34 volunteers who contracted COVID-19, there were no serious symptoms. Sixteen of the 18 had mild cold like symptoms, while the other 16 volunteers did not become infected.
The data supports the safety of the infection challenge model for assessing vaccines and therapies, Open Orphan said. Similar challenge studies are routinely used in testing treatments for other respiratory diseases, including flu and respiratory syncytial virus infections.
The human challenge study was funded by the UK government and carried out at the Royal Free Hospital in London. The research is continuing, to adapt the model for emerging variants of SARS-CoV-2 and to reflect the fact that unlike the volunteers in this first study, most of the UK population has now been vaccinated or had a natural infection.
Andrew Catchpole, chief scientist at hVivo, the unit of Open Orphan that oversaw the study, and co-investigator on the trial said, “Importantly the study demonstrated that SARS-CoV-2 challenge studies are safe and well tolerated by the volunteers with no serious symptoms and no serious adverse events.”
While the study used the original SARS-CoV-2 strain, and there are differences in transmissibility between it and the other variants, the same factors will be responsible for protection against it, meaning the findings remain valuable for variants such as Delta or Omicron, Catchpole said. “These data provide a clear platform to now utilise the human challenge model to expedite product efficacy testing for new vaccines or antivirals.”
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