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

Two studies published in the journal Science use complementary approaches, involving spatial, environmental and molecular analyses, to provide evidence that the Huanan seafood market in Wuhan, China, was the early epicentre for the COVID-19 pandemic.

The scientists conclude it was very likely that SARS-CoV-2 was present in live mammals sold at this market in late 2019 and suggest the virus spilled over into people working or shopping there from two separate zoonotic transmissions, in which lineage A and B progenitor viruses were both circulating in non-human mammals prior to their introduction into humans.

The authors of both studies say future research should be focused on better understanding events preceding of the introduction of SARS-CoV-2 to the market, including where the wild mammals for sale at Huanan came from, to lower the risk of future pandemics.

Despite the observation that most of earliest known COVID-19 cases that were flagged by hospitals in Wuhan in December 2019, were linked to the Huanan market, this did not definitively establish the market as the trigger for the pandemic.

Indeed, two authors named on both of the papers had previously said they thought the pandemic could have been sparked by the accidental release of the virus from the Wuhan Institute of Virology.

Both say their opinions have changed as result of detailed re-analyses of data collected immediately after the initial outbreak in Wuhan.

“While the exact circumstances remain obscure, our analyses indicate that the emergence of SARS-CoV-2 occurred via the live wildlife trade in China, and show that the Huanan market was the epicentre of the COVID-19 pandemic,” concludes the paper which re-examined epidemiological data.

To test the hypothesis the market was the epicentre as the pandemic’s epicentre, the researchers used mapping tools to estimate the longitude and latitude locations of more than 150 of the earliest reported virus cases from December 2019, including those without reported direct links to the market.

The highest density of these early cases centred around the Huanan market. Then, by mapping cases from January and February 2020 using data from the social media app Weibo, which had set up a channel for people with COVID-19 to seek medical help, the researchers identified cases in other parts of central Wuhan radiating from the market as the pandemic progressed.

Using social media data, the researchers ruled out the many other locations in Wuhan, a city of 11 million, that would have been equally or more likely than the market to sustain the first cluster of a new respiratory pathogen.

They also had access to data showing multiple plausible intermediate animal hosts of SARS-CoV-2 progenitor viruses were sold live at the Huanan market until at least November of 2019. Using data from swabs taken from surfaces in the market, the researchers identified five market stalls that were likely to have been selling live or freshly butchered mammals. The proximity to such live mammal vendors was predictive of human virus cases.

Further increasing understanding of the pandemic's origin, the second paper reports an analysis of the genomic diversity of SARS-CoV-2 early in the pandemic.

While the diversity of SARS-CoV-2 increased as the pandemic spread from China to other countries, two lineages of SARS-CoV-2 – designated A and B – marked the beginning of the COVID-19 pandemic in Wuhan.

Only lineage B was represented in the eleven sequenced genomes from humans directly associated with the Huanan market, while the earliest lineage A genomes from humans lacked any known contact to the market, but were sampled from humans who lived close by.

It has been hypothesised that the two lineages emerged separately and this was confirmed by the analysis, with lineage B first appearing in humans no earlier than late October 2019 and likely in mid-November 2019, and lineage A being introduced within days to weeks of this event.

These findings indicate that it is unlikely that SARS-CoV-2 circulated widely in humans prior to November 2019 and define the narrow window between when SARS-CoV-2 first jumped into humans and when the first cases of COVID-19 were reported, the researchers say.

Researchers at the Francis Crick Institute in London have shown that a specific part of the SARS-CoV-2 spike protein is a promising target for a pan-coronavirus vaccine that could offer some protection against new virus variants and the common cold - and help prepare for future pandemics.

As the latest wave of COVID-19 infections caused by the Omicron variant demonstrates, the frequent mutations seen in the SARS-Cov-2 virus is undermining the level of protection provided by vaccines that were designed to combat the original virus that emerged in Wuhan, China.

These existing vaccines trigger antibodies against the S1 sub unit of the spike protein via which SARS-CoV-2 latches on to human host cells.

There has been little attention to the S2 subunit of the spike protein, despite the fact that its structure is similar across a number of coronaviruses, and that it is less subject to mutating.

The Crick researchers investigated whether antibodies that target the S2 subunit would also neutralise other coronaviruses. Mice vaccinated with a vaccine against S2 generated antibodies that were able to neutralise a number of other animal and human coronaviruses, including the seasonal common cold coronavirus, the original Wuhan strain of SARS-CoV-2; the D614G mutant that dominated in the first wave; the Alpha, Beta, Delta and BA-1 and BA.2 Omicron variants; and two bat coronaviruses.

“The S2 area of the spike protein is a promising target for a potential pan-coronavirus vaccine because this area is much more similar across different coronaviruses than the S1 area,” said Kevin Ng, of the Crick’s Retroviral Immunology Laboratory at the Crick. “It is less subject to mutations, and so a vaccine targeted at this area should be more robust.”

The expectation for a vaccine that targets S2 is that it could offer some protection against all current, as well as future, coronaviruses. This differs from vaccines that target the more variable S1 area which, while effective against the matching variant they are designed against, are less able to target other variants, or a broad range of coronaviruses.

The S2 sub unit of the spike protein has, until recently, been overlooked because certain critical targets are only revealed after the virus has bound to a cell. As a result, there may be a narrower window of opportunity for S2 antibodies to neutralise the virus than is the case for antibodies that target the S1 sub unit.

While a potential S2 vaccine would not stop people being infected, the idea is it would prime their immune system to respond to a future coronavirus infection. This would hopefully provide enough protection to survive an initial infection during which they could develop further immunity specific to that particular virus.

The researchers say they are continuing to study the potential of a pan-coronavirus that targets the S2 area of the spike protein and how it could be integrated with licenced vaccines.

The European Medicines Agency has started to review the data for a potential new treatment for COVID-19 in advance of the manufacturer applying for marketing approval.

The drug, sabizabulin has shown a beneficial effect in a study involving hospitalised patients with moderate-to-severe COVID-19 who were at high risk of acute respiratory distress syndrome and death, with the results indicating it reduces deaths compared to placebo.

Although the developer, US biotech Veru, has not applied for marketing approval or a rolling review, EMA’s assessment is intended to inform member states which are considering use of sabizabulin before authorisation.

This review is the first to be triggered under the new EU regulation that expanded the role of EMA during public health emergencies.

Sabizabulin works by disrupting microtubules, which form part of the internal skeleton in cells. These microtubules play a role in helping SARS-CoV-2 enter and leave human host cells. By binding to parts of the microtubules, sabizabulin limits the replication and spread of the virus.

Sabizabulin is also expected to supress some inflammatory responses that occur following infection with SARS-CoV-2, including reactions that can lead to acute respiratory distress syndrome and death.

The review of sabizabulin was started on 27 July 2022 following a request from Germany.

Twenty-one different COVID-19 variants were effectively neutralised after a third booster dose of COVID-19 vaccine, according to a new UK study.

While the results indicate that immunity from infection by the SARS-CoV-2 virus decreases 20 weeks after receiving two doses of vaccine, a third booster dose, in this case of the Pfizer/BioNTech vaccine, revived the immune system, enabling to neutralise 21 different variants.

The researchers used an antigenic map developed by scientists at Surrey University, to measure how each variant impacted the immune system.

They analysed 72 blood samples from 37 individuals, aged 70 – 89 years, vaccinated with two doses of Pfizer/BioNTech vaccine, for neutralising antibody responses to the original strain of SARS-CoV-2 that was first detected in Wuhan, China.

Between 3 and 20 weeks after the second vaccine dose, neutralising antibody levels fell 4.9-fold to a median of 21.3, with 21.6% of individuals having no detectable neutralising antibodies at the later time point.

Next, the researchers examined neutralisation of 21 distinct SARS-CoV-2 variant spike proteins by these blood samples and confirmed there was substantial antigenic escape, especially for the Omicron, Delta and Beta variants.

However, following administration of a third booster dose, neutralising antibody levels increased, providing cross-protection against Omicron BA.1 and BA.2. The researchers say that despite SARS-CoV-2 immunity waning over time in older adults, booster vaccines are able to elicit broad neutralising antibodies against a large number of SARS-CoV-2 variants in this clinically vulnerable cohort.

"Understanding how the levels of neutralising antibodies relate to a well-defined immune response will be an important step in understanding how the immune system responds to SARS-CoV-2 and could also help in the management of COVID-19,” said researcher Dalan Bailey.

"This information could help us to understand whether the risk of breakthrough infections, hospitalisation and death is increased by waning immunity or new variants. Research comparing immune responses to different SARS-CoV-2 variants and understanding the role of different mutations is vital,” Bailey said.

The viral spike protein by which SARS-CoV-2 enters human cells has changed at more than 50 sites in the Omicron variant that is causing the current wave of infections, compared to the original virus first identified in Wuhan, China.

As a consequence, the antibodies formed after an infection or vaccination do not recognise these variants as efficiently. That means despite having overcome an infection, people can again become infected with the Omicron variant, and that there are breakthrough infections in people who are vaccinated.

Researchers in Frankfurt headed by Marek Widera and Sandra Ciesek from the Institute for Medical Virology at the University Hospital of the Goethe University, have examined how long antibodies present in blood after a vaccination or recovery from an infection are able to neutralise the virus variants Omicron BA.1 and BA.2.

They collected blood samples from people who had been vaccinated twice or three times.

Six months after the second vaccination, the blood samples had practically no neutralising effect on the Omicron variants BA.1 and BA.2.

The effect of a booster vaccination also declined rapidly. Although there was very good protection shortly after the booster vaccination, three months later the protective effect was very weak and the samples were no longer capable of neutralising BA.1 and BA.2.

The in vitro data does not allow any conclusions to be drawn about the severity of COVID-19, because it takes no account of the cellular immune response.

However, the results do pose a problem for the use of monoclonal antibodies as a precautionary measure in patients with compromised immune systems. For three such monoclonal antibodies studied in the lab, the level of efficacy was very heavily dependent on the virus variant.

SARS-CoV-2 has been associated with a range of symptoms in the immediate aftermath of infection, but now a retrospective UK study has catalogued previously reported and new symptoms non-hospitalised adults are suffering from more than three months after infection, and the risk factors associated with developing these persistent symptoms.

The researchers at Birmingham University matched the primary care records of 486,149 adults with confirmed SARS-CoV-2 infection, to the records of 1,944,580 adults with no recorded evidence of SARS-CoV-2 infection.

The outcomes included 115 individual symptoms, as well as Long COVID, which is defined as a composite outcome of 33 symptoms by the World Health Organisation clinical case definition.

A total of 62 symptoms were significantly associated with SARS-CoV-2 infection after 12 weeks. The largest associations were for anosmia (loss of smell), hair loss, sneezing, ejaculation difficulty and reduced libido.

Among the cohort of patients infected with SARS-CoV-2, risk factors for Long COVID included female sex, belonging to an ethnic minority, socioeconomic deprivation, smoking, obesity and a wide range of comorbidities.

A key strength of the study is the large sample size. This provided the statistical power to assess differences in the reporting of a wide range of symptoms between the two cohorts and estimation of the association between reporting of symptoms and important sociodemographic and clinical risk factors with a high level of precision, the researchers say

Researchers at the Medical University of Vienna have developed a blood test that measures cellular T-cell immunity to SARS-CoV-2 in just 48 hours. That compares to the current test which takes up a week to process.

They say the test will be particularly relevant for assessing the immune status of vulnerable patients, whose weakened immune systems mean they do not mount a meaningful antibody response.

Using the test, it is possible to tell if immunity is the result of vaccination or natural infection.

The new test is based on the memory response of T cells to three different mixtures of peptides from COVID-19 patients.

T cells are an important part of the specific cellular immune defence, eliminating cells that are infected with SARS-CoV-2 and supporting antibody production by B cells. "Currently, it takes at least a week to perform and evaluate such T-cell tests, and the tests can only be performed in specialised laboratories. In contrast, our newly developed test is performed directly with a whole blood sample and can be evaluated after only 48 hours," said study leader Winfried Pickl.

In the study, T-cell responses were measured at ten weeks and ten months after infection with SARS-CoV-2. It was shown that T-cell responses were as strong at ten months, as at ten weeks after an infection.

The researchers say this is remarkable because antibody levels dropped significantly ten months after infection. This long-lasting T-cell response may protect against severe disease in the event of re-infection with SARS-CoV-2.

Protection against severe COVID-19 provided by two doses of the Pfizer/BioNTech or AstraZeneca COVID-19 vaccine remained high up to six months after second doses, according to an analysis of health record data of over seven million adults in the UK.

The study found that protection was maintained in older adults aged over 65 years, and in clinically vulnerable adults.

Using linked general practitioner, hospital, and COVID-19 records on 1,951,866 adults who had received two doses of Pfizer/BioNTech, 3,219,349 adults who had two doses of AstraZeneca vaccine and 2,422,980 people who were unvaccinated, researchers were able to provide a clearer picture of vaccine effectiveness against COVID-19 hospital admission, COVID-19 death, and a positive SARS-CoV-2 test.

Rates of COVID-19 hospital admission and COVID-19 deaths were substantially lower among vaccinated than unvaccinated adults up to six months after their second dose. Vaccine effectiveness was at least 80% for Pfizer/BioNTech, and at least 75% for AstraZeneca.

But while protecting against severe disease, waning vaccine effectiveness against infection with SARS-CoV-2 meant that vaccinated people were about as likely to get infected as people who were unvaccinated by six months after the second dose.

Elsie Horne, senior research associate in medical statistics at Bristol University’s Medical School, the study’s lead author, said, “Until now there has been limited and conflicting evidence relating to the rate of waning following second dose of COVID-19 vaccines, whether it extends to severe COVID-19, and whether the rate differs according to age and clinical vulnerability.”

“Although we found that protection against severe COVID-19 provided by two doses of vaccine wanes over time, the very high initial protection means that, despite waning, protection remains high six months after the second dose. This finding was consistent across all adults, including older adults and those who are at risk of severe COVID-19.”

The rate at which vaccine effectiveness waned was consistent across subgroups defined by age and clinical vulnerability.

Studying how long COVID-19 vaccines is important for scheduling and targeting of booster vaccinations.

The researchers now plan a follow-up study looking at vaccine effectiveness up to one year post-second dose, and against Omicron variant.

European Commission has cut its order for Valneva’s whole-virus COVID-19 vaccine, VLA2001, from 60 million to 1.25 doses, with the option to purchase an equivalent quantity later this year for delivery in 2022.

The first vaccine doses will be delivered to Germany, Austria, Denmark, Finland and Bulgaria in the coming weeks.

Valneva is late to the party, with its product only receiving approval in June, but the company was hoping that as a traditional whole virus vaccine, it would find a niche market in people who chose not to be vaccinated with mRNA or viral vectored vaccines.

Thomas Lingelbach, CEO of Valneva said, “We welcome the fact that the European Commission has decided not to terminate the advance purchase agreement, although we feel the order volume does not reflect the interest we see from European citizens. Despite this, we have decided to enter into this amendment to make our vaccine available to the Europeans who have been waiting for it. “

While the pandemic had been declining, the latest COVID-19 wave in Europe clearly underlines the need for alternative vaccines, Lingelbach said. “Fifteen per cent of Europeans over 18 are not yet vaccinated and we continue to receive messages from Europeans who are awaiting a more traditional vaccine technology. Recent market studies conducted in several EU member states suggest that making our inactivated vaccine available in Europe could increase vaccine uptake and have a meaningful impact on public health.”

VLA2001 is the first COVID-19 vaccine to receive a standard marketing authorisation, as opposed to emergency use authorisation in Europe.

Skin swabs have been shown to be "surprisingly effective" at identifying COVID-19, pointing the way to a non-invasive diagnostic test.

Researchers at Surrey University used swabs to collect sebum, the oily, waxy substance produced by the sebaceous glands, from 83 hospitalised patients, some of whom were diagnosed with COVID-19. They also collected blood and saliva samples for this comparative study.

Melanie Bailey, co-author of a paper describing the research said, "COVID-19 has shown us that rapid testing is vital in monitoring and identifying new illnesses. In our research, we explored the relationships between different biofluids, and what changes in one part of the human body can tell us about the overall health of a patient.”

Blood was the most accurate way of testing for the virus, but skin swabs were not too far behind “In fact, the skin swab results were surprisingly accurate," Bailey said.

COVID-19 significantly change the makeup of lipids in biofluids such as blood and sebum.

By measuring changes in lipids and other metabolites of the samples, the research team observed that blood samples scored 0.97 of a possible 1.0, while skin swab tests scored 0.88, and saliva tests 0.80.

Matt Spick, a co-author said, “Our research suggests that skin sebum responds to changes to the immune system in COVID-19 patients. In fact, we believe that illness can alter the body’s natural balance across the whole range of biological systems, including skin, digestive health and others.