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

A lack of glove changes at COVID-19 testing centres in Belgium led to major cross-contamination of samples and a high rate of false positive results, according to research presented at the European Congress of Clinical Microbiology & Infectious Diseases in Lisbon this week.

The need for rapid roll-out of large-scale PCR testing for COVID-19 presented a number of logistical challenges, including a scarcity of personnel adequately trained to do nasopharyngeal swabbing.

Research from a government-funded lab in Belgium has identified inadequate management of personal protective equipment in testing centres as a source of major cross-contamination.

Scientists at the COVID-19 Federal Platform, Department of Laboratory Medicine UZ Leuven, were alerted to the problem in September 2021 when they noticed that 70% of samples taken that day at a testing centre in Brabant, Flanders, had tested positive for COVID-19. The average positivity rate at the time was around 5-10%.

Of the positive samples, 90% had a very low viral load, which hinted that they had been contaminated with the SARS-CoV-2 virus, rather than being true positives. 

The results were withheld and an investigation into the cause of the spike in positive samples carried out.

“After excluding lab contamination, we arranged the results from that day in chronological order by time of sample collection,” said lead researcher Bram Slechten. “We saw that no one had tested negative after a sample was collected from a patient with a very high viral load.

This led them to identify lack of glove changing, in combination with high-paced collection of samples by someone who was new to the job, and the breaking of a swab, as the likely source of the contamination.

Protocols were tightened up overnight and all those whose results were withheld were recalled for a new sample the next day, with all testing negative.

To assess the scale of the problem, Slechten and colleagues retrospectively checked four months of results, from June-Sept 2021, of PCR tests from 11 testing centres for false positives.

The analysis identified potential cross-contamination events in 73% (8/11) of the test centres. The percentage of samples suspected of being wrongly reported as positive widely varied each day and for each centre.   The four-month average ranged from 0% to 3.4% per testing centre.

The highest number of false positives at one testing centre on a single day was 77 of 382 tests, 20% of people tested. 

Site visits confirmed a lack of glove changes between one patient and the next as being the source of cross-contamination.

“If the staff didn’t change gloves between each patient, it was almost certain that contamination would occur,” said Slechten. “We identified four reasons why changing of gloves didn’t happen: it was simply not in the protocol; correct protocol was in place but it was not followed due to lack of training of new members of staff; not having the right size of glove available; and work pressure - some swabbers had to sample one patient every two minutes.”

More rigorous policies were put in place at all 11 testing centres from the end of October 2021, in response to the study results.

Follow-up of one test centre revealed the impact. Before the intervention, it had a daily positivity rate of 11% and an average false positivity rate of 3.4%. But occasionally, the false positive rate rose to 20%.  After the intervention, the false positive rate fell to almost zero.

Slechten believes the false positives artificially inflated the COVID-19 case numbers for Belgium, but said, “It is hard to put a number on it however, because we saw a lot of differences between the test centres we studied.  In addition, we only looked at test centres in one part of Belgium, making it hard to get the whole picture.”

It is very probable that this same cross contamination also occurred in other countries.

“While I don’t have detailed knowledge of the protocols in testing centres in other countries, the focus is generally on potential events within the lab environment. However, our research provides a perfect example of the importance of looking beyond the lab and keeping an eye on the entire testing chain,” Slechten said.

The possible toll of long COVID is highlighted in a new UK study of more than 2,000 patients who were hospitalised with COVID-19, which shows that a year after having COVID-19, only around one in four patients feel fully well again.

The research, presented at the European Congress of Clinical Microbiology & Infectious Diseases in Lisbon this week and published in the Lancet Respiratory Medicine, shows being female, being obese and having had mechanical ventilation in hospital were all associated with a lower probability of feeling fully recovered at one year.

The most common ongoing long-COVID symptoms were fatigue, muscle pain, physically slowing down, poor sleep, and breathlessness.

The researchers used data from the post-hospitalisation COVID-19 (PHOSP-COVID) study which assessed adults who had been hospitalised with COVID-19 across the UK. Patients from 39 hospitals were included, who agreed to five-month and 1-year follow-up assessments in addition to their clinical care.

Recovery was assessed using patient-reported outcome measures, physical performance, and organ function at 5 months and 1 year after hospital discharge. The researchers also took samples of participants’ blood at the five month visit to analyse it for the presence of various inflammatory proteins.

A total of 2,320 participants discharged from hospital between March 7, 2020, and April 18, 2021, were assessed at 5 months after discharge and 807 completed both the 5-month and 1-year visits at the time of analysis (the study is ongoing). 

These 807 patients had a mean age of 59 years, 279 were women and 28% received invasive mechanical ventilation. The proportion of patients reporting full recovery was similar between 5 months at 26% of 1,965 and 1 year, at 29% of 804.

In an earlier publication from this study the authors had identified four clusters of symptom severity at five months, which were confirmed by this new study at one year.

“The limited recovery from 5 months to 1 year after hospitalisation in our study across symptoms, mental health, exercise capacity, organ impairment, and quality-of-life is striking,” said researcher Louise Wain of the National Institute for Health Research at Leicester University. “No specific therapeutics exist for long COVID and our data highlight that effective interventions are urgently required,” she said.

Without effective treatments, long COVID could become a highly prevalent new long-term condition, the researchers said.

New research presented at the European Congress of Clinical Microbiology & Infectious Diseases in Lisbon this week shows that a longer interval between primary COVID-19 vaccine doses can boost antibody production up to nine-fold.

To find out factors affecting antibody responses following Pfizer/BioNTech vaccination, Ashley Otter and colleagues at the UK Health Security Agency (UKHSA) measured antibody levels in blood samples taken from almost 6,000 healthcare workers from across the UK.

Of these, 3,989 had their first dose of the vaccine at least 21 days earlier, while 1,882 had their second dose at least 14 days earlier. The participants were classified by infection history as either previously having had COVID-19, or naïve, with no history of infection. Almost all of those who hadn’t had COVID-19 generated antibodies against the virus on vaccination.

After dose 1, those with previous infection had up to ten times higher antibody levels than naïve individuals, whilst after dose 2, those with previous infection had antibody levels more than twice as high as those who hadn’t had previous infection.

Looking at dosing intervals, it was found that a longer dosing interval was associated with antibody levels that were up to nine times higher in naïve participants, with a more pronounced effect observed in younger participants.

Regardless of timing between infection and vaccination, all individuals mounted a very high antibody response after dose 2.

“This study shows that a longer time between vaccine dose 1 and dose 2 results in higher antibody responses in naïve participants,” Otter said. “We’ve also shown that in those with previous infection, timing between exposure and vaccination plays a critical role in post-vaccination antibody responses.”

Further research is needed to determine whether these higher antibody levels provide greater protection against COVID-19, and how longer dosing intervals affect the response to boosters, Otter said.

Scientists at the University of Geneva have provided direct evidence that COVID-19 vaccination not only protects individuals from SARS-CoV-2 infection, but also reduces the spread of disease, including of the highly transmissible Omicron BA1 variant.

While diagnosis of COVID-19 using a PCR test is very effective in identifying infected people, it does not indicate whether they are infectious and capable of transmitting the virus to other people, said Isabella Eckerle, who led the research, published in Nature Medicine. “However, [understanding] of contagiousness is essential for deciding on collective prevention measures, such as periods of isolation,” she said.

PCR tests detect the presence of viral RNA, but do not indicate whether the virus is still intact and able to spread. The measurement of the infectious viral load necessarily involves culturing the virus for several days in a biosafety level 3 laboratory, a procedure impossible to perform routinely.

Since the beginning of the pandemic, samples taken at the University Hospital of Geneva screening centre have been kept for research purposes, enabling the scientists to re-analyse samples from previous waves of infection. They measured the infectious viral load of three cohorts of patients during the first five days of symptoms, to compare the viral load caused by the original virus that first emerged in Wuhan, China (118 samples, spring 2020), the Delta variant (293 samples, autumn 2021) and the Omicron variant sublineage BA.1 (154 samples, winter 2022). In addition, for the second and third cohorts, the researchers looked to see whether a significant difference could be detected in vaccinated and unvaccinated individuals.

Overall, the infectious viral load for the Delta cohort was significantly higher than the cohort with the original virus.

However, people infected by Delta who received two doses of mRNA vaccine had a significantly lower infectious viral load than unvaccinated people.

“For the Omicron cohort, contrary to what can be assumed given its rapid spread, the infectious viral load was overall lower than that of the Delta cohort,” said Eckerle. However, only people who were boosted with a third dose of vaccine had a decreased viral load; people who had received two doses only had the same viral load as unvaccinated people.

“This is immunologically consistent: many vaccines require three doses spaced several months apart to induce a sustained immune response,” Eckerle said.

This begs the question of why the Omicron variant is so contagious, if the viral load it induces is lower than its predecessors. “We still don’t know, but our data suggest that other infectious mechanisms are at play,” said Pauline Vetter, clinic director of the University of Geneva Centre for Emerging Diseases. “It is now clear that the mutations of Omicron strongly differentiate it from other variants, allowing it to partially escape the vaccine, and diminish the effectiveness of some antiviral treatments used so far,” she said.

The Geneva study shows that knowledge acquired for previous variants must be updated every time a new variant emerges, to be able to adapt the means of combating COVID-19.  “In view of our results, the greatest caution should be exercised in the face of a virus whose evolution is not fully understood, and against which currently existing treatments lose some of their effectiveness,” the paper concludes.

First line treatments for patients hospitalised with COVID-19 include monoclonal antibodies to neutralise the SARS-CoV-2 virus and the steroid drug dexamethasone, which has strong anti-inflammatory properties.

Researchers in Berlin have now studied the mechanisms of action of both types of treatment and found evidence to suggest that combination therapy of antibodies and dexamethasone is more effective than either of these treatments alone.

The researchers tested the effects of single and combined antiviral and anti-inflammatory therapies in two hamster models of COVID-19, looking at the extent of lung tissue damage and the quantities of infectious virus and viral RNA present in the tissues at various time points.

This enabled them to check whether and how viral activity might change over the course of treatment. They found clear evidence of synergistic action when monoclonal antibodies and dexamethasone are administered in combination.

Using single-cell analyses, it was shown that antibodies are effective at reducing the amount of virus present. However, it is not the virus that damages the lung tissue, but the strong inflammatory response the virus triggers. That is where dexamethasone takes over, suppressing the immune system and preventing an escalation of the immune response.

The best treatment outcomes were achieved when the researchers administered a combination of antiviral and anti-inflammatory treatments. This type of combination therapy is not included in existing clinical guidelines, and what is more, current guidance says that in high-risk patients, antibody therapy can only be given in the first seven days following symptom onset.

In clinical practice, dexamethasone is only used once a patient requires oxygen therapy, at an extremely advanced stage of the disease. Its use in combination with antibodies however, opens entirely new treatment time windows.

This new approach must now be evaluated in clinical trials before it can be adopted in clinical practice, the researchers say.
 

Moderna has published new clinical data on its bivalent COVID-19 booster platform including its first bivalent booster candidate, mRNA-1273.211, which includes mutations found in the Beta variant, several of which persist in more recent variants of concern, including Omicron.

A booster dose of mRNA-1273.211 provided protection against Beta, Delta and Omicron variants one month after administration, and continued to be effective six months after administration for Beta and Omicron variants.

“We believe that these results validate our bivalent strategy,” said Stéphane Bancel, CEO of Moderna. They indicate mRNA-1273.211 induces higher antibody responses than a booster dose of Moderna’s original monovalent vaccine mRNA-1273, even though it is not specifically designed to protect against the variants that have emerged since Beta.

"Our latest bivalent booster candidate, mRNA-1273.214, which combines the currently authorised Moderna COVID-19 booster with our Omicron-specific booster candidate, remains our lead candidate for the fall 2022 northern hemisphere booster​,” Bancel said.

Moderna is developing updated booster vaccines to address the continued evolution of the SARS-CoV-2 virus, including monovalent and bivalent candidates targeting multiple variants of concern. The company has multiple bivalent booster candidates that have been evaluated to date, including mRNA-1273.211, which has nine spike protein mutations based on the Beta variant, and mRNA-1273.214, which has 32 spike protein mutations based on the Omicron variant.

German biotech company Adrenomed announced that adrecizumab, its treatment for severe COVID-19 infections, is to get funding of €7.4 million from the German Federal Ministry of Education and Research as part of government initiatives to promote the clinical development of COVID-19 drugs.

The University Medical Centre Eppendorf Hamburg and Adrenomed will use the money to conduct a phase II clinical trial of adrecizumab in hospitalised patients with moderate to severe COVID-19. The grant will also support manufacturing of the drug for a phase III clinical trial.

Adrecizumab is a first-in-class antibody that is in development for treating of loss of blood vessel integrity in sepsis and septic shock. Similar dysregulation of the endothelial barrier is also a common feature of COVID-19 and leads to vascular leakage and severe impairment of lung and other organ functions.

In a novel precision medicine approach, patients with elevated levels of adrenomedullin, the target of adrecizumab, will be treated with the drug.

Another biomarker (dipeptidyl peptidase-3, DPP3) will used to exclude patients with complications that make them unsuitable for treatment with adrecizumab.

The phase II trial will enrol more than 200 patients with moderate to severe COVID-19 and elevated adrenomedullin levels.

Stefan Kluge, director of the department of Intensive Care Medicine at the Hamburg University medical centre, said there is an urgent need for therapies that can be used in severe cases and can be given at later disease stages. “Adrecizumab could potentially be a therapy that can address this treatment gap,” he said.

In a previous named-patient programme with critically ill COVID-19 patients treated with Adrecizumab, there was a rapid improvement in organ function.

The funding commitment of €7.4 million from the BMBF is a significant endorsement of Adrenomed’s biomarker-guided precision medicine approach for patients in the acute care setting, said Richard Jones, CEO of Adrenomed. “This clinical study further compliments our overall development programme of adrecizumab for the treatment of loss of vascular integrity in sepsis and septic shock,” he said.

The Coalition for Epidemic Preparedness Innovations (CEPI) and the Japanese electronics company NEC, have joined forces in the latest funding award under CEPI’s $200m programme to advance the development of vaccines that provide broad protection against SARS-CoV-2 variants and other betacoronaviruses.

CEPI will provide seed funding of up to $4.8 million to NEC OncoImmunity, a Norway-based subsidiary of NEC, which specialises in applying artificial intelligence to drug design, to support the initial development of a broadly protective coronavirus vaccine.

NEC will lead a research consortium, including the European Vaccine Initiative (EVI) and Oslo University Hospital, to deliver preclinical proof of concept for the vaccine, which will be based on the mRNA technology that underpins the approved Pfizer/BioNTech and Moderna COVID-19 vaccines.

NEC will apply its experience and capabilities in AI-powered design of vaccines, which will be complemented with insights from vaccine development against known coronaviruses including SARS-CoV, SARS-CoV-2 and MERS-CoV.

If this approach is successful, it may also be applicable to the development of vaccines against other pathogens in the CEPI portfolio, including ‘Disease X’, the unknown pathogen(s) with pandemic potential that have yet to emerge.

“Our experience with COVID-19 has taught us that an ideal vaccine must remain robust against an ever-evolving viral landscape. Our AI will assess viral regions that do not mutate rapidly and are shared among SARS, SARS-CoV-2, MERS-CoV and other known coronaviruses,” said Richard Stratford, CEO of NED OncoImmunity.

“I am confident that our unique approach in identifying and selecting antigens that could elicit broader cytotoxic T cell and antibody responses is well positioned to help create broadly protective betacorona virus vaccines,” Stratford said.

NEC is the first Japanese company to be involved in CEPI's work promoting vaccine development. In February 2022, the government of Japan announced a new contribution of $300 million to CEPI over the next five years.

Through COVID-19, coronaviruses have now demonstrated their devastating pandemic potential. The emergence of a coronavirus combining the transmissibility of COVID-19 with the lethality of SARS or MERS would be catastrophic, so developing vaccines that provide broad protection against the whole betacoronavirus genus is therefore vital to global health security. CEPI is working with partners to advance work in this area as quickly as possible.

The award is the eighth programme to be funded by CEPI to advance the development of broad spectrum vaccines as part of a 5-year plan, published in March 2021.

CEPI has announced plans to create a network of existing vaccine facilities that will work to develop, produce, store, and test vaccine candidates in response to new infectious disease outbreaks.

The initiative is intended to support CEPI’s goal of having the capabilities to develop vaccines in 100 days in response to disease outbreaks.

Existing vaccine developers and production sites are now being invited to express their interest in being part of the network.

The facilities selected by CEPI will be called upon to respond to an emerging infectious disease outbreak by rapidly manufacturing and supplying vaccine for clinical testing or mass vaccination. CEPI will offer support with workforce training and matching vaccine developers with manufacturers, so that facilities are ready to quickly manufacture at scale.

Preparing facilities ahead of future outbreaks will support CEPI’s goal of shortening the time taken to develop future vaccines to 100 days, or a third of the time it took to develop the first COVID-19 vaccine.

At the same time this will improve vaccine production capacity and capability in regions currently underserved, or with no such provision.

The sites will be globally distributed, enabling rapid access to vaccine doses worldwide, with a focus on improving access to doses in low- and middle- income regions. It could also allow for vaccine production to take place closer to the source of an outbreak, thereby potentially enabling faster vaccine distribution where it is needed.

CEPI aims to keep the vaccine facilities sustainable and ‘warm’ during inter-pandemic periods, by asking the network to support development and production of vaccines against endemic diseases like Lassa fever or yellow fever.

An expression of interest is open for developers, manufacturers, and government agencies. Applications will be initially reviewed against a set of criteria. Additional funding may be provided to facilities where there are current gaps in their set-up.

CEPI expects to identify facilities by November 2022, and aims to establish up to seven high potential facilities over the next 2 years as part of the network.

EMA and the European Centre for Disease Control and Prevention have concluded it is too early to consider using a fourth dose of COVID-19 vaccine in the general population.

However both agencies agreed that a fourth dose, or second booster, can be given to adults 80 years of age and above, after reviewing data on the higher risk of severe COVID-19 in this age group and the protection provided by a fourth dose.

There is currently no clear evidence in the EU that vaccine protection against severe disease is waning substantially in adults with normal immune systems aged 60 to 79 years, but the data will continue to be monitored to determine if there is an increasing risk of severe illness among those who are vaccinated.

National authorities will also consider local data in deciding whether to use a fourth dose in those people at higher risk.

For adults below 60 years of age with normal immune systems, there is currently no conclusive evidence that vaccine protection against severe disease is waning or that there is an added value of a fourth dose.

Re-vaccination campaigns could start in the autumn, when there will be consideration of the best timing for additional doses. There may possibly be updated versions of vaccines by then.

So far, no safety concerns have emerged from the studies on additional boosters.

As of the end of March 2022, 83% of adults had received full initial vaccinations and only 64% had received a booster dose.

Evidence of the effectiveness of a fourth dose comes largely from Israel, where data indicate that a second booster given at least four months after first booster restores antibody levels without raising any new safety concerns. Data also suggest that a second booster provides additional protection against severe disease, although the duration of the benefits is not yet known and the evidence is still limited.

Details of the evidence assessed is in the joint ECDC-EMA statement on second boosters.