Tag Archive for: COVID-19

Omicron may be significantly better at evading vaccine-induced immunity, but less likely to cause severe disease

December 21, 2021

The Omicron variant of SARS-CoV-2 may be significantly better than previous variants at evading vaccine-induced antibodies, according to new research from Cambridge – but preliminary evidence suggests it is less likely to cause severe COVID-19 illness in the lungs.

As the SARS-CoV-2 virus replicates and spreads, errors in its genetic code can lead to changes in the virus. On 26 November 2021, the World Health Organization designated the variant B.1.1.529, first identified in South Africa, a variant of concern, named Omicron. The variant carries a large number of mutations, leading to concern that it will leave vaccines less effective at protecting against infection and illness.

Working in secure conditions, a team led by Professor Ravi Gupta at the Cambridge Institute of Therapeutic Immunology and Infectious Disease, University of Cambridge, created synthetic viruses – known as ‘pseudoviruses’ – that carried key mutations found in the Delta and Omicron strains. They used these to study the virus’s behaviour.

The team, which included collaborators from Japan, including Dr Kei Sato of the University of Tokyo, has released its data ahead of peer review because of the urgent need to share information relating to the pandemic, and particularly the new Omicron variant.

Professor Gupta and colleagues tested the pseudoviruses against blood samples donated to the NIHR COVID-19 BioResource. The blood samples were from vaccinated individuals who had received two doses of either the AstraZeneca (ChAdOx-1) or Pfizer (BNT162b2) vaccines.

On average, Omicron required around a ten-fold increase in the concentration of serum antibody in order to neutralise the virus, compared to Delta. Of particular concern, antibodies from the majority of individuals who had received two doses of the AstraZeneca vaccine were unable to neutralise the virus. The data were confirmed in live virus experiments.

Reassuringly, however, following a third dose of the Pfizer vaccine, both groups saw a significant increase in neutralisation.

Professor Gupta said: “The Omicron variant appears to be much better than Delta at evading neutralising antibodies in individuals who have received just two doses of the vaccine. A third dose ‘booster’ with the Pfizer vaccine was able to overturn this in the short term, though we’d still expect a waning in immunity to occur over time.”

Spike proteins on the surface of SARS-CoV-2 bind to ACE2, a protein receptor found on the surface of cells in the lung. Both the spike protein and ACE2 are then cleaved, allowing genetic material from the virus to enter the host cell. The virus manipulates the host cell’s machinery to allow the virus to replicate and spread.

To see how effective Omicron is at entering our cells, the team used their pseudoviruses to infect cells in lung organoids – ‘mini-lungs’ that model parts of the lung. Despite having three mutations that were predicted to favour the spike cleavage, the researchers found the Omicron spike protein to be less efficient than the Delta spike at cleaving the ACE2 receptor and entering the lung cells.

In addition, once Omicron had entered the cells, it was also less able than Delta to cause fusion between cells, a phenomenon associated with impaired cell-to-cell spread. Fused cells are often seen in respiratory tissues taken following severe disease. Indeed, when the team used a live Omicron virus and compared it to Delta in a spreading infection experiment using lung cells, Omicron was significantly poorer in replication, confirming the findings regarding impaired entry.

Professor Gupta added: “We speculate that the more efficient the virus is at infecting our cells, the more severe the disease might be. The fact that Omicron is not so good at entering lung cells and that it causes fewer fused cells with lower infection levels in the lab suggests this new variant may cause less severe lung-associated disease.

“While further work is needed to corroborate these findings, overall, it suggests that Omicron’s mutations present the virus with a double-edged sword: it’s got better at evading the immune system, but it might have lost some of its ability to cause severe disease.”

However, Professor Gupta urged caution.

“Omicron still represents a major public health challenge. Individuals who have only received two doses of the vaccine – or worse, none at all – are still at significant risk of COVID-19, and some will develop severe disease. The sheer number of new cases we are seeing every day reinforces the need for everyone to get their boosters as quickly as possible.”

The research was supported by Wellcome and the NIHR Cambridge Biomedical Research Centre.

Paper Reference
Meng, B, et al. SARS-CoV-2 Omicron neutralising antibody evasion, replication and cell-cell fusion.

Com-COV 3 COVID-19 vaccine study calls on teenager volunteers in Cambridgeshire

November 25, 2021

Researchers running the University of Oxford-led Com-COV programme have started enrolling young people aged 12 to 16 years old to receive a second dose of a COVID-19 vaccine, including in Cambridgeshire.

Backed through funding from the Vaccines Taskforce and National Institute for Health Research (NIHR) and run across several NIHR-supported sites by the National Immunisation Schedule Evaluation Consortium, the Com-COV 3 trial is seeking to recruit 270 volunteers. The study has already opened at six sites in the UK, and is expanding to nine new recruiting areas, with recruitment happening locally at NIHR Cambridge Clinical Research Facility at Cambridge University Hospitals NHS Foundation Trust (CUH).

Professor Matthew Snape, Associate Professor in Paediatrics and Vaccinology at the Oxford Vaccine Group, and Chief Investigator on the trial, said: “Teenagers are currently experiencing the highest rate of infections of all age groups in the UK. This study will be critical to delivering vital information on the range of options for immunising teenagers against COVID-19 in the UK to help control this. Therefore, we are asking for 12 to 16 years old to take this opportunity to receive a second dose of vaccine and help us understand how best to immunise teenagers to protect them and their families.”

All participants will be randomly allocated at the time of their second dose to receive either a full second dose of the Pfizer vaccine, a one-third dose of the Pfizer vaccine, or a full dose of the Novavax vaccine. These vaccines will be administered at least eight weeks after their first dose.

The current UK guidance is that all 12 to 15 year olds receive a single dose of vaccine, while 16 to 17 year olds receive 2 doses of vaccine, 12 weeks apart. Younger people at a greater risk of serious illness if they catch COVID-19 are currently offered two doses. The results from the study will provide the JCVI (Joint Committee on Vaccination and Immunisation) with timely and crucial information about immunising teenagers in the UK.

Dr Theofilos Polychronakis, consultant in paediatric respiratory medicine, who is leading the trial at CUH, said: “Participation in research by people of Cambridgeshire has always contributed enormously to the discovery of new treatments, particularly over the last two years, and we are extremely grateful to them and all those who help our researchers to make a difference.

“It’s very important that a broad range of people from all parts of the country, and of all ages, take part in research in order to find the most effective solutions to COVID-19 possible. Therefore, we welcome 12-16 year olds from our local community to take part in this study and help us determine the best options for immunisation for all teenagers, everywhere.”

Professor Matthew Snape said: “We are very grateful to those young volunteers and their parents who have signed up for the study so far. We hope the addition of the trial site at CUH will encourage even more participants to get involved in this critically important research.”

The study is single-blind and randomised, meaning participants will not know what second dose vaccine they are receiving. Researchers will assess reactogenicity (any side effects) and immune system responses to these new combinations of vaccines.

Professor Andrew Ustianowski, NIHR Clinical Lead for COVID-19 Vaccination Programme and Joint National Infection Specialty Lead, said: “By getting involved in this study, volunteers will be able to help researchers develop our understanding of how we can best protect teenagers against COVID-19.

“Thanks to the generosity of thousands of vaccine study participants over the past 18 months, we have been able to reduce the impact and spread of COVID-19 with approved vaccines. Once it has reached its target, Com-COV 3 will be a pivotal study that is expected to provide important data that will lead directly to UK guidance on protecting young people and their families.”

If you would like to register to take part in the study at CUH, visit the study website.

Using air filters on hospital wards remove almost all airborne Covid virus

November 17, 2021

A new study has found placing air filtration machines in COVID-19 wards at Addenbrooke’s Hospital, removed almost all traces of airborne SARS-CoV-2 virus.

Supported by the NIHR Cambridge BRC, the research was led by doctors, scientists and engineers at Addenbrooke’s and the University of Cambridge in January, at the height of the second wave of the pandemic.

This discovery could have implications for improving the safety of repurposed ‘surge wards’, the researchers say it also opens up the possibility of being able to set standards for cleaner air to reduce the risk of airborne transmission of infections.

Over the duration of the pandemic there has been a steady rise in the evidence that the SARS-CoV-2 virus can be transmitted through the air in small droplets (aerosols). But as hospitals have seen their capacity overwhelmed, they have been forced to manage many of their COVID-19 patients in repurposed ‘surge’ wards, which often lack the ability to change the air with a high frequency. While the use of appropriate personal protective equipment (PPE) protects staff and patients significantly reduces the risk of transmission, there are still reports of patient-to-healthcare worker transmission of the virus, potentially through the inhalation of viral particles.

A team at the University of Cambridge and Cambridge University Hospitals (CUH) NHS Foundation Trust investigated whether portable air filtration/UV sterilisation devices could reduce airborne SARS- CoV-2 in general wards that had been repurposed as a COVID ward and a COVID Intensive Care Unit (ICU). The results are published in Clinical Infectious Diseases.

An airfilter machine and Dr Vilas Navapurkar, who led the study

Dr Vilas Navapurkar, a Consultant in Intensive Care Medicine at CUH, who led the study, said: “Reducing airborne transmission of the coronavirus is extremely important for the safety of both patients and staff. Effective PPE has made a huge difference, but anything we can do to reduce the risk further is important.”

“Because of the numbers of patients being admitted with COVID-19, hospitals have had to use wards not designed for managing respiratory infections. During an intensely busy time, we were able to pull together a team from across the hospital and University to test whether portable air filtration devices, which are relatively inexpensive, might remove airborne SARS-CoV-2 and make these wards safer.”

The team performed their study in two repurposed COVID-19 units in Addenbrooke’s Hospital. One area was a surge ward managing patients who required simple oxygen treatment or no respiratory support; the second was a surge ICU managing patients who required ventilation either through non-invasive mask ventilation or invasive respiratory support, such as involving the use of an invasive tube and tracheostomy.

The team installed a High Efficiency Particulate Air (HEPA) air filter/UV steriliser. HEPA filters are made up of thousands of fibres knitted together to form a material that filters out particles above a certain size. The machines were placed in fixed positions and operated continuously for seven days, filtering the full volume of air in each room between five and ten times per hour.

In the surge ward, during the first week prior to the air filter being activated, the researchers were able to detect SARS-CoV-2 on all sampling days. Once the air filter was switched on and run continuously, the team were unable to detect SARS-CoV-2 on any of the five testing days. They then switched off the machine and repeated the sampling – once again, they were able to detect SARS-CoV-2 on three of the five sampling days.

On the ICU, the team found limited evidence of airborne SARS-CoV-2 in the weeks when the machine was switched off and traces of the virus on one sampling day when the machine was active.

Additionally, the air filters significantly reduced levels of bacterial, fungal and other viral bioaerosols on the both the surge ward and the ICU, highlighting an added benefit of the system.

First author Dr Andrew Conway Morris, from the Department of Medicine at the University of Cambridge, said: “We were really surprised by quite how effect air filters were at removing airborne SARS-CoV-2 on the wards. Although it was only a small study, it highlights their potential to improve the safety of wards, particularly in areas not designed for managing highly infectious diseases such as COVID-19.”

Crucially, the research team developed a robust technique for assessing the quality of air, involving placing air samplers at various points in the room and then testing the samples using PCR assays similar those used in the ‘gold standard’ COVID-19 tests.

Professor Stephen Baker, from the Cambridge Institute of Therapeutic Immunology and Infectious Disease at the University of Cambridge, said: “Cleaner air will reduce the risk of airborne disease transmission, but it’s unlikely to be the case that just installing an air filter will be enough to guarantee the air is clean enough. Every room and every situation will be different. A key part of our work has been developing a robust way of measuring air quality.”

Dr Navapurkar added: “We’re all familiar with the idea of having standards for clean water and of hygiene standards for food. We need now to agree standards for what is acceptable air quality and how we meet and monitor those standards.”

The research was also supported by Wellcome and the Medical Research Council.

Adapted from University of Cambridge release

‘Biological fingerprint’ in blood could help identify COVID patients with no symptoms

July 19, 2021

Cambridge researchers are able to identify people who have had COVID-19 even if they displayed no symptoms. They have developed a way to find markers in the blood several months after infection, even if the individual had only mild or showed no symptoms at all.

Most people who have COVID-19 may recover in a few weeks but there are some who will develop severe symptoms that can last for several months.

Current practice requires people to take a PCR test at the time of infection or an antibody test, looking at the immune cells, to reveal if someone may have previously had the virus but were asymptomatic. Now Cambridge researchers have discovered a biomarker – a biological fingerprint – in the blood of patients who previously had COVID-19.

This has led the team to receive £370,000 from the National Institute for Health Research (NIHR) to develop a COVID-19 diagnostic test that will complement existing antibody tests, as well as develop a test that could diagnose and monitor long Covid.

The research builds on a pilot project supported by the Addenbrooke’s Charitable Trust which has been recruiting patients from the Long COVID Clinic established in May 2020 at Addenbrooke’s Hospital.

Finding the biomarker

During the pilot, the team recruited 85 patients to the Cambridge-led NIHR COVID BioResource, which collects blood samples from patients when they are first diagnosed and then at follow-up intervals over several months.

In their initial findings, they identified a molecule known as a cytokine produced by T cells in response to infection. As with antibodies, this biomarker persists in the blood for a long time after infection.

Dr Mark Wills from the Department of Medicine at the University of Cambridge, who co-leads the team, said: “We need a reliable and objective way of saying whether someone has had COVID-19. Antibodies are one sign we look for, but not everyone makes a very strong response and this can wane over time and become undetectable.

“We’ve identified a cytokine that is also produced in response to infection by T cells and is likely to be detectable for several months – and potentially years – following infection. We believe this will help us develop a much more reliable diagnostic for those individuals who did not get a diagnosis at the time of infection.”

By following patients for up to 18 months post-infection, the team hopes to address several questions, including whether immunity wanes over time. This will be an important part of helping understand whether people who have been vaccinated will need to receive boosters to keep them protected.

As part of their pilot study, the team also identified a particular biomarker found in patients with long COVID. Their work suggests these patients produce a second type of cytokine, which persists in patients with long COVID compared to those that recover quickly and might be one of the drivers behind the many symptoms that patients experience. This might therefore prove to be useful for diagnosing long COVID.

Dr Nyarie Sithole, also from the Department of Medicine at the University of Cambridge, who co-leads the team and helps to manage long COVID patients, said: “Because we currently have no reliable way of diagnosing long COVID, the uncertainty can cause added stress to people who are experiencing potential symptoms. If we can say to them ‘yes, you have a biomarker and so you have long COVID’, we believe this will help allay some of their fears and anxieties.

“There is anecdotal evidence that patients see an improvement in symptoms of long COVID once they have been vaccinated – something that we have seen in a small number of patients in our clinic. Our study will allow us to see how this biomarker changes over a longer period of time in response to vaccination.”

At the moment, the team is using the tests for research purposes, but by increasing the size of their study cohort and carrying out further work, they hope to adapt and optimise the tests that can be scaled up and speeded up, able to be used by clinical diagnostic labs.

As well as developing a reliable test, the researchers hope their work will help provide an in-depth understanding of how the immune system responds to coronavirus infection – and why it triggers long COVID in some people.

Dr Sithole added: “One of the theories of what’s driving long COVID is that it’s a hyperactive immune response – in other words, the immune system switches on at the initial infection and for some reason never switches off or never goes back to the baseline. As we’ll be following our patients for many months post-infection, we hope to better understand whether this is indeed the case.”

In addition, having a reliable biomarker could help in the development of new treatments against COVID. Clinical trials require an objective measure of whether a drug is effective. Changes in – or the disappearance of – long-COVID-related cytokine biomarkers with corresponding symptom improvement in response to drug treatment would suggest that a treatment intervention is working.

Understanding COVID-19

An extensive programme of 15 new research studies, backed by government funding through the NIHR, will allow researchers across the UK to draw together their expertise from analysing long COVID among those suffering long-term effects and the health and care professionals supporting them. These groundbreaking studies aim to help those people affected return to their normal lives.

Health and Social Care Secretary, Sajid Javid, said: “Long COVID can have serious and debilitating long term effects for thousands of people across the UK, which can make daily life extremely challenging.

“This new research is absolutely essential to improve diagnosis and treatments and will be life-changing for those who are battling long-term symptoms of the virus.

“It will build on our existing support with over 80 long COVID assessment services open across England as part of a £100 million expansion of care for those suffering from the condition and over £50 million invested in research to better understand the lasting effects of this condition.”

Key mutations in Alpha variant enable SARS-CoV-2 to overcome evolutionary weak points

June 29, 2021

One of the key mutations seen in the ‘Alpha variant’ of SARS-CoV-2 – the deletion of two amino acids, H69/V70 – enables the virus to overcome chinks in its armour as it evolves, say an international team of scientists.

SARS-CoV-2 is a coronavirus, so named because spike proteins on its surface give it the appearance of a crown (‘corona’). The spike proteins bind to ACE2, a protein receptor found on the surface of cells in our body. Both the spike protein and ACE2 are then cleaved, allowing genetic material from the virus to enter the host cell. The virus manipulates the host cell’s machinery to allow the virus to replicate and spread.

As SARS-CoV-2 divides and replicates, errors in its genetic makeup cause it to mutate. Some mutations make the virus more transmissible or more infectious, some help it evade the immune response, potentially making vaccines less effective, while others have little effect.

Towards the end of 2020, Cambridge scientists observed SARS-CoV-2 mutating in the case of an immunocompromised patient treated with convalescent plasma. In particular, they saw the emergence of a key mutation – the deletion of two amino acids, H69/V70, in the spike protein. This deletion was later found in B1.1.7, the variant that led to the UK being forced once again into strict lockdown in December (now referred to as the ‘Alpha variant’).

Now, in research published in the journal Cell Reports, researchers show that the deletion H69/V70 is present in more than 600,000 SARS-CoV-2 genome sequences worldwide, and has seen global expansion, particularly across much of Europe, Africa and Asia.

The research was led by scientists at the University of Cambridge, MRC-University of Glasgow Centre for Virus Research, The Pirbright Institute, MRC Laboratory of Molecular Biology, and Vir Biotechnology.

Professor Ravi Gupta from the Cambridge Institute of Therapeutic Immunology and Infectious Disease at the University of Cambridge, the study’s senior author, said: “Although we first saw this mutation in an immunocompromised patient and then in the Kent – now ‘Alpha’ – variant, when we looked at samples from around the world, we saw that this mutation has occurred and spread multiple times independently.”

Working under secure conditions, Professor Gupta and colleagues used a ‘pseudotype virus’ – a harmless virus that displays SARS-CoV-2 spike proteins with the H69/V70 deletion – to understand how the spike protein interacts with host cells and what makes this mutation so important.

When they tested this virus against blood sera taken from fifteen individuals who had recovered from infection, they found that the deletion did not allow the virus to ‘escape’ neutralising antibodies made after being vaccinated or after previous infection. Instead, the team found that the deletion makes the virus twice as infective – that is, at breaking into the host’s cells – as a virus that dominated global infections during the latter half of 2020. This was because virus particles carrying the deletion had a greater number of mature spike proteins on their surface. This allows the virus to then replicate efficiently even when it has other mutations that might otherwise hinder the virus.

“When viruses replicate, any mutations they acquire can act as a double-edged sword: a mutation that enables the virus to evade the immune system might, for example, affect how well it is able to replicate,” said Professor Gupta.

“What we saw with the H69/V70 deletion was that in some cases, the deletion helped the virus compensate for the negative effects that came with other mutations which allowed the virus to escape the immune response. In other words, the deletion allowed these variants to have their cake and eat it – they were both better at escaping immunity and more infectious.”

Dr Dalan Bailey from The Pirbright Institute, who co-led the research, added: “In evolutionary terms, when a virus develops a weakness, it can lead to its demise, but the H69/V70 deletion means that the virus is able to mutate further than it otherwise would. This is likely to explain why these deletions are now so widespread.”

Bo Meng from the Department of Medicine at the University of Cambridge, first author on the paper, said: “Understanding the significance of key mutations is important because it enables us to predict how a new variant might behave in humans when it is first identified. This means we can implement public health and containment strategies early on.”

The research was supported by Wellcome, the Medical Research Council, the Bill & Melinda Gates Foundation and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre.

The paper Recurrent emergence of SARS-CoV-2 spike deletion H69/V70 and its role in the variant of concern lineage B.1.1.7 is available online in the open-access journal Cell Reports.

Upgrading PPE for staff working on COVID-19 wards cut hospital-acquired infections dramatically

June 29, 2021

When Addenbrooke’s Hospital in Cambridge upgraded its face masks for staff working on COVID-19 wards to filtering face piece 3 (FFP3) respirators, it saw a dramatic fall – up to 100% – in hospital-acquired SARS-CoV-2 infections among these staff.

The findings are reported by a team at the University of Cambridge and Cambridge University Hospitals (CUH) NHS Foundation Trust. The research has not yet been peer-reviewed, but is being released early because of the urgent need to share information relating to the pandemic.

Until recently, advice from Public Health England recommended that healthcare workers caring for patients with COVID-19 should use fluid resistant surgical masks type IIR (FRSMs) as respiratory protective equipment; if aerosol-generating procedures were being carried out (for example inserting a breathing tube into the patient’s windpipe), then the guidance recommended the use of an FFP3 respirator. PHE has recently updated its guidance to oblige NHS organisations to assess the risk that COVID-19 poses to staff and provide FFP3 respirators where appropriate.

Since the start of the pandemic, CUH has been screening its healthcare workers regularly for SARS-CoV-2, even where they show no symptoms. They found that healthcare workers caring for patients with COVID-19 were at a greater risk of infection than staff on non-COVID-19 wards, even when using the recommended respiratory protective equipment. As a result, its infection control committee implemented a change in respiratory protective equipment for staff on COVID-19 wards, from FRSMs to FFP3 respirators.

Prior to the change in respiratory protective equipment, cases were higher on COVID-19 wards compared with non-COVID-19 wards in seven out of the eight weeks analysed by the team. Following the change in protective equipment, the incidence of infection on the two types of ward was similar.

The results suggest that prior to the change, almost all cases among healthcare workers on non-COVID-19 wards were caused by community-acquired infection, whereas cases among healthcare workers on COVID-19 wards were caused by both community-acquired infection and direct, ward-based infection from patients with COVID-19 – but that these direct infections were effectively mitigated by the use of FFP3 respirators.

To calculate the risk of infection for healthcare workers working on COVID-19 and non-COVID-19 wards, the researchers developed a simple mathematical model.

Dr Mark Ferris from the University of Cambridge’s Occupational Health Service, one of the study’s authors, said: “Healthcare workers – particularly those working on COVID-19 wards – are much more likely to be exposed to coronavirus, so it’s important we understand the best ways of keeping them safe.

“Based on data collected during the second wave of the SARS-CoV-2 pandemic in the UK, we developed a mathematical model to look at the risks faced by those staff dealing with COVID-19 patients on a day to day basis. This showed us the huge effect that using better PPE could have in reducing the risk to healthcare workers.”

According to their model, the risk of direct infection from working on a non-COVID-19 ward was low throughout the study period, and consistently lower than the risk of community-based exposure.

By contrast, the risk of direct infection from working on a COVID-19 ward before the change in respiratory protective equipment was considerably higher than the risk of community-based exposure: staff on COVID-19 wards were at 47 times greater risk of acquiring infection while on the ward than staff working on a non-COVID-19 ward.

Crucially, however, the model showed that the introduction of FFP3 respirators provided up to 100% protection against direct, ward-based COVID-19 infection.

Dr Chris Illingworth from the MRC Biostatistics Unit at the University of Cambridge, said: “Before the face masks were upgraded, the majority of infections among healthcare workers on the COVID-19 wards were likely due to direct exposure to patients with COVID-19.

“Once FFP3 respirators were introduced, the number of cases attributed to exposure on COVID-19 wards dropped dramatically – in fact, our model suggests that FFP3 respirators may have cut ward-based infection to zero.”

Dr Nicholas Matheson from the Department of Medicine at the University of Cambridge, said: “Although more research will be needed to confirm our findings, we recommend that, in accordance with the precautionary principle, guidelines for respiratory protective equipment are further revised until more definitive information is available.”

Dr Michael Weekes from the Department of Medicine at the University of Cambridge, added: “Our data suggest there’s an urgent need to look at the PPE offered to healthcare workers on the frontline. Upgrading the equipment so that FFP3 masks are offered to all healthcare workers caring for patients with COVID-19 could reduce the number of infections, keep more hospital staff safe and remove some of the burden on already stretched healthcare services caused by absence of key staff due to illness. Vaccination is clearly also an absolute priority for anyone who hasn’t yet taken up their offer.”

The research was funded by Wellcome, the Addenbrooke’s Charitable Trust, UK Research and Innovation, and the NIHR Cambridge Biomedical Research Centre.

For a copy of the paper see: FFP3 respirators protect healthcare workers against infection with SARS-CoV-2.

BloodCounts! Consortium wins Trinity Challenge Prize for breakthrough in infectious disease detection

June 28, 2021

BloodCounts! – an international consortium of scientists, led by Professor Carola-Bibiane Schönlieb of the Department of Applied Mathematics and Theoretical Physics at the University of Cambridge, has been awarded a substantial prize by the Trinity Challenge to further develop their innovative infectious disease outbreak detection system.

The loss of 3.8 million lives in the ongoing COVID-19 pandemic has highlighted that there is a critical need for simple, affordable, and scalable technologies for early detection of novel emerging infectious disease outbreaks. To drive development of these tools the Trinity Challenge, a global call for solutions to this problem, was set.

The BloodCounts! solution, developed by Dr Michael Roberts and Dr Nicholas Gleadall, uses data from routine blood tests and powerful AI-based techniques to provide a “Tsunami-like” early warning system for novel disease outbreaks.

Dr Roberts from the University of Cambridge said: “Since the beginning of the pandemic I have been developing AI-based methods to aid in medical decision making for COVID-19 patients, starting with analysis of Chest X-ray data. Echoing the observations made by the clinical teams, we saw profound and unique differences in the medical measurements of infected individuals, particularly in their full blood count data. It is these changes that we can train models to detect at scale.”

Unlike many current test methods their approach doesn’t require any prior knowledge of a specific pathogen to work, instead, they use full blood count data to exploit the pathogen detecting abilities of the human immune system by observing changes in the blood measurements associated with infection.

As the full blood count is the world’s most common medical laboratory test, with over 3.6 billion being performed worldwide each year, the BloodCounts! team can rapidly apply their methods to scan for abnormal changes in the blood cells of large populations – alerting public health agencies to potential outbreaks of pathogen infection.

This unique solution is a powerful demonstration of how the application of AI-based methods, built upon rigorous mathematics, can lead to huge healthcare benefits when applied in many areas of medicine. It also highlights the importance of strong collaboration between leading organisations, as the development of these algorithms was only possible due the EpiCov data sharing initiative pioneered by Cambridge University Hospitals and supported by the NIHR Cambridge BRC.

Dr Gleadall from the University of Cambridge and NHS Blood and Transplant said: “We realised that hundreds of millions of full blood count tests were being performed every day worldwide, and this meant that we could apply our AI-methods at population scale. Usually the rich measurement data are discarded after summary results have been reported, but by working with Cambridge University, Barts Health London, and University College London, NHS Hospitals we have rescued throughout the pandemic the rich data from 2.8 million full blood count tests.”

Professor Bryan Williams, the Director of the NIHR University College London Hospitals Biomedical Research Centre who was an early supporter of applying AI to the full blood count data, said: “The BloodCounts! approach has huge potential and if this works, it could provide a readily scalable and cheap population surveillance method for outbreak detection of SARS-CoV-2 and other viruses. A major advantage is that the NHS already performs more than 100 million FBC tests every year, with over half of these performed by general practitioners in the community, so the programme aims to get more information from tests we already perform.”

Cambridge begins world-first COVID-19 vaccine booster study

June 14, 2021

Researchers in Cambridge have welcomed their first participants in a new UK study to understand the effects of a ‘booster’ dose of a COVID-19 vaccine.

The Cov-Boost study, a world-first clinical trial, offers individuals a chance to have a third dose of COVID-19 vaccine to see whether such a booster dose can better protect against the virus.

This Government-funded trial, led by the University of Southampton, has now opened a site at the National institute for Health Research (NIHR) Cambridge Clinical Research Facility at Cambridge University Hospitals (CUH).

It is the first study in the world to provide vital data on the impact of a third dose on patients’ immune responses.

It will give scientists from around the world and the experts behind the UK’s COVID-19 vaccination programme a better idea of how effective a booster of each vaccine is in protecting the individual from the virus.

The trial will look at seven different COVID-19 vaccines (including the Pfizer/BioNTech, and Valneva vaccines) as potential boosters, given at least 10 to 12 weeks after a second dose as part of the ongoing vaccination programme. One booster will be provided to each participant and could be a different brand to the one they were originally vaccinated with.

Researchers at the NIHR Cambridge Clinical Research Facility will see more than 180 participants from the Cambridgeshire area take part. Volunteers will be aged 30 years or older and will have already received their full COVID-19 immunisation.

On arrival, participants will be fully informed about the study. If they agree to take part they will be randomly allocated to receive one of several different COVID-19 vaccines or a placebo vaccine. After the booster, the study will monitor any reaction and also measure the immune response to vaccination over the next year.

Professor Krishna Chatterjee, Director of the NIHR Clinical Research Facility in Cambridge, who is leading the trial at CUH, said on the day of opening:

“We are delighted to support this study here in Cambridge. We have conducted trials of several COVID-19 vaccine studies over the last year. It’s an exciting opportunity to now work on a study to determine the effects of a third ‘booster’ dose of vaccines and I want to thank both the trial participants and our staff who are helping with this important research.”

All the data will be analysed with initial results expected in September. This will help inform decisions by the Joint Committee on Vaccination and Immunisation (JCVI) on any potential booster programme from autumn this year, ensuring the country’s most vulnerable are given the strongest possible protection over the winter period.

Volunteering for COVID-19 vaccine clinical trials

People wishing to volunteer to support clinical trials can sign up for information on Covid-19 vaccine trials with the NHS COVID-19 Vaccine Research Registry, developed in partnership with NHS Digital. It is helping large numbers of people to be recruited into trials, meaning more effective vaccines for coronavirus can be found as soon as possible.

The service was commissioned as part of the UK Government’s Vaccine Taskforce in conjunction with the NIHR and the Northern Ireland, Scottish and Welsh Governments. Anyone living in the UK can sign up online to take part in the trials through the NHS, giving permission for researchers to contact you if they think you’re a good fit. Once you sign up, you can withdraw at any time and request that your details be removed from the COVID-19 Vaccine Research Registry. The process takes about 5 minutes to complete

Differing immune responses discovered in asymptomatic cases and those with severe COVID-19

April 22, 2021

A UK-wide study part-funded by the NIHR has identified differences in people’s immune responses to COVID-19, depending on whether they have no symptoms or more serious reactions to the virus.

In the study “Single-cell multi-omics analysis of the immune response in COVID-19”, published this month in Nature Medicine, researchers and their collaborators in the Human Cell Atlas initiative analysed blood from 130 people with COVID-19. These patients came from three different UK centres in Newcastle, Cambridge and London and ranged from asymptomatic to critically severe.

The researchers found raised levels of specific immune cells in asymptomatic people to help fight infection – but that patients with more serious symptoms had lost these protective cell types and instead gained inflammatory cells. In severe cases this led to lung inflammation, blood clotting difficulties and hospitalisation.

While it is not yet understood how the infection stimulates these immune responses, the study gives a molecular explanation for how COVID-19 could cause an increased risk of blood clotting and inflammation in the lungs, which can lead to the patient needing a ventilator.

This also uncovers potential new therapeutic targets to help protect patients against inflammation and severe disease.

Professor Menna Clatworthy, senior co-author of the study and Capacity Building Theme Lead, said: “This is one of the most detailed studies of immune responses in COVID-19 to date, and begins to help us understand why some people get really sick while others fight off the virus without even knowing they have it.

“This new knowledge will help identify specific targets for therapy for patients who get sick with COVID-19.”

In the future, research may identify those who are more likely to experience moderate to severe disease by looking at levels of these immune cells in their blood.

Genomics study identifies routes of transmission of coronavirus in care homes

March 3, 2021

Genomic surveillance – using information about genetic differences between virus samples – can help identify how SARS-CoV-2 spreads in care home settings, whose residents are at particular risk.

Care homes are at high risk of experiencing outbreaks of COVID-19, the disease caused by SARS-CoV-2. Older people and those affected by heart disease, respiratory disease and type 2 diabetes – all of which increase with age – are at greatest risk of severe disease and even death, making the care home population especially vulnerable.

Care homes are known to be high-risk settings for infectious diseases, owing to a combination of the underlying vulnerability of residents who are often frail and elderly, the shared living environment with multiple communal spaces, and the high number of contacts between residents, staff and visitors in an enclosed space.

In research published in eLife, a team led by scientists at the University of Cambridge and Wellcome Sanger Institute used a combination of genome sequencing and detailed epidemiological information to examine the impact of COVID-19 on care homes and to look at how the virus spreads in these settings.

SARS-CoV-2 is an RNA virus and as such its genetic code is prone to errors each time it replicates. It is currently estimated that the virus mutates at a rate of 2.5 nucleotides (the A, C, G and U of its genetic code) per month. Reading – or ‘sequencing’ – the genetic code of the virus can provide valuable information on its biology and transmission. It allows researchers to create ‘family trees’ – known as phylogenetic trees – that show how samples relate to each other.

Scientists and clinicians in Cambridge have pioneered the use of genome sequencing and epidemiological information to trace outbreaks and transmission networks in hospitals and community-based healthcare settings, helping inform infection control measures and break the chains of transmission. Since March 2020, they have been applying this method to SARS-CoV-2 as part of the COVID-19 Genomics UK (COG-UK) Consortium.

In this new study, researchers analysed samples collected from 6,600 patients between 26 February and 10 May 2020 and tested at the Public Health England (PHE) Laboratory in Cambridge. Out of all the cases, 1,167 (18%) were care home residents from 337 care homes, 193 of which were residential homes and 144 nursing homes, the majority in the East of England. The median age of care home residents was 86 years.

While the median number of cases per care home was two, the ten care homes with the largest number of cases accounted for 164 cases. There was a slight trend for nursing homes to have more cases per home than residential homes, with a median of three cases.

Compared with non-care home residents admitted to hospital with COVID-19, hospitalised care home residents were less likely to be admitted to intensive care units (less than 7% versus 21%) and more likely to die (47% versus 20%).

The researchers also explored links between care homes and hospitals. 68% of care home residents were admitted to hospital during the study period. 57% were admitted with COVID-19, 6% of cases had suspected hospital-acquired infection, and 33% were discharged from hospital within 7 days of a positive test. These findings highlight the ample opportunities for SARS-CoV-2 transmission between hospital and care home settings.

When the researchers examined the viral sequences, they found that for several of the care homes with the highest number of cases, all of the cases clustered closely together on a phylogenetic tree with either identical genomes or just one base pair difference. This was consistent with a single outbreak spreading within the care home.

By contrast, for several other care homes, cases were distributed across the phylogenetic tree, with more widespread genetic differences, suggesting that each of these cases was independent and not related to a shared transmission source.

“Older people, particularly those in care homes who may be frail, are at particular risk from COVID-19, so it’s essential we do all that we can to protect them,” said Dr Estée Török, an Honorary Consultant at Addenbrooke’s Hospital, Cambridge University Hospitals (CUH), and an Honorary Senior Visiting Fellow at the University of Cambridge.

“Preventing the introduction of new infections into care homes should be a key priority to limit outbreaks, alongside infection control efforts to limit transmission within care homes, including once an outbreak has been identified.”

The team found two clusters that were linked to healthcare workers. One of these involved care home residents, a carer from that home and another from an unknown care home, paramedics and people living with them. The second involved several care home residents and acute medical staff at Cambridge University Hospitals NHS Foundation Trust who cared for at least one of the residents. It was not possible to say where these clusters originated from and how the virus spread.

“Using this technique of ‘genomic surveillance’ can help institutions such as care homes and hospitals better understand the transmission networks that allow the spread of COVID-19,” added Dr William Hamilton from the University of Cambridge and CUH. “This can then inform infection control measures, helping ensure that these places are as safe as possible for residents, patients, staff and visitors.”

The absolute number of diagnosed COVID-19 cases from care home residents declined more slowly in April than for non-care home residents, increasing the proportion of cases from care homes and contributing to the slow rate of decline in total case numbers during April and early May 2020.

“Our data suggest that care home transmission was more resistant to lockdown measures than non-care home settings. This may reflect the underlying vulnerability of the care home population, and the infection control challenges of nursing multiple residents who may also share communal living spaces,” said Gerry Tonkin-Hill from the Wellcome Sanger Institute.

The team found no new viral lineages from outside the UK, which may reflect the success of travel restrictions in limiting new viral introductions into the general population during the first epidemic wave and lockdown period.

This work was funded by COG-UK, Wellcome, the Academy of Medical Sciences, the Health Foundation and the NIHR Cambridge Biomedical Research Centre.

Paper reference

Hamilton, W et al.
COVID-19 infection dynamics in care homes in the East of England: a retrospective genomic epidemiology study. eLife; 2 March 2021; DIO: 10.7554/eLife.64618

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