̽��ֱ�� of Cambridge - Addenbrooke’s Charitable Trust

Prioritise vaccine boosters for vulnerable immunocompromised patients, say scientists

cjb250 — Wed, 12 Feb 2025 19:00:46 +0000

̽��ֱ��findings, published today in Science Advances, suggest that such individuals will need regular vaccine boosters to protect them and reduce the risk of infections that could be severe and also lead to new ‘variants of concern’ emerging.

Almost 16 million people worldwide are estimated to have died from Covid-19 during 2020 and 2021, though nearly 20 million deaths are thought to have been prevented as a result of the rapid rollout of vaccines against SARS-CoV-2, the virus that caused the pandemic.

During the pandemic, researchers discovered that immunocompromised individuals had difficulty clearing the virus, even when vaccinated. These are people whose immune systems are not functioning correctly, either as a direct result of disease or because they are on medication to dampen down their immune systems, for example to prevent organ transplant rejection. This meant that their infections lasted longer, giving the virus more opportunities to mutate.

Research from early in the pandemic showed that chronic infections can give rise to variants of concern that can then cause new waves of infection in the wider population.

When an individual is vaccinated, their immune systems produce antibodies that recognise and launch an attack on the virus. Such a process is known as seroconversion. Additional ‘booster’ vaccinations increase seroconversion and hence the likelihood of clearing infection.

However, although most immunocompromised individuals will have received three or more doses of the Covid-19 vaccine, they still account for more than a fifth of hospitalisations, admissions to intensive care units, and overall deaths associated with the disease.

To see why this is the case, scientists at the Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID) at the ̽��ֱ�� of Cambridge examined immunocompromised individuals who had been vaccinated against Covid-19. These patients, recruited from Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust, were living with vasculitis, a group of disorders that cause inflammation of blood vessels. Data from this group was compared against individuals who were not immunocompromised.

Treatments for vasculitis rely on immunosuppressant medicines. These include drugs such as rituximab, which depletes the number of B-cells in the body – but B-cells are the immune cells responsible for producing antibodies. As such, these individuals are a severely at-risk population.

When the researchers analysed bloods samples from the vasculitis patients, they found that even though vaccination induced seroconversion, this in itself was not always sufficient to neutralise the virus. Every immunocompromised individual required at least three doses of the vaccine to protect them across a range of variants up to and include Omicron (the variant that appeared towards the end of 2021 and caused a new wave of infections). In some cases, even four vaccinations were not sufficient to adequately protect them.

Kimia Kamelian, a Gates Cambridge Scholar at CITIID and St Edmund's College, Cambridge, said: “We know that immunocompromised individuals are particularly vulnerable to diseases such as Covid-19 because their immune systems struggle to clear infections. Vaccinations offer some protection, but our study shows that only repeated vaccinations – often four or more – offer the necessary protection.”

Professor Ravi Gupta, also from CITIID and a Fellow at Homerton College, Cambridge, added: “This of course has implications for the individual, who is more likely to have prolonged infection and a much greater risk of severe infection, but it also gives the virus multiple opportunities to mutate.

“We know from our previous work that at least some of the variants of concern probably emerged during chronic infections. That’s why these individuals must be given priority for updated vaccines against new variants.”

̽��ֱ��research was funded by Wellcome, Gates Cambridge, Addenbrooke’s Charitable Trust and Vasculitis UK, with additional support by the National Institute for Health and Care Research Cambridge Biomedical Research Centre.

Reference
Kamelian, K et al. Humoral responses to SARS-CoV-2 vaccine in vasculitis-related immune suppression. Sci Adv; 12 Feb 2025; DOI: 10.1126/sciadv.adq3342

Vaccinations alone may not be enough to protect people with compromised immune systems from infection, even if the vaccine has generated the production of antibodies, new research from the ̽��ֱ�� of Cambridge has shown.

We know that immunocompromised individuals are particularly vulnerable to diseases such as Covid-19 because their immune systems struggle to clear infections

Kimia Kamelian

NoSystem images

Vaccination of an senior male

̽��ֱ��text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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‘Programmable molecular scissors’ could help fight COVID-19 infection

cjb250 — Wed, 16 Nov 2022 10:00:18 +0000

Enzymes are naturally occurring biological catalysts, which enable the chemical transformations required for our bodies to function – from translating the genetic code into proteins, right through to digesting food. Although most enzymes are proteins, some of these crucial reactions are catalysed by RNA, a chemical cousin of DNA, which can fold into enzymes known as ribozymes. Some classes of ribozyme are able to target specific sequences in other RNA molecules and cut them precisely.

In 2014, Dr Alex Taylor and colleagues discovered that artificial genetic material known as XNA – in other words, synthetic chemical alternatives to RNA and DNA not found in nature – could be used to create the world’s first fully-artificial enzymes, which Taylor named XNAzymes.

At the beginning, XNAzymes were inefficient, requiring unrealistic laboratory conditions to function. Earlier this year, however, his lab reported a new generation of XNAzymes, engineered to be much more stable and efficient under conditions inside cells. These artificial enzymes can cut long, complex RNA molecules and are so precise that if the target sequence differs by just a single nucleotide (the basic structural unit of RNA), they will recognise not to cut it. This means they can be programmed to attack mutated RNAs involved in cancer or other diseases, leaving normal RNA molecules well alone.

Now, in research published today in Nature Communications, Taylor and his team at the Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), ̽��ֱ�� of Cambridge, report how they have used this technology to successfully ‘kill’ live SARS-CoV-2 virus.

Taylor, a Sir Henry Dale Fellow and Affiliated Researcher at St John’s College, Cambridge, said: “Put simply, XNAzymes are molecular scissors which recognise a particular sequence in the RNA, then chop it up. As soon as scientists published the RNA sequence of SARS-CoV-2, we started scanning through looking for sequences for our XNAzymes to attack.”

While these artificial enzymes can be programmed to recognise specific RNA sequences, the catalytic core of the XNAzyme – the machinery that operates the ‘scissors’ – does not change. This means that creating new XNAzymes can be done in far less time than it normally takes to develop antiviral drugs.

As Taylor explained: “It’s like having a pair of scissors where the overall design remains the same, but you can change the blades or handles depending on the material you want to cut. ̽��ֱ��power of this approach is that, even working by myself in the lab at the start of the pandemic, I was able to generate and screen a handful of these XNAzymes in a matter of days.”

Taylor then teamed up with Dr Nicholas Matheson to show that his XNAzymes were active against live SARS-CoV-2 virus, taking advantage of CITIID’s state-of-the-art Containment Level 3 Laboratory – the largest academic facility for studying high risk biological agents like SARS-CoV-2 in the country.

“It's really encouraging that for the first time – and this has been a big goal of the field – we actually have them working as enzymes inside cells, and inhibiting replication of live virus,” said Dr Pehuén Pereyra Gerber, who performed the experiments on SARS-CoV-2 in Matheson’s lab.

“What we’ve shown is proof of principle, and it’s still early days,” added Matheson, “It’s worth remembering, however, that the amazingly successful Pfizer and Moderna COVID-19 vaccines are themselves based on synthetic RNA molecules – so it’s a really exciting and rapidly developing field, with enormous potential.”

Taylor checked the target viral sequences against databases of human RNAs to ensure they were not present in our own RNA. Because the XNAzymes are highly specific, this should in theory prevent some of the ‘off-target’ side-effects that similar, less accurate molecular therapeutics may cause, such as liver toxicity.

SARS-CoV-2 has the ability to evolve and change its genetic code, leading to new variants against which vaccines are less effective. To get around this problem, Taylor not only targeted regions of the viral RNA that mutate less frequently, but he also designed three of the XNAzymes to self-assemble into a ‘nanostructure’ that cuts different parts of the virus genome.

“We’re targeting multiple sequences, so for the virus to evade the therapy it would have to mutate at several sites at once,” he said. “In principle, you could combine lots of these XNAzymes together into a cocktail. But even if a new variant does appear that is capable of getting round this, because we already have the catalytic core, we can rapidly make new enzymes to keep ahead of it.”

XNAzymes could potentially be administered as drugs to protect people exposed to COVID-19, to prevent the virus taking hold, or to treat patients with infection, helping rid the body of the virus. This sort of approach might be particularly important for patients who, because of a weakened immune system, struggle to clear the virus on their own.

̽��ֱ��next step for Taylor and his team is to make XNAzymes that are even more specific and robust – “bulletproof,” he says – allowing them to remain in the body for longer, and work as even more effective catalysts, in smaller doses.

̽��ֱ��research was funded by the Wellcome Trust, the Royal Society, the Medical Research Council, NHS Blood and Transplant, and Addenbrooke’s Charitable Trust.

Reference
Pereyra Gerber, P, Donde, MJ, Matheson, NJ and Taylor, AI. XNAzymes targeting the SARS-CoV-2 genome inhibit viral infection. Nature Communications (2022). DOI: 10.1038/s41467-022-34339-w

Cambridge scientists have used synthetic biology to create artificial enzymes programmed to target the genetic code of SARS-CoV-2 and destroy the virus, an approach that could be used to develop a new generation of antiviral drugs.

XNAzymes are molecular scissors which recognise a particular sequence in the RNA, then chop it up

Alex Taylor

Jordan Siemens (Getty Images)

A 3d animation of the COVID-19 Virus or Coronavirus being broken apart

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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Referrals to long COVID clinic fell by 79% following roll-out of the vaccine

cjb250 — Thu, 06 Oct 2022 07:00:15 +0000

According to the Office of National Statistics, in July this year an estimated 2 million people in the UK were living with self-reported long COVID – that is, symptoms continuing for more than four weeks after their first suspected coronavirus (COVID-19) infection. Patients report symptoms including fatigue, muscle aches, memory problems and shortness of breath more than six months post-acute COVID-19, and a significant number of patients have not fully recovered two years since the initial infection.

Two recent studies have suggested that vaccination strongly reduced long COVID symptoms one-to-three months after infection, but another study using a cohort of US Army Veterans suggested a more modest, 15% reduction at six months.

In May 2020, Addenbrooke’s Hospital, part of Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust (CUH), set up a long COVID clinic, with patients referred to the clinic based on a number of criteria, one of which is symptoms duration of at least five months. These patients tend to be those on the severe end of the symptom spectrum, having been referred following assessment by a team that includes a GP, mental health practitioners, physio and occupational therapists amongst other specialists.

Researchers at the Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID) at the ̽��ֱ�� of Cambridge and CUH, analysed data from the clinic and found a 79% drop in the number of patients being referred to the clinic from August 2021 to June 2022, compared to August 2020 to July 2021. ̽��ֱ��decrease began five months after people started receiving second doses of COVID-19 vaccines.

Six-month moving averages fell from around 10 referrals per month to just one or two referrals per month. This effect has so far been sustained until at least June 2022, despite four times more cases per month of acute COVID-19 in England across the same time periods.

Dr Ben Krishna from the ̽��ֱ�� of Cambridge said: “Long COVID can have a significant impact on an individual’s life, and the large number of patients still experiencing symptoms many months after infection is placing additional strain on our healthcare services.

“We know that rollout of the vaccines has had a major impact on the number and severity of COVID infections, and evidence from our clinic suggests that it has also played an important role in reducing the rates of the most severe long COVID cases.”

̽��ֱ��researchers say that it is possible – but unlikely – that the emergence of the Delta variant may also have affected long COVID rates. However, the observed reduction in long COVID rates in August 2021 was from patients experiencing symptoms for five months, which they say would suggest a change beginning in March 2021. This correlates well with the second doses of vaccination in the UK, but the Delta wave did not begin until April 2021.

̽��ֱ��team say they also cannot rule out prior infections providing immunity that protects against long COVID from reinfections; however, primary infections were more common than reinfections around March-April 2021.

̽��ֱ��team observed no changes in symptoms between those referred for long COVID before or after vaccination for any of the major symptoms such as fatigue (73% pre-vaccination vs 76% post vaccination) and shortness of breath (18% pre-vaccination vs 23% post-vaccination).

It is not yet clear what level of immunity is required to protect against long COVID, say the researchers. As immunity wanes over time, booster shots – including variant-specific booster shots – may be necessary to minimise long COVID risk.

Dr Nyaradzai Sithole from CUH said: “As the virus continues to circulate and infect – and in many cases, re-infect – people, it’s important that everyone is up-to-date with their vaccinations. This will not only help prevent, or at least lessen, their primary COVID infection, but should reduce their risk of long COVID. But whether with the emergence of new variants we will begin to see an uptick in the number of cases of long COVID remains to be seen.”

̽��ֱ��study is published in Clinical Infectious Diseases.

̽��ֱ��research as funded by the Addenbrooke’s Charitable Trust and the National Institute for Health and Care Research (NIHR), with support from the NIHR Cambridge Biomedical Research Centre.

Reference
Krishna, B et al. Reduced incidence of Long COVID referrals to the Cambridge ̽��ֱ�� Teaching Hospital Long COVID clinic. Clinical Infectious Diseases; 1 Aug 2022; DOI: 10.1093/cid/ciac630

Referrals to Cambridge’s long COVID clinic fell dramatically in the period August 2021 to June 2022, which researchers say is likely due to the successful rollout of the vaccine.

We know that rollout of the vaccines has had a major impact on the number and severity of COVID infections, and evidence from our clinic suggests that it has also played an important role in reducing the rates of the most severe long COVID cases

Ben Krishna

pearson0612

Model of coronavirus and hypodermic needle

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Cognitive impairment from severe COVID-19 equivalent to 20 years of ageing, study finds

cjb250 — Tue, 03 May 2022 07:00:18 +0000

̽��ֱ��findings, published in the journal eClinicalMedicine, emerge from the NIHR COVID-19 BioResource. ̽��ֱ��results of the study suggest the effects are still detectable more than six months after the acute illness, and that any recovery is at best gradual.

There is growing evidence that COVID-19 can cause lasting cognitive and mental health problems, with recovered patients reporting symptoms including fatigue, ‘brain fog’, problems recalling words, sleep disturbances, anxiety and even post-traumatic stress disorder (PTSD) months after infection. In the UK, a study found that around one in seven individuals surveyed reported having symptoms that included cognitive difficulties 12 weeks after a positive COVID-19 test.

While even mild cases can lead to persistent cognitive symptoms, between a third and three-quarters of hospitalised patients report still suffering cognitive symptoms three to six months later.

To explore this link in greater detail, researchers analysed data from 46 individuals who received in-hospital care, on the ward or intensive care unit, for COVID-19 at Addenbrooke’s Hospital, part of Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust. 16 patients were put on mechanical ventilation during their stay in hospital. All the patients were admitted between March and July 2020 and were recruited to the NIHR COVID-19 BioResource.

̽��ֱ��individuals underwent detailed computerised cognitive tests an average of six months after their acute illness using the Cognitron platform, which measures different aspects of mental faculties such as memory, attention and reasoning. Scales measuring anxiety, depression and post-traumatic stress disorder were also assessed. Their data were compared against matched controls.

This is the first time that such rigorous assessment and comparison has been carried out in relation to the after effects of severe COVID-19.

COVID-19 survivors were less accurate and with slower response times than the matched control population – and these deficits were still detectable when the patients were following up six months later. ̽��ֱ��effects were strongest for those who required mechanical ventilation. By comparing the patients to 66,008 members of the general public, the researchers estimate that the magnitude of cognitive loss is similar on average to that sustained with 20 years ageing, between 50 and 70 years of age, and that this is equivalent to losing 10 IQ points.

Survivors scored particularly poorly on tasks such as verbal analogical reasoning, a finding that supports the commonly-reported problem of difficulty finding words. They also showed slower processing speeds, which aligns with previous observations post COVID-19 of decreased brain glucose consumption within the frontoparietal network of the brain, responsible for attention, complex problem-solving and working memory, among other functions.

Professor David Menon from the Division of Anaesthesia at the ̽��ֱ�� of Cambridge, the study’s senior author, said: “Cognitive impairment is common to a wide range of neurological disorders, including dementia, and even routine ageing, but the patterns we saw – the cognitive 'fingerprint' of COVID-19 – was distinct from all of these.”

While it is now well established that people who have recovered from severe COVID-19 illness can have a broad spectrum of symptoms of poor mental health – depression, anxiety, post-traumatic stress, low motivation, fatigue, low mood, and disturbed sleep – the team found that acute illness severity was better at predicting the cognitive deficits.

̽��ֱ��patients’ scores and reaction times began to improve over time, but the researchers say that any recovery in cognitive faculties was at best gradual and likely to be influenced by a number of factors including illness severity and its neurological or psychological impacts.

Professor Menon added: “We followed some patients up as late as ten months after their acute infection, so were able to see a very slow improvement. While this was not statistically significant, it is at least heading in the right direction, but it is very possible that some of these individuals will never fully recover.”

There are several factors that could cause the cognitive deficits, say the researchers. Direct viral infection is possible, but unlikely to be a major cause; instead, it is more likely that a combination of factors contribute, including inadequate oxygen or blood supply to the brain, blockage of large or small blood vessels due to clotting, and microscopic bleeds. However, emerging evidence suggests that the most important mechanism may be damage caused by the body’s own inflammatory response and immune system.

While this study looked at hospitalised cases, the team say that even those patients not sick enough to be admitted may also have tell-tale signs of mild impairment.

Professor Adam Hampshire from the Department of Brain Sciences at Imperial College London, the study’s first author, said: “Around 40,000 people have been through intensive care with COVID-19 in England alone and many more will have been very sick, but not admitted to hospital. This means there is a large number of people out there still experiencing problems with cognition many months later. We urgently need to look at what can be done to help these people.”

Professor Menon and Professor Ed Bullmore from Cambridge’s Department of Psychiatry are co-leading working groups as part of the COVID-19 Clinical Neuroscience Study (COVID-CNS) that aim to identify biomarkers that relate to neurological impairments as a result of COVID-19, and the neuroimaging changes that are associated with these.

̽��ֱ��research was funded by the NIHR BioResource, NIHR Cambridge Biomedical Research Centre and the Addenbrooke’s Charitable Trust, with support from the NIHR Cambridge Clinical Research Facility.

Reference
Hampshire, A et al. Multivariate profile and acute-phase correlates of cognitive deficits in a COVID-19 hospitalised cohort. eClinicalMedicine; 28 Apr 2022; DOI: 10.1016/j.eclinm.2022.101417

Cognitive impairment as a result of severe COVID-19 is similar to that sustained between 50 and 70 years of age and is the equivalent to losing 10 IQ points, say a team of scientists from the ̽��ֱ�� of Cambridge and Imperial College London.

Cognitive impairment is common to a wide range of neurological disorders, but the patterns we saw – the cognitive 'fingerprint' of COVID-19 – was distinct from all of these

David Menon

RUBEN BONILLA GONZALO

Senior woman wearing face mask lying on hospital bed

Yes

Lab-grown beating heart cells identify potential drug to prevent COVID-19-related heart damage

cjb250 — Thu, 05 Aug 2021 08:35:20 +0000

̽��ֱ��heart is one the major organs damaged by infection with SARS-CoV-2, particularly the heart cells, or ‘cardiomyocytes’, which contract and circulate blood. It is also thought that damage to heart cells may contribute to the symptoms of long COVID.

Patients with underlying heart problems are more than four times as likely to die from COVID-19, the disease caused by SARS-CoV-2 infection. ̽��ֱ��case fatality rate in patients with COVID-19 rises from 2.3% to 10.5% in these individuals.

To gain entry into our cells, SARS-CoV-2 hijacks a protein on the surface of the cells, a receptor known as ACE2. Spike proteins on the surface of SARS-CoV-2 – which give it its characteristic ‘corona’-like appearance – bind to ACE2. Both the spike protein and ACE2 are then cleaved, allowing genetic material from the virus to enter the host cell. ̽��ֱ��virus manipulates the host cell’s machinery to allow itself to replicate and spread.

A team of scientists at the ̽��ֱ�� of Cambridge has used human embryonic stem cells to grow clusters of heart cells in the lab and shown that these cells mimic the behaviour of the cells in the body, beating as if to pump blood. Crucially, these model heart cells also contained the key components necessary for SARS-CoV-2 infection – in particular, the ACE2 receptor.

Working in special biosafety laboratories and using a safer, modified synthetic (‘pseudotyped’) virus decorated with the SARS-CoV-2 spike protein, the team mimicked how the virus infects the heart cells. They then used this model to screen for potential drugs to block infection.

Dr Sanjay Sinha from the Wellcome-MRC Cambridge Stem Cell Institute said: “Using stem cells, we’ve managed to create a model which, in many ways, behaves just like a heart does, beating in rhythm. This has allowed us to look at how the coronavirus infects cells and, importantly, helps us screen possible drugs that might prevent damage to the heart.”

̽��ֱ��team showed that some drugs that targeted the proteins involved in SARS-CoV-2 viral entry signiﬁcantly reduced levels of infection. These included an ACE2 antibody that has been shown previously to neutralise pseudotyped SARS-CoV-2 virus, and DX600, an experimental drug.

DX600 is an ACE2 peptide antagonist – that is, a molecule that specifically targets ACE2 and inhibits the activity of peptides that play a role in allowing the virus to break into the cell.

DX600 was around seven times more effective at preventing infection compared to the antibody, though the researchers say this may be because it was used in higher concentrations. ̽��ֱ��drug did not affect the number of heart cells, implying that it would be unlikely to be toxic.

Professor Anthony Davenport from the Department of Medicine and a fellow at St Catharine’s College, Cambridge said: “ ̽��ֱ��spike protein is like a key that fits into the ‘lock’ on the surface of the cells – the ACE2 receptor – allowing it entry. DX600 acts like gum, jamming the lock’s mechanism, making it much more difficult for the key to turn and unlock the cell door.

“We need to do further research on this drug, but it could provide us with a new treatment to help reduce harm to the heart in patients recently infected with the virus, particularly those who already have underlying heart conditions or who have not been vaccinated. We believe it may also help reduce the symptoms of long COVID.”

̽��ֱ��research was largely supported by Wellcome, Addenbrooke’s Charitable Trust, Rosetrees Trust Charity and British Heart Foundation.

Reference
Williams, TL et al. Human embryonic stem cell-derived cardiomyocyte platform screens inhibitors of SARS-CoV-2 infection. Communications Biology; 29 Jul 2021; DOI: 10.1038/s42003-021-02453-y

Cambridge scientists have grown beating heart cells in the lab and shown how they are vulnerable to SARS-CoV-2 infection. In a study published in Communications Biology, they used this system to show that an experimental peptide drug called DX600 can prevent the virus entering the heart cells.

Using stem cells, we’ve managed to create a model which, in many ways, behaves just like a heart does, beating in rhythm. This has allowed us to look at how the coronavirus infects cells and, importantly, helps us screen possible drugs that might prevent damage to the heart

Sanjay Sinha

Beating heart cells infected with virus

sbtlneet

Heart

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Public Domain

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

cjb250 — Tue, 29 Jun 2021 07:20:09 +0000

̽��ֱ��findings are reported by a team at the ̽��ֱ�� of Cambridge and Cambridge ̽��ֱ�� Hospitals (CUH) NHS Foundation Trust. ̽��ֱ��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 UK Infection Protection Control guidance 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. ̽��ֱ��guidance has recently been updated 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.

̽��ֱ��results suggest that 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 ̽��ֱ�� 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 ̽��ֱ�� 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 ̽��ֱ�� 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 ̽��ֱ�� 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.”

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

Reference
Ferris, M, Ferris, R et al. FFP3 respirators protect healthcare workers against infection with SARS-CoV-2. DOI: 10.22541/au.162454911.17263721/v1

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.

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

Mark Ferris

Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust

Healthcare worker wearing FFP3 mask

Yes

Gene therapy technique shows potential for repairing damage caused by glaucoma and dementia

cjb250 — Wed, 31 Mar 2021 18:00:54 +0000

Gene therapy – where a missing or defective gene is replaced by a healthy version – is becoming increasingly common for a number of neurological conditions including Leber’s Congenital Amaurosis, Spinal Muscular Atrophy and Leber’s Hereditary Optic Neuropathy. However, each of these conditions is rare, and monogenic – that is, caused by a single defective gene. ̽��ֱ��application of gene therapy to complex polygenic conditions, which make up the majority of neurodegenerative diseases, has been limited to date.

A common feature of neurodegenerative diseases is disruption of axonal transport, a cellular process responsible for movement of key molecules and cellular ‘building blocks’ including mitochondria, lipids and proteins to and from the body of a nerve cell. Axons are long fibres that transmit electrical signals, allowing nerve cells to communicate with other nerve cells and muscles. Scientists have suggested that stimulating axonal transport by enhancing intrinsic neuronal processes in the diseased central nervous system might be a way to repair damaged nerve cells.

Two candidate molecules for improving axonal function in injured nerve cells are brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin receptor kinase B (TrkB).

In research published today in Science Advances, scientists at the ̽��ֱ�� of Cambridge show that delivering both of these molecules simultaneously to nerve cells using a single virus has a strong effect in stimulating axonal growth compared to delivering either molecule on its own. They tested their idea in two models of neurodegenerative disease known to be associated with reduced axonal transport, namely glaucoma and tauopathy (a degenerative disease associated with dementia).

Dr Tasneem Khatib from the John van Geest Centre for Brain Repair at the ̽��ֱ�� of Cambridge, the study’s first author, said: “ ̽��ֱ��axons of nerve cells function a bit like a railway system, where the cargo is essential components required for the cells to survive and function. In neurodegenerative diseases, this railway system can get damaged or blocked. We reckoned that replacing two molecules that we know work effectively together would help to repair this transport network more effectively than delivering either one alone, and that is exactly what we found.

“This combined approach also leads to a much more sustained therapeutic effect, which is very important for a treatment aimed at a chronic degenerative disease.

“Rather than using the standard gene therapy approach of replacing or repairing damaged genes, we used the technique to supplement these molecules in the brain.”

Glaucoma is damage to the optic nerve often, but not always, associated with abnormally high pressure in the eye. In an experimental glaucoma model, the researchers used a tracer dye to show that axonal transport between the eye and brain was impaired in glaucoma. Similarly, a reduction in electrical activity in the retina in response to light suggested that vision was also impaired.

Dr Khatib and colleagues used ‘viral vectors’ – gene therapy delivery systems – to deliver TrkB and BDNF to the retina of rats. They found that this restored axonal transport between the retina and the brain, as observed by movement of the dye. ̽��ֱ��retinas also showed an improved electrical response to light, a key prerequisite for visual restoration.

Next, the team used transgenic mice bred to model tauopathy, the build-up of ‘tangles’ of tau protein in the brain. Tauopathy is seen in a number of neurodegenerative diseases including Alzheimer’s disease and frontotemporal dementia. Once again, injection of the dye showed that axonal transport was impaired between the eye and the brain – and that this was restored using the viral vectors.

Intriguingly, the team also found preliminary evidence of possible improvement in the mice’s short-term memory. Prior to treatment, the researchers tested the mice on an object recognition task. ̽��ֱ��mouse was placed at the start of a Y-shaped maze and left to explore two identical objects at the end of the two arms. After a short while, the mouse was once again placed in the maze, but this time one arm contained a new object, while the other contained a copy of the repeated object. ̽��ֱ��researchers measured the amount of the time the mouse spent exploring each object to see whether it had remembered the object from the previous task.

This task was repeated after the viral vector had been injected into the mouse’s brain and the results were suggestive of a small improvement in short-term memory. While the results of this particular study did not quite achieve statistical significance – a measure of how robust the findings are – the researchers say they are promising and a larger study is now planned to confirm the effect.

Professor Keith Martin from the Centre for Eye Research Australia and the ̽��ֱ�� of Melbourne, who led the study while at Cambridge, added: “While this is currently early stage research, we believe it shows promise for helping to treat neurodegenerative diseases that have so far proved intractable. Gene therapy has already proved effective for some rare monogenic conditions, and we hope it will be similarly useful for these more complex diseases which are much more common.”

̽��ֱ��research was supported by Fight for Sight, Addenbrooke’s Charitable Trust, the Cambridge Eye Trust, the Jukes Glaucoma Research Fund, Quethera Ltd, Alzheimer's Research UK, Gates Cambridge Trust, Wellcome and the Medical Research Council.

Reference
Khatib, TZ et al. Receptor-ligand supplementation via a self-cleaving 2A peptide-based gene therapy promotes CNS axon transport with functional recovery. Science Advances; 31 Mar 2021; DOI: 10.1126/sciadv.abd2590

Scientists at the ̽��ֱ�� of Cambridge have shown in animal studies that gene therapy may help repair some of the damage caused in chronic neurodegenerative conditions such as glaucoma and dementia. Their approach demonstrates the potential effectiveness of gene therapy in polygenic conditions – that is, complex conditions with no single genetic cause.

[Our] approach also leads to a much more sustained therapeutic effect, which is very important for a treatment aimed at a chronic degenerative disease

Tasneem Khatib

IAPB/VISION 2020

Screening for glaucoma

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Cambridge leads trial to see if tapeworm drug can boost protection from COVID-19 among vulnerable

cjb250 — Mon, 22 Mar 2021 08:16:58 +0000

If the trial is successful, it may pave the way for a new treatment to prevent or alleviate the impact of COVID-19 in people on dialysis, people who have had a kidney transplant, and people with auto-immune diseases affecting the kidneys such as vasculitis who require treatment to suppress their immune system. ̽��ֱ��treatment will last up to nine months.

Led by scientists from the Cambridge ̽��ֱ�� Hospitals NHS Trust and the ̽��ֱ�� of Cambridge, the PROphylaxis for vulnerable paTiEnts at risk of COVID-19 infecTion (PROTECT-V) trial will start in Cambridge with a plan to expand to other UK healthcare centres. It will recruit at least 1,500 kidney patients, who will be randomised to receive either a placebo (or dummy) drug, or UNI911 (niclosamide) as a nasal spray, both provided by the manufacturer UNION therapeutics, in addition to all their usual treatments. Participants can receive the vaccine and still take part in this trial, which will identify whether niclosamide can protect people from the virus either on its own, or in combination with any of the vaccines currently available.

Niclosamide has been re-formulated into a nasal spray so it can be delivered directly to the lining of the nasal cavity, like a hayfever spray. In the trial, people will take one puff up each nostril twice a day, as this is the part of the body where the virus can take hold. This ‘local’ drug delivery is likely to reduce the chances of people experiencing any side effects.

Usually used to treat intestinal worms and taken as a tablet, niclosamide has shown real promise in the lab. Early tests revealed niclosamide could stop SARS-CoV-2 multiplying and entering cells of the upper airways.

Dr Rona Smith, senior research associate at the ̽��ֱ�� of Cambridge and honorary consultant nephrologist at Addenbrooke’s Hospital, who is leading the UK study, said: “It is vital that we find a way to protect patients on haemodialysis and other high-risk kidney patients from catching SARS-CoV-2 and developing COVID-19. If they get it, they are more likely to fall seriously ill or die, and we need to find a way to change that.

“We believe testing niclosamide is particularly important for people who are immunosuppressed and have kidney disease, because their immune responses to vaccines can sometimes be less effective. While the vaccine will offer a level of protection, niclosamide may provide further protection against COVID-19 that doesn’t rely on the immune system mounting a response.

“If successful, our innovative trial could mean that the treatment becomes available to kidney patients more widely within months. It would mean they could receive their regular life-saving dialysis or take their immunosuppressant drugs without additional worry. And if it’s successful it could even be rolled out more widely – and benefit more vulnerable people.”

̽��ֱ��trial involves researchers and patients from across the UK. It is funded by LifeArc, Kidney Research UK, the Addenbrooke’s Charitable Trust and UNION therapeutics and is supported by the NIHR Cambridge Biomedical Research Centre. UNION therapeutics is supplying the drug.

Professor Jeremy Hughes, kidney doctor and chair of trustees at Kidney Research UK, said: “Sadly, one in five kidney patients receiving dialysis in hospital or who have a kidney transplant and tested positive for the virus died within four weeks. Many of those on dialysis are having to put themselves at risk and attend their renal unit for life-saving dialysis treatment several times each week. And those who have had a kidney transplant must continue taking their immunosuppressant drugs, despite these making them more susceptible to infection.”

“Repurposing already available drugs or those in the late stage of development offers the fastest route to bring benefit to patients at this critical time,” said Melanie Lee, CEO of LifeArc.

Announcing the PROTECT-V trial, Matt Hancock, Health and Social Care Secretary, said: “Since the beginning of the pandemic, we have worked to find the best treatments the world has to offer for COVID-19.

“We have been clear from the outset that it will be a combination of safe and effective vaccines, testing and therapeutics that will bring an end to this pandemic, and we will not rest until every individual in the country is protected against this awful disease.”

Kidney patients who would like to take part in the PROTECT-V trial should speak to their nephrologist in their local centre to find out if their centre is participating in the trial and if they are eligible to take part.

Adapted from a press release by Kidney Research UK.

UK researchers are launching a clinical trial to investigate if the drug niclosamide, usually used to treat tapeworms, can prevent COVID-19 infection in vulnerable, high risk kidney patients and reduce the number of people who become seriously ill or die from it.

It is vital that we find a way to protect patients on haemodialysis and other high-risk kidney patients from catching SARS-CoV-2 and developing COVID-19

Rona Smith

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Coronavirus

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