探花直播 of Cambridge - Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID)

Prioritise vaccine boosters for vulnerable immunocompromised patients, say scientists

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

探花直播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 鈥榲ariants of concern鈥� 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 鈥榖ooster鈥� 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 探花直播 of Cambridge examined immunocompromised individuals who had been vaccinated against Covid-19. These patients, recruited from Cambridge 探花直播 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 鈥� 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: 鈥淲e 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 鈥� often four or more 鈥� offer the necessary protection.鈥�

Professor Ravi Gupta, also from CITIID and a Fellow at Homerton College, Cambridge, added: 鈥淭his 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.

鈥淲e know from our previous work that at least some of the variants of concern probably emerged during chronic infections. That鈥檚 why these individuals must be given priority for updated vaccines against new variants.鈥�

探花直播research was funded by Wellcome, Gates Cambridge, Addenbrooke鈥檚 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 探花直播 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

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Vaccination of an senior male

探花直播text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright 漏探花直播 of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways 鈥� 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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Monoclonal antibodies offer hope for tackling antimicrobial resistance

cjb250 — Mon, 16 Sep 2024 10:31:11 +0000

A team lead by researchers at the 探花直播 of Cambridge has developed a monoclonal antibody drug, using a technique involving genetically engineered mice, that may help prevent infection from Acinetobacter baumannii, a bacteria associated with hospital-acquired infections, which is particularly common in Asia.

A. baumannii bacteria can cause life-threatening respiratory illness and sepsis in vulnerable individuals, particularly in newborn babies whose immune systems have not fully developed. It is usually spread through contaminated surfaces, medical equipment and via contact with others. In recent years infections with strains of this bacteria that are resistant to almost every antibiotic available have become common.

Professor Stephen Baker from the Cambridge Institute of Therapeutic Immunology and Infectious Disease at the 探花直播 of Cambridge said 鈥�A. baumannii is good at sticking to medical equipment, and if people are vulnerable or don't have a particularly well-developed immune system, they can succumb to this infection and get aggressive pneumonia requiring ventilation 鈥� and in many cases, the patients can acquire the infection from the ventilation itself.

鈥� 探花直播bacteria are naturally resistant to many antimicrobials, but as they鈥檙e now found in hospitals, they鈥檝e acquired resistance to almost everything we can use. In some hospitals in Asia, where the infections are most common, there isn't a single antibiotic that will work against them. They鈥檝e become impossible to treat.鈥�

In a study published today in Nature Communications, the team produced monoclonal antibodies using transgenic mice 鈥� mice that have been genetically-engineered to have a human-like immune system, producing human antibodies instead of mouse antibodies. They went on to show that these monoclonal antibodies were able prevent infection with A. baumannii derived from clinical samples.

Monoclonal antibodies are a growing area of medicine, commonly used to treat conditions including cancer (for example, Herceptin for treating some breast cancers) and autoimmune disease (for example, Humira for treating rheumatoid arthritis, psoriasis, Crohn's disease, and ulcerative colitis).

Usually, monoclonal antibodies are developed from the antibodies of patients who have recovered from an infection, or they are designed to recognise and target a particular antigen. For example, monoclonal antibodies targeting the 鈥榮pike protein鈥� of the SARS-CoV-2 coronavirus were explored as a way of treating COVID-19.

In the approach taken by the Cambridge team, however, transgenic mice were exposed to the outer membrane of A. baumannii bacteria, triggering an immune response. 探花直播researchers then isolated almost 300 different antibodies and tested which of these was the most effective at recognising live bacteria, identifying the single monoclonal antibody mAb1416 as the best.

Professor Baker said: 鈥淯sing this method, we don't infect the mice with the live bacteria, but we instead immunise them using multiple different elements and let the mouse鈥檚 immune system work out which ones to develop antibodies against. Because these mice have 鈥榟umanised鈥� immune systems, we wouldn鈥檛 then need to reengineer the antibodies to work in humans.鈥�

探花直播team treated mice with mAb1416, and 24 hours later exposed them to A. baumannii isolated from a child with sepsis in an intensive care unit. They found that those mice treated with the drug saw a significant reduction in bacterial load in their lungs a further 24 hours later, compared to mice that were not treated.

All of the isolates used to produce and test the monoclonal antibodies were from patients in Ho Chi Minh City, Vietnam, but the isolate used to test mAb1416 was taken from a patient ten years later than the other isolates. This is important because it shows that mAb1416 was protective against A. baumannii bacteria that may have evolved over time.

Professor Baker said: 鈥淯sing this technique, you can take any bacterial antigen or cocktail of antigens, rather than waiting for somebody that's recovered from a particular infection 鈥� who you assume has developed an appropriate antibody response 鈥� give it to the mice and extract the antibodies you think are the most important.鈥�

More work is now needed to understand the mechanism by which mAb1416 protects against infection, as this could allow the team to develop an even more effective treatment. Any potential new drug will then need to be tested in safety trials in animals before being trialled in patients.

Professor Baker added: 鈥淲e know that monoclonal antibodies are safe and that they work, and the technology exists to produce them 鈥� what we have done is identify how to hit bacteria with them. Apart from the cost effectiveness, there's no reason why this couldn鈥檛 become a medicine within a few years. Given the emergency presented by antimicrobial resistance, this could become a powerful new weapon to fight back.鈥�

探花直播research was funded by the Bill & Melinda Gates Foundation, the UK Medical Research Council Newton Fund, the Viet Nam Ministry of Science and Technology, and Wellcome.

Professor Baker is a fellow at Wolfson College, Cambridge.

Reference
Baker, S, Krishna, A & Higham, S. Exploiting human immune repertoire transgenic mice to identify protective monoclonal antibodies against an extensively antimicrobial resistant nosocomial bacterial pathogen. Nat Comms; 12 Sept 2024; DOI: 10.1038/s41467-024-52357-8

Monoclonal antibodies 鈥� treatments developed by cloning a cell that makes an antibody 鈥� could help provide an answer to the growing problem of antimicrobial resistance, say scientists.

We know that monoclonal antibodies are safe and that they work, and the technology exists to produce them 鈥� what we have done is identify how to hit bacteria with them

Stephen Baker

TopMicrobialStock (Getty Images)

A Petri dish with a culture of the Superbug Acinetobacter baumannii next to antibiotics

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Early career researchers win major European funding

ta385 — Thu, 05 Sep 2024 09:30:00 +0000

Of 3,500 proposals reviewed by the ERC, only 14% were selected for funding 鈥� Cambridge has the highest number of grants of any UK institution.

ERC Starting Grants 鈥� totalling聽nearly 鈧�780 million 鈥� support cutting-edge research in a wide range of fields, from life sciences and physics to social sciences and humanities.

探花直播awards help researchers at the beginning of their careers to launch their own projects, form their teams and pursue their most promising ideas. Starting Grants amount to 鈧�1.5 million per grant for a period of five years but additional funds can be made available.

In total, the grants are estimated to create 3,160 jobs for postdoctoral fellows, PhD students and other staff at host institutions.

Cambridge鈥檚 recipients work in a wide range of fields including plant sciences, mathematics and medicine. They are among 494 laureates who will be leading projects at universities and research centres in 24 EU Member States and associated countries. This year, the UK has received grants for 50 projects, Germany 98, France 49, and the Netherlands 51.

Cambridge鈥檚 grant recipients for 2024 are:

Adrian Baez-Ortega (Dept. of Veterinary Medicine, Wellcome Sanger Institute) for Exploring the mechanisms of long-term tumour evolution and genomic instability in marine transmissible cancers

Claudia Bonfio (MRC Laboratory of Molecular Biology) for Lipid Diversity at the Onset of Life

Tom Gur (Dept. of Computer Science and Technology) for Sublinear Quantum Computation

Leonie Luginbuehl (Dept. of Plant Sciences) for Harnessing mechanisms for plant carbon delivery to symbiotic soil fungi for sustainable food production

Julian Sahasrabudhe (Dept. of Pure Mathematics and Mathematical Statistics) for High Dimensional Probability and Combinatorics

Richard Timms (Cambridge Institute聽for聽Therapeutic Immunology聽and Infectious Disease) for Deciphering the regulatory logic of the ubiquitin system

Hannah 脺bler (Dept. of Physics) for Active galactic nuclei and Population III stars in early galaxies

Julian Willis (Yusuf Hamied Department of Chemistry) for Studying viral protein-primed DNA replication to develop new gene editing technologies

Federica Gigante (Faculty of History) for Unveiling Networks: Slavery and the European Encounter with Islamic Material Culture (1580鈥� 1700) 鈥� Grant hosted by the 探花直播 of Oxford

聽

Professor Sir John Aston FRS, Pro-Vice-Chancellor for Research at the 探花直播 of Cambridge, said:

鈥淢any congratulations to the recipients of these awards which reflect the innovation and the vision of these outstanding investigators. We are fortunate to have many exceptional young researchers across a wide range of disciplines here in Cambridge and awards such as these highlight some of the amazing research taking place across the university. I wish this year鈥檚 recipients all the very best as they begin their new programmes and can鈥檛 wait to see the outcomes of their work.鈥�

Iliana Ivanova, European Commissioner for Innovation, Research, Culture, Education and Youth, said:

鈥� 探花直播European Commission is proud to support the curiosity and passion of our early-career talent under our Horizon Europe programme. 探花直播new ERC Starting Grants winners aim to deepen our understanding of the world. Their creativity is vital to finding solutions to some of the most pressing societal challenges. In this call, I am happy to see one of the highest shares of female grantees to date, a trend that I hope will continue. Congratulations to all!鈥�

President of the European Research Council, Prof. Maria Leptin, said:

鈥淓mpowering researchers early on in their careers is at the heart of the mission of the ERC. I am particularly pleased to welcome UK researchers back to the ERC. They have been sorely missed over the past years. With fifty grants awarded to researchers based in the UK, this influx is good for the research community overall.鈥�

Nine Cambridge researchers are among the latest recipients of highly competitive and prestigious European Research Council (ERC) Starting Grants.

Luginbuehl lab

Plant roots interacting with arbuscular mycorrhizal fungi. Image: Luginbuehl lab

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Low iron levels resulting from infection could be key trigger of long COVID

cjb250 — Mon, 04 Mar 2024 10:00:41 +0000

探花直播discovery not only points to possible ways to prevent or treat the condition, but could help explain why symptoms similar to those of long COVID are also commonly seen in a number of post-viral conditions and chronic inflammation.

Although estimates are highly variable, as many as three in 10 people infected with SARS-CoV-2 could go on to develop long COVID, with symptoms including fatigue, shortness of breath, muscle aches and problems with memory and concentration (鈥榖rain fog鈥�). An estimated 1.9 million people in the UK alone were experiencing self-reported long COVID as of March 2023, according to the Office of National Statistics.

Shortly after the start of the COVID-19 pandemic, researchers at the 探花直播 of Cambridge began recruiting people who had tested positive for the virus to the COVID-19 cohort of the National Institute for Health and Care Research (NIHR) BioResource. These included asymptomatic healthcare staff identified via routine screening through to patients admitted to Cambridge 探花直播 Hospitals NHS Foundation Trust, some to its intensive care unit.

Over the course of a year, participants provided blood samples, allowing researchers to monitor changes in the blood post-infection. As it became clear that a significant number of patients would go on to have symptoms that persisted 鈥� long COVID 鈥� researchers were able to track back through these samples to see whether any changes in the blood correlated with their later condition.

In findings published in Nature Immunology, researchers at the Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID), 探花直播 of Cambridge, together with colleagues at Oxford, analysed blood samples from 214 individuals. Approximately 45% of those questioned about their recovery reported symptoms of long COVID between three and ten months later.

Professor Ken Smith, who was Director of CITIID at the time of the study and will take up a position as Director of the Walter and Eliza Hall Institute of Medical Research (WEHI) in Melbourne, Australia, in April, said: 鈥淗aving recruited a group of people with SARS-CoV-2 early in the pandemic, analysis of several blood samples and clinical information collected over a 12 month period after infection has proved invaluable in giving us important and unexpected insights into why, for some unlucky individuals, initial SARS-CoV-2 infection is followed by months of persistent symptoms.鈥�

探花直播team discovered that ongoing inflammation 鈥� a natural part of the immune response to infection 鈥� and low iron levels in blood, contributing to anaemia and disrupting healthy red blood cell production, could be seen as early as two weeks post COVID-19 in those individuals reporting long COVID many months later.

Early iron dysregulation was detectable in the long COVID group independent of age, sex, or initial COVID-19 severity, suggesting a possible impact on recovery even in those who were at low risk for severe COVID-19, or who did not require hospitalisation or oxygen therapy when sick.

Dr Aimee Hanson, who worked on the study while at the 探花直播 of Cambridge, and is now at the 探花直播 of Bristol, said: 鈥淚ron levels, and the way the body regulates iron, were disrupted early on during SARS-CoV-2 infection, and took a very long time to recover, particularly in those people who went on to report long COVID months later.

鈥淎lthough we saw evidence that the body was trying to rectify low iron availability and the resulting anaemia by producing more red blood cells, it was not doing a particularly good job of it in the face of ongoing inflammation.鈥�

Interestingly, although iron dysregulation was more profound during and following severe COVID-19, those who went on to develop long COVID after a milder course of acute COVID-19 showed similar patterns in the blood. 探花直播most pronounced association with long COVID was how quickly inflammation, iron levels and regulation returned to normal following SARS-CoV-2 infection 鈥� though symptoms tended to continue long after iron levels had recovered.

Co-author Professor Hal Drakesmith, from the MRC Weatherall Institute of Molecular Medicine at the 探花直播 of Oxford, said iron dysregulation is a common consequence of inflammation and is a natural response to infection.

鈥淲hen the body has an infection, it responds by removing iron from the bloodstream. This protects us from potentially lethal bacteria that capture the iron in the bloodstream and grow rapidly. It鈥檚 an evolutionary response that redistributes iron in the body, and the blood plasma becomes an iron desert.

鈥淗owever, if this goes on for a long time, there is less iron for red blood cells, so oxygen is transported less efficiently affecting metabolism and energy production, and for white blood cells, which need iron to work properly. 探花直播protective mechanism ends up becoming a problem.鈥�

探花直播findings may help explain why symptoms such as fatigue and exercise intolerance are common in long COVID, as well as in several other post-viral syndromes with lasting symptoms.

探花直播researchers say the study points to potential ways of preventing or reducing the impact of long COVID by rectifying iron dysregulation in early COVID-19 to prevent adverse long-term health outcomes.

One approach might be controlling the extreme inflammation as early as possible, before it impacts on iron regulation. Another approach might involve iron supplementation; however as Dr Hanson pointed out, this may not be straightforward.

鈥淚t isn't necessarily the case that individuals don't have enough iron in their body, it's just that it鈥檚 trapped in the wrong place,鈥� she said. 鈥淲hat we need is a way to remobilise the iron and pull it back into the bloodstream, where it becomes more useful to the red blood cells.鈥�

探花直播research also supports 鈥榓ccidental鈥� findings from other studies, including the IRONMAN study, which was looking at whether iron supplements benefited patients with heart failure 鈥� the study was disrupted due to the COVID-19 pandemic, but preliminary findings suggest that trial participants were less likely to develop severe adverse effects from COVID-19. Similar effects have been observed among people living with the blood disorder beta-thalassemia, which can cause individuals to produce too much iron in their blood.

探花直播research was funded by Wellcome, the Medical Research Council, NIHR and European Union Horizon 2020 Programme.

Reference
Hanson, AL et al. Iron dysregulation and inflammatory stress erythropoiesis associates with long-term outcome of COVID-19. Nat Imm; 1 March 2024; DOI: 10.1038/s41590-024-01754-8

Problems with iron levels in the blood and the body鈥檚 ability to regulate this important nutrient as a result of SARS-CoV-2 infection could be a key trigger for long COVID, new research has discovered.

Iron levels, and the way the body regulates iron, were disrupted early on during SARS-CoV-2 infection, and took a very long time to recover, particularly in those people who went on to report long COVID months later

Aimee Hanson

Malachi Cowie

A man sitting on a couch holding his head in his hands

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Long COVID linked to persistently high levels of inflammatory protein: a potential biomarker and target for treatments

ta385 — Wed, 21 Feb 2024 18:45:00 +0000

A 探花直播 of Cambridge-led study identifies the protein interferon gamma (IFN-纬) as a potential biomarker for Long COVID fatigue and highlights an immunological mechanism underlying the disease, which could pave the way for the development of much needed therapies, and provide a head start in the event of a future coronavirus pandemic.聽

探花直播study, published today in Science Advances, followed a group of patients with Long COVID fatigue for over 2.5 years, to understand why some recovered and others did not.聽

Long COVID continues to affect millions of people globally and is placing a major burden on health services. An estimated 1.9 million people in the UK alone (2.9% of the population) were experiencing self-reported Long COVID as of March 2023, according to the ONS. Fatigue remains by far the most common and debilitating symptom and patients are still waiting for an effective treatment.

探花直播study shows that initial infection with SARS-CoV-2 triggers production of the antiviral protein IFN-纬, which is a normal reaction from the immune system. For most people, when their infection clears, COVID-19 symptoms cease and production of this protein stops, but the researchers found that high levels of IFN-纬 persisted in some Long COVID patients for up to 31 months.

鈥淲e have found a potential mechanism underlying Long COVID which could represent a biomarker 鈥� that is, a tell-tale signature of the condition. We hope that this could help to pave the way to develop therapies and give some patients a firm diagnosis,鈥� said co-author, Dr Benjamin Krishna, from the Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID).

探花直播research began in 2020 when Dr Nyarie Sithole (Hughes Hall) set up a Long COVID clinic in Cambridge鈥檚 Addenbrooke鈥檚 Hospital, where he started collecting blood samples from patients and set about studying their immunology. Sithole soon enlisted the support of Dr Benjamin Krishna and Dr Mark Wills from the 探花直播 of Cambridge鈥檚 Department聽of Medicine.

鈥淲hen the clinic started, a lot of people didn't even believe Long COVID was real,鈥� Dr Sithole said. 鈥淲e are indebted to all the patients who volunteered for this study, without whose support and participation we would obviously not have accomplished this study鈥�.

探花直播team studied 111 COVID-confirmed patients admitted to Addenbrooke鈥檚 Hospital CUH, Royal Papworth Hospital and Cambridge and Peterborough NHS Foundation Trusts at 28 days, 90 days and 180 days following symptom onset. Between August 2020 and July 2021, they recruited 55 Long COVID patients 鈥� all experiencing severe symptoms at least 5 months after acute COVID-19 鈥� attending the Long COVID clinic at Addenbrooke鈥檚.

探花直播researchers analysed blood samples for signs of cytokines, small proteins crucial to the functioning of immune system cells and blood cells. They found that the white blood cells of individuals infected with SARS-CoV-2 produced IFN-纬, a pro inflammatory molecule, and that this persisted in Long COVID patients.

Dr Krishna said: 鈥淚nterferon gamma can be used to treat viral infections such as hepatitis C but it causes symptoms including fatigue, fever, headache, aching muscles and depression. These symptoms are all too familiar to Long COVID patients. For us, that was another smoking gun.鈥�

By conducting 鈥榗ell depletion assays鈥�, the team managed to identify the precise cell types responsible for producing IFN-纬. They pinpointed immune cells known as CD8+ T cells but found that they required contact with another immune cell type: CD14+ monocytes.

Previous studies have identified IFN-纬 signatures using different approaches and cohorts, but this study鈥檚 focus on fatigue revealed a much stronger influence. Also, while previous studies have noticed IFN-y levels rising, they have not followed patients long enough to observe when they might drop back down.

探花直播Cambridge team followed its Long COVID cohort for up to 31 months post-infection. During this follow up period, over 60% of patients experienced resolution of some, if not all, of their symptoms which coincided with a drop in IFN-纬.

Vaccination helping Long COVID patients

探花直播team measured IFN-纬 release in Long COVID patients before and after vaccination and found a significant decrease in IFN-纬 post vaccination in patients whose symptoms resolved.

鈥淚f SARS-CoV-2 continues to persist in people with Long COVID, triggering an IFN-纬 response, then vaccination may be helping to clear this. But we still need to find effective therapies,鈥� Dr Krishna said.

鈥� 探花直播number of people with Long COVID is gradually falling, and vaccination seems to be playing a significant role in that. But new cases are still cropping up, and then there is the big question of what happens when the next coronavirus pandemic comes along. We could face another wave of Long COVID. Understanding what causes Long COVID now could give us a crucial head start.鈥�

Microclotting

Some well-publicised previous studies have proposed microclotting as a principle cause of Long COVID. While not ruling out a role of some kind, these new findings suggest that microclotting cannot be the only or the most significant cause.

Classifying Long COVID

This study argues that the presence of IFN-纬 could be used to classify Long COVID into subtypes which could be used to personalise treatment.聽

鈥淚t鈥檚 unlikely that all the different Long COVID symptoms are caused by the same thing. We need to differentiate between people and tailor treatments. Some patients are slowly recovering and there are those who are stuck in a cycle of fatigue for years on end. We need to know why,鈥� Dr Krishna said.

Reference

B A Krishna et al., 鈥�Spontaneous, persistent, T-cell dependent IFN-纬 release in patients who progress to long COVID鈥�, Science Advances (2024). DOI: 10.1126/sciadv.adi9379

SARS-CoV-2 triggers the production of the antiviral protein IFN-纬, which is associated with fatigue, muscle ache and depression. New research shows that in Long COVID patients, IFN-y production persists until symptoms improve, highlighting a potential biomarker and a target for therapies.聽

We hope that this could help to pave the way to develop therapies and give some patients a firm diagnosis

Benjamin Krishna

Annie Spratt via Unsplash

Woman sitting on sofa in the dark, placing a hand to her forehead

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Widely-used COVID-19 antiviral could be helping SARS-CoV-2 to evolve

cjb250 — Mon, 25 Sep 2023 15:00:41 +0000

探花直播drug works by disrupting the virus鈥檚 genome, causing it to develop random mutations as it replicates, weakening the virus to prevent replication, thereby enabling clearance of infection.

But in research published today in Nature, scientists have shown that in some cases, mutated forms of the virus have been able to be transmitted from patients treated with molnupiravir and spread within the community.

Dr Christopher Ruis from the Department of Medicine at the 探花直播 of Cambridge said: 鈥淢olnupiravir is one of a number of drugs being used to fight COVID-19. It belongs to a class of drugs that can cause the virus to mutate so much that it is fatally weakened. But what we鈥檝e found is that in some patients, this process doesn鈥檛 kill all the viruses, and some mutated viruses can spread. This is important to take into account when assessing the overall benefits and risks of molnupiravir and similar drugs.鈥�

Molnupiravir, marketed under the brand name Lagevrio, is licensed for the treatment of COVID-19 in several countries, including the UK, USA and Japan. It has been used to treat the disease since late 2021.

In the body, molnupiravir is converted into a molecule that disrupts the genome of the SARS-CoV-2 virus, introducing some nucleotide mutations in its RNA 鈥� randomly changing some Cs to Ts and some Gs to As. These changes mean that as the virus replicates, its progeny get weaker, reducing how quickly the virus is able to replicate and ridding the body of the virus.

However, concern has been expressed that in some cases, a number of mutated viruses may not be killed off quickly enough and so are able to infect other individuals, potentially allowing new mutated viruses to spread.

During the COVID-19 pandemic, a number of countries 鈥� spearheaded by the Cambridge-led COVID-19 Genomics UK Consortium 鈥� sequenced virus samples, depositing the information in databases such as the Global Initiative on Sharing All Influenza Data (GISAID) and the聽International Nucleotide Sequence Database Collaboration聽(INSDC). This allowed scientists and public health agencies to track the evolution and spread of the virus, and in particular to look out for so-called 鈥榲ariants of concern鈥� 鈥� versions of the virus with mutations that might make them more transmissible, more lethal, or able to evade the immune system of vaccinated individuals, such as the Delta and Omicron variants.

A team of researchers from the UK and South Africa noticed a number of viral genomes that contained a large number of mutations, particularly where Cs had changed to Ts and Gs to As. While C-to-T mutations are relatively common overall in SARS-CoV-2 evolution, G-to-A mutations occur much less frequently, and a higher proportion of G-to-A mutations is associated with molnupiravir treatment.

探花直播team then analysed a family tree of more than 15 million SARS-CoV-2 sequences in the GISAID and INSDC databases looking for which mutations had occurred at each point in the virus鈥檚 evolutionary history. They found that viruses with this signature of mutations had begun to emerge almost exclusively from 2022 onwards and in countries and age groups where molnupiravir was being widely used to treat COVID-19.

To confirm the link, the researchers examined treatment records in England and found that at least one in three of viruses showing the mutational signature involved the use of molnupiravir.

探花直播researchers also saw small clusters of patients infected with mutated viruses, which suggests that these new viruses were being passed from one person to another. However, none of the known variants of concern has so far been linked to the use of molnupiravir.

Dr Theo Sanderson from the Francis Crick Institute, said: 鈥淐OVID-19 is still having a major effect on human health, and some people have difficulty clearing the virus, so it鈥檚 important we develop drugs which aim to cut short the length of infection. But our evidence shows that a specific antiviral drug, molnupiravir, also results in new mutations, increasing the genetic diversity in the surviving viral population.

鈥淥ur findings are useful for ongoing assessment of the risks and benefits of molnupiravir treatment. 探花直播possibility of persistent antiviral-induced mutations needs to be taken into account for the development of new drugs which work in a similar way.鈥�

探花直播research was funded by Wellcome, Cancer Research UK, the Medical Research Council, National Institute for Health and Care Research, Fondation Botnar, UK Cystic Fibrosis Trust and the Oxford Martin School.

Reference
Sanderson, T et al. A molnupiravir-associated mutational signature in global SARS-CoV-2 genomes. Nature; 25 Sept 2023: DOI: 10.1038/s41586-023-06649-6

Molnupiravir, an antiviral drug used to treat patients with COVID-19, appears to be driving SARS-CoV-2 to mutate and evolve, with some of these new viruses being transmitted onwards, a new study has shown. It is not clear, however, whether these mutated viruses pose an increased risk to patients or are able to evade the vaccine.

Molnupiravir belongs to a class of drugs that can cause the virus to mutate so much that it is fatally weakened. But what we鈥檝e found is that in some patients, this process doesn鈥檛 kill all the viruses

Christopher Ruis

visuals3Dde

SARS-CoV-2 viruses

探花直播text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright 漏探花直播 of Cambridge and licensors/contributors as identified.聽 All rights reserved. We make our image and video content available in a number of ways 鈥� 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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鈥楢geing鈥� immune cell levels could predict how well we respond to vaccines

cjb250 — Tue, 27 Jun 2023 09:00:30 +0000

During the COVID-19 pandemic, it has become clear that some patients are better protected by vaccination than others. Many studies have shown that SARS-CoV-2 vaccines are less effective in people with weakened immune systems, but also that this effect is not uniform.

Vaccination involves priming the immune system to look for 鈥� and get rid of 鈥� invading pathogens, such as viruses and bacteria. In part, this involves stimulating the production of antibodies uniquely programmed to identify a particular invader. These antibodies are themselves produced by a type of immune cell known as a B cell.

One specific subset of B cells is known as age-associated B cells (ABCs). While, on average, less than one in 20 of a healthy individual鈥檚 B cells is an ABC, the proportion gradually increases as we get older. 探花直播reasons for this increase are not yet fully understood, but may include previous infections. Certain people with weakened immune systems accumulate ABCs still faster.

A team from the Medical Research Council (MRC) Toxicology Unit at the 探花直播 of Cambridge, led by Dr James Thaventhiran, examined ABCs from two very different patient groups 鈥� one comprised of people with an inherited condition that impairs the activity of their immune systems and a second group comprised of cancer patients taking immunotherapy drugs 鈥� as well as from healthy individuals.

Emily Horner, from Thaventhiran鈥檚 lab, explained the aim of this research: 鈥淏y looking at patients鈥� B cells, we hoped to learn how we could stratify vulnerable patients 鈥� in other words, work out whether some patients were at greater risk from infection, even after vaccination, than others.鈥�

探花直播researchers measured the relative proportion of ABCs compared to healthy B cells, and used a technique known as single cell RNA sequencing to look in detail at the activity of cells. They also teamed up with Dr Nicholas Matheson, from the Cambridge Institute of Therapeutic Immunology and Infectious Disease, to test how these factors influenced the ability of a vaccinated individual鈥檚 immune system to neutralise live SARS-CoV-2 virus.

Dr Juan Carlos Yam-Puc, also from the MRC Toxicology Unit, said: 鈥淲hat we found, much to our surprise, was that the age-associated B cells in these very different groups looked the same. 探花直播key difference was in the amount of these cells 鈥� the greater the proportion of ABCs in an individual鈥檚 blood, the less effective that individual was post-vaccination at neutralising the virus.鈥�

This could help explain the variability seen within particular patient groups in responses to the vaccine: people with fewer ABCs are likely to respond better to vaccines.

Although the researchers examined ABCs in the context of responses to the SARS-CoV-2 vaccine, they believe that this phenomenon will almost certainly apply more widely, for example to the annual influenza vaccine.

Dr Pehu茅n Pereyra Gerber, who performed the experiments with live SARS-CoV-2 virus in Matheson鈥檚 lab, added: 鈥淟ooking at blood levels of ABCs could tell us that person A should respond well to a vaccine, while person B might need a stronger vaccine or to be prioritised to receive a booster.鈥�

Thaventhiran added: 鈥淯ltimately, this research could lead to the development of a clinical test to predict vaccine efficacy for immunodeficient patients, and for the population more generally.鈥�

探花直播research was funded by the Medical Research Council, the Medical Research Foundation, and 探花直播Evelyn Trust.

Reference
Yam-Puc, JC et al. Age-Associated B cells predict impaired humoral immunity after COVID-19 vaccination in patients receiving immune checkpoint blockade. Nat Comms; 27 June 2023; DOI: 10.1038/s41467-023-38810-0

Cambridge scientists have identified a signature in the blood that could help predict how well an individual will respond to vaccines. 探花直播discovery, published today in Nature Communications, may explain why, even among vulnerable patient groups, some individuals have better responses to vaccines than others.

By looking at patients鈥� B cells, we hoped to learn how we could stratify vulnerable patients 鈥� in other words, work out whether some patients were at greater risk from infection, even after vaccination, than others

Emily Horner

Ed Us

Vaccination

探花直播text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright 漏探花直播 of Cambridge and licensors/contributors as identified.聽 All rights reserved. We make our image and video content available in a number of ways 鈥� 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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Cambridge start-up wins funding to develop new diagnostics

skbf2 — Mon, 20 Mar 2023 14:25:48 +0000

探花直播first Innovate UK award, received in 2021, allowed SMi to partner with聽the Cambridge Institute of Therapeutic Immunology and Infectious Disease, the Medicines Discovery Catapult and聽the National Physical Laboratory to develop its technology for testing for respiratory diseases. 探花直播second award, made in early 2023, is helping SMi and its partners apply the same technology to detecting cancer.

Co-founded in 2018 by former 探花直播 of Cambridge researcher Dr Andrew Thompson, SMi is developing a new technology that analyses samples using super-resolution imaging. 探花直播technology can detect, quantify and characterise single molecules that are of interest, including DNA, RNA and protein molecules associated with specific diseases. It can visualise what other technologies cannot see and very rapidly batch analyse hundreds of samples with extremely high accuracy.

探花直播first round of 拢1.9m funding enabled SMi to develop its platform, used for the simultaneous screening of common respiratory diseases. 探花直播COVID-19 pandemic demonstrated the need for rapid and cost-effective diagnostic testing on a massive scale. Test accuracy and the ability to identify new variants were critical.

探花直播second Innovate UK award has funded the application of SMi鈥檚 platform to cancer diagnosis by enabling work with another team of specialists at the Medicines Discovery Catapult. Here the same single molecule visualisation approach is being used to detect and quantify cancer biomarkers in patient blood samples. This will help clinicians to make more accurate assessments, and combined with the flexibility, accuracy, speed and high throughput of SMi鈥檚 technology, could reduce diagnostic backlogs and provide patients with their results much sooner.

SMi鈥檚 aim has always been to create a user-friendly, automated benchtop instrument that can be used in both research and healthcare settings. Initial instrument designs were guided by consultation with NHS trusts and the NIHR Medical Devices Testing and Evaluation Centre (MD-TEC), while prototypes have been tested in labs at the 探花直播 of Cambridge, the Medicines Discovery Catapult and the National Physical Laboratory. Commercial production will be outsourced to a medical device manufacturer in the East of England.

SMi鈥檚 CEO Dr Andrew Thompson said: 鈥淪Mi is creating a highly accurate and user-friendly platform that is based upon single molecule imaging, meaning that we can detect individual molecules that are invisible to other technologies. With an approach that allows them to reliably monitor single molecules, SMi provides scientists and clinicians with a quality of data that is unprecedented. Such capabilities are likely to have far-reaching benefits for diagnosis and the discovery of new medicines. Our Innovate UK funding is allowing us to work with very highly qualified research and clinical partners, providing a means to accelerate our product development and realise these opportunities sooner.鈥�

探花直播Cambridge Institute for Therapeutic Immunology and Infectious Diseases has been leading the 探花直播 of Cambridge鈥檚 collaboration with SMi. Ravindra Gupta, Professor of Clinical Microbiology, and named as one of Time Magazine鈥檚 100 most influential people of the year in 2020 for his work on HIV, said: 鈥淪Mi鈥檚 platform is incredibly exciting and could revolutionise testing for a range of diseases. We have been fortunate to partner with SMi on SARS-CoV-2 detection, and application could extend to identification of specific genetic variants of pathogens as well as cancers.鈥�

Dr Tammy Dougan, Life Science and Healthcare Partnership Lead in the 探花直播鈥檚 Strategic Partnerships Office, said: 鈥淭his is a great example of a Cambridge start-up winning Innovate UK funding and using it to build effective collaborations between research partners to take a new technology out of the lab and into clinical practice.鈥�

Since 2018, SMi has grown into a team of sixteen, including scientists, mechanical engineers, software engineers and medical device specialists based in two locations: the outskirts of Cambridge and the West Coast of the USA.

Cambridge start-up SMi and its research partners have received two Innovate UK awards to progress their work on testing for infectious diseases and detecting biomarkers for cancer.

Andrew Brookes, Getty Images:

Pipetting sample into a tray

探花直播text in this work is licensed under a Creative Commons Attribution 4.0 International License. Images, including our videos, are Copyright 漏探花直播 of Cambridge and licensors/contributors as identified.聽 All rights reserved. We make our image and video content available in a number of ways 鈥� 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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