̽��ֱ�� of Cambridge - immunology

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

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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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Cambridge and GSK announce new five-year collaboration aiming for improved outcomes for patients with hard-to-treat kidney and respiratory diseases

skbf2 — Sun, 20 Oct 2024 23:01:00 +0000

̽��ֱ��Cambridge-GSK Translational Immunology Collaboration (CG-TIC) combines ̽��ֱ�� and GSK expertise in the science of the immune system, AI and clinical development with access to patients and their data provided by Cambridge ̽��ֱ�� Hospitals.
GSK is investing more than £50 million in CG-TIC, further strengthening Cambridge’s position as Europe’s leading life sciences cluster.

GSK plc is making this investment to establish the Cambridge-GSK Translational Immunology Collaboration (CG-TIC), a five-year collaboration with the ̽��ֱ�� of Cambridge and Cambridge ̽��ֱ�� Hospitals. ̽��ֱ��collaboration is focused on understanding the onset of a disease, its progression, how patients respond to therapies and on developing biomarkers for rapid diagnosis. Ultimately, the goal is to trial more effective, personalised medicines.

̽��ֱ��collaboration will focus on kidney and respiratory diseases, both of which affect large numbers of people worldwide. Kidney disease is estimated to affect 850 million people (roughly 10% of the world’s population) (International Society of Nephrology) and chronic respiratory diseases around 545 million ( ̽��ֱ��Lancet).

Many types of kidney disease remain poorly understood and treatments, where they exist, tend to have limited efficacy. Chronic kidney disease is particularly unpleasant and debilitating for patients, often leading to end-stage disease. Treatments such as transplant and dialysis involve complex medical regimes and frequent hospital visits, making effective prevention and treatment the aim.

To make progress in treating these challenging disease areas, CG-TIC will apply an array of new techniques, including the use of cutting-edge single cell technologies to characterise how genes are expressed in individual cells. AI and machine learning have a critical role to play in transforming how data is combined and interrogated.

Using these techniques, the ambition is to be able to initiate new studies and early phase trials of new therapies for a number of hard-to-treat diseases which affect the kidneys. ̽��ֱ��same techniques will be applied to respiratory diseases and findings will be shared across the disease areas potentially to help identify and share better treatments across these different targets.

Peter Kyle, Secretary of State for Science, Innovation and Technology, welcomed the collaboration: " ̽��ֱ��UK's life sciences industry is thriving, driving innovation and improving lives. This collaboration between GSK and the ̽��ֱ�� of Cambridge demonstrates our country's leading research and development capabilities.

“By focusing on cutting-edge research and harnessing the power of AI, this has the potential to advance the treatment of immune-related diseases, which could benefit patients both here in the UK and internationally. It's a clear example of how collaboration between industry, academia, and healthcare can deliver tangible results and strengthen the UK's position in healthcare innovation."

Tony Wood, Chief Scientific Officer, GSK, added: “Collaboration is at the heart of scientific progress and is fundamental to how we do R&D at GSK. We’re excited to build on our existing work with the ̽��ֱ�� of Cambridge to further this world-leading scientific and technological capability in the UK. By bringing together Cambridge’s expertise and our own internal capabilities, including understanding of the immune system and the use of AI to accelerate drug development, we have an opportunity to help patients struggling with complex disease.”

̽��ֱ��aim of CG-TIC is to improve outcomes for patients and Cambridge provides a unique environment in which to involve them, with Cambridge ̽��ֱ�� Hospitals playing a pivotal role in the collaboration and Royal Papworth Hospital NHS Foundation Trust, the UK’s leading heart and lung hospital, a likely future partner.

Home to the hospitals and to much of the collaboration’s research activity, the Cambridge Biomedical Campus provides a unique environment where academia, industry and healthcare can come together and where human translational research is supported by the National Institute for Health and Care Research (NIHR) Cambridge Biomedical Research Centre.

Professor Deborah Prentice, Vice-Chancellor of the ̽��ֱ�� of Cambridge, said: “ ̽��ֱ�� ̽��ֱ�� sits at the heart of Europe’s leading life sciences cluster, where excellent research and the NHS’s clinical resources combine with the talent generated by the many innovative bioscience companies that call Cambridge home. Through this very important collaboration with GSK, Cambridge will be able to drive economic growth for the UK while improving the health of people in this country and around the world.”

Roland Sinker, CEO of Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust, also welcomed the collaboration, saying: “We are very excited to be part of this important partnership, which is another example of Cambridge experts working together to develop transformational new therapies, and use existing ones more precisely, to improve outcomes for patients with chronic and debilitating conditions.”

̽��ֱ��Cambridge-GSK Translational Immunology Collaboration will be co-led by Nicolas Wisniacki, VP, Clinical Research Head, GSK (above left) and David Thomas, Professor of Renal Medicine, ̽��ֱ�� of Cambridge and principal investigator at the Cambridge Institute for Therapeutic Immunology and Infectious Diseases.

̽��ֱ��ambition of the partnership is to treat immune-related diseases more precisely with existing therapies and to rapidly develop new ones.

̽��ֱ��UK's life sciences industry is thriving, driving innovation and improving lives. This collaboration between GSK and the ̽��ֱ�� of Cambridge demonstrates our country's leading research and development capabilities.

Peter Kyle, Secretary of State for Science, Innovation and Technology

StillVision

David Thomas, Professor of Renal Medicine, ̽��ֱ�� of Cambridge and Dr Nicolas Wisniacki, VP, Clinical Research Head, GSK

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Changemakers in cancer: Oluwasegun Alofaranmi

zs332 — Mon, 15 Jul 2024 07:00:08 +0000

As a young medical student in Nigeria, Segun was shocked by the disproportionate rate of death from treatable cancers across Africa. To help bring about change, he’s supporting knowledge sharing and skills training for students in Africa. He also co-founded an initiative to provide career guidance and mentoring for schoolchildren in Nigeria. In Cambridge, he hopes his PhD will lead to a way to enhance immune cells to deliver a ‘kiss of death’ to cancer.

Changemakers in cancer: Swetha Kannan

zs332 — Wed, 05 Jun 2024 12:48:36 +0000

Swetha was 12 years old when she decided she would help to unravel the mysteries of cancer. Twelve years later, she's studying for a PhD on cancer immunology, has launched a social enterprise to support the mental health of cancer patients in India and has designed a portable diagnostics tool to detect head and neck cancers.

‘Ageing’ 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 – and get rid of – 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’s B cells is an ABC, the proportion gradually increases as we get older. ̽��ֱ��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 ̽��ֱ�� of Cambridge, led by Dr James Thaventhiran, examined ABCs from two very different patient groups – 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 – as well as from healthy individuals.

Emily Horner, from Thaventhiran’s lab, explained the aim of this research: “By looking at patients’ B cells, we hoped to learn how we could stratify vulnerable patients – in other words, work out whether some patients were at greater risk from infection, even after vaccination, than others.”

̽��ֱ��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’s immune system to neutralise live SARS-CoV-2 virus.

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

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 Pehuén Pereyra Gerber, who performed the experiments with live SARS-CoV-2 virus in Matheson’s lab, added: “Looking 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.”

Thaventhiran added: “Ultimately, this research could lead to the development of a clinical test to predict vaccine efficacy for immunodeficient patients, and for the population more generally.”

̽��ֱ��research was funded by the Medical Research Council, the Medical Research Foundation, and ̽��ֱ��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. ̽��ֱ��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’ B cells, we hoped to learn how we could stratify vulnerable patients – in other words, work out whether some patients were at greater risk from infection, even after vaccination, than others

Emily Horner

Ed Us

Vaccination

̽��ֱ��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 – 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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Immune cell characteristics mapped across multiple tissues

cjb250 — Fri, 13 May 2022 15:41:02 +0000

̽��ֱ��research, from the ̽��ֱ�� of Cambridge, Wellcome Sanger Institute, and collaborators, has created an open-access atlas of the immune cells in the human body and focuses on those found within tissues, which are understudied, compared to those circulating in the blood.

This study is part of the international Human Cell Atlas (HCA) consortium, which is aiming to map every cell type in the human body as a basis for both understanding human health and for diagnosing, monitoring, and treating disease.

Published in Science, the research explores the similarities and differences of the same types of immune cells across 16 different tissues. Knowing more about immune cell traits and reactions in these tissues could help future research into therapies that aim to produce or enhance an immune response to fight disease, such as vaccinations or anti-cancer treatments.

It is one of a trio of milestone collaborative papers published together in Science this week, which have created comprehensive and openly available cross-tissue cell atlases. ̽��ֱ��complementary studies shed light on health and disease, and will contribute towards a single Human Cell Atlas.

̽��ֱ��human immune system is made up of many different types of cells that can be found throughout the body, all playing crucial roles. They not only fight off pathogens when they appear, but remember them so they can be eliminated in the future.

In this new research, scientists simultaneously analysed immune cells across 16 tissues from 12 individual organ donors. ̽��ֱ��team developed a database that automatically classifies different cell types, called CellTypist, to handle the large volume and variation of immune cells. Through this, they were able to identify around 100 distinct cell types.

Using CellTypist and further in-depth analysis, the researchers created a cross-tissue immune cell atlas that revealed the relationship between immune cells in one tissue and their counterparts in others. They found similarities across certain families of immune cells, such as macrophages, as well as differences in others. For example, some memory T cells show unique features depending on which tissue they are in.

̽��ֱ��team also uncovered new insights into immune system memory by sequencing the antigen receptors that are found on T and B cells. This part of the study showed the different states that T and B cells undergo if they are exposed to an antigen, such as those found on bacteria and viruses.

̽��ֱ��wider research community can use this cross-tissue immune cell atlas to help interpret and inform future research. It could also serve as a framework to identify which immune cells could be useful to activate when designing new therapeutics that focus on guiding or supporting the immune system, such as vaccination and immunotherapies, for both infectious diseases and solid tumours.

Dr Cecilia Domínguez Conde, co-first author from the Wellcome Sanger Institute, said: “We have created a novel catalogue of immune cells within the human body, allowing us to automatically identify cell types across multiple tissues. By using single-cell sequencing data we have been able to reveal around a hundred different kinds of immune cells including macrophages, B cells, and T cells, uncovering crucial information about how the immune system works. We would like to thank the donors and their families for making this research possible.”

Dr Joanne Jones, co-senior author from the Department of Clinical Neurosciences at the ̽��ֱ�� of Cambridge, said: “In this research, we not only identified distinct types of immune cells, we also found that certain immune cell types follow specific tissue distribution patterns. Understanding the varying behaviours of the same type of immune cell in multiple areas of the body can help inform research into disease and how treatments that target these cells might impact other tissues.”

Dr Sarah Teichmann from the Wellcome Sanger Institute and the Department of Physics at the ̽��ֱ�� of Cambridge, co-founder of the Human Cell Atlas, said: “Our multi-tissue immune cell atlas is a step towards understanding how the immune system functions throughout the entire body and is an important contribution towards the Human Cell Atlas. In addition to creating a new resource for researchers to classify different cell types, our work will have many translational implications, including serving as a framework for developing therapies to fight immune-related diseases and managing infections.”

Reference
Domínguez Conde. C, Xu. C, Jarvis. LB, Rainbow. DB, Wells. SB, et al. (2022) Cross-tissue immune cell analysis reveals tissue-specific features in humans. Science. DOI: 10.1126/science.abl5197

Adapted from a press release by the Wellcome Sanger Institute

Previously underexplored immune cell populations have been genetically mapped across multiple tissues to provide new insights into how our immune systems work.

Understanding the varying behaviours of the same type of immune cell in multiple areas of the body can help inform research into disease and how treatments that target these cells might impact other tissues

Joanne Jones

Chenqu Suo, Sophie Pritchard, Nadav Yayon (Wellcome Sanger Institute)

Developing immune cells (B cells) from prenatal gut tissue

̽��ֱ��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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Biological ‘fingerprints’ of long COVID in blood could lead to diagnostic test, say Cambridge scientists

cjb250 — Mon, 19 Jul 2021 07:39:19 +0000

̽��ֱ��team has received funding from the National Institute for Health Research to develop a test that could complement existing antibody tests. They also aim to use similar biological signatures to develop a test and monitor for long COVID.

While most people recover from COVID-19 in a matter of days or weeks, around one in ten people go on to develop symptoms that can last for several months. This can be the case irrespective of the severity of their COVID-19 – even individuals who were asymptomatic can experience so-called ‘long COVID’.

Diagnosing long COVID can be a challenge, however. A patient with asymptomatic or mild disease may not have taken a PCR test at the time of infection – the gold standard for diagnosing COVID-19 – and so has never had a confirmed diagnosis. Even antibody tests – which look for immune cells produced in response to infection – are estimated to miss around 30% of cases, particularly among those who have had only mild disease and or beyond six months post-initial illness.

A team at the ̽��ֱ�� of Cambridge and Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust has received £370,000 from the National Institute for Health Research to develop a COVID-19 diagnostic test that would complement existing antibody tests and a test that could objectively diagnose and monitor long COVID.

̽��ֱ��research builds on a pilot project supported by the Addenbrooke’s Charitable Trust. ̽��ֱ��team has been recruiting patients from the Long COVID Clinic established in May 2020 at Addenbrooke’s Hospital, part of Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust.

During the pilot, the team recruited 85 patients to the Cambridge NIHR COVID BioResource, which collects blood samples from patients when they are first diagnosed and then at follow-up intervals over several months. They now hope to expand their cohort to 500 patients, recruited from Cambridgeshire and Peterborough.

In their initial findings, the team identified a biomarker – a biological fingerprint – in the blood of patients who had previously had COVID-19. This biomarker is a molecule known as a cytokine produced by T cells in response to infection. As with antibodies, this biomarker persists in the blood for a long time after infection. ̽��ֱ��team plans to publish their results shortly.

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

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

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

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

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

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

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

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

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

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

Markers in our blood – ‘fingerprints’ of infection – could help identify individuals who have been infected by SARS-CoV-2, the coronavirus that causes COVID-19, several months after infection even if the individual had only mild symptoms or showed no symptoms at all, say Cambridge researchers.

Because we currently have no reliable way of diagnosing long COVID, the uncertainty can cause added stress to people who are experiencing potential symptoms. If we can say to them ‘yes, you have a biomarker and so you have long COVID’, we believe this will help allay some of their fears and anxieties

Nyarie Sithole

Annie Spratt

Tired looking woman

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Likelihood of severe and ‘long’ COVID may be established very early on following infection

cjb250 — Mon, 18 Jan 2021 12:39:36 +0000

Among the key findings, which have not yet been peer-reviewed, are:

Individuals who have asymptomatic or mild disease show a robust immune response early on during infection.
Patients requiring admission to hospital have impaired immune responses and systemic inflammation (that is, chronic inflammation that may affect several organs) from the time of symptom onset.
Persistent abnormalities in immune cells and a change in the body’s inflammatory response may contribute to ‘long COVID’.

̽��ֱ��immune response associated with COVID-19 is complex. Most people who get infected by SARS-CoV-2 mount a successful antiviral response, resulting in few if any symptoms. In a minority of patients, however, there is evidence that the immune system over-reacts, leading to a flood of immune cells (a ‘cytokine storm’) and to chronic inflammation and damage to multiple organs, often resulting in death.

To better understand the relationship between the immune response and COVID-19 symptoms, scientists at the ̽��ֱ�� of Cambridge and Addenbrooke’s Hospital, Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust, have been recruiting individuals who test positive for SARS-CoV-2 to the COVID-19 cohort of the NIHR BioResource. These individuals range from asymptomatic healthcare workers in whom the virus was detected on routine screening, through to patients requiring assisted ventilation. ̽��ֱ��team take blood samples from patients over several months, as well as continuing to measure their symptoms.

In research published today, the team analysed samples from 207 COVID-19 patients with a range of disease severities taken at regular interviews over three months following the onset of symptoms. They compared the samples against those taken from 45 healthy controls.

Because of the urgent need to share information relating to the pandemic, the researchers have published their report on MedRXiv. It has not yet been peer-reviewed.

Professor Ken Smith, senior co-author and Director of the Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), said: “ ̽��ֱ��NIHR BioResource has allowed us to address two important questions regarding SARS-CoV-2. Firstly, how does the very early immune response in patients who recovered from disease with few or no symptoms, compare with those who experienced severe disease? And secondly, for those patients who experience severe disease, how rapidly does their immune system recover and how might this relate to ‘long COVID’?”

Listen to Professor Ken Smith discuss the findings with the Naked Scientists

̽��ֱ��team found evidence of an early, robust adaptive immune response in those infected individuals whose disease was asymptomatic or mildly symptomatic. An adaptive immune response is where the immune system identifies an infection and then produces T cells, B cells and antibodies specific to the virus to fight back. These individuals produced the immune components in larger numbers than patients with more severe COVID-19 managed, and within the first week of infection – after which these numbers rapidly returned to normal. There was no evidence in these individuals of systemic inflammation that can lead to damage in multiple organs.

In patients requiring admission to hospital, the early adaptive immune response was delayed, and profound abnormalities in a number of white cell subsets were present. Also present in the first blood sample taken from these patients was evidence of increased inflammation, something not seen in those with asymptomatic or mild disease. This suggests that an abnormal inflammatory component to the immune response is present even around the time of diagnosis in individuals who progress to severe disease.

̽��ֱ��team found that key molecular signatures produced in response to inflammation were present in patients admitted to hospital. They say that these signatures could potentially be used to predict the severity of a patient’s disease, as well as correlating with their risk of COVID-19 associated death.

Dr Paul Lyons, senior co-author, also from CITIID, said: “Our evidence suggests that the journey to severe COVID-19 may be established immediately after infection, or at the latest around the time that they begin to show symptoms. This finding could have major implications as to how the disease needs to be managed, as it suggests we need to begin treatment to stop the immune system causing damage very early on, and perhaps even pre-emptively in high risk groups screened and diagnosed before symptoms develop.”

̽��ֱ��researchers found no evidence of a relationship between viral load and progression to inflammatory disease. However, once inflammatory disease was established, viral load was associated with subsequent outcome.

̽��ֱ��study also provides clues to the biology underlying cases of ‘long COVID’ – where patients report experiencing symptoms of the disease, including fatigue, for several months after infection, even when they no longer test positive for SARS-CoV-2.

̽��ֱ��team found that profound alterations in many immune cell types often persisted for weeks or even months after SARS-CoV-2 infection, and these problems resolved themselves very differently depending on the type of immune cell. Some recover as systemic inflammation itself resolves, while others recover even in the face of persistent systemic inflammation. However, some cell populations remain markedly abnormal, or show only limited recovery, even after systemic inflammation has resolved and patients have been discharged from hospital.

Dr Laura Bergamaschi, the study’s first author, said: “It’s these populations of immune cells that still show abnormalities even when everything else seems to have resolved itself that might be of importance in long COVID. For some cell types, it may be that they are just slow to regenerate, but for others, including some types of T and B cells, it appears something is continuing to drive their activity. ̽��ֱ��more we understand about this, the more likely we will be able to better treat patients whose lives continue to be blighted by the after-effects of COVID-19.”

Professor John Bradley, Chief Investigator of the NIHR BioResource, said: “ ̽��ֱ��NIHR BioResource is a unique resource made possible by the strong links that exist in the UK between doctors and scientists in the NHS and at our universities. It’s because of collaborations such as this that we have learnt so much in such a short time about SARS-CoV-2.”

̽��ֱ��research was supported by CVC Capital Partners, the Evelyn Trust, UK Research & Innovation COVID Immunology Consortium, Addenbrooke’s Charitable Trust, the NIHR Cambridge Biomedical Research Centre and Wellcome.

Reference
Bergamaschi, L et al. Early immune pathology and persistent dysregulation characterise severe COVID-19. MedRXiV; 15 Jan 2021; DOI: 10.1101/2021.01.11.20248765

New research provides important insights into the role played by the immune system in preventing – and in some cases increasing the severity of – COVID-19 symptoms in patients. It also finds clues to why some people experience ‘long COVID’.

Our evidence suggests that the journey to severe COVID-19 may be established immediately after infection, or at the latest around the time that they begin to show symptoms

Paul Lyons

NIH Image Gallery

SARS-CoV-2 virus particles are shown emerging from the surface of cells cultured in the lab

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