̽��ֱ�� of Cambridge - Stephen Baker

Monoclonal antibodies offer hope for tackling antimicrobial resistance

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

A team lead by researchers at the ̽��ֱ�� 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 ̽��ֱ�� of Cambridge said “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 – and in many cases, the patients can acquire the infection from the ventilation itself.

“ ̽��ֱ��bacteria are naturally resistant to many antimicrobials, but as they’re now found in hospitals, they’ve 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’ve become impossible to treat.”

In a study published today in Nature Communications, the team produced monoclonal antibodies using transgenic mice – 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 ‘spike protein’ 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. ̽��ֱ��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: “Using 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’s immune system work out which ones to develop antibodies against. Because these mice have ‘humanised’ immune systems, we wouldn’t then need to reengineer the antibodies to work in humans.”

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

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: “We know that monoclonal antibodies are safe and that they work, and the technology exists to produce them – what we have done is identify how to hit bacteria with them. Apart from the cost effectiveness, there's no reason why this couldn’t become a medicine within a few years. Given the emergency presented by antimicrobial resistance, this could become a powerful new weapon to fight back.”

̽��ֱ��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 – treatments developed by cloning a cell that makes an antibody – 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 – 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

̽��ֱ��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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Gone fishing: highly accurate test for common respiratory viruses uses DNA as ‘bait’

sc604 — Mon, 16 Jan 2023 16:00:00 +0000

̽��ֱ��test uses DNA ‘nanobait’ to detect the most common respiratory viruses – including influenza, rhinovirus, RSV and COVID-19 – at the same time. In comparison, PCR (polymerase chain reaction) tests, while highly specific and highly accurate, can only test for a single virus at a time and take several hours to return a result.

While many common respiratory viruses have similar symptoms, they require different treatments. By testing for multiple viruses at once, the researchers say their test will ensure patients get the right treatment quickly and could also reduce the unwarranted use of antibiotics.

In addition, the tests can be used in any setting, and can be easily modified to detect different bacteria and viruses, including potential new variants of SARS-CoV-2, the virus which causes COVID-19. ̽��ֱ��results are reported in the journal Nature Nanotechnology.

̽��ֱ��winter cold, flu and RSV season has arrived in the northern hemisphere, and healthcare workers must make quick decisions about treatment when patients show up in their hospital or clinic.

“Many respiratory viruses have similar symptoms but require different treatments: we wanted to see if we could search for multiple viruses in parallel,” said Filip Bošković from Cambridge’s Cavendish Laboratory, the paper’s first author. “According to the World Health Organization, respiratory viruses are the cause of death for 20% of children who die under the age of five. If you could come up with a test that could detect multiple viruses quickly and accurately, it could make a huge difference.”

For Bošković, the research is also personal: as a young child, he was in hospital for almost a month with a high fever. Doctors could not figure out the cause of his illness until a PCR machine became available.

“Good diagnostics are the key to good treatments,” said Bošković, who is a PhD student at St John’s College, Cambridge. “People show up at hospital in need of treatment and they might be carrying multiple different viruses, but unless you can discriminate between different viruses, there is a risk patients could receive incorrect treatment.”

PCR tests are powerful, sensitive and accurate, but they require a piece of genome to be copied millions of times, which takes several hours.

̽��ֱ��Cambridge researchers wanted to develop a test that uses RNA to detect viruses directly, without the need to copy the genome, but with high enough sensitivity to be useful in a healthcare setting.

“For patients, we know that rapid diagnosis improves their outcome, so being able to detect the infectious agent quickly could save their life,” said co-author Professor Stephen Baker, from the Cambridge Institute of Therapeutic Immunology and Infectious Disease. “For healthcare workers, such a test could be used anywhere, in the UK or in any low- or middle-income setting, which helps ensure patients get the correct treatment quickly and reduce the use of unwarranted antibiotics.”

̽��ֱ��researchers based their test on structures built from double strands of DNA with overhanging single strands. These single strands are the ‘bait’: they are programmed to ‘fish’ for specific regions in the RNA of target viruses. ̽��ֱ��nanobaits are then passed through very tiny holes called nanopores. Nanopore sensing is like a ticker tape reader that transforms molecular structures into digital information in milliseconds. ̽��ֱ��structure of each nanobait reveals the target virus or its variant.

̽��ֱ��researchers showed that the test can easily be reprogrammed to discriminate between viral variants, including variants of the virus that causes COVID-19. ̽��ֱ��approach enables near 100% specificity due to the precision of the programmable nanobait structures.

“This work elegantly uses new technology to solve multiple current limitations in one go,” said Baker. “One of the things we struggle with most is the rapid and accurate identification of the organisms causing the infection. This technology is a potential game-changer; a rapid, low-cost diagnostic platform that is simple and can be used anywhere on any sample.”

A patent on the technology has been filed by Cambridge Enterprise, the ̽��ֱ��’s commercialisation arm, and co-author Professor Ulrich Keyser has co-founded a company, Cambridge Nucleomics, focused on RNA detection with single-molecule precision.

“Nanobait is based on DNA nanotechnology and will allow for many more exciting applications in the future,” said Keyser, who is based at the Cavendish Laboratory. “For commercial applications and roll-out to the public we will have to convert our nanopore platform into a hand-held device.”

“Bringing together researchers from medicine, physics, engineering and chemistry helped us come up with a truly meaningful solution to a difficult problem,” said Bošković, who received a 2022 PhD award from Cambridge Society for Applied Research for this work.

̽��ֱ��research was supported in part by the European Research Council, the Winton Programme for the Physics of Sustainability, St John’s College, UK Research and Innovation (UKRI), Wellcome, and the National Institute for Health and Care Research (NIHR) Cambridge Biomedical Research Centre.

Reference:
Filip Bošković et al. ‘Simultaneous identification of viruses and viral variants with programmable DNA nanobait.’ Nature Nanotechnology (2022). DOI: 10.1038/s41565-022-01287-x

A new test that ‘fishes’ for multiple respiratory viruses at once using single strands of DNA as ‘bait’, and gives highly accurate results in under an hour, has been developed by Cambridge researchers.

Good diagnostics are the key to good treatments

Filip Bošković

Natalia Gdovskaia via Getty Images

Doctor examining a patient

̽��ֱ��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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̽��ֱ��microbiologist tackling humanity’s next biggest killer

cg605 — Wed, 17 Nov 2021 12:43:31 +0000

Since childhood Stephen Baker says he had a grim fascination with poo. He caught the bug for microbiology and spent 12 years in Vietnam researching bacteria that cause diarrhoea. Stephen thinks that antibiotic-resistant bacteria is likely to be humanity’s biggest killer in the future. But says that if we keep doing the science, we have hope.

Air filter significantly reduces presence of airborne SARS-CoV-2 in COVID-19 wards

cjb250 — Tue, 16 Nov 2021 08:36:58 +0000

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

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

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

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

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

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

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

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

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

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

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

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

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

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

̽��ֱ��research was supported by Wellcome, the Medical Research Council and the National Institute for Health Research Cambridge Biomedical Research Centre.

Reference
Conway Morris, A, et al. ̽��ֱ��removal of airborne SARS-CoV-2 and other microbial bioaerosols by air filtration on COVID-19 surge units. Clin Inf Dis; 30 Oct 2021; DOI: 10.1093/cid/ciab933

Image: Dr Vilas Navapurkar in ICU beside an air filter

When a team of doctors, scientists and engineers at Addenbrooke’s Hospital and the ̽��ֱ�� of Cambridge placed an air filtration machine in COVID-19 wards, they found that it removed almost all traces of airborne SARS-CoV-2.

Reducing airborne transmission of the coronavirus is extremely important for the safety of both patients and staff

Vilas Navapurkar

Medi2Go

Coronavirus

Yes

Licence type:

Public Domain

Testing suggests 3% of NHS hospital staff may be unknowingly infected with coronavirus

cjb250 — Tue, 12 May 2020 10:42:25 +0000

Patients admitted to NHS hospitals are now routinely screened for the SARS-CoV-2 virus, and isolated if necessary. But NHS workers, including patient-facing staff on the front line, such as doctors, nurses and physiotherapists, are tested and excluded from work only if they develop symptoms of the illness. Many of them, however, may show no symptoms at all even if infected, as a new study published in the journal eLife demonstrates.

̽��ֱ��Cambridge team pro-actively swabbed and tested over 1,200 NHS staff at Addenbrooke’s Hospital, Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust, throughout April. ̽��ֱ��samples were analysed using a technique called PCR to copy and read the genetic information of material present on the swab, producing a colour change whenever the coronavirus was present in a specimen. At the same time, staff members were asked about relevant coronavirus symptoms.

Of the more than 1,000 staff members reporting fit for duty during the study period, 3% nevertheless tested positive for the coronavirus. On closer questioning, around one in five reported no symptoms, two in five had very mild symptoms that they had dismissed as inconsequential, and a further two in five reported COVID-19 symptoms that had stopped more than a week previously.

To probe routes of possible transmission of the virus through the hospital and among staff, the researchers also looked at whether rates of infection were greater among staff working in “red” areas of the hospital, those areas caring for COVID-19 patients. Despite wearing appropriate personal protective equipment (PPE), “red” area staff were three times more likely to tested positive than staff working in COVID-19 free “green” areas. It’s not clear whether this genuinely reflects greater rates of transmission from patients to staff in red areas. Staff may have instead transmitted the virus to each other or acquired it at home. Staff working in the “red” areas were also swabbed earlier in the study, closer to when the lockdown was first initiated, so the higher rates of infection in this group might just be a symptom of higher rates of virus circulating in the community at the time.

Nevertheless, extrapolating these results to the more than half a million patient-facing staff working across the NHS UK-wide suggests that as many as 15,000 workers may have been on duty and infected, with the potential to transmit the virus to co-workers, family members and patients, during the month of April. In fact, this figure could be even higher in settings where the supply of PPE has been very problematic.

̽��ֱ��implications of the new study, say senior authors Dr Mike Weekes and Professor Stephen Baker from the Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID), are that hospitals need to be vigilant and introduce screening programmes across their workforces.

“Test! Test! Test! And then test some more,” Dr Weekes explains. “All staff need to get tested regularly for COVID-19, regardless of whether they have any sort of symptoms – this will be vital to stop infection spreading within the hospital setting.”

̽��ֱ��research was mainly funded by Wellcome and the Addenbrooke’s Charitable Trust.

Reference
Rivett, L, et al. Screening of healthcare workers for SARS-CoV-2 highlights the role of asymptomatic carriage in COVID-19 transmission. eLife; 11 May 2020; DOI: 10.7554/eLife.58728

Hospital staff may be carrying SARS-CoV-2, the coronavirus that causes COVID-19 disease, without realising they are infected, according to a study by researchers at the ̽��ֱ�� of Cambridge.

Test! Test! Test! And then test some more

Mike Weekes

Hospital CLÍNIC

Hospital staff

Yes

Licence type:

Attribution

Cambridge researchers develop new coronavirus test for frontline NHS workers

cjb250 — Thu, 09 Apr 2020 11:31:12 +0000

Using a modified PCR test, the CITIID team are able to diagnose infection in four hours, much faster than the current tests, which take over 24 hours to return a result. They are using the test on NHS healthcare workers at Addenbrooke’s Hospital, part of Cambridge ̽��ֱ�� Hospitals (CUH) NHS Trust, as well as on staff who have been asked to isolate due to potential contact with infected individuals but who may or may not be themselves infected.

̽��ֱ��polymerase chain reaction (PCR) test allows scientists to extract a miniscule amount of RNA from the virus and copy it millions of times, creating an amount large enough to confirm presence of the virus. However, because of the infectious nature of the virus, which causes COVID-19 disease, until now samples have had to be processed in containment level 3 facilities, which slows down the testing process because of the safety requirements.

Now, a team led by Professor Stephen Baker at CITIID has found a way of inactivating the virus at the point of sampling, enabling them to carry out their work rapidly in level 2 facilities, which are more widely available and have less restrictions on their use. Their method is based on previous work led by Professor Ian Goodfellow and colleagues in the Department of Pathology.

“PCR tests for coronavirus infection are slow because of the safety requirements necessary for handing this potentially lethal virus,” said Professor Baker. “Now that we are able to inactivate it, we can dramatically improve the turnaround time from swab to result. This will be extremely useful in helping test NHS frontline staff and helping clarify whether self-isolating healthcare staff are infected or negative, potentially allowing them to return to work.”

Samples are taken using nasal swabs. Once the virus has been inactivated, the samples are sent to the lab and tested. ̽��ֱ��whole process takes just four hours.

Professor Baker says that the team has enough reagents – the chemical substances used to detect the virus – to allow them to test 200 samples a day, five days a week, for the next 10-12 weeks. He hopes to be able to expand this capacity in the future.

̽��ֱ��PCR test has been adapted from the in-house, real-time PCR developed in the routine diagnostics laboratory at Addenbrooke’s by Dr Martin Curran. It has been validated against the approved Public Health England tests and is now being offered as a screening tool for NHS staff. Establishing and validating the process for staff testing has been a successful collaboration between clinical and occupational health staff at CUH with the ̽��ֱ�� team.

̽��ֱ�� ̽��ֱ��, together with CUH, is already at the forefront of responding to the UK Government’s five pillar plan to boost testing for COVID-19. Yesterday, it announced a partnership with AstraZeneca and GSK to set up a new testing laboratory at the ̽��ֱ��’s Anne McLaren Building. This facility will be used for high throughput screening for COVID-19 testing and to explore the use of alternative chemical reagents for test kits in order to help overcome current supply shortages.

Last week, it announced that a spinout company had developed a point-of-care, rapid diagnostic test for patients that was capable of diagnosing COVID-19 in 90 minutes. This test is also being evaluated at CITIID.

A new test for infection with SARS-CoV2 that which inactivates the virus at the point of sampling, has been developed by a team of researchers at the Cambridge Institute for Therapeutic Immunology and Infectious Disease (CITIID). It is now being used to test and screen frontline NHS staff at a Cambridge hospital.

PCR tests for coronavirus infection are slow because of the safety requirements necessary for handing this potentially lethal virus. Now that we are able to inactivate it, we can dramatically improve the turnaround time from swab to result

Stephen Baker

Researchers at CITIID using the new PCR test

Yes