̽��ֱ�� of Cambridge - ̽��ֱ�� of Liverpool

Researchers redesign future mRNA therapeutics to prevent potentially harmful immune responses

jg533 — Wed, 06 Dec 2023 16:02:31 +0000

mRNA - or ‘messenger ribonucleic acid’ - is the genetic material that tells cells in the body how to make a specific protein. Researchers from the Medical Research Council (MRC) Toxicology Unit have discovered that the cellular machinery that ‘reads’ mRNAs ‘slips’ when confronted with repeats of a chemical modification commonly found in mRNA therapeutics. In addition to the target protein, these slips lead to the production of ‘off-target’ proteins triggering an unintended immune response.

mRNA vaccines are considered game-changing. They have been used to control the COVID-19 pandemic and are already proposed to treat various cancers, cardiovascular, respiratory, and immunological diseases in the future.

This revolutionary class of therapeutics was made possible in part through the work of biochemist Katalin Karikó and immunologist Drew Weissman. They demonstrated that by adding chemical modifications to the bases – the building blocks of mRNA – the synthetic mRNAs could bypass some of our body’s immune defences allowing a therapeutic to enter the cell and exert its effects. This discovery led to their award of the Nobel Prize in Physiology and Medicine in 2023.

̽��ֱ��latest developments, led by biochemist Professor Anne Willis and immunologist Dr James Thaventhiran from the MRC Toxicology Unit at the ̽��ֱ�� of Cambridge, build upon previous advances to ensure the prevention of any safety issues linked with future mRNA-based therapeutics. Their report was published on 6 December in the journal Nature.

̽��ֱ��researchers identified that bases with a chemical modification called N1-methylpseudouridine – which are currently contained in mRNA therapies – are responsible for the ‘slips’ along the mRNA sequence.

In collaboration with researchers at the Universities of Kent, Oxford and Liverpool, the MRC Toxicology Unit team tested for evidence of the production of ‘off-target’ proteins in people who received the mRNA Pfizer vaccine against COVID-19. They found an unintended immune response occurred in one third of the 21 patients in the study who were vaccinated – but with no ill-effects, in keeping with the extensive safety data available on these COVID-19 vaccines.

̽��ֱ��team then redesigned mRNA sequences to avoid these ‘off-target’ effects, by correcting the error-prone genetic sequences in the synthetic mRNA. This produced the intended protein. Such design modifications can easily be applied to future mRNA vaccines to produce their desired effects while preventing hazardous and unintended immune responses.

“Research has shown beyond doubt that mRNA vaccination against COVID-19 is safe. Billions of doses of the Moderna and Pfizer mRNA vaccines have been safely delivered, saving lives worldwide,” said Dr James Thaventhiran from the MRC Toxicology Unit, joint senior author of the report.

He added: “We need to ensure that mRNA vaccines of the future are as reliable. Our demonstration of ‘slip-resistant’ mRNAs is a vital contribution to future safety of this medicine platform.”

“These new therapeutics hold much promise for the treatment of a wide range of diseases. As billions of pounds flow into the next set of mRNA treatments, it is essential that these therapeutics are designed to be free from unintended side-effects,” said Professor Anne Willis, Director of the MRC Toxicology Unit and joint senior author of the report.

Thaventhiran, who is also a practising clinician at Addenbrooke’s hospital, said: “We can remove the error-prone code from the mRNA in vaccines so the body will make the proteins we want for an immune response without inadvertently making other proteins as well. ̽��ֱ��safety concern for future mRNA medicines is that mis-directed immunity has huge potential to be harmful, so off-target immune responses should always be avoided.”

Willis added: “Our work presents both a concern and a solution for this new type of medicine, and result from crucial collaborations between researchers from different disciplines and backgrounds. These findings can be implemented rapidly to prevent any future safety problems arising and ensure that new mRNA therapies are as safe and effective as the COVID-19 vaccines.”

Using synthetic mRNA for therapeutic purposes is attractive because it is cheap to produce, so can address substantial health inequalities across the globe by making these medicines more accessible. Moreover, synthetic mRNAs can be changed rapidly – for example to create a new COVID-19 variant vaccine.

In the Moderna and Pfizer COVID-19 vaccines, synthetic mRNA is used to enable the body to make the spike protein from SARS-CoV-2. ̽��ֱ��body recognises the viral proteins generated by mRNA vaccines as foreign and generates protective immunity. This persists, and if the body is later exposed to the virus its immune cells can neutralise it before it can cause serious illness.

̽��ֱ��cell’s decoding machinery is called a ribosome. It ‘reads’ the genetic code of both natural and synthetic mRNAs to produce proteins. ̽��ֱ��precise positioning of the ribosome on the mRNA is essential to make the right proteins because the ribosome ‘reads’ the mRNA sequence three bases at a time. Those three bases determine what amino acid is added next into the protein chain. Therefore, even a tiny shift in the ribosome along the mRNA will massively distort the code and the resulting protein.

When the ribosome is confronted with a string of these modified bases called N1-methylpseudouridine in the mRNA, it slips around 10% of the time causing the mRNA to be misread and unintended proteins to be produced – enough to trigger an immune response. Removing these runs of N1-methylpseudouridine from the mRNAs prevents ‘off-target’ protein production.

This research was funded by the Medical Research Council and the Wellcome LEAP R3 programme, and supported by the NIHR Cambridge BRC.

Reference: Mulroney, T E et al: ‘(N)1-methylpseudouridylation of mRNA causes +1 ribosomal frameshifting.’ Nature, Dec 23. DOI: 10.1038/s41586-023-06800-3

Researchers have discovered that misreading of therapeutic mRNAs by the cell’s decoding machinery can cause an unintended immune response in the body. They have identified the sequence within the mRNA that causes this to occur and found a way to prevent ‘off-target’ immune responses to enable the safer design of future mRNA therapeutics.

As billions of pounds flow into the next set of mRNA treatments, it is essential that these therapeutics are designed to be free from unintended side-effects.

Anne Willis

Libre de droit/ Getty Images

Strand of mRNA

̽��ֱ��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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̽��ֱ��off-patent drug that could protect us from future COVID-19 variants

cjb250 — Mon, 05 Dec 2022 16:00:00 +0000

Cambridge scientists have identified a drug that can be repurposed to prevent COVID-19 in research involving a unique mix of ‘mini-organs’, donor organs, animal studies and patients.

Set up reserve lab capacity now for faster response to next pandemic, say researchers

jg533 — Tue, 27 Sep 2022 23:01:15 +0000

̽��ֱ��researchers, who were on the front line of the UK’s early response to COVID-19 in 2020, say a system of reservist lab scientists should to be set up now to provide surge capacity that will help the country respond faster – and more effectively – to future outbreaks of infectious disease.

They considered a number of options for providing scientific surge capacity and concluded that the best scenario would be a mix of highly skilled paid reservists, and volunteers who could be called on when required and trained rapidly.

In their report, published today in the journal ̽��ֱ��BMJ, the researchers say the lack of early COVID-19 PCR testing capacity had a knock-on effect on other health services in 2020. This included delaying the ability to make sure hospitals were COVID-secure and patients had surgery as safely as possible, and slowing down the identification of people with COVID-19 in the community – which delayed contact tracing.

“Because COVID-19 testing wasn’t scaled up quickly enough, we couldn’t detect all cases quickly enough to try and stop the spread of the disease,” said Dr Jordan Skittrall in the ̽��ֱ�� of Cambridge’s Department of Pathology and first author of the report.

“It was frustrating to hear politicians’ promises to repeatedly scale up COVID-19 testing capacity during the early stage of the pandemic. ̽��ֱ��scale-up was extremely challenging: a lot of expertise is needed to get the tests working in the early stages of dealing with a new pathogen,” he added.

In early 2020, PCR testing for SARS-CoV-2, the virus that causes COVID-19, was a highly skilled job that required lab staff to undergo lengthy training. As the testing process was developed it became increasingly automated.

̽��ֱ��researchers say that the risk of another pandemic like COVID-19 happening is ever-present: there have been outbreaks of infectious disease throughout history. But nobody can say for sure when it will happen.

They suggest that effective preparation for the next pandemic includes recruiting a relatively small number of highly skilled scientists, who would be paid on retainer, to help in the initial phases of an emergency.

It would also involve a large reserve of volunteer staff to provide essential testing capacity; these people would not need to have specialist skills but could be trained quickly in an emergency and paid only when needed. Those working in sectors of the economy likely to close during a pandemic - such as entertainment and hospitality - would be ideal candidates as voluntary reserves, the researchers say.

“There’s an extent to which the emergence of an infectious disease is a random process, but a pandemic like COVID-19 is guaranteed to happen again at some point,” said Skittrall, who is also an Honorary Specialty Registrar in Infectious Diseases and Medical Virology at Addenbrooke’s Hospital, part of Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust.

He added: “In the UK we’re in the privileged position of having the right scientific skills to respond to the next big outbreak. But we need to make sure that we have these people ready, so that when something does happen they can hit the ground running.”

As a clinician at Addenbrooke’s Hospital in Cambridge Skittrall put his normal work on hold to help interpret COVID-19 test results in the lab in early 2020, and ensure the right clinical responses were carried out.

“In early 2020 we were working until late at night, with very few people processing tests for the whole country,” said Skittrall. “ ̽��ֱ��speed at which people were having to work, and the difficulty of trying to scale up the process in a busy hospital lab made me realise there was a real human bottleneck. We needed more people to process the tests.”

In their paper the scientists compare COVID-19 with other large-scale emergencies including war, where the military has a system of reservists for built-in surge capacity. But they say that unlike the military where reservists serve to deter warfare, having an ‘always-on’ capacity to deal with public health emergencies wouldn’t do anything to deter a new pandemic from emerging – and that’s why there has always been a pressure to close labs and streamline public health services.

Their suggested solution does not require sustained, cross-party political will to fund so is more likely to succeed; the researchers acknowledge there are many other pressures on the UK economy that must take priority.

They recommend that other countries should consider their requirements for surge capacity based on their own circumstances.

UK laboratories have now conducted over 200 million PCR tests for SARS-CoV-2, the virus that causes COVID-19.

Reference

Skittrall, JP et al. ‘Preparing for the next pandemic: reserve laboratory staff.’ ̽��ֱ��BMJ, September 2022. DOI: 10.1136/BMJ-2022-072467

Researchers say a ‘human bottleneck’, due to historical cuts in public health funding, delayed the UK’s scale-up of COVID-19 testing in the early stages of the country’s pandemic response.

A pandemic like COVID-19 is guaranteed to happen again at some point.

Jordan Skittrall

Cultura RM Exclusive/Matt Lincoln

Female scientist in laboratory

̽��ֱ��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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Nutritious fish stocks are being squandered by salmon farming, say scientists

jg533 — Tue, 01 Mar 2022 19:00:06 +0000

Scientists studying the Scottish salmon farming industry say that using only fish by-products - such as trimmings - for salmon feed, rather than whole wild-caught fish, would deliver significant nutritional and sustainability gains.

This would allow 3.7 million tonnes of fish to be left in the sea, and enable global annual seafood production to increase by 6.1 million tonnes.

̽��ֱ��study, led by a team of scientists from the Universities of Cambridge, Lancaster and Liverpool and environmental NGO Feedback Global is published today in the journal PLOS Sustainability and Transformation.

As the world’s fastest growing food sector, aquaculture is often presented as a way to relieve pressure on wild fish stocks. But many aquaculture fish - such as Atlantic salmon - are farmed using fish oil and meal made from millions of tonnes of wild-caught fish, most of which is food-grade and could be eaten directly to provide vital nutrition.

̽��ֱ��team collected data on fish nutrient content, fishmeal and fish oil composition, and salmon production, and examined the transfer of micronutrients from feed to fish in Scotland's farmed salmon industry. They found that over half of the essential dietary minerals and fatty acids available in wild fish are lost when these fish are fed to farmed salmon.

Dr David Willer, a researcher in the ̽��ֱ�� of Cambridge’s Department of Zoology and first author of the paper, said: “Fish and seafood provide a vital and valuable micronutrient-rich food source to people worldwide, and we must make sure we are using this resource efficiently. Eating more wild fish and using alternative feeds in salmon farms can achieve this.”

̽��ֱ��team developed various alternative production scenarios where salmon were only produced using fish by-products, and then added more wild-caught fish, mussels or carp for human consumption. All scenarios produced more seafood that was more nutritious than salmon, and left 66-82% of feed fish in the sea.

Feedback’s Dr Karen Luyckx said: “If we want to feed a growing global population well and sustainably, we must stop catching wild fish to feed farmed fish. Until the salmon industry kicks its wild-caught fish oil and fishmeal habit, chefs and retailers should help citizens switch away from unsustainable salmon by offering ultra-nutritious mussels and small oily fish instead.”

Based on their findings on the Scottish salmon industry, the researchers collected global salmon, fishmeal and oil production data to apply their alternative scenarios at a global scale. One scenario shows that farming more carp and less salmon, using only feed from fish by-products, could leave 3.7 million tonnes of wild fish in the sea while producing 39% more seafood overall.

̽��ֱ��authors caution that not enough is known about the source and species composition of fishmeal, but there are positive signs that the use of plant-based feeds is growing.

Dr James Robinson of Lancaster ̽��ֱ�� said: “Aquaculture, including salmon farming, has an important role in meeting global food demand, but nutritious wild fish should be prioritised for local consumption rather than salmon feed, particularly if it is caught in food-insecure places.

“Support for alternative feeds can help this transition, but we still need more data on the volumes and species used for fishmeal and fish oil, as this can show where salmon farming places additional pressure on fish stocks.”

Ultimately, the authors call for a reduction in marine aquaculture feeds, as this will offer opportunities to produce more nutritious seafood while reducing pressure on marine ecosystems.

Willer added: “If we want to feed the growing global population well and sustainably, we must stop catching wild fish to feed farmed fish. There is an urgent need for the food industry to promote consumption of more sustainable seafood species - like mussels or carp - that don’t require other fish as feed.”

This research was funded by the Cambridge Philosophical Society, via a Henslow Fellowship to David Willer.

Reference
Willer, D.F., et al: ‘Maximising sustainable nutrient production from coupled fisheries-aquaculture systems.’ PLOS Sustainability and Transformation, 2022. DOI: 10.1371/journal.pstr.0000005

Adapted from a press release by Feedback Global.

Eating wild-caught fish instead of using it as feed in salmon farming would allow nearly four million tonnes of fish to be left in the sea, while providing an extra six million tonnes of seafood for human consumption, a study finds.

If we want to feed the growing global population well and sustainably, we must stop catching wild fish to feed farmed fish.

David Willer

Fengyou Wan on Unsplash

Shoal of fish

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Widespread use of control measures such as facemasks is vital to suppress the pandemic as lockdown lifts, say scientists

jg533 — Tue, 30 Mar 2021 23:01:00 +0000

̽��ֱ��model, developed by scientists at the Universities of Cambridge and Liverpool, is published today in the Journal of the Royal Society Interface. It uses mathematical equations to provide general insights about how COVID-19 will spread under different potential control scenarios.

Control measures involving facemasks, handwashing and short-scale (1-2 metre) social distancing can all limit the number of virus particles being spread between people. These are termed ‘non spatial’ measures to distinguish them from a second category of ‘spatial’ control measures that include lockdown and travel restrictions, which reduce how far virus particles can spread. ̽��ֱ��new model compares the efficacy of different combinations of measures in controlling the spread of COVID-19, and shows how non-spatial control needs to be ramped up as lockdown is lifted.

“More effective use of control measures like facemasks and handwashing would help us to stop the pandemic faster, or to get better results in halting transmission through the vaccination programme. This also means we could avoid another potential lockdown,” said Dr Yevhen Suprunenko, a Research Associate in the ̽��ֱ�� of Cambridge’s Department of Plant Sciences and first author of the paper. ̽��ֱ��authors stress that their predictions rely on such non-spatial control measures being implemented effectively.

̽��ֱ��model also considered the socio-economic impact of both types of measure, and how this changes during the pandemic. ̽��ֱ��socio-economic consequences of spatial measures such as lockdown have increased over time, while the cost of non-spatial control measures has decreased -for example, facemasks have become more widely available and people have become used to wearing them.

“Measures such as lockdowns that limit how far potentially infected people move can have a stronger impact on controlling the spread of disease, but methods that reduce the risk of transmission whenever people mix provide an inexpensive way to supplement them,” said Dr Stephen Cornell at the ̽��ֱ�� of Liverpool, co-author of the paper.

̽��ֱ��model arose from a broader research programme to identify control strategies for plant diseases threatening staple crops. By using a mathematical approach rather than a conventional computer simulation model, the authors were able to identify - for a wide range of scenarios - general insights on how to deal with newly emerging infectious diseases of plants and animals.

“Our new model will help us study how different infectious diseases can spread and become endemic. This will enable us to find better control strategies, and stop future epidemics faster and more efficiently,” said Professor Chris Gilligan in the ̽��ֱ�� of Cambridge’s Department of Plant Sciences, co-author of the paper.

Part of this research was funded by the Bill and Melinda Gates Foundation.

Reference

Suprunenko, Y.F. et al: ‘Analytical approximation for invasion and endemic thresholds, and the optimal control of epidemics in spatially explicit individual-based models.’ J.R.Soc. Interface, March 2021. DOI: 10.1098/rsif.2020.0966

A new mathematical model suggests that the easing of lockdown must be accompanied by wider and more effective use of control measures such as facemasks, even with vaccination, in order to suppress COVID-19 more quickly and reduce the likelihood of another lockdown.

More effective use of control measures like facemasks and handwashing would help us to stop the pandemic faster.

Yevhen Suprunenko

Kobby Mendez on Unsplash

Man putting on a facemask

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