̽��ֱ�� of Cambridge - Pehuén Pereyra Gerber

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Alex Taylor

Jordan Siemens (Getty Images)

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

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