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Studying our ageing immune system with help of Cambridge BioResource

The study of how our immune system changes as we age has been aided by volunteers in the Cambridge BioResource.

Immunologist Dr Michelle Linterman, a group leader at the Babraham Institute, is exploring how this impacts on the body’s response to the annual influenza vaccination, and how it might be improved.

Dr Michelle Linterman re Bioresource and her Lister Prize seen here at the Babraham Institute. Picture: Keith Heppell. (13798889)
Dr Michelle Linterman re Bioresource and her Lister Prize seen here at the Babraham Institute. Picture: Keith Heppell. (13798889)

Speaking at a BioResource collaboration event at Babraham, she said: “As we age, we become more suspectible to infection. This is important because we have an ageing population.”

Vaccinations against infectious diseases are very effective in younger individuals but because they rely on the immune system response, this effectiveness declines with age.

The annual flu jab – which has to be administered annually to confer protection against that year’s prevailing strain – illustrates this change clearly.

“In younger individuals, you have about 80 per cent protection against subsequent infection but in those over 70 it’s less than a quarter and these are the people we need to protect because they are more likely to have severe consequences.”

But why does our immune response decline with age – and is there anything we can do about it?

“Immunisation works because you get specific antibodies produced from your white blood cells. If you are infected after immunisation, it enables your immune system to mount a fast, potent immune response that quickly neutralises the infection, often before you even know you are sick,” explained Dr Linterman, who has won the Lister Prize in 2019.

Among the types of white blood cell involved in producing antibodies is the B cell. But it requires help from another – a T cell – to complete the task.

If sufficient antibodies are produced against a particular pathogen, then they are able to coat it should it infect the body.

“This blocks the virus from being able to infect more cells, and they act as little flags to target pathogens for destruction,” said Dr Linterman.

“Production of antibodies underpins every successful vaccination on the market, with the exception of one.

“We wanted to understand how the immune system changes after vaccination – can we see the T cells and B cells?”

The flu jab is adjusted each year to alter the prevailing strain
The flu jab is adjusted each year to alter the prevailing strain

Studies show numbers of these cells do in fact increase after vaccination, but then decline again.

“What persists is the antibodies,” said Dr Linterman. “But as we age we produce fewer antibodies after a vaccine. We wanted to understand the biology of this.“

To do this, Dr Linterman’s group turned to the Cambridge BioResource – a database of volunteers who have given a sample of their blood or saliva for genomic analysis, along with access to their medical history.

“The BioResource is unique,” noted Dr Linterman. “We have run two independent seasonal influenza vaccination studies with the Cambridge BioResource – a discovery and replication cohort.”

Taking blood samples in genetically-matched BioResource volunteers before they had the annual flu vaccination, then seven days later and again after 42 days gave the researchers an unrivalled picture of how their immune system responded.

“It was quite a commitment to take part and the research nurses were great at making sure we got every single blood sample at day seven.

“The reason the Cambridge BioResource was important to us was because we could select by genotype [genetic make-up] to enable us to track the T cells that are responding to influenza.

“What we found was that you get fewer of the T cells that help B cells make antibodies.

Our immune system changes as we age (13799289)
Our immune system changes as we age (13799289)

We think this is one of the reasons why the vaccine isn’t working as well in older people.”

In studies with mice, the team was able to uncover the genetic defect underpinning the poor production of helper T cells.

They then increased production of a particular chemokine – a type of signalling protein secreted by cells – by repurposing a cream used to treat genital warts.

“It is known to stimulate the immune system very well and in particular the pathway that is defective in ageing,” said Dr Linterman. “When you do this you increase the number of helper T cells in aged mice. So we can show this is not an irreversible defect.

“What we would like to do is understand if this can work in older humans.”

The researchers had access to a clinical trial of an experimental malaria vaccine, run using young adults in Tanzania.

It explored a different adjuvant – a substance used to stimulate the immune system – compared to the usual alum, or aluminium salts.

“What we could see in this trial is the novel adjuvant does a much better job of stimulating the T cells that help B cells make antibodies. The more of these T cells you have, the more long-lived the antibodies are.

“It’s a proof of principle that by changing formulations, you can improve vaccine response.

“What we are keen to know is whether you could take an approach like this to make vaccines work better in older people.”

Dr Michelle Linterman at the Babraham Institute. Picture: Keith Heppell
Dr Michelle Linterman at the Babraham Institute. Picture: Keith Heppell

After her presentation last week, Dr Linterman told the Cambridge Independent that the likely route to further the research is to collaborate with a company running clinical trials on adjuvants.

She added: “We would be keen to run another study through the BioResource. We find it’s the very early events after vaccination that are important for amounting a good response later on.

“From a basic biology point of view, we want to characterise in more detail what these early events are that give a better vaccine response in humans.”

Dr Linterman’s studies on the relationship between the immune response in the gut and the composition of the microbiome – also reported in the Cambridge Independent – was further evidence that defects in the ageing immune system are not irreversible.

“We need to think about giving those treatments in parallel with something that can rejuvenate the immune system in older people,” she concluded.

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