Collaborating to understand COVID-19
Coronavirus Immune Response and Clinical Outcomes (CIRCO) is a unique study bringing together more than 100 immunology experts and NHS staff to better understand and treat COVID-19.
Since the start of the pandemic, the effort of the scientific community to find vaccines and treatments has been a global one. One team of researchers is making a valuable contribution to this effort by turning its expertise in immunology to understanding how the virus affects the body.
But they weren’t able to do it alone – within weeks of the first national lockdown in the UK, they had organised a supply of fresh blood samples from local hospitals to analyse using a technique called immunophenotyping.
“This is a story,” explains Professor Hussell, Director of the Lydia Becker Institute of Immunology and Inflammation, “about how we were able to galvanise an army of phlebotomists, nurses, clinicians, academics and scientists to create this huge machine that is allowing us to follow patients across their whole hospital journey and into the community so that we can see how their immune systems recover.”
In March 2020, as the country was coming to a standstill, the project was gaining momentum.
Professor Hussell would drive daily to the four hospitals taking part in the study – Wythenshawe, Salford Royal, Manchester Royal Infirmary and North Manchester General – to collect samples from clinical staff.
“We’ve had to be adaptable, certainly,” says Professor Hussell. “This was only really possible due to the willingness of people to come in at a time when we were all supposed to be locked down at home.”
“We jumped on it straight away and soon managed to get couriers in place to bring all the samples to the Institute and then we drew together this web of experts in different aspects of immunology to analyse them.”
It is no coincidence that Manchester is home to so many immunology experts from diverse scientific backgrounds. Many of them were already here, working as part of the Institute Professor Hussell founded in 2018, making it uniquely placed to be able to undertake this work.
Collaborating with the NHS is also second nature, with many members holding clinical academic positions and translating scientific discoveries into treatments for some time.
“Not so long ago, basic science and clinical science had been quite separate,” says Professor Hussell.
“But the way we work at Manchester has changed this. When we established the Institute, we already had those interactions with the hospitals and the clinicians, so we were very translationally-focused from the start.”
Unique by nature
CIRCO is one of the only longitudinal studies being carried out on COVID-19, which means each participant is tracked at multiple points in time.
“Our study showed that testing at only one-time point can be a dangerous thing to do,” explains Professor Hussell, “because you don’t know what stage the patients are at in their immune response. If you only take a single point you’ll miss the most important outcomes.”
“Because of our approach,” she says, “we’re able to propose new therapeutics and when individuals are more likely to benefit from receiving those therapeutics. For example, everyone’s been treating people just before they go into the intensive care unit with anti-inflammatories, when actually they would be better on admission.”
Another unique aspect has been the early focus on working with fresh samples, which could only be collected so swiftly due to existing links to local hospitals.
“Fresh samples have been absolutely crucial. Most studies bank their samples and then analyse them all at the same time,” says Professor Hussell.
“We found that, if we did this, when we brought them back up again out of storage we lost most of the immune signature. So our key readouts, we wouldn’t have been able to see.”
It appears that going their own way has paid off, with the team publishing their first discovery in September 2020.
They found that white blood cells called monocytes released into the blood from bone marrow have abnormal features in people with COVID-19, meaning doctors may be able to predict which patients are more likely to develop severe disease.
“It became clear very quickly that there was an excessive inflammatory response going on in COVID-19 patients. So it was natural to ask which bits of the immune system are abnormal and which sort of strategies could we use to put them back?”
For Professor Hussell, a pragmatic approach was key to their early findings.
“This didn’t need very complex techniques, we just needed to know what was going wrong. We didn’t need to know that at a single cell level. So we were able to understand before most other people that the problem is with your innate immune response.”
Dealing with data
These discoveries were made by mining huge amounts of clinical data provided by the hospitals.
“Having bioinformaticians in the Institute has been critical because we have so much data. It’s almost like the answer to the pandemic is already out there, we just need a way of revealing the data.”
This may be one step closer, now that the Institute has been tasked with combining all the immune data sets across the country, which will allow researchers to ask even bigger questions.
However, data can be meaningless if it’s not applied, so the team set about making it clinically useful.
“We’ve come up with an algorithm that can determine a patient’s likely outcome on their admission to hospital, so they could possibly be fast-tracked for treatment. We’re also able to use this immune algorithm to look in the community and see, do patients’ immune systems ever recover?”
“We’re answering questions like if you’ve had COVID-19, do you need a vaccine? Is having COVID-19 better than a vaccine?”
“We’ve also discovered a mechanism which may explain why older people are more susceptible and it’s due to the interaction between immune cells, rather than a particular immune cell itself.”
At the time of publication, the team is due to publish another four papers.
Professor Hussell is eager to share the credit for their findings with every member of CIRCO.
“The credit is everybody’s”, she says. “Hospital staff have been providing us with daily blood samples from patients. They’ve been recruiting and consenting the patient as well as treating them.”
“They’ve had to collate all the clinical information into a database. They’ve really contributed an enormous amount of time. Without any of those components, the whole thing would have just fallen apart.”
One way individuals have been recognised has been to include them as an author on published papers.
“Often, to be an author, you have to make an ‘intellectual’ contribution. But knowing how to handle patients, obtain consent and get their blood out of them……I don’t know how to do that. It can’t happen without them. So I think if you’re involved then you deserve to be an author.”
“It’s a way to say thank you,” Tracy continues, “to the technicians in the lab who came in during a lockdown and the research nurses who have so many other things to worry about. Without you, this wouldn’t have worked.”
Working collaboratively and efficiently is at the heart of the Lydia Becker Institute, so it has naturally been able to take a leading role in this way of working.
“I will always open up the questions I’m addressing to everyone else in my group,” says Professor Hussell, “because somebody might want to look at the same question but via a different organ or pathway. It’s like I always say to our early career researchers, every experiment you want to do has been done or is being done.”
This is what’s happening now on a bigger scale.
“The Institute has become a focal point for lots of other studies getting samples within the University and beyond, which has enabled a ton of studies to be initiated,” Professor Hussell says.
“We’re sharing our data with the other institutions in the UK Coronavirus Immunology Consortium, which we’re a member of, and we’re providing our know-how to others. We’re also trying to come up with standardised protocols across the country so we can compare data sets better.”
Professor Hussell is optimistic about the spirit of collaboration – at a local, national and global level – that has been one positive to come out of the pandemic.
“This situation has really pulled the immunology research community together and given us focus, as well as creating an environment where barriers to getting things done have been reduced.
“You have to understand the disease in order to move forward and you need scientists working on that problem. I think that’s what everyone’s grasped really, right from the start, from the government all the way through to the hospital staff.
“It just goes to show what we can do, regardless of a pandemic. This machinery exists now, people are aware of it, and in the future, we will think, well, how can we swing that machinery around to answer other big problems?”
“It all sort of stemmed from this massive machine we created at the beginning,” Professor Hussell concludes, “that we’re now able to be involved in all these other studies and make these discoveries.”
Find out more about the CIRCO study discoveries.