LONDON – The U.K. is funding a national program of research to investigate the major unanswered questions related to the immune response to COVID-19.

The aim of the research, involving teams of immunologists in 17 research institutions, is to unpick the immunological backdrop of one of the most notable aspects of COVID-19 infection, which is the huge spectrum of severity of symptoms.

“The key task is to understand why there is so much variability in disease,” said Tracy Hussell, professor of inflammatory disease at Manchester University, who will lead a project looking at immune response to COVID-19 outside hospitals, in people who have tested positive but shown no symptoms, and those with symptoms who did not need hospitalization.

“This is an opportunity to understand good and bad responses,” Hussell said. “As a consortium, we can get down to the cellular and molecular level, to understand the breadth of immune response. She expects to recruit around 4,000 people to the community study, whose immune responses will be analyzed at admission and at 3, 6, 9 and 12 months.

The U.K. coronavirus immunology consortium (UK-CIC), brought together by the British Society of Immunology, has government funding of £6.5 million (US$8.7 million) for the 12-month program of research. Alongside enrolling people in the community, it will analyze patient samples from U.K. COVID-19 projects already underway, including the ISARIC-4C coronavirus clinical characterization consortium, which has £5.9 million funding to characterize and follow more than 80,000 people hospitalized with COVID-19.

ISARIC-4C already has delivered significant results relating to age and severity, but is sitting on a huge dataset of immune markers it has measured in hospitalized patients, said Peter Openshaw, professor of experimental medicine at Imperial College London, who is lead immunologist for ISARIC-4C.

It is possible to link these biomarkers to specific subgroups of patients, for example, those with severe lung disease. “We’ve got 37,000 datapoints to deconvolute, it will be great to bring the British Society of Immunologists to bear,” Openshaw said.

UK-CIC also will draw on a £28 million project which is sequencing the whole genome of every COVID-19 patient in the country treated in intensive care, to look for host genetic factors that lead some people to be more severely affected by the infection. This study involves up to 20,000 people currently or previously treated in one of 170 intensive care units, whose genomes will be compared to 15,000 people with a confirmed infection who had mild or moderate symptoms.

In addition, UK-CIC will use data from the COVID-19 genomics consortium, which has £20 million funding to carry out large-scale whole genome sequencing of the SARS-CoV-2 virus in patient samples. To date 46,293 viral genomes have been sequenced, amounting to around 50 percent of the global total.

Changes in the sequence as SARS-CoV-2 evolves can be cross referenced to the severity of the immune response, to see if the virus is becoming attenuated. Mutations causing this to happen would be potential therapeutic targets.

What constitutes immunity?

“We’ve got a lot of data to analyze, and as a consortium we’ve got to bring it together,” Hassell said. “Analyzing good responses is as important as analyzing bad ones.”

While characterizing how the immune response varies according to severity of disease, it also is hoped to shed light on how this relates to known risk factors, of gender, age, obesity and ethnicity. “For example, the increased risk for BAME [Black, Asian and Minority Ethnic] people – is it due to differences in immune response, or about social interactions?” Hassell said.

Other questions it is hoped to answer are what constitutes immunity to COVID-19 and how long does it last; if infection with other coronaviruses like the common cold is protective or leads to more severe disease; and how SARS-CoV-2 hides from the immune system.

“Overall, this time, the U.K. and the world has acquired pockets of detailed data on the immune response. We can pull all this together,” said Hassell.

A separate £1.5 million study, Humoral Immune Correlates of COVID-19, will look at the role of antibodies in immunity, to try and establish the difference between protective antibody responses and those that cause disease.

One aim is to confirm the early evidence that people with stronger antibody responses have more severe disease. Another is to develop better tests for assessing protective immunity and to determine how long protective antibodies persist after exposure to SARS-CoV-2.

The humoral correlates consortium will focus on a cohort of patients who were hospitalized, and at frontline health care workers who have volunteered to take part in a study looking to see if prior infection with SARS-CoV-2 protects against future infection.

Understanding the role of antibody responses to SARS-CoV-2, and the role overactivation of the immediate innate immune response plays – through complement activation – in the initiation and maintenance of inflammatory disease, is critical to improve patient care, said Wilhelm Schwaeble, director of research in the department of veterinary medicine at Cambridge University, one of the leaders of the project.

“In critical care, we know most patients have high levels of antibody to SARS-CoV-2. However, what we don’t know is whether these antibodies are helpful,” Schwaeble said.

Meanwhile, pilot data has shown that many health care staff have been exposed to SARS-CoV-2. “We need to find out whether this means they are protected from further infection, either in the short or the long term, or may be at risk of disease in the future,” said Schwaeble.

A third study proposed by the British Society of Immunologists is examining key features of fatal COVID-19, in particular, the effect the virus has on the lungs and other organs, in post-mortem tissue samples.

“We are hampered by looking at the response in blood, whereas we need to know what is happening in the mucosa. That is extremely hard to measure,” Openshaw said.

Christopher Lucas, consultant in respiratory medicine at Edinburgh University, who is leading the study, agreed. “We have learned so much from COVID-19 patients during the past six months. However, there is only so much that we can learn from clinical examinations and blood tests. By having a deeper look at those who have died from COVID-19 through post-mortem examination, we will increase our understanding of what is happening to the body in the most severe cases of this disease.”

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