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Children’s better immune response to Covid-19 explained by Wellcome Sanger Institute study

Why are children less likely to become seriously ill from Covid-19?

It is a question that researchers from the Wellcome Sanger Institute, University College London and others have helped to answer following research into the fundamental differences in the immune response of adults and children.

Molecular model of interferon-alpha IFN-alpha, a protein produced by leukocytes and involved in innate immune responce against viral infections
Molecular model of interferon-alpha IFN-alpha, a protein produced by leukocytes and involved in innate immune responce against viral infections

They found a stronger innate immune response in the airways of children restricts early replication of the virus. Adults, however, have a less rapid immune response, which means the virus is able to invade other parts of the body, where the infection is harder to control.

The findings could be used to predict personal risk from the SARS-CoV-2 virus via a nasal swab to measure the immune response in newly-infected adults.

Those at higher risk could then be candidates for pre-emptive monoclonal antibody treatments, which can be expensive and in short supply.

There is also recent research that suggests inhalation of interferons - proteins that are rapidly deployed by children’s immune systems - could be a viable therapy.

The innate immune system of children is good at recognising dangerous viruses or bacteria automatically, which triggers ‘‘naïve’ B and T cells to adapt to the threat.

Adults also have an innate response, but it is less active. Instead, they have a more adaptive immune system with a huge repertoire of ‘memory’ B and T cell types trained through past exposure to respond to a particular threat.

Dr Masahiro Yoshida, a first author of the study from University College London, said: “Because SARS-CoV-2 is a new virus, it isn’t something that the adaptive immune system of adults has learned to respond to.

“The innate immune system of children is more flexible and better able to respond to new threats.

“What we see at a molecular level are high levels of interferons and a very quick immune response in children that helps to explain why they are less severely affected by Covid-19 than adults.”

Innate and adaptive immune systems explained
Innate and adaptive immune systems explained

Both immune systems feature an important group of proteins called interferons that are released in response to viral or bacterial threats and instruct nearby cells to tighten their defences.

The B and T cells that are activated by them kill infected cells and prevent pathogens from spreading further.

Researchers at University College London (UCL) and affiliated hospitals collected and processing matched airway and blood samples from 19 paediatric and 18 adult Covid-19 patients with symptoms ranging from asymptomatic to severe, as well as control samples from 41 healthy children and adults,

The Wellcome Sanger Institute at Hinxton then carried out single-cell sequencing of the samples, generating a dataset of 659,217 individual cells.

Analysis showed 59 different cell types in airways and 34 cell types in blood, including some never previously described.

Since interferons were more strongly expressed in healthy children, they had an advantage in preventing the virus from infecting the blood and other organs.

The adult immune system’s high numbers of ‘killer’ immune cells - such as the B and T cells - can also work against the patient once the virus has spread to other parts of the body.

Dr Marko Nikolić, a senior author of the study from University College London, MRC intermediate fellow and honorary consultant in respiratory medicine, said: “Compared to children, adult blood has a greater number and variety of cytotoxic immune cells, which are designed to kill infected cells to prevent an infection spreading. But it is a fine line between helping and hindering.

“Once the virus has spread to several areas of the body, organ damage can be caused by the immune system trying and failing to control the infection. Our study shows that not only do children respond better initially, if the virus does enter the blood the cytotoxic response is less forceful.”

An illustration of the Covid-19 virus
An illustration of the Covid-19 virus

Checking airway interferon levels in an adult could help predict the course of the disease. Higher levels, like those found in children, would suggest a lower risk of severe disease, but lower interferon levels would imply higher risk, enabling the best use of pre-emptive treatments, while those with weak or absent interferon activation could be good candidates for inhaled interferon beta 1a.

Dr Kerstin Meyer, a senior author of the study from the Wellcome Sanger Institute, said: “To put it simply, the innate immune response is better at fighting Covid-19 and children have stronger innate immunity, but immunity is also a complex ballet involving many types of cells.

“The timing and the types of cells that are triggered will influence how an infection develops, and this will vary between individuals for all sorts of reasons in addition to age. Some of the differences we observe between children and adults may help us to think about how we gauge personal risk for adults as a way of mitigating serious illness and death.”

The work, published in Nature on December 22, is the most comprehensive single-cell study to compare infection by the SARS-CoV-2 infection in adults and children across multiple organs and is part of the Human Cell Atlas initiative to map every cell type in the human body.

Jonah Cool, program officer for single-cell biology at the Chan-Zuckerberg Initiative, said: “The results are insightful not only for addressing Covid-19, but more broadly for understanding changes in the airway and blood throughout childhood. They demonstrate the power of single-cell resolution to reveal differences in the biology of children and adults, while pointing to very different considerations when thinking about how a specific disease arises and may be treated.”

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