New analysis based on Imperial’s COVID-19 human challenge study has helped to uncover how some people avoid getting sick.

Researchers have found that people who are able to fend off the SARS-CoV-2 virus have unique immune responses which help them to avoid sustained infection.

The findings, which are based on samples obtained from the Imperial-led COVID-19 human challenge study, suggest that a localised immune response in the lining of the nose enables individuals to identify the virus and stop it from gaining a foothold to cause infection.

The research, led by the Wellcome Sanger Institute, University College London (UCL), Imperial College London, the Netherlands Cancer Institute and more, analysed samples from individuals before and immediately after exposure to the virus to study their immune responses in great detail.

Using single-cell sequencing technology, they found that some people showed previously unrecognised immune responses which enable them to resist sustained viral infection and disease, and a detailed snapshot of the cell types involved.

The researchers say the study, published in the journal Nature, provides the most comprehensive timeline to date of how the body responds to SARS-CoV-2 first-time exposure, or any infectious disease.

Professor Christopher Chiu, from the Department of Infectious Disease at Imperial College London, and who led the COVID-19 human challenge study, said: “This paper highlights the value of the powerful, cutting-edge approaches applied through collaboration in the first-in-the-world SARS-CoV-2 human challenge study.

“This programme of research continues to provide unique insights into how the immune system protects us from infection that cannot be achieved in any other setting.

"Not only will these findings have an important impact on the development of next-generation interventions for SARS-CoV-2, but they should also be generalisable for other future outbreaks and pandemics.”

Detailed timeline of immunity

As part of the UK COVID-19 Human Challenge study, led by Imperial College London, 36 healthy adult volunteers without previous history of COVID-19 infection or vaccination were administered SARS-CoV-2 virus through the nose.

This programme of research continues to provide unique insights into how the immune system protects us from infection that cannot be achieved in any other setting Professor Christopher Chiu Department of Infectious Disease

Their environment was carefully controlled to enable researchers to capture the path of infection from the moment a person is exposed to the virus, through their infection, and beyond the point they are clear of virus.

Researchers performed detailed monitoring in the blood and lining of their noses, tracking the entire infection as well as the immune cell activity prior to the infection event itself for 16 volunteers.

Teams at the Wellcome Sanger Institute and UCL then used single-cell sequencing to generate a dataset of over 600,000 individual cells. The work is part of the Human Cell Atlas initiative to map every cell type in the human body. 

Across all participants, the team discovered previously unreported responses involved in immediate virus detection. This included activation of specialised mucosal immune cells in the nose and changes in inflammatory white blood cells that normally engulf and destroy pathogens.

Previously unrecognised immune response

Individuals who immediately cleared the virus did not show a typical widespread immune response but instead mounted subtle, never-seen-before innate immune responses in the nose. Researchers suggest high levels of a gene called HLA-DQA2 before exposure also helped people prevent a sustained infection from taking hold.

In contrast, the six individuals who developed a sustained SARS-CoV-2 infection exhibited a rapid immune response in the blood but a slower immune response in the nose, allowing the virus to establish itself there.

The researchers further identified common patterns among activated T cell receptors, which recognise and clear virus-infected cells. This offers insights into immune cell communication and potential for developing targeted T cell therapies against not just COVID-19, but other diseases.

Dr Rik Lindeboom, co-first author of the study, now at the Netherlands Cancer Institute, said: “This was an incredibly unique opportunity to see what immune responses look like in adults with no prior history of COVID-19, in a setting where factors such as time of infection and comorbidities could be controlled.”

Dr Marko Nikolic, senior author of the study at UCL and honorary consultant in respiratory medicine, said: “These findings shed new light on the crucial early events that either allow the virus to take hold or rapidly clear it before symptoms develop. We now have a much greater understanding of the full range of immune responses, which could provide a basis for developing potential treatments and vaccines that mimic these natural protective responses.”

Dr Sarah Teichmann, senior author of the study, formerly at the Wellcome Sanger Institute, co-founder of the Human Cell Atlas and now based at the Cambridge Stem Cell Institute, University of Cambridge, said: “As we’re building the Human Cell Atlas we can better identify which of our cells are critical for fighting infections and understand why different people respond to coronavirus in varied ways. Future studies can compare with our reference dataset to understand how a normal immune response to a new pathogen compares to a vaccine-induced immune response.”

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‘Human SARS-CoV-2 challenge uncovers local and systemic response dynamics’ by Rik G. H. Lindeboom, Kaylee B. Worlock, Lisa M. Dratva, et al. is published in Nature. DOI: https://doi.org/10.1038/s41586-024-07575-x

This article is based on materials from the Wellcome Sanger Institute.

Images: Imperial College London / Thomas Angus, and Shutterstock.