Would you volunteer to be deliberately infected with COVID-19, all in the name of science? For most of us, the answer is probably a resounding “no”, yet 36 healthy people agreed to do just that as part of the world’s first COVID human challenge study. Now, some new results are in, and they’ve revealed a previously unknown quirk of the immune system that allows some people to clear the virus before it has a chance to take hold.

We know by now that people’s experiences with COVID-19 are massively varied. Some have very severe, life-threatening illness; some have mild symptoms but develop long COVID; some have no symptoms at all. Starting early in the pandemic, the UK COVID-19 Human Challenge study, led by Imperial College London, set out to capture exactly what happens in the body when the virus strikes.

Thirty-six healthy adults with no prior exposure to COVID (and before vaccines were available) signed up to be deliberately infected with SARS-CoV-2 via the nose. Among this group, 16 people were monitored more closely to track the entire course of the infection at the single-cell level. Baseline tests of their immune function were carried out before the infection, and then continued afterwards along with sampling of their blood and nasal lining.

Through single-cell sequencing, teams of analysts at UCL and the Wellcome Sanger Institute were able to generate data from over 600,000 individual cells from the participants. This rich dataset revealed immune responses that had never been observed with COVID-19 before.

“This was an incredibly unique opportunity to see what immune responses look like when encountering a new pathogen – in adults with no prior history of COVID-19, in a setting where factors such as time of infection and comorbidities could be controlled,” said co-first author Dr Rik Lindeboom in a statement.

Six out of the group of 16 people developed a COVID infection with mild symptoms and several positive antigen tests. Three others got what the scientists classified as a “transient infection”, with borderline positive PCR tests at various points during the study.

But the remaining seven people stayed PCR-negative throughout, even after COVID-19 was literally shoved up their noses. Data analysis revealed that their innate immune systems had responded initially to the virus, leading the authors to term these “abortive infections” – they didn’t have a specific, antibody-led response as you might expect from someone vaccinated against COVID, for example, but their innate immune response was so good that it cleared the virus out before any symptoms had a chance to show.

Digging a little deeper, the scientists identified a gene called HLA-DQA2 that was active in certain immune cells in the blood and nose in people with abortive infections. Previous research has indicated that the HLA-DQA2 protein may be associated with milder COVID-19 disease, so it’s possible this is a key factor in why some people have escaped the virus all this time.

By contrast, the people who developed symptomatic COVID displayed a rapid immune response in the blood but not in the nasal tissues themselves, allowing the virus to establish itself there.

“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,” said senior author Dr Marko Nikolić. “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.”

The results could also help us respond to the coronaviruses of the future, as senior author Dr Sarah Teichmann explained: “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.”

“Lindeboom and colleagues’ study is a notable step forward in understanding the complexities of SARS-CoV-2 infection,” wrote Benjamin Israelow and Akiko Iwasaki, who were not part of the study team, in a News & Views piece to accompany the study. “By unravelling the mysteries of early immune responses, the study offers promising avenues for future research and therapeutic development in the ongoing fight against COVID-19.”

The study is published in Nature.