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WE FINALLY KNOW WHY SOME PEOPLE GOT COVID WHILE OTHERS DIDN’T  
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Marko Nikolic and Kaylee Worlock
May 28, 2024
The Conversation
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_ In our "challenge study," one gene produced much more of a specific
protein in volunteers who did not develop a sustained COVID infection.
This finding has significant implications for future treatments and
for vaccine development. _

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Throughout the pandemic, one of the key questions on everyone’s mind
was why some people avoided getting COVID, while others caught the
virus multiple times.

Through a collaboration between University College London, the
Wellcome Sanger Institute and Imperial College London in the UK, we
set out to answer this question using the world’s first controlled
“challenge trial” for COVID
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volunteers were deliberately exposed to SARS-CoV-2, the virus that
causes COVID, so that it could be studied in great detail.

Unvaccinated healthy volunteers with no prior history of COVID were
exposed – via a nasal spray – to an extremely low dose of the
original strain of SARS-CoV-2. The volunteers were then closely
monitored in a quarantine unit, with regular tests and samples taken
to study their response to the virus in a highly controlled and safe
environment.

For our recent study
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Nature, we collected samples from tissue located midway between the
nose and the throat as well as blood samples from 16 volunteers. These
samples were taken before the participants were exposed to the virus,
to give us a baseline measurement, and afterwards at regular
intervals.

The samples were then processed and analysed using single-cell
sequencing technology, which allowed us to extract and sequence the
genetic material of individual cells. Using this cutting-edge
technology, we could track the evolution of the disease in
unprecedented detail, from pre-infection to recovery.

To our surprise, we found that, despite all the volunteers being
carefully exposed to the exact same dose of the virus in the same
manner, not everyone ended up testing positive for COVID.

In fact, we were able to divide the volunteers into three distinct
infection groups (see illustration). Six out of the 16 volunteers
developed typical mild COVID, testing positive for several days with
cold-like symptoms. We referred to this group as the “sustained
infection group”.

Out of the ten volunteers who did not develop a sustained infection,
suggesting that they were able to fight off the virus early on, three
went on to develop an “intermediate” infection with intermittent
single positive viral tests and limited symptoms. We called them the
“transient infection group”.

The final seven volunteers remained negative on testing and did not
develop any symptoms. This was the “abortive infection group”.
This is the first confirmation of abortive infections, which were
previously unproven
[[link removed]]. Despite
differences in infection outcomes, participants in all groups shared
some specific novel immune responses, including in those whose immune
systems prevented the infection.

When we compared the timings of the cellular response between the
three infection groups, we saw distinct patterns. For example, in the
transiently infected volunteers where the virus was only briefly
detected, we saw a strong and immediate accumulation of immune cells
in the nose one day after infection.

This contrasted with the sustained infection group, where a more
delayed response was seen, starting five days after infection and
potentially enabling the virus to take hold in these volunteers.

In these people, we were able to identify cells stimulated by a key
antiviral defence response in both the nose and the blood. This
response, called the “interferon” response, is one of the ways our
bodies signal to our immune system to help fight off viruses and other
infections. We were surprised to find that this response was detected
in the blood before it was detected in the nose, suggesting that the
immune response spreads from the nose very quickly.

Protective gene

Lastly, we identified a specific gene called HLA-DQA2, which was
expressed (activated to produce a protein) at a much higher level in
the volunteers who did not go on to develop a sustained infection and
could hence be used as a marker of protection. Therefore, we might be
able to use this information and identify those who are probably going
to be protected from severe COVID.

These findings help us fill in some gaps in our knowledge, painting a
much more detailed picture regarding how our bodies react to a new
virus, particularly in the first couple of days of an infection, which
is crucial.

We can use this information to compare our data to other data we are
currently generating, specifically where we are “challenging”
volunteers to other viruses and more recent strains of COVID. In
contrast to our current study, these will mostly include volunteers
who have been vaccinated or naturally infected – that is, people who
already have immunity.

Our study has significant implications for future treatments and
vaccine development. By comparing our data to volunteers who have
never been exposed to the virus with those who already have immunity,
we may be able to identify new ways of inducing protection, while also
helping the development of more effective vaccines for future
pandemics. In essence, our research is a step towards better
preparedness for the next pandemic.

_Marko Nikolic
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Principal Research Fellow/Honorary consultant Respiratory Medicine,
UCL [[link removed]] and Kaylee
Worlock [[link removed]],
Postdoc Research Fellow, Molecular and Cellular Biology, UCL
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_This article is republished from The Conversation
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the original article
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* Science
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* vaccines
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* COVID-19
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* Medicine
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