The race to crack the code of natural COVID immunity

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London: It’s the question on everyone’s lips. How come I’ve had COVID twice, despite being fully vaccinated? How has my neighbour – who spent the last month isolating with her fully omicronned children – managed to avoid catching it? Why do some people fall foul of coronavirus again and again, and others remain steadfastly immune? Is it luck, genes, or what?

This week, Sir Keir Starmer tested positive for COVID for the second time in just over two months. It came four weeks after the Labour leader received his third vaccine dose, and is the sixth time Sir Keir will have to self-isolate since the beginning of the pandemic. Few people in Britain have been locked in isolation as many times as Sir Keir.

Dodging the virus

There are people like Sarah, who in October last year, assumed COVID-19 had finally come for her. The 25-year-old teacher had until that point managed to dodge the virus. But then a colleague at her central London primary school tested positive. Then another, and another. Eventually, the school had to close. Sarah had been in close contact with some of the positive cases, in meetings and in the staff room.

Scientists in Britain and Brazil have established that some people seem to clear the virus from their systems before they can even register an infection. Credit:AP

But curiously, her lateral flow tests kept returning negative results. Then, two months later, two of her three flatmates tested positive. Fuelled by the Omicron variant, COVID cases were exploding in London among Sarah’s age group during that week, ONS figures show. Every time she checked her phone, her social media was flooded with more positive results from friends. But still, Sarah’s test results remained stubbornly negative.

“I was just waiting to get it; I definitely felt like it was coming for us all,” she remembers.

We all know people like Sarah: the seemingly untouchable COVID “never-getters” who remain standing while everyone around them falls ill.

On the other side of the coin are those unlucky souls who seem to catch COVID again and again. For a long time, the question of why some caught the virus more than others was written off as a consequence of sheer luck. Whether or not you catch COVID can be explained by something as random as whether you talk to a certain person at a party, or whether you sit near an open window on a bus, virologists say. Testing issues are also a factor; some people are simply better than others at swabbing their nose and throat.

Members of the public queue for COVID-19 vaccinations and booster jabs at a community centre in London.Credit:Getty

But now, top immunologists suspect there might be a more profound explanation. Researchers in Britain and Brazil are looking at whether some people might possess a natural immunity to the virus. Even before the pandemic began, their immune systems already knew how to fight the virus, it is believed. If their blood and cells are studied carefully, this fortunate few could give scientists crucial insights into the nature of immunity. And they might just hold the key to the holy grail of pandemic research: a universal COVID vaccine, with the ability to knock out any variant.

What is immunity, really?

We tend to think of immunity as something of an absolute – either we’re immune to a virus, or we’re not. But that hides a world of complications, says Danny Altmann, professor of medicine and immunology at Imperial College London. The genes that control our immunity are among the most diverse in the human body, he says, differing hugely from person to person.

When thinking about something like your blood type, he says, “there’s a very limited chequerboard” of gene combinations. But for immunity, “I’m talking about thousands of possibilities on your chequerboard; no two people will ever look the same.”

As a result, we shouldn’t be surprised that some are more prone to catching viruses than others. We can see this happening in real-time in the laboratory. Researchers at Oxford University and Imperial College London are currently carrying out “challenge studies”, where volunteers are deliberately exposed to COVID, usually through a liquid solution sniffed into their nose, then kept in isolation and observed for two weeks.

All volunteers have received the same number of vaccines, and all are exposed to exactly the same quantity of SARS-CoV-2 (the virus that causes COVID), in exactly the same way. And yet, if it’s anything like previous challenge studies, scientists expect volunteers will mount notably different immune responses. Some will see their antibody and T-cells burst into action; others will not.

We can also see this playing out in hospitals. At the beginning of the pandemic, researchers at University College London recruited a large cohort of London-based healthcare staff for their COVIDsortium study. All of the volunteers were probably exposed to SARS-CoV-2 during their jobs. Their test results were monitored thoroughly. At the end of the trial, about 20 per cent of the healthcare staff showed signs of a clear-cut COVID infection, whilst 65 per cent had patently not been infected.

Studies of health care workers repeatedly exposed to coronavirus found that some people never seemed to catch it, or at least, never became ill. Credit:

But most interesting was the remaining 15 per cent. Members of this third group appeared to have experienced low-level “abortive infections”, not picked up on PCR tests. They didn’t have COVID antibodies in their blood, but they had a much higher T-cell count than average, with particularly high levels of the specific T-cell known to combat COVID. Essentially, their T-cells had nipped the virus in the bud before it ever got the chance to set up camp inside their bodies. It looked as though their immune systems already knew how to fight COVID, even though it was still the early days of the pandemic.

“Those patients didn’t completely resist the infection, but they eliminated it so rapidly that it couldn’t be picked up by the standard test,” says Mala Maini, a professor of viral immunology at University College London, and co-author of the study.

Here was clear evidence that some people may be naturally immune to COVID. Altmann, who was not involved in the study, says the results look “convincing”.

Did a cold give them immunity or their DNA?

But what explains this natural immunity? The most likely theory is that these people’s immune systems had already been exposed to similar viruses, years or decades earlier. SARS-CoV-2 is one of a family of seven human coronaviruses, most of which cause the common cold. All of these viruses look fairly similar. When your T-cells learn how to fight one, they get better at fighting them all, it is thought.

Another, less well-researched answer lies in our genes. Some people might simply be born with an immunity to certain viruses, scientists suspect. This possibility emerged in 2008, when virologists in Kenya found a group of sex workers who had never caught HIV, despite having unprotected sex with numerous positive cases. It turns out their cells lacked a crucial receptor – the same receptor used by HIV particles to break into our cells.

“Big studies are going on now to see if something similar might be happening in some people with COVID, but there’s no clear evidence for that yet,” says Maini.

Indeed, at the University of São Paulo, researchers are recruiting 100 cohabiting couples. In each case, one half of the couple tested positive for symptomatic COVID, whilst the other stayed COVID-free (with blood tests confirming they had no COVID-specific antibodies). All 200 will have their DNA analysed to search for genetic differences.

A universal vaccine

If it turns out that some people are indeed naturally immune to COVID, it’s wonderful news for them. But it might also help the rest of us, speeding up development of a pan-coronavirus vaccine capable of defeating any variant. The current generation of COVID vaccines were all designed to target the spike protein, on the virus’s outer edge. But the spike protein also changes frequently, each time the virus mutates. This means vaccines are slightly less effective against each new variant.

But natural immunity appears to work differently. In the UCL trial, researchers looked carefully at the blood of those volunteers who seemed to have pre-existing immunity to the virus. Rather than targeting the spike protein, their T-cells were targeting proteins at the centre of the virus. These proteins are much less likely to change from mutation to mutation. In fact, they tend to be found in most coronaviruses, not just SARS-CoV-2. If a vaccine could be built to target these inner proteins, it might just be able to defeat all variants – as well as a range of other coronaviruses.

Experts stress that the science is still in progress. Nobody should “go around feeling Teflon-coated in some way”, Altmann urges. But as we enter our third year of the pandemic, it’s a hopeful sign, for sure.

The Telegraph, London

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