February 26, 2024

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Why are some people not infected with COVID-19?

Why are some people not infected with COVID-19?


Why are some people not infected with COVID-19? Scientists are looking for answers.

According to ArsTechnica, people who have never had the COVID-19 are called “COVID virgins” or “Novid”.

Could the secret of these people’s immunity be found in their genes? Could it be the key to fighting the virus?

In the early days of the COVID-19 pandemic, scientists from around the world formed a small, tight-knit group to form an international consortium called the COVID Human Genetics Work, whose goal was to find a genetic explanation for how Why some people get severe with COVID while others get only a mild case of rhinitis.


After a while, the team noticed that some people were not infected at all — despite repeated and intensive exposure.

The most intriguing cases were the partners of those who were actually sick and ended up in intensive care. “We learned that some of these people’s spouses — who were not given masks despite caring for their husbands or wives — were apparently not infected,” said András Spaan, a clinical microbiologist at The Rockefeller University in New York.


Why are some people not infected with COVID-19?




Spaan was tasked with establishing a branch of the project to investigate these seemingly immune individuals. But they have to find enough people first. So the team published a paper in Nature Immunology outlining their efforts, with the last line discreetly mentioning, “Subjects from all over the world are welcome.”


The response, Spaan said, has been overwhelming. “We literally got thousands of emails,” he said. “The number of active applicants forced them to set up a multilingual online screening survey. So far, they’ve had about 15,000 applications from all over the world.”


The theory that these people may have pre-existing immunity is supported by historical examples.

There are genetic mutations that confer natural immunity to HIV, norovirus and a parasite that causes relapsing malaria.

Why, the team thinks, is COVID any different? However, in the long history of immunology, innate resistance to infection is a fairly new and esoteric concept.

Even only a few scientists are interested in it. “It’s a niche field, and it’s a somewhat overlooked concept even in medicine and research,” said Donald Vinh, an associate professor in the Department of Medicine at McGill University in Canada.

Geneticists don’t acknowledge it’s correct inheritance, he said. Science, immunologists also do not admit it is correct immunology.

Although there is a clear treatment goal. “If you can figure out why someone can’t get infected, then you can figure out how to prevent people from getting infected,” Vinh said.


But finding people with immunity is an increasingly tricky task. While many volunteered, only a few met the narrow criteria of possibly having encountered the virus but not having antibodies against it (which would indicate infection).

The most promising candidates are those who defy all logic and do not have COVID-19 in high-risk situations: healthcare workers who frequently come into contact with COVID-positive patients, or those who live with someone who is confirmed to be infected, or even Better yet, the person who sleeps with them.


When the team set out to find the right people, their work also ran counter to a mass vaccination program.

“On the one hand, a lot of people are getting vaccinated, which is good, don’t get me wrong,” Vinh said. “But these are not the people we want. On the other hand, looking for unvaccinated people does attract some marginalized people.”

Of the thousands who poured in after the call, about 800 to 1,000 volunteers meet this stringent standard.


Then, the highly contagious variant of Omicron arrives. “Omicron really ruined the project, and I have to be honest with you,” Vinh said.

It drastically reduces their candidate pool. But Spaan sees omicron in a more positive light: Some people are not infected with the omicron variant, which does support the existence of innate resistance.


Across the Atlantic in Dublin, Ireland, another member of the team – Cliona O’Farrelly, a professor of comparative immunology at Trinity University Dublin – set out to recruit health care workers at a Dublin hospital.

In the cohort she managed to put together, omicron did cause trouble for the job — half of the people they sent for sequencing had their DNA eventually infected with a variant that wiped out their putative resistance.

To promote their research and find more suitable people, O’Farrelly went on the radio show and expanded the call to the rest of the country.

Once again, the enthusiasm of the people is high. More than 16,000 people have come forward, claiming they have beaten the infection. “We’re trying to deal with all these issues right now.

We hope we get one or two hundred out of these people, it’s going to be an incredibly valuable asset,” she said.


Now that they have a sizable cohort, the group will take a dual approach to finding a genetic explanation for the resistance.

First, they’ll run a computer blindly through each person’s genome to see if any genetic variants start popping up frequently.

At the same time, they look specifically at the list of existing genes they suspect may be the culprit — and if it’s different than usual, it’s reasonable to infer resistance.

One example is the gene encoding the ACE2 receptor, a protein on the surface of cells that viruses use to slip inside cells.


The consortium has about 50 sequencing centers around the world, from Poland to Brazil to Italy, where data will be analyzed.

While the recruitment of volunteers is still ongoing, at some point, they will have to decide they have enough data to carry out their research in depth.

“That’s going to be the biologically meaningful moment when we have people with clear genetic mutations,” Spaan said.


Once they’ve come up with a list of candidate genes, the next step is to narrow it down and narrow that list down.

They will review the list one by one, testing each gene’s impact on defense against COVID in a cellular model. Vinh estimates that the process will take four to six months.


The global nature of the project may create another complication; cohorts will be massively heterogeneous.

People from Slavic-speaking countries do not necessarily have the same genetic variants that confer resistance as Southeast Asian populations.

Spaan again sees this diversity as an advantage: “It means we can correct for racial origins in our analysis,” he said. But it also means, Vinh says, that they’re not just looking for a ‘needle in a haystack’ — you’re looking for gold, silver and copper. “


It is unlikely that it is a single gene that confers immunity, but a series of combinations of genetic variants.

“I don’t think it’s going to boil down to one sentence on an Excel sheet, ‘this is the gene,'” Vinh said. “If it happened to be a single gene, we would be shocked.”


With all this work done, it is likely that natural genetic resistance will prove to be extremely rare. Still, if they find protective genes, it could help inform future treatments.

There are good reasons to think so. In the 1990s, a group of sex workers in Nairobi, Kenya, defied all logic and went HIV-free during a three-year follow-up test.

It was found that some people carry a genetic mutation that produces a scrambled version of a protein called the CCR5 receptor, one of the proteins HIV uses to enter cells and replicate itself.

This mutation means that HIV cannot attach to cells, creating a natural resistance.

This inspired maraviro, an antiretroviral drug used to treat infections, and the most promising “cure” for HIV, in which two patients received stem cell transplants from donors with mutations to become HIV-free people.


It’s also possible that genetics doesn’t tell the whole story for those who are desperate to fight infection.

For some people, the reason they are protected may instead lie in their immune system. During the first wave of the pandemic, Mala Maini, professor of viral immunology at UCL, and her colleagues intensively monitored a group of healthcare workers who could theoretically have been infected with COVID but for some reason did not. 

The team also looked at blood samples from another group of people that had been taken before the pandemic.

When examining samples from both groups, Maini’s team discovered a “secret weapon” in their blood: memory T cells — immune cells that form a second line of defense against “foreign invaders.”


In a paper published in the journal Nature in November 2021, her team hypothesized that these cells, dormant due to previous dealings with other coronaviruses, such as those that cause the common cold, may provide SARS-CoV-2 cross protection.



Why are some people not infected with COVID-19?



Other studies support the theory that these cross-reactive T cells exist and may explain why some people avoid infection.

Maini likens the way these memory T cells might quickly attack SARS-CoV-2 to driving a car.

If the car isn’t like anything you’ve driven before — a manual for a lifelong self-driving person, then it’s going to take you a while to get the hang of the controls.

But assuming that the original T cells are used to autopilot, and encountering SARS-CoV-2 is like jumping in the autopilot seat, you can see how they will mount a faster and stronger immune attack.


Previous seasonal coronavirus infections may generate T cells that provide this pre-existing immunity.

But Maini points to a key caveat: That doesn’t mean you can skip the vaccine on the potential basis that you carry these T cells.


More recently, Maini and her colleague Leo Swadling published another paper looking at cells in the airways of volunteers that were sampled and frozen before the pandemic.

They reasoned that if the infection had been shut down so quickly, the cells responsible must have been primed and waiting at the first signs of infection.

The study’s cohort was small, just 10 people, but 6 out of 10 people had cross-reactive T cells present in their airways.


Building on her research, Maini is working with researchers at the University of Oxford to develop a vaccine that specifically induces these T cells in the airway mucosa, which could provide not only broad protection against SARS-CoV-2, but various kind of coronavirus.

The vaccine could stop the COVID virus from escaping from existing vaccines because while the spike protein — the focus of current vaccines — has the potential to mutate and change, the T cells target the highly similar among all human and animal coronaviruses Virus fragments.


And a mucosal vaccine could prime these T cells in the nose and throat, the origin of infection, giving COVID the worst chance of getting a root. “We are fairly optimistic that this approach could provide better protection against emerging variants and, ideally, the transfer of new zoonotic viruses in animals,” Maini said.


As for Spaan and his team, they also had to consider the possibility that genetic resistance to SARS-CoV-2 had become a pipe dream after much effort.

“It’s our fear — we’re going to do it all, but we’re going to get nothing,” Vinh said. “That’s okay. Because that’s science, right?”

On the other hand, O’Farrelly is unwaveringly optimistic that they’ll find something. “You can’t let people die without having something corresponding on the other end of the spectrum.”




Why are some people not infected with COVID-19?

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