Everyone is familiar with a “Covid virgin” or “Novid,” a person who has avoided contracting the coronavirus despite all odds. Could the key to these people’s immunity, however, be found nestled in their genes, rather than just judicious caution, good fortune, or a lack of friends? And might it be the secret to eradicating the virus?
The COVID Human Genetic Effort was founded in the early stages of the pandemic by a small, close-knit group of scientists from around the world. Its mission was to look for a genetic explanation for why some COVID patients developed severe illness while others only experienced mild symptoms.
After some time, the group realized that, despite frequent and intense exposures, some people weren’t becoming infected at all. The partners of those who became seriously ill and ended up in intensive care were the most fascinating cases. András Spaan, a clinical microbiologist at Rockefeller University in New York, says, “We learned about a few spouses of those people who—despite caring for their husband or wife, without having access to face masks—apparently did not contract infection.”
Spaan was tasked with organizing a division of the project to look into these individuals who appeared immune. However, they had to first locate a sizable number of them. So, the team wrote a paper about their project and put it in Nature Immunology. In the last sentence, they said that “subjects from all over the world are welcome.”
According to Spaan, the response was tremendous. He claims, “We literally received thousands of emails.” They had to create a multilingual online screening survey due to the overwhelming number of people rushing to sign up. They’ve received roughly 15,000 applications so far from all over the world.
Historical examples lend credence to the hypothesis that these individuals may already be immune. HIV, norovirus, and a parasite that causes recurrent malaria are all protected from genetic mutations that confer natural immunity. The team wondered why COVID would differ from other companies. However, the idea of inborn resistance to infection is a relatively new and obscure one in the lengthy history of immunology. Only a small number of scientists are even interested. Donald Vinh, an associate professor in the Department of Medicine at McGill University in Canada, claims that because it is such a specialized field, it is somewhat derided even within the medical and scientific communities. According to him, neither geneticists nor immunologists regard it as proper genetics or immunology. This is true even though the therapeutic objective is obvious. “If you can understand why someone cannot contract the infection, then you can understand how to stop people from contracting the infection,” says Vinh.
Finding immune individuals is a challenging task, though. Despite the large number of volunteers, only a small percentage meet the strict requirements of probably having come into contact with the virus but lacking antibodies to it (which would indicate an infection). The most likely candidates are those who have avoided Covid despite being at a very high risk, such as healthcare workers who often see Covid-positive patients or people who have lived with or, even better, shared a bed with confirmed infected people.
By the time the team began looking for suitable candidates, they were also opposed to mass immunization campaigns. Don’t get me wrong; it’s great that so many people are getting immunized, Vinh says. However, looking for the unvaccinated “does invite a bit of a fringe population,” and only about 800 to 1,000 recruits fit that strict criteria out of the thousands who flooded in after the call.
Then the virulent Omicron variant showed up. I have to be honest with you; Omicron has really ruined this project, says Vinh. It significantly decreased their pool of potential employees. Spaan, however, sees Omicron’s destruction in a more positive light; the fact that some recruits survived the Omicron waves actually supports the idea that people have an innate resistance to certain things.
Another member of the team, Cliona O’Farrelly, a professor of comparative immunology at Trinity College Dublin, began the process of hiring medical staff at a hospital in Dublin, Ireland, across the Atlantic. Omicron did throw a spanner in the works for the cohort she was able to assemble; half of the individuals whose DNA they had sent off to be sequenced ended up contracting the variant, wiping out their presumptive resistance. O’Farrelly went on the radio and extended the call to the rest of the nation in order to raise awareness of their research and find more suitable candidates. More than 16,000 people came forward, claiming to have resisted infection, sparking renewed enthusiasm. We’re currently attempting to deal with everything, she says. We might have one or two hundred of those, which would be incredibly valuable, I hope.
The group will employ a two-pronged approach to look for a genetic explanation for resistance now that they have a sizable cohort. To start, they will run each person’s genome through a computer blindly to check for any gene variations that begin to emerge frequently. At the same time, they will focus on a list of genes that they already know about and believe to be the culprits—genes that, if they differed from normal, would naturally suggest resistance. One illustration is the gene that creates the ACE2 receptor, a protein on cells’ exteriors that the virus uses to enter cells.
The consortium will crunch the data at about 50 sequencing hubs spread out across the globe, from Poland to Brazil to Italy. They must eventually decide whether they have enough data to continue their research while enrollment is still open. According to Spaan, that will be the time when we have individuals with obvious genetic mutations that make biological sense.
It will then be a matter of continually narrowing down that list of gene candidates once they have one. They will go through the list one at a time, examining the effects of each gene on COVID defenses in cell models. Vinh predicts that the process will take four to six months.
The project’s global scope and the cohort’s extreme heterogeneity could lead to additional complications. People of Southeast Asian ancestry may not necessarily share the same genetic variation that confers resistance as people in Slavic nations. This diversity, according to Spaan, is a positive: “This means that we can correct for ethnic origin in our analysis,” he says. But it also implies, in Vinh’s words, that they are searching through a factory of haystacks rather than just searching for one needle in a single haystack. “You’re looking for the golden needle, the silver needle, and the bronze needle,” he says.
Immunity is most likely conferred by a combination of genetic variations rather than by a single gene. It won’t be as simple as writing “This is the gene” in a single line on the Excel spreadsheet, says Vinh. We will be shocked if it turns out to be a single gene.
After all of this effort, it’s likely that naturally occurring genetic resistance will become incredibly rare. However, if they do discover any protective genes, it might help to guide future medical procedures. There is reason to believe this because, during three years of follow-up testing in the 1990s, a group of sex workers in Nairobi, Kenya, defied all odds by not contracting HIV. It was found that some of them carried a genetic mutation that results in an aberrant form of the CCR5 receptor protein, one of the proteins that HIV uses to enter cells and multiply. Because HIV cannot attach to cells if the mutation is present, it provides inherent resistance.This led to the creation of maraviroc, which is the most promising antiretroviral drug for treating infections. Two patients who had stem cell transplants from a donor who had the mutation and was HIV-free after the transplants.
It’s also possible that genetics doesn’t fully explain why some people manage to fend off infection in the face of overwhelming odds. Instead, their immune systems may be the cause of their protection in some cases. Mala Maini, a professor of viral immunology at University College London, and her colleagues closely watched a group of healthcare professionals who theoretically should have been infected with COVID during the first wave of the pandemic but weren’t. The blood samples from a different cohort of people, drawn long before the pandemic, were also examined by the team. When Maini’s team examined the blood samples from the two groups more closely, they discovered a hidden weapon: memory T cells, which are immune cells that serve as the second line of defense against an outside invader. Her team postulated in their paper published in Nature in November 2021 that these cells, dormant from prior encounters with other coronaviruses like those that cause the common cold, may be offering cross-protectivity against SARS-CoV-2.
The idea that these cross-reactive T cells exist and may help to explain why some people resist infection has received additional support from additional studies. According to Maini, attacking SARS-CoV-2 quickly is similar to operating a vehicle. It would take you some time to get used to the controls if the car was unfamiliar to you—say, a manual for a lifelong automatic driver. However, if the pre-existing T cells are used to automatics and a SARS-CoV-2 encounter is like stepping into one, it is easy to see how they would launch a much faster and stronger immune attack.
This preexisting immunity may have been produced by T cells from an earlier seasonal coronavirus infection or an abortive COVID infection in the initial wave. However, Maini emphasizes an important qualification: this does not imply that you can forgo the vaccine because you might be carrying these T cells.
More recently, Maini and her coworker Leo Swadling published a different paper that examined volunteer volunteers’ airway cells that were collected and frozen prior to the pandemic. They reasoned that if the infection was being eradicated so quickly, the cells in charge must be waiting and ready at the initial site of infection. Only 10 participants made up the study’s cohort, but six of them each had cross-reactive T cells in their airways.
Based on her findings, Maini is collaborating with scientists at the University of Oxford on the development of a vaccine that specifically induces these T cells in the mucous membranes of the airways and may provide comprehensive protection against coronaviruses, including SARS-CoV-2. Since T cells target portions of viruses that are remarkably similar across all human and animal coronaviruses, whereas the spike protein—the focus of current vaccines—is susceptible to mutation and change, such a vaccine could prevent the COVID virus from eluding the reach of the existing vaccines.
Additionally, a mucosal vaccine might prime these T cells in the nose and throat, the infection’s source, giving COVID the worst possible chance to establish itself. According to Maini, “We’re quite optimistic that this kind of approach could provide better protection against new emerging variants and, ideally, also against a new transfer of a new animal zoonotic virus.”
Spaan and his team must also consider the possibility that genetic resistance to SARS-CoV-2 will prove to be a pipe dream after all the hard work. We worry that after doing all of this, we won’t find anything, says Vinh. And it’s alright. Because, you know, science. O’Farrelly, on the other hand, is unwavering in his confidence that they will uncover something. It is simply impossible to have someone pass away without having the equivalent at the other end of the spectrum.
