Most people in the U.S have had Covid-19 at least once — likely more than 70% of the country, White House Covid-19 Response Coordinator Ashish Jha said on Thursday, citing data from the Centers for Disease Control and Prevention.
Many have gotten infected multiple times. In a preprint study looking at 257,000 U.S. veterans who’d gotten Covid at least once, 12% had a reinfection by April and around 1% had been infected three times or more.
This raises an obvious question: What is keeping that shrinking minority of people from getting sick?
Disease experts are homing in on a few predictive factors beyond individual behavior, including genetics, T cell immunity and the effects of inflammatory conditions like allergies and asthma.
But even as experts learn more about the reasons people may be better able to avoid Covid, they caution that some of these defenses may not hold up against the latest version of omicron, BA.5, which is remarkably good at spreading and evading vaccine protection.
“It really takes two to tango,” said Neville Sanjana, a bioengineer at the New York Genome Center. “If you think about having an infection and any of the bad stuff that happens after that, it really is a product of two different organisms: the virus and the human.”
Genetics could decrease the risk of Covid
In 2020, NYU researchers identified a multitude of genes that could impact a person’s susceptibility to the coronavirus. In particular, they found that inhibiting certain genes that code for a receptor known as ACE-2, which allows the virus to enter cells, could reduce a person’s likelihood of infection.
Sanjana, who conducted that research, estimated that about 100 to 500 genes could influence Covid-19 susceptibility in sites like the lungs or nasal cavity.
Genetics is “likely to be a large contributor” to protection from Covid-19, he said. “I would never say it’s the only contributor.”
In July, researchers identified a common genetic factor that could influence the severity of a coronavirus infection. In a study of more than 3,000 people, two genetic variations decreased the expression of a gene called OAS1, which is part of the innate immune response to viral infections. That was associated with an increased risk of Covid-19 hospitalization.
Increasing the gene’s expression, then, should have the opposite effect — reducing the risk of severe disease — though it wouldn’t necessarily prevent infection altogether.
“It’s very natural to get infected once you are exposed. There’s no magic bullet for that. But after you get infected, how you’re going to respond to this infection, that’s what is going to be affected by your genetic variants,” said Ludmila Prokunina-Olsson, the study’s lead researcher and chief of the Laboratory of Translational Genomics at the National Cancer Institute.
Still, Benjamin tenOever, a microbiology professor at the NYU Grossman School of Medicine who helped conduct the 2020 research, said it will be difficult for scientists to pinpoint a particular gene responsible for preventing a Covid infection.
“While there might still be certainly some genetics out there that do render people completely resistant, they’re going to be incredibly hard to find,” tenOever said. “People have already been looking intensely for two years with no actual results.”
T cells could remember past coronavirus encounters
Aside from this new coronavirus, SARS-CoV-2, four other coronaviruses commonly infect people, typically causing mild to moderate upper respiratory illnesses like the common cold.
A recent study suggested that repeated exposure to or occasional infections from these common cold coronaviruses may confer some protection from SARS-CoV-2.
The researchers found that T cells, a type of white blood cell that recognizes and fights invaders, seem to recognize SARS-CoV-2 based on past exposure to other coronaviruses. So when a person who has been infected with a common cold coronavirus is later exposed to SARS-CoV-2, they might not get as sick.
But that T cell memory probably can’t prevent Covid entirely.
“While neutralizing antibodies are key to prevent an infection, T cells are key to terminate an infection and to modulate the severity of infection,” said Alessandro Sette, the study’s author and a professor at the La Jolla Institute for Immunology.
Sette said it’s possible that some people’s T cells clear the virus so quickly that the person never tests positive for Covid. But researchers aren’t yet sure if that’s what’s happening.
“It’s possible that, despite being negative on the test, it was a very abortive, transient infection that was not detected,” Sette said.
At the very least, he said, T cells from past Covid infections or vaccines should continue to offer some protection against coronavirus variants, including BA.5.
Allergies may result in a little extra protection
Although asthma was considered a potential risk factor for severe Covid earlier in the pandemic, more recent research suggests that low-grade inflammation from conditions like allergies or asthma may have a protective benefit.
“You’ll hear these stories about some individuals getting sick and having full-blown symptoms of Covid, and having slept beside their partner for an entire week during that period without having given it to them. People think that they must have some genetic resistance to it, [but] a big part of that could be if the partner beside them in any way has a higher than normal inflammatory response going on their lungs,” tenOever said.
A May study found that having a food allergy halved the risk of a coronavirus infection among nearly 1,400 U.S. households. Asthma didn’t lower people’s risk of infection in the study, but it didn’t raise it, either.
One theory, according to the researchers, is that people with food allergies express fewer ACE2 receptors on the surface of their airway cells, making it harder for the virus to enter.
“Because there are fewer receptors, you will have either a much lower grade infection or just be less likely to even become infected,” said Tina Hartert, a professor of medicine and pediatrics at the Vanderbilt University School of Medicine who co-led that research.
The study took place from May 2020 to February 2021, before the omicron variant emerged. But Hartert said BA.5 likely wouldn’t eliminate cross-protection from allergies.
“If something like allergic inflammation is protective, I think it would be true for all variants,” Hartert said. “The degree to which it could be protective could certainly differ.”
Avoiding infection is more challenging with BA.5
For many, the first explanation that springs to mind when thinking about Covid avoidance is one’s personal level of caution. tenOever believes that individual behavior, more than genetics or T cells, is the key factor. He and his family in New York City are among those who’ve never had Covid, which he attributes to precautions like staying home and wearing masks.
“I don’t think for a second that we have anything special in our genetics that makes us resistant,” he said.
It’s now common knowledge that Covid was easier to avoid before omicron, back when a small percentage of infected people were responsible for the majority of the virus’s spread. A 2020 study, for example, found that 10–20% of infected people accounted for 80% of transmission.
But omicron and its subvariants have made any social interaction riskier for everyone involved.
“It’s probably far more of an equal playing field with the omicron variants than it ever was for the earlier variants,” tenOever said.
BA.5 in particular has increased the odds that people who’ve avoided Covid thus far will get sick. President Joe Biden is a prime example: He tested positive for the first time this week.
But even so, Jha said on Thursday, “I don’t believe that every American will be infected.”