Three years into the pandemic, a select group of people have achieved something some once thought impossible: They have never tested positive for Covid. Scientists around the world are searching for the genetic reasons these people have dodged Covid — despite repeated exposure to the virus.
Were they born with a form of super immunity? What's behind their Houdini-like success at escaping infection?
"Mostly luck," said Adam Zimmerman, 40, of Rockville, Maryland, laughing. Neither Zimmerman nor his wife and children have tested positive for Covid.
"We took whatever mitigation steps we could and then hoped for the best," Zimmerman said, noting that his family is up to date with their vaccines. "So far, so good."
Since March 11, 2020, more than 676 million people around the world have had a confirmed infection. Nearly 60 percent of the U.S. population has had Covid, according to the Centers for Disease Control and Prevention. There could be millions more missed cases because the individuals never had symptoms.
Even though millions of people have been vaccinated and followed precautions similar to the Zimmermans, they still got sick from Covid, either because of breakthrough infections or waning immunity.
Yet scientists believe it is possible that some people have never been infected because they entered the pandemic equipped with a kind of biological armor against the virus that causes Covid.
Now they want to unravel the mysteries hidden in the immune systems of true "Covid dodgers."
Is it possible to be immune to Covid?
"We are searching for rare genetic variants that make people resistant to SARS-CoV-2 infection," said Dr. Jean-Laurant Casanova, a pediatric immunologist, geneticist and professor at Rockefeller University in New York. "If we were to discover them, the impact would be significant."
Casanova is working with an international team of scientists in a project called the Covid Human Genetic Effort.
"There's a couple of genes that have our attention," said Dr. Andras Spaan, a clinical microbiologist on the team. "One of them, of course, is ACE2," a gene known to help Covid infiltrate the body.
In theory, some people may have DNA that does the opposite: preventing ACE2 or other genes from allowing a Covid invasion. If researchers can zero in on a protective genetic factor, it's possible that they could develop drugs to prevent infection and further spread of the virus.
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The team has recruited approximately 1,000 people worldwide, using saliva samples to study volunteers' DNA.
Not surprisingly, many of the study's early recruits eventually tested positive for the virus, especially after the highly contagious omicron took hold in 2022.
Some never became infected, Spaan said, "even with omicron and repeated, intense exposure."
Rachel Zucker-Wong, 29, of San Francisco has a similar story. She recalled a time in September 2021, as the "hypertransmissible" delta variant was driving cases nationwide, when she sat next to a man at a wedding dinner who she later learned had Covid.
"We were sitting right next to him. We were hugging him. We were all toasting," Zucker-Wong said. "And I never got it."
In fact, she has never tested positive, despite her husband getting Covid and her repeated exposure to the virus as a nursing school student.
Brian Peach worked as a nurse in the Covid intensive care unit at Orlando Regional Medical Center in Florida early in the pandemic, before Covid vaccines were widely available.
"We were in patients' rooms constantly, giving them medications, supporting their blood pressure," said Peach, also an assistant professor in the College of Nursing at the University of Central Florida. "We'd be in there suctioning their breathing tubes and doing regular oral care to prevent ventilator-associated pneumonias."
He's never tested positive, and is fascinated by the thought of having some kind of protective DNA.
"I'd love to know if I have something in particular that's helped me, other than the vaccines," Peach said.
It's not unheard of: There are people whose genes protect them from other viruses, such as HIV. That discovery has led to a handful of cases in which people living with HIV have possibly been cured with a stem cell transplant from naturally resistant donors.
Early in the pandemic scientists in the United Kingdom intentionally tried to infect people to see what would happen.
The Human Challenge Programme was small, including just 36 healthy young men and women. Researchers at Imperial College London squirted a tiny bit of the virus up the participants' noses and then waited. (Participants were all carefully monitored for any complications, but none occurred.)
Half of the participants became infected, experiencing mild symptoms. The other half, despite literally having Covid placed into their nasal cavity, remained infection-free.
As the pandemic progressed, however, most participants eventually developed the infection, said Peter Openshaw, a professor of experimental medicine at Imperial College London who led the research.
That is, any natural-born Covid immunity was unlikely.
"We don't think that there was anything inherent that was preventing them from being infected," Openshaw said. It was "probably some chance event" that shielded the participants.
Perhaps "the very low concentration of the virus that was given got caught up in a lump of mucus and was expelled rather than managing to penetrate and cause infection," Openshaw said.
Exposed to Covid, but no symptoms
As the search continues for an elusive immunity gene, asymptomatic infections may be the real story.
That is, people never knew they had Covid because their body stopped the virus from making them sick — no cough, no fever, no trouble breathing.
One study conducted early in the pandemic, when routine testing was common, suggested that more than 40% of cases could be asymptomatic. The CDC stopped trying to track the percentage of asymptomatic cases when regular testing became less common.
Openshaw finds asymptomatic cases "absolutely fascinating."
"What is it that clears the virus before it gets a foothold?," he asked.
That's exactly what Jill Hollenbach, a professor in the department of neurology, as well as the department of epidemiology and biostatistics at the University of California, San Francisco, is trying to discover.
"Some people just don't have symptoms at all," Hollenbach said. "There's something happening at a really fundamental level in the immune response that is helping those people to just completely wipe out this infection."
Hollenbach's lab is focusing on human leukocyte antigen, or HLA. The molecule sits on the surface of all of the cells in the body, basically acting like an overzealous guard dog.
HLA constantly shows the immune system what it finds near cells. Usually, they're harmless bits that are supposed to be in the body. Immune systems are generally unfazed by this.
Sometimes HLA holds up something that the immune system doesn't recognize, such as a virus like Covid. That's when it is supposed to launch an attack.
But HLA's abilities vary widely from person to person, and Hollenbach needed to find which version of HLA is especially adept at prompting the immune system to rid the body of Covid.
She turned to the National Donor Program, which includes roughly 13 million people — all with neatly logged HLA types.
HLA genes are the same that must be matched in people seeing an organ or stem cell transplant.
Hollenbach's team then followed about 30,000 people from that registry from the beginning of the pandemic until April 2021, when the vaccines became widely available.
More than 13,000 ultimately tested positive. Ten percent were totally asymptomatic.
"We were pretty stringent in our definition of asymptomatic. You don't even have a scratchy throat," Hollenbach said.
Strong immunity, a common genetic thread
Her team discovered a common genetic thread: a gene called HLA-B*15:01. People who have this HLA version were more than twice as likely to have an asymptomatic infection, Hollenbach found. That protection was increased by more than eight times if a person had two copies of the gene.
Her research was published on a preprint server, and is currently under consideration with a peer-reviewed journal, Hollenbach said.
People who have asymptomatic infections may be useful to study in other ways, as well. Akiko Iwasaki, a professor of immunobiology at Yale University, suggests the tantalizing possibility that they might never be infected with Covid again.
"That would be important because that's really what we want to achieve in the population," Iwasaki said.
People who are infected but never show symptoms may develop a "strong mucosal immune system," Iwasaki suggested.
That is, when they breathe in bits of the virus, an army of immune cells quickly assembles in their mouth and noses. Those cells remember to be on the lookout for the virus if the person is exposed again.
"That could indicate that these people have developed very robust local immune responses that prevent future infections," Iwasaki said. Future research using saliva samples may be able to tell whether those mucosal immune cells do indeed hold onto the memory of Covid.
Hollenbach said that it appears people whose immune systems include the form of the HLA gene also have a fantastic ability to remember prior infections, jumping into action immediately when it finds something menacing that's been there before.
Hollenbach believes this is why kids have generally been spared the worst outcomes of Covid. Their little bodies are already extremely familiar with respiratory viruses.
"They basically spend years just completely snotty from ages 1 to 7," she said. "They're experiencing these seasonal coronaviruses at a really rapid clip, passing them around all of the time."
The idea is intriguing to other experts.
"There's a lot of work going on to try to see whether cross-reactive immunity stimulated by common cold coronaviruses could be a factor that causes differences in the way in which people respond to Covid," Openshaw said.
It may be a reason that Sue Nowatzke, a semi-retired nurse in Ames, Iowa, has remained Covid-free.
"Ever since I was a kid, I easily caught any kind of respiratory crud," said Nowatzke, 64. "And when I worked in the hospital, I was always sick."
The last time Nowatzke remembers being ill was in December 2019. Since then, "I can't even remember a sniffle," she said.
She has never tested positive, despite repeated exposures to Covid while working as a nurse in June 2021.
Her husband, Duane, 68, has also never tested positive, but they aren't sure it's because of some innate ability to fend off Covid. They say they've relied heavily on masking and staying up to date on vaccination.
"They come up with a shot, we get it," Duane Nowatzke said.
Is Covid infection inevitable?
As scientists search for genetic factors that may render a lucky few immune to Covid, experts encourage caution.
"You never want to be like, 'I haven't gotten Covid, therefore I am invincible,'" said Dr. Michael Angarone, an infectious diseases specialist at Northwestern Medicine.
Some believe it's inevitable that the entire population will become infected sooner or later. While masking and vaccines are effective, they're not foolproof.
"There's very few people left that I know of who have not had the infection," said Angarone. "Even the people I know who were washing their groceries and whatnot ended up getting infected."
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