The first time my daughter, Rosy, was exposed to SARS-CoV-2, I panicked.
It was November 2020, before vaccines were available. Someone in Rosy's class had tested positive and been contagious in the classroom for two days. So we all quarantined at home and braced ourselves for a horrible few weeks of sickness.
But after 10 days, nothing had happened. Rosy never showed signs of an infection and never tested positive. She had dodged the coronavirus.
Then about 10 months later, the same thing happened. And again two weeks later. And four months later. After each exposure, we did the same routine: Quarantine. Wait. And test repeatedly.
Over the course of the pandemic, my daughter has been exposed to SARS-CoV-2, the coronavirus that causes the disease COVID-19, at least four times. Mostly at school. Once at a party. Every time, somehow, she seems to have escaped an infection.
So my question is, why?
Of course, the simplest answer is that she has been infected and we just didn't know it. Despite all our testing, we missed it. An analysis from the Centers for Disease Control and Prevention found that at least 58% of children under age 18 — that's about 42 million children — had been infected with SARS-CoV-2 as of Jan. 22, according to antibody testing. Yet the U.S. has recorded only about 13 million pediatric cases. So many coronavirus cases among kids have gone unnoticed, unreported or undetected. And Rosy could fall into that category.
But she's also just as likely to fall into another category — kids who have been exposed to the coronavirus but who haven't caught it.
So how has Rosy done it? How has she seemingly pulled this rabbit from the hat or, in this case, pulled the coronavirus from her nose?
Over the past year, several studies have offered a tantalizing hint: Some people, even before being vaccinated, are really good at clearing the coronavirus from their respiratory tract and do it so quickly that the virus never reaches detectable levels. And the immune system accomplishes this coup with two key tools: immune cells originally made to fight another coronavirus — four key ones are out there — and an arm of the immune system that gets little attention in the media but is doing a huge amount of work to protect us all from SARS-CoV-2.
Exposure to another coronavirus could be protecting Rosy against SARS-CoV-2
Back in November, immunologists at University College London published a study in the journal Nature that left many other scientists a bit surprised. The study presented striking evidence that prior exposure to another coronavirus can prepare the immune system to fight off SARS-CoV-2. "Before we published the full data, there were some people who said, 'Oh, how is it possible?' " says Mala Maini, who led the research.
In the study, Maini and her colleagues analyzed the blood of about 60 health care workers at a hospital over and over again. It was during the first wave of the pandemic, when vaccines weren't available. The workers repeatedly tested negative for SARS-CoV-2 despite being heavily exposed.
Maini started to wonder whether these health workers had, inside their blood, some type of protective element against SARS-CoV-2. Perhaps their previous encounters with other coronaviruses — before the COVID-19 pandemic began — had generated immune cells that could fight off a SARS-CoV-2 infection.
"That's what it looked like in this small subset of people," Maini says.
Inside the blood of 20 health care workers, she and her team found a special group of T cells that could do just that: recognize and stop SARS-CoV-2.
These special cells are called cross-reactive T cells. In general, T cells are thought to be second-line defenders in the immune system's hierarchy, Maini says. "First, antibodies come in and protect you against infection, and then T cells mop up the infected cells."
But in her study, the T cells appear at a very early stage of the infection, before the body can make antibodies. "There's increasing amount of data in SARS-CoV-2 that the T cells are having an unexpectedly early effect." And they seem to stop the infection in its tracks because the virus never reached detectable levels in the health care workers' respiratory tracts. (The cells are called cross-reactive because they recognize several types of coronaviruses. So just like cross-training involves several sports, cross-reactive cells work on several different viruses.)
As the pandemic surged, 19 of these 60 health workers eventually showed signs of a nascent infection. At the same time, these cross-reactive T cells rapidly replicated inside the health care workers' blood, and right away the infection stopped. The appearance of the T cells coincided with the cessation of the infection. They appeared to stymy the infection, Maini and her colleagues theorize. "It looks as if the T cells were able to protect them from a full-blown overt infection," she says.
In contrast, in blood samples taken from health care workers who did test positive for SARS-CoV-2, these cross-reactive T cells were missing or present at much lower levels. "People who had higher levels of these cross-reactive T cells at the baseline didn't get infected, versus the group who didn't," she adds.
And here's the kicker: These special T cells likely arose in the health care workers before the pandemic began. Their immune systems likely generated them when the workers were infected with another of the several coronaviruses that can strike humans.
"We don't know that for sure, but the most likely candidate would be the common cold coronaviruses that we're all exposed to," Maini says.
About 30% of colds are caused by four other coronaviruses known as seasonal coronaviruses (because they typically come around in winter and cause winter colds). These viruses circulate around the world and have been making people sick for decades, perhaps even centuries. Basically, every kid catches all four of them before age 5 or 6.
Even though these seasonal coronaviruses typically don't cause more than a runny nose and cough, your body still has to clear out the virus to prevent it from turning into a more serious problem. To do that, the immune system makes antibodies and T cells that recognize these coronaviruses. Some of these T cells stick around and watch out for the virus — or a similar one — to return again. The others die; the body can't afford to keep a whole T cell arsenal at the ready.
If you're lucky — and have the right genes — some of these T cells will also be able to recognize and help stop SARS-CoV-2. Maini estimates these cross-reactive T cells occur in only 10% to 15% of people.
Those previous coronaviruses that "have infected you can influence whether you have a response from cross-reactive T cells," says Brianne Barker, who's an immunologist at Drew University in New Jersey. In other words, all the colds Rosy (and I) endured before the pandemic could be helping her fight off SARS-CoV-2 via cross-reactive T cells.
Now, there are many caveats to this study. For starters, Maini says, the experiment occurred during the first wave of the pandemic, when the coronavirus was quite different from what it is now. She doesn't know if these cross-reactive T cells would be able to stop the omicron variant of the coronavirus. "So in the first wave, the virus wasn't as infectious as, for example, omicron," Maini says.
Also, the study finds only a correlation between the cross-reactive T cells and protection against infection. "It's an association," says immunologist Donna Farber of Columbia University. "I think it's difficult to say what actually prevented the infection. There are a variety of mechanisms that can just stop the virus in its tracks." (We'll get to a few of those in the next section of this story.)
That said, another study, published in Nature Communications in January, supports a role for cross-reactive T cells in fighting a SARS-CoV-2 infection. That study analyzed immune responses in people living with an infected household member. Again, the presence of cross-reactive T cells correlated with protection against infection.
On top of all that, T cells aren't the only immune component that can do this cross-reacting. Antibodies made to fight off seasonal coronavirus can also recognize SARS-CoV-2, says Raiees Andrabi, who's a vaccine immunologist at Scripps Research Institute. He and his team have evidence that the immune system brings these seasonal coronavirus antibodies back into action when you're exposed to SARS-CoV-2. "You can see a spike in the antibody levels when you're infected or immunized," Andrabi says.
But, he says, researchers don't know yet how much protection these cross-reactive antibodies offer in terms of fighting the infection. "There's not any concrete evidence from the literature that these antibodies can protect against severe disease."
Rosy's immune system is RIG-ed up for protecting against any virus
Even if Rosy's immune system doesn't have cross-reactive antibodies or cross-reactive T cells to protect her from SARS-CoV-2, there's a 100% guarantee she has another protective device. And it's a powerful one.
SARS-CoV-2 is crafty. It has figured out how to sneak inside the cells of the respiratory tract quite easily. But once inside, the cells have their own trick up their sleeve.
It's called the RIG-I pathway. In a nutshell, it's an early-warning system for viruses that not only destroys the virus inside the cell but also prevents the virus from spreading to surrounding cells.
Inside your respiratory cells, tiny molecules, called RIG-I receptors, recognize and bind to a virus's genome (specifically its RNA). Once a RIG-I receptor sticks to a piece of viral RNA, it launches a massive immune response. "It tries to limit the viral infection as well as warn its neighbors so other cells can also go into an antiviral response" and not get infected too, says Drew University's Barker. Eventually, this response kills the infected cell, protects surrounding cells from infection and possibly brings in immune cells (like T cells) to help control the infection.
There's evidence the RIG-I pathway can clear out a SARS-CoV-2 infection before viral loads reach detectable levels or the immune system even has a chance to make antibodies, Barker says. "That's the idea."
Just as with cross-reactive T cells, some people are better able to detect SARS-CoV-2 inside their cells and stomp out the infection more quickly.
"Yes, there's evidence that some people are making a stronger RIG-I response and that's helping them clear the virus," Barker says. "A lot of people hypothesize that's what's going on with children."
For example, one study, published in Nature Biotechnology, found that compared with adults, children have more RIG-I receptors inside their nasal cells. And this higher concentration helps them respond more quickly to an infection.
"Yes, there's emerging data that this immune response in children is a little bit more sensitive and may react a bit stronger to different viral infections," Barker adds.
But at the end of the day, she says, Rosy's response to a SARS-CoV-2 exposure, in many ways, boils down to luck. It depends on her previous encounters with other coronaviruses as well as her genes. The latter determine how many RIG-I receptors she has inside her cells and how strongly they react to SARS-CoV-2, Barker says.
Finally, children are really, really good at stopping infections of any new virus, says Farber of Columbia University, because to them, essentially all viruses are "new" (except the ones they encountered through vaccines).
"For adults, a new pathogen is a really rare event. We hardly ever see new ones, right? But children are adapted to respond to new pathogens," she says. "They're ready to respond, and they do it more efficiently than we do."
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