Back in the 1980s, scientists in the U.K. performed an experiment that — at first glance — sounds unethical. "Volunteers came into the lab, and someone squirted virus up their nose," says computational biologist Jennie Lavine.

The researchers took a liquid packed with coronavirus particles and intentionally tried to make 15 volunteers sick.

Ten people got infected. The other five fought off the virus, says Lavine, who's now at the biotechnology company Karius but was at Emory University when she spoke to NPR.

Then the researchers waited a year and repeated the experiment. They wondered: Did getting sick from the coronavirus the first time protect people from the second exposure a year later? Or could people get reinfected a year later?

Now, this coronavirus injected up the volunteers' noses wasn't SARS-CoV-2, the coronavirus that causes the disease COVID-19, Lavine is quick to point out. "No. No. Nobody got very sick. I think they measured disease severity by how many tissue boxes a person used. The experiment was performed with all of the proper ethical considerations."

The researchers were studying another coronavirus, called 229E, that causes only a mild cold in humans. But the results of that experiment offer some intriguing insights into the possible endgame of the COVID-19 pandemic. After this delta-variant surge wanes this winter, as scientists forecast, what's next? Will the virus come back next year? And the year after that?

Why there was early hope of eradicating SARS-CoV-2

When COVID-19 erupted worldwide, there was some hope we could put the genie back into the bottle, so to speak. That is, the world could completely wipe out the virus from the human population as it did for the first SARS coronavirus back in 2003.

But as the current virus spread rapidly from continent to continent and cases exploded in every nook and cranny, the hope shifted to local eradication. Perhaps some regions could reach herd immunity via exposure and vaccinations and thus push out the virus from their communities and keep it out with travel restrictions and immunization requirements.

"It's like, OK, if we're not going to be able to fully eliminate SARS-CoV-2 from the world," Lavine says, "then maybe we would achieve local eradication, like we do for measles or polio."

For that to be possible, the virus must be stable, says virologist Paul Bieniasz, of Rockefeller University. Its genetic sequence can't mutate or change over time; that way, the vaccine's protection can last for a long time. "If you have a measles infection or a course of the vaccine, you have essentially lifelong protection," he says, because that virus doesn't evolve much.

But not all viruses are like that. For instance, influenza viruses mutate really rapidly, and those mutations can decrease a vaccine's effectiveness. That's one reason you can get reinfected with the flu over and over again — "and why we have to update vaccines every year," says molecular biologist Kathryn Kistler, of the University of Washington, in Seattle. "The virus is evolving so much that our immune system no longer recognizes it."

So whether communities can locally eradicate SARS-CoV-2 depends largely on how fast its genetic sequence is changing. At the beginning of the pandemic, the virus seemed to look more like the measles than the flu. The general belief among the scientific community was that the SARS-CoV-2 virus wouldn't change much over time.

Six months into the pandemic, the virus seemed to be following the predicted course. "To date, there have been very few mutations observed," molecular biologist Peter Thielen at Johns Hopkins University told NPR in June 2020 for a story with the headline: "This Coronavirus Doesn't Change Quickly, And That's Good News For Vaccine Makers."

Then in December 2020, right around the holidays, SARS-CoV-2 shifted course, drastically.

Scientists in South Africa announced that they had detected a mutant version of the virus that seemed capable of reinfecting people — that is, avoiding the immune response created by a previous infection. A few weeks later, scientists in the U.K. identified a rapidly spreading mutant that looked to be about 50% more transmissible than the original versions of the virus. A few weeks later, another mutant cropped up in Brazil, causing a massive second surge then.

An unexpected change in the course of SARS-CoV-2

So all of a sudden, it looked like SARS-CoV-2 not only was mutating but was doing so quite rapidly. Last month, Kistler and her colleagues at the University of Washington published a new metric to measure how quickly SARS-CoV-2 is evolving as it adapts to living inside humans. When Kistler first saw the value, she was shocked. "SARS-CoV-2's rate of adaptation is remarkably high right now," she says, "like roughly four times higher for SARS-CoV-2 than it is for seasonal flu."

Remember, the flu changes so fast that people can be vulnerable to it each year.

"I don't think SARS-CoV-2 will stop adapting," Kistler says. "It may slow down, but viruses that evolve adaptively tend to keep doing that. They don't tend to hit the limit of evolution."

This fast evolution has immense implications, many scientists say. It essentially dashes the hopes of eradicating SARS-CoV-2 in the U.S. or even in smaller communities. As with the flu, the coronavirus will likely be able to reinfect people over and over again. It will keep returning year after year.

"Eventually everyone will be exposed to SARS-CoV-2," says Dr. Abraar Karan, who's an infectious disease specialist at Stanford University. "It's a matter of whether you're exposed when you're fully vaccinated or when you're not vaccinated."

On the surface, these findings sound like horrible news. It sounds like the COVID-19 pandemic — along with the masks, physical distancing and quarantining — will never go away.

But Karan doesn't believe that will be the case. Although he predicts that SARS-CoV-2 will circulate in the U.S. indefinitely, he says that COVID-19, the dreadful disease, as we now know it, will likely go away.

"When you're fully vaccinated [or been exposed several times], you're dealing with a very, very different disease and a very different process," Karan says. In fact, you're likely dealing with a disease that many of us have already had, perhaps dozens of times, in our lifetimes.

You've caught coronaviruses many, many times

This might come as a surprise, but the U.S. has dealt with many — and massive — coronavirus outbreaks before the COVID-19 pandemic.

Besides SARS-CoV-2, there are four other coronaviruses in widespread circulation: NL63, 229E, OC43 and HKU1. The first two have likely been infecting people for centuries, and the latter two for decades, perhaps longer. They're related to SARS-CoV-2 but are not the same.

Each year, one or more of these other coronaviruses sweeps through the U.S. — in schools, day care centers, churches and offices — and makes people sick. Many, many people. These coronaviruses are so common that by the time a child starts kindergarten, the youngster has likely been infected with all four of them.

Virologist Rachel Eguia of the Fred Hutchinson Cancer Research Center in Seattle and her colleagues have been studying one of these coronaviruses.

"So we've been studying strains of a coronavirus from 1984, 1992, 2001, 2008 and 2016," says Eguia. She wanted to see if people could get reinfected every eight years or so.

Here's the sneaky thing about these coronaviruses: Just because you caught one of them last year doesn't mean you're protected from that same coronavirus infection the next year.

Remember that British experiment described at the beginning of this piece, in which volunteers had virus particles injected up their noses, not just once but twice? In that study, the researchers also measured people's antibodies in their blood before the second exposure to the virus. They found that having antibodies against that specific virus didn't necessarily protect people from being infected a second time — but there was a benefit nonetheless. Having higher antibody levels prevented people from developing symptoms altogether and shortened the time they spread the virus.

"Several studies suggest that every few years you're probably able to get reinfected with these coronaviruses," Eguia says. A study, published last year in Nature Medicine, found that immunity to these seasonal coronaviruses lasts less than 12 months. Throughout a person's lifetime, they've likely caught them several dozen times.

Yet nobody notices them. We catch these coronaviruses, and "normal" life goes on. Schools and churches stay open. People gather inside bars and clubs. House parties continue. Why? Because these coronaviruses typically cause only colds. They give you the sniffles, a cough, some sneezing, congestion, maybe a low-grade fever. The illness is generally milder than the flu and resolves on its own in a week or so.

Together, these coronaviruses cause about 10% to 30% of all colds in adults, studies have found. So in many ways, these coronaviruses are part of modern life. We simply coexist with them, without much fanfare.

Could the same be true for SARS-CoV-2?

Could SARS-CoV-2 become a common cold?

Some scientists are starting to think that eventually COVID-19 could turn into a disease that looks more similar to those from these other coronaviruses — in other words, a mild flu-like illness.

"That's what our computer models predict," says Lavine, the computational biologist at Karius. For the past year and half, she and her colleagues have combined what's known about the four other seasonal coronaviruses to try to forecast what SARS-CoV-2 will do two, five and even 10 years from now. They published their findings in the journal Science this past February.

For the new virus to turn into a mild cold, she says, two conditions need to be met. First, immune protection against severe disease has to persist. "Being infected a few times or having a few doses of the vaccine needs to provide really long-lasting immunity against severe disease," she says. It doesn't have to prevent transmission or a mild disease. But it has to keep you from being hospitalized.

With the vaccine, so far immunity looks like it's holding up for at least six months or so for healthy adults, says Rustom Antia, a colleague of Lavine's at Emory. But right now it's unclear how long that critical immunity will last for people more at risk for severe disease.

"We don't know how it will hold up for older individuals, above 60 or so. We don't know how many doses of the vaccine will be needed to build up our immunity so that when we do get infected naturally, it's not severe."

But if the vaccine — and/or natural exposure — does provide long-lasting immunity for everyone, then over time the vast majority of the population will eventually be protected against severe COVID-19. That would leave only one population unexposed and vulnerable: brand-new people — newborns.

And that brings us to the second condition required for SARS-CoV-2 to become a seasonal cold: The virus has to continue to be relatively mild in kids.

Although children and babies can, in rare cases, experience dangerous complications, in general COVID-19 poses low risk to young children. Although the reason for this lower risk is unknown, one study, published in August, showed children's immune cells in their noses can more quickly detect SARS-Cov-2 than the corresponding cells in adults — and take action to ward it off. The data suggest that "immune cells of the upper airways (nose) of children are pre-activated and primed for virus sensing," the authors wrote.

As long as SARS-CoV-2 continues to be a low risk in children — that is, as long as a new variant that's dangerous to kids doesn't emerge — then they can get infected early on when they're young, build up their immunity to the virus and have protection from severe disease as adults. So in theory, everyone around the world would eventually be protected from the horrible disease that COVID-19 can become.

Now, the buildup of this immunity across a whole population can take time — perhaps years. That's why, Antia says, it's so important for people to get vaccinated, because the faster everyone is protected against severe disease, the faster COVID-19 could transform from a disease that causes great fear to a disease that fades into the background of our lives.

Of course, as with all predictions about viruses, this one could be completely wrong. Over the past year and a half, SARS-CoV-2 has surprised even the smartest — and most skeptical — scientists. But the more that researchers learn about our immune response to SARS-CoV-2, says Bieniasz, the Rockefeller University virologist, the more optimistic he becomes that this endgame scenario (or a variation of it) will come true. "Based on what we're finding, it does look like the immune system is eventually going to have the edge over this virus."

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