Rat feces from New York City. Poop from dog parks in Wisconsin. Human waste from a hospital in Missouri. These are some of the materials that prepare us for the next chapter of the coronavirus saga.
More than four years into the pandemic, the virus has loosened its grip on most people’s bodies and minds. But a new variant could still emerge that is better able to evade our immune defenses, derailing a hard-fought return to normality.
Scientists across the country are watching for the first signs.
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“We are no longer in the acute phases of a pandemic, and I think it’s understandable and probably a good thing” that most people, including scientists, have returned to their pre-pandemic lives, said Jesse Bloom, a evolutionary biologist at the University of California. Fred Hutchinson Cancer Center in Seattle.
“That said, the virus is still evolving; it is still infecting large numbers of people,” he added. “We have to continue to monitor this.”
Bloom and other researchers are trying to understand how the coronavirus behaves and evolves as populations build immunity. Other teams are investigating the body’s response to the infection, including the complex syndrome called long COVID.
And some scientists have taken on an increasingly difficult task: estimating the effectiveness of vaccines in a crowded respiratory environment.
“Intellectually, this virus, at least to me, is just getting more interesting,” said Sarah Cobey, an evolutionary biologist at the University of Chicago.
“In some ways, SARS-CoV-2 has been a fantastic reminder of some of the deepest questions in the field and also of how far we have to go in answering many of them.”
Carefully analyzing new variants that appear in wastewater can help predict what additional forms might emerge, says Marc Johnson, a virus expert at the University of Missouri who has looked for repeats of the coronavirus in stool samples from rodents and humans.
“They will help inform the evolution of this virus and what is likely to happen next, and may even inform how a better vaccine can be made,” Johnson said.
The ‘Black Swan Event’
Evolutionary biology was once an esoteric pursuit that involved staring at a computer screen for hours. The public health implications of the work were often weak.
The pandemic has changed that. Vaccines can now be made more easily and much faster than before, so “truly understanding how viruses evolve has increasing practical use,” Bloom said.
Many evolutionary biologists now studying the coronavirus, including Bloom, were experts on influenza, which evolves into a new variant of its most immediate predecessor every two to eight years.
The scientists expected the coronavirus to behave similarly. But ommicron arrived with dozens of new mutations — a shocking “black swan” event, Bloom said. Then came BA.2.86, another huge leap in evolution, indicating that the virus remained unpredictable.
The iterations of a virus that thrives in an entire population have some advantage: perhaps the ability to evade the immune system, or extreme contagiousness. In an individual, “there’s no such evolutionary pressure,” says Katia Koelle, an evolutionary biologist at Emory University in Atlanta.
The result is that a chronic infection – usually in a person with a weakened immune system – gives the virus an opportunity to experiment with new formats, allowing it to press the evolutionary equivalent of a fast-forward button. (Viral persistence in the body is also thought to play a role in long-term COVID.)
Chronic coronavirus infections are rare, even in immunocompromised people. But the alpha variant at the end of 2020, the omicron variant at the end of 2021 and BA.2.86, first discovered in the summer of 2023 – all are now thought to have come from people with weakened immune systems.
Some mutations acquired as the virus evolves may provide no benefit at all or may even hinder it, Koelle said. Not all virus versions pose a widespread threat to the population; BA.2.86, for example, ultimately does not.
But these genetic changes can nevertheless predict the future.
After BA.2.86 emerged, careful analysis of its genome revealed one spot where the virus remained susceptible to the body’s immune defenses. Johnson suspected that the virus’s next step would be to acquire a mutation at that site.
“And indeed, it just appeared,” he said, referring to JN.1, the variant now responsible for a large majority of infections.
“The more we see these lines like BA.2.86, which seem to arise from chronic infections, the more we have an argument like, hey, this is really something we need to pay attention to,” he added.
Analyzing more than 20,000 wastewater samples from across the country, Johnson found fewer than 60 viral genetic sequences that likely came from immunocompromised people.
Such sequences only pop up if a “supershedder” – a person who sheds massive amounts of viruses in their feces – happens to live in an area where wastewater is monitored. “I’m sure there are many more,” Johnson said. “I just don’t know how much more.”
Spotty surveillance
Scientists looking for signs of renewed danger are limited by limited surveillance of coronavirus variants in the United States and elsewhere.
Many countries, including the United States, stepped up tracking efforts at the height of the pandemic. But they have since been scaled back, leaving scientists guessing at the extent of respiratory virus infections. Wastewater and hospital admissions may provide clues, but neither is a sensitive measure.
“We’ve never had particularly systematic surveillance of respiratory pathogens in the United States, but now it’s even less systematic,” Cobey said. “Our understanding of the burden of these pathogens, much less their evolution, is really compromised.”
Not closely monitoring viruses has another consequence: with multiple respiratory viruses to be combatted every year, it is now extremely challenging to estimate how effective the vaccines are.
Before COVID, scientists estimated the effectiveness of the flu vaccine by comparing the vaccination status of those who tested positive for flu with those who did not.
But now that vaccines for COVID and respiratory syncytial virus are in the mix, the calculations are no longer simple. Patients show up at clinics and hospitals with similar symptoms, and each vaccine prevents these symptoms to varying degrees.
“It becomes a much more complex network of prevention,” said Emily Martin, a public health researcher at the University of Michigan. “It does funny things to the numbers.”
An accurate estimate of effectiveness will be critical for designing a vaccine for each season, and for preparing doctors and patients for a tough respiratory season.
For example, in 2021, the University of Michigan experienced a flu outbreak. When the researchers learned that the seasonal vaccine did not protect against that strain, they were able to alert other college campuses to prepare for clusters in their dorms and hospitals to stock up on antiviral drugs.
Solving the problem could itself pose complications, as several divisions of the Centers for Disease Control and Prevention deal with flu, COVID and other respiratory diseases.
“It requires solving problems across these kinds of artificial lines of different departments,” Martin said.
Immunity and long COVID
As variant after variant of the coronavirus emerged, it became clear that while the vaccines provided a powerful bulwark against severe illness and death, they were far less effective at stopping the virus from spreading.
If a vaccine wants to prevent infections, it must not only generate antibodies in the blood, but also at places where the virus enters the body.
“Ideally you would want them in mucosal locations, so in your nose, in your lungs,” says Marion Pepper, an immunologist at the University of Washington in Seattle.
Scientists discovered about 15 years ago that much of the body’s defenses come not just from the cells and organs of the immune system, but from these other tissues.
“One of the things we’ve really been focused on is trying to understand immune responses in the tissues better than we could before,” Pepper said.
In a small group of people, the virus itself can also be present in different parts of the body and be one of the causes of long-term COVID. Vaccination and antiviral medications alleviate some of the symptoms, making this idea more credible.
At Yale University, Akiko Iwasaki and her colleagues are testing whether a fifteen-day course of the antiviral drug Paxlovid can eliminate a slowly replicating virus reservoir in the body.
“We hope to determine the cause if that is the cause of people’s illness,” Iwasaki said.
She and her colleagues began studying immune responses to the coronavirus almost as soon as the virus appeared. As the pandemic progressed, collaborations became larger and more international.
And it became clear that the coronavirus is leaving a lasting legacy of immune-related problems in many people.
Two years ago, Iwasaki proposed a new center to study the myriad questions that have arisen. Infections with many other viruses, bacteria and parasites also cause long-term complications, including autoimmunity.
The new virtual institute, which launched in the summer, focuses on studying post-infection syndromes and strategies to prevent and treat them.
Before the pandemic, Iwasaki was already studying viral infections with a large laboratory and multiple projects. But it doesn’t compare to her life now, she said.
“Scientists are often obsessed with the things they are working on, but not with this level of urgency,” she said. “I work pretty much every waking hour.”
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