Rat droppings from New York City. Poop from dog parks in Wisconsin. Human waste from a Missouri hospital. These are some of the materials that are readying us for the next chapter of the coronavirus saga.

More than four years into the pandemic, the virus has loosened its hold on most people’s bodies and minds. But a new variant better able to dodge our immune defenses may yet appear, derailing a hard-won return to normalcy.

Scientists around the country are watching for the first signs.

“We’re not in the acute phases of a pandemic anymore, 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, an evolutionary biologist at the Fred Hutchinson Cancer Center in Seattle.

“That said, the virus is still evolving; it’s still infecting large numbers of people,” he added. “We need to keep tracking this.”

Bloom and other researchers are trying to understand how the coronavirus behaves and evolves as populations amass immunity. Other teams are probing 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 vaccine effectiveness in a crowded respiratory milieu.

“Intellectually, this virus, to me at least, is only becoming more interesting,” said Sarah Cobey, an evolutionary biologist at the University of Chicago.

“In some ways, SARS-CoV-2 has been a fabulous reminder of some of the deepest questions in the field and also how far we have to go in answering a lot of them.”

Closely analyzing new variants appearing in wastewater may help predict what additional forms may surface, said Marc Johnson, a virus expert at the University of Missouri, who has hunted for iterations of the coronavirus in stool samples from rodents and humans.

“They help inform the evolution of this virus and what’s likely to happen next, and possibly could even inform how to make a better vaccine,” Johnson said.

The ‘Black Swan Event’

Evolutionary biology was once an esoteric pursuit involving humdrum hours staring at a computer screen. The work’s implications for public health were often tenuous.

The pandemic changed that. Vaccines can now be made more easily and much faster than before, so “really understanding how viruses evolve has more and more practical utility,” Bloom said.

Many evolutionary biologists who now study the coronavirus, including Bloom, were experts in influenza, which evolves into a new variant every two to eight years from its most immediate predecessor.

The scientists expected the coronavirus to behave similarly. But omicron arrived with dozens of new mutations — a shocking “black swan event,” Bloom said. Then came BA.2.86, another huge jump in evolution, signaling that the virus remained unpredictable.

The iterations of a virus that thrive throughout a population have some sort of advantage — an ability to sidestep the immune system, perhaps, or extreme contagiousness. In an individual, “there is no such evolutionary pressure,” said Katia Koelle, an evolutionary biologist at Emory University in Atlanta.

The result is that a chronic infection — usually in an immunocompromised person — offers the virus an opportunity to experiment with new formats, allowing it to hit the evolutionary equivalent of a fast-forward button. (Viral persistence in the body is also thought to play a role in long COVID.)

Chronic infections with the coronavirus are rare, even among immunocompromised people. But the alpha variant of late 2020, the omicron variant in late 2021 and BA.2.86, first detected in the summer of 2023 — all are now thought to have emerged from immunocompromised people.

Some mutations acquired as the virus evolves may offer no benefit at all or may even hinder it, Koelle said. Not all of the virus versions pose a widespread threat to the population — BA.2.86 ultimately did not, for example.

But these genetic alterations may nevertheless foreshadow the future.

After BA.2.86 emerged, close analysis of its genome revealed one spot where the virus remained sensitive to the body’s immune defenses. Johnson guessed that the virus’ next move would be to acquire a mutation in that very spot.

“And sure enough, it just appeared,” he said, referring to JN.1, the variant that now accounts for a vast majority of infections.

“The more we see these lineages like BA.2.86, which appear to be from chronic infections, the more we have an argument like, hey, this really is something we should be paying attention to,” he added.

Analyzing more than 20,000 samples of wastewater from across the country, Johnson has found fewer than 60 viral genetic sequences that are likely to be from immunocompromised people.

Such sequences turn up only when a “super shedder” — an individual who sheds huge amounts of virus in their feces — happens to live in an area with wastewater surveillance. “I’m sure there are a ton more out there,” Johnson said. “I just don’t know how many more.”

Spotty Surveillance

Scientists looking for signs of renewed danger are constrained by the limited surveillance for coronavirus variants in the United States and elsewhere.

Many countries, including the United States, ramped up tracking efforts at the height of the pandemic. But they have since been cut back, leaving scientists to guess the scale of respiratory virus infections. Wastewater and hospitalizations can provide clues, but neither is a sensitive measure.

“We never have had especially systematic surveillance for respiratory pathogens in the United States, but it’s even less systematic now,” Cobey said. “Our understanding of the burden of these pathogens, much less their evolution, has been really compromised.”

Not tracking viruses closely has another consequence: With multiple respiratory viruses to combat each year, it is now extremely challenging to gauge how effective the vaccines are.

Before COVID, scientists estimated the effectiveness of the influenza vaccine by comparing the vaccination status of those who tested positive for flu with those who did not.

But now, with vaccines for COVID and respiratory syncytial virus in the mix, the calculations are no longer simple. Patients turn up at clinics and hospitals with similar symptoms, and each vaccine prevents those symptoms to a different degree.

“It becomes this much more complex network of prevention that’s happening,” 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 crucial for designing each season’s vaccine, and for preparing doctors and patients to face a rough respiratory season.

In 2021, for example, the University of Michigan experienced an outbreak of influenza. When the researchers worked out that the season’s vaccine didn’t protect against that strain, they were able to warn other college campuses to prepare for clusters in their dorms and hospitals to stock up on antiviral drugs.

Solving the problem may itself pose complications, because different divisions at the Centers for Disease Control and Prevention work on influenza, COVID and other respiratory diseases.

“It requires problem-solving across these sort of artificial lines of different departments,” Martin said.

Immunity and Long COVID

As coronavirus variant after variant materialized, it became clear that while the vaccines provided a powerful bulwark against severe illness and death, they were much less effective at stopping viral spread.

For a vaccine to prevent infections, it must induce antibodies not just in the blood, but at sites where the virus invades the body.

“Ideally, you’d want them across mucosal sites — so, in your nose, in your lungs,” said Marion Pepper, an immunologist at the University of Washington in Seattle.

Scientists discovered about 15 years ago that a large part of the body’s defenses comes not just from the cells and organs of the immune system, but from these other tissues.

“One of the things that we’ve been really focused on is trying to understand immune responses in the tissues better than we did before,” Pepper said.

In a small set of people, the virus itself may also persist in various parts of the body and may be one of the causes of long COVID. Vaccination and antiviral drugs alleviate some of the symptoms, lending credence to this idea.

At Yale University, Akiko Iwasaki and her colleagues are testing whether a 15-day course of antiviral drug Paxlovid can eliminate a slowly replicating reservoir of virus in the body.

“We’re hoping to get to the root cause if that’s what’s causing 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, the collaborations grew larger and more international.

And it became obvious that in many people, the coronavirus leaves a lasting legacy of immune-related problems.

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 set off long-term complications, including autoimmunity.

The new virtual institute, started in the summer, is dedicated to studying post-infection syndromes and strategies to prevent and treat them.

Before the pandemic, Iwasaki was already busy studying viral infections with a big lab and multiple projects. But it doesn’t begin to compare with her life now, she said.

“Scientists tend to be obsessed about things that they work on, but not with this level of urgency,” she said. “I’m pretty much working every waking hour.”

This article originally appeared in The New York Times.

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