Rat droppings from New York. Heavy from dog parks in Wisconsin. Human waste from a Missouri hospital. These are some of the materials that prepare us for the next chapter of the coronavirus story.
More than four years after the pandemic, the virus has taken its toll on most people’s bodies and minds. But a new variant that can better evade our immune defenses may yet emerge, derailing a hard-won return to normalcy.
Scientists across the country are watching for early signs.
“We’re no longer in the acute phase 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, an evolutionary biologist at Fred Hutchinson. Seattle Cancer Center.
“That said, the virus is still evolving, still infecting large numbers of people,” he added. “We have to continue to monitor it.”
Dr. Bloom and other researchers are trying to understand how the coronavirus behaves and evolves as populations build up immunity. Other groups are investigating the body’s response to infection, including the complex syndrome called prolonged Covid.
And some scientists have taken on an increasingly difficult task: assessing vaccine effectiveness in a crowded respiratory environment.
“Intellectually, this virus, at least to me, is becoming more and more interesting,” said Sarah Coby, an evolutionary biologist at the University of Chicago.
“In a way, SARS-CoV-2 brought to mind some of the deepest questions in the field, and how far we have to go to answer many of them.”
Careful analysis of new variants that appear in wastewater can help predict additional forms that may appear, said Marc Johnson, a virologist at the University of Missouri who has hunted for coronavirus replication in rodent and human stool samples.
“They help inform the evolution of this virus and what’s likely to happen next, and potentially could even inform how to make a better vaccine,” said Dr. Johnson.
The “Black Swan Event”
Evolutionary biology was once an internal pursuit that involved boring hours staring at a computer screen. The public health effects of the project were often weak.
The pandemic changed that. Vaccines can now be made more easily and much more quickly than before, so “really understanding how viruses evolve has more and more practical utility,” Dr Bloom said.
Many evolutionary biologists now studying the coronavirus, including Dr Bloom, were experts on influenza, which evolves into a new variant every two to eight years from its most immediate predecessor.
Scientists expected the coronavirus to behave similarly. But Omicron arrived with dozens of new mutations — a shocking “black swan event,” said Dr. Bloom. Then came BA.2.86, another huge leap in evolution, signaling that the virus remained unpredictable.
Replications of a virus that thrive in a population have some kind of advantage—an ability to bypass 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.
The result is that a chronic infection—usually in an immunocompromised person—offers the virus an opportunity to experiment with new forms, allowing it to hit the evolutionary equivalent of a fast-forward button. (Persistence of the virus in the body is also thought to play a role in prolonged Covid.)
Chronic infections with the coronavirus are rare, even in immunocompromised individuals. But the Alpha variant in late 2020, the Omicron variant in late 2021 and BA.2.86, first detected last summer — are all now believed to have arisen from immunocompromised humans.
Some mutations acquired as the virus evolves may provide no benefit or even prevent it, Dr. Koelle said. Not all versions of the virus pose a widespread threat to the population — BA.2.86 ultimately did not, for example.
However, these genetic alterations may nevertheless portend the future.
After BA.2.86 emerged, careful analysis of its genome revealed a point where the virus remained susceptible to the body’s immune defenses. Dr. Johnson guessed that the virus’s next move would be to acquire a mutation at this very point.
“And sure enough, it just appeared,” he said, referring to JN.1, the variant now responsible for the vast majority of infections.
“The more we see these lineages like BA.2.86, which seem to come from chronic infections, the more we have an argument like, hey, this is really something to watch out for,” he added.
Analyzing more than 20,000 sewage samples from around the country, Dr. Johnson found fewer than 60 genetic sequences of viruses likely to have come from immunocompromised people.
Such sequences only occur when a “super-sewer” – a person who excretes massive amounts of virus in their faeces – happens to live in an area with sewage surveillance. “I’m sure there are many more out there,” Dr. Johnson said. “I just don’t know how many more.”
Spotty Surveillance
Scientists looking for signs of renewed danger are limited by limited surveillance for coronavirus variants in the United States and elsewhere.
Many countries, including the United States, increased surveillance efforts at the height of the pandemic. But they have since been cut back, leaving scientists guessing at the scale of respiratory virus infections. Wastewater and hospitalizations can provide clues, but neither measure is sensitive.
“We’ve never had very systematic surveillance for respiratory pathogens in the United States, but it’s even less systematic now,” Dr. Coby said. “Our understanding of the burden of these pathogens, much less their evolution, has really been compromised.”
Not carefully monitoring viruses has another consequence: With many respiratory viruses being fought each year, it is now extremely difficult to measure how effective vaccines are.
Before Covid, scientists assessed flu vaccine effectiveness by comparing the vaccination status of those who tested positive for the flu with those who did not.
But now, with Covid and respiratory syncytial virus vaccines in the mix, the calculations are no longer simple. Patients show up in clinics and hospitals with similar symptoms, and each vaccine prevents these symptoms to a different extent.
“It becomes this much more complex prevention network that’s happening,” said Emily Martin, an epidemiologist at the University of Michigan. “It does funny things to the numbers.”
An accurate assessment of efficacy will be critical to planning each season’s vaccine and preparing doctors and patients to face a difficult respiratory season.
In 2021, for example, the University of Michigan experienced a flu outbreak. When researchers discovered that the season’s vaccine did not protect against this strain, they were able to warn other campuses to prepare for clusters in their dorms and hospitals to stock up on antiviral drugs.
Solving the problem itself can create complications because different departments at the Centers for Disease Control and Prevention work on flu, Covid and other respiratory illnesses.
“It requires problem solving across these kinds of artificial lines of different departments,” Dr. Martin said.
Immunity and long lasting Covid
As variant after variant of the coronavirus materialized, it became clear that while vaccines provided a strong bulwark against serious illness and death, they were much less effective at stopping the spread of the virus.
For a vaccine to prevent infections, it must induce antibodies not only in the blood, but at sites where the virus invades the body.
“Ideally, you’d want them in 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 defense comes not only from the cells and organs of the immune system, but from these other tissues.
“One of the things we’ve really focused on is trying to understand the immune responses in tissues better than we did before,” Dr. Pepper said.
In a small set of people, the virus itself can also persist in various parts of the body and can be one of the causes of long-term Covid. Vaccination and antiviral drugs relieve 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 the antiviral drug Paxlovid can eliminate a reservoir of slowly replicating virus in the body.
“We’re hoping to get to the root cause if that’s what’s causing the disease in people,” Dr Iwasaki said.
She and her colleagues began studying immune responses to the coronavirus almost as soon as the virus emerged. As the pandemic progressed, partnerships became larger and more international.
And it became clear that for many people, the coronavirus leaves a lasting legacy of immune-related problems.
Two years ago, Dr. 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, launched last summer, is dedicated to the study of post-infection syndromes and strategies for their prevention and treatment.
Before the pandemic, Dr. Iwasaki was already busy studying viral infections with a large laboratory and several projects. But it doesn’t begin to compare to her life now, she said.
“Scientists tend to obsess about things they’re working on, but not with this level of urgency,” he said. “I work almost every waking hour.”
