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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 preparing us for the next chapter of the coronavirus saga.
More than four years into the pandemic, the virus has lost its grip on most people’s bodies and minds. But a new variant more capable of dodging our immune defenses may yet emerge, derailing the hard-won return to normality.
Scientists across the country are watching for the first signs.
“We’re 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, an evolutionary biologist at the Cancer Center. Fred Hutchinson in Seattle.
“That said, the virus is still evolving; “It is still infecting a large number 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 build up immunity. Other teams are investigating the body’s response to 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 environment.
“Intellectually, this virus, at least to me, is becoming more and 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 this field and also how far we have to go to answer many of them.”
Closely analyzing new variants that appear in wastewater can help predict what additional forms may emerge, said Marc Johnson, a virus expert at the University of Missouri who has searched for iterations of the coronavirus in stool samples from rodents and humans.
“They help inform the evolution of this virus and what is likely to happen next, and could possibly even inform how to make a better vaccine,” Johnson said.
The ‘black swan event’
Evolutionary biology was once an esoteric pursuit that involved spending monotonous hours staring at a computer screen. The public health implications of the work were often tenuous.
The pandemic changed that. Vaccines can now be made more easily and quickly than before, so “truly understanding how viruses evolve is becoming more and more practically useful,” Bloom said.
Many evolutionary biologists now studying the coronavirus, including 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,” Bloom said. Then came BA.2.86, another big leap in evolution, indicating that the virus remained unpredictable.
Iterations of a virus that thrive in a population have some kind of advantage: the ability to evade the immune system, perhaps, or extreme contagion. 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 the 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 COVID.)
Chronic coronavirus infections are rare, even among immunocompromised people. But the alpha variant from late 2020, the omicron variant from late 2021 and BA.2.86, first detected in the summer of 2023, are now believed to have emerged from immunocompromised people.
Some mutations acquired as the virus evolves may offer no benefit or even hinder it, Koelle said. Not all versions of the virus represent a widespread threat to the population; BA.2.86 ultimately did not, for example.
However, these genetic alterations can portend the future.
After BA.2.86 emerged, a detailed analysis of its genome revealed a point where the virus remained sensitive to the body’s immune defenses. Johnson hypothesized that the next step for the virus would be to acquire a mutation at that same location.
“And sure enough, it just appeared,” he said, referring to JN.1, the variant that now accounts 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 arguments we have like, hey, this is something we should really pay attention to,” he added.
Irregular surveillance
Scientists looking for signs of renewed danger are constrained by limited surveillance of coronavirus variants in the United States and elsewhere.
Many countries, including the United States, stepped up their monitoring efforts at the height of the pandemic. But they have since declined, leaving scientists to guess at the magnitude of respiratory virus infections. Wastewater and hospitalizations may provide clues, but neither is a sensitive measure.
“We’ve never had particularly systematic surveillance of respiratory pathogens in the United States, but it’s even less systematic now,” Cobey said. “Our understanding of the burden of these pathogens, let alone their evolution, has been really compromised.”
Failure to monitor viruses has another consequence: With multiple respiratory viruses to combat each year, it is now extremely difficult to assess how effective vaccines are.
Before COVID, scientists estimated 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 come to clinics and hospitals with similar symptoms, and each vaccine prevents those symptoms to a different degree.
“What’s happening becomes a much more complex web of prevention,” said Emily Martin, a public health researcher at the University of Michigan. “It does weird things to numbers.”
An accurate estimate of efficacy will be crucial to designing each season’s vaccine and preparing doctors and patients to face a difficult respiratory season.
Immunity and Ilong COVID
As variant after variant of the coronavirus materialized, it became clear that while vaccines provided a powerful bulwark against serious illness and death, they were far less effective at stopping viral spread.
For a vaccine to prevent infections, it must induce antibodies not only in the blood, but also at sites where the virus invades the body.
“Ideally, you’d want them to get through the mucous membranes, meaning into the nose and into the 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 come 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 immune responses in tissues better than before,” Pepper said.
In a small group of people, the virus itself can also persist in various parts of the body and may be one of the causes of long COVID. Vaccination and antiviral medications relieve some of the symptoms, lending credence to this idea.
At Yale University, Akiko Iwasaki and her colleagues are testing whether a 15-day treatment with the antiviral drug Paxlovid can eliminate a slowly replicating reservoir of viruses in the body.
“We’re hoping to get to the root cause, if that’s what’s causing people to get sick,” Iwasaki said.
Two years ago, Iwasaki proposed a new center to study the countless questions that have arisen. Infections with many other viruses, bacteria, and parasites also trigger long-term complications, including autoimmunity.
The new virtual institute, launched in the summer, is dedicated to studying post-infection syndromes and strategies to prevent and treat them.