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  • The Other Group of Viruses That Could Cause the Next Pandemic

    The Other Group of Viruses That Could Cause the Next Pandemic

    Whether it begins next week, next year, or next decade, another pandemic is on its way. Researchers can’t predict precisely when or how the outbreak might begin. Some 1.6 million viruses are estimated to lurk in the world’s mammalian and avian wildlife, up to half of which could spill into humans; an untold number are attempting exactly that, at this very moment, bumping up against the people hunting, eating, and encroaching on those creatures. (And that’s just viruses: Parasites, fungi, and bacteria represent major infectious dangers too.) The only true certainty in the pandemic forecast is that the next threat will be here sooner than anyone would like.

    But scientists can at least make an educated guess about what might catalyze the next Big One. Three main families of viruses, more than most others, keep scientists up at night: flu viruses, coronaviruses, and paramyxoviruses, in descending order of threat. Together, those groups make up “the trifecta of respiratory death,” Sara Cherry, a virologist at the University of Pennsylvania, told me.

    Flu and coronavirus have a recent track record of trouble: Since 1918, flu viruses have sparked four pandemics, all the while continuing to pester us on a seasonal basis; some scientists worry that another major human outbreak may be brewing now, as multiple H5 flu viruses continue to spread from birds to mammals. The past two decades have also featured three major and deadly coronavirus outbreaks: the original SARS epidemic that began in late 2002; MERS, which spilled into humans—likely from camels—in 2012; and SARS-CoV-2, the pandemic pathogen that’s been plaguing us since the end of 2019. Common-cold-causing coronaviruses, too, remain a fixture of daily living—likely relics of ancient animal-to-human spillovers that we kept transmitting amongst ourselves.

    Read: Bird flu has never done this before

    Paramyxoviruses, meanwhile, have mostly been “simmering in the background,” says Raina Plowright, a disease ecologist at Cornell. Unlike flu viruses and coronaviruses, which have already clearly “proven themselves” as tier-one outbreak risks, paramyxoviruses haven’t yet been caught causing a bona fide pandemic. But they seem poised to do so, and they likely have managed the feat in the past. Like flu viruses and coronaviruses, paramyxoviruses can spread through the air, sometimes very rapidly. That’s certainly been the case with measles, a paramyxovirus that is “literally the most transmissible human virus on the planet,” says Paul Duprex, a virologist at the University of Pittsburgh. And, like flu viruses and coronaviruses, paramyxoviruses are found in a wide range of animals; more are being discovered wherever researchers look. Consider canine distemper virus, which has been found in, yes, canines, but also in raccoons, skunks, ferrets, otters, badgers, tigers, and seals. Paramyxoviruses, like flu viruses and coronaviruses, have also repeatedly shown their potential to hopscotch from those wild creatures into us. Since 1994, Hendra virus has caused multiple highly lethal outbreaks in horses, killing four humans along the way; the closely related Nipah virus has, since 1998, spread repeatedly among both pigs and people, carrying fatality rates that can soar upwards of 50 percent.

    The human versions of those past few outbreaks have petered out. But that may not always be the case—for Nipah, or for another paramyxovirus that’s yet to emerge. It’s entirely possible, Plowright told me, that the world may soon encounter a new paramyxovirus that’s both highly transmissible and ultra deadly—an “absolutely catastrophic” scenario, she said, that could dwarf the death toll of any epidemic in recent memory. (In the past four years, COVID-19, a disease with a fatality rate well below Nipah’s, has killed an estimated 7 million people.)

    All that said, though, paramyxoviruses are a third-place contender for several good reasons. Whereas flu viruses and coronaviruses are speedy shape-shifters—they frequently tweak their own genomes and exchange genetic material with others of their own kind—paramyxoviruses have historically been a bit more reluctant to change. “That takes them down a level,” says Danielle Anderson, a virologist at the Doherty Institute, in Melbourne. For one, these viruses’ sluggishness could make it much tougher for them to acquire transmission-boosting traits or adapt rapidly to spread among new hosts. Nipah virus, for instance, can spread among people via respiratory droplets at close contact. But even though it’s had many chances to do so, “it still hasn’t gotten very good at transmitting among humans,” Patricia Thibault, a biologist at the University of Saskatchewan who studied paramyxoviruses for years, told me.

    The genetic stability of paramyxoviruses can also make them straightforward to vaccinate against. Our flu and coronavirus shots need regular updates—as often as annually—to keep our immune system apace with viral evolution. But we’ve been using essentially the same measles vaccine for more than half a century, Duprex told me, and immunity to the virus seems to last for decades. Strong, durable vaccines are one of the main reasons that several countries have managed to eliminate measles—and why a paramyxovirus called rinderpest, once a major scourge of cattle, is one of the only infectious diseases we’ve ever managed to eradicate. In both cases, it helped that the paramyxovirus at play wasn’t great at infecting a ton of different animals: Measles is almost exclusive to us; rinderpest primarily troubled cows and their close kin. Most flu viruses and SARS-CoV-2, meanwhile, can spread widely across the tree of animal life; “I don’t know how you can eradicate that,” Anderson told me.

    The problem with all of these trends, though, is that they represent only what researchers know of the paramyxoviruses they’ve studied—which is, inevitably, a paltry subset of what exists, says Benhur Lee, a virologist at Mount Sinai’s Icahn School of Medicine. “The devil we don’t know can be just as frightening,” if not more, Lee told me. A pattern-defying paramyxovirus may already be readying itself to jump.

    Researchers are keyed into these looming threats. The World Health Organization highlights Nipah virus and its close cousins as some of its top-priority pathogens; in the U.S., paramyxoviruses recently made a National Institute of Allergy and Infectious Diseases list of pathogens essential to study for pandemic preparedness. Last year, the Bill & Melinda Gates Foundation announced a hefty initiative to fund paramyxovirus antiviral drugs. Several new paramyxovirus vaccines—many of them targeting Nipah viruses and their close relatives—may soon be ready to debut.

    Read: We have a mink problem

    At the same time, though, paramyxoviruses remain neglected—at least relative to the sheer perils they pose, experts told me. “Influenza has been sequenced to death,” Lee said. (That’s now pretty true for SARS-CoV-2 as well.) Paramyxoviruses, meanwhile, aren’t regularly surveilled for; development of their treatments and vaccines also commands less attention, especially outside of Nipah and its kin. And although the family has been plaguing us for countless generations, researchers still don’t know exactly how paramyxoviruses move into new species, or what mutations they would need to become more transmissible among us; they don’t know why some paramyxoviruses spark only minor respiratory infections, whereas others run amok through the body until the host is dead.

    Even the paramyxoviruses that feel somewhat familiar are still surprising us. In recent years, scientists have begun to realize that immunity to the paramyxovirus mumps, once thought to be pretty long-lasting and robust, wanes in the first few decades after vaccination; a version of the virus, once thought to be a problem only for humans and a few other primates, has also been detected in bats. For these and other reasons, rubulaviruses—the paramyxovirus subfamily that includes mumps—are among the potential pandemic agents that most concern Duprex. Emmie de Wit, the chief of the molecular-pathogenesis unit at Rocky Mountain Laboratories, told me that the world could also become more vulnerable to morbilliviruses, the subfamily that includes measles. If measles is ever eradicated, some regulators may push for an end to measles shots. But in the same way that the end of smallpox vaccination left the world vulnerable to mpox, the fall of measles immunity could leave an opening for a close cousin to rise.

    The next pandemic won’t necessarily be a paramyxovirus, or even a flu virus or a coronavirus. But it has an excellent chance of starting as so many other known pandemics have—with a spillover from animals, in parts of the world where we’ve invaded wild habitats. We may not be able to predict which pathogen or creature might be involved in our next big outbreak, but the common denominator will always be us.

    Katherine J. Wu

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  • The Strongest Signal That Americans Should Worry About Flu This Winter

    The Strongest Signal That Americans Should Worry About Flu This Winter

    Sometime in the spring of 2020, after centuries, perhaps millennia, of tumultuous coexistence with humans, influenza abruptly went dark. Around the globe, documented cases of the viral infection completely cratered as the world tried to counteract SARS-CoV-2. This time last year, American experts began to fret that the flu’s unprecedented sabbatical was too bizarre to last: Perhaps the group of viruses that cause the disease would be poised for an epic comeback, slamming us with “a little more punch” than usual, Richard Webby, an influenza expert at St. Jude Children’s Research Hospital, in Tennessee, told me at the time.

    But those fears did not not come to pass. Flu’s winter 2021 season in the Southern Hemisphere was once again eerily silent; in the north, cases sneaked up in December—only to peter out before a lackluster reprise in the spring.

    Now, as the weather once again chills in this hemisphere and the winter holidays loom, experts are nervously looking ahead. After skipping two seasons in the Southern Hemisphere, flu spent 2022 hopping across the planet’s lower half with more fervor than it’s had since the COVID crisis began. And of the three years of the pandemic that have played out so far, this one is previewing the strongest signs yet of a rough flu season ahead.

    It’s still very possible that the flu will fizzle into mildness for the third year in a row, making experts’ gloomier suspicions welcomingly wrong. Then again, this year is, virologically, nothing like the last. Australia recently wrapped an unusually early and “very significant” season with flu viruses, says Kanta Subbarao, the director of the WHO Collaborating Centre for Reference and Research on Influenza at the Doherty Institute. By sheer confirmed case counts, this season was one of the country’s worst in several years. In South Africa, “it’s been a very typical flu season” by pre-pandemic standards, which is still enough to be of note, according to Cheryl Cohen, a co-head of the country’s Centre for Respiratory Disease and Meningitis at the National Institute for Communicable Diseases. After a long, long hiatus, Subbarao told me, flu in the Southern Hemisphere “is certainly back.”

    Read: The pandemic broke the flu

    That does not bode terribly well for those of us up north. The same viruses that seed outbreaks in the south tend to be the ones that sprout epidemics here as the seasons do their annual flip. “I take the south as an indicator,” says Seema Lakdawala, a flu-transmission expert at Emory University. And should flu return here, too, with a vengeance, it will collide with a population that hasn’t seen its likes in years, and is already trying to marshal responses to several dangerous pathogens at once.

    The worst-case scenario won’t necessarily pan out. What goes on below the equator is never a perfect predictor for what will occur above it: Even during peacetime, “we’re pretty bad in terms of predicting what a flu season is going to look like,” Webby, of St. Jude, told me. COVID, and the world’s responses to it, have put experts’ few forecasting tools further on the fritz. But the south’s experiences can still be telling. In South Africa and Australia, for instance, many COVID-mitigation measures, such as universal masking recommendations and post-travel quarantines, lifted as winter arrived, allowing a glut of respiratory viruses to percolate through the population. The flu flood also began after two essentially flu-less years—which is a good thing at face value, but also represents many months of missed opportunities to refresh people’s anti-flu defenses, leaving them more vulnerable at the season’s start.

    Some of the same factors are working against those of us north of the equator, perhaps to an even greater degree. Here, too, the population is starting at a lower defensive baseline against flu—especially young children, many of whom have never tussled with the viruses. It’s “very, very likely” that kids may end up disproportionately hit, Webby said, as they appear to have been in Australia—though Subbarao notes that this trend may have been driven by more cautious behaviors among older populations, skewing illness younger.

    Interest in inoculations has also dropped during the pandemic: After more than a year of calls for booster after booster, “people have a lot of fatigue,” says Helen Chu, a physician and flu expert at the University of Washington, and that exhaustion may be driving already low interest in flu shots even further down. (During good years, flu-shot uptake in the U.S. peaks around 50 percent.) And the few protections against viruses that were still in place last winter have now almost entirely vanished. In particular, schools—a fixture of flu transmission—have loosened up enormously since last year. There’s also just “much more flu around,” all over the global map, Webby said. With international travel back in full swing, the viruses will get that many more chances to hopscotch across borders and ignite an outbreak. And should such an epidemic emerge, with its health infrastructure already under strain from simultaneous outbreaks of COVID, monkeypox, and polio, America may not handle another addition well. “Overall,” Chu told me, “we are not well prepared.”

    Read: The most important vaccine I’ll get this fall

    At the same time, though, countries around the world have taken such different approaches to COVID mitigation that the pandemic may have further uncoupled their flu-season fate. Australia’s experience with the flu, for instance, started, peaked, and ended early this year; the new arrival of more relaxed travel policies likely played a role in the outbreak’s beginning, before a mid-year BA.5 surge potentially hastened the sudden drop. It’s also very unclear whether the U.S. may be better or worse off because its last flu season was wimpy, weirdly shaped, and unusually late. South Africa saw an atypical summer bump in flu activity as well; those infections may have left behind a fresh dusting of immunity and blunted the severity of the following season, Cohen told me. But it’s always hard to tell. “I was quite strong in saying that I really believed that South Africa was going to have a severe season,” she said. “And it seems that I was wrong.” The long summer tail of the Northern Hemisphere’s most recent flu season could also exacerbate the intensity of the coming winter season, says John McCauley, the director of the Worldwide Influenza Centre at the Francis Crick Institute, in London. Kept going in their off-season, the viruses may have an easier vantage point from which to reemerge this winter.

    COVID’s crush has shifted flu dynamics on the whole as well. The pandemic “squeezed out” a lot of diversity from the influenza-virus population, Webby told me; some lineages may have even entirely blipped out. But others could also still be stewing and mutating, potentially in animals or unmonitored pockets of the world. That these strains—which harbor especially large pandemic potential—could emerge into the general population is “my bigger concern,” Lakdawala, of Emory, told me. And although the particular strains of flu that are circulating most avidly seem reasonably well matched to this year’s vaccines, the dominant strains that attack the north could yet shift, says Florian Krammer, a flu virologist at Mount Sinai’s Icahn School of Medicine. Viruses also tend to wobble and hop when they return from long vacations; it may take a season or two before the flu finds its usual rhythm.

    Another epic SARS-CoV-2 variant could also quash a would-be influenza peak. Flu cases rose at the end of 2021, and the dreaded “twindemic” loomed. But then, Omicron hit—and flu “basically disappeared for one and a half months,” Krammer told me, only tiptoeing back onto the scene after COVID cases dropped. Some experts suspect that the immune system may have played a role in this tag-team act: Although co-infections or sequential infections of SARS-CoV-2 and flu viruses are possible, the aggressive spread of a new coronavirus variant may have set people’s defenses on high alert, making it that much harder for another pathogen to gain a foothold.

    Read: Don’t worry, it’s not the flu

    No matter the odds we enter flu season with, human behavior can still alter winter’s course. One of the main reasons that flu viruses have been so absent the past few years is because mitigation measures have kept them at bay. “People understand transmission more than they ever did before,” Lakdawala told me. Subbarao thinks COVID wisdom is what helped keep Australian flu deaths down, despite the gargantuan swell in cases: Older people took note of the actions that thwarted the coronavirus and applied those same lessons to flu. Perhaps populations across the Northern Hemisphere will act in similar ways. “I would hope that we’ve actually learned how to deal with infectious disease more seriously,” McCauley told me.

    But Webby isn’t sure that he’s optimistic. “People have had enough hearing about viruses in general,” he told me. Flu, unfortunately, does not feel similarly about us.

    Katherine J. Wu

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