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.
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.
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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