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Tag: recent months

  • We Can Finally Do Something About the Third ‘Tripledemic’ Virus

    We Can Finally Do Something About the Third ‘Tripledemic’ Virus

    Every fall, when the air turns chilly and the leaves red, pediatric ICUs begin preparing for the onslaught of the virus known as RSV. Not flu, not COVID, but RSV, or respiratory syncytial virus, is the No. 1 reason babies are hospitalized, year after year. Their tiny airways can become inflamed, and the sickest ones struggle to breathe. RSV is deadly on the other end of the age spectrum too, killing 6,000 to 10,000 elderly Americans every year.

    For decades though, there was no way to stop the virus’s seasonal tide. The quest for a vaccine always came up short. And then suddenly, the vaccines started working.

    This year, doctors have not just one but multiple new shots to prevent RSV. Three gained FDA approval in rapid succession in recent months: an antibody shot for infants called nirsevimab, a form of passive immunization for babies too young to get proper vaccines; a vaccine from Pfizer for both adults over 60 and pregnant mothers, who can pass the immunity on to their babies; and finally, a vaccine from GlaxoSmithKline also aimed at adults older than 60. Together, these herald a new era for RSV.

    That these three new RSV shots are coming out at once is no coincidence. They succeed where others failed because they all target a specific weak spot in the virus, first identified in 2013. This strategy of finding a virus’s most vulnerable points applies to other pathogens too, and experts say it can revolutionize the design of vaccines for other diseases. In fact, it was quietly used to make the COVID vaccines from Pfizer and Moderna. Scientists had originally perfected the idea with RSV, only to repurpose it for the COVID vaccine, which raced ahead, given the urgency of the pandemic. This year, though, the shots are coming for RSV.

    “We’re in a really good position, finally, after more than 65 years,” says Asunción Mejías, an infectious-diseases doctor at St. Jude Children’s Research Hospital.

    The first attempts to make an RSV vaccine began not long after the virus’s discovery, in 1956, but an early trial ended so catastrophically that it had a chilling effect for decades.

    It had started off with promise. The early vaccine was modeled after a successful one for polio, in which the virus is inactivated with a chemical called formalin. But when infants given the early RSV vaccine later caught the virus, a whopping 80 percent had to be hospitalized—compared with only 5 percent in the control group. Two of the babies died, their lungs ravaged. The vaccine did worse than offer no protection; it made the disease more severe. “It was such a disaster,” says Ann Falsey, an infectious-diseases doctor at the University of Rochester. Scientists spent years piecing together why—the vaccine riled up the wrong part of the immune system in very young babies—but they got no closer to making a vaccine that worked. The field was stuck.

    Then, in 2008, a serendipitous meeting led to an eventual breakthrough. A young, freshly minted Ph.D. named Jason McLellan, who studies the structure of proteins, began a new job at the National Institutes of Health to work on HIV vaccines. The lab he had joined, on the fourth floor, had run out of room, though, so he got put in another, on the second. There, he ran into Barney Graham, a virologist who had been trying to solve the puzzle of RSV since the 1980s. He convinced McLellan that this virus was worth a look too.

    By then, scientists had at least homed in on a plausible vaccine target. Much as COVID uses spike protein to infect cells, RSV uses a protein—called F for “fusion”—to physically fuse the virus particle to a human cell. F comes in two forms, though: an extremely unstable prefusion state and a far more stable postfusion state. And once it switches to the postfusion state—which can also happen spontaneously— “it can’t come back,” McLellan told me.

    When RSV vaccines are manufactured, all the F protein eventually switches to the postfusion state. But the antibodies against postfusion F weren’t very effective. McLellan soon figured out why. He found that extremely potent neutralizing antibodies bind to a specific site—the very tip of the prefusion F—that is lost when the protein rearranges into its postfusion form. With that, Graham told me, “you lose ten- to 1,000-fold potency.” An effective RSV vaccine would need to target the prefusion F.

    The team knew what to do, but had a practical dilemma: How to stabilize F in its prefusion form, so the team could put it in a vaccine? McLellan rejiggered the protein slightly, adding molecular “staples” and filling a hole in the protein structure. These changes froze F in its prefusion shape. When the team tested this version of the vaccine in mice, the results could not have been clearer. The vaccine induced the highest levels of neutralizing antibodies Graham had ever seen in his three decades of studying RSV. “This is it,” McLellan remembers thinking.

    Soon, pharmaceutical companies came calling, and the race was on. (The experts in this article—like nearly everyone who works on RSV vaccines—have all received research grants, consulted for, or worked in some other way with one or more of the companies developing shots for RSV.) Today, Pfizer’s and GlaxoSmithKline’s newly approved RSV vaccines target the prefusion F protein, as does nirsevimab, the antibody shot for infants from AstraZeneca and Sanofi. Both the vaccines and the antibody shot trigger immunity against RSV: Vaccines stimulate the immune system to make its own antibodies, and nirsevimab is a direct infusion of antibodies.

    Trials for all three shots were already under way when the coronavirus pandemic hit. But because RSV nearly disappeared during social distancing, the trials got delayed. Meanwhile, McLellan and Graham devised a similar molecular trick to stabilize COVID’s spike protein, which Pfizer and Moderna later used in their vaccines. (The stabilization wasn’t make-or-break for COVID, as it was for RSV, though—AstraZeneca’s COVID vaccine was effective despite not having this modification.) But unstable fusion proteins are found in many different classes of viruses beyond RSV. McLellan, now at the University of Texas at Austin, is working on shots against the prefusion structure of other stubborn viruses such as cytomegalovirus and Crimean-Congo hemorrhagic fever. (Graham is now a professor at Morehouse School of Medicine.) This approach—called structure-based vaccine design—could unlock new ways of targeting once-elusive viruses.

    For RSV, this fall and winter will be a test of how well the shots fare in the real world. As the adage goes, vaccines don’t save lives; vaccinations do. Falsey, the University of Rochester doctor, specializes in studying RSV in the elderly, and she worries that too few Americans over 60 will get the new vaccines this year. A CDC advisory panel decided that elderly Americans can get the vaccines through “shared clinical decision-making” with their doctors but did not go as far as to fully recommend vaccination, which would have triggered private insurers to cover the shots under the Affordable Care Act. Out of pocket, they can cost more than $300. The vaccine for pregnant women, meanwhile, has FDA approval, but the same CDC panel is voting today on whether to recommend it. The panel will likely scrutinize a possible link to premature births, which has shown up before with RSV vaccines.

    Nirsevimab, the antibody shot for infants, has gotten a full-throated endorsement, though, and it’s poised to have the biggest impact this season. It replaces an existing RSV-antibody shot called palivizumab, which is not widely used. Palivizumab targets a less potent site that is on both the pre- and postfusion F, and it needs to be administered up to five times a season (compared with once for nirsevimab), at a cost of some $1,500 a dose. For these reasons, it’s been reserved for the highest-risk babies, such as preemies with underdeveloped lungs. But most babies who end up hospitalized were healthy to begin with, says St. Jude’s Mejías, so the older shot didn’t put much of a dent in overall hospitalizations.

    Nirsevimab is meant to be more widely used: The shot is approved for all infants in their first RSV season. “It’s going to change the way we manage and treat RSV,” Mejías told me. It should be available for babies starting in October. And if all goes according to plan, pediatric ICUs could be a little quieter this winter.

    Sarah Zhang

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  • Only the Emergency Has Ended

    Only the Emergency Has Ended

    Emergency responses—being, well, emergency responses—aren’t designed to last forever, and this morning, the World Health Organization declared the one that’s been in place for the COVID-19 pandemic since January 2020 officially done. “This virus is here to stay. It is still killing, and it’s still changing,” Tedros Adhanom Ghebreyesus, the director general of the WHO, said at a press conference; although the coronavirus will continue to pose a threat, the time had simply come, he and his colleagues said, for countries to move away from treating it as a global crisis.

    And, really, they already have: The United States, for instance, ended its national emergency last month and will sunset its public-health emergency next week; countries around the world have long since shelved testing programs, lifted lockdowns, dispensed with masking mandates, and even stopped recommending frequent COVID shots to healthy people in certain age groups. In some ways, the WHO was already a straggler. Had it waited much longer, the power of its designation of COVID as a “public health emergency of international concern,” or PHEIC, “would have been undermined,” says Salim Abdool Karim, the director of the Centre for the AIDS Program of Research in South Africa.

    There’s no disputing that the virus’s threat has ebbed since the pandemic’s worst days. By and large, “we are in our recovery phase now”—not perfectly stabilized, but no longer in chaotic flux, says René Najera, the director of public health at the College of Physicians of Philadelphia. Still, ending the emergency doesn’t mean that the world has fully addressed the problems that made this an emergency. Global vaccine distribution remains wildly inequitable, leaving many people susceptible to the virus’s worst effects; deaths are still concentrated among those most vulnerable; the virus’s evolutionary and transmission patterns are far from predictable or seasonal. Now, ending the emergency is less an epidemiological decision than a political one: Our tolerance for these dangers has grown to the extent that most people are doing their best to look away from the remaining risk, and will continue to until the virus forces us to turn back.

    The end to the PHEIC, to be clear, isn’t a declaration that COVID is over—or even that the pandemic is. Both a PHEIC and a pandemic tend to involve the rapid and international spread of a dangerous disease, and the two typically do go hand in hand. But no set-in-stone rules delineate when either starts or ends. Plenty of diseases have met pandemic criteria—noted by many epidemiologists as an epidemic that’s rapidly spread to several continents—without ever being granted a PHEIC, as is the case with HIV. And several PHEICs, including two of the Ebola outbreaks of the past decade and the Zika epidemic that began in 2015, did not consistently earn the pan- prefix among experts. With COVID, the WHO called a PHEIC more than a month before it publicly labeled the outbreak a pandemic on March 11. Now the organization has bookended its declaration with a similar mismatch: one crisis designation on and the other off. That once again leaves the world in a bizarre risk limbo, with the threat everywhere but our concern for it on the wane.

    For other diseases with pandemic potential, understanding the start and end of crisis has been simpler. After a new strain of H1N1 influenza sparked a global outbreak in 2009, disrupting the disease’s normal seasonal ebb and flow, scientists simply waited until the virus’s annual transmission patterns went back to their pre-outbreak baseline, then declared that particular pandemic done. But “we don’t really have a baseline” to return to for SARS-CoV-2, says Sam Scarpino, an infectious-disease modeler at Northeastern University. This has left officials floundering for an end-of-pandemic threshold to meet. Once, envisioning that coda seemed more possible: In February 2021, when the COVID shots were still new, Alexis Madrigal wrote in The Atlantic that, in the U.S. at least, pandemic restrictions might end once the country reached some relatively high rate of vaccination, or drove daily deaths below 100—approximating the low-ish end of the flu’s annual toll.

    Those criteria aren’t perfect. Given how the virus has evolved, even, say, an 85 percent vaccination rate probably wouldn’t have squelched the virus in a way public-health experts were envisioning in 2021 (and wouldn’t have absolved us of booster maintenance). And even if the death toll slipped below 100 deaths a day, the virus’s chronic effects would still pose an immense threat. But thresholds such as those, flawed though they were, were never even set. “I’m not sure we ever set any goals at all” to designate when we’d have the virus beat, Céline Gounder, an infectious-disease physician at NYU and an editor-at-large for public health at KFF Health News, told me. And if they had been, we probably still would not have met them: Two years out, we certainly have not.

    Instead, efforts to mitigate the virus have only gotten laxer. Most individuals are no longer masking, testing, or staying up to date on their shots; on community scales, the public goods that once seemed essential—ventilation, sick leave, equitable access to insurance and health care—have already faded from most discourse. That COVID has been more muted in recent months feels “more like luck” than a product of concerted muffling from us, Scarpino told me. Should another SARS-CoV-2 variant sweep the world or develop resistance to Paxlovid, “we don’t have much in the way of a plan,” he said.

    If and when the virus troubles us again, our lack of preparedness will be a reflection of America’s classically reactive approach to public health. Even amid a years-long emergency declaration that spanned national and international scales, we squandered the opportunity “to make the system more resilient to the next crisis,” Gounder said. There is little foresight for what might come next. And individuals are still largely being asked to fend for themselves—which means that as this emergency declaration ends, we are setting ourselves up for another to inevitably come, and hit us just as hard.

    As the final roadblocks to declaring normalcy disappear, we’re unlikely to patch those gaps. The PHEIC, at this point, was more symbolic than practical—but that didn’t make it inconsequential. Experts worry that its end will sap what remaining incentive there was for some countries to sustain a COVID-focused response—one that would, say, keep vaccines, treatments, and tests in the hands of those who need them most. “Public interest is very binary—it’s either an emergency or it’s not,” says Saskia Popescu, an infection-prevention expert at George Mason University. With the PHEIC now gone, the world has officially toggled itself to “not.” But there’s no going back to 2019. Between that and the height of the pandemic is middle-ground maintenance, a level of concern and response that the world has still not managed to properly calibrate.

    Katherine J. Wu

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  • The COVID Question That Will Take Decades to Answer

    The COVID Question That Will Take Decades to Answer

    To be a newborn in the year 2023—and, almost certainly, every year that follows—means emerging into a world where the coronavirus is ubiquitous. Babies might not meet the virus in the first week or month of life, but soon enough, SARS-CoV-2 will find them. “For anyone born into this world, it’s not going to take a lot of time for them to become infected,” maybe a year, maybe two, says Katia Koelle, a virologist and infectious-disease modeler at Emory University. Beyond a shadow of a doubt, this virus will be one of the very first serious pathogens that today’s infants—and all future infants—meet.

    Three years into the coronavirus pandemic, these babies are on the leading edge of a generational turnover that will define the rest of our relationship with SARS-CoV-2. They and their slightly older peers are slated to be the first humans who may still be alive when COVID-19 truly hits a new turning point: when almost everyone on Earth has acquired a degree of immunity to the virus as a very young child.

    Read: Is COVID a common cold yet?

    That future crossroads might not sound all that different from where the world is currently. With vaccines now common in most countries and the virus so transmissible, a significant majority of people have some degree of immunity. And in recent months, the world has begun to witness the consequences of that shift. The flux of COVID cases and hospitalizations in most countries seems to be stabilizing into a seasonal-ish sine wave; disease has gotten, on average, less severe, and long COVID seems to be somewhat less likely among those who have recently gotten shots. Even the virus’s evolution seems to be plodding, making minor tweaks to its genetic code, rather than major changes that require another Greek-letter name.

    But today’s status quo may be more of a layover than a final destination in our journey toward COVID’s final form. Against SARS-CoV-2, most little kids have fared reasonably well. And as more babies have been born into a SARS-CoV-2-ridden world, the average age of first exposure to this coronavirus has been steadily dropping—a trend that could continue to massage COVID-19 into a milder disease. Eventually, the expectation is that the illness will reach a stable nadir, at which point it may truly be “another common cold,” says Rustom Antia, an infectious-disease modeler at Emory.

    The full outcome of this living experiment, though, won’t be clear for decades—well after the billions of people who encountered the coronavirus for the first time in adulthood are long gone. The experiences that today’s youngest children have with the virus are only just beginning to shape what it will mean to have COVID throughout a lifetime, when we all coexist with it from birth to death as a matter of course.

    At the beginning of SARS-CoV-2’s global tear, the coronavirus was eager to infect all of us, and we had no immunity to rebuff its attempts. But vulnerability wasn’t just about immune defenses: Age, too, has turned out to be key to resilience. Much of the horror of the disease could be traced to having not only a large population that lacked protection against the virus—but a large adult population that lacked protection against the virus. Had the entire world been made up of grade-schoolers when the pandemic arrived, “I don’t think it would have been nearly as severe,” says Juliet Pulliam, an infectious-disease modeler at Stellenbosch University, in South Africa.

    Across several viral diseases—polio, chicken pox, mumps, SARS, measles, and more—getting sick as an adult is notably more dangerous than as a kid, a trend that’s typically exacerbated when people don’t have any vaccinations or infections to those pathogens in their rearview. The manageable infections that strike toddlers and grade-schoolers may turn serious when they first manifest at older ages, landing people in the hospital with pneumonia, brain swelling, even blindness, and eventually killing some. When scientists plot mortality data by age, many curves bend into “a pretty striking J shape,” says Dylan Morris, an infectious-disease modeler at UCLA.

    The reason for that age differential isn’t always clear. Some of kids’ resilience probably comes from having a young, spry body, far less likely to be burdened with chronic medical conditions that raise severe disease risk. But the quick-wittedness of the young immune system is also likely playing a role. Several studies have found that children are much better at marshaling hordes of interferon—an immune molecule that armors cells against viruses—and may harbor larger, more efficient cavalries of infected-cell-annihilating T cells. That performance peaks sometime around grade school or middle school, says Janet Chou, a pediatrician at Boston Children’s Hospital. After that, our molecular defenses begin a rapid tumble, growing progressively creakier, clumsier, sluggish, and likelier to launch misguided attacks against the tissues that house them. By the time we’re deep into adulthood, our immune systems are no longer sprightly, or terribly well calibrated. When we get sick, our bodies end up rife with inflammation. And our immune cells, weary and depleted, are far less unable to fight off the pathogens they once so easily trounced.

    Whatever the explanations, children are far less likely to experience serious symptoms, or to end up in the hospital or the ICU after being infected with SARS-CoV-2. Long COVID, too, seems to be less prevalent in younger cohorts, says Alexandra Yonts, a pediatrician at Children’s National Hospital. And although some children still develop MIS-C, a rare and dangerous inflammatory condition that can appear weeks after they catch the virus, the condition “seems to have dissipated” as the pandemic has worn on, says Betsy Herold, the chief of pediatric infectious disease at the Children’s Hospital at Montefiore, in the Bronx.

    Should those patterns hold, and as the age of first exposure continues to fall, COVID is likely to become less intense. The relative mildness of childhood encounters with the virus could mean that almost everyone’s first infection—which tends, on average, to be more severe than the ones that immediately follow—could rank low in intensity, setting a sort of ceiling for subsequent bouts. That might make concentrating first encounters “in the younger age group actually a good thing,” says Ruian Ke, an infectious-disease modeler at Los Alamos National Laboratory.

    COVID will likely remain capable of killing, hospitalizing, and chronically debilitating a subset of adults and kids alike. But the hope, experts told me, is that the proportion of individuals who face the worst outcomes will continue to drop. That may be what happened in the aftermath of the 1918 flu pandemic, Antia, of Emory, told me: That strain of the virus stuck around, but never caused the same devastation again. Some researchers suspect that something similar may have even played out with another human coronavirus, OC43: After sparking a devastating pandemic in the 19th century, it’s possible that the virus no longer managed to wreak much more havoc than a common cold in a population that had almost universally encountered it early in life.

    Such a fate for COVID, though, isn’t a guarantee. The virus’s propensity to linger in the body’s nooks and crannies, sometimes causing symptoms that last many months or years, could make it an outlier among its coronaviral kin, says Melody Zeng, an immunologist at Cornell University. And even if the disease is likely to get better than what it is now, that is not a very high bar to clear.

    Some small subset of the population will always be naive to the virus—and it’s not exactly a comfort that in the future, that cohort will almost exclusively be composed of our kids. Pediatric immune systems are robust, UCLA’s Morris told me. But “robust is not the same as infallible.” Since the start of the pandemic, more than 2,000 Americans under the age of 18 have died from COVID—a small fraction of total deaths, but enough to make the disease a leading cause of death for children in the U.S. MIS-C and long COVID may not be common, but their consequences are no less devastating for the children who experience them. Some risks are especially concentrated among our youngest kids, under the age 5, whose immune defenses are still revving up, making them more vulnerable than their slightly older peers. There’s especially little to safeguard newborns just under six months, who aren’t yet eligible for most vaccines—including COVID shots—and who are rapidly losing the antibody-based protection passed down from their mothers while they were in the womb.

    A younger average age of first infection will also probably increase the total number of exposures people have to SARS-CoV-2 in a typical lifetime—each instance carrying some risk of severe or chronic disease. Ke worries the cumulative toll that this repetition could exact: Studies have shown that each subsequent tussle with the virus has the potential to further erode the functioning or structural integrity of organs throughout the body, raising the chances of chronic damage. There’s no telling how many encounters might push an individual past a healthy tipping point.

    Racking up exposures also won’t always bode well for the later chapters of these children’s lives. Decades from now, nearly everyone will have banked plenty of encounters with SARS-CoV-2 by the time they reach advanced age, Chou, from Boston Children’s Hospital, told me. But the virus will also continue to change its appearance, and occasionally escape the immunity that some people built up as kids. Even absent those evasions, as their immune systems wither, many older people may not be able to leverage past experiences with the disease to much benefit. The American experience with influenza is telling. Despite a lifetime of infections and available vaccines, tens of thousands of people typically die annually of the disease in the United States alone, says Ofer Levy, the director of the Precision Vaccines Program at Boston Children’s Hospital. So even with the expected COVID softening, “I don’t think we’re going to reach a point where it’s, Oh well, tra-la-la,” Levy told me. And the protection that immunity offers can have caveats: Decades of research with influenza suggest that immune systems can get a bit hung up on the first versions of a virus that they see, biasing them against mounting strong attacks against other strains; SARS-CoV-2 now seems to be following that pattern. Depending on the coronavirus variants that kids encounter first, their responses and vulnerability to future bouts of illness may vary, says Scott Hensley, an immunologist at the University of Pennsylvania.

    Read: Are our immune systems stuck in 2020?

    Early vaccinations—that ideally target multiple versions of SARS-CoV-2—could make a big difference in reducing just about every bad outcome the virus threatens. Severe disease, long COVID, and transmission to other children and vulnerable adults all would likely be “reduced, prevented, and avoided,” Chou told me. But that’s only if very young kids are taking those shots, which, right now, isn’t at all the case. Nor are they necessarily getting protection passed down during gestation or early life from their mothers, because many adults are not up to date on COVID shots.

    Some of these issues could, in theory, end up moot. A hundred or so years from now, COVID could simply be another common cold, indistinguishable in practice from any other. But Morris points out that this reality, too, wouldn’t fully spare us. “When we bother to look at the burden of the other human coronaviruses, the ones who have been with us for ages? In the elderly, it’s real,” he told me. One study found that a nursing-home outbreak of OC43—the purported former pandemic coronavirus—carried an 8 percent fatality rate; another, caused by NL63, killed three out of the 20 people who caught it in a long-term-care facility in 2017. These and other “mild” respiratory viruses also continue to pose a threat to people of any age who are immunocompromised.

    SARS-CoV-2 doesn’t need to follow in those footsteps. It’s the only human coronavirus against which we have vaccines—which makes the true best-case scenario one in which it ends up even milder than a common cold, because we proactively protect against it. Disease would not need to be as inevitable; the vaccine, rather than the virus, could be the first bit of intel on the disease that kids receive. Tomorrow’s children probably won’t live in a COVID-free world. But they could at least be spared many of the burdens we’re carrying now.

    Katherine J. Wu

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  • Norovirus Is Almost Impossible to Stop

    Norovirus Is Almost Impossible to Stop

    In one very specific and mostly benign way, it’s starting to feel a lot like the spring of 2020: Disinfection is back.

    “Bleach is my friend right now,” says Annette Cameron, a pediatrician at Yale School of Medicine, who spent the first half of this week spraying and sloshing the potent chemical all over her home. It’s one of the few tools she has to combat norovirus, the nasty gut pathogen that her 15-year-old son was recently shedding in gobs.

    Right now, hordes of people in the Northern Hemisphere are in a similarly crummy situation. In recent weeks, norovirus has seeded outbreaks in several countries, including the United Kingdom, Canada, and the United States. Last week, the U.K. Health Security Agency announced that laboratory reports of the virus had risen to levels 66 percent higher than what’s typical this time of year. Especially hard-hit are Brits 65 and older, who are falling ill at rates that “haven’t been seen in over a decade.”

    Americans could be heading into a rough stretch themselves, Caitlin Rivers, an infectious-disease epidemiologist at Johns Hopkins University, told me, given how closely the U.S.’s epidemiological patterns tend to follow those of the U.K. “It does seem like there’s a burst of activity right now,” says Nihal Altan-Bonnet, a norovirus researcher at the National Institutes of Health. At her own practice, Cameron has been seeing the number of vomiting and diarrhea cases among her patients steadily tick up. (Other pathogens can cause gastrointestinal symptoms as well, but norovirus is the most common cause of foodborne illness in the United States.)

    To be clear, this is more a nauseating nuisance than a public-health crisis. In most people, norovirus triggers, at most, a few miserable days of GI distress that can include vomiting, diarrhea, and fevers, then resolves on its own; the keys are to stay hydrated and avoid spreading it to anyone vulnerable—little kids, older adults, the immunocompromised. The U.S. logs fewer than 1,000 annual deaths out of millions of documented cases. In other high-income countries, too, severe outcomes are very rare, though the virus is far more deadly in parts of the world with limited access to sanitation and potable water.

    Still, fighting norovirus isn’t easy, as plenty of parents can attest. The pathogen, which prompts the body to expel infectious material from both ends of the digestive tract, is seriously gross and frustratingly hardy. Even the old COVID standby, a spritz of hand sanitizer, doesn’t work against it—the virus is encased in a tough protein shell that makes it insensitive to alcohol. Some have estimated that ingesting as few as 18 infectious units of virus can be enough to sicken someone, “and normally, what’s getting shed is in the billions,” says Megan Baldridge, a virologist and immunologist at Washington University in St. Louis. At an extreme, a single gram of feces—roughly the heft of a jelly bean—could contain as many as 5.5 billion infectious doses, enough to send the entire population of Eurasia sprinting for the toilet.

    Unlike flu and RSV, two other pathogens that have bounced back to prominence in recent months, norovirus mainly targets the gut, and spreads especially well when people swallow viral particles that have been released in someone else’s vomit or stool. (Despite its “stomach flu” nickname, norovirus is not a flu virus.) But direct contact with those substances, or the food or water they contaminate, may not even be necessary: Sometimes people vomit with such force that the virus gets aerosolized; toilets, especially lidless ones, can send out plumes of infection like an Air Wick from hell. And Altan-Bonnet’s team has found that saliva may be an unappreciated reservoir for norovirus, at least in laboratory animals. If the spittle finding holds for humans, then talking, singing, and laughing in close proximity could be risky too.

    Read: Whatever happened to toilet plumes?

    Once emitted into the environment, norovirus particles can persist on surfaces for days—making frequent hand-washing and surface disinfection key measures to prevent spread, says Ibukun Kalu, a pediatric infectious-disease specialist at Duke University. Handshakes and shared meals tend to get dicey during outbreaks, along with frequently touched items such as utensils, door handles, and phones. One 2012 study pointed to a woven plastic grocery bag as the source of a small outbreak among a group of teenage soccer players; the bag had just been sitting in a bathroom used by one of the girls when she fell sick the night before.

    Once a norovirus transmission chain begins, it can be very difficult to break. The virus can spread before symptoms start, and then for more than a week after they resolve. To make matters worse, immunity to the virus tends to be short-lived, lasting just a few months even against a genetically identical strain, Baldridge told me.

    Day cares, cruise ships, schools, restaurants, military training camps, prisons, and long-term-care facilities can be common venues for norovirus spread. “I did research with the Navy, and it just goes through like wildfire,” often sickening more than half the people on tightly packed ships, says Robert Frenck, the director of the Vaccine Research Center at Cincinnati Children’s Hospital. Households, too, are highly susceptible to spread: Once the virus arrives, the entire family is almost sure to be infected. Baldridge, who has two young children, told me that her household has weathered at least four bouts of norovirus in the past several years.

    (A pause for some irony: In spite of norovirus’s infectiousness, scientists did not succeed in culturing it in labs until just a few years ago, after nearly half a century of research. When researchers design challenge trials to, say, test new vaccines, they still need to dose volunteers with norovirus that’s been extracted from patient stool, a gnarly practice that’s been around for more than 50 years.)

    Norovirus spread doesn’t have to be a foregone conclusion. Some people do get lucky: Roughly 20 percent of European populations, for instance, are genetically resistant to common norovirus strains. “So you can hope,” Frenck told me. For the rest of us, it comes down to hygiene. Altan-Bonnet recommends diligent hand-washing, plus masking to ward off droplet-borne virus. Sick people should isolate themselves if they can. “And keep your saliva to yourself,” she told me.

    Read: The stomach-flu mystery

    Rivers and Cameron have both managed to halt the virus in their homes in the past; Cameron may have pulled it off again this week. The family fastidiously scrubbed their hands with hot water and soap, donned disposable gloves when touching shared surfaces, and took advantage of the virus’s susceptibility to harsh chemicals and heat. When her son threw up on the floor, Cameron sprayed it down with bleach; when he vomited on his quilt, she blasted it twice in the washing machine on the sanitizing setting, then put it through the dryer at a super high temp. Now a couple of days out from the end of their son’s sickness, Cameron and her husband appear to have escaped unscathed.

    Norovirus isn’t new, and this won’t be the last time it hits. In a lot of ways, “this is back to basics,” says Samina Bhumbra, the medical director of infection prevention at Riley Children’s Hospital. After three years of COVID, the world has gotten used to thinking about infections in terms of airways. “We need to recalibrate,” Bhumbra told me, “and remember that other things exist.”

    Katherine J. Wu

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  • The Future of Long COVID

    The Future of Long COVID

    In the early spring of 2020, the condition we now call long COVID didn’t have a name, much less a large community of patient advocates. For the most part, clinicians dismissed its symptoms, and researchers focused on SARS-CoV-2 infections’ short-term effects. Now, as the pandemic approaches the end of its third winter in the Northern Hemisphere, the chronic toll of the coronavirus is much more familiar. Long COVID has been acknowledged by prominent experts, national leaders, and the World Health Organization; the National Institutes of Health has set up a billion-dollar research program to understand how and in whom its symptoms unfurl. Hundreds of long-COVID clinics now freckle the American landscape, offering services in nearly every state; and recent data hint that well-vetted drugs to treat or prevent long COVID may someday be widespread. Long COVID and the people battling it are commanding more respect, says Hannah Davis, a co-founder of the Patient-Led Research Collaborative, who has had long COVID for nearly three years: Finally, many people “seem willing to understand.”

    But for all the ground that’s been gained, the road ahead is arduous. Long COVID still lacks a universal clinical definition and a standard diagnosis protocol; there’s no consensus on its prevalence, or even what symptoms fall under its purview. Although experts now agree that long COVID does not refer to a single illness, but rather is an umbrella term, like cancer, they disagree on the number of subtypes that fall within it and how, exactly, each might manifest. Some risk factors—among them, a COVID hospitalization, female sex, and certain preexisting medical conditions—have been identified, but researchers are still trying to identify others amid fluctuating population immunity and the endless slog of viral variants. And for people who have long COVID now, or might develop it soon, the interventions are still scant. To this day, “when someone asks me, ‘How can I not get long COVID?’ I can still only say, ‘Don’t get COVID,’” says David Putrino, a neuroscientist and physical therapist who leads a long-COVID rehabilitation clinic at Mount Sinai’s Icahn School of Medicine.

    As the world turns its gaze away from the coronavirus pandemic, with country after country declaring the virus “endemic” and allowing crisis-caliber interventions to lapse, long-COVID researchers, patients, and activists worry that even past progress could be undone. The momentum of the past three years now feels bittersweet, they told me, in that it represents what the community might lose. Experts can’t yet say whether the number of long-haulers will continue to increase, or offer a definitive prognosis for those who have been battling the condition for months or years. All that’s clear right now is that, despite America’s current stance on the coronavirus, long COVID is far from being beaten.

    Despite an influx of resources into long-COVID research in recent months, data on the condition’s current reach remain a mess—and scientists still can’t fully quantify its risks.

    Recent evidence from two long-term surveys have hinted that the pool of long-haulers might be shrinking, even as new infection rates remain sky-high: Earlier this month, the United Kingdom’s Office for National Statistics released data showing that 2 million people self-reported lingering symptoms at the very start of 2023, down from 2.3 million in August 2022. The U.S. CDC’s Household Pulse Survey, another study based on self-reporting, also recorded a small drop in long-COVID prevalence in the same time frame, from about 7.5 percent of all American adults to roughly 6. Against the massive number of infections that have continued to slam both countries in the pandemic’s third year and beyond, these surveys might seem to imply that long-haulers are leaving the pool faster than newcomers are arriving.

    Experts cautioned, however, that there are plenty of reasons to treat these patterns carefully—and to not assume that the trends will be sustained. It’s certainly better that these data aren’t showing a sustained, dramatic uptick in long-COVID cases. But that doesn’t mean the situation is improving. Throughout the pandemic, the size of the long-COVID pool has contracted or expanded for only two reasons: a change in the rate at which people enter, or at which they exit. Both figures are likely to be in constant flux, as surges of infections come and go, masking habits change, and vaccine and antiviral uptake fluctuates. Davis pointed out that the slight downward tick in both studies captured just a half-year stretch, so the downward slope could be one small portion of an undulating wave. A few hours spent at the beach while the tide is going out wouldn’t be enough to prove that the ocean is drying up.

    Read: We’re bungling the COVID wind-down

    Recent counts of new long-COVID cases might also be undercounts, as testing slows and people encounter more challenges getting diagnosed. That said, it’s still possible that, on a case-by-case basis, the likelihood of any individual developing long COVID after a SARS-CoV-2 infection may have fallen since the pandemic’s start, says Deepti Gurdasani, a clinical epidemiologist at Queen Mary University of London and the University of New South Wales. Population immunity—especially acquired via vaccination—has, over the past three years, better steeled people’s bodies against the virus, and strong evidence supports the notion that vaccines can moderately reduce the risk of developing long COVID. Treatments and behavioral interventions that have become more commonplace may have chipped away at incidence as well. Antivirals can now help to corral the virus early in infection; ventilation, distancing, and masks—when they’re used—can trim the amount of virus that infiltrates the body. And if overall exposure to the virus can influence the likelihood of developing long COVID, that could help explain why so many debilitating cases arose at the very start of the pandemic, when interventions were few and far between, says Steven Deeks, a physician researcher at UC San Francisco.

    There’s not much comfort to derive from those individual-level stats, though, when considering what’s happening on broader scales. Even if immunity makes the average infected person less likely to fall into the long-COVID pool, so many people have been catching the virus that the inbound rate still feels like a flood. “The level of infection in many countries has gone up substantially since 2021,” Gurdasani told me. The majority of long-COVID cases arise after mild infections, the sort for which our immune defenses fade most rapidly. Now that masking and physical distancing have fallen by the wayside, people may be getting exposed to higher viral doses than they were a year or two ago. In absolute terms, then, the number of people entering the long-COVID pool may not really be decreasing. Even if the pool were getting slightly smaller, its size would still be staggering, an ocean of patients with titanic needs. “Anecdotally, we still have an enormous waitlist to get into our clinic,” Putrino told me.

    Deeks told me that he’s seen another possible reason for optimism: People with newer cases of long COVID might be experiencing less debilitating or faster-improving disease, based on what he’s seen. “The worst cases we’ve seen come from the first wave in 2020,” he said. But Putrino isn’t so sure. “If you put an Omicron long-COVID patient in front of me, versus one from the first wave, I wouldn’t be able to tell you who was who,” he said. The two cases would also be difficult to compare, because they’re separated by so much time. Long COVID’s symptoms can wax, wane, and qualitatively change; a couple of years into the future, some long-haulers who’ve just developed the condition may be in a spot that’s similar to where many veterans with the condition are now.

    Read: The flu-ification of COVID policy is almost complete

    Experts’ understanding of how often people depart the long-COVID pool is also meager. Some long-haulers have undoubtedly seen improvement—but without clear lines distinguishing short COVID from medium and long COVID, entry and exit into these various groups is easy to over- or underestimate. What few data exist on the likelihood of recovery or remission is inconsistent, and not always rosy: Investigators of RECOVER, a large national study of long COVID, have calculated that about two-thirds of the long-haulers in their cohort do not return to baseline health. Putrino, who has worked with hundreds of long-haulers since the pandemic began, estimates that although most of his patients experience at least some benefit from a few months of rehabilitation, only about one-fifth to one-quarter of them eventually reach the point of feeling about as well as they did before catching the virus, while the majority hit a middling plateau. A small minority of the people he has treated, he told me, never seem to improve at all.

    Letícia Soares, a long-hauler in Brazil who caught the virus near the start of the pandemic, falls into that final category. Once a disease ecologist who studied parasite transmission in birds, she is now mostly housebound, working when she is able as a researcher for the Patient-Led Research Collaborative. Her days revolve around medications and behavioral modifications she uses for her fatigue, sleeplessness, and chronic pain. Soares no longer has the capacity to cook or frequently venture outside. And she has resigned herself to this status quo until the treatment landscape changes drastically. It is not the life she pictured for herself, Soares told me. “Sometimes I think the person I used to be died in April of 2020.”

    Even long-haulers who have noticed an improvement in their symptoms are wary of overconfidence. Some absolutely do experience what could be called recovery—but for others, the term has gotten loaded, almost a jinx. “If the question is, ‘Are you doing the things you were doing in 2019?’ the answer is largely no,” says JD Davids, a chronic-illness advocate based in New York. For some, he told me, “getting better” has been more defined by a resetting of expectations than a return to good health. Relapses are also not uncommon, especially after repeat encounters with the virus. Lisa McCorkell, a long-hauler and a co-founder of the Patient-Led Research Collaborative, has felt her symptoms partly abate since she first fell ill in the spring of 2020. But, she told me, she suspects that her condition is more likely to deteriorate than further improve—partly because of “how easy it is to get reinfected now.”

    Last week, in his State of the Union address, President Joe Biden told the American public that “we have broken COVID’s grip on us.” Highlighting the declines in the rates of COVID deaths, the millions of lives saved, and the importance of remembering the more than 1 million lost, Biden reminded the nation of what was to come: “Soon we’ll end the public-health emergency.”

    When the U.S.’s state of emergency was declared nearly three years ago, as hospitals were overrun and morgues overflowed, the focus was on severe, short-term disease. Perhaps in that sense, the emergency is close to being over, Deeks told me. But long COVID, though slower to command attention, has since become its own emergency, never formally declared; for the millions of Americans who have been affected by the condition, their relationship with the virus does not yet seem to be in a better place.

    Read: Trying to stop long COVID before it even starts

    Even with many more health-care providers clued into long COVID’s ills, the waiting lists for rehabilitation and treatment remain untenable, Hannah Davis told me. “I consider myself someone who gets exceptional care compared to other people,” she said. “And still, I hear from my doctor every nine or 10 months.” Calling a wrap on COVID’s “emergency” phase could worsen that already skewed supply-demand ratio. Changes to the nation’s funding tactics could strip resources—among them, access to telehealth; Medicaid coverage; and affordable antivirals, tests, and vaccines—from vulnerable populations, including people of color, that aren’t getting their needs met even as things stand, McCorkell told me. And as clinicians internalize the message that the coronavirus has largely been addressed, attention to its chronic impacts may dwindle. At least one of the country’s long-COVID clinics has, in recent months, announced plans to close, and Davis worries that more could follow soon.

    Scientists researching long COVID are also expecting new challenges. Reduced access to testing will complicate efforts to figure out how many people are developing the condition, and who’s most at risk. Should researchers turn their scientific focus away from studying causes and cures for long COVID when the emergency declaration lifts, Davids and others worry that there will be ripple effects on the scientific community’s interest in other, neglected chronic illnesses, such as ME/CFS (myalgic encephalomyelitis or chronic fatigue syndrome), a diagnosis that many long-haulers have also received.

    The end of the U.S.’s official crisis mode on COVID could stymie research in other ways as well. At Johns Hopkins University, the infectious-disease epidemiologists Priya Duggal, Shruti Mehta, and Bryan Lau have been running a large study to better understand the conditions and circumstances that lead to long COVID, and how symptoms evolve over time. In the past two years, they have gathered online survey data from thousands of people who both have and haven’t been infected, and who have and haven’t seen their symptoms rapidly resolve. But as of late, they’ve been struggling to recruit enough people who caught the virus and didn’t feel their symptoms linger. “I think that the people who are suffering from long COVID will always do their best to participate,” Duggal told me. That may not be the case for individuals whose experiences with the virus were brief. A lot of them “are completely over it,” Duggal said. “Their life has moved on.”

    Kate Porter, a Massachusetts-based marketing director, told me that she worries about her family’s future, should long COVID fade from the national discourse. She and her teenage daughter both caught the virus in the spring of 2020, and went on to develop chronic symptoms; their experience with the disease isn’t yet over. “Just because the emergency declaration is expiring, that doesn’t mean that suddenly people are magically going to get better and this issue is going to go away,” Porter told me. After months of relative improvement, her daughter is now fighting prolonged bouts of fatigue that are affecting her school life—and Porter isn’t sure how receptive people will be to her explanations, should their illnesses persist for years to come. “Two years from now, how am I going to explain, ‘Well, this is from COVID, five years ago’?” she said.

    A condition that was once mired in skepticism, scorn, and gaslighting, long COVID now has recognition—but empathy for long-haulers could yet experience a backslide. Nisreen Alwan, a public-health researcher at the University of Southampton, in the U.K., and her colleagues have found that many long-haulers still worry about disclosing their condition, fearing that it could jeopardize their employment, social interactions, and more. Long COVID could soon be slated to become just one of many neglected chronic diseases, poorly understood and rarely discussed.

    Davis doesn’t think that marginalization is inevitable. Her reasoning is grim: Other chronic illnesses have been easier to push to the sidelines, she said, on account of their smaller clinical footprint, but the pool of long-haulers is enormous—comprising millions of people in the U.S. alone. “I think it’s going to be impossible to ignore,” she told me. One way or another, the world will have no choice but to look.

    Katherine J. Wu

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  • Outdoor Dining Is Doomed

    Outdoor Dining Is Doomed

    These days, strolling through downtown New York, where I live, is like picking your way through the aftermath of a party. In many ways, it is exactly that: The limp string lights, trash-strewn puddles, and splintering plywood are all relics of the raucous celebration known as outdoor dining.

    These wooden “streeteries” and the makeshift tables lining sidewalks first popped up during the depths of the pandemic in 2020, when restaurants needed to get diners back in their seats. It was novel, creative, spontaneous—and fun during a time when there wasn’t much fun to be had. For a while, outdoor dining really seemed as though it could outlast the pandemic. Just last October, New York Magazine wrote that it would stick around, “probably permanently.”

    But now someone has switched on the lights and cut the music. Across the country, something about outdoor dining has changed in recent months. With fears about COVID subsiding, people are losing their appetite for eating among the elements. This winter, many streeteries are empty, save for the few COVID-cautious holdouts willing to put up with the cold. Hannah Cutting-Jones, the director of food studies at the University of Oregon, told me that, in Eugene, where she lives,  outdoor dining is “ absolutely not happening” right now. In recent weeks, cities such as New York and Philadelphia have started tearing down unused streeteries. Outdoor dining’s sheen of novelty has faded; what once evoked the grands boulevards of Paris has turned out to be a janky table next to a parked car. Even a pandemic, it turns out, couldn’t overcome the reasons Americans never liked eating outdoors in the first place.

    For a while, the allure of outdoor dining was clear. COVID safety aside, it kept struggling restaurants afloat, boosted some low-income communities, and cultivated joie de vivre in bleak times. At one point, more than 12,700 New York restaurants had taken to the streets, and the city—along with others, including Boston, Los Angeles, Chicago, and Philadelphia—proposed making dining sheds permanent. But so far, few cities have actually adopted any official rules. At this point, whether they ever will is unclear. Without official sanctions, mounting pressure from outdoor-dining opponents will likely lead to the destruction of existing sheds; already, they keep tweeting disapproving photos at sanitation departments. Part of the issue is that as most Americans’ COVID concerns retreat, the potential downsides have gotten harder to overlook: less parking, more trash, tacky aesthetics, and, oh God, the rats. Many top New York restaurants have voluntarily gotten rid of their sheds this winter.

    The economics of outdoor dining may no longer make sense for restaurants, too. Although it was lauded as a boon to struggling restaurants during the height of the pandemic, the practice may make less sense now that indoor dining is back. For one thing, dining sheds tend to take up parking spaces needed to attract customers, Cutting-Jones said. The fact that most restaurants are chains doesn’t help: “If whatever conglomerate owns Longhorn Steakhouse doesn’t want to invest in outdoor dining, it will not become the norm,” Rebecca Spang, a food historian at Indiana University Bloomington, told me. Besides, she added, many restaurants are already short-staffed, even without the extra seats.

    In a sense, outdoor dining was doomed to fail. It always ran counter to the physical makeup of most of the country, as anyone who ate outside during the pandemic inevitably noticed. The most obvious constraint is the weather, which is sometimes pleasant but is more often not. “Who wants to eat on the sidewalk in Phoenix in July?” Spang said.

    The other is the uncomfortable proximity to vehicles. Dining sheds spilled into the streets like patrons after too many drinks. The problem was that U.S. roads were built for cars, not people. This tends not to be true in places renowned for outdoor dining, such as Europe, the Middle East, and Southeast Asia, which urbanized before cars, Megan Elias, a historian and the director of the gastronomy program at Boston University, told me. At best, this means that outdoor meals in America are typically enjoyed with a side of traffic. At worst, they end in dangerous collisions.

    Cars and bad weather were easier to put up with when eating indoors seemed like a more serious health hazard than breathing in fumes and trembling with cold. It had a certain romance—camaraderie born of discomfort. You have to admit, there was a time when cozying up under a heat lamp with a hot drink was downright charming. But now outdoor dining has gone back to what it always was: something that most Americans would like to avoid in all but the most ideal of conditions. This sort of relapse could lead to fewer opportunities to eat outdoors even when the weather does cooperate.

    But outdoor dining is also affected by more existential issues that have surmounted nearly  three years of COVID life. Eating at restaurants is expensive, and Americans like to get their money’s worth. When safety isn’t a concern, shelling out for a streetside meal may simply not seem worthwhile for most diners. “There’s got to be a point to being outdoors, either because the climate is so beautiful or there’s a view,” Paul Freedman, a Yale history professor specializing in cuisine, told me. For some diners, outdoor seating may feel too casual: Historically, Americans associated eating at restaurants with special occasions, like celebrating a milestone at Delmonico’s, the legendary fine-dining establishment that opened in the 1800s, Cutting-Jones said.

    Eating outdoors, in contrast, was linked to more casual experiences, like having a hot dog at Coney Island. “We have high expectations for what dining out should be like,” she said, noting that American diners are especially fussy about comfort. Even the most opulent COVID cabin may be unable to override these associations. “If the restaurant is going to be fancy and charge $200 a person,” said Freedman, most people can’t escape the feeling of having spent that much for “a picnic on the street.”

    Outdoor dining isn’t disappearing entirely. In the coming years there’s a good chance that more Americans will have the opportunity to eat outside in the nicer months than they did before the pandemic—even if it’s not the widespread practice many had anticipated earlier in the pandemic. Where it continues, it will almost certainly be different: more buttoned-up, less lawless—probably less exciting. Santa Barbara, for example, made dining sheds permanent last year but specified that they must be painted an approved “iron color.” It may also be less popular among restaurant owners: If outdoor-dining regulations are too far-reaching or costly, cautioned Hayrettin Günç, an architect with Global Designing Cities Initiative, that will “create barriers for businesses.”

    For now, outdoor dining is yet another COVID-related convention that hasn’t quite stuck—like avoiding handshakes and universal remote work. As the pandemic subsides, the tendency is to default to the ways things used to be. Doing so is easier, certainly, than coming up with policies to accommodate new habits. In the case of outdoor dining, it’s most comfortable, too. If this continues to be the case, then outdoor dining in the U.S. may return to what it was before the pandemic: dining “al fresco” along the streetlamp-lined terraces of the Venetian Las Vegas, and beneath the verdant canopy of the Rainforest Cafe.

    Yasmin Tayag

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  • Is COVID Immunity Hung Up on Old Variants?

    Is COVID Immunity Hung Up on Old Variants?

    In the two-plus years that COVID vaccines have been available in America, the basic recipe has changed just once. The virus, meanwhile, has belched out five variants concerning enough to earn their own Greek-letter names, followed by a menagerie of weirdly monikered Omicron subvariants, each seeming to spread faster than the last. Vaccines, which take months to reformulate, just can’t keep up with a virus that seems to reinvent itself by the week.

    But SARS-CoV-2’s evolutionary sprint might not be the only reason that immunity can get bogged down in the past. The body seems to fixate on the first version of the virus that it encountered, either through injection or infection—a preoccupation with the past that researchers call “original antigenic sin,” and that may leave us with defenses that are poorly tailored to circulating variants. In recent months, some experts have begun to worry that this “sin” might now be undermining updated vaccines. At an extreme, the thinking goes, people may not get much protection from a COVID shot that is a perfect match for the viral variant du jour.

    Recent data hint at this possibility. Past brushes with the virus or the original vaccine seem to mold, or even muffle, people’s reactions to bivalent shots—“I have no doubt about that,” Jenna Guthmiller, an immunologist at the University of Colorado School of Medicine, told me. The immune system just doesn’t make Omicron-focused antibodies in the quantity or quality it probably would have had it seen the updated jabs first. But there’s also an upside to this stubbornness that we could not live without, says Katelyn Gostic, an immunologist and infectious-disease modeler who has studied the phenomenon with flu. Original antigenic sin is the reason repeat infections, on average, get milder over time, and the oomph that enables vaccines to work as well as they do. “It’s a fundamental part,” Gostic told me, “of being able to create immunological memory.”

    This is not just basic biology. The body’s powerful first impressions of this coronavirus can and should influence how, when, and how often we revaccinate against it, and with what. Better understanding of the degree to which these impressions linger could also help scientists figure out why people are (or are not) fighting off the latest variants—and how their defenses will fare against the virus as it continues to change.

    The worst thing about “original antigenic sin” is its name. The blame for that technically lies with Thomas Francis Jr., the immunologist who coined the phrase more than six decades ago after noticing that the initial flu infections people weathered in childhood could bias how they fared against subsequent strains. “Basically, the flu you get first in life is the one you respond to most avidly for the long term,” says Gabriel Victora, an immunologist at Rockefeller University. That can become somewhat of an issue when a very different-looking strain comes knocking.

    In scenarios like these, original antigenic sin may sound like the molecular equivalent of a lovesick teen pining over an ex, or a student who never graduates out of immunological grade school. But from the immune system’s point of view, never forgetting your first is logically sound. New encounters with a pathogen catch the body off guard—and tend to be the most severe. A deep-rooted defensive reaction, then, is practical: It ups the chances that the next time the same invader shows up, it will be swiftly identified and dispatched. “Having good memory and being able to boost it very quickly is sometimes a very good thing,” Victora told me. It’s the body’s way of ensuring that it won’t get fooled twice.

    Read: Annual COVID shots mean we can stop counting

    These old grudges come with clear advantages even when microbes morph into new forms, as flu viruses and coronaviruses often do. Pathogens don’t remake themselves all at once, so immune cells that home in on familiar snippets of a virus can still in many cases snuff out enough invaders to prevent an infection’s worst effects. That’s why even flu shots that aren’t perfectly matched to the season’s most prominent strains are usually still quite good at keeping people out of hospitals and morgues. “There’s a lot of leniency in how much the virus can change before we really lose protection,” Guthmiller told me. The wiggle room should be even bigger, she said, with SARS-CoV-2, whose subvariants tend to be far more similar to one another than, say, different flu strains are.

    With all the positives that immune memory can offer, many immunologists tend to roll their eyes at the negative and bizarrely moralizing implications of the phrase original antigenic sin. “I really, really hate that term,” says Deepta Bhattacharya, an immunologist at the University of Arizona. Instead, Bhattacharya and others prefer to use more neutral words such as imprinting, evocative of a duckling latching onto the first maternal figure it spots. “This is not some strange immunological phenomenon,” says Rafi Ahmed, an immunologist at Emory University. It’s more a textbook example of what an adaptable, high-functioning immune system does, and one that can have positive or negative effects, depending on context. Recent flu outbreaks have showcased a little bit of each: During the 2009 H1N1 pandemic, many elderly people, normally more susceptible to flu viruses, fared better than expected against the late-aughts strain, because they’d banked exposures to a similar-looking H1N1—a derivative of the culprit behind the 1918 pandemic—in their youth. But in some seasons that followed, H1N1 disproportionately sickened middle-aged adults whose early-life flu indoctrinations may have tilted them away from a protective response.

    Read: COVID science is moving backwards

    The backward-gazing immune systems of those adults may have done more than preferentially amplify defensive responses to a less relevant viral strain. They might have also actively suppressed the formation of a response to the new one. Part of that is sheer kinetics: Veteran immune cells, trained up on past variants and strains, tend to be quicker on the draw than fresh recruits, says Scott Hensley, an immunologist at the Perelman School of Medicine at the University of Pennsylvania. And the greater the number of experienced soldiers, the more likely they are to crowd out rookie fighters—depriving them of battlefield experience they might otherwise accrue. Should the newer viral strain eventually return for a repeat infection, those less experienced immune cells may not be adequately prepared—leaving people more vulnerable, perhaps, than they might otherwise have been.

    Some researchers think that form of imprinting might now be playing out with the bivalent COVID vaccines. Several studies have found that the BA.5-focused shots are, at best, moderately more effective at producing an Omicron-targeted antibody response than the original-recipe jab—not the knockout results that some might have hoped for. Recent work in mice from Victora’s lab backs up that idea: B cells, the manufacturers of antibodies, do seem to have trouble moving past the impressions of SARS-CoV-2’s spike protein that they got from first exposure. But the findings don’t really trouble Victora, who gladly received his own bivalent COVID shot. (He’ll take the next update, too, whenever it’s ready.) A blunted response to a new vaccine, he told me, is not a nonexistent one—and the more foreign a second shot recipe is compared with the first, the more novice fighters should be expected to participate in the fight. “You’re still adding new responses,” he said, that will rev back up when they become relevant. The coronavirus is a fast evolver. But the immune system also adapts. Which means that people who receive the bivalent shot can still expect to be better protected against Omicron variants than those who don’t.

    Historical flu data support this idea. Many of the middle-aged adults slammed by recent H1N1 infections may not have mounted perfect attacks on the unfamiliar virus, but as immune cells continued to tussle with the pathogen, the body “pretty quickly filled in the gaps,” Gostic told me. Although it’s tempting to view imprinting as a form of destiny, “that’s just not how the immune system works,” Guthmiller told me. Preferences can be overwritten; biases can be undone.

    Original antigenic sin might not be a crisis, but its existence does suggest ways to optimize our vaccination strategies with past biases in mind. Sometimes, those preferences might need to be avoided; in other instances, they should be actively embraced.

    For that to happen, though, immunologists would need to fill in some holes in their knowledge of imprinting: how often it occurs, the rules by which it operates, what can entrench or alleviate it. Even among flu viruses, where the pattern has been best-studied, plenty of murkiness remains. It’s not clear whether imprinting is stronger, for instance, when the first exposure comes via infection or vaccination. Scientists can’t yet say whether children, with their fiery yet impressionable immune systems, might be more or less prone to getting stuck on their very first flu strain. Researchers don’t even know for certain whether repetition of a first exposure—say, through multiple doses of the same vaccine, or reinfections with the same variant—will more deeply embed a particular imprint.

    It does seem intuitive that multiple doses of a vaccine could exacerbate an early bias, Ahmed told me. But if that’s the case, then the same principle might also work the other way: Maybe multiple exposures to a new version of the virus could help break an old habit, and nudge the immune system to move on. Recent evidence has hinted that people previously infected with an early Omicron subvariant responded more enthusiastically to a bivalent BA.1-focused vaccine—available in the United Kingdom—than those who’d never encountered the lineage before. Hensley, at the University of Pennsylvania, is now trying to figure out if the same is true for Americans who got the BA.5-based bivalent shot after getting sick with one of the many Omicron subvariants.

    Ahmed thinks that giving people two updated shots—a safer approach, he points out, than adding an infection to the mix—could untether the body from old imprints too. A few years ago, he and his colleagues showed that a second dose of a particular flu vaccine could help shift the ratio of people’s immune responses. A second dose of the fall’s bivalent vaccine might not be practical or palatable for most people, especially now that BA.5 is on its way out. But if next autumn’s recipe overlaps with BA.5 in ways that it doesn’t with the original variant—as it likely will to at least some degree, given the Omicron lineage’s continuing reign—a later, slightly different shot could still be a boon.

    Keeping vaccine doses relatively spaced out—on an annual basis, say, à la flu shots—will likely help too, Bhattacharya said. His recent studies, not yet published, hint that the body might “forget” old variants, as it were, if it’s simply given more time: As antibodies raised against prior infections and injections fall away, vaccine ingredients could linger in the body rather than be destroyed by prior immunity on sight. That slightly extended stay might offer the junior members of the immune system—lesser in number, and slower on the uptake—more of an opportunity to cook up an Omicron-specific response.

    In an ideal world, researchers might someday know enough about imprinting to account for its finickiness whenever they select and roll out new shots. Flu shots, for instance, could be personalized to account for which strains babies were first exposed to, based on birth year; combinations of COVID vaccine doses and infections could dictate the timing and composition of a next jab. But the world is not yet living that reality, Gostic told me. And after three years of an ever-changing coronavirus and a fluctuating approach to public health, it’s clear that there won’t be a single vaccine recipe that’s ideal for everyone at once.

    Even Thomas Francis Jr. did not consider original antigenic sin to be a total negative, Hensley told me. According to Francis, the true issue with the “sin” was that humans were missing out on the chance to imprint on multiple strains at once in childhood, when the immune system is still a blank slate—something that modern researchers could soon accomplish with the development of universal vaccines. Our reliance on first impressions can be a drawback. But the same phenomenon can be an opportunity to acquaint the body with diversity early on—to give it a richer narrative, and memories of many threats to come.

    Katherine J. Wu

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  • What Does It Mean to Care About COVID Anymore?

    What Does It Mean to Care About COVID Anymore?

    After nearly three years of constantly thinking about COVID, it’s alarming how easily I can stop. The truth is, as a healthy, vaxxed-to-the-brim young person who has already had COVID, the pandemic now often feels more like an abstraction than a crisis. My perception of personal risk has dropped in recent months, as has my stamina for precautions. I still care about COVID, but I also eat in crowded cafés and go mask-free at parties.

    Heading into the third pandemic winter, things have changed. Most Americans seem to have tuned out COVID. Precautions have virtually disappeared; except for in the deepest-blue cities, wearing a mask is, well, weird. Reported cases are way down since the spring and summer, but perhaps the biggest reason for America’s behavioral let-up is that much of the country sees COVID as a minor nuisance, no more bothersome than a cold or the flu.

    And to a certain degree, they’re right: Most healthy, working-age adults who are up-to-date on their vaccinations won’t get severely ill—especially now that antivirals such as Paxlovid are available. Other treatments can help if a patient does get very sick. “People who are vaccinated and relatively healthy who are getting COVID are not getting that sick,” Lisa Lee, an epidemiologist at Virginia Tech, told me. “And so people are thinking, Wow, I’ve had COVID. It wasn’t that bad. I don’t really care anymore.”

    Still, there are many reasons to continue caring about COVID. About 300 people are still dying every day; COVID is on track to be the third-leading cause of death in the U.S. for the third year running. The prospect of developing long COVID is real and terrifying, as are mounting concerns about reinfections. But admittedly, these sometimes manifest in my mind as a dull, omnipresent horror, not an urgent affront. Continuing to care about COVID while also loosening up behaviors is an uncomfortable position to be in. Most of the time, I just try to ignore the guilt gnawing at my brain. At this point, when so few people feel that the potential benefit of dodging an infection is worth the inconvenience of precautions, what does it even mean to care about COVID?

    Read: Hundreds of Americans will die from COVID today

    In an ideal epidemiological scenario, everyone would willingly deploy the full arsenal of COVID precautions, such as masking and forgoing crowded indoor activities, especially during waves. But that kind of all-out response no longer makes sense. “It’s probably not realistic to expect people to take precautions every time, perpetually, or even every winter or fall, unless there is a particularly concerning reason to do that,” Jennifer Nuzzo, an epidemiologist at Brown University, told me.

    But, now more than ever, we must remember that COVID is not just a personal threat but a community one. For older and immunocompromised people, the risks are still significant. For example, people over 50 account for 93 percent of COVID-related deaths in the U.S., even though they represent just 35.7 percent of the population. As long as the death rate remains as high as it is, caring about COVID should mean orienting precautions to protect them. This idea has been around since the pandemic began, but its prominence faded as Americans put their personal health first. “If you’re otherwise healthy, it’s so easy just to think about yourself,” Lee said. “We have to think very carefully about that other part of infectious disease, which is the part where we can potentially hurt other people.”

    Orienting behavior in this way gives low-risk people a way to care about COVID that doesn’t entail constant masking or skipping all indoor activities: They can relax when they know they aren’t going to encounter vulnerable people. Like the productivity adage “work smarter, not harder,” this perspective allows people to take precautions strategically, not always. In practice, all it takes is some foresight. If you don’t live with vulnerable people, make it second nature to ask: Will I be seeing vulnerable people anytime soon? If the answer is no, do whatever you’re comfortable with given your own risk. If you are a healthy 30-something who lives alone, going to a Friendsgiving with other people your age is different from spending Thanksgiving dinner with parents and grandparents.

    If you will be seeing someone vulnerable, the most straightforward way to avoid giving them COVID is to avoid getting infected yourself, which means wearing a good mask in public settings and minimizing your interactions with others the week before, in what some experts have called a “mini-quarantine.” Not everyone has that luxury: Parents, for example, have to send their kids to school.

    Spontaneous interactions with vulnerable people are trickier to plan for, but they follow the same principle. On a crowded bus, for example, “there’s no question that if you’re close enough to someone who could be hurt by getting COVID and you could have it, then, yeah, a mask is the way to go,” Lee said. Of course, it isn’t always possible to know when someone is high-risk; young people, too, can be medically vulnerable. There’s no clear guidance for those situations, but remaining cautious doesn’t require much effort. “Carry a mask with you,” Lee said. “It’s not a big lift.”

    Get boosted—if not for yourself, then for them. Just 11.3 percent of eligible Americans have gotten the latest, bivalent shot, which potentially reduces your chances of getting COVID and passing it along. It also means getting tested, so you know when you’re infectious, and being aware of respiratory symptoms—of any kind. Alongside COVID, the flu and RSV are putting many people in the hospital, especially the very young and the very old. No matter how low your personal risk, if you have symptoms, avoiding transmission is crucial. “A reasonable thing to prioritize is: If you have symptoms, take care to prevent it from spreading,” Caitlin Rivers, an epidemiologist at Johns Hopkins University, told me.

    Read: It’s a bad time to be a booster slacker

    As we move away from a personal approach to COVID, we have an opportunity to expand the idea of what caring looks like. Low-risk people can, and should, take an active role in bolstering the protection of vulnerable people they know. In practical terms, this means ensuring that people in your life who are over 50—especially those over 65—are boosted and have a plan to get Paxlovid if they fall sick, Nuzzo said. “I think our biggest problem right now is that not everybody has enough access to the tools, and that’s a place where people can help.” She noted that she is particularly concerned about older people who struggle to book vaccine appointments online. Caring “doesn’t mean abstaining, per se. It means facilitating. It means enabling and helping people in your community.” This holiday season, caring could mean sitting down at a computer to make Grandma’s booster appointment, or driving her to the drugstore to get it.

    If you have lost your motivation to care about COVID, you might find it in the people you love. I didn’t feel a personal need to wear a mask at the concert I attended yesterday, but I did it because I don’t want to accidentally infect my partner’s 94-year-old grandfather when I see him next week. To have this experience of the pandemic is a privilege. Many don’t have the option to stop caring, even for a moment.

    Barring another Omicron-esque event, we thankfully won’t ever return to a moment where Americans obsess over COVID en masse. But this virus isn’t going away, so we can’t escape having a population that is split between the high-risk minority and the low-risk majority. Rethinking what it means to care allows for a more nuanced and liveable idea of what responsible behavior looks like. Right now, Nuzzo told me, the language we use to describe one’s position on COVID is “black-and-white, absolutist—you either care or you don’t.” There is space between those extremes. At least for now, it’s the only way to compromise between the world we have and the world we want.

    Yasmin Tayag

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