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Tag: immune response

  • The Pregnancy Risk That Doctors Won’t Mention

    The Pregnancy Risk That Doctors Won’t Mention

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    The nonexhaustive list of things women are told to avoid while pregnant includes cat litter, alfalfa sprouts, deli meat, runny egg yolks, pet hamsters, sushi, herbal teas, gardening, brie cheeses, aspirin, meat with even a hint of pink, hot tubs. The chance that any of these will harm the baby is small, but why risk it?

    Yet few doctors in the U.S. tell pregnant women about the risk of catching a ubiquitous virus called cytomegalovirus, or CMV. The name might be obscure, but CMV is the leading infectious cause of birth defects in America—far ahead of toxoplasmosis from cat litter or microbes from hamsters. Bafflingly, the majority of babies infected in the womb are unaffected, but an estimated 400 born with CMV die every year. Thousands more end up with hearing and vision loss, epilepsy, developmental delays, or microcephaly, in which the head and brain are unusually small. Exactly why the virus so dramatically affects some babies but not others is unknown. There is no cure and no vaccine.

    Amanda Devereaux’s younger child, Pippa, was born with CMV, which caused damage to her brain. Pippa is prone to seizures. She could not walk until she was 2 and a half, and she is nonverbal at age 7. “I was just flabbergasted that no one told me about CMV,” says Devereaux, who is now the program director for the National CMV Foundation, which raises awareness of the virus. The nonprofit was founded by parents of children with congenital CMV. “Every single one of them says, ‘Why didn’t I hear about this?’” Devereaux told me.

    One reason that doctors have hesitated to spread the word is that the most obvious way to avoid this virus is to avoid infected toddlers. Symptoms from CMV are usually mild to nonexistent in healthy adults and children. Toddlers, who frequently pick up CMV at day care, can continue shedding the virus in their bodily fluids for months and even years while totally healthy. “I’ve encountered a classroom of 2-year-olds where every single child was shedding CMV,” Robert Pass, a retired pediatrician and longtime CMV researcher at the University of Alabama, told me when we spoke in 2021. (He recently died, at age 81.)

    This creates a common scenario for congenital CMV: A toddler in day care brings CMV home and infects Mom, who is pregnant with a younger sibling. One recent study found that congenital CMV is nearly twice as common in second-born children than in firstborns. Devereaux’s toddler son was in day care when she was pregnant. “I was sharing food with him because he would not finish his breakfast,” she told me. She had no idea that his half-eaten muffin could end up harming her unborn daughter. In hindsight, she says, “I wish I had spent less time worrying about not eating deli meat and more time focused on, Hey I’ve got this toddler at day care. I’m at risk for CMV.”

    CMV is such a tricky virus because few things about it are absolute. A mother cannot avoid her toddler categorically. Most pregnant women infected with CMV do not pass it to their babies. Most infected babies end up just fine. Doctors warn patients against many risks in pregnancy—see the list above—but in this case thousands of parents every year are blindsided by a very common virus. No one has a perfect answer for how to stop it.

    Day cares have been known as hot spots for CMV since at least the 1980s, when Pass, in Alabama, and other researchers in Virginia first began tracking congenital cases back to child-care centers. The virus is rampant in day cares for the same reason that other viruses are rampant in day cares: Young children are born with no immunity, and they aren’t very diligent about avoiding one another’s saliva, urine, snot, and tears, all of which harbor CMV. Of mothers with infected toddlers in day care, a third who have never had the virus catch it within a year. And getting CMV for the first time while pregnant is the riskiest scenario; these so-called primary infections are most likely to result in serious complications for the fetus. But recent research has found that reinfections and reactivations of the virus can lead to congenital CMV too. (CMV remains inside the body forever after the first infection, much like chickenpox, which is caused by a related virus.)

    So eliminating the risk of congenital CMV entirely is impossible. But some CMV experts advocate giving women a short list of actions to reduce their risk during the nine months of pregnancy: Avoid sharing food or utensils with toddlers in day care; kiss them on the top of the head instead of on the mouth; wash your hands frequently, especially after diaper changes; and clean surfaces that come in contact with saliva or urine. A study in Italy found that pregnant women who were taught these measures cut their risk of catching CMV by sixfold. A study in France found that it lowered risk too.

    In the U.S., patients are unlikely to hear this advice from their obstetricians, though. The American College of Obstetricians and Gynecologists doesn’t recommend telling patients about ways to reduce CMV risk. According to ACOG, the evidence that behavioral changes can make a difference—from just a handful of studies—is not strong enough, and the organization sees downsides to the approach. Advice such as not kissing babies and toddlers could harm “a mother’s ability to bond with her children,” and these hygiene recommendations could “falsely reassure patients” about their risk of CMV, Christopher Zahn, ACOG’s interim CEO, said in a statement to The Atlantic.

    The CMV community disagrees. “I think they’re being a bit paternalistic,” says Gail Demmler-Harrison, a pediatric-infectious-diseases doctor at Texas Children’s Hospital. A group of international CMV experts, including Demmler-Harrison, endorsed patient education in a set of consensus recommendations in 2017. Devereaux, with the CMV Foundation, frames it as a matter of choice. It shouldn’t be “somebody else is saying, ‘You can’t handle this information; I’m not going to share that with you,” she told me. Without knowing about CMV, women can’t decide what kind of risk they’re comfortable with or what kind of hygiene changes are too burdensome. “It’s your choice whether you make them or not,” she says. “Having that choice is important.”

    More data on how well these behavioral changes work might be coming soon: Karen Fowler, an epidemiologist at the University of Alabama at Birmingham, is enrolling hundreds of pregnant women in a clinical trial. Only 8 percent of participants had heard of CMV before joining the study, she says. Patients get a short information session about CMV and then 12 weeks of text-message reminders. Importantly, she says, “we’re keeping our message very simple”: Reduce saliva sharing: no eating leftover food, no sharing utensils, and no cleaning a pacifier in your mouth. This simple rule cuts off the most probable routes of transmission. Sure, CMV is also shed in urine, tears, and other bodily fluids—but mothers aren’t routinely putting any of those in their mouth.

    Prevention of CMV ends up the focus of so much attention because once a fetus is infected, the treatment options are not particularly good. The best antiviral against CMV is not considered safe to use during pregnancy, and another antiviral, although safer, is not that potent. After infected babies are born, antiviral therapy can help preserve hearing in those with other moderate to severe symptoms from CMV, but it can’t reverse damage in the brain. And it’s unclear how much antivirals help those with only mild symptoms. When does benefit outweigh risk? “There’s a big gray area,” says Laura Gibson, a pediatric-infectious-diseases doctor at the University of Massachusetts Chan Medical School. For these reasons, policies of whether to screen all newborns vary state to state, even hospital to hospital. Knowledge can be power—but with a virus as confusing as CMV, knowledge of an infection doesn’t always point to an obvious best choice.

    In an ideal world, all of this could be made obsolete with a CMV vaccine. But such a vaccine has proved elusive despite a lot of interest. In the U.S., the Institute of Medicine deemed a CMV vaccine the highest priority around the turn of the millennium, and about two dozen vaccine candidates have been or are being studied. All of the completed clinical trials, though, have failed. “The immunity may look robust in the first month or year, but then it wanes,” Demmler-Harrison says. And even vaccines that elicit some immune response are not necessarily able to elicit one strong enough to protect against CMV infection entirely.

    CMV is such a challenging virus to vaccinate against because it knows our immune system’s tricks. “It’s evolved with humans for millions of years,” Gibson says. “It knows how to get around and live with our immune system.” Our immune system is never able to eliminate the virus, which emerges occasionally from our cells to replicate and try to find another host. And so a vaccine that completely protects against CMV would need to prompt our immune system to do something it cannot naturally do. It would need to be better than our immune system. “As time goes on, I think fewer and fewer people are thinking that might work,” Gibson says. But a vaccine doesn’t have to protect against all infections to be useful. Because first infections are the riskiest for fetuses, being vaccinated could still reduce risk of congenital CMV.

    Whom to vaccinate is another complicated question to answer for CMV. We could vaccinate all toddlers, as we do against rubella, which is also most dangerous when passed from mother to fetus. This has the potential advantage of promoting widespread immunity that tamps down circulation of CMV, period. But the virus doesn’t actually harm toddlers much, and immunity could wane by the time they grow up to childbearing age. Or we could vaccinate teenagers, as we do against meningococcal disease, but teens are more likely to miss vaccines and again, immunity could wane too soon. So what about all pregnant women? By the time someone shows up at the doctor pregnant, it’s probably too late to protect during CMV’s highest risk period, in the first trimester. A better understanding of CMV immunity and spread could help scientists decide on the best strategy. Gibson is conducting a study (funded by Moderna, which is testing a CMV-vaccine candidate) on how the virus spreads and what kinds of immune responses are correlated with shedding.

    Until a vaccine is developed—should it happen at all—the only way to prevent CMV infection is the very old-tech method of avoiding bodily fluids. It’s imperfect. Its exact effectiveness is hard to quantify. Some people might not find it worthwhile, given the small absolute risk of CMV in any single pregnancy. There are, after all, already so many things to worry about when expecting a baby. Yet another one? Or, you might think of it, what’s one more?

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    Sarah Zhang

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  • Anti-Allergy Formula Is on the Rise. Milk Allergies Might Not Be.

    Anti-Allergy Formula Is on the Rise. Milk Allergies Might Not Be.

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    This article was originally published by Undark Magazine.

    For Taylor Arnold, a registered dietitian nutritionist, feeding her second baby was not easy. At eight weeks old, he screamed when he ate and wouldn’t gain much weight. Arnold brought him to a gastroenterologist, who diagnosed him with allergic proctocolitis—an immune response to the proteins found in certain foods, which she narrowed down to cow’s milk.

    Cow’s-milk-protein allergies, or CMPA, might be on the rise—following a similar trend in other children’s food allergies—and they can upend a caregiver’s feeding plans: In many cases, a breastfeeding parent is told to eliminate dairy from their diet, or switch to a specialized hypoallergenic formula, which can be expensive.

    But although some evidence suggests that CMPA rates are climbing, the source and extent of that increase remain unclear. Some experts say that the uptick is partly because doctors are getting better at recognizing symptoms. Others claim that the condition is overdiagnosed. And among those who believe that milk-allergy rates are inflated, some suspect that the global formula industry, valued at $55 billion according to a 2022 report from the World Health Organization and UNICEF, may have an undue influence.

    Meanwhile, “no one has ever studied these kids in a systematic way,” Victoria Martin, a pediatric gastroenterologist and allergy researcher at Massachusetts General Hospital, told me. “It’s pretty unusual in disease that is this common, that has been going on for this long, that there hasn’t been more careful, controlled study.”

    This lack of clarity can leave doctors in the dark about how to diagnose the condition and leave parents with more questions than answers about how best to treat it.

    When Arnold’s son became sick with CMPA symptoms, it was “really, really stressful,” she told me. Plus, “I didn’t get a lot of support from the doctors, and that was frustrating.”

    Though the gastroenterologist recommended that she switch to formula, Arnold ultimately used a lactation consultant and gave up dairy so she could continue breastfeeding. But she said she can understand why others might not make the same choice: “A lot of moms go to formula because there’s not a lot of support for how to manage the diet.”

    Food allergies primarily come in two forms: One, called an IgE-mediated allergy, has symptoms that appear soon after ingesting a food—such as swelling, hives, or difficulty breathing—and may be confirmed by a skin-prick test. The second, which Arnold’s son was diagnosed with, is a non-IgE-mediated allergy, or food-protein-induced allergic proctocolitis, and is harder to diagnose.

    With non-IgE allergies, symptom onset doesn’t tend to happen immediately after a person eats a triggering food, and there is no definitive test to confirm a diagnosis. (Some specialists don’t like to call the condition an allergy, because it doesn’t present with classic allergy symptoms.) Instead, physicians often rely on past training, online resources, or published guidelines written by experts in the field, which list symptoms and help doctors make a treatment plan.

    Read: We’ve never been good at feeding babies

    Numerous such guidelines exist to help providers diagnose milk allergies, but the process is not always straightforward. “It’s a perfect storm” of vague and common symptoms and no diagnostic test, Adam Fox, a pediatric allergist and a professor at King’s College London, told me, noting that commercial interests such as formula-company marketing can also be misleading. “It’s not really a surprise that you’ve got confused patients and, frankly, a lot of very confused doctors.”

    Fox is the lead author of the International Milk Allergy in Primary Care, or iMAP, guidelines, one of many similar documents intended to help physicians diagnose CMPA. But some guidelines—including iMAP, which was known as the Milk Allergy in Primary Care Guideline until 2017—have been criticized for listing a broad range of symptoms, like colic, nonspecific rashes, and constipation, which can be common in healthy infants during the first year of their life.

    “Lots of babies cry, or they [regurgitate milk], or they get a little minor rash or something,” Michael Perkin, a pediatric allergist based in the U.K., told me. “But that doesn’t mean they’ve got a pathological process going on.”

    In a paper published online in December 2021, Perkin and colleagues found that in a food-allergy trial, nearly three-quarters of the infants’ parents reported at least two symptoms that matched the iMAP guidelines’ “mild-moderate” non-IgE-mediated cow’s-milk-allergy symptoms, such as vomiting. But another study, whose authors included Perkin and Robert Boyle, a children’s-allergy specialist at Imperial College London, reviewed available evidence and found estimated that only about 1 percent of babies have a milk allergy that has been proved by what’s called a “food challenge,” in which a person is exposed to the allergen and their reactions are monitored.

    That same study reported that as many as 14 percent of families believe their baby has a milk allergy. Another study by Boyle and colleagues showed that milk-allergy formula prescriptions increased 2.8-fold in England from 2007 to 2018. Researchers at the University of Rochester found similar trends stateside: Hypoallergenic-formula sales rose from 4.9 percent of formula sold in the U.S. in 2017 to 7.6 percent in 2019.

    Perkin and Boyle suspect that the formula industry has influenced diagnosis guidelines. In their 2020 report, published in JAMA Pediatrics, they found that 81 percent of authors who had worked on various physicians’ guidelines for the condition—including several for iMAP’s 2013 guidance—reported a financial conflict of interest with formula manufacturers.

    The formula industry also sends representatives and promotional materials to some pediatric clinics. One recent study found that about 85 percent of U.S. pediatricians surveyed reported a visit by a representative, some of whom sponsored meals with them.

    Formula companies “like people getting the idea that whenever a baby cries, or does a runny poo, or anything,” it might be a milk allergy, Boyle told me.

    In response to criticism that the guidelines have influenced the increase in specialized-formula sales, Fox, the lead author of the iMap guidelines, noted that the rise began in the early 2000s. One of the first diagnosis guidelines, meanwhile, was published in 2007. He also said that the symptoms listed in the iMAP guidelines are those outlined by the U.K.’s National Institute for Health and Care Excellence and the U.S.’s National Institute of Allergy and Infectious Diseases.

    As for the conflicts of interest, Fox said: “We never made any money from this; there was never any money for the development of it. We’ve done this with best intentions. We absolutely recognize where that may not have turned out the way that we intended it; we have tried our best to address that.”

    Following backlash over close ties between the formula industry and health-care professionals, including author conflicts of interest, iMAP updated its guidelines in 2019. The new version responded directly to criticism and said the guidelines received no direct industry funding, but it acknowledged “a potential risk of unconscious bias” related to research funding, educational grants, and consultant fees. The authors noted that the new guidelines had tried to mitigate such influence through independent patient input.

    Read: What’s behind America’s shocking baby-formula shortage?

    Fox also said he cut all formula ties in 2018, and led the British Society for Allergy & Clinical Immunology to do the same when he was president.

    I reached out to the Infant Nutrition Council of America, an association of some of the largest U.S. manufacturers of infant formula, multiple times but did not receive any comment in response.

    Though the guidelines have issues, Nigel Rollins, a pediatrician and researcher at the World Health Organization, told me, he sees the rise in diagnoses as driven by formula-industry marketing to parents, which can fuel the idea that fussiness or colic might be signs of a milk allergy. Parents then go to their pediatrician to talk about milk allergy, Rollins said, and “the family doctor isn’t actually well positioned to argue otherwise.”

    Rollins led much of the research in the 2022 report from the WHO and UNICEF, which surveyed more than 8,500 pregnant and postpartum people in eight countries (not including the U.S.). Of those participants, 51 percent were exposed to aggressive formula-milk marketing, which the report states “represents one of the most underappreciated risks to infants and young children’s health.”

    Amy Burris, a pediatric allergist and immunologist at the University of Rochester Medical Center, told me that there are many likely causes of overdiagnosis: “I don’t know that there’s one particular thing that stands out in my head as the reason it’s overdiagnosed.”

    Some physicians rely on their own criteria, rather than the guidelines, to diagnose non-IgE milk allergy—for instance, conducting a test that detects microscopic blood in stool. But Burris and Rollins both pointed out that healthy infants, or infants who have recently had a virus or stomach bug, can have traces of blood in their stool too.

    Martin, the allergy researcher at Massachusetts General Hospital, said the better way to confirm an infant dairy allergy is to reintroduce milk about a month after it has been eliminated: If the symptoms reappear, then the baby most likely has the allergy. The guidelines say to do this, but both Martin and Perkin told me that this almost never happens; parents can be reluctant to reintroduce a food if their baby seems better without it.

    “I wish every physician followed the guidelines right now, until we write better guidelines, because, unequivocally, what folks are doing not following the guidelines is worse,” Martin said, adding that kids are on a restricted diet for a longer time than they should be.

    Giving up potentially allergenic foods, including dairy, isn’t without consequences. “I think there’s a lot of potential risk in having moms unnecessarily avoid cow’s milk or other foods,” Burris said. “Also, you’re putting the breastfeeding relationship at risk.”

    By the time Burris sees a baby, she said, the mother has in many cases already given up breastfeeding after a primary-care provider suggested a food allergy, and “at that point, it’s too late to restimulate the supply.” It also remains an open question whether allergens in breast milk actually trigger infant allergies. According to Perkin, the amount of cow’s-milk protein that enters breast milk is “tiny.”

    For babies, Martin said, dietary elimination may affect sensitivity to other foods. She pointed to research indicating that early introduction of food allergens such as peanuts can reduce the likelihood of developing allergies.

    Martin also said that some babies with a CMPA diagnosis may not have to give up milk entirely. She led a 2020 study suggesting that even when parents don’t elect to make any dietary changes for babies with a non-IgE-mediated food-allergy diagnosis, they later report an improvement in their baby’s symptoms by taking other steps, such as acid suppression. But when parents do make changes to their baby’s diet, in Martin’s experience, if they later reintroduce milk, “the vast majority of them do fine,” she said. “I think some people would argue that maybe you had the wrong diagnosis initially. But I think the other possibility is that it’s the right diagnosis; it just turns around pretty fast.”

    Still, many parents who give up dairy or switch to a hypoallergenic formula report an improvement in their baby’s symptoms. Arnold said her son’s symptoms improved when she eliminated dairy. But when he was about eight months old, they reintroduced the food group to his diet, and he had no issues.

    Whether that’s because the cow’s-milk-protein allergy was short-lived or because his symptoms were due to something else is unclear. But Arnold sees moms self-diagnosing their baby with food allergies on social media, and believes that many are experiencing a placebo effect when they say their baby improves. “Nobody’s immune to that. Even me,” she said. “There’s absolutely a chance that that was the case with my baby.”

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    Christina Szalinski

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  • What Should Go Into This Year’s COVID Vaccine?

    What Should Go Into This Year’s COVID Vaccine?

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    This fall, millions of Americans might be lining up for yet another kind of COVID vaccine:  their first-ever dose that lacks the strain that ignited the pandemic more than three and a half years ago. Unlike the current, bivalent vaccine, which guards against two variants at once, the next one could, like the first version of the shot, have only one main ingredient—the spike protein of the XBB.1 lineage of the Omicron variant, the globe’s current dominant clade.

    That plan isn’t yet set. The FDA still has to convene a panel of experts, then is expected to make a final call on autumn’s recipe next month. But several experts told me they hope the agency follows the recent recommendation of a World Health Organization advisory group and focuses the next vaccine only on the strains now circulating.

    The switch in strategy—from two variants to one, from original SARS-CoV-2 plus Omicron to XBB.1 alone—would be momentous but wise, experts told me, reflecting the world’s updated understanding of the virus’s evolution and the immune system’s quirks. “It just makes a lot of sense,” said Melanie Ott, the director of the Gladstone Institute of Virology, in San Francisco. XBB.1 is the main coronavirus group circulating today; neither the original variant nor BA.5, the two coronavirus flavors in the bivalent shot, is meaningfully around anymore. And an XBB.1-focused vaccine may give the global population a particularly good shot at broadening immunity.

    At the same time, COVID vaccines are still in a sort of beta-testing stage. In the past three-plus years, the virus has spawned countless iterations, many of which have been extremely good at outsmarting us; we humans, meanwhile, are only on our third-ish attempt at designing a vaccine that can keep pace with the pathogen’s evolutionary sprints. And we’re very much still learning about the coronavirus’s capacity for flexibility and change, says Rafi Ahmed, an immunologist at Emory University. By now, it’s long been clear that vaccines are essential for preventing severe disease and death, and that some cadence of boosting is probably necessary to keep the shots’ effectiveness high. But when the virus alters its evolutionary tactics, our vaccination strategy must follow—and experts are still puzzling out how to account for those changes as they select the shots for each year.

    In the spring and summer of 2022, the last time the U.S. was mulling on a new vaccine formula, Omicron was still relatively new, and the coronavirus’s evolution seemed very much in flux. The pathogen had spent more than two years erratically slingshotting out Greek-letter variants without an obvious succession plan. Instead of accumulating genetic changes within a single lineage—a more iterative form of evolution, roughly akin to what flu strains do—the coronavirus produced a bunch of distantly related variants that jockeyed for control. Delta was not a direct descendant of Alpha; Omicron was not a Delta offshoot; no one could say with any certainty what would arise next, or when. “We didn’t understand the trajectory,” says Kanta Subbarao, the head of the WHO advisory group convened to make recommendations on COVID vaccines.

    And so the experts played it safe. Including an Omicron variant in the shot felt essential, because of how much the virus had changed. But going all in on Omicron seemed too risky—some experts worried that “the virus would flip back,” Subbarao told me, to a variant more similar to Alpha or Delta or something else. As a compromise, several countries, including the United States, went with a combination: half original, half Omicron, in an attempt to reinvigorate OG immunity while laying down new defenses against the circulating strains du jour.

    And those shots did bolster preexisting immunity, as boosters should. But they didn’t rouse a fresh set of responses against Omicron to the degree that some experts had hoped they would, Ott told me. Already trained on the ancestral version of the virus, people’s bodies seemed to have gotten a bit myopic—repeatedly reawakening defenses against past variants, at the expense of new ones that might have more potently attacked Omicron. The outcome was never thought to be damaging, Subbarao told me: The bivalent, for instance, still broadened people’s immune responses against SARS-CoV-2 compared with, say, another dose of the original-recipe shot, and was effective at tamping down hospitalization rates. But Ahmed told me that, in retrospect, he thinks an Omicron-only boost might have further revved that already powerful effect.

    Going full bore on XBB.1 now could keep the world from falling into that same trap twice. People who get an updated shot with that strain alone would receive only the new, unfamiliar ingredient, allowing the immune system to focus on the fresh material and potentially break out of an ancestral-strain rut. XBB.1’s spike protein also would not be diluted with one from an older variant—a concern Ahmed has with the current bivalent shot. When researchers added Omicron to their vaccine recipes, they didn’t double the total amount of spike protein; they subbed out half of what was there before. That left vaccine recipients with just half the Omicron-focused mRNA they might have gotten had the shot been monovalent, and probably a more lackluster antibody response.

    Recent work from the lab of Vineet Menachery, a virologist at the University of Texas Medical Branch, suggests another reason the Omicron half of the shot didn’t pack enough of an immunizing punch. Subvariants from this lineage, including BA.5 and XBB.1, carry at least one mutation that makes their spike protein unstable—to the point where it seems less likely than other versions of the spike protein to stick around for long enough to sufficiently school immune cells. In a bivalent vaccine, in particular, the immune response could end up biased toward non-Omicron ingredients, exacerbating the tendencies of already immunized people to focus their energy on the ancestral strain. For the same reason, a monovalent XBB.1, too, might not deliver the anticipated immunizing dose, Menachery told me. But if people take it (still a big if), and hospitalizations remain low among those up-to-date on their shots, a once-a-year total-strain switch-out might be the choice for next year’s vaccine too.

    Dropping the ancestral strain from the vaccine isn’t without risk. The virus could still produce a variant totally different from XBB.1, though that does, at this point, seem unlikely. For a year and a half now, Omicron has endured, and it now has the longest tenure of a single Greek-letter variant since the pandemic’s start. Even the subvariants within the Omicron family seem to be sprouting off each other more predictably; after a long stint of inconsistency, the virus’s shape-shifting now seems “less jumpy,” says Leo Poon, a virologist at the University of Hong Kong. It may be a sign that humans and the virus have reached a détente now that the population is blanketed in a relatively stable layer of immunity. Plus, even if a stray Alpha or Delta descendant were to rise up, the world wouldn’t be caught entirely off guard: So many people have banked protection against those and other past variants that they’d probably still be well buffered against COVID’s worst acute outcomes. (That reassurance doesn’t hold, though, for people who still need primary-series shots, including the kids being born into the world every day. An XBB.1 boost might be a great option for people with preexisting immunity. But a bivalent that can offer more breadth might still be the more risk-averse choice for someone whose immunological slate is blank.)

    More vaccination-strategy shifts will undoubtedly come. SARS-CoV-2 is still new to us; so are our shots. But the virus’s evolution, as of late, has been getting a shade more flu-like, and its transmission patterns a touch more seasonal. Regulators in the U.S. have already announced that COVID vaccines will probably be offered each year in the fall—as annual flu shots are. The viruses aren’t at all the same. But as the years progress, the comparison between COVID and flu shots could get more apt still—if, say, the coronavirus also starts to produce multiple, genetically distinct strains that simultaneously circulate. In that case, vaccinating against multiple versions of the virus at once might be the most effective defense.

    Flu shots could be a useful template in another way: Although those shots have followed roughly the same guidelines for many years, with experts meeting twice a year to decide whether and how to update each autumn’s vaccine ingredients, they, too, have needed some flexibility. Until 2012, the vaccines were trivalent, containing ingredients that would immunize people against three separate strains at once; now many, including all of the U.S.’s, are quadrivalent—and soon, based on new evidence, researchers may push for those to return to a three-strain recipe. At the same time, flu and COVID vaccines share a major drawback. Our shots’ ingredients are still selected months ahead of when the injections actually reach us—leaving immune systems lagging behind a virus that has, in the interim, sprinted ahead. Until the world has something more universal, our vaccination strategies will have to be reactive, scrambling to play catch-up with these pathogens’ evolutionary whims.

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    Katherine J. Wu

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  • Will Nasal COVID Vaccines Save Us?

    Will Nasal COVID Vaccines Save Us?

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    Since the early days of the coronavirus pandemic, a niche subset of experimental vaccines has offered the world a tantalizing promise: a sustained slowdown in the spread of disease. Formulated to spritz protection into the body via the nose or the mouth—the same portals of entry most accessible to the virus itself—mucosal vaccines could head SARS-CoV-2 off at the pass, stamping out infection to a degree that their injectable counterparts might never hope to achieve.

    Now, nearly three years into the pandemic, mucosal vaccines are popping up all over the map. In September, India authorized one delivered as drops into the nostrils; around the same time, mainland China green-lit an inhalable immunization, and later on, a nasal-spray vaccine, now both being rolled out amid a massive case wave. Two more mucosal recipes have been quietly bopping around in Russia and Iran for many months. Some of the world’s largest and most populous countries now have access to the technology—and yet it isn’t clear how well that’s working out. “Nothing has been published; no data has been made available,” says Mike Diamond, an immunologist at Washington University in St. Louis, whose own approach to mucosal vaccines has been licensed for use in India via a company called Bharat. If mucosal vaccines are delivering on their promise, we don’t know it yet; we don’t know if they will ever deliver.

    The allure of a mucosal vaccine is all about geography. Injectable shots are great at coaxing out immune defenses in the blood, where they’re able to cut down on the risk of severe disease and death. But they aren’t as good at marshaling a protective response in the upper airway, leaving an opening for the virus to still infect and transmit. When viral invaders throng the nose, blood-borne defenses have to scamper to the site of infection at a bit of a delay—it’s like stationing guards next to a bank’s central vault, only to have them rush to the entrance every time a robber trips an external alarm. Mucosal vaccines, meanwhile, would presumably be working at the door.

    That same logic drives the effectiveness of the powerful oral polio vaccine, which bolsters defenses in its target virus’s preferred environment—the gut. Just one mucosal vaccine exists to combat a pathogen that enters through the nose: a nasal spray made up of weakened flu viruses, a version of which is branded as FluMist. The up-the-nose spritz is reasonably protective in kids, in some cases even outperforming its injected counterparts (though not always). But FluMist is much less potent for adults: The immunity they accumulate from a lifetime of influenza infections can wipe out the vaccine before it has time to lay down new protection. When it comes to cooking up a mucosal vaccine for a respiratory virus, “we don’t have a great template to follow,” says Deepta Bhattacharya, an immunologist at the University of Arizona.

    To circumvent the FluMist problem, some researchers have instead concocted viral-vector-based vaccines—the same group of immunizations to which the Johnson & Johnson and AstraZeneca COVID shots belong. China’s two mucosal vaccines fall into this category; so does India’s nose-drop concoction, as well as a nasal version of Russia’s Sputnik V shot. Other researchers are cooking up vaccines that contain ready-made molecules of the coronavirus’s spike protein, more akin to the shot from Novavax. Among them are Iran’s mucosal COVID vaccine and a newer, still-in-development candidate from the immunologist Akiko Iwasaki and her colleagues at Yale. The Yale group is also testing an mRNA-based nasal recipe. And the company Vaxart has been tinkering with a COVID-vaccine pill that could be swallowed to provoke immune cells in the gut, which would then deploy fighters throughout the body’s mucosal surfaces, up through the nose.

    Early data in animals have spurred some optimism. Trial versions of Diamond’s vaccine guarded mice, hamsters, and monkeys from the virus, in some cases seeming to stave off infection entirely; a miniaturized version of Vaxart’s oral vaccine was able to keep infected hamsters from spreading the coronavirus through the air. Iwasaki is pursuing an approach that deploys mucosal vaccines exclusively as boosters to injected shots, in the hopes that the initial jab can lay down bodywide immunity, a subset of which can then be tugged into a specialized compartment in the nose. Her nasal-protein recipe seems to trim transmission rates among rodents that have first received an in-the-muscle shot.

    But attempts to re-create these results in people yielded mixed results. After an intranasal version of the AstraZeneca vaccine roused great defenses in animals, a team at Oxford moved the immunization into a small human trial—and last month, published results showing that it hardly triggered any immune response, even as a booster to an in-the-arm shot. Adam Ritchie, one of the Oxford immunologists behind the study, told me the results don’t necessarily spell disaster for other mucosal attempts, and that with more finagling, AstraZeneca’s vaccine might someday do better up the nose. Still, the results “definitely put a damper on the excitement around intranasal vaccines,” says Stephanie Langel, an immunologist at Case Western Reserve University, who’s partnering with Vaxart to develop a COVID-vaccine pill.

    The mucosal COVID vaccines in India and China, at least, have reportedly shown a bit more promise in small, early human trials. Bharat’s info sheet on its nasal-drop vaccine—the Indian riff on Diamond’s recipe—says it bested another locally made vaccine, Covaxin, at tickling out antibodies, while provoking fewer side effects. China’s inhaled vaccine, too, seems to do reasonably well on the human-antibody front. But antibodies aren’t the same as true effectiveness: Vaccine makers and local health ministries, experts told me, have yet to release large-scale, real-world data showing that the vaccines substantially cut down on transmission or infection. And although some studies have hinted that nasal protection can stick around in animals for many, many months, there’s no guarantee the same will be true in humans, in whom mucosal antibodies, in particular, “are kind of known to wane pretty quickly,” Langel told me.

    SARS-CoV-2 infections have offered sobering lessons of their own. The nasal immune response to the virus itself is neither impenetrable nor particularly long-lived, says David Martinez, a viral immunologist at the University of North Carolina at Chapel Hill. Even people who have been both vaccinated and infected can still get infected again, he told me, and it would be difficult for a nasal vaccine to do much better. “I don’t think mucosal vaccines are going to be the deus ex machina that some people think they’re going to be.”

    Read: America’s flu-shot problem is also its next COVID-shot problem

    Mucosal vaccines don’t need to provide a perfect blockade against infection to prove valuable. Packaged into sprays, drops, or pills, immunizations tailor-made for the mouth or the nose might make COVID vaccines easier to ship, store, and distribute en masse. “They often don’t require specialized training,” says Gregory Poland, a vaccinologist at the Mayo Clinic—a major advantage for rural or low-resource areas. The immunizing experience could also be easier for kids or anyone else who’d rather not endure a needle. Should something like Vaxart’s encapsulated vaccine work out, Langel told me, COVID vaccines could even one day be shipped via mail, in a form safe and easy enough to swallow with a glass of water at home. Some formulations may also come with far fewer side effects than, say, the mRNA-based shots, which “really kick my ass,” Bhattacharya told me. Even if mucosal vaccines weren’t a transmission-blocking knockout, “if it meant I didn’t have to get the mRNA vaccine, I would consider it.”

    But the longer that countries such as the U.S. have gone without mucosal COVID vaccines, the harder it’s gotten to get one across the finish line. Transmission, in particular, is tough to study, and Langel pointed out that any new immunizations will likely have to prove that they can outperform our current crop of injected shots to secure funding, possibly even FDA approval. “It’s an uphill battle,” she told me.

    Top White House advisers remain resolute that transmission-reducing tech has to be part of the next generation of COVID vaccines. Ideally, those advancements would be paired with ingredients that enhance the life span of immune responses and combat a wider swath of variants; skimp on any of them, and the U.S. might remain in repeat-vaccination purgatory for a while yet. “We need to do better on all three fronts,” Anthony Fauci, the outgoing director of the National Institute of Allergy and Infectious Diseases, told me. But packaging all that together will require another major financial investment. “We need Warp Speed 2.0,” says Shankar Musunuri, the CEO of Ocugen, the American company that has licensed Diamond’s recipe. “And so far, there is no action.” When I asked Fauci about this, he didn’t seem optimistic that this would change. “I think that they’ve reached the point where they feel, ‘We’ve given enough money to it,’” he told me. In the absence of dedicated government funds, some scientists, Iwasaki among them, have decided to spin off companies of their own. But without more public urgency and cash flow, “it could be years to decades to market,” Iwasaki told me. “And that’s if everything goes well.”

    Read: The three COVID developments I’m still holding out hope for

    Then there’s the issue of uptake. Musunuri told me that he’s confident that the introduction of mucosal COVID vaccines in the U.S.—however long it takes to happen—will “attract all populations, including kids … people like new things.” But Rupali Limaye, a behavioral scientist at Johns Hopkins University, worries that for some, novelty will drive the exact opposite effect. The “newness” of COVID vaccines, she told me, is exactly what has prompted many to adopt an attitude of “wait and see” or even “that’s not for me.” An even newer one that jets ingredients up into the head might be met with additional reproach.

    Vaccine fatigue has also set in for much of the public. In the United States, hospitalizations are once again rising, and yet less than 15 percent of people eligible for bivalent shots have gotten them. That sort of uptake is at odds with the dream of a mucosal vaccine that can drive down transmission. “It would have to be a lot of people getting vaccinated in order to have that public-health population impact,” says Ben Cowling, an epidemiologist at the University of Hong Kong. And there’s no guarantee that even a widely administered mucosal vaccine would be the population’s final dose. The pace at which we’re doling out shots is driven in part by “the virus changing so quickly,” says Ali Ellebedy, an immunologist at Washington University in St. Louis. Even a sustained encampment of antibodies in the nose could end up being a poor match for the next variant that comes along, necessitating yet another update.

    The experts I spoke with worried that some members of the scientific community—even some members of the public—have begun to pin all their hopes about stopping the spread of SARS-CoV-2 on mucosal vaccines. It’s a recipe for disappointment. “People love the idea of a magic pill,” Langel told me. “But it’s just not reality.” The virus is here to stay; the goal continues to be to make that reality more survivable. “We’re trying to reduce infection and transmission, not eliminate it; that would be almost impossible,” Iwasaki told me. That’s true for any vaccine, no matter how, or where, the body first encounters it.

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    Katherine J. Wu

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