Tag: fewer side effects

Ozempic Can Turn Into No-zempic

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No medication in the history of modern weight loss has inspired as much awe as the latest class of obesity drugs. Wegovy and Zepbound are so effective that they are often likened to “magic ” and “miracles.” Indeed, the weekly injections, which belong to a broader class known as GLP-1s, can lead to weight loss of 20 percent or more, fueling hype about a future in which many more millions of Americans take them. Major food companies including Nestlé and Conagra are considering tailoring their products to suit GLP-1 users. Underlying all this excitement is a huge assumption: They work for everyone.

But for a lot of people, they just don’t. Anita, who lives in Arizona, told me she “took it for granted” that she would lose weight on a GLP-1 drug because “the people around me who were on it were just dropping weight like mad.” Instead, she didn’t shed any pounds. Likewise, Kathryn, from Florida, hasn’t lost any weight since starting the medication in October. “I was really hoping this was something that would be a game changer for me, but it feels like it was just a lot of wasted money,” she told me. (I’m identifying both Anita and Kathryn by their first name only to allow them to speak openly about their health issues.)

Some people can’t tolerate the side effects of the drugs and have to stop taking them. Others simply don’t respond. For some, the strength of the dose, or length of the treatment, does not seem to make a difference. Appetites might remain robust; the “food chatter” in the brain may stay noisy. Together, both groups of less successful GLP-1 users account for a not-insignificant share of patients on these drugs—potentially up to a third. “We don’t really know why it happens, [but] we know it does happen,” Louis Aronne, an obesity-medicine specialist at Weill Cornell Medical College, told me. Despite the promise of a so-called Ozempic revolution, lots of “No-zempics” have been left behind.

Of the two biggest reasons some people don’t lose weight on GLP-1 drugs—side effects and nonresponse—the former is much more straightforward. The GLP-1 drugs Wegovy and Zepbound (which contain the active ingredients semaglutide and tirzepatide, respectively), are known for causing potentially gnarly gastrointestinal symptoms, such as nausea and vomiting, although most people’s reactions are mild and temporary. Yet some have it far worse. Severe, albeit uncommon, side effects include pancreatitis, severe gastrointestinal distress, low blood sugar, and even hair loss, which “can push people off” the drugs, Steven Heymsfield, a professor who studies obesity at Louisiana State University, told me. In one of the biggest studies of semaglutide, encompassing more than 17,000 people over about five years, nearly 17 percent of patients discontinued the medication because of side effects.

Far more mysterious are the people who tolerate the drugs but respond weakly to them—or sometimes not at all. Researchers have known this might happen since these drugs were in early clinical trials. About 14 percent of people who took semaglutide for obesity saw minimal impacts of less than 5 percent weight loss in one study, as did 9 to 15 percent of people who took tirzepatide in a similar one. In her own experience working with patients, “somewhere between a quarter and a third” are nonresponders, Fatima Cody Stanford, an obesity-medicine specialist at Harvard, told me, adding that it can take up to three months to determine whether the drug is working or not. That the same medication at the same dosage can lead to dramatic weight loss in one person and hardly any in another “remains confounding,” Aronne told me.

The broad explanation is that it has something to do with genetics. The drugs work by masquerading as the appetite-suppressing hormone GLP-1 and binding to its receptor, like a key fitting into a lock. Although the lock’s overall shape is generally consistent from person to person, its nooks and crannies can vary because of genetic differences. “For some people, that key just won’t fit right,” Eduardo Grunvald, an obesity-medicine doctor at UC San Diego Health, told me. In other cases, genes may limit the effects of these drugs after they bind to GLP-1 receptors. One possibility is that people metabolize the drugs differently: Some patients may break them down too quickly for them to take effect; others may process them too slowly, potentially building up such high levels of the medications that they become toxic, Heymsfield said.

For No-zempic patients, perhaps the most consequential impact of individual variation is on the propensity for obesity itself. “We are all very different from a genetic standpoint, in terms of our risk of weight gain,” Grunvald said. Numerous factors can drive obesity, including diet, environment, stress, and—most pertinent to GLP-1 drugs—altered brain function.

GLP-1 drugs target a pathway that regulates appetite and insulin levels. Some cases of obesity can be caused by a disruption in that particular mechanism, in which case GLP-1s can indeed be wondrous. But “not everyone has dysfunction in this particular pathway,” Stanford said. When that is the case, the drugs won’t be very effective. A different pathway, for example, controls the absorption of fat from food; another increases energy expenditure. In these people, GLP-1s might tamp down appetite to a degree, maybe leading to some weight loss, but a different drug may be required to treat obesity at its root. “It is not all about food intake,” Stanford said.

That’s not to say that No-zempics are out of options. They might have better success switching from one GLP-1 to the other, or even stacking them, Heymsfield said. Some patients who don’t respond to GLP-1s at all can get better results with older drugs that work on different obesity pathways, Aronne said. One, called Qysmia, a combination of the decades-old drugs phentermine and topiramate, can lead to an average weight loss of 14 percent body weight at its highest dose. If medications don’t work, bariatric surgery remains a powerful option, one that may even be growing in popularity. Last year, the number of bariatric surgeries performed in the U.S. grew despite the boom in GLP-1 usage, a trend that some expect to continue, because so many people don’t tolerate the drugs.

The intense hype around the game-changing nature of GLP-1s makes it easy to forget that they are, in fact, just drugs. “Every drug that’s ever been made” works in some people and not in others, Heymsfield said; there’s no reason to think GLP-1s would be any different. Remembering that they are in an early stage of development has a sobering effect. Eventually, obesity drugs may leave fewer people behind. The category is expanding rapidly: By one count, more than 90 new drug candidates are in development.

They are evolving to attack obesity from multiple fronts, which, at least in theory, widens their net of potential users. In an early study on an experimental candidate named retatrutide—called a triple agonist because it acts on GLP-1 as well as two other targets involved in obesity, GIP and glucagon receptors—100 percent of people on the highest dose lost 5 percent or more of their body weight. New candidates are also expected to have fewer side effects. They have to, Heymsfield said, because the competition is so steep that any new drug has to be “as good with less side effects, or better.”

But no matter how good these drugs get, it’s unrealistic to think that they’ll become a one-size-fits-all treatment for everyone with obesity. The disease is simply too complex, with too many drivers, for a single type of medication to treat it. More than 200 different drugs exist for treating high blood pressure alone; in comparison, Aronne said, regulating weight is “far more complicated.” The future, rife with options, holds promise that No-zempics may find a way forward. Yet considering all the unknowns about obesity and what causes it, that may not be enough to guarantee that they will see the results they want.

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Yasmin Tayag

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February 9, 2024
Ozempic in Teens Is a Confusing Mess

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Somehow, America’s desire for Ozempic is only growing. The drug’s active ingredient, semaglutide, is sold as an obesity medication under the brand name Wegovy—and it has become so popular that its manufacturer, Novo Nordisk, recently limited shipments to the U.S. and paused advertising to prevent shortages. Its promise has enticed would-be patients and set off a pharmaceutical arms race to create more potent drugs.

Part of the interest stems from Ozempic’s potential in teens: In December, the FDA approved Wegovy as a treatment for teenagers with obesity, which affects 22 percent of 12-to-19-year-olds in the United States. The drug’s ability to spur weight loss in adolescents has been described as “mind-blowing.” In January, in its new childhood-obesity-treatment guidelines, the American Academy of Pediatrics (AAP) recommended that doctors consider adding weight-loss drugs such as semaglutide as a treatment for some patients.

But although many doctors and obesity experts have embraced semaglutide as a treatment for adults, some are concerned that taking it at such a young age—and at such a precarious stage of life—could pose serious risks, especially because the long-term physical and mental-health effects of the medication are still unknown. Others, however, believe that not using this medication in adolescents is riskier, because obesity makes teens vulnerable to serious health conditions and premature death. In part because of the apprehension among doctors, prescriptions for semaglutide in teens are not taking off like they are for adults. At this point, whether these drugs will ever catch on as a treatment for teens remains deeply uncertain.

Semaglutide isn’t just effective for teens; it may be even more effective than it is in adults. In a large Novo Nordisk–funded study published in The New England Journal of Medicine, “the degree of weight reduction in adolescents was better than what was observed in the adult trials,” Aaron S. Kelly, a co-director of the Center for Pediatric Obesity Medicine at the University of Minnesota Medical School, told me. In another Novo Nordisk–funded study published last week, a team led by Kelly showed that the drug, combined with counseling and exercise, nearly halved the number of teens with obesity after they received 68 weeks of treatment. Both for adolescents and adults, the weekly injection doesn’t “magically melt away body fat,” Kelly said; instead, it works by triggering a sense of fullness and quieting hunger pangs.

Teenagers’ experience with obesity is different—in some ways more intense—than that of older people. Puberty is a time of lots of growth and development, so the body fights off attempts at weight loss “with every mechanism that it has,” Tamara Hannon, a pediatric endocrinologist at the Indiana University School of Medicine, told me. Teenagers may also have less control than adults over what they eat or how much activity they get, because these are largely circumscribed by their family and school, as well as by social pressure to conform to how their peers eat. “Making good choices means doing something different than the majority of the other kids,” Hannon said. “At every corner, there’s something that is in direct opposition to losing weight.”

Because obesity is a chronic disease, developing it early can be devastating. In many cases, it can result in illnesses such as type 2 diabetes and fatty liver at a young age. Children with obesity are five times more likely than their peers to have it in adulthood; as teens with obesity become adults with obesity, they can “develop very, very aggressive disease,” Fatima Stanford, an obesity-medicine physician at Massachusetts General Hospital and Harvard Medical School, told me. Weight-loss drugs give doctors the ability to intervene before the effects of obesity snowball, she said, which is why AAP’s new childhood-obesity guidelines advocate for using them as part of early, aggressive treatment—along with many hours of in-person health and lifestyle therapy. Used early enough, semaglutide or other medications could possibly reroute the trajectory of a teenager’s entire life.

But semaglutide could also possibly throw a teen’s trajectory off course. Because treatment is considered a lifelong endeavor—stopping usually leads to rapid weight regain—adolescents who start the medication will be taking it for many decades. “We have no way of knowing whether these drugs, used so early in life for so long, could have unanticipated adverse effects,” David Ludwig, an endocrinologist at Boston Children’s Hospital, told me. Although adults face many of the same unknowns, the risks for teens could be more severe, because their body and brain are in constant flux. Of particular concern are the drug’s potential impacts on physiological changes specific to adolescence. “We need to keep an eye on pubertal development and menstrual history for girls,” Hannon said. In addition, the drugs can lead to unsavory side effects such as gastrointestinal issues and may have other impacts, including significant muscle loss and rewiring of the brain’s reward circuitry. Scientists are just beginning to understand these effects; at this point, only two major studies have been conducted on semaglutide in teens, and neither has involved a long follow-up period.

The repercussions of semaglutide treatment on mental health, an important aspect of obesity care, are even less understood. Teens are “more likely than an adult to have intermittent access to medication,” Kathleen Miller, an adolescent-medicine specialist at Children’s Minnesota hospital, told me—and skipping several doses in a row could pose physical and well as psychological risks. Another concern is that the overall effect of taking semaglutide—a decreased appetite, which leads to eating less—is essentially the same as that of dieting. When teens go on very restrictive diets, whether or not they involve weight-loss medications, “we know that may be harmful to their mental health and promote disordered eating,” Hannon said. Because their brain is so plastic during puberty, “there’s a risk of ingraining those patterns in adolescence,” Miller said.

With so many unknowns, would teens with obesity be better off avoiding semaglutide? At least for now, many pediatricians are reluctant to prescribe it. “The idea of using anti-obesity pharmacotherapy was challenging even in adults a couple of years ago,” says Angela Fitch, an assistant professor at Harvard Medical School and the president of the Obesity Medicine Association; acceptance of its role in pediatric care is even further behind. But denying teens the drug, she told me, is the biggest risk: Teens develop an unhealthy mentality about their body when they don’t get help losing weight. Explaining to a teen that obesity is not their fault, and correcting the underlying biological issue with medication or other treatment, helps them to develop “a better body image about themselves,” she said.

None of the experts I spoke with flat-out said that semaglutide should never be used in adolescent treatment. Even those who were wary of the drug acknowledged that it might be medically appropriate in teens who really struggle with their weight and have little success losing it through any other means. That argument may only strengthen as more convenient drugs—or those with fewer side effects—are approved for teen use. This week, both Novo Nordisk and Pfizer announced that pill versions of these medications were successful in early trials.

Even without all of the answers on how this drug might affect teens in the long term, Fitch predicted that “the uptake of semaglutide and other anti-obesity medications in pediatric clinical care will be slow and gradual.” Eventually, they may come to be seen as just one of several weight-loss tools to help set up kids for healthier lives. Treating adolescent obesity shouldn’t be an “either-or” choice, Ludwig said: “It’s everything-and.” He has proposed that combining semaglutide with a low-carbohydrate diet, for example, could have synergistic effects on adolescent weight loss.

For the foreseeable future, semaglutide isn’t poised to take off for teens in the way that it has for adults. In spite of all the hype surrounding Ozempic, experts and their patients are left with a difficult choice based on different assessments of risk: what might happen if teens are treated with drugs, and what might happen if they’re not. Either way, teenagers have the most to benefit—and the most to lose.

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Yasmin Tayag

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May 25, 2023
Ozempic Is About to Be Old News

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All of a sudden, Ozempic is everywhere. The weight-loss drug that it contains, semaglutide, is a potent treatment for obesity, and Hollywood and TikTok celebrities have turned it into a sensation. In just a few months, the medication has been branded as “revolutionary” and “game-changing,” with the power to permanently alter society’s conceptions of fatness and thinness. Certainly, a drug like semaglutide could be all of those things: Never in the history of medicine has one so safely led to such dramatic weight loss in so many people.

But let’s not get ahead of ourselves. As weight-loss medications go, Ozempic is far from perfect. Though the drug has profound impacts, it requires weekly injections, a tolerance for uncomfortable side effects, and the stamina—not to mention the budget—for long-term treatment. (Ozempic has somehow become a catchall term for semaglutide but technically that product has gotten FDA sign-off only as a diabetes medication. A larger dose of semaglutide, marketed as Wegovy, has been approved for weight loss.)

Made by the Danish drugmaker Novo Nordisk, semaglutide dominates the U.S. weight-loss market right now, but its reign might be short-lived. The colossal demand for these drugs has spurred a competition in the pharmaceutical industry to develop even more potent and powerful medications. The first of them could become available as soon as this summer. For all its hype, semaglutide is the stepping stone and not the final destination of a new class of obesity drugs. Just how good they get, and how quickly, will go a long way in determining whether this pharmaceutical revolution actually meets its full promise.

In a sense, semaglutide hardly represents a major step forward in science. Diet drugs are nothing new, and even the category of pharmaceuticals that these new products belong to, called “GLP-1 agonists,” has been around for several years. These drugs mimic the hormone GLP-1 (glucagon-like peptide one) and bind to its receptor in the body. This triggers a sense of fullness associated with having just eaten, and also slows the release of food from the stomach. (It also increases insulin secretion, keeping blood sugar in check, which is why Ozempic is still intended as a diabetes drug.) Already, these pharmaceuticals have gotten better over time: A daily injection called liraglutide and sold as Saxenda, which was approved by the FDA in 2014 for obesity, leads to the loss of 5 to 10 percent of a person’s body weight in most cases. But one reason semaglutide took off in a way that liraglutide didn’t is that it can lead to weight loss of up to 20 percent. “Now you have a shot that’s once a week instead of every day, you’re making dramatic improvements, and people notice more,” Angela Fitch, the president of the Obesity Medicine Association and the chief medical officer of the obesity-care start-up Knownwell, told me.

But not everyone who takes these drugs can achieve that level of weight loss. More than 60 percent of those on Wegovy experience smaller changes, in part because the drug can’t account for the complex drivers of obesity that aren’t related to food. The next generation of drugs is reaching for more. The first leap forward is Mounjaro, known generically as tirzepatide, a diabetes drug from Eli Lilly that the FDA is expected to approve for weight loss this year. In one study, it led to 20 percent or more weight loss in up to 57 percent of peopl e who took the highest dose; The Wall Street Journal recently called it the “King Kong” of weight-loss drugs. People on Mounjaro tend to lose more weight more quickly and generally have a “better experience” than those on Wegovy, Keith Tapper, a biotech analyst at BMO Capital Markets, told me. It’s also cheaper, though by no means cheap, at roughly $980 for the highest-dose option, he said; a dose of Wegovy costs about $1,350.

These leaps in potency are happening on the molecular level. Like semaglutide, Mounjaro mimics the effects of GLP-1, but it also hits receptors for another hormone—GIP. That leads to even more weight loss by further attenuating focus on food and potentially also increasing the activity of a fat-burning enzyme, said Tapper. So-called dual-agonist drugs “offer a step change” in both weight loss and blood-sugar control, he added.

And why stop at two receptors when so many others are involved in regulating hunger? “This area is exploding in terms of research and testing different combinations of hormones,” which are still poorly understood, Shauna Levy, a professor specializing in bariatric surgery at Tulane University School of Medicine, told me. Eli Lilly has another drug in the works that targets three receptors; one from the drugmaker Amgen works by “putting the brakes” on the GIP receptor and “putting the gas” on GLP-1’s, a company spokesperson told me. Several other companies have already joined what some have dubbed a “race” to develop the next great obesity drug, in which Lilly, Pfizer, Amgen, Structure Therapeutics, and Viking Therapeutics are expected to be the front-runners, said Tapper.

The potency of weight-less drugs is not the only factor that will determine the shape of their future trajectory. Wegovy and Mounjaro injections are tolerable for most people, but they are less convenient than a pill. Making oral versions of these drugs isn’t as easy as packing everything into a capsule, though. Semaglutide is a molecule that gets chewed up in the stomach. For this reason, the semaglutide pill Rybelsus, which is already approved for diabetes, leads to far less dramatic weight loss than its injectable kin. But drugmakers are undeterred by this complication, because a pill even more powerful than semaglutide would no doubt have many customers. In January, Pfizer’s CEO Albert Bourla said that an oral weight-loss drug “unlocks the market,” which he estimated could eventually be worth $90 billion. Pfizer doesn’t have any weight-loss drugs yet but is developing a twice-daily GLP-1 agonist pill; Eli Lilly also has an oral version in the works. Tapper expects those drugs to become available in 2026, and a similar offering from Structure Therapeutics is likely to follow the next year.

Drugmakers will also likely vie to create drugs with fewer side effects. Novo Nordisk notes that gastrointestinal issues are common with semaglutide; accounts of horrible nausea, constipation, and vomiting have proliferated online. As one actor put it to New York Magazine, people on Ozempic are “shitting their brains out.” With Wegovy, more serious issues, such as pancreatitis, thyroid cancer, and kidney failure, are also possible but are considered rare. Although nothing to scoff at, side effects tend to subside with prolonged treatment and can usually be managed with help from a doctor, said both Fitch and Levy, who regularly prescribe semaglutide to patients with obesity. It’s possible, Levy added, that people experiencing really terrible effects may be getting their drugs from shady compounding pharmacies or even from other countries.

The fact that people are turning to sketchy outlets to get weight-loss drugs underscores the biggest issue with them: access. Medicare and most private insurance companies don’t cover anti-obesity drugs. (Such drugs are classified as “cosmetic” by the Centers for Medicare and Medicaid Services, and thus don’t qualify for coverage.) “I am hopeful that the price will come down with more competition,” Fitch told me. But there’s no guarantee that will happen: Competition typically makes a product cheaper over time, but research suggests that isn’t always the case in pharmaceuticals. Even if the drugs do become cheaper, they may not become cheap enough. The oral forms of these drugs, some of which could be available by 2026, are expected to cost about $500 a month, Tapper said. By 2030, the cost of obesity drugs could come down to about $350 a month, according to a recent Morgan Stanley analysis, which would still be out of reach for many Americans.

Levy estimates that the next five years will bring about a “huge explosion” of next-gen obesity drugs. In that case, the market will likely expand to accommodate a variety of drugs with different price points and efficacies. Some people may aim to lose 20 or more percent of their body weight; some may be content with less. The market is so diverse that it will likely “support a broad range of options,” said Tapper, such as cheaper, lower-dose oral drugs for people who have milder medical issues, and more expensive injectables for those with more severe medical concerns. That opens up the possibility that medically mediated weight loss could soon be an option for a far greater proportion of people.

Regardless of how much these drugs’ costs may decrease, they will always add up if people are paying out of pocket for them. They are meant to be taken long term: Once a person stops taking Wegovy, the weight tends to come right back. The current crop of weight-loss medications are essentially maintenance drugs, much like the cholesterol-busting drug Lipitor, which is taken daily to treat long-term disease. But Lipitor, unlike obesity drugs, is generally covered by insurance. Unless obesity drugs receive the same kind of coverage, no level of improvement will lead them to deliver on what Ozempic is promising us now.

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Yasmin Tayag

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April 4, 2023
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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December 21, 2022
Will the Bivalent Booster Cause Worse Side Effects?

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For as long as my marriage lasts, my household will be divided by reactions to vaccines.

I am, fortunately, speaking of physical reactions rather than ideological ones; my partner and I are both shot enthusiasts, a fact we verified on our first date. But if my immune system is a bashful wallflower, rarely triggering more than a sore arm in the hours after I get a vaccine, then my spouse’s is a party animal. Every immunization I’ve watched him receive—among them, four doses of Moderna’s COVID-19 vaccine—has absolutely clobbered him with fevers, chills, fatigue, and headaches for about a full day. When he got the flu shot and the bivalent COVID jab together a few weeks ago, he ended up taking his first day off work in more than a decade. As usual, the same injections caused me so few symptoms that I wondered if I was truly dead inside.

“Why don’t you feel anything?” my spouse howled at me from the bedroom, where his sweat was soaking through the sheets. “Sorry,” I yelled back from the kitchen, where I was prepping four days’ worth of meals between work calls after returning from an eight-mile run.

If this is how every autumn will go from now on, so be it: A few hours of discomfort is still worth the rev-up in defenses that vaccines offer against serious disease and death. But it’s not hard to see that gnarly side effects will only add to the many other factors that work against COVID-vaccine uptake, including lack of awareness, sloppy messaging, dwindling access, and spotty community outreach. Back in the spring, when I spoke with several people who hadn’t gotten boosters despite being eligible for many, many months, several of them cited the post-shot discomfort as a reason. Now I’m getting texts and calls from family members and friends—all up to date on their previous COVID vaccines—admitting they’ve been dillydallying on the bivalent to avoid those symptoms too. “I don’t know if we’re going to continue to get strong buy-in from the public if they have this sort of reaction every year,” says Cindy Leifer, an immunologist at Cornell University.

Read: America created its own booster problems

The good news, at least, is that experts told me they don’t expect this bivalent recipe—or future autumn COVID shots, for that matter—to be worse, side-effect-wise, than the ones we’ve received before. It’ll take a while for data to confirm that, especially considering that more than a month into this fall’s rollout, fewer than 15 million Americans have received the updated shot. But Kathleen Neuzil, a vaccinologist at the University of Maryland School of Medicine who has studied the performance of COVID vaccines in clinical trials, pointed out to me that the mRNA shots’ ingredients have been swapped out before without altering the rate of side effects. As the alphabet soup of variants began to sweep the world in early 2021, she told me, vaccine makers started to tinker with alternate formulations, sometimes combining multiple versions of the spike protein into a single shot—“and they’re all comparable.” (If anything, early data suggest that bivalent shots containing an Omicron variant spike may be easier to take.) The same goes for flu vaccines, which are also retooled each year: When measured across the population, the frequency and intensity of side effects remain more or less the same.

On average, then, mRNA-vaxxed people can probably expect to have an annual experience that’s pretty similar to the one they had with their first COVID booster. As studies have shown, that one was actually better for most people than dose No. 2, the most unpleasant of the injections so far. (The math, of course, becomes tougher for people getting another vaccine, such as the flu shot, at the same time.) There are probably two main reasons why side effects have lessened overall, experts told me. First, the spacing: Most people received the second dose in their Pfizer or Moderna primary series just three or four weeks after the first. That’s an efficient way to get a lot of people “fully vaccinated” in a short period of time, but it means that many of the immune system’s defensive cells and molecules will still be on high alert. The second shot could end up fanning a blaze of inflammation that was never quite put out. In line with that, researchers have found that spacing out the primary-series doses to eight weeks, 12 weeks, or even longer can prune some side effects.

Dose matters a lot too: Vaccines are, in a way, stimulants meant to goad the immune system into reacting; bigger servings should induce bigger jolts. When vaccine makers were tinkering with their recipes in early trials, higher doses—including ones that were deemed too large for further testing—produced more side effects. Each injection in Moderna’s primary series contains more than three times the mRNA packaged into Pfizer’s, and Moderna has, on average, caused more intense side effects. But Moderna’s booster and bivalent doses contain a smaller scoop of the stimulating material: People 12 and older, for instance, get 50 micrograms instead of the 100 micrograms in each primary dose; kids 6 to 11 years old get 25 micrograms instead of 50. (All of Pfizer’s doses stay the same size across primaries and boosters, as long as people stay in the same age group.) People who switch between brands, then, may also notice a difference in symptoms.

It’s a tricky balance, though. Sometimes, the immune system adjusts the magnitude of its protection to match the danger posed by a pathogen (or shot), a bit like titrating a crisis response to the severity of a threat—so it’s important that vaccine makers don’t undershoot. For better or worse, the mRNA-based COVID vaccines do seem to cause a rougher response than most other vaccines, including annual flu shots. One of the offending ingredients might be the mRNA itself, which codes for SARS-CoV-2’s spike protein. But Michela Locci, an immunologist at the University of Pennsylvania, told me that the mRNA’s packaging—a greasy fat bubble called a lipid nanoparticle—may be the more likely culprit. For some people, in any case, the side effects of COVID shots might be on par with those of the two-dose Shingrix vaccine, one of the most infamously reactogenic immunizations in our roster. Leifer, who has received both, told me the second dose of each “floored” her to about the same extent.

The fact that I get fewer side effects than my spouse does not imply that I’m any less protected. A ton of factors—genetics, hormone levels, age, diet, sleep, stress, pain tolerance, and more—could potentially influence how someone experiences a shot. Women tend to have more reactive bodies, as do younger people. But there are exceptions to those trends: I’m one of them. The whole topic is understudied, Locci told me. Her own recent experience with the bivalent threw her for a loop. After her first, second, and third dose of Moderna each ratcheted up in side-effect severity, she cleared her calendar for the couple of days following her bivalent, “afraid I was going to be in bed with a fever again,” she said: “But it was a light headache for a morning, and then it was over.” She has no idea what next year will bring.

Either way, side effects such as fevers and chills tend to be short-lived. “Very few side effects are severe,” Neuzil told me, “and COVID continues to be a severe disease.” Still, Grace Lee, a pediatrician at Stanford and the chair of the CDC’s Advisory Committee on Immunization Practices, hopes that scientists will keep developing new COVID vaccines that might come with fewer post-shot issues—including the very rare ones, such as myocarditis—without sacrificing immune protection. Lee doesn’t tend to react much to vaccines, but her daughter “always misses school the next day,” she told me. “I plan her shots for a Friday afternoon so she can lay out all Saturday.” Early on, when hardly anyone had immunity to the virus, signing everyone up for somewhat reactogenic shots was a no-brainer—especially given the hope that two doses would yield many, many years of protection. Now that we know it’s a repeated need, Neuzil said, “the equation changes a bit.”

People aren’t totally helpless against side effects. Deepta Bhattacharya, an immunologist at the University of Arizona, had an “awful, terrible” experience with his second and third doses, which slammed him with 102- and 103-degree fevers, respectively. He weathered the side effects without intervention, worried that a painkiller would curb not just the agony, but also his protective immune response. This time, though, armed with new knowledge from his own lab that anti-inflammatory and pain-relieving drugs don’t blunt antibody levels, “the first sign I feel even the slightest bit shitty,” he told me, “I’m dosing up.”

I’ll probably do the same for my spouse the next time he’s due for a vaccine of any kind … likely while I chill on the sidelines. Bhattacharya’s spouse, too, is kind of an immune introvert, a fact that he bemoans. “Her only side effect was she felt thirsty,” he said. “It’s just not fair.”

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Katherine J. Wu

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October 21, 2022