Tag: Washington University

Norovirus Is Almost Impossible to Stop

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

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

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

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

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

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

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

Read: Whatever happened to toilet plumes?

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

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

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

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

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

Read: The stomach-flu mystery

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

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

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Katherine J. Wu

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February 18, 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
When’s the Perfect Time to Get a Flu Shot?

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For about 60 years, health authorities in the United States have been championing a routine for at least some sector of the public: a yearly flu shot. That recommendation now applies to every American over the age of six months, and for many of us, flu vaccines have become a fixture of fall.

The logic of that timeline seems solid enough. A shot in the autumn preps the body for each winter’s circulating viral strains. But years into researching flu immunity, experts have yet to reach a consensus on the optimal time to receive the vaccine—or even the number of injections that should be doled out.

Each year, a new flu shot recipe debuts in the U.S. sometime around July or August, and according to the CDC the best time for most people to show up for an injection is about now: preferably no sooner than September, ideally no later than the end of October. Many health-care systems require their employees to get the shot in this time frame as well. But those who opt to follow the CDC current guidelines, as I recently did, then mention that fact in a forum frequented by a bunch of experts, as I also recently did, might rapidly hear that they’ve made a terrible, terrible choice.

“There’s no way I would do what you did,” one virologist texted me. “It’s poor advice to get the flu vaccine now.” Florian Krammer, a virologist at Mount Sinai’s Icahn School of Medicine, echoed that sentiment in a tweet: “I think it is too early to get a flu shot.” When I prodded other experts to share their scheduling preferences, I found that some are September shooters, but others won’t juice up till December or later. One vaccinologist I spoke with goes totally avant-garde, and nabs multiple doses a year.

Read: Should your flu and COVID shots go in different arms?

There is definitely such a thing as getting a flu shot too early, as Helen Branswell has reported for Stat. After people get their vaccine, levels of antibodies rocket up, buoying protection against both infection and disease. But after only weeks, the number of those molecules begins to steadily tick downward, raising people’s risk of developing a symptomatic case of flu by about 6 to 18 percent, various studies have found. On average, people can expect that a good portion of their anti-flu antibodies “are meaningfully gone by about three or so months” after a shot, says Lauren Rodda, an immunologist at the University of Washington.

That decline is why some researchers, Krammer among them, think that September and even October shots could be premature, especially if flu activity peaks well after winter begins. In about three-quarters of the flu seasons from 1982 to 2020, the virus didn’t hit its apex until January or later. Krammer, for one, told me that he usually waits until at least late November to dose up. Stanley Plotkin, a 90-year-old vaccinologist and vaccine consultant, has a different solution. People in his age group—over 65—don’t respond as well to vaccines in general, and seem to lose protection more rapidly. So for the past several years, Plotkin has doubled up on flu shots, getting one sometime before Halloween and another in January, to ensure he’s chock-full of antibodies throughout the entire risky, wintry stretch. “The higher the titers,” or antibody levels, Plotkin told me, “the better the efficacy, so I’m trying to take advantage of that.” (He made clear to me that he wasn’t “making recommendations for the rest of the world”—just “playing the odds” given his age.)

Data on doubling up is quite sparse. But Ben Cowling, an epidemiologist and flu researcher at Hong Kong University, has been running a years-long study to figure out whether offering two vaccines a year, separated by roughly six months, could keep vulnerable people safe for longer. His target population is Hong Kongers, who often experience multiple annual flu peaks, one seeded by the Northern Hemisphere’s winter wave and another by the Southern Hemisphere’s. So far, “getting that second dose seems to give you additional protection,” Cowling told me, “and it seems like there’s no harm of getting vaccinated twice a year,” apart from the financial and logistical cost of a double rollout.

Read: The strongest sign that Americans should worry about flu this winter

In the U.S., though, flu season is usually synonymous with winter. And the closer together two shots are given, the more blunted the effects of the second injection might be: People who are already bustling with antibodies may obliterate a second shot’s contents before the vaccine has a chance to teach immune cells anything new. That might be why several studies that have looked at double-dosing flu shots within weeks of each other “showed no benefit” in older people and certain immunocompromised groups, Poland told me. (One exception? Organ–transplant recipients. Kids getting their very first flu shot are also supposed to get two of them, four weeks apart.)

Even at the three-ish-month mark past vaccination, the body’s anti-flu defenses don’t reset to zero, Rodda told me. Shots shore up B cells and T cells, which can survive for many months or years in various anatomical nooks and crannies. Those arsenals are especially hefty in people who have banked a lifetime of exposures to flu viruses and vaccines, and they can guard people against severe disease, hospitalization, and death, even after an antibody surge has faded. A recent study found that vaccine protection against flu hospitalizations ebbed by less than 10 percent a month after people got their shot, though the rates among adults older than 65 were a smidge higher. Still other numbers barely noted any changes in post-vaccine safeguards against symptomatic flu cases of a range of severities, at least within the first few months. “I do think the best protection is within three months of vaccination,” Cowling told me. “But there’s still a good amount by six.”

For some young, healthy adults, a decent number of flu antibodies may actually stick around for more than a year. “You can test my blood right now,” Rodda told me. “I haven’t gotten vaccinated just yet this year, and I have detectable titers.” Ali Ellebedy, an immunologist at Washington University in St. Louis, told me he has found that some people who have regularly received flu vaccines have almost no antibody bump when they get a fresh shot: Their blood is already hopping with the molecules. Preexisting immunity also seems to be a big reason that nasal-spray-based flu vaccines don’t work terribly well in adults, whose airways have hosted far more flu viruses than children’s.

Getting a second flu shot in a single season is pretty unlikely to hurt. But Ellebedy compares it to taking out a second insurance policy on a car that’s rarely driven: likely of quite marginal benefit for most people. Plus, because it’s not a sanctioned flu-vaccine regimen, pharmacists might be reluctant to acquiesce, Poland pointed out. Double-dosing probably wouldn’t stand much of a chance as an official CDC recommendation, either. “We do a bad enough job,” Poland said, getting Americans to take even one dose a year.

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

That’s why the push to vaccinate in late summer and early fall is so essential for the single shot we currently have, says Huong McLean, a vaccine researcher at the Marshfield Clinic Research Institute in Wisconsin. “People get busy, and health systems are making sure that most people can get protected before the season starts,” she told me. Ellebedy, who’s usually a September vaccinator, told me he “doesn’t see the point of delaying vaccination for fear of having a lower antibody level in February.” Flu seasons are unpredictable, with some starting as early as October, and the viruses aren’t usually keen on giving their hosts a heads-up. That makes dillydallying a risk: Put the shot off till November or December, and “you might get infected in between,” Ellebedy said—or simply forget to make an appointment at all, especially as the holidays draw near.

In the future, improvements to flu-shot tech could help cleave off some of the ambiguity. Higher doses of vaccine, which are given to older people, could rile up the immune system to a greater degree; the same could be true for more provocative vaccines, made with ingredients called adjuvants that trip more of the body’s defensive sensors. Injections such as those seem to “maintain higher antibody titers year-round,” says Sophie Valkenburg, an immunologist at Hong Kong University and the University of Melbourne—a trend that Ellebedy attributes to the body investing more resources in training its fighters against what it perceives to be a larger threat. Such a switch would likely come with a cost, though, McLean said: Higher doses and adjuvants “also mean more adverse events, more reactions to the vaccine.”

For now, the only obvious choice, Rodda told me, is to “definitely get vaccinated this year.” After the past two flu seasons, one essentially absent and one super light, and with flu-vaccination rates still lackluster, Americans are more likely than not in immunity deficit. Flu-vaccination rates have also ticked downward since the coronavirus pandemic began, which means there may be an argument for erring on the early side this season, if only to ensure that people reinforce their defenses against severe disease, Rodda said. Plus, Australia’s recent flu season, often a bellwether for ours, arrived ahead of schedule.

Even so, people who vaccinate too early could end up sicker in late winter—in the same way that people who vaccinate too late could end up sicker now. Plotkin told me that staying apprised of the epidemiology helps: “If I heard influenza outbreaks were starting to occur now, I would go and get my first dose.” But timing remains a gamble, subject to the virus’s whims. Flu is ornery and unpredictable, and often unwilling to be forecasted at all.

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Katherine J. Wu

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September 26, 2022
Should Your Flu and COVID Shots Go in Different Arms?

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At a press briefing earlier this month, Ashish Jha, the White House’s COVID czar, laid out some pretty lofty expectations for America’s immunity this fall. “Millions” of Americans, he said, would be flocking to pharmacies for the newest version of the COVID vaccine in September and October, at the same appointment where they’d get their yearly flu shot. “It’s actually a good idea,” he told the press. “I really believe this is why God gave us two arms.”

That’s how I got immunized last week at my local CVS: COVID shot on the left, flu shot on the right. I spent the next day or so nursing not one but two achy upper arms. Reaching high shelves was hard; putting on deodorant was worse. And it did make me wonder what would have happened if I’d ignored Jha’s teleological advice and gotten both jabs in the same arm. Maybe my annoyance would have been lessened. Or perhaps the same-side shots would have made the soreness in my left arm way worse. When I posed this puzzle to immunologists, vaccinologists, and pharmacists, I got back a lot of hems and haws. For the millions of Americans who will be getting two-shot appointments by fall’s end, they told me, the choice really does come down to personal preference in the absence of clear data: You’ve just gotta pick a side. Or, you know, two.

On the one hand (sorry), there are the vaccine double-downers. Sallie Permar, a pediatrician at Weill Cornell Medicine, and Stephanie Langel, an immunologist at Duke University, both said they’d probably get both shots in the same shoulder; so would Rishi Goel, an immunologist at the University of Pennsylvania. “Personally, I’d rather have one arm that’s slightly uncomfortable than both,” Goel told me.

On the other hand, we’ve got Team Divide-and-Conquer. Several experts said they’d follow the White House protocol of splitting shots left and right. Ali Ellebedy, an immunologist at Washington University in St. Louis, told me he’d prefer to have two slightly sore arms to one totally dead one. Jacinda Abdul-Mutakabbir, a pharmacist at Loma Linda University, says she generally recommends that her patients get the vaccines on separate sides “for comfort.” Last year, she opted to get the flu shot and a COVID booster within a few inches of each other, and “I wanted to chop my arm off,” she told me. “Never again.”

Read: America’s fall booster plan has a fatal paradox

The deciding logic here should be pretty intuitive, Permar told me. Two shots on one side might be expected to double how sore that arm will get, though the experience of each vaccine recipient will depend on a bevy of factors, including the ingredients in the shots and that person’s infection and vaccination history, as well as their immune-system health. Also, for people like my husband—who’s prone to very heavy vaccine side effects—the choice may not matter at all. He was so knocked out by the fever and chills that came with his COVID-flu-shot combo, he couldn’t have cared less which arms got the shots.

I dug around for studies examining the consequences of the one-versus-two-arm choice and found only one: a Canadian trial from 2003, which vaccinated a few hundred sixth-graders at two dozen middle schools against group C meningitis and hepatitis B at the same time. Roughly half the kids got both shots in the same arm; the others received one on each side. (Some kids in the latter group requested that their shots be administered by a pair of nurses who could plunge both syringes at the same time.) Among students in the same-arm group, 18 percent ended up with tenderness at the injection site that they rated “moderate or severe.” But those kids fared better than the ones in the two-arm group, 28 percent of whom experienced moderate or severe tenderness in at least one arm, and 8 percent of whom had it in both arms at the same time.

But those results apply only to that group of kids in that setting, with those two specific vaccines; there’s no telling whether the same trends would be seen with flu shots and COVID shots when given to children or adults. Michela Locci, an immunologist at the University of Pennsylvania, told me she suspects that combining flu and COVID inoculations in the same arm could actually drive extra side effects: “The overall inflammation might be higher,” she said.

Many pediatricians, who often have to administer four or five shots to a baby at once, are habitual splitters. “If there’s more than one vaccine syringe to give to a baby, generally, two legs are used,” Permar told me. (Kids usually upgrade to arm shots sometime in toddlerhood—it’s all about finding a muscle that’s big enough for the needle to hit its mark.) Doctors also have a nerdy reason to split shots between arms or legs. “If there’s a local reaction to the vaccine,” Permar said, “you can identify which vaccine it was if you separate them by space.” (For the record, I had a more painful reaction in my left arm, where I got the COVID shot. Others I’ve spoken with have reported the same disparity.)

Read: Families are going rogue with rapid tests

The CDC advocates for separating vaccination shots by at least one inch of space. Per the agency, if a COVID shot is being given at the same time as a vaccine “that might be more likely to cause a local injection site reaction,” the shots should be dosed into “different limbs, if possible.” Two types of flu shots cleared for use in people 65 years and older—the high-dose vaccine and the adjuvanted one—fall into that category. But the different-limb advice doesn’t seem to apply to other flu shots, including those cleared for use in younger adults and kids.

However someone ends up taking simultaneous flu and COVID shots, the placement is unlikely to affect how much protection the vaccines provide. There could be an argument for letting “each side focus on its own thing,” says Gabriel Victora, an immunologist at Rockefeller University. “But it probably doesn’t make a whole lot of difference.” Children routinely get combo vaccines, such as DTaP and MMR, each of which combines multiple disease-fighting ingredients in a single syringe. The triple-threat formulas work just as well as injecting their individual parts. The immune system is used to multitasking: It spends all day being bombarded by microbes, so there’s good reason to believe that with vaccines, too, our body will see simultaneous shots “as independent events,” Goel told me.

Which arm gets picked for which shot, though, will affect where the jab’s contents end up. After a vaccine is injected, its immunity-inducing ingredients meander to the nearest lymph node, such as the ones in the armpits. There, hordes of immune cells fight over the vaccine’s bits, and the fittest and fiercest among them are selected to leave the lymph node and fight. Here, again, doubling up on one arm shouldn’t be an issue, Goel said: The immune-cell boot camps in these lymph nodes have “a good amount of real estate.”

It might even be a good idea to stick the same limb—and thereby, the same lymph node—every time you get another dose of a particular vaccine. After immune cells in a lymph node spot a particular bit of pathogen, some of them march off into battle, but others may hang around like reserve troops, mulling over what they’ve learned. A couple of recent studies, one of them in mice, hint that repeated delivery of the same ingredients to those veteran learners could give the body a slight edge—though the extent of that advantage “might be marginal,” Victora told me. Still, Langel, of Duke, told me jokingly that because she usually gets all of her vaccines in her “non-writing” arm, the lymph node beneath it could now be especially superpowered—a “nice bonus” for her defenses on the whole.

That said, no one should stress too much about getting a shot in the “wrong” arm. “It’s not like you’re immune on the left side and not on the right side,” Goel told me. Immune cells travel throughout the body; there is no midline DMZ. Permar even points out that getting the newly formulated COVID vaccine, which includes new ingredients tailored to fight Omicron subvariants, on the opposite side from the previous rounds could help its ingredients reach a fresher slate of cells. “I think you could convince yourself either way,” she told me. Which, honestly, leaves me totally at peace with my choice. Apart from arm achiness, I had no other side effects—and in a way, I preferred the symmetry of the one-on-each-side injections.

With all that said, it’s worth briefly acknowledging a third option: Splitting the flu and COVID vaccines into separate visits. I was, before my most recent COVID shot, some 10 months out from my previous dose. But it felt awfully early for my flu shot, which might be better timed for peak protection if taken later in the season. Still, the allure of getting it all over with was too tantalizing, especially because I happen to have a lot of travel up ahead. In the grand scheme of things, the bigger, more important choice was opting into the shots at all.

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Katherine J. Wu

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September 15, 2022