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  • Will the Bivalent Booster Cause Worse Side Effects?

    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.

    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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  • Warning Signs About the First Post-pandemic Winter

    Warning Signs About the First Post-pandemic Winter

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    This fall, unlike the one before it, and the one before that, America looks almost like its old self. Schools and universities are in session; malls, airports, and gyms are bustling with the pre-holiday rush; handwashing is passé, handshakes are back, and strangers are packed together on public transport, nary a mask to be seen. On its surface, the country seems ready to enjoy what some might say is our first post-pandemic winter.

    Americans are certainly acting as if the crisis has abated, and so in that way, at least, you could argue that it has. “If you notice, no one’s wearing masks,” President Joe Biden told 60 Minutes in September, after proclaiming the pandemic “over.” Almost no emergency protections against the virus are left standing; we’re dismantling the few that are. At the same time, COVID is undeniably, as Biden says, “a problem.” Each passing day still brings hundreds of deaths and thousands of hospitalizations; untold numbers of people continue to deal with long COVID, as more join them. In several parts of the country, health-care systems are struggling to stay afloat. Local public-health departments, underfunded and understaffed, are hanging by a thread. And a double surge of COVID and flu may finally be brewing.

    So we can call this winter “post-pandemic” if we want. But given the policy failures and institutional dysfunctions that have accumulated over the past three years, it won’t be anything like a pre-pandemic winter, either. The more we resist that reality, the worse it will become. If we treat this winter as normal, it will be anything but.


    By now, we’ve grown acquainted with the variables that dictate how a season with SARS-CoV-2 will go. In our first COVID winter, the vaccines had only just begun their trickle out into the public, while most Americans hadn’t yet been infected by the virus. In our second COVID winter, the country’s collective immunity was higher, but Omicron sneaked past some of those defenses. On the cusp of our third COVID winter, it may seem that SARS-CoV-2 has few plot twists left to toss us.

    But the way in which we respond to COVID could still sprinkle in some chaos. During those first two winters, at least a few virus-mitigating policies and precautions remained in place—nearly all of which have since come down, lowering the hurdles the virus must clear, at a time when America’s health infrastructure is facing new and serious threats.

    The nation is still fighting to contain a months-long monkeypox outbreak; polio continues to plague unvaccinated sectors of New York. A riot of respiratory viruses, too, may spread as temperatures cool and people flock indoors. Rates of RSV are rising; flu returned early in the season from a nearly three-year sabbatical to clobber Australia, boding poorly for us in the north. Should flu show up here ahead of schedule, Americans, too, could be pummeled as we were around the start of 2018, “one of the worst seasons in the recent past,” says Srinivasan Venkatramanan, an infectious-disease modeler at the University of Virginia and a member of the COVID-19 Scenario Modeling Hub.

    The consequences of this infectious churn are already starting to play out. In Jackson, Mississippi, health workers are watching SARS-CoV-2 and other respiratory viruses tear through children “like nothing we’ve ever seen before,” says Charlotte Hobbs, a pediatric-infectious-disease specialist at the University of Mississippi Medical Center. Flu season has yet to go into full swing, and Hobbs is already experiencing one of the roughest stretches she’s had in her nearly two decades of practicing. Some kids are being slammed with one virus after the other, their sicknesses separated by just a couple of weeks—an especially dangerous prospect for the very youngest among them, few of whom have received COVID shots.

    The toll of doctor visits missed during the pandemic has ballooned as well. Left untreated, many people’s chronic conditions have worsened, and some specialists’ schedules remain booked out for months. Add to this the cases of long COVID that pile on with each passing surge of infections, and there are “more sick people than there used to be, period,” says Emily Landon, an infectious-disease physician at the University of Chicago. That’s with COVID case counts at a relative low, amid a massive undercount. Even if a new, antibody-dodging variant doesn’t come banging on the nation’s door, “the models predict an increase in infections,” Venkatramanan told me. (In parts of Europe, hospitalizations are already making a foreboding climb.)

    And where the demand for care increases, supply does not always follow suit. Health workers continue to evacuate their posts. Some have taken early retirement, worried that COVID could exacerbate their chronic conditions, or vice versa; others have sought employment with better hours and pay, or left the profession entirely to salvage their mental health. A wave of illness this winter will pare down forces further, especially as the CDC backs off its recommendations for health-care workers to mask. At UAB Hospital, in Birmingham, Alabama, “we’ve struggled to have enough people to work,” says Sarah Nafziger, an emergency physician and the medical director for employee health. “And once we get them here, we have a hard time getting them to stay.”

    Clinical-laboratory staff at Deaconess Hospital, in Indiana, who are responsible for testing patient samples, are feeling similar strain, says April Abbott, the institution’s microbiology director. Abbott’s team has spent most of the past month below usual minimum-staffing levels, and has had to cut some duties and services to compensate, even after calling in reinforcements from other, already shorthanded parts of the lab. “We’re already at this threshold of barely making it,” Abbott told me. Symptoms of burnout have surged as well, while health workers continue to clock long hours, sometimes amid verbal abuse, physical attacks, and death threats. Infrastructure is especially fragile in America’s rural regions, which have suffered hospital closures and an especially large exodus of health workers. In Madison County, Montana, where real-estate values have risen, “the average nurse cannot afford a house,” says Margaret Bortko, a nurse practitioner and the region’s health officer and medical director. When help and facilities aren’t available, the outcome is straightforward, says Janice Probst, a rural-health researcher at the University of South Carolina: “You will have more deaths.”

    In health departments, too, the workforce is threadbare. As local leaders tackle multiple infectious diseases at once, “it’s becoming a zero-sum game,” says Maria Sundaram, an epidemiologist at the Marshfield Clinic Research Institute. “With limited resources, do they go to monkeypox? To polio? To COVID-19? To influenza? We have to choose.” Mati Hlatshwayo Davis, the director of health in St. Louis, told me that her department has shrunk to a quarter of the size it was five years ago. “I have staff doing the jobs of three to five people,” she said. “We are in absolute crisis.” Staff have left to take positions as Amazon drivers, who “make so much more per hour.” Looking across her state, Hlatshwayo Davis keeps watching health directors “resign, resign, resign.” Despite all that she has poured into her job, or perhaps because of it, “I can’t guarantee I won’t be one of those losses too.”


    This winter is unlikely to be an encore of the pandemic’s worst days. Thanks to the growing roster of tools we now have to combat the coronavirus—among them, effective vaccines and antivirals—infected people are less often getting seriously sick; even long COVID seems to be at least a bit scarcer among people who are up-to-date on their shots. But considering how well our shots and treatments work, the plateau of suffering at which we’ve arrived is bizarrely, unacceptably high. More than a year has passed since the daily COVID death toll was around 200; nearly twice that number—roughly three times the daily toll during a moderate flu season—now seems to be a norm.

    Part of the problem remains the nation’s failed approach to vaccines, says Avnika Amin, a vaccine epidemiologist at Emory University: The government has repeatedly championed shots as a “be-all and end-all” strategy, while failing to rally sufficient uptake. Boosting is one of the few anti-COVID measures still promoted, yet the U.S. remains among the least-vaccinated high-income countries; interest in every dose that’s followed the primary series has been paltry at best. Even with the allure of the newly reformulated COVID shot, “I’m not really getting a good sense that people are busting down the doors,” says Michael Dulitz, a health worker in Grand Forks, North Dakota. Nor can vaccines hold the line against the virus alone. Even if everyone got every shot they were eligible for, Amin told me, “it wouldn’t make COVID go away.”

    The ongoing dry-up of emergency funds has also made the many tools of disease prevention and monitoring more difficult to access. Free at-home tests are no longer being shipped out en masse; asymptomatic testing is becoming less available; and vaccines and treatments are shifting to the private sector, putting them out of reach for many who live in poor regions or who are uninsured and can least afford to fall ill.

    It doesn’t help, either, that the country’s level of preparedness lays out as a patchwork. People who vaccinate and mask tend to cluster, Amin told me, which means that not all American experiences of winter will be the same. Less prominent, less privileged parts of the country will quietly bear the brunt of outbreaks. “The biggest worry is the burden becoming unnoticed,” Venkatramanan told me. Without data, policies can’t change; the nation can’t react. “It’s like flying without altitude or speed sensors. You’re looking out the window and trying to guess.”


    There’s an alternative winter the country might envision—one unencumbered by the policy backslides the U.S. has made in recent months, and one in which Americans acknowledge that COVID remains not just “a problem” but a crisis worth responding to.

    In that version of reality, far more people would be up-to-date on their vaccines. The most vulnerable in society would be the most protected. Ventilation systems would hum in buildings across the country. Workers would have access to ample sick leave. Health-care systems would have excesses of protective gear, and local health departments wouldn’t want for funds. Masks would come out in times of high transmission, especially in schools, pharmacies, government buildings, and essential businesses; free tests, boosters, and treatments would be available to all. No one would be asked to return to work while sick—not just with COVID but with any transmissible disease. SARS-CoV-2 infections would not disappear, but they would remain at more manageable levels; cases of flu and other cold-weather sicknesses that travel through the air would follow suit. Surveillance systems would whir in every state and territory, ready to detect the next threat. Leaders might even set policies that choreograph, rather than simply capitulate to, how Americans behave.

    We won’t be getting that winter this year, or likely any year soon. Many policies have already reverted to their 2019 status quo; by other metrics, the nation’s well-being even seems to have regressed. Life expectancy in the U.S. has fallen, especially among Native Americans and Alaskan Natives. Institutions of health are beleaguered; community-outreach efforts have been pruned.

    The pandemic has also prompted a deterioration of trust in several mainstays of public health. In many parts of the country, there’s worry that the vaccine hesitancy around COVID has “spread its tentacles into other diseases,” Hobbs told me, keeping parents from bringing their kids in for flu shots and other routine vaccines. Mississippi, once known for its stellar rate of immunizing children, now consistently ranks among those with the fewest young people vaccinated against COVID. “The one thing we do well is vaccinate children,” Hobbs said. That the coronavirus has reversed the trend “has astounded me.” In Montana, sweeping political changes, including legislation that bans employers from requiring vaccines of any kind, have made health-care settings less safe. Fewer than half of Madison County’s residents have received even their primary series of COVID shots, and “now a nurse can turn down the Hepatitis B series,” Bortko told me. Health workers, too, feel more imperiled than before. Since the start of the pandemic, Bortko’s own patients of 30 years, “who trusted me with their lives,” have pivoted to “yelling at us about vaccination concerns and mask mandates and quarantining and their freedoms,” she told me. “We have become public enemy No. 1.”

    At the same time, many people with chronic and debilitating conditions are more vulnerable than they were before the pandemic began. The policies that protected them during the pandemic’s height are gone—and yet SARS-CoV-2 is still here, adding to the dangers they face. The losses have been written off, Bortko told me: Cases of long COVID in Madison County have been dismissed as products of “risk factors” that don’t apply to others; deaths, too, have been met with a shrug of “Oh, they were old; they were unhealthy.” If, this winter, COVID sickens or kills more people who are older, more people who are immunocompromised, more people of color, more essential and low-income workers, more people in rural communities, “there will be no press coverage,” Hlatshwayo Davis said. Americans already expect that members of these groups will die.

    It’s not too late to change course. The winter’s path has not been set: Many Americans are still signing up for fall flu and COVID shots; we may luck out on the viral evolution front, too, and still be dealing largely with members of the Omicron clan for the next few months. But neither immunity nor a slowdown in variant emergence is a guarantee. What we can count on is the malleability of human behavior—what will help set the trajectory of this winter, and others to come. The U.S. botched the pandemic’s beginning, and its middle. That doesn’t mean we have to bungle its end, whenever that truly, finally arrives.

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    Katherine J. Wu

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