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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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    Sarah Zhang

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  • America’s COVID Booster Rates Are a Bad Sign for Winter

    America’s COVID Booster Rates Are a Bad Sign for Winter

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    And just like that, with the passing of Labor Day, fall was upon us. Seemingly overnight, six-packs of pumpkin beer materialized on grocery shelves, hordes of city dwellers descended upon apple orchards—and America rolled out new COVID boosters. The timing wasn’t a coincidence. Since the beginning of the pandemic, cases in North America and Europe have risen during the fall and winter, and there was no reason to expect anything different this year. Spreading during colder weather is simply what respiratory diseases like COVID do. The hope for the fall booster rollout was that Americans would take it as an opportunity to supercharge their immunological defenses against the coronavirus in advance of a winter wave that we know is going to come.

    So far, reality isn’t living up to that hope. Since the new booster became available in early September, fewer than 20 million Americans have gotten the shot, according to the CDC—just 8.5 percent of those who are eligible. The White House COVID-19 response coordinator, Ashish Jha, said at a press conference earlier this month that he expects booster uptake to increase in October as the temperatures drop and people start taking winter diseases more seriously. That doesn’t seem to be happening yet. America’s booster campaign is going so badly that by late September, only half of Americans had heard even “some” information about the bivalent boosters, according to a recent survey. The low numbers are especially unfortunate because the remaining 91.5 percent of booster-eligible people have already shown that they’re open to vaccines by getting at least their first two shots—if not already at least one booster.

    Now the bungled booster rollout could soon run headfirst into the winter wave. The virus is not yet surging in the United States—at least as far as we can tell—but as the weather cools down, cases have been on the rise in Western Europe, which has previously foreshadowed what happens in the U.S. At the same time, new Omicron offshoots such as BQ.1 and BQ.1.1 are gaining traction in the U.S., and others, including XBB, are creating problems in Singapore. Boosters are our best chance at protecting ourselves from getting swept up in whatever this virus throws at us next, but too few of us are getting them. What will happen if that doesn’t change?

    The whole reason for new shots is that though the protection conferred by the original vaccines is tremendous, it has waned over time and with new variants. The latest booster, which is called “bivalent” because it targets both the original SARS-CoV-2 virus and BA.5, is meant to kick-start the production of more neutralizing antibodies, which in turn should prevent new infection in the short term, Katelyn Jetelina, a public-health expert who writes the newsletter Your Local Epidemiologist, told me. The other two goals for the vaccine are still being studied: The hope is that it will also broaden protection by teaching the immune system to recognize other aspects of the virus, and that it will make protection longer-lasting.

    In theory, this souped-up booster would make a big difference heading into another wave. In September, a forecast presented by the Advisory Committee on Immunization Practices (ACIP), which advises the CDC, showed that if people get the bivalent booster at the same rate as they do the flu vaccine—optimistic, given that about 50 percent of people have gotten the flu vaccine in recent years—roughly 25 million infections, 1 million hospitalizations, and 100,000 deaths could be averted by the end of March 2023.

    But these numbers shouldn’t be taken as gospel, because protection across the population varies widely and modeling can’t account for all of the nuance that happens in real life. Gaming out exactly what our dreadful booster rates mean going forward is not a simple endeavor “given that the immune landscape is becoming more and more complex,” Jetelina told me. People received their first shots and boosters at different times, if they got them at all. And the same is true of infections over the past year, with the added wrinkle that those who fell sick all didn’t get the same type of Omicron. All of these factors play a role in how much America’s immunological guardrails will hold up in the coming months. “But it’s very clear that a high booster rate would certainly help this winter,” Jetelina said.

    At this point in the pandemic, getting COVID is far less daunting for healthy people than it was a year or two ago (although the prospect of developing long COVID still looms). The biggest concerns are hospitalizations and deaths, which make low booster uptake among vulnerable groups such as the elderly and immunocompromised especially worrying. That said, everyone aged 5 and up who has received their primary vaccine is encouraged to get the new boosters. It bears repeating that vaccination not only protects against severe illness and death but has the secondary effect of preventing transmission, thereby reducing the chances of infecting the vulnerable.

    What will happen next is hard to predict, Michael Osterholm, an epidemiologist at the University of Minnesota, told me, but now is a bad time for booster rates to be this low. Conditions are ripe for COVID’s spread. Protection is waning among the unboosted, immunity-dodging variants are emerging, and Americans just don’t seem to care about COVID anymore, Osterholm explained. The combination of these factors, he said, is “not a pretty picture.” By skipping boosters, people are missing out on the chance to offset these risks, though non-vaccine interventions such as masking and ventilation improvements can help, too.

    That’s not to say that the immunity conferred by the vaccination and the initial boosters is moot. Earlier doses still offer “pretty substantial protection,” Saad Omer, a Yale epidemiologist, told me. Not only are eligible Americans slacking on booster uptake, but lately vaccine uptake among the unvaccinated hasn’t risen much either. Before the new bivalent shots came around, less than half of eligible Americans had gotten a booster. “That means we are, as a population, much more vulnerable going into this fall,” James Lawler, an infectious-diseases expert at the University of Nebraska Medical Center, told me.

    If booster uptake—and vaccine uptake overall—remains low, expecting more illness, particularly among the vulnerable, would be reasonable, William Schaffner, a professor of infectious diseases at Vanderbilt University Medical Center, told me. Hospitalizations will rise more than they would otherwise, and with them the stress on the health-care system, which will also be grappling with the hundreds of thousands of people likely to be hospitalized for flu. While Omicron causes relatively minor symptoms, “it’s quite capable of producing severe disease,” Schaffner said. Since August, it has killed an average of 300 to 400 people each day.

    All of this assumes that we won’t get a completely new variant, of course. So far, the BA.5 subvariant targeted by the bivalent booster is still dominating cases around the world. Newer ones, such as XBB, BQ.1.1, and BQ.1, are steadily gaining traction, but they’re still offshoots of Omicron. “We’re still very hopeful that the booster will be effective,” Jetelina said. But the odds of what she called an “Omicron-like event,” in which a completely new SARS-CoV-2 lineage—one that warrants a new Greek letter—emerges out of left field, are about 20 to 30 percent, she estimated. Even in this case, the bivalent nature of the booster would come in handy, helping protect against a wider crop of potential variants. The effectiveness of our shots against a brand-new variant depends on its mutations, and how much they overlap with those we’ve already seen, so “we’ll see,” Omer said.

    Just as it isn’t too late to get boosted, there’s still time to improve uptake in advance of a wave. If you’re three to six months out from an infection or your last shot, the best thing you can do for your immune system right now is to get another dose, and do it soon. Though there’s no perfect and easy solution that can overcome widespread vaccine fatigue, that doesn’t mean trying isn’t worthwhile. “Right now, we don’t have a lot of people that feel the pandemic is that big of a problem,” and people are more likely to get vaccinated if they feel their health is challenged, Osterholm said.

    There’s also plenty of room to crank the volume on the messaging in general: Not long ago, the initial vaccine campaign involved blasting social media with celebrity endorsers such as Dolly Parton and Olivia Rodrigo. Where is that now? Lots of pharmacies are swimming in vaccines, but making getting boosted even easier and more convenient can go a long way too. “We need to catch them where they come,” said Omer, who thinks boosters should be offered at workplaces, in churches and community centers, and at specialty clinics such as dialysis centers where patients are vulnerable by default.

    After more than two years of covering and living through the pandemic, believe me: I get that people are over it. It’s easy not to care when the risks of COVID seem to be negligible. But while shedding masks is one thing, taking a blasé attitude toward boosters is another. Shots alone can’t solve all of our pandemic problems, but their unrivaled protective effects are fading. Without a re-up, when the winter wave reaches U.S. shores and more people start getting sick, the risks may no longer be so easy to ignore.

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    Yasmin Tayag

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