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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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  • The Cold-Medication Racket

    The Cold-Medication Racket

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    You wake up with a stuffy nose, so you head to the pharmacy, where a plethora of options awaits in the cold-and-flu aisle. Ah, how lucky you are to live in 21st-century America. There’s Sudafed PE, which promises “maximum-strength sinus pressure and nasal congestion relief.” Sounds great. Or why not grab DayQuil in case other symptoms show up, or Tylenol Cold + Flu Severe should whatever it is get really bad? Could you have allergies instead? Good thing you can get Benadryl Allergy Plus Congestion, too.

    Unfortunately for you and me and everyone else in this country, the decongestant in all of these pills and syrups is entirely ineffective. The brand names might be different, but the active ingredient aimed at congestion is the same: phenylephrine. Roughly two decades ago, oral phenylephrine began proliferating on pharmacy shelves despite mounting—and now damning—evidence that the drug simply does not work.

    “It has been an open secret among pharmacists,” says Randy Hatton, a pharmacy professor at the University of Florida, who filed a citizen petition in 2007 and again in 2015 asking the FDA to reevaluate phenylephrine. This week, an advisory panel to the FDA voted 16–0 that the drug is ineffective orally, which could pave the way for the agency to finally pull the drug.

    If so, the impact would be huge. Phenylephrine is combined with fever reducers, cough suppressants, or antihistamines in many popular multidrug products such as the aforementioned DayQuil. Americans collectively shell out $1.763 billion a year for cold and allergy meds with phenylephrine, according to the FDA, which also calls the number a likely underestimate. That’s a lot of money for a decongestant that, again, does not work.

    Over-the-counter oral decongestants weren’t always this bad. But in the early 2000s, states began restricting access to pseudoephedrine—a different drug that actually is effective against congestion—because it could be used to make meth; the Combat Methamphetamine Epidemic Act, signed in 2006, took the restrictions national. You can still buy real-deal Sudafed containing pseudoephedrine, but you have to show an ID and sign a logbook. Meanwhile, manufacturers filled over-the-counter shelves with phenylephrine replacements such as Sudafed PE. The PE is for phenylephrine, but you would be forgiven for not noticing the different name.

    “Thet switch from pseudoephedrine to phenylephrine was a big mistake,” says Ronald Eccles, who ran the Common Cold Unit at Cardiff University until his retirement. Eccles was critical of the switch back in 2006. The evidence, he wrote at the time, was already pointing to phenylephrine as a lousy oral drug.

    Problems started showing up quickly. Hatton, who was then a co-director of the University of Florida Drug Information Center, started getting a flurry of questions about phenylephrine: Does it work? What’s the right dose? Because my patients are complaining that it’s not doing anything. He decided to investigate, and he went deep. Hatton filed a Freedom of Information Act request for the data behind FDA’s initial evaluation of the drug in 1976. He soon found himself searching through a banker’s box of records, looking for studies whose raw data he and a postdoctoral resident typed up by hand to reanalyze. The 14 studies the FDA had considered at the time had mixed results. Five of the positive ones were all conducted at the same research center, whose results looked better than everyone else’s. Hutton’s team thought that was suspicious. If you excluded those studies, the drug no longer looked effective at its usual dose.

    All told, the case for phenylephrine was not great, but the case against was no slam dunk either. When Hatton and colleagues at the University of Florida, including Leslie Hendeles, filed a citizen petition, they asked the agency to increase the maximum dose to something that could be more effective. They did not ask to pull the drug entirely.

    There was more damning evidence to come, though. The petition led to a first FDA advisory committee meeting, in 2007, where scientists from a pharmaceutical company named Schering-Plough, which later became Merck, presented brand-new data. The company had begun studying the drug, Hatton and Hendeles recalled, because it was interested in replacing the pseudoepinephrine in its allergy drug Claritin-D. But these industry scientists did not come to defend phenylephrine. Instead, they dismantled the very foundation of the drug’s supposed efficacy.

    They showed that almost no phenylephrine reaches the nasal passages, where it theoretically could reduce congestion and swelling by causing blood vessels to constrict. When taken orally, most of it gets destroyed in the gut; only 1 percent is active in the bloodstream. This seemed to be borne out by what people experienced when they took the drug—which was nothing. The scientists presented two more studies that found phenylephrine to be no better than placebo in people congested because of pollen allergies.

    These studies, the FDA later wrote, were “remarkable,” changing the way the agency thought about how oral phenylephrine works in the body. But experts still weren’t ready to write the drug off entirely. The 2007 meeting ended with the advisory committee asking for data from higher doses.

    The story for phenylephrine only got worse from there. In hopes of making an effective product, Merck went to study higher doses in two randomized clinical trials published in 2015 and 2016. “We went double, triple, quadruple—showed no benefit,” Eli Meltzer, an allergist who helped conduct the trials for Merck, said at the FDA-advisory-panel meeting this week. In other words, not only is phenylephrine ineffective at the labeled dosage of 10 milligrams every four hours, it is not even effective at four times that dose. These data prompted Hatton and Hendeles to file a second citizen petition and helped prompt this week’s advisory meeting. This time, the panel didn’t need any more data. “We’re kind of beating a dead horse … This is a done deal as far as I’m concerned. It doesn’t work,” one committee member, Paul Pisarik, said at the meeting. The advisory’s 16–0 vote is not binding, though, so it’s still up to the FDA to decide what to do about phenylephrine.

    In any case, phenylephrine is not the only cold-and-flu drug with questionable effectiveness in its approved form. The common cough drugs guaifenesin and dextromethorphan have both come under fire. But we lack the robust clinical-trial data to draw a definitive conclusion on those one way or the other. “What really helped our case is the fact that Merck funded those studies,” Hatton says. And that Merck let its scientists publish them. Failed studies from drug companies usually don’t see the light of day because they present few incentives for publication. Changing the consensus on phenylephrine took an extraordinary set of circumstances.

    It also required two dogged guys who have now been at this work for nearly two decades. “We’re just a couple of older professors from the University of Florida trying to do what’s best for society,” Hatton told me. When I asked whether they would be tackling other cold medications, he demurred: “I don’t know if either one of us has another 20 years in us.” He would instead like to see public funding for trials like Merck’s to reevaluate other over-the-counter drugs.

    There are other effective decongestants on pharmacy shelves. Even though phenylephrine does not work in pill form, “phenylephrine is very effective if you spray it into the nose,” Hendeles says. Neo-Synephrine is one such phenylephrine spray. Other nasal sprays containing other decongestants, such as Afrin, are also effective. But the only other common oral decongestant is pseudoephedrine, which requires that extra step of asking the pharmacist.
    Restricting pseudoephedrine has not  curbed the meth epidemic, either. Meth-related overdoses are skyrocketing, after Mexican drug rings perfected a newer, cheap way to make methamphetamine without using pseudoephedrine at all. This actually effective drug still remains behind the counter, while ineffective ones fill the shelves.

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    Sarah Zhang

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