Why a Three-Dose Vaccine for Young Kids Might Actually Work Out
For many months now, Pfizer’s COVID-19 vaccine has been slowly making its way into smaller arms in smaller doses—from teens to adolescents to elementary-school-age kids in the fall. Now it’s just the under-5 crowd left, and the word on the lips of parents raring to protect their children is still, simply, when. Somehow, no one yet seems to know.
Back in September, the party line was that under-5 trial data would arrive “before the end of the year,” as Pfizer CEO Albert Bourla declared at The Atlantic Festival. Those data never appeared. Instead, the week before Christmas, Pfizer announced in a maddeningly cryptic press release that two little-kid-size doses of vaccine had failed to elicit a hefty-enough immune response in 2-, 3-, and 4-year olds in late-stage trials. (Doubly dosed kids in the six-month-to-2-year-old range, though, did produce enough antibodies to satisfy the company’s criteria.) But the company had a plan—researchers would test a third injection eight weeks after the second—and a new timeline, with data arriving in the “first half of 2022,” maybe April-ish. Add to that the few weeks the FDA typically takes to review the data submitted for emergency-use authorization, and the earliest shots for this group are still probably two or three months away.
Then, this week, the White House’s chief medical adviser, Anthony Fauci, seemed to drop a mysterious bombshell: Surprise! Perhaps a trio of mini shots will be greenlit for use in kids under 5 “within the next month or so”—weeks ahead of the updated schedule. But he quickly backpedaled—that was just a hope, and absolutely not a guarantee. The predictions on when we’ll get the data, much less the shots, have ricocheted all the way back to idk I guess spring?
Amid all this chaos, Pfizer still hasn’t publicized any data from this youngest age group; if federal officials have that information, they, too, are staying mum. (I reached out to the CDC, which pointed me to the FDA, which pointed me to Pfizer, which said: “Unfortunately we are not offering any interviews on this right now.” Unfortunately indeed.) Parents who just want to know what’s happening are now, understandably, feeling pretty jerked around by all this talk of later? sooner? who knows! “The wait has been excruciating,” Risa Hoshino, a public-health pediatrician in New York City, told me. “They feel the world has moved on without them.” Families have been asking “every single day,” she said, when infant-and-toddler vaccines will finally make their public debut.
Hoshino can’t give a definitive answer; outside of Pfizer and BioNTech, and perhaps the FDA, few people can even try. (Remember, no public data.) Still, several experts I spoke with this week remain optimistic that kids under 5 will get shots within the next few months. After seeing disappointing results in the original iteration of its trial, Pfizer took something of a gamble by adding one more small dose to the series for under-5s. But there may be good reason to believe that this bet, the company’s first official departure from the standard two-shot primary series, will pay off spectacularly. The company’s new kid-dosing strategy, experts told me, was likely designed to marry logistics to science—something that would fast-track the vaccine’s rollout while keeping the shots’ risk-benefit ratio ultrahigh.
In some ways, vaccines are vaccines are vaccines. But tailoring them to individual populations—which each harbor different needs, risks, and vulnerabilities—is essential to doling them out right. Dosing is a balancing act: The more vaccine in each shot, the likelier that shot is to rile up the immune system—and the likelier it is to make the experience of getting the injection pretty uncomfortable. That means “we’re after the smallest dose possible that will still be as effective as possible,” says Buddy Creech, a pediatric-infectious-disease specialist at Vanderbilt University Medical Center, who’s leading a study of Moderna’s pediatric COVID vaccine. Pfizer already intentionally shrank the dose: Adults have been getting 30 micrograms of mRNA in each injection; in the under-5s, the company is trying three micrograms apiece. But the hope is still to, roughly, get “the response to the childhood vaccine to match what we see in adults,” typically measured by antibody counts, Creech told me. So if a pair of injections weren’t quite enough to get 2-to-4-year-olds there, a bonus third shot could be expected to push them over the top. “I’m hopeful,” Sallie Permar, a pediatrician, immunologist, and vaccinologist at Weill Cornell Medical Center, told me. “The only way to go, really, is up.”
It helps to first consider what Pfizer’s other choices might have been. Subpar antibody levels in the blood might suggest that the vaccines couldn’t quite convince little bodies to take them seriously. One option could have involved sticking with two doses, but spacing them further apart—essentially giving the immune system more time to mull what it means to fight SARS-CoV-2. That strategy has been shown, at least in adults, to buoy the quantity, quality, and longevity of immune responses, and parts of Canada have been pursuing it for months in 5-to-11-year-old kids. Another alternative could have been to simply increase the dose, while keeping all else the same; each would deliver a sharper, and perhaps more memorable, scolding to defensive cells. Kids could then stay on the speediest possible track to sufficient protection: three weeks between doses, then another two of immunological cook time. “In a pandemic, you want to do that as fast as humanly possible,” Hoshino said. If Pfizer’s three-dose strategy pans out, the five-week timeline balloons to three months.
But revamping the two-dose strategy would have also restarted the clock on trials and meant recruiting and enrolling a new cohort of participants. A series of injections, potential side effects, and weeks of blood draws and other follow-ups are a cumbersome commitment for a person of any age, and “the hardest trials to get done are these young ones,” Permar said. “It’s never easy to ask a parent to consider more procedures, especially for toddlers, who are going to cry.” Even vaccine trials for older kids struggled to reach capacity. Tacking on a third dose, then, ends up being the most time-efficient option—not necessarily to get each individual child to the end of a vaccine series, but to obtain regulatory authorization, and to roll out first shots to the public.
A two-big-dose option could also be unsavory for another reason—an increased chance of side effects, including fever, fatigue, and headaches, or perhaps something much rarer but more severe. In teenage boys and young men, mRNA vaccines like Pfizer’s and Moderna’s have been linked to cases of heart inflammation, though new results from the 5-to-11-year-old crowd suggest that younger kids may be spared. In any case, dose definitely matters: When it comes to vaccinating super-young kids, whose risk of contracting serious cases of COVID-19 remains relatively low, the shots “have to be supersafe, remarkably safe,” Permar said. “These are healthy, young children who might not be able to say, ‘I feel crummy.’” Perhaps the three-microgram dose was already producing some discomfort. (Do we know? No—again, there’s no data.)
It might have been unwise, then, to go up to the next dose in size, the one for 5-to-11-year-olds—which, at 10 micrograms, is a more-than-threefold increase. Creech agrees: Any worries about shot tolerability could end up subjecting study participants to a bevy of irksome tests, and causing distress for the entire family. These concerns and more were part of the logic that motivated Pfizer to choose the three-microgram dose for the under-5s in the first place: In an early-phase study, that was the tiniest dose tested that still coaxed out decent numbers of antibodies in children as young as six months. It’s not clear why those results didn’t carry over perfectly into the company’s more recent trials. But Creech told me that if he’s going to hear deflating news from a kids’ vaccine trial, he’d rather it be about lackluster antibody levels than troubling side effects. With kids this young, “we’re going to put a little more weight on our safety foot than our effectiveness foot.”
And three smaller doses could even be more effective than two slightly larger ones. Raising defenses to a threat is a costly endeavor for the body; sometimes, the immune system just needs another nudge before it decides to commit. Some vaccines in the pediatric-medicine roster are already doled out in two, three, or even five doses for that reason. Without Pfizer’s data, it’s impossible to know just how far below the desired threshold kids’ antibody levels fell after two three-microgram doses, but “I have to imagine they already weren’t too far off,” Permar told me. And because each shot should build on the last, three doses could succeed where two have failed.
Waiting two months to give the third dose should “refine and mature” toddlers’ immune responses, Creech said. Their bodies will spend that limbo period studying and restudying the doses they’ve already gotten, and sharpening their SARS-CoV-2-sniping skills. Third shots can also goad the immune system into broadening its range of coronavirus-fighting tools, so that kids end up ready to duel even antibody-dodging variants such as Omicron. (And third doses, when injected after a delay, don’t seem to produce any more side effects than seconds, probably because the body gets the chance to cool down in the interim, based on studies in adults.) “Keeping the dose low and adding on a third just makes a ton of sense,” Permar said. Toddlers could even help pave the path to an initial trio of COVID shots being standard fodder for all.
One smidgen of weirdness remains: why kids under 2 beat out their slightly older peers, as Pfizer reported in December. The magnitude of the difference isn’t yet known. (Imagine, if you will, what might be helpful here: data.) But sussing out this discrepancy could reveal some peculiarities about how immune systems transition from infancy to toddlerhood. Permar pointed out that kids’ immune systems are much more quick-witted than adults’: They can learn a lot from very little vaccine. (That’s why pediatric vaccines are dosed by immunological age, not weight.) Even newborn babies, whose immune systems don’t come out fully fledged, “are actually pretty ready to respond robustly to certain types of vaccines,” Permar said. The results are intriguing enough that some experts may want to explore the option of keeping infants on a two-dose Pfizer track. But Pfizer is still testing the effects of a third dose for this group, which may end up being practical in the long run, especially if it simplifies the number of injection regimens that doctors have to juggle all at once. (The company has not broken out the infant group to seek its own authorization first.)
Creech told me he feels great about what he’s observing so far in Moderna’s pediatric trials, and he’s confident things on the kids’-vaccine front will take a turn for the better by early summer—if not for Pfizer’s shot, then for its similar-looking competitor. Moderna’s vaccine also comes in a two-dose series, but the injections are four weeks apart, and bigger: The company is testing 50 micrograms of mRNA in 6-to-11-year-olds, and 25 micrograms in kids 5 and younger (compared with 100 micrograms for adults). If Pfizer’s three-doser doesn’t work, Moderna could be toddlers’ vaccine dark horse. “I have wondered if this is the time Moderna will finally beat Pfizer” to the finish line, Permar told me. It may truly be neck and neck: Moderna’s expecting to report the first of its 5-and-under data in March, not far off from Pfizer’s own early-spring goal. Either way, it’ll be the data—of course—that dictate what happens next.