Last Friday, Lakshmi Ganapathi’s son turned 5, and finally became eligible for his first Pfizer COVID shot. Ganapathi’s family had been anticipating that moment for more than a year, yet as of late, she can’t help but feel the slightest bit deflated. At first, the COVID vaccines’ trickle down the age brackets felt worth the wait because the shots were doing such a stellar job at blocking symptoms. The clinical trials kept delivering knockout results: 94 percent efficacy, 95 percent efficacy, 100 percent efficacy, 91 percent efficacy—a near-perfect performance in every tested group from adults to elementary-school-age kids. Then Omicron swept in, slipping around the vaccines’ shields.
Researchers studying Pfizer’s vaccine, the only shot available for American kids, began to report drops in protection, especially in children under 12, who receive a lower dose and haven’t yet been told to boost. Moderna, which reportedly plans to seek FDA clearance for its own kid-size shot in mid-April, has turned up lackluster stats too: In clinical trials, the vaccine blocked symptomatic illness just 40 percent of the time, thanks again in part to Omicron’s antibody-dodging ways. After all the anticipation, Ganapathi, a pediatric-infectious-disease specialist at Boston Children’s Hospital, still wants what any parent does—the best option possible for their child—which is why her son got his first dose this morning. But that hope suddenly feels a little hard to square with such anticlimactic data. “If he’s going to face COVID,” she told me, “I want to set him up to be as prepared as he can be.”
An infant-and-toddler COVID vaccine, perhaps even two, could debut by summer’s start, if the FDA and the CDC give their official nods. But those long-awaited shots may not be met with much fanfare. “If this were January, I’d be like, Oh my god, get me whatever,” says Stephanie Langel, an immunologist at Duke University, whose son will turn 2 in July. Now that cases have come down, and Omicron has all but guaranteed that our original-recipe shots won’t deliver the same perks they once did, the decisions are tougher for everyone involved. The other COVID vaccines in our roster easily cleared the thresholds that had been set for success. In this last inoculation stretch, the tiniest doses on the table will push parents and federal regulators to grapple, in ways they haven’t before, with what makes a COVID vaccine good enough.
The path to regulatory clearance for kids’ COVID vaccines has, by necessity, looked different from the one for adults. When our shots were untested, it made sense to inject huge numbers of adults and wait to see who fell ill. But throughout the pandemic, kids haven’t gotten sick as seriously or frequently as adults. Chasing efficacy data for them would have required “a very long, very large study,” says Ofer Levy, the director of the precision-vaccines program at Boston Children’s Hospital, who also sits on a committee that advises the FDA on COVID vaccines. Instead, the FDA let vaccine makers opt for a common alternative called immunobridging, in which researchers identify a group of people in whom vaccines are working very well (say, healthy adults), figure out what immune responses (such as antibody levels) are typical to them, then try to coax the same results out of another population (kids).
The process is trickier than it might at first sound. The first and foremost consideration for any kids’ immunization has to be safety, experts told me. The more vaccine in each shot, the more side effects it might cause. So companies tend to go after “the smallest dose possible that will still be as effective as possible,” Buddy Creech, a pediatric-infectious-disease specialist at Vanderbilt University Medical Center, where he’s running one of Moderna’s pediatric vaccine trials, told me in January. After tinkering with different amounts of mRNA in early-stage trials, Pfizer sliced its doses in rough thirds, offering 30 micrograms to individuals 12 and older, 10 micrograms to 5-to-11-year-olds, and three micrograms to kids under 5. Moderna, meanwhile, cut in halves, giving 100 micrograms to everyone 12 and up, 50 micrograms to 6-to-11-year-olds, and 25 micrograms to children under 6.
Each company then ran much larger trials, to see if the antibody data—the information they’d need to present to the FDA—would hold, and to keep monitoring for bad side effects. At this juncture, both companies say they’re meeting safety criteria. Based on the information the firms have made public, “the rates of significant fevers are about on par with other vaccines” we give to kids, which is encouraging, Creech told me. (In Pfizer’s trial, researchers marked fevers as “severe” when they crested above 102 degrees Fahrenheit; in the Moderna trial, a few kids had fevers above 104 degrees.) But in the antibody realm, two doses of Pfizer’s three-microgram dose, which is still in trials, fell short in the 2-to-4-year-old group, prompting the company to add a third shot for all kids younger than 5. Moderna’s two 25-microgram doses for the under-6 crowd, however, did eke out enough antibodies to go toe-to-toe with adults.
If antibodies were the end-all-be-all, Moderna’s infant-and-toddler vaccine might, in theory, be a total shoo-in. But alas, they are not. When efficacy numbers are available, they tend to trump all else—and during Moderna’s trials, enough infections, many of them caused by Omicron, swept through the kids enrolled in the study that the company suddenly had sufficient data to calculate the vaccine’s bigger-picture performance. And there, some might argue, is where the shot started to fall short.
Back in June 2020, when COVID vaccines were still early in the pipeline, the FDA put its foot down: Successful COVID-19 shots, the agency said at the time, would need to “prevent disease or decrease its severity in at least 50 percent of people who are vaccinated.” The results in adult populations blew straight past that benchmark; now the data from kids seems like they may barely be grasping at it. (The FDA did not respond to my questions about whether that 50 percent efficacy standard applied to kids, who were meant to get by with immunobridging. A spokesperson said only that “we remain committed to conducting a timely and thorough evaluation of the available data and information on the use of COVID-19 vaccines in the youngest children.”)
The numbers for infants and toddlers haven’t been … the best. “No one would argue that 40 percent protection is great,” Chandy John, a pediatrician at Indiana University, told me. Here, it’s tempting to blame the dose: Maybe just a little more mRNA would have nudged Moderna’s numbers right over the edge. Similar concerns have been raised about Pfizer’s vaccine, which in a recent study didn’t protect 5-to-11-year-old kids from infection or disease for as long as expected, even though the 10-microgram dose they received had met its immunobridging benchmark in clinical trials. (Another study released shortly after, however, found more encouraging results.) Perhaps immunobridging actually led each company to slightly undershoot their dose size.
At this point, such questions are fair game. Immunobridging can be a bigger gamble when researchers haven’t yet identified a specific antibody level above which people can generally be considered well shielded from disease. If such a threshold exists for SARS-CoV-2, it may not translate perfectly among age groups, Levy points out. Perhaps kids actually need more antibodies than adults do to hit the same efficacy benchmarks. Immunobridging was the most practical option for getting vaccines to kids swiftly, Levy said. But “it may not tell the whole story.”
That said, Levy and the other experts I spoke with tend to more strongly implicate another culprit: the virus itself. Realistically, with kids’ trials running two doses of original-recipe vaccine during the Omicron era, the shots were probably never going to generate the knockout numbers that the adult shots did. There are now too many viral mutations in the picture; Moderna’s ballpark efficacy of 40 percent is “kind of what we would expect,” especially when transmission rates were as high as they were this past winter, Langel told me. It’s better, even, than the effectiveness of flu shots in years with vaccine-strain mismatches. In a press briefing last week, Anthony Fauci shared similar sentiments. Moderna’s new stats are “quite comparable,” he said, to what scientists have been seeing in other populations as of late. In adults, two mRNA doses just haven’t been as potent as three. All things considered, Fauci said, “the data looks pretty good.” It’s very possible that, were we to rerun studies in adults now, against Omicron, two full-size doses would struggle to get to 50 percent efficacy too.
Forty-ish percent efficacy against symptomatic illness may be about as good as we can get with two doses of mRNA vaccines without sacrificing safety. Maybe a bigger dose for kids would budge the numbers up, but “we have to consider the downside in terms of adverse events,” says Kathryn Edwards, a pediatrician and vaccine expert at Vanderbilt University. (Edwards is a former adviser to the FDA on vaccines, and sits on a safety-monitoring board for Pfizer’s shot.) Fevers in the littlest kids are an especially big concern because they can cause (self-resolving) seizures, so, even if rare, they could pose a major hurdle to clearing a new shot for use. Myocarditis, too, could be a problem: Moderna’s vaccine, which includes more mRNA in each injection, appears to have produced slightly higher rates of the rare heart-inflammation issue than Pfizer’s in young men. (No cases of myocarditis were picked up in Moderna’s under-6 trials.) “I don’t know that we need higher doses,” Creech told me. Rather, he and others think success will come down to the number of doses and their pacing. Vaccine makers could add a third or fourth injection or space the shots further apart, or both. They could even include an extra immune-system-tickling ingredient to rev the body’s defenses further.
Some experts said they were already thinking about 40-ish percent as a sort of interim efficacy; third shots for kids now feel more or less inevitable. Ahead of its request for emergency use authorization for its under-6-shot, Moderna is already considering asking the FDA to okay a pediatric booster somewhere down the line, Kate Cronin, the company’s chief brand officer, told me in an email. At this point, Pfizer’s under-5 vaccine will almost certainly be a three-doser, at least to start, and the company is “evaluating a third dose” in 5-to-11-year-olds as a booster, says Jerica Pitts, a company spokesperson.
Just a few weeks ago, Sallie Permar, a vaccine expert, an i
mmunologist, and the pediatrician in chief at New York–Presbyterian Hospital and Weill Cornell Medicine, told me that she hoped a COVID vaccine for kids would hit that 50 percent efficacy mark before getting the FDA’s emergency authorization. Still, if Moderna’s 40 percent efficacy estimate, which is still tentative, holds, “I’m comfortable with that,” she said. Maybe if kids were still dealing with the original version of the coronavirus, efficacy numbers would match what previous trials had produced. But OG SARS-CoV-2 is long gone.
Vaccination is a series of judgment calls by institutions and individuals alike: authorizing a new shot, recommending a booster, deciding to sign up for any dose at all. Data can help inform these decisions, but these choices ultimately depend, in part, on the goal they’re meant to further, which might be shielding against severe disease alone—or blocking as many infections as possible. Policies in the U.S. still aren’t clear about what the ultimate aim of COVID vaccination is. And for kids, fewer of whom end up hospitalized with the virus, the possible gains of vaccination are that much murkier. Such a small number of little kids in the clinical trials ended up seriously sick, in fact, that neither Moderna nor Pifzer has yet produced reliable efficacy numbers against severe disease.
But children do fall seriously ill with COVID-19. Since the pandemic’s start, the virus has killed more than a thousand kids; thousands more have developed a serious inflammatory condition called MIS-C. The Omicron wave hospitalized the youngest Americans—the least vaccinated Americans—at rates higher than in any other surge. Any chance to avoid those outcomes is a welcome one. Which is where vaccines should shine. In all other age groups, COVID vaccines have been best at guarding people from the most serious forms of disease, and “there’s no reason that wouldn’t hold true” in the youngest among us as well, says Ibukun Kalu, a pediatric-infectious-disease specialist at Duke. Here, again, experts have to lean on comparisons between adults and kids. But the stubbornness of our shots’ strongholds against severe disease should transcend even the hiccups of cross-age immunobridging, even the wiliness of Omicron; that’s fundamental to how the immune system should work. Even in a downer of a scenario, in which efficacy against serious outcomes came out to exactly 40 percent as well, that “would spare a lot of kids being hospitalized,” John, of Indiana University, told me. If the fundamental question facing the FDA is what performance floor it will accept for kids’ COVID vaccines, Permar and other pediatricians think that threshold must ensure that the shots at least stave off the most serious forms of disease. Moderna seems to be banking on this a bit. The antibody levels the company observed in late-stage trials “should provide protection against important and serious disease,” Cronin told me.
Creech also points to a benefit of vaccines that efficacy numbers alone don’t capture. The umbrella of “symptomatic illness” can cover a light bout of the sniffles, a critical case of COVID-19 that’s bad enough to land someone in the ICU or even kill them, and anything in between. But when post-vaccination infections occur, they’re less serious on average, effectively shifting people toward the gentler end of that spectrum of severity. As a parent, Creech told me, he still considers it a huge deal to make a kid’s course of illness less lengthy and cumbersome, even if the shots can’t block symptomatic disease entirely. (Vaccines may also help curb long COVID, which affects children of all ages.) Every year, experts recommend flu shots even though those vaccines, too, tend to top out at about 60 percent effectiveness against illness.
These arguments won’t necessarily sway the FDA, especially if case rates stay low. The United States has eased pandemic precautions almost entirely; the FDA’s coming deliberations could reflect that attitude, and mire pediatric shots in dillydallying muck. Vaccines that are “good enough” to green-light when the virus is running roughshod over the country may not pass muster during a quieter period, when the costs of not vaccinating shrink. And without actual efficacy numbers against severe disease, that bit of the risk-benefit equation will be very tough to weigh. Moderna, if it comes before the FDA and CDC first, may even end up getting a conditional okay—recommended only for high-risk kids, for example. At an extreme, if the FDA is dissatisfied with Moderna’s final stats, the agency could ask the company to add a third dose before it gets the official green light.
The FDA’s and CDC’s finish lines won’t be the last for the shots to cross, either. For the youngest among us, the final arbiters of which shots are and are not worth their salt are America’s parents—who so far have been rather reluctant to queue their kids up for injections. As the COVID vaccines have shuffled down the age brackets, uptake has declined; with so many people now eager to put the pandemic behind them, these smallest shots may be our least welcome yet. In many ways, the fate of the next crop of pediatric shots may, more than anything else, mirror Americans’ current sense of the crisis.
For now, the future feels foggy—which is exactly why Ganapathi, of Boston Children’s Hospital, was so eager to clinch protection for her 5-year-old son. (Her younger son will turn 2 in July, and will hopefully soon follow his brother into an inoculation line.) The next surge, she told me, is a matter of “when, not if.” She briefly considered holding off on giving her son Pfizer, so they could wait for Moderna’s higher-dose, longer-interval under-6 shot to come through. But of the two brands, only Pfizer was available now. “Do I want a more efficacious vaccine for symptomatic disease? The answer is yes,” she told me. “But we can only deal with what we have on hand, and make the best of it.”