Why Are We Microdosing Vaccines for Kids?

The age cutoffs for COVID-19 vaccine sizes (mostly) make sense.

A row of children in face masks
Frederic J. Brown / AFP / Getty

In the months since Pfizer announced its plans to adapt its COVID-19 vaccine for kids, the nicknames have been rolling in. Lil Pfizer, Pfizer-Mini, Pfizer Jr. (sorry, BioNTech; everyone tends to forget you). Others offer a cheeky play on Comirnaty, the shot’s tongue-twisting official title: Comirnito, Baby Comirnaty, or my personal favorite, ComirNatty Light.

These monikers not only nod to the smaller humans the shots are designed for, but the actual size of the doses themselves. If Pfizer earns the expected thumbs-up from CDC Director Rochelle Walensky this week, children 5 to 11 years old will be getting 10 micrograms of RNA in each Pfizer shot, a third of the 30-microgram recipe that’s given to people 12 and older. Further down the road, pending another set of votes, authorizations, and recommendations, kids 4 and younger will get a wee 3 micrograms, a tenth of what their parents get.

It sounds, at first, like some pretty weird COVID math. Five-year-old bodies look nothing like 11-year-old bodies; it might seem bizarre that they’d get the same dose. And certainly nothing physiologically revelatory happens when someone turns 12: “You don’t wake up one day and have a different immune system,” Kathryn Edwards, a pediatrician and vaccinologist at Vanderbilt University Medical Center, told me. But somehow, the difference of a day can triple a child’s inoculation dose. The picture appears even murkier when considering other brands, like Moderna, which did its calculations differently: 100 micrograms of RNA for adults; 50 micrograms for 6-to-11-year-olds; 25 micrograms for 5 and younger. Scientifically, what gives?

Thankfully, there is a logic to how pediatric shots are designed and dosed. Children aren’t just miniaturized adults, and vaccines aren’t sandwiches: Pairing the two appropriately requires more than splitting shots into quarters or halves. The goal is to get the shot to be not just kid-size, but kid-friendly, which means finagling a whole slew of factors, including dosing—but also how vaccine recipes are stabilized and stored, how much liquid gets injected into arms, and even who doles the vaccines out and the color of the vials they use.

Consider, first, that kids’ vaccines aren’t dosed like most medications are. Many drugs don’t work unless they hit a certain concentration in the blood, and so need to be dosed by a child’s size (think Tylenol). It’s a Goldilocks principle: There needs to be enough drug around to be therapeutic, but not so much that it risks toxicity. A similar sweet spot exists for vaccines—not too little, not too much—but the math plays out differently. Here, researchers are paying less attention to weight, and more to how readily a body is able to marshal an anti-pathogen defense. Many aspects of kids’ immune systems are feistier than adults’; their bodies pack a more natural punch. Ten-year-olds of different sizes should be expected to react to vaccines in ways that are “basically, functionally the same,” Edwards told me. (Obesity, notedly, has been shown to blunt responses to some vaccines, but whether or how that might impact COVID shots isn’t known.)

“Children’s immune systems are probably at their best around 15 years of age,” Archana Chatterjee, a pediatric infectious-disease specialist at Rosalind Franklin University, told me. Data submitted by Pfizer to the FDA, for instance, showed that freshly vaccinated 12-to-15-year-olds produced more antibodies than adults do after a full-size shot. (A similar phenomenon was observed with the HPV vaccine, which is targeted to adolescents.) After that, defensive moxie declines, growing more sluggish and forgetful over time. The less natural defense the immune system can offer, the more vaccine it needs.

This broad pattern means it can be safer and more practical to give even younger children trimmed-down versions of adult doses, a strategy already employed for the shots we use to block other viral diseases, such as influenza and hepatitis A and B. (The trend can also work in reverse: Flu vaccines are given at higher doses to people over 65—an extra jolt for an immune system on the wane.) Dosing conservatively is also a good way to minimize bad outcomes, which tend to get more common the more the immune system is provoked, Chatterjee told me.

Pfizer tested that idea out in an early-phase clinical trial that included kids aged 6 months to 11 years, who were given four different doses of the company’s vaccine: 3 micrograms, 10 micrograms, 20 micrograms, and 30 micrograms (the adult dose). Researchers monitored side effects and immune responses, and selected the two smallest doses for further study. The 10-microgram dose for 5-to-11-year-olds, in particular, seemed to tickle out blood antibody levels “comparable” to what the company had seen in older teens and young adults, Pfizer said in a recent press release. And the company’s final numbers, submitted to the FDA, show that the pediatric dose was 90.7 percent effective at preventing symptomatic cases of COVID-19 in this age group in the few months after inoculation, including over the summer, against the Delta coronavirus variant. The low dose’s side effects were also the standard stuff that’s been seen in older children and young adults—arm pain, fatigue, headaches—but many of them were milder and more tolerable. (Those symptoms got a bit worse at higher vaccine doses, a disincentive to move the kids up the scale.)

With 10 micrograms, “we think that we have optimized immune response and minimized reactions,” Bill Gruber, Pfizer’s senior vice president of vaccine clinical research and development, told a panel of advisers to the FDA last week. Striking that balance is crucial, Grace Lee, the chair of the committee that advises the CDC’s recommendations on vaccines, told me. “If you can get the same level of protection at a lower dose, that just makes sense.”

One asterisk on Pfizer’s so-far-comforting safety data is a pair of rare but serious side effects that have been detected in other age groups who have gotten mRNA vaccines: myocarditis and pericarditis, inflammation of the heart and its surrounding tissue, which seem to appear more frequently in boys and young men. Pfizer’s trial of 5-to-11-year-olds didn’t detect any cases, but it enrolled only thousands of children, too few to reliably pick up a signal. The hope is that a lower dose will slash risks of these events too—and if there’s a link between myocarditis and testosterone, as some researchers have hypothesized, kids who haven’t yet hit puberty might be less vulnerable. But the urgency of protecting young kids—who, almost a year into the vaccine rollout, still don’t have a full inoculation green light—means “we have to make some decisions under uncertainty … and be willing to change our minds if more data emerge,” Lee told me.

None of this is to say that the exact age groups Pfizer chose represent hard scientific boundaries. When I asked the company how it had selected its age cutoffs for vaccination, Kit Longley, Pfizer’s senior manager of science media relations, told me that “we chose those ages based on our vast experience in vaccine development for pediatric populations and in consultation and agreement with FDA.” Sure.

Kate Cronin, Moderna’s chief brand officer, was a bit less cryptic. She pointed to puberty as one of the considerations her company used to cordon off age ranges, above and below 12. (Hormones can gently futz with immune function.) There are logistical considerations, too, for when kids start to mingle with others, and what schedules have been used for other vaccines. Children tend to head off to school around age 5 or 6, a time when a lot of vaccine boosters are administered. And up to age 2 might be a reasonable range to demarcate “infancy,” a period when the newborn immune system is finding its footing. (There’s actually little point to giving certain shots before six months of age: Babies teem with antibodies inherited from their mother, and need time to tee up their own immune defenses.)

Some of the lingering squishiness is probably why a lot of parents have been wondering what to do with kids who are teetering on 12—an age jump that would instantly triple their vaccine dose. But experts told me that parents shouldn’t fret about the precision of age. “Your immune system doesn’t know exactly when your birthday is,” she said; kids on this precipice will likely respond enthusiastically to either dose. (A draft of the CDC’s interim clinical considerations for Pfizer’s pediatric vaccine, posted today, notes that children should receive their doses based on “age on the day of vaccination”—which means a kid who turns 12 between Pfizer’s two doses could get 10 micrograms, then 30. But two 10-microgram doses “is not considered an error”; Pfizer had some participants who turned 12 during its kids’ trial, and they got the same injection each time.)

The bigger consideration is about how soon an inoculation can raise a kid’s defensive shields. Protection takes a while to kick in, even after the second shot, and “you never know when COVID will enter your life or your child’s life,” Sallie Permar, a pediatrician and vaccine expert at Weill Cornell Medicine, told me last week. Edwards, the Vanderbilt vaccinologist, agrees that waiting is a gamble. Five of her seven grandchildren are in the 5-to-11 age group, she said. “All five of them will be getting the vaccine the first day they can.”