What Actually Changed for Little Kids’ Vaccines?

After months and months of being told to wait, then wait, then wait some more, parents eager to vaccinate their littlest kids against COVID-19 have been gifted some good and very confusing news. Yesterday, after weeks of weird and cryptic waffling, Pfizer kick-started the process of requesting an emergency use authorization from the FDA for their infant-and-toddler COVID-19 vaccine; if the agency’s advisory-panel meeting, scheduled for the 15th, goes smoothly, the under-5 shots could be available as a two-dose series shortly thereafter, pending a CDC recommendation. The most optimistic timeline for the arrival of an under-5 vaccine has suddenly shrunk to just a few more weeks.

This pivot is, at first glance, bizarre. Six weeks ago, right before Christmas, Pfizer announced that late-stage trials of two mini shots had produced somewhat lackluster antibody results in 2-to-4-year-olds, and a third dose could be necessary to clinch protection. Nothing about the vaccine itself has changed since then; no new data (actually, no data at all) have been publicized. Pfizer still says that a third dose will probably be necessary, and may report results on the effects of that dose around early spring. And yet, the stance on the shots for this group of kids has shifted substantially. Somehow, we’ve gone in an instant from two doses aren’t enough to actually, they kind of are. And both statements, somehow, are meant to be true at once.

Presumably, Pfizer and the FDA (which asked Pfizer to make its bid) have hit upon the fastest way for the company to jet at least some vaccine into little arms. But “it’s an odd message: We think you’re going to need a third dose, but take two now,” Chandy John, a pediatric infectious-disease physician and malaria researcher at Indiana University, told me.

[Read: Why a three-dose vaccine for young kids might actually work out]

Pfizer did not answer my questions about its new strategy when I reached out, only pointing me to a Tuesday press release announcing that it has sent its first round of data to the FDA. (But not, sadly, to the rest of us.) The company does seem to have collected and analyzed more data on how well the initial duo of shots is working since its last official update, a development reported by The Washington Post on Monday. And those data could well explain how two shots might have once appeared to fall short but now look pretty decent—decent enough, perhaps, to earn the FDA’s emergency okay.

The key here is understanding the metrics by which the shots’ success will be judged. Back in December, Pfizer was sussing out its shots’ success on a micro, immunological scale: how much of an immune response the vaccines tickled out. Now the company has added another lens that operates on the macro, clinical level: how well the shots lowered the risk of some sort of disease-related outcome.

Knowing that, Pfizer’s pivot does make some chronological sense. The company’s pediatric-vaccine trials were originally designed to focus on that first micro scale. Researchers had hoped that a pair of three-microgram doses of the company’s vaccine, administered three weeks apart, would prompt an antibody response comparable to that seen in older teens and young adults, who received two 30-microgram shots. This tactic, of trying to match outcomes between groups, is called “immunobridging.” The researchers did see a preview of that exact result in a small, early-stage trial, which included 32 children under the age of 5. (A 10-microgram dose also coaxed out a nice antibody response in this same age group, but saddled more toddlers with severe fevers as a side effect. Pfizer decided to nix that option.) But that tiny study was only meant to find the ideal dose so Pfizer could move forward with a larger trial, with a few thousand kids enrolled. And for some yet-to-be-determined reasons, the protective pattern didn’t play out in the larger group. In late-stage trials, kids under 2 churned out plenty of antibodies in response to two three-microgram doses; the 2-to-4-year olds, however, fell some undisclosed percentage short of the target, prompting Pfizer to reassess. (Scientists call this “not meeting non-inferiority.”) The company put forth a public Plan B—a third dose, given at least two months after the second, which would hopefully yank antibody levels up past the threshold.

[Read: Why are we microdosing vaccines for kids?]

Compared with full-on efficacy trials, which must wait for participants to get sick, immunobridging is fast and relatively easy. But the strategy also has to rely on some assumptions, Sallie Permar, a pediatrician, immunologist, and vaccine expert at Weill Cornell Medical Center, told me. It works best when researchers have already vetted a vaccine in a specific population (for instance, healthy adults) and pinpointed a certain, measurable immune response, called a correlate of protection, above which most folks in that group can be considered well shielded from disease. That number can then serve as a gold standard for other as-yet-unvaccinated populations (for instance, not-healthy adults).

Alas: We still have not confirmed that perfect, magic correlate of protection against COVID-19. For many months now, data have been pointing to antibody levels as a great candidate, especially if we’re thinking about less severe infections. But there’s still a lot of uncertainty, and antibodies are not the entire defensive picture. (Hello, T cells. Hello, B cells.) Correlates of protection are dependent on what we’re trying to protect against (infection, severe disease, something else), and in whom. These key protective levels can also toggle up or down if a new variant appears, or even, sometimes, if we move from one age group to another.

Infant and toddler immune systems are not identical to adults’. So maybe antibodies weren’t the best place to be looking. Or maybe the problem was just that teens and young adults, whose immune systems are still quite feisty, presented a “higher-than-necessary bar” for such an urgently needed vaccine, says Roby Bhattacharyya, an infectious-disease physician at Massachusetts General Hospital. “If antibody levels are not non-inferior to 16-to-25-year-olds, well, that’s a very different bar than not helpful.” (That said, the 16-to-25-year-old group has been the benchmark for Pfizer’s other pediatric trials as well.)

Still, the antibody data were some of the best that the trial runners had to go on, at first. Now Omicron appears to have rejiggered the game board. Enough infections may have swept through the trial’s participants, according to the Post, that the company suddenly had data describing vaccine efficacy against bona fide COVID outcomes. Maybe Pfizer found that fewer kids among those who received the actual vaccine in the trial were getting infected or sickened by the virus, even after just their first two shots.

[Read: Our relationship with COVID vaccines is just getting started]

Without seeing the actual data, it’s hard to judge Pfizer’s new dosing plan, experts told me. But the company has already said that its infant-and-toddler vaccine appears to have a good safety profile. That, coupled with adequate preliminary efficacy, might be reason enough to grant the EUA for two doses, then wait for the third-dose data and hope they further buoy the shots’ success. (Third doses, in general, are also expected to help broaden immune responses against variants.) Permar thinks an efficacy of 50 percent against symptomatic COVID might be a sensible bar for the first two shots, although “the closer you get to 80, 90 percent, the better,” she told me. John, of Indiana University, feels similarly, though his final metric is a bit different. “I think most of us would accept it if it’s safe, which they’ve already said it is, and effective against severe disease … something like 70 percent effective against hospitalizations, or more,” he said. “Then it’s worth giving,” even if the antibody data aren’t a knockout. Shifting the goalposts to severe disease, experts told me, may end up being prudent here. All of our vaccines are an imperfect match for the highly mutated Omicron; while safeguards against hospitalization and death have held quite strong, antibodies have struggled to block less serious infections.

Still, it’s reasonable to assume that the total number of COVID cases—especially serious ones—in the trial was not that high, making it tough to confidently compare vaccinated and unvaccinated cohorts. That alone could artificially inflate or deflate vaccine efficacy. Ibukun Kalu, a pediatric-infectious-disease physician at Duke University, also points out that vaccines should be expected to perform more poorly against infection during a surge caused by an antibody-dodging variant; the first efficacy numbers we record now might not be reflective of how our shots will fare in the future, against another variant or when case numbers dwindle. That punts some of the descriptive burden back to antibodies, which can, ideally, paint “a more complete picture about how and why vaccines work in the youngest groups,” Kalu told me.

All of this adds up to some tough decisions for the FDA’s advisory panel. If Pfizer’s vaccine-performance data were unilaterally marvelous, we would have heard by now, but they’re also unlikely to be unilaterally abysmal. Data that sit between those two extremes do not make for a slam dunk. And compared with most other age groups, very young kids remain at relatively low risk of having a severe case of COVID-19, making a super-thorough risk-benefit analysis for infant-and-toddler vaccination especially important. To complicate things further, experts advising the FDA will also have to navigate the odd antibody split between the under-2s, who did mount a sufficient antibody response, and the over-2s, who, by Pfizer’s initial standards, did not. “I did wonder if the older kids could hold the younger ones back,” Permar said.

Without the data from Pfizer’s third shot, authorizing two for now could amount to a high-stakes bet that a pair of initial doses will confer enough protection to make an early push worth it, and that the third will arrive in time to buttress those defenses.

[Read: Calling Omicron ‘mild’ is wishful thinking]

Say two doses do fine for kids—they’re safe, but don’t provide gobs of protection against less serious COVID. Say the FDA greenlights the vaccine, banking on the idea that the pair of shots will still tee up kids to be properly shielded by that third injection. And say that doesn’t pay off—say we don’t see a giant antibody uptick, or a hefty efficacy rise, after shot No. 3. Say the third dose’s effects are very, very temporary. What then? The third dose will almost certainly improve upon the initial response; thrice-vaccinated kids will still be better protected than they were before. But in the eyes of regulators, any additional vaccination still needs to look “worth it.” Parents did not wait this long for a meh vaccine. And prematurely granting an EUA to a vaccine that’s safe but not terribly effective could very well “backfire,” Tina Tan, a pediatrician at Lurie Children’s Hospital of Chicago, told me.

Vaccine uptake has already been patchy among American children; as the age brackets tick down, experts are predicting that the inertia will only grow. Pfizer’s gamble isn’t just about immunology. It’s also about communication—that this new plan can keep parents on board without losing their trust. A snafu now could make it tough to vaccinate kids in the future, against COVID or anything else.

At the same time, although COVID does pose a relatively low risk to little kids on “a population basis,” John told me, that risk is not zero. Children can catch and spread the virus; they can develop long COVID. And “we don’t want any kids to go to the hospital or die,” John said. In the past two years, more than 11.4 million coronavirus infections have been reported in children; close to a fifth of them have been logged in the past two weeks alone. Omicron’s surge has sent pediatric hospitalization numbers soaring to new heights. The under-5s are the last group of Americans to remain ineligible for vaccination. And the new variant, which seems to favor the upper respiratory tract, appears to cause treatable but serious crouplike symptoms that are very tough for the littlest kids to take, Kalu told me. Their airways are tiny; “they have fewer resources to deal with it than older kids or adults,” she said.

Bhattacharyya, of Massachusetts General Hospital, told me the data will still be guiding his thinking, as both a researcher and a parent—his son is 3. But “I think the only thing that would give me pause at this stage is a new safety signal, or a complete absence of antibody response,” he said. After so many months of having no options to safely give his child immunity, he’s ready for a change.