Why Do Children’s COVID-Vaccine Results Differ From Adults?

Why Do Children's COVID-Vaccine Results Differ From Adults?
pic credit : Healthline

Lakshmi Ganapathi’s kid turned 5 on Friday, making him eligible for his first Pfizer COVID shot. Ganapathi’s family had been looking forward to that moment for over a year, but she’s been feeling a little let down lately. At first, the slow rollout of COVID vaccinations appeared worthwhile because the doses were so effective at preventing symptoms.

The clinical trials continued to provide stunning results: 94 percent efficacy, 95 percent efficacy, 100 percent efficacy, 91 percent efficacy—near-perfect performance in every studied group, from adults to elementary-school-age children. Then Omicron swooped in, sneaking beyond the vaccinations’ protective barriers.

Research examining Pfizer’s vaccine, the only one accessible to American children, began to see a reduction in protection, particularly in children under the age of 12, who receive a lesser dose and haven’t yet been urged to boost. Moderna, which apparently aims to seek FDA approval for its own kid-size injectable in mid-April, has also shown mediocre results: In clinical studies, the vaccination only prevented symptomatic disease 40% of the time, owing in part to Omicron’s antibody-dodging abilities.

Ganapathi, a pediatric infectious-disease expert at Boston Children’s Hospital, nevertheless wants what any parent wants: the greatest option for their child, which is why her son received his first dosage this morning. But that hope feels a little difficult to reconcile with such depressing data. “If he’s going to face COVID,” she explained, “I want to make sure he’s as prepared as he can be.”

If the FDA and the CDC provide their official approvals, an infant-and-toddler COVID vaccination, possibly two, might be available by the start of the summer. Those long-awaited shots, though, may not be welcomed with much celebration. “If it were January, I’d be like, Oh my gosh, bring me whatever,” says Stephanie Langel, an immunologist at Duke University whose kid turns two in July.

Now that the lawsuits have been resolved, and Omicron has all but assured that our original-recipe injections will no longer provide the same benefits they once did, the options are becoming more difficult for everyone involved. The other COVID vaccinations on our list easily passed the success criteria. The smallest dosages on the table in this final round of immunizations will force parents and government regulators to contend with what constitutes a COVID vaccine in ways they haven’t previously.

The approach to regulatory approval for children’s COVID vaccinations has, by necessity, differed from that for adults. When our vaccines were experimental, it made logical to inject a large number of adults and see who became sick. However, children have not been sick as gravely or as frequently as adults throughout the pandemic.

Obtaining effectiveness evidence for them would have necessitated “a very long, very large research,” according to Ofer Levy, director of the precision vaccines program at Boston Children’s Hospital and a member of the FDA’s COVID vaccine advisory council.

Instead, the FDA allowed vaccine makers to opt for a common alternative known as 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 of them, and then try to coax the same results out of another population (kids).

The procedure is more difficult than it appears. Experts advised me that the first and most important factor for each child’s immunization must be safety. The more vaccination there is in each shot, the more negative effects there may be. As a result, firms want “the smallest dose feasible that will still be as effective as possible,” Buddy Creech, a pediatric infectious disease expert at Vanderbilt University Medical Center, where he’s overseeing one of Moderna’s pediatric vaccination trials, told me in January.

After experimenting with different amounts of mRNA in early-stage studies, Pfizer cut their doses in roughly thirds, delivering 30 micrograms to people over the age of 12, 10 micrograms to people aged 5 to 11, and three micrograms to children under the age of 5. Meanwhile, Moderna divided the dose in half, providing 100 micrograms to those aged 12 and up, 50 micrograms to those aged 6 to 11, and 25 micrograms to youngsters under the age of 6.

Each company then conducted much larger trials to see if the antibody data—the information they’d need to offer to the FDA—would hold up, and to keep an eye out for negative side effects. At this point, both corporations claim to be meeting safety standards.

According to the information made public by the companies, “the rates of major fevers are about on a level with other vaccines” we administer to children, which is encouraging, Creech said. (In the Pfizer experiment, researchers classified fevers as “severe” when they exceeded 102 degrees Fahrenheit; in the Moderna trial, a few children experienced fevers that exceeded 104 degrees.)

However, two doses of Pfizer’s three-microgram dosage, which is currently in testing, fell short in the 2-to-4-year-old group, prompting the company to add a third shot for all children under the age of 5. Moderna’s two 25-microgram doses for children under the age of six, on the other hand, produced enough antibodies to compete with adults.

If antibodies were the end-all-be-all, Moderna’s infant-and-toddler vaccination would be a shoo-in. However, they are not. When efficacy numbers are available, they tend to override everything else—and during Moderna’s trials, enough illnesses, many of which were caused by Omicron, swept through the children engaged in the study that the business suddenly had enough data to assess the vaccine’s overall performance. Some may claim that this is where the shot began to go short.

Back in June 2020, when COVID vaccinations were still in the early stages of development, the FDA stated that successful COVID-19 shots would need to “prevent disease or reduce its severity in at least 50% of those who are vaccinated.” The results in adult populations went well over that mark; now, the evidence from children appears to be barely comprehending it.

( The FDA did not respond to my concerns regarding whether the 50% efficacy threshold extended to children who were supposed to be able to get by with immunobridging. “We are dedicated to performing a fast and complete examination of the existing data and information on the use of COVID-19 vaccinations in children,” a spokeswoman said.

The figures for newborns and toddlers haven’t been… stellar. “No one would disagree that 40 percent protection is wonderful,” Chandy John, an Indiana University doctor, told me. It’s tempting to blame the dose here: Perhaps a bit more mRNA would have pushed Moderna’s stats over the top.

Similar concerns have been raised regarding Pfizer’s vaccine, which did not protect 5- to 11-year-old children against infection or sickness for as long as expected in recent research, despite the fact that the 10-microgram dose they received met its immunobridging standard in clinical trials. (However, another study published shortly after produced more optimistic outcomes.) Perhaps immunobridging caused each company to underestimate their dose size.

Such inquiries are permissible at this time. When researchers haven’t yet found a precise antibody level above which people can be regarded well guarded against disease, immunobridging can be a bigger bet. According to Levy, if such a threshold exists for SARS-CoV-2, it may not translate completely across age groups. Perhaps children require more antibodies than adults to achieve the same effectiveness levels. Immunobridging was the most realistic approach for providing immunizations to children quickly, according to Levy. However, “it may not tell the entire story.”

However, Levy and the other specialists I spoke with tend to point to another culprit: the virus itself. Realistically, with children’s trials using two doses of the original-recipe vaccine during the Omicron era, the shots were unlikely to produce the same knockout numbers as the adult shots. There are now too many viral variants in the picture; Langel told me that Moderna’s ballpark efficacy of 40% is “sort of what we would expect,”, especially with transmission rates as high as they were this winter. It’s even better than the efficacy of flu vaccines in years with vaccine-strain mismatches.

Anthony Fauci expressed similar comments during a press conference last week. Moderna’s new statistics, he says, are “very analogous” to what scientists have been seeing in other groups recently. Two mRNA dosages in people simply aren’t as effective as three. “All in all,” Fauci remarked, “the data looks fairly good.” It’s probable that if we reran tests in adults today against Omicron, two full-size dosages would also fail to achieve 50% efficacy.

We may be able to achieve forty-ish percent efficacy against symptomatic sickness with two doses of mRNA vaccines without losing safety. Perhaps increasing the dose for children would improve the numbers, but “we have to weigh the cost in terms of adverse events,” says Kathryn Edwards, a pediatrician and vaccination expert at Vanderbilt University.

(Edwards is a former FDA vaccine adviser who now serves on a safety-monitoring board for Pfizer’s injection.) Fevers in the youngest children are especially concerning because they can produce (self-resolving) seizures, which, while uncommon, could provide a significant barrier to approving a new vaccine for use.

Myocarditis could also be a problem: Moderna’s vaccine, which contains more mRNA in each injection, appears to have resulted in a somewhat greater incidence of the rare heart inflammation issue in young males than Pfizer’s. (In Moderna’s under-6 trials, no incidences of myocarditis were detected.) “I’m not sure we need higher doses,” Creech said. Rather, he and others believe that success will be determined by the number of dosages and their timing. Vaccine manufacturers may include a third or fourth injection, or they could schedule the shots further apart or both. They may even contain an extra immune-boosting substance to boost the body’s defenses even more.

Some specialists stated that they were already considering a 40-ish percent efficacy as a sort of intermediate efficacy; third doses for children now seem more or less probable. Moderna’s chief brand officer, Kate Cronin, told me in an email that the firm is already considering seeking the FDA to approve a pediatric booster in the future, ahead of its request for emergency use clearance for the under-6-shot. According to Jerica Pitts, a company spokesperson, Pfizer’s under-5 vaccine will almost probably be a three-doser, to begin with, and the company is “considering the third dose” in 5-to-11-year-olds as a booster.

covid vaccine
pic credit: NBC News

Sallie Permar, a vaccine expert, immunologist, and pediatrician in chief at New York-Presbyterian Hospital and Weill Cornell Medicine, told me just a few weeks ago that she believed a COVID vaccine for children would reach 50 percent efficacy before receiving the FDA’s emergency authorization. Still, if Moderna’s 40 percent efficacy estimate holds true, “I’m fine with it,” she said. Perhaps if children were still infected with the original coronavirus, effectiveness figures would match what earlier trials had generated. However, the original SARS-CoV-2 is no longer present.

Vaccination is a sequence of decisions made by institutions and individuals alike: allowing a new shot, proposing a booster, and determining whether or not to sign up for any dose at all. Data can assist inform these decisions, but they ultimately depend on the purpose they’re designed to achieve, which could be just protecting against serious disease—or preventing as many infections as possible.

The eventual goal of COVID vaccination is still unclear in the United States. And, because fewer children are hospitalized with the illness, the potential benefits of immunization are murkier. In reality, such a small fraction of children in the clinical studies became critically ill that neither Moderna nor Pfizer has yet generated solid efficacy numbers against severe disease.

COVID-19, on the other hand, causes significant illness in youngsters. Since the beginning of the epidemic, the virus has killed over a thousand children, and thousands more have developed a deadly inflammatory illness known as MIS-C. The Omicron wave hospitalized more young Americans—the least vaccinated Americans—than any other surge. Any opportunity to avoid unpleasant outcomes is desirable. Vaccines should shine in this area.

COVID vaccines have proven to be the most effective at protecting people against the most serious forms of the disease in all other age groups, and “there’s no reason that wouldn’t hold true” in the youngest among us, says Ibukun Kalu, a pediatric infectious-disease specialist at Duke. Again, experts must rely on comparisons between adults and children.

But the tenacity of our vaccines’ defenses against serious disease should outlast even the glitches of cross-age immunobridging and the wiliness of Omicron; that’s essential to how the immune system should function. Even in the worst-case scenario, in which efficacy against serious outcomes was also exactly 40%, it “would save a lot of kids from being hospitalized,” according to John of Indiana University.

If the underlying question before the FDA is what performance level it will accept for children’s COVID vaccines, Permar and other physicians believe that threshold must assure that the shots at the very least prevent the most dangerous kinds of disease. Moderna appears to be betting a little on this. Cronin stated that the antibody levels reported in late-stage trials “should provide protection against the critical and deadly disease.”

Creech also highlights an advantage of vaccines that efficacy numbers alone may not represent. The term “symptomatic disease” can refer to anything from a little case of sniffles to a severe case of COVID-19 that can place someone in the ICU or even kill them. However, when post-vaccination illnesses arise, they are generally less severe, essentially pushing persons to the milder end of the severity continuum. Creech told me that as a dad, he still thinks it’s a big deal to shorten a child’s sickness course, even if the shots can’t completely prevent symptomatic disease. (Vaccines may also aid in the prevention of extended COVID, which affects children of all ages.)

Every year, specialists advocate flu shots, despite the fact that those vaccines, too, have a 60 percent success rate against sickness.

These arguments are unlikely to influence the FDA, especially if case rates remain low. The United States has almost fully relaxed pandemic measures; the FDA’s upcoming debates may reflect that mentality, burying pediatric injections in the muck. Vaccines that are “good enough” to be approved when the virus is rampaging over the country may not pass muster during a quieter period when the costs of not vaccinating are lower. And, in the absence of actual efficacy data against severe disease, that aspect of the risk-benefit equation will be difficult to balance.

If Moderna is approved by the FDA and CDC first, it may receive a conditional approval—recommended just for high-risk children, for example. In the worst-case scenario, if the FDA is displeased with Moderna’s final results, the agency may request that the business add a third dose before receiving the official go-ahead.

The finish lines established by the FDA and CDC will not be the last for the injections to cross. For the youngest among us, the final arbiters of which shots are and are not worth their salt are America’s parents, who have been hesitant to line up their children for injections thus far. The uptake of COVID vaccines has decreased as they have moved down the age spectrum; with so many people wanting to put the pandemic behind them, these tiny shots may be our least welcome yet. In many ways, the fate of the next round of pediatric vaccines may reflect Americans’ current sense of crisis more than anything else.

For the time being, the future is hazy, which is why Ganapathi, of Boston Children’s Hospital, was so desperate to secure safety for her 5-year-old son. (Her youngest kid will turn two in July and, hopefully, will soon join his older brother in the immunization line.) She assured me that the next surge is a matter of “when not if.” She momentarily pondered delaying giving Pfizer to her son until Moderna’s higher-dose, longer-interval under-6 shot arrived. However, only Pfizer was available at the time. “Do I desire a more effective vaccine against symptomatic disease?” “The answer is yes,” she said. “However, we can only work with what we have and make the best of it.”

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