More than two years into the pandemic, the United States and Canada have become the first nations to approve two mRNA vaccines for children as young as six months. But the vaccines, made by Pfizer–BioNTech and Moderna, have proven less effective against the Omicron variant. So some parents are considering extending the interval between initial doses — a trick that might make the vaccines more potent.
Previous studies have found that waiting longer than the three to four weeks typically recommended between the first two shots might boost immunity and lower the risk of side effects1. Most studies looked at an eight-week to four-month interval2. But no studies or clinical trials have investigated the effect in infants and toddlers. With a new variant, BA.5, sweeping the globe, many scientists think that it is better to fully vaccinate young children sooner, rather than waiting for their second dose and risking infection.
“You’re delaying the vaccine for a theoretical benefit in the midst of a surge that can do actual harm to children,” says Jessica Snowden, a pediatric infectious-disease specialist at the University of Arkansas for Medical Sciences in Little Rock.
Time to build a defence
Earlier this year, Pfizer, based in New York City, and BioNTech, headquartered in Mainz, Germany, reported in an initial trial that two doses of their COVID-19 mRNA vaccine were less than 50% effective against symptomatic disease in children between six months and four years old. By including a third dose, Pfizer–BioNTech upped the efficacy to 80%, although scientists note that it was such a small trial that the true efficacy could be as low as 14%. In June, the Pfizer–BioNTech shot was approved in the United States for use in this age group. The company recommends administering the first two doses three weeks apart and giving the third dose at least two months after the second.
The mRNA vaccine made by Moderna, based in Cambridge, Massachusetts, requires only two doses, administered four weeks apart. The company’s data suggest that two shots are 51% effective at preventing symptomatic COVID-19 infection among children aged six months to two years, and 37% effective at preventing infection among kids aged two to five years. Moderna’s vaccine was approved for use in the United States the day after the Pfizer–BioNTech shot, and was approved for use in Canada in July.
Those interval recommendations can be traced back to the initial clinical trials in adults in 2020. When faced with a global pandemic that was killing roughly 3,000 people in the United States each day at its peak, adults needed protection as quickly as possible. “Time was lives,” says Katelyn Jetelina, an epidemiologist at the University of Texas Health Science Center in Houston. “There’s no science behind why we picked that three-week or four-week window. It’s pretty arbitrary.”
The idea of waiting a little longer than the three- or four-week window makes sense immunologically, because the immune system needs time to build its defence. Once a vaccine antigen enters the body, immune cells in the blood, known as B cells, start producing antibodies after a few days. Only some of those antibodies will be able to latch onto the virus and block it from entering a cell. The B cells then mutate to enhance their antibodies’ chance of fighting the virus — a process that takes time. The longer the delay before the second injection, the better the immune system will be at recognizing the onslaught and reacting quickly.
That was seen in Canada in March 2021. Vaccines were scarce, so the country opted to delay second shots in adults to reach more of the population with at least one dose. Although the decision was controversial, it allowed researchers to compare the immune response in people who received the first doses three or more months apart versus four weeks apart3, once vaccine availability had increased. They found that a longer interval produced a greater number of more powerful antibodies. Several studies in Britain produced similar results4.
Some studies5 have also shown that a longer vaccine interval translates beyond the laboratory, protecting against hospitalization, and offering a modest increase in protection against infection in one preprint2. But whether that immunity lasts beyond a few months remains an open question. A preprint6 posted this month found that the protection against infection offered by the Pfizer vaccine drops rapidly in older children, regardless of vaccine interval.
Although there is mounting evidence for longer vaccine intervals, many scientists worry because the studies were performed mostly in adults and adolescents — not young children, whose immune systems are not fully developed. But Danuta Skowronski, an epidemiologist at the BC Centre for Disease Control in Vancouver, Canada, notes that most pediatric vaccines are given at intervals longer than three to four weeks.
The US Centers for Disease Control and Prevention (CDC) recommends that children aged six months to four years wait three to eight weeks between the first two doses of the Pfizer vaccine, and children aged six months to five years wait four to eight weeks between the first and second Moderna shots. Canada’s National Advisory Committee on Immunization recommends an eight-week interval for the Moderna vaccine.
The CDC website notes that, on the basis of studies in adults and adolescents, an interval of up to 8 weeks in people aged six months to 64 years might help to increase antibody levels and reduce the small chance of two very rare side effects: myocarditis and pericarditis, which involve inflammation of the heart. No cases of either condition occurred during clinical trials involving young children. And the rates of these conditions in vaccinated children aged 5 to 11 years are barely above the rate in the general population.
So, although the government’s recommendation errs on the side of caution, many scientists think that might be overblown — at least with respect to these rare side effects. “They are saying it because it’s technically unknown, but we have many reasons to believe that myocarditis will be low if not non-existent in these under 5-year-old kiddos,” Jetelina says.
At the end of the day, Snowden thinks the theoretical benefits of parents waiting longer to get their child’s second dose don’t outweigh the risk of contracting COVID-19 during the wait. Jetelina, too, will follow Moderna’s four-week schedule, as opposed to waiting for a wider gap. “We have to remember that these kids aren’t necessarily protected during that gap,” she says.
Skowronski says it is worth thinking about the long-term benefits that a longer interval would confer. “In Canada, we’ve adjudicated that overall, it’s better to wait for the sake of the long term,” she says. And Jetelina notes that not all children are currently in high-transmission settings. “It’s all about risk perception,” she says.