Babies and preschool-aged children in the United States could soon be eligible to get vaccinated against COVID-19, as US health authorities consider approving the first coronavirus jab for kids under the age of five.
Last week, Pfizer and its pharmaceutical partner BioNTech applied for emergency-use authorisation for their COVID-19 vaccine for children aged six months to four years, following a request from the US Food and Drug Administration (FDA).
"Having a safe and effective vaccine available for children in this age group is a priority for the agency and we're committed to a timely review of the data, which the agency asked Pfizer to submit in light of the recent Omicron surge," acting FDA Commissioner Janet Woodcock said in a statement.
On February 15, the FDA will convene a panel of independent advisers to assess the data and decide whether to recommend the low-dose vaccine, which, if approved by the FDA, will require additional sign-off from the US Centers for Disease Control.
But with Pfizer still testing a third shot in children under five, several key questions remain about how many doses will be needed, and how well the vaccine might work.
Then there's the question of if — and when — it might be approved in Australia.
Here's what we know so far.
What have the clinical trials found?
In mid-December, Pfizer announced it had begun testing three doses of its COVID-19 vaccine in children under five, after two doses didn't appear strong enough for all kids in this age group.
The vaccine they're testing is a 3-microgram dose, which is less than a third of the dose authorised for five- to 11-year-olds, and one-tenth of an adult dose.
A preliminary analysis found that among children aged six months to two years old, two shots created an antibody response comparable to that seen in older children and teens.
But in children aged two to four, the response was less robust, prompting the addition of a third dose for all children in the trial.
"The Pfizer trial is being done in a very staged way, which is appropriate because it's a new vaccine," said paediatrician Nick Wood from Australia's National Centre of Immunisation Research and Surveillance.
"We started with adults, we've gone down to 12- to 15-year-olds, then to five- to 11-year-olds, then two- to four-year-olds, and then under twos.
"In that process, [researchers] build on the safety data from older age groups, and importantly, build on the immunity data."
During the trial, children received their first two vaccine doses three weeks apart, followed by a third dose at least two months later.
Dr Wood said blood samples would have been taken before and after vaccination to see whether trial participants achieved adequate immune responses — in this case, antibody levels similar to those known to protect older children from COVID-19.
"It could be that in two- to four-year olds, the 3-microgram dose was a little bit low, and that's why they're now discovering that they might need to give three doses," he said.
Data on the third dose is not expected until late March, and Pfizer is yet to publicly release detailed safety and efficacy data on the first two shots.
Why are they applying for authorisation now?
While Pfizer is still collecting and analysing data on a third shot, federal regulators took the unusual step of urging the company to submit the data it had available on the first two doses.
In the US, child hospitalisations from COVID-19, while much lower than adult hospitalisations, have spiked during the Omicron variant surge, most notably among kids under the age of two.
"The need for a safe and effective vaccine for our youngest children is significant, particularly given the rapid spread of the Omicron variant, the notable rise in the number of hospitalisations in young children with severe disease, and the possibility that future variants could cause severe disease in those who are unvaccinated," Peter Marks, director of the FDA's Center for Biologics Evaluation and Research, said in a statement.
According to Pfizer, the company is seeking authorisation for the first two doses of a planned three-dose regimen, with a promise to deliver more data to the FDA in the coming months.
"Ultimately, we believe that three doses of the vaccine will be needed for children 6 months through 4 years of age to achieve high levels of protection against current and potential future variants," Pfizer CEO Albert Bourla said in a statement.
Rather than waiting until the end of March for Pfizer's full data set, it appears the FDA may authorise two shots now, with the expectation of endorsing a third dose later (if there is adequate safety and efficacy data to support it).
"If two doses are authorised, parents will have the opportunity to begin a COVID-19 vaccination series for their children while awaiting potential authorisation of a third dose," Dr Bourla said.
It's unclear, however, if different recommendations will be made for six-month to two-year-old children and two- to four-year-old children.
Dr Wood said the decision by a regulatory body to potentially approve a two-dose vaccine on the assumption that a third dose would be needed was "a bit unusual".
"In an ideal world, you would wait until they've got the third dose immunogenicity and safety data and then say, 'this is the right dose amount, the right number of doses, and the right dose interval'."
But paediatrician and infectious diseases physician Chris Blyth stressed that an application to the FDA did not necessarily mean immediate approval.
"I think the FDA is very much reasonable to reach out to try and get as much information as possible to inform its processes going forward," said Professor Blyth, director of the Wesfarmers Centre of Vaccines and Infectious Diseases at the Telethon Kids Institute in Perth.
"It's absolutely not a fait accompli that they will approve it."
What are the risks and benefits?
Just like giving the green light to a new vaccine for adults, approving a vaccine for children involves a careful calculation of benefit compared to risk.
Since children tend to be less severely affected by COVID-19, the balance of risks (eg. unwanted side effects) and benefits (eg. protection against disease) is even finer, Professor Blyth says.
"In a decision on whether children need vaccination or not, we absolutely need to see the data from Pfizer about how effective this vaccine is likely to be, and how safe it is," he said.
Direct benefits of vaccinating children may include protection against infection, and more importantly, severe disease, which while uncommon, can occur (children with underlying medical conditions are more at risk).
COVID vaccines have also been shown to reduce the risk of longer term complications in children, including a serious but rare post-COVID-19 condition called multi-system inflammatory syndrome.
When it comes to indirect benefits, vaccination may help to reduce COVID-19 transmission, thereby helping to protect other vulnerable members of the community.
But Dr Wood said it would take time to fully understand how effective Pfizer's COVID-19 vaccine was at preventing infection and serious disease in children under five.
"It's very hard to get really robust effectiveness data from a small number of study participants," he said.
Pfizer's clinical trial of children aged 6 months to 12 years currently involves 8,300 participants.
"Usually, we get more accurate estimates when [the vaccines] get rolled out into the community," he said.
Asked whether the argument for vaccinating children had changed over the course of the pandemic, Dr Wood said the sheer volume of cases caused by Omicron may have tipped the scales.
"Even if the hospitalisation rate is 1 per cent or less, there's more virus around, so we're going to see more hospitalisations," he said.
"The other problem is that we had Delta last year, and since November we've had Omicron. Who knows what's next?"
What do we know about safety?
While Pfizer is yet to publicly release its trial data, the company says no safety concerns have been identified to date.
"The information provided in press statements by the company is reassuring that they're not seeing any significant safety signal at this lower dose," Professor Blyth said.
"But we also need to balance that with the knowledge that the actual clinical trials are still relatively small … so [they] will not have the capacity to detect very rare side effects."
That being said, both Professor Blyth and Dr Wood said they were reassured by the safety data emerging among five- to 11-year-olds who had received a COVID-19 vaccine.
He added that side effects would be monitored very closely to ensure the vaccine was well tolerated in younger children.
"That's part of why [Pfizer] went for a lower dose, because what we don't want in the really young kids is a strong fever response," he said.
Professor Blyth agreed that the vaccine's safety profile needed to be watched "very closely", but that there was nothing to suggest side effects might be more frequent or severe in younger children.
"In the five- to 11-year-old age group who are receiving a reduced dose … the nature of side effects is very similar [to adults], and the rate of side effects appears lower compared to adolescents and young adults," he said.
"I think a similar side effect profile is likely to be seen in [the under five] age group."
When will the vaccine get here?
It's too early to say if or when Pfizer might apply for similar authorisation in Australia — a process which would be handled by the Therapeutic Goods Administration.
Dr Wood said he suspected Pfizer may wait until the FDA makes a decision before approaching other regulatory bodies.
"It's hard to know in the absence of seeing the full trial data," he said.
When it comes to how vaccines might be received by parents of children in this age group, Professor Blyth said it was likely to be mixed.
"I think we've been really encouraged by the enthusiasm of parents of children aged five to 11 to [get their children] vaccinated against COVID-19," he said.
"And so I do think Australian parents would be interested in vaccinating their younger children, particularly in areas with significant COVID activity.
"I also think that some parents will remain hesitant about using a COVID vaccine in that age group, given that the risk is clearly lower than in other age groups."
