COVID-19 and paediatric trials: By when will our children be vaccinated?

On Thursday, the Drugs Controller General of India (DCGI) granted permission for phase 2/3 clinical trial of India's Bharat Biotech's Covaxin COVID-19 vaccine in the age group of 2 to 18 years in the country. Bharat Biotech has already conducted trials on children 12 years and above in India.

If Covaxin clears paediatric clinical trials in India, a total of three vaccine candidates would be available for children in India. Zydus Cadila’s ZyCoV-D has been tested on children above 12 years while on Monday the USFDA authorized use of Pfizer’s mRNA vaccine on kids as young as 12 years.

Barring the Pfizer announcement, globally, COVID-19 vaccine for children is still in the trial stage and that leaves us with a lot of questions. 

Status of paediatric trials of vaccine candidates

Pfizer 

Pfizer began testing the Pfizer–BioNTech vaccine in children under 12 in late March. The Phase 1 trial has already begun, and the phase 2-3 trial is expected to begin mid-May. 

On May 10, the Food and Drug Administration (FDA) expanded the emergency use authorization for the Pfizer-BioNTech COVID-19 vaccine to include adolescents as young as 12 years old. The company expects to request an EUA for 6 months to 2 years old during the final quarter of 2021, it said during its earnings call last week.

Moderna

On March 16, Moderna announced that it has begun phase 2/3 study of mRNA-1273, the company’s vaccine candidate against COVID-19, in children ages 6 months to less than 12 years. The aim was to enroll approximately 6,750 pediatric participants in the US and Canada ages 6 months to less than 12 years. 

The company could request an EUA for 2- to 11-year-olds by early fall.

Johnson & Johnson (Janssen)

The company expanded its vaccine trial in April to include 12- to 17-year-olds. The company has not announced when it expects to have results from this study. 

AstraZeneca 

AstraZeneca has also been doing vaccine trials on children in the age groups of 6-17. However, no data is available yet. The trial will be starting in the UK.

Sinopharm

According to Chinese state media, a clinical trial has found a COVID-19 vaccine in development at a Sinopharm subsidiary to be safe in children aged three to 17 years. Sinovac said its COVID-19 vaccine is safe in children ages 3-17, based on preliminary data, and it has submitted the data to Chinese drug regulators.

Why is it important to vaccinate children?

For any country, herd immunity—or when enough people in a given community have antibodies against a specific disease—cannot be achieved until children get vaccinated. Children can also spread the disease to other people, meaning that vaccinating them is vital both for their own safety and to help bring the pandemic under control.

Children rarely develop severe forms of COVID-19, and deaths from the disease are rarer still. But on rare occasions, kids who’ve experienced even mild infections can later develop a sometimes deadly condition called multi-system inflammatory syndrome in children (MIS-C), a rare but serious condition, which causes inflammation of multiple organs, often the heart. What’s more worrisome is that many children and teenagers who have developed MIS-C, which can occur several weeks after contracting the coronavirus, did not have typical COVID-19 symptoms when they were infected. 

Then there is this phenomenon what the scientists claim as "long Covid", symptoms that linger for months after infection. It’s not clear how much this affects children. “However, we do see teenagers that, a month or two after an infection, maybe can’t run on the track as well as they did before, or if they are swimming, they can’t catch their breath. Basically, they are not really back to their ‘normal’ before the infection,” Dr Inci Yildirim, MD, PhD, a Yale Medicine pediatric infectious disease specialist and a vaccinologist, was quoted by media reports as saying. 

Evidence is building that vaccines might block transmission of SARS-CoV-2, so vaccinating children could have beneficial knock-on effects in the wider community.

How's the trial done?

For the first phase of the trial, the company will identify the preferred dosing level for three age groups – between 6 months and 2 years old, 2 and 5 and from 5 through age 11. The kids will begin by receiving a 10 microgram dose of the vaccine before progressively moving to higher doses, Pfizer said. Participants also have the option to take 3 microgram doses. The Covid vaccine for adults requires two shots that contain 30 micrograms per dose.

Researchers will then evaluate the safety and effectiveness of the selected dose levels in the next phase of the trial, with participants being randomly selected to receive the vaccine or a placebo, the company said. After a six-month follow-up, kids who received a placebo will have the opportunity to receive the vaccine, it said.

How will trials in kids work?

Unlike the adult group where the participating individual gives the consent, a legal guardian agrees to a child's involvement in trials. However, researchers are also obliged to obtain assent from any child participants old enough to understand the trial.

The first recipients—who will be on the older end of the spectrum, although trials will eventually include children as young as six months—will receive a range of doses to find one that triggers a strong immune response without too many side effects.

Once an ideal dose is identified, several thousand participants will be randomized to receive either two doses of vaccine or of a placebo injection. Researchers will then follow the children for months and even years, to study the safety and effectiveness of the vaccines.

Because of these potential differences in responsivity, trial participants will be grouped by age: 6 months to 2 years old, 2 to 6 years, and 6 to 12 years. Each age group, starting with the oldest, will receive a low dose of the vaccine. Once that is proven to be safe, the dose will be increased to see how the children tolerate it and if it is effective. If the lower dose is equally safe and effective, that is what will be used. 

For frame of reference, adult dosing for the Moderna vaccine is 100 micrograms, Dr Yildirim was quoted in a yalemedicine.org report. For children, the dosing will start at 50 micrograms for the older kids and 25 micrograms for the youngest. 

Difference in response 

Children’s immune systems are brimming with cells that haven’t seen pathogens, so they tend to produce a strong immune response to vaccines, Donna Farber, an immunologist at Columbia University in New York City, was quoted in a Nature.com report. 

Hence, researchers will need to strike a balance between triggering a strong immune response and minimising the side effects that come with it. 

Early trial results have shown that 12–15-year-olds who received two standard doses of the Pfizer–BioNTech vaccine developed substantially higher levels of virus-blocking antibodies than did 16–25-year-olds in earlier trials. 

In ever-younger children, researchers will want to make sure they’re not interfering with immunity generated by routine childhood vaccinations

Health experts remind that children under five who might still be due to receive boosters of polio vaccines and jabs against measles, mumps and rubella, as well as other immunizations,  will need to be up to date on their vaccination schedules to participate. 

Vaccine efficacy

In adults, where the sample size is comparatively larger, the efficacy of a vaccine is determined by  compelling differences in the rates of disease between the group that received a vaccine and a placebo. 

However, paediatric trials will involve only a few thousand children. Hence, there might be too few symptomatic infections to measure efficacy in the same way. According to Kawsar Talaat, an infectious-disease physician and vaccine scientist at the Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland, it makes more sense to look at immune markers after vaccination. 

“If we see the paediatric immune responses are the same or better than we saw in adults, we can make inferences that the vaccine will be effective," Talaat was quoted by Nature.com. Both the Moderna and the Pfizer–BioNTech trials list such markers as their primary measures of success.

Paediatric trials should look for immune responses that might exacerbate disease, as well as signs that participants are developing immune reactions similar to those seen in MIS-C.