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Wednesday, February 8, 2023

The Next Covid-19 Battle Will Be About Vaccinating Kids

On Monday, the Tennessee Department of Health fired its top vaccine official, Michelle Fiscus. Her transgression: In May, she had sent a memo to pharmacies and physicians in the state, relaying a Tennessee Supreme Court decision that allows teens to seek medical care, including vaccinations, without their parents’ consent. At the time, the Food and Drug Administration had just authorized the Pfizer vaccine for 12- to 17-year-olds, and one for the Moderna vaccine was soon to follow.

Fiscus’ memo was approved by the governor’s staff, and it contained no policy changes. The legal ruling it discussed was handed down in 1987. State legislators, though, accused her of “prodding” children to seek the vaccine. She was summoned to two hearings; at one, a legislator proposed dissolving the entire state health department in retaliation.

In a statement she gave to The Tennessean Monday evening, Fiscus said that, to protect itself, the department has shut down all its communication campaigns about vaccination. “Not just Covid-19 vaccine outreach for teens, but ALL communications around vaccines of any kind,” she wrote. “No back-to-school messaging to the more than 30,000 parents who did not get their children measles vaccines last year due to the pandemic. No messaging around human papillomavirus vaccine to the residents of the state with one of the highest HPV cancer rates in the country.” (On Tuesday, The Tennessean confirmed that vaccine promotion, and vaccination clinics held at schools, had been shut down.)

Fiscus’ firing came two days after a crowd at the Conservative Political Action Conference in Dallas cheered an announcement that the Biden administration hasn’t achieved its goal of getting one dose of vaccine into 70 percent of Americans by July 4th. It also came three days after the Centers for Disease Control and Prevention relaxed the agency’s previous guidelines about wearing masks inside school buildings. Add those events together, and they’re a storm siren for the next Covid battle, this time over vaccinating children—which will arrive as the virus’s Delta variant advances and the school year is about to begin.

Clinical trials underway now are testing the safety, efficacy, dosing, and timing of mRNA vaccines for kids between the ages of 11 years and 6 months; about 4,500 children are in Pfizer’s trial, and about 7,000 in Moderna’s. A Pfizer official said in June that the first request for emergency authorization should be sent to the FDA in September or October. (Johnson & Johnson is only now beginning trials in teens and has not yet included younger kids.)

Those trials are scattered across medical centers in the US and several European countries—more sites than were initially planned for, according to several principal investigators, because the companies feel it’s urgent to gather data and move toward approval as rapidly as possible. That's because, now that adults can get vaccinated, children make up a larger proportion of those getting sick from Covid.

Kids represented 14.2 percent of all US cases in July, compared to 2 percent in April 2020, according to the American Academy of Pediatrics. Just in the US, more than 4 million children have fallen ill from Covid. And though most experience only mild illness, 16,623 had been hospitalized as of July 8, and 344 had died. As of the end of June, 4,196 children and teens had developed MIS-C, the perplexing and sometimes fatal inflammation that occurs after Covid infection and affects the heart, lungs, kidneys, and brain.

“Covid is a risk for children,” says Mark Sawyer, a professor of pediatrics at the UC San Diego School of Medicine and temporary voting member of the FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC), which reviewed evidence submitted on behalf of the Covid vaccines. “The reported deaths are at least as bad as the worst influenza season in terms of pediatric deaths, and probably a little worse than that. That doesn't even get us into what long-term consequences could occur, either from MIS-C or so-called long-haul Covid. And that doesn't even touch the public health argument, which is that we need children not to be bringing Covid to their grandparents and others who are at extremely high risk.”

As many researchers have pointed out over the years, children aren’t just small adults. Once past the teen years, adults have mostly achieved their final height and size—barring big gains or losses in fat and muscle—and, crucially, a settled immune balance with the world. But children are changing all the time, not just in size and muscle mass, but in how their immune systems defend them against the world.

“The spectrum and the strength of the immune response changes over years,” Inci Yildirim, a vaccinologist and associate professor of pediatrics and global health at the Yale School of Medicine, told WIRED by email. “For example, a healthy 13-month-old child usually has a higher number of lymphocytes, which is one of many components of the immune system playing a role in how we respond to the vaccines, compared with a healthy 15-year-old teenager.”

Even though we have data on how adults respond to the Covid vaccines—from the clinical trials that got the vaccines their emergency authorizations, and also from real-world observations—we can’t assume that children’s reactions will be the same. Weirdly, they might be better. For instance, after the introduction of the HPV vaccine (which prevents cancers of the cervix, neck, and throat), federal authorities decided that 9- to 14-year-olds need only two doses, not three as older teens and adults do, because the younger kids’ response to the vaccine was so strong.

But because Covid is still a new and under-researched disease, we have to do clinical trials to explore what those reactions might be. As the World Health Organization highlighted in a meeting in May, we still have not identified the “correlates of protection” that define immunity. Those would be agreed-upon metrics for immune response—a minimum number of antibodies, for instance, or measurements of the presence of T cells— that would indicate when someone who has received a vaccine is protected against infection. If we could define those correlates, we could skip placebo-controlled trials for head-to-head studies comparing different vaccines, or even use blood tests. Since we don’t, full trials in kids, patterned on the adult ones, are necessary.

“We should not simply recommend the vaccine for children because it's available for older age groups,” says Walter A. Orenstein, a physician and director of vaccine policy and development at Emory University, who previously led immunization programs at the Bill & Melinda Gates Foundation and the CDC. “We need to determine what the optimal doses are and look at what the safety factors are, so that the FDA has a reasonable data set upon which to make a judgment.”

And some safety issues have shown up. In June, the CDC disclosed that 226 people under 30, including 79 16- and 17-year-olds, had developed inflammation in or around their hearts after receiving the vaccine. The agency and its advisers examined the problem in a meeting of the Advisory Committee on Immunization Practices, but did not support any change in vaccine recommendations for teens.

Despite Covid vaccines being subjected to politicized controversy, the trials in younger children haven’t had any difficulty recruiting kids. “We had far more people interested than we have spaces,” says Kawsar Rasmy Talaat, a physician and associate professor of international health at the Johns Hopkins Bloomberg School of Public Health, where she leads a trial of the Pfizer vaccine for kids 12 and under. “Before we even knew we were a site, we had names on a list, parents who said, ‘If you do this, I want my kid to be in the study’—hundreds and hundreds of names.”

(Talaat and other principal investigators said many of the parents enrolling their kids turned out to be faculty from medical schools and other parts of universities conducting the trials, who happened to hear about the trials early because of their jobs. That could turn out to be a problem, because it may have accidentally created trial populations that are low on diversity—not necessarily of race or national origin, but of economic status and living conditions, both of which affected who was vulnerable during Covid’s first wave.)

Within the trials, child entrants are stratified—separated into groups—according to age ranges. The Stanford University School of Medicine, for instance, joined the Pfizer Phase I safety trial for infants and toddlers, who were divided into groups of kids between the ages of 6 months and 2 years, and then kids who were at least 2 but younger than 5. Stanford now is one of the sites hosting Phase II efficacy trials for the under-5 group, and also is running part of the Phase II and III trials for the 5- to 11-year-olds. (A Phase III trial also tests efficacy, but in a larger group, because some rare effects are only observable when more participants are added.)

The Pfizer trial those studies are part of is already returning information showing that the vaccines may create stronger immunity in kids than in adults, according to Yvonne Maldonado, a pediatrician and professor of epidemiology and population health and principal investigator of the Stanford trial site. “The first data that was put out in May, that was submitted to FDA, showed that the Pfizer vaccine had elicited much higher antibody titers in children than it did in adults,” Maldonado says. Those findings could well lead, in the final authorizations, to vaccines containing much smaller doses of active ingredients than are present in the adult vaccines.

Overall, it seems there have been no major setbacks. But there’s a difficult challenge approaching. Once trial data determining children’s doses and shot schedule passes the FDA—as either an emergency use authorization or a full new drug approval—the campaigns that distribute the shots will be run by the individual states, in the same way that the adult vaccines were. This spring, that was chaotic.

What might save the child vaccine, and the health of vulnerable elderly and immunocompromised people in contact with children, is that the system to distribute the shots won’t have to be built from scratch. American public health agencies already recommend that children and teens receive 16 different vaccines by the time they turn 18—against measles, mumps, rubella, diphtheria, pertussis, two types of hepatitis, rotavirus, chicken pox, flu, and so on—and many of those vaccines require multiple doses. A massive infrastructure delivers, tracks, and pays for those shots: physician practices, commercial pharmacies, health department clinics, and county health fairs; health department registries and state school-entry standards; private insurers and an array of federal buying programs. (Outside the US, the mix of funding comes from national governments and international philanthropies, and the vaccinators may be doctors’ offices, public health clinics, or volunteer-run sites.) Adding a Covid vaccine into that distribution would not be trivial, but it should not be impossibly hard.

“If you want to get vaccines out to a population, the most practical way to do that is through pediatric immunization,” says Ofer Levy, a pediatric infectious disease clinician and director of the Precision Vaccines Program at Boston Children’s Hospital, and also a temporary voting member of VRBPAC. “The majority of the world’s infrastructure for delivering vaccines is directed at children, and vaccines that are given to children around the globe get a population penetration of 80 percent to 90 percent.”

Yet any legislation that makes Covid vaccines available to children—or mandates them—is also a matter for every individual state government to decide. And in the seven months since the adult versions were released, openness to vaccination has split into a red-blue divide. That could lead to more of the politicization that exploded in Tennessee this week, and fewer kids able to access the shots. And that means ongoing vulnerability, the emergence of more variants, and a longer pandemic in the end.

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