For those feeling lost in this time-bending pandemic summer, consider this frame of reference: the birthing season of the rhesus macaque. At the California National Primate Research Center, the first infants of the year arrived in February, just as the virus took hold in the surrounding area. The births continued through the spring, during which the virus surged and adult monkeys became a key model to plumb how humans might respond to the virus and vaccines. The last infants of the season showed up a few weeks ago. Among those stragglers, 16 were selected for an experiment: an inoculation with one of two Covid-19 vaccine candidates currently in late-stage clinical trials. It’s a first step toward answering a question that’s received little attention in that warp-speed, all-hands-on-deck effort: how children will respond to a Covid-19 vaccine.
The job of a Covid-19 vaccine is to inoculate broadly against the virus, putting enough roadblocks in its transmission path so that the pandemic stalls. How to do that most efficiently is far from clear, but there is some agreement over who will get priority: those most at risk of death or contagion, such as the elderly and medical workers. “You have to put out the fire first,” says Sallie Permar, an immunologist at Duke University who is coleading the infant monkey study. To get there, vaccine trials first have to establish safety and effectiveness in trials involving healthy adults, followed by studies in those higher-risk groups.
But where does that leave kids? So far, mostly out of the vaccine equation, Permar says, in a way that doesn’t totally add up. In part, that has to do with all the usual hurdles of pediatric research: Kids are harder to enroll in studies, due to safety and ethics concerns, and their maturing immune systems are complex to study. But it’s also because of their quixotic role in this pandemic. Kids appeared to have been spared from the worst effects of the virus, with lower rates of hospitalization and death than older people. And while it’s clear that they can both catch and spread the virus, it’s still unknown how likely they are to do so compared to adults.
But over time, a more nuanced picture has emerged. First came signs of longer-term effects in children that can arise from apparently mild infections—including a mysterious ailment called multisystem inflammatory syndrome, or MIS-C. And, just in time for school, more comprehensive efforts to study children through testing and tracing cases—including during outbreaks in congregate settings like summer camps—have suggested children could play a greater role in transmitting the virus than initially thought. That could put Covid-19 more in line with other respiratory viruses, for which childhood vaccination plays a critical role in curbing the spread of disease and protecting the most vulnerable.
“We should not be leaving children behind in the warp-speed efforts, and that’s clearly what we’re doing now,” says Evan Anderson, a pediatric infectious disease researcher at Emory University. Along with colleagues at the National Institutes of Health, he’s been developing a protocol to help Covid-19 vaccine makers navigate the process of pediatric trials and compare the results for different vaccines. “I think there’s an imperative to get off our derrières and get going on doing careful trials.”
Federal rules require drugmakers to study their products in children and come up with age-specific risk factors and dosing. But the timeline for doing so is up for negotiation between the government and companies. Often, the reflex is to wait. Even in non-pandemic times, the process of adapting a vaccine for children is an arduous process. Pediatric trials typically come after a vaccine’s safety and effectiveness has been well-established in Phase II and III trials in adults. Then, vaccine makers begin a process called “de-escalation,” working from small groups of older children to younger ones, and starting with a low dose that gradually “escalates” towards the level found effective in adults. Following that, they do bigger Phase III studies with yet more children to determine longer-term effectiveness and safety.
The question is when, exactly, vaccine makers should start that process—especially with the pandemic scrambling most normal procedures. Part of the concern is having enough safety data in hand to rule out rare complications. Even side effects that may look mild in adults, like a fever or slightly constricted airways, can be more serious in children, notes Pedro Piedra, who studies respiratory illness in infants at Baylor College of Medicine. The decision to start tests in kids involves a careful evaluation of the risks and benefits for different age groups, he says, noting that the disparate impact of the virus could mean very different answers for a 12-year-old versus an infant. Still, he says, these are fine-grain issues. “From a public health perspective, those would be good problems to have, because that means you have a vaccine,” he says. “First we have to develop our vaccine.”
Plus, there’s the not-so-simple fact that the immune system can work differently in kids than adults. There’s always the chance that young immune systems might react in some unexpected way to a vaccine or elicit a surprise side effect. “You don’t want a study that’s going to derail the process,” Permar says. That’s all the more true in the midst of a pandemic, with the whole world watching the leading candidates for signs of a stumble.
Outside of the US, at least one vaccine effort, the partnership between Oxford University and AstraZeneca, has said it plans to begin pediatric tests, including a small group of children ages 5 to 12 at a later stage of their combined Phase II/Phase III trial, though they have not begun recruiting yet. US-based vaccine makers contacted by WIRED, including Moderna, Pfizer, and Merck, have not publicly shared plans for clinical testing in children.
“At some point we have to make that step into children, and a real ongoing burden of disease and deaths in kids is more than enough to justify doing so now,” Anderson says. But he also points to the overall goal of herd immunity. No vaccine will be 100 percent effective in preventing people from spreading the disease—especially among the elderly, whose immune systems are typically less responsive to vaccines—and it’s unclear how long-lasting protection from any shot will be. If coverage among adults is poor—and there are some indications that uptake could be low, due to skepticism about vaccine safety, a poorly coordinated rollout, or economic inequities—then herd immunity will remain elusive.
“Targeted vaccination for high-risk individuals just tends not to work very well,” says James Campbell, who studies pediatric infectious diseases at the University of Maryland School of Medicine. “It’s hard to set up a vaccination program based on risk rather than something simple, like age.” He points to the pneumococcal vaccine, which prevents bacterial infections that can lead to pneumonia and meningitis. After the vaccine became a routine part of pediatric visits, infections in both adults and children plunged, and researchers found little benefit from targeting high-risk adults for vaccination. A similar dynamic is at play with many diseases caused by respiratory viruses, like the flu, he notes. “It may not be influenza, but it’s likely that vaccinating children for Covid would do something similar,” Campbell says, provided a vaccine is effective at preventing both illness and the spread of the virus.
Will the current crop of vaccines do both of those things? That’s still unclear—for both children and for adults, though ongoing Phase III trials may hold some answers for the latter. In adults, vaccine researchers can try to mirror what we have learned so far about the immune system’s natural response to the virus—the development of neutralizing antibodies, for example, and T cells that can help ramp up production when and if those wane. But there’s less data on children’s natural responses. In a study in North Carolina, Permar’s team is hoping to help close that gap by enrolling 300 children whose adult family members have tested positive for the virus, and tracking the immune responses of 60 of those kids over time.
It’s likely, Permar says, that the goal will be similar for a pediatric vaccine: robust antibodies that are capable of neutralizing the virus. But the conditions for getting there—the array of immune cells that need to respond, how to precisely prime the immune system and boost it—might look a little different in kids. In some cases, she notes, vaccination early in life can actually lead to a stronger and more durable immune response, especially when compared with older people. The precise reason for why that occurs is unclear, but one theory is that the young immune system is comparatively a “blank slate,” Permar says, allowing it to adapt better to a new threat. But more data is necessary; SARS-CoV-2 is a new threat, and the immune system often works in mysterious ways.
In the meantime, the monkeys may provide the first indications. The experiment involves testing two of the leading vaccine approaches: one that delivers the viral protein directly, and another that delivers messenger RNA with instructions for the body’s cells to produce that viral protein themselves—a newer approach to evaluate, for both children and adults. After vaccination, the researchers will test the monkeys’ blood to see if the vaccine induces an immune response. If those results look promising, a few months later they may opt to “challenge” the subjects—exposing them to the virus to see how protective the immune response to the vaccine appears to be.
It’s a first step on a long road to proving a vaccine benefits kids—and the people around them. But the hope, says Koen Van Rompay, an infectious disease researcher at the California National Primate Research Center, is to lay the groundwork for human studies, and potentially hasten them along. “The monkey research is really useful to get some preliminary data and push testing faster into studies with human children,” he says. “I think people will feel more comfortable with some data that shows what is safe and what is protective.”
The team hopes to get started next week. The baby rhesus macaques won’t be babies forever. “They’re getting older every day,” Permar says. “We literally have the syringes waiting to go.” And after all, next spring, when rhesus macaques will start giving birth again, is an eternity away in pandemic time.
