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Coronapod: Kids and COVID vaccines

Benjamin Thompson and Ewen Callaway discuss COVID-19 vaccine trials in young children.

As COVID-19 vaccine roll-outs continue, attentions are turning to one group: children. While research suggests that children rarely develop severe forms of COVID-19, scientists still believe they could play a key role in transmission and a plan needs to be in place for the longer term. But clinical trials in children are more complicated than those in adults as different ethical and practical concerns need to be taken into account.

In this episode of Coronapod, we discuss the ongoing clinical trials to test vaccines in young children, and ask what scientists want to know about safety, and how effective these vaccines might be at preventing disease and transmission.

News: COVID vaccines and kids: five questions as trials begin

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doi: https://doi.org/10.1038/d41586-021-01083-y

Transcript

Benjamin Thompson and Ewen Callaway discuss COVID-19 vaccine trials in young children.

Benjamin Thompson

Welcome to Coronapod.

Noah Baker

In this show, we’re going to bring you Nature’s take on the latest COVID-19 developments.

Benjamin Thompson

And we’ll be speaking to experts around the world about research during the pandemic.

Amy Maxmen

We’re entering a new era now. We have new COVID strategies, there’s some new unknowns and we’ve got a vaccine.

Benjamin Thompson

Hi, listeners. Welcome to Coronapod. Benjamin here in the hosting chair, and I’m joined by Ewen Callaway, senior reporter here at Nature. Ewen, how are you doing today?

Ewen Callaway

I’m doing alright. Thanks for having me.

Benjamin Thompson

Not at all. Well, Ewen, you and I are going to talk about vaccines today, as we often do on Coronapod, and as vaccines, I guess, get rolled out around the world, a lot of governments are doing it in kind of a phased pattern, right, sort of the most at risk at the top, then people over 80, then people over 70, and it goes on. But if you sort of take that to its natural conclusion, the people who are youngest maybe at the bottom of the list are children, and there hasn’t been a huge amount of discussion about what to do when it comes to vaccinating children, and it’s something that you’ve been looking at for Nature this week.

Ewen Callaway

Yeah, exactly this. I mean, number one, when you think of vaccines in general, you think of kids because that’s when we get nearly all of our vaccines. With COVID-19, it’s a different story because these are vaccines that were developed in the midst of a pandemic that seemed to affect people more as they got older. So, when these vaccines were designed and being trialled, the initial goal was like can we keep people out of the hospital, can we keep people from dying. And although there have been really unfortunately deaths and severe cases in kids, they’re exceedingly rare and so kids weren’t kind of thought of as being the number one target for these vaccines. But now, as some countries, some rich countries, are able to vaccine large numbers of their adult populations, they are starting to think that maybe we should be including children in our vaccination programmes.

Benjamin Thompson

Yeah, maybe before we get into some of the trials that are going on, I mean, I think you’ve kind of raised a question there that sort of leapt to my mind straight away, which is do we need to vaccinate children at all? As you say, there are obviously some really sad cases where children have been made sick or in some cases died, but generally speaking it seems that data suggests that overall, most children don’t get severe disease and aren’t seeming to spread the virus to other people to the same amount as adults do.

Ewen Callaway

Yeah, so there is this slightly mysterious syndrome called multi-system inflammatory syndrome that does affect children. One estimate is around a rate of 1 in 1,000, but that could be an overestimate because, as you say, most kids don’t even get sick. But I think one reason for thinking about vaccinating kids, which involves trialling vaccines in kids, is, yes, to prevent these rare cases of severe disease and death. But then as fortunate countries vaccinate ever larger portions of their population, you’re seeing, if you just look at the statistics, that COVID is hottest in younger people right now, and particularly with faster spreading variants. Children, where previously they weren’t really that important in maintaining transmission in the community, might start to play an outsized role, and so then you think about vaccinating children as a means to achieving that elusive herd immunity that we’ve been talking about for a while. And lastly, I mean, I didn’t really explore this in my story but vaccinating children is a luxury. We’re in a world where many countries haven’t even started their vaccination programmes in adults, and is it right to be preparing to vaccinate a portion of the population that doesn’t tend to get ill when other countries can’t even protect their most at risk. I don’t have answers to that question. It doesn’t necessarily mean we shouldn’t be trialling these vaccines in children, but it’s something, I think, to think about.

Benjamin Thompson

Well, trials are undergoing, Ewen, as I understand, to test vaccines, and there’s a bunch of questions I’ve got about that. In the first instance, who’s doing these trials, and I think you’ve been on the show before talking about how companies are very selective about who they get involved in their trials. How does that work when you’re talking about children? It’s one word but it can mean anything from, I guess, 2 years old to sort of 16 years old and what have you, so what’s going on?

Ewen Callaway

So, the first trials were in teens. In fact, Pfizer and BioNTech, which developed a successful mRNA vaccine, included I think 16 and 17 year olds and older in their initial trial, and that vaccine is licensed to be used against that age group. So, they and others, including Moderna, have started trials maybe at the beginning of this year looking at adolescents, so 12-15-years-olds, and those trials were much simpler. They gave the same dose they do to adults. So far, early results are good. What I’ve been looking at though is this idea that maybe we might want to look into younger age groups, so under 12s down all the way to children as young as 6 months. And those same two developers – both Moderna and Pfizer-BioNTech – have launched trials in the last month or so testing COVID-19 vaccines in those age groups, and those trials are going to be run pretty differently from the trials in adults and even the trials in adolescents.

Benjamin Thompson

So, how are companies going about figuring out what dose to use in the first instance?

Ewen Callaway

Yeah, so that’s the first question, I think, and the thing to say is that, I mean, safety is obviously important in all vaccine trials and all medicines trials, but when we’re talking about children, safety is paramount, especially when we’re talking about a new vaccine protecting against this disease that they don’t really, in large numbers, get sick from. So, as a result of that abundance of caution, people want to look at different doses of vaccine in children, and as I said earlier, they were looking at children under 12 down to as young as 6 months. They’re going to be starting with the older end of that category just to make sure they’re people who are most like the 12-15-years-olds who have already safely received the vaccine. And there the calculus will be what gets you the best immune response with the fewest, I mean, ‘side effects’ I guess is the term that people use but the side effects are the vaccine working. We’re talking about fevers and maybe mild headache, things like that. So, it’s about identifying that dose that looks like it will protect against infection but also doesn’t put you out of school for a week. Especially when the virus isn’t going to do that, why should the vaccine?

Benjamin Thompson

And if the first instance is trying to work that sort of thing out, I mean, I suppose, taking that through to its conclusions, how do you know if it’s worked? This is a disease, COVID-19, that really doesn’t necessarily have obvious or severe symptoms in children. How do you know if the vaccine is doing what it should do?

Ewen Callaway

So, once this safe dose is established, these trials have kind of a second portion where they’re going to be a little bit more like the adult trials, which enrol tens of thousands of people and randomly gave people two doses of the vaccine or two doses of placebo and then followed them to see the rates of infection afterwards. With the kids, they’re looking at a few thousand participants, and they will be following them and looking out for signs of COVID, but as you say, because kids don’t tend to get really severe manifestations of disease, they’re going to be looking at their blood, looking at immune markers, as a way to tell if the vaccine is likely to have worked. They’ll be looking and saying, ‘Did you produce the same immune response as the 12-15-year-olds or the young adults who look like they’re protected?’ There’s a slight chance that we might see stronger evidence for efficacy in kids. In the adolescent trial, Pfizer and BioNTech have reported early results and they’ve found a handful of cases in the placebo group and absolutely none in the kids who got the vaccine, accompanied by really good immune responses, so that was a strong signal that the vaccine is working. And I guess the other point on this is that some people have told me that if you’re thinking about these trials and how to measure success, you should be thinking about how you want to use the vaccine in children. So, if you want to prevent disease, you should be able to show that. If you want to prevent transmission and have kids as part of an effort to get herd immunity, you should try and demonstrate that. But showing an effect on transmission is much more difficult. I’m not sure at the end of these trials whether we’ll have strong evidence that these vaccines prevent disease or block transmission. We’ll probably know that they trigger a strong immune response and we’ll have to go from there and infer its effects in other arenas, which is likely to be good. These vaccines are showing signs of preventing disease and blocking transmission in adults so maybe there’s no reason to think they won’t do the same in kids.

Benjamin Thompson

Is there the possibility though that – I mean, the immune system is a fantastically complex thing – we will see something really, really different in a six-month-old than we would in anybody else just because maybe they haven’t been exposed to as many pathogens throughout their life, this sort of thing?

Ewen Callaway

Yeah, I mean, children aren’t little adults. Their immune systems are very dynamic and developing and changing all the time. They’ve seen fewer pathogens. They’ve been exposed to fewer antigens, which are the pathogen molecules that vaccines are based on. So, typically, children mount really good responses against vaccines. In some age categories, they might need extra doses when their young. In older categories, they might need fewer doses, less of a boost than older people do. And I think investigators in these trials understand that, yeah, they have to take this into account when just looking at the immune response you get. But then if you think about safety, which again is number one, they have to be really careful that these vaccines aren’t triggering any sort of immune response that becomes pathogenic or pathologic. In the adult trials, people were looking out for the potential that the vaccines could trigger something called enhanced disease, that you see when somebody is vaccinated later becomes infected, and they found no signs of that, but I think people will want to look extra closely at this possibility in children just because their immune systems are different. And then with this multi-system inflammatory syndrome I talked about earlier, that seems to be triggered by infection, you’ll want to make doubly sure that vaccination isn’t triggering the same syndrome but something that’s indicative of it. So, people will be looking very, very closely, I think, at the immune responses of the child participants in these trials for just any sign that anything is slightly awry.

Benjamin Thompson

One thing we haven’t talked about, of course, is ethics, and obviously if I volunteer for a trial, I’m going into it, the costs and benefits are laid out and nothing is without its risks of course, but I would imagine that in this situation where vaccines are being tested on children, there are a lot of questions about how consent is given and things like that.

Ewen Callaway

For sure. Adults who participate in a trial must provide informed consent, which, there are two words there, so it’s not just saying ‘yes’ to this trial. The investigators have to make sure that you understand what you’re getting into, which involves watching videos and checking a lot of boxes. It’s that sort of thing. Children can’t provide consent. Their parents or guardians must provide that informed consent. But children above a certain age must provide ‘assent’, meaning you have to get their buy-in. So, even if their parents have signed up for it, if a 12-year-old says they’re having a bad day or whatever, ‘I don’t want to do this,’ then they’re not doing it. And the investigators are obliged to that. And they also have to pitch their materials to children so that they can understand what they’re getting into. And the age, I think, varies on jurisdiction, and people are telling me it varies on the child. I spoke with an investigator who is working on the Pfizer-BioNTech trial, and she’s going to try and get assent from children as young as five or even younger. She said these kids, they know what’s going on. They know about the pandemic. That’s why they’re out of school. So, they’re interested and they’re eager to participate in those instances. Yeah, so the ethics are definitely different. And again, I think the calculus on risk-benefit is also different. You want to err much more on the side of safety.

Benjamin Thompson

Ewen, last week on Coronapod, Noah and Heidi were talking about these kind of very rare but incredibly serious blood clots that have been seen in some people who have received vaccines and the scientists who are kind of racing to work out what the link is and if there’s a link between the two. Has news of that maybe affected the trials that are going on or that are being planned, do you think?

Ewen Callaway

Yes, without a doubt. The University of Oxford, in February I believe, started a small trial of several hundred children as young as six, and that trial was paused while investigations continue into the links of that vaccine to these very rare blood clots. And with news that there seems to be a safety signal with the Johnson & Johnson vaccine, a similar signal. Johnson & Johnson was getting ready to enrol children as young as 12 into trials of their vaccine, and that enrolment along with all use of the vaccine, has been paused. So, these trials, they’re not cancelled, they’re paused, but I think when you’re dealing with even a very, very rare side effect, I think people want to see not just a weighing of the risks and the benefits. With children, people told me that we need to understand the mechanisms that might be at play, and it could well be that they’re not at play in children because they’re not of reproductive age, for instance. So, yeah, the discussions are between regulatory agencies and developers and sponsors and investigators, but scientists told me that we need to work out much more about what might be causing these very rare links before we think about giving these vaccines to children again.

Benjamin Thompson

Well, one think that’s been discussed quite a bit is whether in adults you would receive a yearly COVID booster shot, maybe to mitigate the effects of variants and what have you. Could you envisage maybe a situation where a COVID-19 vaccination is given to children as part of their regular vaccination programmes, and of course at various stages, six months, two years and so forth, they’re given a bunch of different ones so do you think COVID will be thrown into the mix?

Ewen Callaway

People are thinking about that but it depends on the answers to a lot of the questions that we don’t know the answers to, such as the future of the pandemic and the results of these trials. But if we want to include COVID vaccines in routine immunisations, I think people will want to know when is the best time to give them in a child’s lifetime, and when is the best time to give boosters et cetera. And you want to make sure that adding a COVID vaccine to that schedule doesn’t interfere with the responses to other important vaccines that children are receiving in the first few years of their lives. And these vaccine interference studies have been done with other vaccines as they’ve been included in children’s’ schedules of immunisations, which you as a parent know are getting longer and longer. So, those studies won’t be done now but they’ll need to be done in the future if we want to make this part of the routine immunisation schedule. The other thing to think about is that maybe this will be a little bit more the like influenza vaccine, which you don’t really think of it as a routine immunisation because they don’t have to get it. One of the large reasons we vaccinate children against influenza is to protect older at-risk adults in the community because maybe you can cut down circulation in children. You might have knock-on effects in the wider community. So, maybe it might be something more like that. But again, a lot to work out. I mean, as the father of a young child, vaccines are amazing, they’re miracles, they’re the greatest thing that we’ve ever invented, but taking your kid to get another vaccine, I mean, you’d do it, you’d definitely do it, but it’s not your favourite day of the year, is it?

Benjamin Thompson

Ewen, I will 100% agree with you there. An absolute miracle but it’s always a sad afternoon once it gets done. But anyway, let’s leave it there for the time being. Ewen Callaway, thank you so much for joining me, as ever.

Ewen Callaway

You’re welcome.

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