Paul A. Offit, MD

 Are there any other topics we didn’t talk about that were of great interest to the VRBPAC [Vaccines and Related Biological Products Advisory Committee] panel?

 Those were the big ones they came up with: efficacy and safety issues. Remember, we’re just an advisory committee, so we give advice. The FDA [Food and Drug Administration] will take that advice and say, “Yes, we will allow these vaccines to be distributed for those age groups.” Then, it goes to the Advisory Committee on Immunization Practices at the Centers for Disease Control and Prevention who are meeting on 17 and 18. They will vote, then Dr Rochelle Walensky, head of the CDC [Centers for Disease Control and Prevention], will presumably take their advice, and the vaccine would likely be available early next week. I don’t know whether you got a chance to watch that meeting yesterday, but at the end, people got a little emotional. We had been meeting intensively for the past year and a half. We first approved the vaccines for Pfizer and Moderna in December 2020, then 6 months later for children aged 12 to 15 years, another 6 months later for children aged 5 to 11 years, and this finishes the circle. Now you can be vaccinated from 6 months of age. For a lot of us, we started to reminisce about that first approval. It’s been a long, hard road.

 I found it interesting that one of the points raised at the end was that the initial vote wasn’t unanimous, and this most recent one was. I think that shows how far we’ve come in the development and understanding of not just how these vaccines work but how safe they are. That’s the biggest take-home message from this discussion, at least for providers to give to parents: that the vaccine is much safer than the disease. It needs to be encouraged for children to get it because it’s going to protect them against something that, even though it might not be a high risk, is not a zero risk.

Any other take-home messages you want to provide to listeners?

 Just that there are no risk-free choices. I think people choose not to get something thinking that’s a risk-free choice. There are no risk-free choices in medicine, just choices that take different risks, so take the lesser risk.

 Thank you for joining us for this discussion of pediatric COVID-19 vaccines. I’d like to thank Dr. Offit for being a panelist, and I’d like to thank the 

® staff for allowing us to have this discussion and the viewers for joining us. I hope you look forward to upcoming 

Videos

Dr Muller and Dr Offit provide take-home messages about COVID-19 vaccines for pediatric patients.

Take-Home Points About COVID-19 Vaccines for Pediatric Patients

 One of the discussion points at the VRBPAC [Vaccines and Related Biological Products Advisory Committee] meeting was coadministration of vaccines, especially for young children who are getting their primary vaccine series for other diseases. Do you have any thoughts about what to tell parents about that?

 Typically, when a vaccine is put onto the schedule, there are concomitant use studies. You have to prove that your vaccine doesn’t interfere with the safety or immunogenicity profile of the vaccines given at the same time. Conversely, that those vaccines don’t interfere with the safety or immunogenicity profile of your vaccine. Those studies haven’t been done for vaccines that are going to be given to children younger than 5 years. The way companies did those studies is they never gave those vaccines at the same time, so you have no information about giving those vaccines at the same time. The American Academy of Pediatrics said in the past 24 hours that when these vaccines roll out, pediatricians could give them at the same time. Personally, I would take a more cautious approach.

The Moderna vaccine had an incidence of fever in the 25% range, and for those with temperatures of 38-39 °C, that was about 18%. For those with temperatures of 39-40 °C, that was about 4% of those children, and for those with temperatures greater than 40 °C, it was 0.4% of the children. And fevers are an issue for younger children. I would prefer, until we get more information, to have a 2-week separation, which is going to be very difficult for pediatricians. Because for a 6-month-old child, if you wanted to start they really should be 6 ½ months of age, and then you need to boost 3 or 4 weeks later, depending on the vaccine. That’s not going to make life easier for the pediatrician. I think what the American Academy of Pediatrics is trying to do is make life easier for the pediatrician by saying you can use it concomitantly. Although I was fortunate enough to be part of a team at Children’s Hospital of Philadelphia in Pennsylvania that created the rotavirus vaccine, concomitant use studies are bare. You have to show you don’t interfere with the immunogenicity profile of existing vaccines, which means you’re doing a lot of testing looking at immune responses. It’s a lot of work that wasn’t done here because it’s a pandemic, and you want to get the vaccine out there. But I would take a more cautious approach until there’s more data.

 And in defense of study design, as we’re generating data on adverse effects of new vaccines, we don’t want to confound that data with existing vaccines, which we already know can promote some adverse effects we’re seeing with the COVID-19 vaccine. I think that’s a concern when you’re trying to design the initial studies, but down the road, we’re going to have to get more data to understand exactly how these vaccines interact with each other. I was a little surprised when the Pfizer vaccine was authorized in older children, and CHIP said to give it without regard to other vaccinations, even though it hadn’t been studied that way.

Expert pediatricians discuss challenges with coadministration of vaccines in children younger than 5 years.

Coadministration of Vaccines for Children Younger Than 5 Years

 Were there any other data from the review committee panel about safety and efficacy that were notable in children younger than 5 years relative to other age groups?

 There was a difference in terms of efficacy to some extent. Typically, the Pfizer and Moderna vaccines, when given as 2-dose vaccines, have tracked right next to each other. It was true for adults, it was true for children aged 12 to 17 years, and it has been true for children aged 6 to 11 years. But for children younger than 5 years, there was clearly evidence of at least some protection. It depends on which subgroup you’re looking at. Somewhere between 37% and 50% protection against mild disease, which I think will predict even better protection against severe disease. After 2 doses with the Pfizer vaccine, you didn’t see evidence of protection, so you can’t assume there would have been “… against mild disease,” because all they were seeing was mild disease. Thus, without evidence of protection against mild disease, it’s hard to assume there is going to be protection against severe disease, and hence Pfizer decided to make it a 3-dose vaccine. Moderna will also be a 3-dose vaccine, but you could argue that from the time of your first dose, where there will be protection within 6 weeks, that may not be true for Pfizer’s vaccine until 14 weeks. But I want to offer the caveat; let’s see what happens when the vaccine gets out there. And we’ll see what the real-world efficacy is after 2 doses for both vaccines, because right now the numbers are small in terms of participants that had mild disease during these efficacy studies. But that was a difference.

 That’s an interesting point, because I’ve been asked by people whether there is a preference for one vs the other in terms of what you give your child. I think our data in other age groups have suggested there’s not a significant clinical difference in outcomes based on which platform you were vaccinated with. I would not expect that to be the case in younger children as well, even though the data suggest that 2 doses of the Pfizer vaccine are not sufficient for significant protection, and a third dose is necessary. But because both vaccines will likely become 3-dose series, it may make a difference which one you get first. Are there any other expectations about authorization that might be worth delving into? Everyone is expecting both these vaccines will be authorized for use in the youngest age group in the future. But it’s also important to emphasize that there are going to be ongoing studies of real-world efficacy in these age groups. Are there any other developments we would expect in terms of the delivery of the vaccine? I think the timing is a little different for some of these. Are we going to try to rationalize this? Do you think in the future that doses will be given on a regular schedule, regardless of the platform?

 The critical question moving forward is, when is it going to be best to vaccinate? And that’s going to depend on immunological memory: How long does memory last? I think we’re going to learn that over time. Also, it’s going to depend on how the variants change. There may be, and it hasn’t happened yet, a variant that arises that is resistant to protection against severe disease, in which case we are starting all over. Thus, I think the critical question is, how long does memory last? If memory is long lived, then the earlier we vaccinate, the better. If memory is shorter lived, then maybe you want to delay it until a time when people are more likely to be hospitalized or die from this disease. But I think we’re going to learn as we go, and there will be better vaccines. I think there will be safer vaccines. You know that the mRNA vaccines are rare causes of myocarditis: inflammation of the heart muscle. You also know that the Novavax vaccine appears to be a rare cause of myocarditis as well. Novavax vaccines are purified protein vaccines, which were a different strategy.

To date, it looks like the AstraZeneca vaccine, which is a viral vector vaccine, doesn’t cause myocarditis, which is interesting. There was a publication in 2020 that showed molecular mimicry between the SARS-CoV-2 spike protein and the ɑ-myosin heavy chain on heart muscle cells, and you would have thought this would be a class effect. That anything that induces antibodies against the SARS-CoV-2 spike protein intuiting the disease would cause myocarditis, but it looks like from the AstraZeneca data that it may not be a class effect, in which case, it may have something to do with the way the proteins are processed or presented based on whether you give a viral vector vaccine mRNA vaccine, or purified protein. There’s a lot of knowledge to be gained there, because the history of vaccine development is always that over time you make safer, better vaccines. Thus, I think we’re going to have plenty of time to figure that out. This virus is going to be with us for decades, and that’s what you’ll see. There will probably be a nasal spray vaccine in the future, which may be better in terms of inducing local immunity and decreasing shedding to some extent. It’ll be interesting to learn more about the whole inactivated viral vaccine that’s being used in China, as well as the receptor-binding domain vaccine that’s being used in India other Asian countries, because that’s just part of the protein. Will that vaccine cause myocarditis, or are you missing a critical part of that protein? Hence, there is much to learn, and we’ve got to keep our eyes open and keep learning.

 I know this has been a little controversial, but there’s been some discussion about whether delaying that second dose for some period of time decreases the risk of myocarditis. It seems to me, from a wider lens, that if we’re talking about affinity maturation and stronger affinity of antibodies and potentially diverse T-cell responses, that it’s really that third dose on top of at least the first dose that does that more than anything else. I wonder whether in the future a 2-dose vaccine series separated by a few months is going to be just as good.

 Myocarditis is a generally male phenomenon, a young male phenomenon specifically, generally within 3 or 4 days of the second dose. I think in terms of spacing, there’s certainly data from Canada that suggests that spacing does make a difference. Again, we’ll learn as we go.

Dr Muller and Dr Offit discuss recent developments in the COVID-19 vaccine for children younger than 5 years.

Developments in COVID-19 Vaccines for Children Younger Than 5 Years

 It’s worth talking about variants, because this is a bit of the discussion at the review committee meeting for the FDA [Food and Drug Administration]. It has 2 components to it. One is, do we expect this will be a 3-dose vaccine for everyone in the future? I think the authorization will be for a 2-dose vaccine from Moderna and 3 doses from Pfizer. But everyone is expecting an eventual third dose from Moderna. They intentionally use the term 

 because we are throwing around the term 

 if there’s no need for a third dose. Do you have any thoughts about that, and do you think we need to message that a little better to parents and the public?

 This is a 3-dose vaccine. Moderna is going to launch a 2-dose vaccine for children younger than 5 years. It’ll probably be available as early as next week, and today is June 16th. By June 20 or 21, it could be available for children younger than 5 years. It launched as a 2-dose vaccine, but the point that several committee members made during these past 2 days is not to think of this as a 2-dose vaccine with the third dose as a booster. This should be a 3-dose primary vaccine if we’re going to get the kind of protection we need against these subvariants. In other words, the primary series is 3 doses, and 

 is the wrong word. Because the way that the CDC [Centers for Disease Control and Prevention] defines this is that you’re fully vaccinated with 2 doses, but you’re up-to-date with a third dose. That is wrong. This is a 3-dose primary series for your children. Pfizer’s vaccine for children younger than 5 years is currently a 3-dose vaccine, but I know that Moderna is doing studies with 3 doses, and they should have those studies available, according to them, by July. Thus, I think very soon we’ll have that third dose, which would be given months after the second dose.

 The next question that a lot of people are raising is whether the third doses that might be given in the coming months would be specifically directed at variants. Moderna had some data last week in adults that suggests, at least in antibody studies, that the neutralizing capacity from people who received a variant vaccine was better than whether they received an extra dose of the vaccine based on the initial strain of the virus.

 That’s an important point. On June 28th, the vaccine advisory committee will be meeting to discuss that issue: Should you give a very specific vaccine in the fall? The so-called bivalent vaccine, where one of the mRNA components is against the ancestral strain, and the other one is for Omicron. There’s a lot of evidence why that wouldn’t be a value. I know this is a contrary point of view, but here’s what I would say. The good news about the ancestral vaccine is that a third dose clearly increases your antibodies against the Omicron subvariant, as was shown by Pfizer in the data presented yesterday for the child younger than 5 years. With 2 doses, they didn’t have neutralizing antibodies against Omicron. With that third dose they did, and that’s the good news about this ancestral vaccine. If you give 2 doses of the ancestral vaccine and a third dose with the ancestral compared with 2 doses of the ancestral vaccine and a third dose with the Omicron vaccine, is it better to have Omicron as your third dose in a person who is seropositive? Because a large percentage of this country is seropositive. Thus, if you’re only looking at people who are seronegative, you’re talking about a very small percentage of people in this country who have already been naturally infected, immunized, or both. You’re probably talking at least 80% to 90% for people who are already seropositive. And when you look at those data in the person who is seropositive, there’s not much difference. Also, in the nonhuman primate studies, when they give 3 doses of the ancestral vaccine or 2 doses of the ancestral vaccine and then the Omicron booster…there is no difference. Unless there are data contrary to those data, I don’t see the point of doing the Omicron-specific vaccine. I may be in the minority here. But if we’re going to follow the science, we need to clearly show the science proves that.

 I don’t disagree with you. I was going in that direction, because one of the questions that a lot of providers are going to get from parents who are about to start vaccinating their children is, “Should I wait until the fall and get the primary series of a variant vaccine?” And from what you’re saying and from what I understand of the data, it makes more sense to get vaccinated sooner than it does to wait for a specific vaccine, because your protection is likely to be similar, at least against severe disease, which is the goal, whether or not you get antibody levels that are significantly higher in neutralization capacity. And an in vitro study doesn’t necessarily tell you whether you get protection from disease, and the 2 do correlate to some extent. But if I have 5 times the level I need for protection of disease vs twice the level I need for protection of disease, it may not matter. I want to get twice the level sooner.

 That is exactly right. If you look at the people who are seropositive who get the Omicron booster or the booster for the ancestral strain, the Omicron is about 1.7-fold higher, which although statistically significant, is unlikely to be clinically significant and will no doubt be short lived. It’s probably not associated with an increase in memory B cells or T cells. If those are the best data to show, then it’s hard to embrace a more expensive strategy.

 I think that’s an important point for the providers who are listening to us to understand.

Dr Muller and Dr Offit discuss COVID-19 variants and their effect on vaccine development.

The Effect of COVID-19 Variants on Vaccines for Children

 We went through some of the arguments in favor of vaccinating children, the most important one being that even though the risk is low, it’s not zero, and that it’s important for protecting themselves. I don’t know that there’s necessarily a lot of data on this, but it certainly seems to be rational to consider that these vaccines may also decrease the risk of spread. Was there any discussion of that at the review committee meeting or any data presented at the review committee meeting, that discussed whether or not we can start to get some information on whether or not we can also decrease the spread of disease within the population?

 It’s a short incubation period, respiratory mucosal virus, so it’s really hard for a vaccine to dramatically reduce, say spread associated or shedding associated with asymptomatic infection. That’s a lot to ask it. For the longer incubation period diseases, like measles, smallpox, German measles, that’s much more doable than it is here. Hence, there are studies that clearly have been done that have shown in an adult population that if you look at somebody, for example, who was vaccinated, who has mild disease, and compared with someone who wasn’t vaccinated, who has mild disease, and then you do the right kind of study, which is you don’t do antigen detection, you don’t do a PCR, you do infectious virus titers. And, when you do that, you see that those who were vaccinated do shed far less virus for a shorter period of time. Thus, I think they are less contagious, but that you’d still be contagious even though you’re vaccinated. I think, even if the entire world were vaccinated, you would still have spread of this virus, and you will still have mild disease, and that’s something we’re going to eventually have to get used to.

 I think that’s the expectation. And I think that’s what a lot of people are, hopefully, understanding that, the bar for efficacy depends on what you’re using to define as efficacy. If we’re trying to keep people out of the hospital, these vaccines are very good at that. If we’re trying to keep people from getting severe disease and dying, these vaccines are very good at that. We’re trying to keep people from getting an infection whatsoever, even asymptomatic infection, that’s really, I think a very difficult requests to make of any medical intervention, particularly a vaccine. Thus, in the in-between space, there might be some variability, but that’s maybe not the goal that we’re trying to achieve here. Maybe the goal we’re trying to achieve here is to decrease the amount of disease in the community, so that we can allow more normal life to go on.

 And I think probably the best current example of where we are in this pandemic is Dr Anthony Fauci. Dr Fauci now has a mildly symptomatic COVID-19 infection. He’s been vaccinated 4 times. But what happens is, is that it’s very hard, especially with these Omicron subvariants to have protection against mildly, so he’s a mild illness, that’s a win. Here’s a man who’s in his 80s, who certainly had high risk of severe disease, who doesn’t have severe disease, because he’s been vaccinated. That’s the future, that’s what you want; you want to protect those who are most vulnerable, in his case, the elderly, from getting severe disease, and that’s a vaccine that’s working well. The media often doesn’t carry it that way, but that is the vaccine that’s working well.

Paul A. Offit, MD, comments on spread of the COVID-19 virus in children who are vaccinated.

The Impact of the COVID-19 Vaccine on Spread of Disease

 I think 1 of the topics probably most important to delve into and spend some time talking about, are the issues that parents have that raised their concerns about getting their children vaccinated. And I think a lot of us are aware that there’s probably somewhere between 15% and 20% of the population that are lining up to get it for their children. There’s another 25% to 30% that are going to be resistant or reluctant to get vaccinated, but there’s a big portion of the population in between that has this “wait-and-see” attitude. And what sorts of things do you start to tell parents about who may have some hesitation to get their children vaccinated?

 If you look, the vaccine for the 12- to 15-year-olds was recommended about a year ago, maybe 55% of children in that age group are vaccinated. If you look at the way that happened, there was a spike in vaccination and then it dramatically came down and stayed down. Hence, for those parents who said, “Well, I just want to make sure there’s not a problem, that it’s not a surprising safety problem,” I don’t think that was true. I think there were people who wanted to get it and people who weren’t going to get it, and those who got it, got it early, and those who didn’t want to get it never got it. Six months ago, we had a vaccine available for those who were 5 to 11 years of age, and there was about 30% of parents who chose to vaccinate children in the age group, and 70% didn’t. And again, it was a dramatic spike early, came down, and stayed down. If you look at sort of the surveys that are done by a number of Agencies asking parents, “Do you think you’re going to vaccinate your younger than 5-year-old?”It makes me think that the numbers of parents who are going to be even lower than it was for say, the 5- to 11-year-olds. I’d be surprised actually, if more than 20% of parents of younger than 5-year-olds, have chosen to vaccinate their children. We’ll see how it plays out, but that’s generally the way this has gone. Thus, I’m not sure what pediatricians can do. I think we have to make it clear to parents that this virus can seriously hurt children. I spent a fair amount of time with parent advocacy groups like families fighting flu, meningitis, national Meningitis Angels organization, and those parents all tell the same story, which is “I can’t believe this happened to me” until it happens to them, and then they become vigorous activists to educate about the disease, educate about the vaccine. And you think it’s never going to happen to you, my children surprisingly were fully vaccinated when they were little, I never imagined they would actually get those diseases, but you can’t put children in harm’s way unnecessarily. It’s a game of Russian roulette, and although maybe there’s a 100,000 empty chambers in the gun, there’s no sense putting the gun to the head. It’s just not necessary.

 I think, and that’s the point we’re probably going to get back to a couple times as we have this discussion, the concept that the anything that you may be concerned about from the vaccine is worse from the actual disease. And I think that might be the important take home message for a lot of people. But maybe we should go through some of the individual objections that some parents bring up. I think one of the common ones, and this came up even before we started to talk about vaccines and children, is that it is the rapidity with which these vaccines were developed. Thus, when people come to us and say, I’m really concerned that this process was rushed, how do you answer that?

 I think it’s a reasonable concern, this is the fastest vaccine ever made. The virus was isolated in January 2020, we had a vaccine available 11 months later, we did complete it large clinical trials 11 months later. The Operation Warp Speed, which put $11 billion into the effort, essentially took the risk out of it for pharmaceutical companies. We went very quickly from phase 1 trials, which means dose and dose ranging trials to phase 2 trials, where you think you know the dose, and you know that the dosing intervals very quickly to efficacy trials, I can understand that. And thus, the father of modern vaccines was a man named Maurice Hilleman, PhD, who was responsible for either doing the primary research or development on 9 of the 14 vaccines we give to children. And, he said it best when he said, “I never breathe a sigh of relief until the first 3 million doses were out there.” Well, the first 3 billion doses are out there, so I think that that question has been answered. I get the initial reticence. I can understand the initial reticence, but again, there are no risk-free choices, a choice not to get a vaccine is not a risk-free choice, it’s a choice to take a different risk and more serious risks. There are no risk-free choices, it’s to make the choice that puts the child in the safest position possible, to take the least of the lesser risk, and vaccines obviously, are that lesser risk.

 I think there’s a couple other ways that people can consider approaching this question from parents. The one is that the process actually was the same, it was faster, but it was the same. We went through, like you said, phase 1, phase 2, phase 3, we did dose ranging, we did safety and tolerability, and then we did efficacy studies, all in that order with decreasing age ranges, and this is the way all medical products are developed. And hence, there’s really nothing different about this process, except it was done more quickly. And, the way you do things more quickly, is by spending a lot of money, and that’s what Operation Warp Speed did.

 I think it’s exactly right. The reason it was fast, is the government took the risk out of the company. The way that companies typically work is they do phase 1 trials, then they do phase 2 trials, then they do phase 3 trials, then if assuming everything works, then they build a building, then they mass produce it, then they submit it for licensure, and then it gets licensed. Here, what the government did, was they said just mass-produced the vaccine at risk, meaning mass-produce it without having done that phase 3 trial, you don’t know yet whether it’s safe, you don’t know whether it’s effective, “We’ll do all that at the same time. We’ll do that efficacy trial, phase three trial while you’re mass producing the vaccine, so that if it shows that it is working it say and so that we can make it immediately available to the public.” No company would never do that, so it really just took the risk out of it. But the size of those trials initially, the Pfizer trial, which was a 40,000-person trial, the Moderna trial was a 30,000-person trial. That’s the size of any typical pediatric or adult vaccine trial, so it really wasn’t skipped. I think, what did confuse people, and it’s understandable at some level was the use of the term emergency use authorization. You had during the Trump administration, we approved through emergency use authorization, hydroxychloroquine, which had never been shown to work, to treat, or prevent this disease, and they approved it. And then, 3 months later, when it was shown to do neither, and, in fact, met at some level dangerous, they went through that emergency use authorization. I think that sort of scared people that this was a very flimsy process, but it really doesn’t apply to vaccines. I wish we had a different term other than emergency use for authorization for vaccines.

 That’s fair. I understand the rationale of the FDA [US Food and Drug Administration] to try to make a distinction between the authorization and approval, but people are using those terms interchangeably now, and it becomes really confusing, not just for parents and the general public, but also for providers.

Vaccine and infectious disease experts address vaccine hesitancy and the importance of the COVID-19 vaccine in children.