Under 5 Vaccines: FDA Decides, I Dig Into the Data

Update (6/19/2022) Yesterday, the CDC ACIP panel recommended approval of both vaccines. They voted yes on the question of whether the vaccines “should be recommended” for children 6 months to 4 years. Along with the approval of the CDC director, this has paved the way for vaccination starting Tuesday. I’m pulling a few FAQ up to the top here, keeping the rest of the post as it was on Wednesday. So scroll down for the data. Which vaccine should I get? The vaccines both show good antibody responses. The advantages of Moderna are: Full protection sooner (42 days rather than about 90, given the 3 shots needed for Pfizer) More compelling current evidence of efficacy against symptomatic illness (the Pfizer claim of 80% protection is based on 10 cases, so I think should be completely discounted as totally uninformative at this point. The advantages of Pfizer are fewer side effects. If I had children in this age group, I would go with Moderna. As a note: states ordered about half as many doses of Moderna as Pfizer so this vaccine may be harder to find. What if my kid had COVID? The CDC is recommending vaccines even for kids who have had COVID. There are a few reasons, notably that hybrid immunity tends to be more protective. Kaytlyn Jetelina has a longer discussion of why she thinks this makes sense here. My sense is many pediatricians and parents will find this a more complicated choice. At a minimum, it likely makes sense to wait 90 days out from infection before vaccinating. Are these vaccines really “effective” -- it doesn’t sound like it. Yes. The evidence of efficacy is in the antibody response. In adults and older children we observe this antibody response to the vaccine as evidence of protection against serious illness and death. It is true that protection against symptomatic illness is more limited, but that’s also true for adults. The value of the vaccines is protection against serious illness. It’s absolutely correct that kids in this age group are low risk for serious illness, but given the evidence of safety in these vaccines -- in the kids in the trial, but also in the millions and millions of older children who have been vaccinated -- the risk-benefit tradeoff seems like a reasonable one to me personally. What about mandates for these vaccines? I think we will see some individual early childhood programs mandate vaccines for these age groups (in fact, we already have). My hope, though, is that mandates will be limited. Given the low risk in this group, and the fact that many kids have had COVID, I believe the choice about vaccination should lie with parents and pediatricians. Certainly there will be people who disagree with that position. Ultimately: the thing to celebrate now is that parents of children in this age group have the choice to add this additional layer of protection. Original Post: Today the FDA met to discuss emergency use authorization for two vaccines for children six months to 5 years old. They voted this afternoon to approve the vaccines (the vote was 21 to 0 in favor for both vaccines). I will not go through all of the meeting details here, although you can read more here in a great “live blog” of the meeting. The meeting held relatively few surprises — they reviewed the data, heard from stakeholders, asked some questions and voted. There are a few more steps. There is formal FDA approval, then a CDC meeting on Friday or Saturday of this week to make recommendations. The CDC’s Advisory Committee on Immunization Practices is expected to recommend vaccination for this age group, possibly with ironed-out details about, e.g., what to do for children who have had COVID recently. I’ll update this post, and re-post on Instagram and Twitter, when that is up. Once the committee issues its decision, the White House has developed a plan for vaccination rollout that largely relies on pediatricians’ offices and may start as soon as next week. In preparation for yesterday’s meeting, the FDA issued reports on the Moderna and Pfizer filings. I wanted to run through that data today. Some FAQ (including “which vaccine?” at the bottom). Big picture Both pediatric vaccines are lower formulations of the adult and older-child vaccines. Millions and millions of doses of those vaccines have been given, across a wide range of age groups. Based on these, I’d draw out a few key lessons. Vaccines provoke an antibody response to COVID-19. The vaccines are extremely effective against severe illness and death, even during Omicron. (Note: this is remarkable and impressive.) The vaccines show much more limited efficacy against symptomatic illness with Omicron (and current variants). The safety profile of the vaccines is excellent. The most serious issues have been an increased risk of myocarditis in young men. Pediatric vaccine trials, like all vaccine trials, are intended to evaluate efficacy and safety. In terms of efficacy: The trials evaluating pediatric vaccines, in a real sense, lean heavily on what we know from vaccines for older people. These trials are what are called immunobridging studies. They infer vaccine effectiveness not by looking directly at the efficacy against symptomatic or serious illness (as was true in the primary adult trials) but by comparing antibody response with the antibody response in adults. If the antibody levels are similar to what is seen in adults, the vaccine is considered effective. By “effective,” we mean that it works similarly to how it works in adults in terms of protection against illness. Looking at what we know from adults, this effectiveness would mean: (1) excellent protection against serious illness and (2) possibly some protection against symptomatic illness. We shouldn’t have expected to see much direct confirmation of either of these in the pediatric trials. These age groups are very low-risk for serious illness, and in a population of a few thousand children you would not expect any serious illness or death to occur. We would expect to see symptomatic illness, but at relatively low levels, and given the limited protection of the vaccine, efficacy numbers are unlikely to be very precise. This is why we rely on the antibody data. The vaccine trials also focus on safety, separating out effectively three safety concerns. First, local reactions at the injection site. Second, systemic reactions (fever, fatigue, crying, etc.). And third, serious adverse events. For obvious reasons, the reports on this data focus a lot on the serious adverse events, and on evaluating whether they are likely to be because of the vaccine. Moderna and Pfizer trial details With that background, let’s summarize what the trial data says. The Moderna trial is the more straightforward. Moderna tested a two-dose regimen, with a quarter of the adult dose. It included about 4,000 children in the 2-to-5 group and about 2,400 in the six-to-23-month group. The summary of results, which I pulled from the FDA document here, is in the table below. I will emphasize that this is only a subset of the hundreds of pages of information, although I think these are the key points. MODERNA On efficacy: There were no serious illness episodes or deaths in either age group (as expected). But the antibody responses were excellent in both age groups (in the 2-to-5 group similar to that of adults, and about 30% higher in the younger group). In addition, both age groups have statistically significant levels of protection against symptomatic illness (and against a fuller definition that includes asymptomatic illness). These levels are below or at 50%, and about in line with what we’d expect based on adult protection post-Omicron. On safety: We see evidence of both local and, in the older age group, systemic reactions to the vaccine. This is, again, not surprising given what we see in adults with Moderna. Fevers were common, although they were mostly low and short-lived. But there is no question that these “typical” vaccine side effects occurred at a relatively high rate in this age group. In terms of serious issues, there was one episode in the 2-to-5 group that was judged as possibly related and one in the younger group that was thought to be related. Both were resolved fairly quickly. Pfizer The Pfizer trial proceeded in two stages. First, Pfizer tried a two-dose system, using one-tenth the adult dose. However, this did not produce a sufficient antibody response. With that setback, the researchers moved to a third dose. The sample for the third dose was significantly smaller than their original sample. This left them with many fewer people, so their results are much less precise. I’ve pulled the key results — not completely parallel to Moderna, but similar categories — in the table below. The overall summary document is here. On efficacy: There were no serious illnesses or deaths from COVID in either age group after dose 3 (there were a small number before that dose). In terms of the primary efficacy endpoint, in both age groups the antibody numbers were about 15% to 20% higher than in young adults. The extremely small samples mean we cannot conclude much of anything about efficacy against confirmed illness. (For example: in the six-to-23-month group there were three total cases, rendering statistical precision effectively nonexistent.) On safety: Overall, we do not see strong evidence of excess local or systemic reactions to the vaccine in either age group. There were two serious reactions that were judged as possibly related to the vaccine. Both resolved, and neither was clearly linked with the vaccine. Summary and a few questions Big picture here: these vaccines seem to work in kids like they work in adults. Which is to say: they provoke a significant antibody response, which we expect to protect against serious illness. This is a low-risk group for serious illness, but it’s not no-risk, and vaccines will lower it. The safety profile is good. Both vaccines show limited, if any, evidence of serious adverse events. Local and systemic reactions do happen — more so with Moderna — but seem limited. Despite what may end up feeling like a complicated decision for a lot of people, the facts we have here point to two effective vaccines with limited side effects. Which vaccine should I get? The vaccines both show good antibody responses. Moderna has more compelling evidence of efficacy against symptomatic illness. Moderna also has a higher rate of moderate side effects, probably due to the larger dose. Moderna is two doses; Pfizer is three. There are some clear tradeoffs here. If you want the maximum protection as quickly as possible, get Moderna. This is what I would do if my children were in this age group. However: the Pfizer vaccine also provokes a good antibody response, and the side effects are more limited. For some families, this is going to feel like the easier choice. What if my kid had COVID? This is something I expect the CDC to weigh in on, and I’ll update when it does. In adults, natural immunity has been shown to be quite protective against future serious illness. Hybrid immunity (COVID + vaccine, in either order) is generally even better. For this reason, I can see the agency recommending a single dose for kids who had COVID already. I can also see them recommending this group not yet be vaccinated. My pediatrician isn’t recommending the vaccine, especially since my kid had COVID. How should I navigate this? A corollary of the above, and one I get a lot. Given the protective role of natural immunity, this isn’t unreasonable. And, in fact, there was disagreement among the FDA panelists about how urgently vaccines should be recommended, even as they all agreed the option should be there. Ultimately, the decision about vaccinating your kid is one you need to make, with the input of the CDC, your pediatrician, and the data. Once my kid is vaccinated, how long will immunity last? Based on what we know from adults, we should expect the serious illness protection to be very robust. In terms of protection against symptomatic illness, this is moderate in the first place and probably does wane within a few months. Again, this is based on what we know from adults and older children. Will daycares and preschools mandate the vaccine? I’m not sure. This hinges a lot on what the CDC says. My guess is this will depend a lot on where you live and your individual child care center. Will we be able to stop quarantining? I really, really hope so. If anyone at the CDC or similar is reading this, please consider quickly and clearly revising guidelines for early childhood centers to allow for a relaxation of quarantine rules post-vaccine. Parents are still struggling. What data do we need moving forward? Within the next few weeks, many children under 5 will be vaccinated. They will be carefully followed over time, we’ll get a sense of any adverse events in a much larger scale. This is an important part of safety and efficacy monitoring, and I hope we’ll have good reporting out. I know many parents are eager to vaccinate, but others want to wait to see more. That more will be coming (and you know I’ll write about it, the way I did with the 5-11 group). Overall: I hope this is clarifying. It’s been a long time coming, and my sense is that some people have moved from eager to angry to disillusioned. Perhaps the final approval here will be a ray of hope.

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