Pfizer COVID-19 Vaccine for Children Aged 5–11: VRBPAC Meeting Summary and Mythbusting— Deplatform Disease

The vaccine for 5 to 11 year-olds is slightly different.

  • The first is the dose: the mRNA content for this age group is 10 mcg instead of 30 mcg (1 mcg = 1 millionth of 1 gram). The reason for this is because Pfizer conducted a dose-finding study and found that the 10 mcg dose was less reactogenic (caused fewer side effects) but equally immunogenic (elicited an immune response as good as higher doses) compared with higher doses in this age group. Immunogenicity was broadly similar within age groups of the 5- to 11-year-olds. Theoretically, this may also offer some safety advantages as there are suggestions that the risk of serious adverse events, with special interest in myocarditis risk (more on that shortly), may be related to the dose of the mRNA in the product, but this is still speculative. In other words, if you have an 11-year-old, there is no need to wait for them to turn 12 to get this vaccine (provided it all gets approved for them). The vaccine showed 90.7% efficacy in this study (16 cases in the placebo group, 3 in the vaccine group, all due to the delta variant). This is a small number of cases, but the focus of the study was immunobridging- demonstrating that the immune response to the vaccine is as good as for other groups in whom the vaccine has already demonstrated efficacy. Thus, this is acceptable.
  • The buffer formulation is slightly different. A buffer is an inactive ingredient whose job is to resist pH changes (changes in acidity or alkalinity). Biological systems are filled with buffers because the large biological molecules that comprise them are very sensitive to pH changes and can only function in a narrow range of pHs. In the case of RNA, alkalinity of any kind is very poorly tolerated and can cause the RNA to degrade in a reaction called hydrolysis. The buffer solution ensures that the vaccine vial never gets too alkaline. This is also helped by the very low storage conditions. The Pfizer/BioNTech COVID-19 vaccine (aka Comirnaty) has used a buffer called phosphate-buffered saline before (a mixture of common salts occurring in our own bodies- potassium chloride, monobasic potassium phosphate, dibasic potassium phosphate, and sodium chloride aka table salt). However, this is a bit nonstandard for storage of nucleic acids like the mRNA vaccines are made of; tris, also called tromethamine, is much more typical and preferred (for long term storage of RNA, tris-EDTA buffer is typically used, sometimes called TE buffer. The EDTA is a chelating agent that sucks up metal ions like magnesium, which can rapidly degrade the RNA. No EDTA is contained within the updated Pfizer vaccine however). Incidentally, this component of the buffer is used in the Moderna vaccine. The vaccine will no longer contain table salt (sodium chloride) or potassium chloride. The vaccine was tested in the 5 to 11 year old age group using the old buffer, but as this is an inactive ingredient, this isn’t concerning for any issues of safety or efficacy, and Pfizer conducted standard studies on shelf life to confirm the integrity of the RNA vaccine over time and found that now it can be stored at standard refrigeration for 10 weeks! That’s really excellent because it means it can be given in pediatricians offices, and it opens up possibilities for its use in lower and middle income countries as this shift happens with the other Pfizer/BioNTech mRNA vaccines.
  • Because the dose of the vaccine is smaller in this age group, there are some changes to the vials. Firstly, it’s hard to accurately draw up very small volumes, and the vaccine which had triple the dose was just 0.3 mLs, so this one would have to be 0.1 mLs if you used the same concentration. Thus, the vials are more diluted to allow for accurate dosing (they are to have 0.9% sodium chloride solution added to a volume of 1.3 mLs so that a concentration of 0.1 mg/mL of RNA is achieved). Because the vial composition is slightly different, it will also come with an orange cap and now 10 doses can be extracted instead of 6.

COVID-19 is a very serious public health issue in this age cohort.

  • We are not overestimating COVID-19 hospitalizations in this age group. The data presented earlier are from COVID-NET, which covers about 10% of the US population and includes 14 states and 250 medical centers. A major concern raised several times by members of the public and VRBPAC members is whether or not COVID-19 cases included in the COVID-NET data could reflect incidental infections as patients have to be screened as part of infection control measures. Dr. Havers of the CDC presented the data and explained that this is not likely to be a significant issue because the CDC has officers who review charts to see what the reasons for hospitalizations were, and thus incidental COVID-19 is not included. It is actually possible that they may underestimate it because sometimes the child comes in for an unrelated condition, is found to have COVID-19, and then that becomes the principal reason for their illness. So, the unfortunate and very sobering data we have here are likely accurate.

Myocarditis

  • A few aspects of classic myocarditis’s epidemiology are really critical and can lend clues for what to expect in this younger age group. First is the sex disparity: it biases males significantly and peaks among younger adult and adolescent males, dropping at the prepubescent period. This is thought to reflect a role for sex hormones, especially testosterone. When looking at females, the risk across age group is relatively constant. Notably, with the vaccine-associated cases, the risk drops when you look at 12–15 year olds relative to 16–19 year olds. Excess risk of vaccine myocarditis in females at virtually any age is very small, and though there is a significant increase in the relative risk of the condition, the absolute increase in terms of case numbers is also small for males. Given the natural history and epidemiology of classic myocarditis, and potentially the role of the smaller dose, the risk of myocarditis for 5 to 11-year-old kids, in particular males, is likely to be quite low. Indeed, no cases of myocarditis were observed in Pfizer’s trial despite approximately 3000 children in the age group receiving it.
  • Myocarditis may sometimes be asymptomatic, and the significance of such cases is controversial. Sudden cardiac death in adults may occur following resolution of acute myocarditis even with functional normalization (but in kids the picture is a lot murkier) and it is noted on 5 to 10% of autopsies on young adults who die suddenly. For this reason, work is underway to define the burden of asymptomatic myocarditis in this age group. The issue, however, is that there really isn’t a good way to do that. The principal mechanism one might consider is measuring blood troponin levels. Troponin is a marker of myocardial injury and is released when the heart experiences damage. The issue is, it is not specific to myocarditis and is released into the blood with any kind of damage. In fact, it can become elevated from vigorous exercise alone. Because the background rate of the condition is so rare, if you go by troponins, it is probable that most of your positive myocarditis cases are going to be false positives, rendering finding an accurate rate impossible. Pfizer is currently trying to work out a way to study this in more detail, however.

“We won’t know about the safety of the vaccine until we roll it out”

Miscellaneous FAQs

  • Anti-vaccine zealots love the public comment period at ACIP and VRBPAC meetings because they can appear as official-looking experts and spread lies and distort facts about the vaccines. Unfortunately, the bulk of comments at this VRBPAC meeting were issued by such zealots. Most of what was claimed was shown explicitly to be false by the presentations during the VRBPAC meeting, so I recommend either watching the presentations or reading the Twitter thread to address them in detail. I will make note of two particular individuals, however. One is Steve Kirsch, who has previously offered his own fortune to explore early treatments for COVID-19 which is an extremely noble and commendable thing to do. Unfortunately, things soured quite a bit since that, and he decided he knew better than the investigators he himself was funding about what did and didn’t work, and has become a tireless source of anti-vaccine falsities. Kirsch holds no relevant expertise about the subjects he opines on and simply has more stamina than many of his rhetorical opponents. Kirsch has previously collaborated with Jessica Rose who claims the title of viral immunologist in this meeting for her comment, and then proceeds to shamelessly lie (though the possibility exists that her grasp of immunology is so poor that she makes the errors unintentionally). Specifically, Rose insinuates that the vaccines induce a Th2-driven immunopathology in the form of myocarditis (the use of the mRNA platform was designed specifically to avoid the risk of Th2 immunopathology, which myocarditis in general is not regarded as being part of), when in reality the vaccines were demonstrated in preclinical and early clinical trials to produce a strongly Th1-biased response with “minute or undetectable levels of the T-helper-2 (TH2) cytokines”, and detailed profiling of myocarditis patients shows no apparent evidence for a Th2-driven response. It’s also worth noting that she and Peter McCullough, acolyte of hydroxychloroquine and grifter currently engaged in a lawsuit with Baylor College of Medicine for claiming an affiliation there that he does not hold, currently have a publication that is currently experiencing a temporary removal (from a skim of the abstract though, it appears to be a classic example of VAERS dumpster diving, which definitely should not meet publication standards for… well… any journal). My honest advice is to ignore public comments. Occasionally, good and honest people raise valid concerns or points about the subject matter, but overwhelmingly it is an opportunity for anti-vaccine activists to espouse lies that, even if easy enough to spot as untrue, can create inappropriate doubts that can make you question good decisions.
  • There is no data on what, if anything, this would accomplish. I think this is a reference to the recent mouse study showing intravenous administration of the mRNA vaccines caused myocarditis in mice but few things to note: (1) the doses the mice received are far higher than the equivalent dose in humans, (2) intradermal route for vaccination is used only with the BCG vaccine. This isn’t something that should be attempted without at least a study showing that the immune response is just as good and there aren’t obvious safety issues.
  • It’s not currently recommended (though you don’t need to restart the series if you go past 3 weeks), but going more than 3 weeks seems to be fine, and may even have immunological advantages for the durability of the response and quality of the antibodies elicited. However, it’s unclear how this might affect the safety profile e.g. regarding myocarditis. Moderna for instance is given 4 weeks apart (Pfizer/BioNTech’s vaccine is given 3 weeks apart) and seems to have a slightly higher risk of myocarditis, so a longer interval might not reduce it. It’s also possible this is related to the dose. Alternatively, data from Israel shows a much lower risk of myocarditis with dose 3 than dose 2, which is given 6 months later. Is this because of the interval, or because the vast majority of people susceptible to myocarditis from the vaccine already got it with dose 2?
  • This is currently unknown but is the subject of active investigation.
  • Hard to say. To previously infected people? Maybe but this wasn’t really tested. Data suggests that the second dose is really critical for both the T cell and neutralizing antibody response, and seems to be important for maintaining durability of the protection from the vaccine. The issue with giving 1 dose to infected people is part logistical and part scientific. One question is how you define previously infected. For instance, a transient positive PCR may have been an infection but may not have resulted in significant immunity that the vaccines can build on for protection. Using antibody testing is one option, but is logistically difficult, expensive, and runs into epidemiological complexities (i.e. false positives and false-negatives), mostly limiting the use of these tests to serological surveillance. What’s more is that anti-N antibodies, which demonstrate prior infection, wane more quickly than those directed against spike protein, but anti-spike cannot distinguish between vaccine-elicited and those from prior infection. In that sense, it’s possible that anti-spike antibodies might be used, but again, this is subject to the same issues of sensitivity and specificity mentioned earlier. Furthermore, no data currently available suggest that the vaccine is more dangerous in recovered individuals, though there is a consistent theme that the first dose is more intense, but the second is milder.
  • No evidence currently suggests that. Many vaccines on the childhood immunization schedule require multiple doses as part of a primary series and then may not need boosters or may need them only infrequently. As additional doses of COVID-19 vaccine are given, immunological memory is fortified further and takes longer to decline to baseline.

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I write about vaccines here. You can find me on Twitter @enirenberg and at deplatformdisease.com (where I publish the same content without a paywall)

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Edward Nirenberg

Edward Nirenberg

I write about vaccines here. You can find me on Twitter @enirenberg and at deplatformdisease.com (where I publish the same content without a paywall)

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