Re: myocarditis -- what about the mRNA vaccines might be causing the problem? In a recent article in Pediatrics examining the issue (https://pediatrics.aappublications.org/content/early/2021/06/04/peds.2021-052478) it was proposed that it might be related to the increased systemic reactogenicity seen (along with increased immunogenicity) in younger patients. If this is the case, might it be addressed by decreasing the dose, or changing the timing of the second dose? Are there any other plausible explanations? (This is the only one I've seen suggested.)
I'm a little concerned about what this means for vaccinating children under 12. Myocarditis tends to peak in younger men, but also in very young children (peaking in infancy, declining steadily over the following couple of years or so until reaching the baseline). And for the latter, it is more frequently severe. Pfizer has settled on a 3-µg dose for children aged 2-5 -- one-tenth that given to all ages so far -- which I hope mitigates this concern. But how could we know without a much larger trial?
“Increased systemic reactogenicity” is a fancy way to say these vaccines cause inflammatory reactions in the whole body. Myocarditis is, itself, an inflammatory reaction. So, I’m not into that as an explanation because it seems kind of circular to me—myocarditis, an inflammatory reaction, happens because the vaccine causes systemic inflammatory reactions? We can do better than that.
It seems to me that this systemic reactogenicity—as well as immunogenicity—are due to the ability of these vaccines to attract immune responses. In my opinion, that is because introducing non-self nucleic acids can activate several different immune pathways that attract and induce wider systemic responses. I think what’s happening is that these vaccines induce cytokines, those cytokines cause systemic effects, and in some people, that leads to myocarditis. This isn’t a much more satisfying explanation, I realize, but I think it’s a better hypothesis-generating explanation. We should investigate the cytokine response to mRNA vaccination, and understand the profile of the immune response they generate. I hypothesize that there is a specific cytokine or pattern of cytokines that, in very rare circumstances and in very specific patients, can encourage myocarditis.
If that’s true, then it’s possible you’re right—spacing out the vaccines a little further might help avoid the effect. Except, I’m not sure the effect is serious enough to bother with this. Myocarditis goes away and doesn’t seem to have been serious in anyone affected. It might be best just to manage it medically if it is detected.
As far as changing the dose in adults and older children, this isn’t going to happen. The dosing trials were conducted a long while ago, and the dose that went into Phase 3 is essentially locked in without another Phase 3 trial. Since the dose was carefully calibrated to be immunogenicity, I don’t think that there is much upside to trying to mess around with the dose here. Since the myocarditis effect—which is still unconfirmed—is very rare, it would be hard to detect any effect of a dosing change in the few patients per million who are actually impacted. It would also be more likely to compromise the efficacy that is observed with the current dosing. Since even if real, the myocarditis situation doesn’t seem to compromise the vaccine’s risk-benefit profile, I don’t think it is a worthwhile investment of resources to perform such a trial.
For younger children, I think it’s a valid question, but I’m still not very deeply concerned about the impact of this. This is a manageable and extremely rare condition, and it’s not at all clear that it’s vaccine-emergent. The reduced dose may have a positive impact in this younger population, but since we don’t know what’s actually causing this pattern to emerge I’m hesitant to speculate about what might happen. Because the signal is so rare, it may come down to postapproval monitoring to figure out if this is happening in younger patients. Considering the potential debilitating threats posed by COVID-19 in all ages, the FDA advisory committee reviewing the expanded authorization will need to carefully consider the potential risk-benefit. By then I suspect we will also know more about the patient circumstances in the observed cases, and perhaps understand the causality here better. Let’s return to this line of questioning when we have more information.
Good question. I expect that this is not a unique event to Pfizer, but rather shared across the mRNA vaccines in total. The overwhelming majority of vaccine administrations in the US are mRNA vaccinations thus far.
Re: myocarditis -- what about the mRNA vaccines might be causing the problem? In a recent article in Pediatrics examining the issue (https://pediatrics.aappublications.org/content/early/2021/06/04/peds.2021-052478) it was proposed that it might be related to the increased systemic reactogenicity seen (along with increased immunogenicity) in younger patients. If this is the case, might it be addressed by decreasing the dose, or changing the timing of the second dose? Are there any other plausible explanations? (This is the only one I've seen suggested.)
I'm a little concerned about what this means for vaccinating children under 12. Myocarditis tends to peak in younger men, but also in very young children (peaking in infancy, declining steadily over the following couple of years or so until reaching the baseline). And for the latter, it is more frequently severe. Pfizer has settled on a 3-µg dose for children aged 2-5 -- one-tenth that given to all ages so far -- which I hope mitigates this concern. But how could we know without a much larger trial?
“Increased systemic reactogenicity” is a fancy way to say these vaccines cause inflammatory reactions in the whole body. Myocarditis is, itself, an inflammatory reaction. So, I’m not into that as an explanation because it seems kind of circular to me—myocarditis, an inflammatory reaction, happens because the vaccine causes systemic inflammatory reactions? We can do better than that.
It seems to me that this systemic reactogenicity—as well as immunogenicity—are due to the ability of these vaccines to attract immune responses. In my opinion, that is because introducing non-self nucleic acids can activate several different immune pathways that attract and induce wider systemic responses. I think what’s happening is that these vaccines induce cytokines, those cytokines cause systemic effects, and in some people, that leads to myocarditis. This isn’t a much more satisfying explanation, I realize, but I think it’s a better hypothesis-generating explanation. We should investigate the cytokine response to mRNA vaccination, and understand the profile of the immune response they generate. I hypothesize that there is a specific cytokine or pattern of cytokines that, in very rare circumstances and in very specific patients, can encourage myocarditis.
If that’s true, then it’s possible you’re right—spacing out the vaccines a little further might help avoid the effect. Except, I’m not sure the effect is serious enough to bother with this. Myocarditis goes away and doesn’t seem to have been serious in anyone affected. It might be best just to manage it medically if it is detected.
As far as changing the dose in adults and older children, this isn’t going to happen. The dosing trials were conducted a long while ago, and the dose that went into Phase 3 is essentially locked in without another Phase 3 trial. Since the dose was carefully calibrated to be immunogenicity, I don’t think that there is much upside to trying to mess around with the dose here. Since the myocarditis effect—which is still unconfirmed—is very rare, it would be hard to detect any effect of a dosing change in the few patients per million who are actually impacted. It would also be more likely to compromise the efficacy that is observed with the current dosing. Since even if real, the myocarditis situation doesn’t seem to compromise the vaccine’s risk-benefit profile, I don’t think it is a worthwhile investment of resources to perform such a trial.
For younger children, I think it’s a valid question, but I’m still not very deeply concerned about the impact of this. This is a manageable and extremely rare condition, and it’s not at all clear that it’s vaccine-emergent. The reduced dose may have a positive impact in this younger population, but since we don’t know what’s actually causing this pattern to emerge I’m hesitant to speculate about what might happen. Because the signal is so rare, it may come down to postapproval monitoring to figure out if this is happening in younger patients. Considering the potential debilitating threats posed by COVID-19 in all ages, the FDA advisory committee reviewing the expanded authorization will need to carefully consider the potential risk-benefit. By then I suspect we will also know more about the patient circumstances in the observed cases, and perhaps understand the causality here better. Let’s return to this line of questioning when we have more information.
Aren't the vaccine uptake numbers you give for *all* vaccines, not just Pfizer?
Good question. I expect that this is not a unique event to Pfizer, but rather shared across the mRNA vaccines in total. The overwhelming majority of vaccine administrations in the US are mRNA vaccinations thus far.