On Friday, Pfizer announced results of their Phase II/III trial in children 6 months to under 5 years of age. There were two big wins and one massive set back:
1) If the 6 mon- 2 yr trial was a success, why isn't Pfizer going to the FDA for approval on that now?
2) Wouldn't some protection be better than no protection? Why not get the 2-4 year olds started and then they could get a third dose when it is approved in the first half of the year? In the middle of the serge it seems two doses would provide some protection while they figure out the third dose, just the same as they did with the adults.
I honestly don't think they are allowed to get the 6mo-2 year olds vaccinated because these are age de-escalation designs. they have to rely on the previous age's data safety and effectiveness before moving down.
I’m just so sad. I’m so tempted to get my 4.5 year old vaccinated. I know lying isn’t the right move here but I am just so upset that we have to continue to live like this. I thought we might have a tiny shred of comfort coming relatively soon.
Purely a guess based upon what we know about vaccine design and how the pediatric immune system responds to different antigens:
* Immature immune systems don’t recognize antigens like adults until a child is at least two years old. Case in point: the polysaccharide antennae on the dozens of different serotypes of Strep pneumonia. Prevnar and Pneumovax target the same bug and those same antennae. But...
- The pediatric vaccine against Strep pneumonia (Prevnar) conjugates those antigens to a diphtheria protein to draw the attention of the immune system.
- In adults, we can just glop the different serotypes into a stable formula and trigger an immune response. Designing the adult vaccine (Pneumovax) was fairly straight forward compared to the pediatric version.
Sounds like the answer for a pediatric Covid vaccine (kids under 4) may be to present the spike protein to the immune system in a different way:
- Either conjugated to a protein (like Prevnar does)
- Or with an extra "adjuvant" chemical (like Tdap uses does) to trigger an immune response in the youngest children.
mRNA vaccines are so immunogenic that you shouldn't need an adjuvant. They just didn't get the dosing right, probably because the Phase I was underpowered, as others have said.
So obviously the 3 µg dosage was incorrect for 2- to under 5-year olds. But why wasn’t this detected in Phase I “dosage finding” stage? I don’t know. No one knows, because this data has not been publicly released or published. I have a bigger question, WHY isn't this data released, what else don't we know? Safety issues?
It's likely the the opposite. Pfizer has been ultra-conservative with dosing to avoid side effects or safety issues. Much more so than Moderna. It looks like they just used too small a dose, probably because the Phase 1 trial included too few toddlers.
First, I think Andrew Saal might be on to something. A common error is to think there's no difference in the immune system as humans mature.
Second, I suspect the Phase 1 trial was under-powered, so they didn't really do the dose-determining statistical magic properly. Because Phase 1 trials are notoriously small, the age-range distribution could have been skewed enough to miss efficacy of dose in that group.
Would greatly appreciate your answers to these 3 questions: 1) What specific behavior(s) account for the high number of breakthrough cases among boosted adults who are already conscientiously following recommended safety protocols? 2) In terms of omicron's inherent transmissibility, what specific behaviors are leading to the increased transmission? 3)Should 'close contact' be redefined (e.g. no longer 15 minutes over 24 hours)? Thank you!
my theory is that the underlying risk of Omicron infection is so large that even reducing it by 70-75% (the estimated efficacy against symptomatic infection) still leaves a quite large risk.
would love any expert's thoughts on this but i haven't been able to get a single response
You do so much work for the good of everyone! Thank you for every second! You deserve to have your family safe, given all of your sacrifice. I’m so sorry for what must feel like a huge loss to you. I’m sure I’m not the only one wanting to console you for your grief! Huge comforting hugs!!
Any word on what is going on with Moderna’s pediatric Phase III trial? Given their more ‘aggressive’ approach you outline above, could we hear back from Moderna before Pfizer finishes this revised Phase III trial?
maybe. but just like with pfizer, i don’t think they are allowed to skip ages in an age de-escalation design. this is really a question for the FDA and what they would approve for emergency use
Is it possible that they will have their results for both age groups at the same time? I am truly devastated after we have been so vigilant for 2 years. I’m in tears reading this.
He also says Moderna's dose for <6yr olds was 25 micrograms, 25% of the adult dose and 8x that of Pfizer's young children trial (with caveat that they're not exactly comparable due to different lipid nanoparticles). Personally, would prefer two-doses rather than three.
Both of my kids are in this Moderna trial. One in the 5-12 year old group and one in the under 5 years group. We’ve been asked to not say much about the study but I sure hope it works so other children can be vaccinated. I was so disheartened to read the news about the Pfizer vaccine.
Your article is very well written and I admire your ability to blend compassion with critical analysis. But I do have a comment.
I object to you comment that the industry does not test the most vulnerable patients first.
In Covid-19, children are not the most vulnerable, unlike influenza.
More importantly, children are growing. Their metabolic pathways are not mature, as their metabolic and elimination organs are not typical of adults. The unexpected results of this trial underscore this point.
For these reasons we develop drugs in adults first, lest we inadvertently cause harm to children, not knowing the appropriate dosage. Imagine what would happen if a drug/vaccine caused adverse events in some pediatric subjects because we proceeded too aggressively, without understanding the nuances of development that resulted, for example, in the accumulation of a metabolic byproduct that does not occur in adults but does in children.
I think you misunderstood her. She was said we test in adults first and gradually step down because children are more "vulnerable". You seem to have interpreted that as meaning "vulnerable to COVID infection". That seems unlikely to me. One possibility is that she meant "vulnerable" in the sense that very young children lack the capacity to give anything remotely resembling informed consent, which an adult, teen, or even older child can. Another possibility is that she was referring to vulnerability to harm from a poorly formulated or poorly dosed vaccine, as you suggest.
Right, in the case of age deescalation, we're not talking about vulnerability to covid. We're talking about other kinds of vulnerability -- e.g. side effects, and also social vulnerability. To get clinical trials approved in children, you need to make a strong case that the benefit will outweigh the risk. That case is made, in part, by showing the data from other age groups showing that the vaccine was well tolerated and conferred good protection.
Moderna doesn't have full FDA approval; Pfizer does. Part of what's been holding Moderna back is the higher incidence of myocarditis in young adult males.
Thank you SO much for the info your giving us! I'm finding it really helpful to look back on some prior posts as my personal situation changes. Keep up this great service!
It's very frustrating and disappointing I agree. Thanks for the information. As it is, we keep changing our minds (or at least, the way we're "leaning") on our holiday travel plans too. The omicron news looks increasingly bad.
What's the status on trials for 6 months to 5 years for Moderna and J&J? Might one of those be able to leapfrog Pfizer now, and if so, when might we expect EUA or final approval?
Can anyone find any meaningful data on the risks of a higher vaccine dose for the 2-5 age group? I can’t find any data showing that the risk of a 10 microgram (or greater) vaccine is more dangerous than a child actually getting COVID. And COVID exposure feels imminent with omicron. Any thoughts on this or where to look for more info?
Trusting you will be celebrating this holidays and without any dramatic news we will not hear from you so I wish you a very HAPPY HOLIDAY to you and your family.
So helpful, thank you! Two questions:
1) If the 6 mon- 2 yr trial was a success, why isn't Pfizer going to the FDA for approval on that now?
2) Wouldn't some protection be better than no protection? Why not get the 2-4 year olds started and then they could get a third dose when it is approved in the first half of the year? In the middle of the serge it seems two doses would provide some protection while they figure out the third dose, just the same as they did with the adults.
I honestly don't think they are allowed to get the 6mo-2 year olds vaccinated because these are age de-escalation designs. they have to rely on the previous age's data safety and effectiveness before moving down.
I’m just so sad. I’m so tempted to get my 4.5 year old vaccinated. I know lying isn’t the right move here but I am just so upset that we have to continue to live like this. I thought we might have a tiny shred of comfort coming relatively soon.
Purely a guess based upon what we know about vaccine design and how the pediatric immune system responds to different antigens:
* Immature immune systems don’t recognize antigens like adults until a child is at least two years old. Case in point: the polysaccharide antennae on the dozens of different serotypes of Strep pneumonia. Prevnar and Pneumovax target the same bug and those same antennae. But...
- The pediatric vaccine against Strep pneumonia (Prevnar) conjugates those antigens to a diphtheria protein to draw the attention of the immune system.
- In adults, we can just glop the different serotypes into a stable formula and trigger an immune response. Designing the adult vaccine (Pneumovax) was fairly straight forward compared to the pediatric version.
Sounds like the answer for a pediatric Covid vaccine (kids under 4) may be to present the spike protein to the immune system in a different way:
- Either conjugated to a protein (like Prevnar does)
- Or with an extra "adjuvant" chemical (like Tdap uses does) to trigger an immune response in the youngest children.
Sure, how about some nice aluminum.
mRNA vaccines are so immunogenic that you shouldn't need an adjuvant. They just didn't get the dosing right, probably because the Phase I was underpowered, as others have said.
So obviously the 3 µg dosage was incorrect for 2- to under 5-year olds. But why wasn’t this detected in Phase I “dosage finding” stage? I don’t know. No one knows, because this data has not been publicly released or published. I have a bigger question, WHY isn't this data released, what else don't we know? Safety issues?
It's likely the the opposite. Pfizer has been ultra-conservative with dosing to avoid side effects or safety issues. Much more so than Moderna. It looks like they just used too small a dose, probably because the Phase 1 trial included too few toddlers.
First, I think Andrew Saal might be on to something. A common error is to think there's no difference in the immune system as humans mature.
Second, I suspect the Phase 1 trial was under-powered, so they didn't really do the dose-determining statistical magic properly. Because Phase 1 trials are notoriously small, the age-range distribution could have been skewed enough to miss efficacy of dose in that group.
Would greatly appreciate your answers to these 3 questions: 1) What specific behavior(s) account for the high number of breakthrough cases among boosted adults who are already conscientiously following recommended safety protocols? 2) In terms of omicron's inherent transmissibility, what specific behaviors are leading to the increased transmission? 3)Should 'close contact' be redefined (e.g. no longer 15 minutes over 24 hours)? Thank you!
my theory is that the underlying risk of Omicron infection is so large that even reducing it by 70-75% (the estimated efficacy against symptomatic infection) still leaves a quite large risk.
would love any expert's thoughts on this but i haven't been able to get a single response
The increased transmission is the product of the virus' high replication rate, not relaxed behaviors.
You do so much work for the good of everyone! Thank you for every second! You deserve to have your family safe, given all of your sacrifice. I’m so sorry for what must feel like a huge loss to you. I’m sure I’m not the only one wanting to console you for your grief! Huge comforting hugs!!
Any word on what is going on with Moderna’s pediatric Phase III trial? Given their more ‘aggressive’ approach you outline above, could we hear back from Moderna before Pfizer finishes this revised Phase III trial?
maybe. but just like with pfizer, i don’t think they are allowed to skip ages in an age de-escalation design. this is really a question for the FDA and what they would approve for emergency use
Is it possible that they will have their results for both age groups at the same time? I am truly devastated after we have been so vigilant for 2 years. I’m in tears reading this.
Dr. Bill Hartman, principal investigator for the UW site of Moderna's study, anticipates Moderna will be able to begin interpreting data in mid-January based on an interview from 12/7 (about halfway down the page) https://www.today.com/health/health/will-kids-5-able-get-covid-19-vaccine-rcna7761
He also says Moderna's dose for <6yr olds was 25 micrograms, 25% of the adult dose and 8x that of Pfizer's young children trial (with caveat that they're not exactly comparable due to different lipid nanoparticles). Personally, would prefer two-doses rather than three.
Both of my kids are in this Moderna trial. One in the 5-12 year old group and one in the under 5 years group. We’ve been asked to not say much about the study but I sure hope it works so other children can be vaccinated. I was so disheartened to read the news about the Pfizer vaccine.
Your article is very well written and I admire your ability to blend compassion with critical analysis. But I do have a comment.
I object to you comment that the industry does not test the most vulnerable patients first.
In Covid-19, children are not the most vulnerable, unlike influenza.
More importantly, children are growing. Their metabolic pathways are not mature, as their metabolic and elimination organs are not typical of adults. The unexpected results of this trial underscore this point.
For these reasons we develop drugs in adults first, lest we inadvertently cause harm to children, not knowing the appropriate dosage. Imagine what would happen if a drug/vaccine caused adverse events in some pediatric subjects because we proceeded too aggressively, without understanding the nuances of development that resulted, for example, in the accumulation of a metabolic byproduct that does not occur in adults but does in children.
No one wants to risk injuring a child.
I think you misunderstood her. She was said we test in adults first and gradually step down because children are more "vulnerable". You seem to have interpreted that as meaning "vulnerable to COVID infection". That seems unlikely to me. One possibility is that she meant "vulnerable" in the sense that very young children lack the capacity to give anything remotely resembling informed consent, which an adult, teen, or even older child can. Another possibility is that she was referring to vulnerability to harm from a poorly formulated or poorly dosed vaccine, as you suggest.
Right, in the case of age deescalation, we're not talking about vulnerability to covid. We're talking about other kinds of vulnerability -- e.g. side effects, and also social vulnerability. To get clinical trials approved in children, you need to make a strong case that the benefit will outweigh the risk. That case is made, in part, by showing the data from other age groups showing that the vaccine was well tolerated and conferred good protection.
Second: "Moderna is now facing the possibility of no authorization due to myocarditis concerns" Which age group, primary or booster?
Moderna doesn't have full FDA approval; Pfizer does. Part of what's been holding Moderna back is the higher incidence of myocarditis in young adult males.
Thank you SO much for the info your giving us! I'm finding it really helpful to look back on some prior posts as my personal situation changes. Keep up this great service!
It's very frustrating and disappointing I agree. Thanks for the information. As it is, we keep changing our minds (or at least, the way we're "leaning") on our holiday travel plans too. The omicron news looks increasingly bad.
What's the status on trials for 6 months to 5 years for Moderna and J&J? Might one of those be able to leapfrog Pfizer now, and if so, when might we expect EUA or final approval?
Can anyone find any meaningful data on the risks of a higher vaccine dose for the 2-5 age group? I can’t find any data showing that the risk of a 10 microgram (or greater) vaccine is more dangerous than a child actually getting COVID. And COVID exposure feels imminent with omicron. Any thoughts on this or where to look for more info?
Any idea yet if Pfizer will be doing a simultaneous trial with a higher dosage for 2-5?
Once again you knock it out of the park.
Trusting you will be celebrating this holidays and without any dramatic news we will not hear from you so I wish you a very HAPPY HOLIDAY to you and your family.