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There's no adjuvants being used at all with mRNA vaccines. Also, there were smaller sub-trials done with just one shot, and those showed significantly weaker i

There's no adjuvants being used at all with mRNA vaccines. Also, there were smaller sub-trials done with just one shot, and those showed significantly weaker immunization, although telling exactly how much weaker is hard due to little data available and thus very large margins of error.

throwaway189262 6y ago
No traditional adjuvants is interesting, but I know the RNA is modified. It's not the exact mRNA spike protein. I believe they modify the amino acids to modulate immune reaction which may accomplish the same thing. The immune system doesn't like non-human RNA. Certain sequences, or even abundance of certain amino acids out of balance with human codes can set it off. Special RNA coding may be used in place of traditional adjuvants but much of it is proprietary at this point
- mmmrtl 6y ago
  You've kind of got it backwards. The RNA modifications (uracil depletion and using less immunogenic analogues) and in these vaccines are to avoid the getting too much immune response to the mRNA itself, and allow time for spike protein to be translated and lead to the immune response.
  - throwaway189262 6y ago
    It could be both. The goal is to evade the innate extracellular immune system while priming adaptive immunity. I don't think we know enough about their RNA modifications to say they put all their focus on one instead of the other. Traditionally, mRNA vaccines were not very effective. There's definitely some magic "trade secret" sauce in these vaccines.
    - mmmrtl 6y ago
      I can tell you for sure that the amino acid content isn't changed in any obscure way - it's exactly the original Wuhan genome's spike protein, with two proline mutations that put it in a prefusion conformation that makes a more stable target for antibodies, a strategy developed in research for SARS/MERS vaccines. The codons and overall RNA sequence are heavily optimized in ways that outsiders and I suspect they companies themselves don't really understand. Pfizer's production version of BNT162b2 is actually BNT162b2 V9, suggesting they tried combinations of many different strategies and took the one that worked the best. You could be right that some of the optimizations had immune effects that no one knows or understands yet, but I doubt there was real intention behind it. Magic sauce indeed! The sequence is actually public, but as far as I know no one has figured out what optimizations worked in the end aside from the uracil-depletion + 1-methylpseudouridine trick to avoid an immune response to what looks like viral RNA. https://mednet-communities.net/inn/db/media/docs/11889.doc https://mednet-communities.net/inn/db/media/docs/11889.doc
jhayward 6y ago
The lipid nanoparticles that the mRNA is bonded to play a dual role, enabling the mRNA to traverse the cell boundary, and also as an adjuvant.
mlyle 6y ago
Polyethylene glycol is an adjuvant, as are many of the lipids chosen. It's looking like PEG is maybe a bit too effective at getting the immune system's attention, and that's why we're getting so much anaphylaxis. We know that both the Moderna and Pfizer vaccines look about 80% effective from 10 days after dose 1 up to dose 2. We really should be doing a trial on delaying dose 2 a bit: it might very well make the dose 2 side effects smaller, increase efficacy, and stretch vaccine supplies.
- maxerickson 6y ago
  11 or 12 per million might better be described as "higher rates of anaphylaxis than other widely used vaccines". In absolute terms it's not a lot. Even for younger adults, chances of dying if infected with Covid are much higher than that.
  - mlyle 6y ago
    Oh, of course. The vaccines have a higher side effect rate than we're used to, but they're orders of magnitude safer than the risk we have from being exposed to COVID, infected, and then having a bad outcome. Some of this relates to the rush to market and the desire for very high efficacy even if we were somewhat surprised/incorrect on required neutralization titers. When COVID-19 is rarer, we likely will need safer vaccines against it, though. This may just be a question of turning down dosage a bit.
  - EpiMath 6y ago
    Agreed, and current estimates are more on the order of 4 to 5 per million. A high proportion of these cases are among people with a history of anaphylactic reactions to drugs, needle sticks or food/tree nuts ( many were already carrying their own epi pens! ) so it includes people who probably would skip an annual flu vaccine but of course do not want to skip this one. I'm not trying to suggest that the rate isn't higher than other vaccines, but it may not be as much higher as it first appeared. ( Also, to be fair, now that there is so much vigilance, it's possible that a number of pre-anaphylaxis are being caught early and treated with epi or benadryl before they could become full-blown anaphylaxis. So, this could make the rate appear lower. These things always need to be considered thoughtfully! ) As others have pointed out, the risk/benefit calculation here is extreme: a few bad reactions per million vs. a disease that has already killed more than 1000 people per million population in the US.

throwaway189262 6y ago

No traditional adjuvants is interesting, but I know the RNA is modified. It's not the exact mRNA spike protein. I believe they modify the amino acids to modulate immune reaction which may accomplish the same thing. The immune system doesn't like non-human RNA. Certain sequences, or even abundance of certain amino acids out of balance with human codes can set it off. Special RNA coding may be used in place of traditional adjuvants but much of it is proprietary at this point

mmmrtl 6y ago
You've kind of got it backwards. The RNA modifications (uracil depletion and using less immunogenic analogues) and in these vaccines are to avoid the getting too much immune response to the mRNA itself, and allow time for spike protein to be translated and lead to the immune response.
- throwaway189262 6y ago
  It could be both. The goal is to evade the innate extracellular immune system while priming adaptive immunity. I don't think we know enough about their RNA modifications to say they put all their focus on one instead of the other. Traditionally, mRNA vaccines were not very effective. There's definitely some magic "trade secret" sauce in these vaccines.
  - mmmrtl 6y ago
    I can tell you for sure that the amino acid content isn't changed in any obscure way - it's exactly the original Wuhan genome's spike protein, with two proline mutations that put it in a prefusion conformation that makes a more stable target for antibodies, a strategy developed in research for SARS/MERS vaccines. The codons and overall RNA sequence are heavily optimized in ways that outsiders and I suspect they companies themselves don't really understand. Pfizer's production version of BNT162b2 is actually BNT162b2 V9, suggesting they tried combinations of many different strategies and took the one that worked the best. You could be right that some of the optimizations had immune effects that no one knows or understands yet, but I doubt there was real intention behind it. Magic sauce indeed! The sequence is actually public, but as far as I know no one has figured out what optimizations worked in the end aside from the uracil-depletion + 1-methylpseudouridine trick to avoid an immune response to what looks like viral RNA. https://mednet-communities.net/inn/db/media/docs/11889.doc https://mednet-communities.net/inn/db/media/docs/11889.doc

jhayward 6y ago

The lipid nanoparticles that the mRNA is bonded to play a dual role, enabling the mRNA to traverse the cell boundary, and also as an adjuvant.

mlyle 6y ago

Polyethylene glycol is an adjuvant, as are many of the lipids chosen. It's looking like PEG is maybe a bit too effective at getting the immune system's attention, and that's why we're getting so much anaphylaxis. We know that both the Moderna and Pfizer vaccines look about 80% effective from 10 days after dose 1 up to dose 2. We really should be doing a trial on delaying dose 2 a bit: it might very well make the dose 2 side effects smaller, increase efficacy, and stretch vaccine supplies.

maxerickson 6y ago
11 or 12 per million might better be described as "higher rates of anaphylaxis than other widely used vaccines". In absolute terms it's not a lot. Even for younger adults, chances of dying if infected with Covid are much higher than that.
- mlyle 6y ago
  Oh, of course. The vaccines have a higher side effect rate than we're used to, but they're orders of magnitude safer than the risk we have from being exposed to COVID, infected, and then having a bad outcome. Some of this relates to the rush to market and the desire for very high efficacy even if we were somewhat surprised/incorrect on required neutralization titers. When COVID-19 is rarer, we likely will need safer vaccines against it, though. This may just be a question of turning down dosage a bit.
- EpiMath 6y ago
  Agreed, and current estimates are more on the order of 4 to 5 per million. A high proportion of these cases are among people with a history of anaphylactic reactions to drugs, needle sticks or food/tree nuts ( many were already carrying their own epi pens! ) so it includes people who probably would skip an annual flu vaccine but of course do not want to skip this one. I'm not trying to suggest that the rate isn't higher than other vaccines, but it may not be as much higher as it first appeared. ( Also, to be fair, now that there is so much vigilance, it's possible that a number of pre-anaphylaxis are being caught early and treated with epi or benadryl before they could become full-blown anaphylaxis. So, this could make the rate appear lower. These things always need to be considered thoughtfully! ) As others have pointed out, the risk/benefit calculation here is extreme: a few bad reactions per million vs. a disease that has already killed more than 1000 people per million population in the US.