28 ms·

If you read the trial data this is a foregone conclusion. The Moderna vaccine produces antibody titres over twice as high as an actual infection from the data I

If you read the trial data this is a foregone conclusion. The Moderna vaccine produces antibody titres over twice as high as an actual infection from the data I've seen. My theory is that these companies knew they only had one chance to make a working vaccine, so they did everything they could to make it not fail. Double doses, 5x what was needed in monkeys, gold standard adjuvants. I would not be amazed in the slightest if they decide to half-dose the vaccine or do away with the second shot or even both. They probably didn't have time to run the trial any other way

CyanLite2 6y ago
If you look at some of their published Phase 2 data, they were actually getting good responses from their 25mcg dosing. But you're correct--this was the fastest vaccine development in the history of mankind, and they errored on doing the 100mcg version just to make sure the efficacy was high enough because they didn't have time to test it on a wider population or do challenge trials. Imagine the blowback on mRNA vaccines in general if they went with the low-dose version and got lowered efficacy...
- throwaway189262 6y ago
  Yup agree 100%. I thought I saw some pre-trial data on 10mcg in monkeys and even that was somewhat effective.
Etheryte 6y ago
There is a conceptual misunderstanding here. Raising the dose doesn't mean you have a higher efficacy, in fact it can just as easily have the reverse effect. Vaccines aren't beer where you consume twice as much and get twice as drunk.
- IgorPartola 6y ago
  Granted. But there is a minimum dose necessary to produce antibodies. If you are in a situation where you are guessing completely blindly (because no trial like yours has been done before), do you worry more about falling below the minimum required dose or above the maximum dose past which you get diminishing returns or even lower efficacy? I think it’s reasonable to worry more about the minimum dose because you can always half the doses later. Finding out at the end of a multi-month trial that you didn’t give enough in your doses would be a big setback. Just look at what happened with Assyria Zeneca when they started mixing up dosing in their phase III. They were the most promising vaccine last summer and they haven’t even concluded their US phase III trial yet as a result.
- throwaway189262 6y ago
  I mean technically an alcohol could exist that makes you less drunk after twice as much but how likely is that? IMO about as likely as a vaccine that produces less immunity with higher dosage
Slartie 6y ago
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
BurningFrog 6y ago
They also picked very short booster dose times (3 or 4 weeks) to get study results quicker. Usually you have a longer pause, which gives somewhat better results. Now those numbers are treated as sacred by so many.
- throwaway189262 6y ago
  It is unfortunate. You can't even avoid downvotes in a fairly rational place like HN :) . I've been following the vaccine development pretty closely and everything looks like a "this can't fail" mentality. People need to realize that it's rational to ask if we really need the dose this high and really need a booster because if we find out we don't, it could double or even quadruple our vaccine supply. That could save half a million lives. It's good to ask questions like this especially when there's a massive worldwide vaccine shortage
  - Guthur 6y ago
    Given HN propensity to bash corporations I'm surprised this is not seen as a way to double or triple profits :)
    - throwaway189262 6y ago
      Indeed. But to bash the large corpos, when medical staff figured out they could get an extra dose from most vials the drug companies immediately reduced their shipment contract requirements accordingly. Pretty scummy.
  - Espressosaurus 6y ago
    This is a case of "let's go with what works, because the downsides are worse", and we can simultaneously kick off studies of other approaches. When those are proven out (or not) changes in the protocols can be applied then. Blindly changing the protocols without proper controls/studies done in widescale deployment and hoping for the best is a great way to screw things up.
    - 6y ago
maxerickson 6y ago
There's not an added adjuvant in either of the mRNA vaccines. The lipid nanoparticles may be acting as one though (in addition to ferrying the mRNA into cells).
lettergram 6y ago
As this method doesn’t teach your body as well... could it be that the higher dose could increase the longevity of protection? My understanding is the mRNA based vaccines already aren’t as effective at long-term protection. But happy to be corrected if someone had insight.
- ericb 6y ago
  > My understanding is the mRNA based vaccines already aren’t as effective at long-term protection. Source? I've never seen anything that suggests that, and can't even think of a rationale why it would ever be true?
macinjosh 6y ago
If this is true, governments (they make the rules after all) must be held accountable (mainly Fauci) for wasting so many vaccines and so many lives we didn't have to. This sort of behavior happens when those in charge care more about optics than actually helping the public. By the sounds of the parent post we would have been just fine with half doses which means our supply would cover many more people. Instead, we have poorly considered government rules that cause vaccines go to waste, they are administering too high of doses (if the above holds true), and people being punished (even fired) for trying to use up doses that are about to go bad but don't have a recipient the gov't has deemed qualifed. Not to mention the recent revelation that Cuomo is at fault for the death of many, many elderly people who didn't have to die. This is a failure of government on ALL counts Republican and Democrat. If it wasn't for the government we'd all be better off. Period, end of story. If it wasn't for their meddling we could be back to normal by now. Edit: Down vote me all you want but continuing to lick the boot the government has on your neck will never improve your situation.
- oscardssmith 6y ago
  This isn't a failure. This is the quickest vaccine rollout ever. The way you do statistics for this means that the overkill speeds up how quickly you can verify effectiveness. For example, if you do a booster after 6 months, that adds 6 months to your study time. If you try to thread the needle to make the smallest possible vaccine, you need way more testing to prove it works. The approach taken is why we have 10% of the US vaccinated now instead of having a vaccine approved in 2 years.
  - macinjosh 6y ago
    > This isn't a failure. This is the quickest vaccine rollout ever Tell that the to the 400,000 dead, buddy. They made the vaccine in January 2020. GOVERNMENT rules mean I STILL have not gotten it well over a year later. My NINETY year old Grandma doesn't have it yet. Nice effort though. How does that leather boot taste?
    - dang 6y ago
yyyk 6y ago
>do away with the second shot Nope. There's data indicating we must have the second shot for T-cell response, or the vaccine will fail against mutations: https://www.researchsquare.com/article/rs-226857/v1 https://www.researchsquare.com/article/rs-226857/v1 https://twitter.com/dvir_a/status/1359603522581454856 https://twitter.com/dvir_a/status/1359603522581454856 (done on the Pfizer vaccine, but it's very similar to Moderna)
- Robotbeat 6y ago
  Maybe. I'm not sure we can tell for certain yet. However, I found it interesting that the vaccine seems to possibly even work somewhat against SARS-1 and MERS, which inspires a lot of hope that the vaccines could be at least partially protective against future variants. Good job, Pfizer (and Moderna)!
  - vladmk 6y ago
    I mean we have over 1 million cases now how much more of a sample size do you need?
  - yyyk 6y ago
    Well, the Clalit preprint relying on more data by an order of magnitude will be out soon, and that should be the definitive analysis. However, current results for a Pfizer 1st-only regiment aren't very encouraging IMHO. It's possible the first dose starts to be really effective exactly at the time Pfizer suggested to have the second dose, and that this increase is rather sharp - But it would be some coincidence, and antibody tests (showing not so good efficiency against variants following 1st dose, and also much larger antibody count after 2nd dose) are contraindicative.
    - Robotbeat 6y ago
      Isn’t the Moderna vaccine dose larger?
      - yyyk 6y ago
rock_artist 6y ago
Coming from Israel, What I'm writing is about Pfizer but related to the article above. Since the Pfizer vaccine is much more complex to maintain. Once you unfreeze it, there's a time window for it to be usable. In addition to many other factors "modified" by the Israeli HMO, an interesting one related to the above is the allowance of an extra dose from each bottle. The Pfizer bottle were tested as 5 dozes per bottle. The HMO here allowed 6 dozes.
- universa1 6y ago
  Iirc they also did that in germany and the result wasn't 20% more shots, but less bottles supplied ;-)
  - ciceryadam 6y ago
    Yup, Pfizer had signed contract on number of vaccine shots, not number of bottles supplied. So Pfizer is technically correct, but it's still a jerk move from their side.
smorephism 6y ago
> gold standard adjuvants Neither Pfizer-BioNTech or Moderna's vaccines bring any additional adjuvants to the yard. mRNA is inherently immunogenic. This speaks generally about mRNA vaccines and touches on that property, among others: https://www.cell.com/trends/molecular-medicine/fulltext/S1471-4914(19)30244-8 https://www.cell.com/trends/molecular-medicine/fulltext/S147...
deepstack 6y ago
> Double doses, 5x what was needed in monkeys I'm not a molecular biologist or medical experimental. But that sounds a bit bad medical testing. To just increase the dosage like this with out proper longitudinal studies. Anyone with that area of expertise care of pitch in here?
- random5634 6y ago
  The studies will eventually come out with "proper longitudinal studies". Some countries are choosing not to wait for that. I do hope they do those studies - it feels like half the current dose size might work fine
thecupisblue 6y ago
As far as I know, second dosage is to extend the duration of antibody production.
monopoledance 6y ago
> gold standard adjuvants I think the mRNA vaccines don't contain any adjuvants at all. They are so awesome, because they are comparatively simple systems. I would choose the mRNA vaccines over adenovirus-based ones, because of that. Drive-by immunity to the adenovirus carriers could render future vaccines useless, when there is no alternative vaccine technology available *. I hope when it's my turn, I will have a choice. * Edit: My guessing. I am no medical professional, or researcher in a related field. Maybe my worries are completely unsubstantiated. I am also of the "worrying type" https://www.youtube.com/watch?v=pUDv3h09VBc https://www.youtube.com/watch?v=pUDv3h09VBc

CyanLite2 6y ago

If you look at some of their published Phase 2 data, they were actually getting good responses from their 25mcg dosing. But you're correct--this was the fastest vaccine development in the history of mankind, and they errored on doing the 100mcg version just to make sure the efficacy was high enough because they didn't have time to test it on a wider population or do challenge trials. Imagine the blowback on mRNA vaccines in general if they went with the low-dose version and got lowered efficacy...

throwaway189262 6y ago
Yup agree 100%. I thought I saw some pre-trial data on 10mcg in monkeys and even that was somewhat effective.

Etheryte 6y ago

There is a conceptual misunderstanding here. Raising the dose doesn't mean you have a higher efficacy, in fact it can just as easily have the reverse effect. Vaccines aren't beer where you consume twice as much and get twice as drunk.

IgorPartola 6y ago
Granted. But there is a minimum dose necessary to produce antibodies. If you are in a situation where you are guessing completely blindly (because no trial like yours has been done before), do you worry more about falling below the minimum required dose or above the maximum dose past which you get diminishing returns or even lower efficacy? I think it’s reasonable to worry more about the minimum dose because you can always half the doses later. Finding out at the end of a multi-month trial that you didn’t give enough in your doses would be a big setback. Just look at what happened with Assyria Zeneca when they started mixing up dosing in their phase III. They were the most promising vaccine last summer and they haven’t even concluded their US phase III trial yet as a result.
throwaway189262 6y ago
I mean technically an alcohol could exist that makes you less drunk after twice as much but how likely is that? IMO about as likely as a vaccine that produces less immunity with higher dosage

Slartie 6y ago

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

BurningFrog 6y ago

They also picked very short booster dose times (3 or 4 weeks) to get study results quicker. Usually you have a longer pause, which gives somewhat better results. Now those numbers are treated as sacred by so many.

throwaway189262 6y ago
It is unfortunate. You can't even avoid downvotes in a fairly rational place like HN :) . I've been following the vaccine development pretty closely and everything looks like a "this can't fail" mentality. People need to realize that it's rational to ask if we really need the dose this high and really need a booster because if we find out we don't, it could double or even quadruple our vaccine supply. That could save half a million lives. It's good to ask questions like this especially when there's a massive worldwide vaccine shortage
- Guthur 6y ago
  Given HN propensity to bash corporations I'm surprised this is not seen as a way to double or triple profits :)
  - throwaway189262 6y ago
    Indeed. But to bash the large corpos, when medical staff figured out they could get an extra dose from most vials the drug companies immediately reduced their shipment contract requirements accordingly. Pretty scummy.
- Espressosaurus 6y ago
  This is a case of "let's go with what works, because the downsides are worse", and we can simultaneously kick off studies of other approaches. When those are proven out (or not) changes in the protocols can be applied then. Blindly changing the protocols without proper controls/studies done in widescale deployment and hoping for the best is a great way to screw things up.
  - 6y ago

maxerickson 6y ago

There's not an added adjuvant in either of the mRNA vaccines. The lipid nanoparticles may be acting as one though (in addition to ferrying the mRNA into cells).

lettergram 6y ago

As this method doesn’t teach your body as well... could it be that the higher dose could increase the longevity of protection? My understanding is the mRNA based vaccines already aren’t as effective at long-term protection. But happy to be corrected if someone had insight.

ericb 6y ago
> My understanding is the mRNA based vaccines already aren’t as effective at long-term protection. Source? I've never seen anything that suggests that, and can't even think of a rationale why it would ever be true?

macinjosh 6y ago

If this is true, governments (they make the rules after all) must be held accountable (mainly Fauci) for wasting so many vaccines and so many lives we didn't have to. This sort of behavior happens when those in charge care more about optics than actually helping the public. By the sounds of the parent post we would have been just fine with half doses which means our supply would cover many more people. Instead, we have poorly considered government rules that cause vaccines go to waste, they are administering too high of doses (if the above holds true), and people being punished (even fired) for trying to use up doses that are about to go bad but don't have a recipient the gov't has deemed qualifed. Not to mention the recent revelation that Cuomo is at fault for the death of many, many elderly people who didn't have to die. This is a failure of government on ALL counts Republican and Democrat. If it wasn't for the government we'd all be better off. Period, end of story. If it wasn't for their meddling we could be back to normal by now. Edit: Down vote me all you want but continuing to lick the boot the government has on your neck will never improve your situation.

oscardssmith 6y ago
This isn't a failure. This is the quickest vaccine rollout ever. The way you do statistics for this means that the overkill speeds up how quickly you can verify effectiveness. For example, if you do a booster after 6 months, that adds 6 months to your study time. If you try to thread the needle to make the smallest possible vaccine, you need way more testing to prove it works. The approach taken is why we have 10% of the US vaccinated now instead of having a vaccine approved in 2 years.
- macinjosh 6y ago
  > This isn't a failure. This is the quickest vaccine rollout ever Tell that the to the 400,000 dead, buddy. They made the vaccine in January 2020. GOVERNMENT rules mean I STILL have not gotten it well over a year later. My NINETY year old Grandma doesn't have it yet. Nice effort though. How does that leather boot taste?
  - dang 6y ago

yyyk 6y ago

>do away with the second shot Nope. There's data indicating we must have the second shot for T-cell response, or the vaccine will fail against mutations: https://www.researchsquare.com/article/rs-226857/v1 https://www.researchsquare.com/article/rs-226857/v1 https://twitter.com/dvir_a/status/1359603522581454856 https://twitter.com/dvir_a/status/1359603522581454856 (done on the Pfizer vaccine, but it's very similar to Moderna)

Robotbeat 6y ago
Maybe. I'm not sure we can tell for certain yet. However, I found it interesting that the vaccine seems to possibly even work somewhat against SARS-1 and MERS, which inspires a lot of hope that the vaccines could be at least partially protective against future variants. Good job, Pfizer (and Moderna)!
- vladmk 6y ago
  I mean we have over 1 million cases now how much more of a sample size do you need?
- yyyk 6y ago
  Well, the Clalit preprint relying on more data by an order of magnitude will be out soon, and that should be the definitive analysis. However, current results for a Pfizer 1st-only regiment aren't very encouraging IMHO. It's possible the first dose starts to be really effective exactly at the time Pfizer suggested to have the second dose, and that this increase is rather sharp - But it would be some coincidence, and antibody tests (showing not so good efficiency against variants following 1st dose, and also much larger antibody count after 2nd dose) are contraindicative.
  - Robotbeat 6y ago
    Isn’t the Moderna vaccine dose larger?
    - yyyk 6y ago

rock_artist 6y ago

Coming from Israel, What I'm writing is about Pfizer but related to the article above. Since the Pfizer vaccine is much more complex to maintain. Once you unfreeze it, there's a time window for it to be usable. In addition to many other factors "modified" by the Israeli HMO, an interesting one related to the above is the allowance of an extra dose from each bottle. The Pfizer bottle were tested as 5 dozes per bottle. The HMO here allowed 6 dozes.

universa1 6y ago
Iirc they also did that in germany and the result wasn't 20% more shots, but less bottles supplied ;-)
- ciceryadam 6y ago
  Yup, Pfizer had signed contract on number of vaccine shots, not number of bottles supplied. So Pfizer is technically correct, but it's still a jerk move from their side.

smorephism 6y ago

> gold standard adjuvants Neither Pfizer-BioNTech or Moderna's vaccines bring any additional adjuvants to the yard. mRNA is inherently immunogenic. This speaks generally about mRNA vaccines and touches on that property, among others: https://www.cell.com/trends/molecular-medicine/fulltext/S1471-4914(19)30244-8 https://www.cell.com/trends/molecular-medicine/fulltext/S147...

deepstack 6y ago

> Double doses, 5x what was needed in monkeys I'm not a molecular biologist or medical experimental. But that sounds a bit bad medical testing. To just increase the dosage like this with out proper longitudinal studies. Anyone with that area of expertise care of pitch in here?

random5634 6y ago
The studies will eventually come out with "proper longitudinal studies". Some countries are choosing not to wait for that. I do hope they do those studies - it feels like half the current dose size might work fine

thecupisblue 6y ago

As far as I know, second dosage is to extend the duration of antibody production.

monopoledance 6y ago

> gold standard adjuvants I think the mRNA vaccines don't contain any adjuvants at all. They are so awesome, because they are comparatively simple systems. I would choose the mRNA vaccines over adenovirus-based ones, because of that. Drive-by immunity to the adenovirus carriers could render future vaccines useless, when there is no alternative vaccine technology available *. I hope when it's my turn, I will have a choice. * Edit: My guessing. I am no medical professional, or researcher in a related field. Maybe my worries are completely unsubstantiated. I am also of the "worrying type" https://www.youtube.com/watch?v=pUDv3h09VBc https://www.youtube.com/watch?v=pUDv3h09VBc