13 ms·

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 p

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.

mlyle 6y ago
A good way to do this: enroll people who have had dose 1 but not dose 2. Give half of them dose 2 and half placebo at the normal interval; then at double interval give those that hadn't gotten dose 2 yet their second dose. This can cut a month off the trial. I also think you don't need a full 4 months of data for this-- just enough to show not-gross-inferiority.
- tw04 6y ago
  Who would volunteer for that study? It would be horribly unethical to give people a placebo who didn't volunteer.
  - mlyle 6y ago
    I'd volunteer. I'm 41 and about to be up for my turn as an educator. I feel OK about the mitigations in my classroom and my overall level of risk, and a bit guilty about getting my dose earlier than most; a 50-50 chance of delaying my second dose doesn't appreciably make the risk picture worse. If my second dose was delayed, odds are I'd end up with better long term immunity, too, even though my risk in the intermediate period would be higher. > It would be horribly unethical to give people a placebo who didn't volunteer. No shit. That's why I said "enroll" -- this includes getting consent. I suspect finding 20k people to volunteer out of the ~10M dosed per week wouldn't be that hard.
  - renewiltord 6y ago
    I’d volunteer for a challenge trial, so obviously I’d volunteer for this.
  - skybrian 6y ago
    Why not volunteer? One dose is apparently quite protective already. Most likely, there will be little difference which arm of the trial you end up on.
  - astura 6y ago
    I would.
  - Rebelgecko 6y ago
    It could be beneficial for people that are further down the priority list and want to get vaccinated sooner. Especially since the people further down the list are less likely to die if they do get covid
  - xboxnolifes 6y ago
    The same kind of people who already enroll in any other kind of drug trial. "Who would volunteer for that study" doesn't make much sense of a question considering people are willing to do phase 0 studies of new drugs which are theoretically far more dangerous.
- stjohnswarts 6y ago
  Seems like it might be better to split one dose in half and give one now and the second half in a month as a booster.
  - mlyle 6y ago
    We at least know for sure that 1 dose is highly effective against actual COVID-19 before the second dose. We have indications from titrating antibody responses that a lower dose might be useful, but that's not quite the same thing. Just delaying second doses for a month would drastically change our posture against the disease, and it's an easier thing to try (same materials, we have lots of people halfway done with the trial condition, etc).
    - yyyk 6y ago
      We do not know for sure the 1 dose is highly effective. There's significant real-world data from Israel suggesting the reverse for the Pfizer vaccine (linked to some in my other comment in this topic), and since it's very similar to Moderna's the results may well transfer.
      - mlyle 6y ago
        I strongly disagree. e.g. in the Pfizer trial, during the entire time period from dose 1 to dose 2 VE was 52.4% (95% CI 29.5, 68.4) and almost the entirety of infections happened in the first 10 days; maximum likelihood efficacy rises to 90% if you look at days 10..21. And, of course, there's figure 13. https://i.imgur.com/wEcClPr.png https://i.imgur.com/wEcClPr.png I think the Israel data is being misinterpreted. Your likelihood of being hospitalized 15 days after the vaccine is not affected much, because you were probably exposed between a few days before to a few days after the first dose. And as pointed out-- there's an obvious confound: people may rush out and partay after getting their first dose in the days before protection starts to kick in.
        yyyk 6y ago
        [EDIT: this was written before I saw the OP's edit] There's a trial and there's real world data, and real-world data is eventually more important. Current real-world data in Israel does not indicate good 1st dose efficiency [0]. It's possible the detailed release of the Clalit data [1] will change our 1st dose picture, but judging by the fact they still demand a 2 dose regiment, I suspect that Clalit data shows the same result. A theory is that the Pfizer data was accurate for the 'vanilla' virus, but 1st dose isn't enough for the B117 variant [2], and that's why the 1st dose efficiency was disappointing. [0] https://twitter.com/dvir_a/status/1359603522581454856 https://twitter.com/dvir_a/status/1359603522581454856 [1] https://www.jpost.com/health-science/clalit-data-pfizer-vaccine-reduces-risk-of-serious-covid-19-658959 https://www.jpost.com/health-science/clalit-data-pfizer-vacc... [2] https://twitter.com/AArgoetti/status/1359994165979983873 https://twitter.com/AArgoetti/status/1359994165979983873 [EDIT following OP's edit: Well, it's possible the data was misinterpreted, but there was a statistical attempt to attune for these effects, and antibody tests seem to give a plausible theory for why 1st dose was effective in trials but not real world. Even if you disagree, it's enough of a substantial objection that we can't say we know for sure 1st dose is enough.]
BurningFrog 6y ago
But it's not "blindly". We know a lot about how vaccines and the human immune system works without going through the ritual of a full scale trial for every parameter tweak. That knowledge strongly indicates that half doses will work just as well as the dose that happened to be chosen for the first trial. Waiting several months for these studies have the major downsides that thousands of people die each day we wait. To make a rational decision, that potential benefit needs to be weighed against the potential risk, but that is usually left out of these arguments.

mlyle 6y ago

A good way to do this: enroll people who have had dose 1 but not dose 2. Give half of them dose 2 and half placebo at the normal interval; then at double interval give those that hadn't gotten dose 2 yet their second dose. This can cut a month off the trial. I also think you don't need a full 4 months of data for this-- just enough to show not-gross-inferiority.

tw04 6y ago
Who would volunteer for that study? It would be horribly unethical to give people a placebo who didn't volunteer.
- mlyle 6y ago
  I'd volunteer. I'm 41 and about to be up for my turn as an educator. I feel OK about the mitigations in my classroom and my overall level of risk, and a bit guilty about getting my dose earlier than most; a 50-50 chance of delaying my second dose doesn't appreciably make the risk picture worse. If my second dose was delayed, odds are I'd end up with better long term immunity, too, even though my risk in the intermediate period would be higher. > It would be horribly unethical to give people a placebo who didn't volunteer. No shit. That's why I said "enroll" -- this includes getting consent. I suspect finding 20k people to volunteer out of the ~10M dosed per week wouldn't be that hard.
- renewiltord 6y ago
  I’d volunteer for a challenge trial, so obviously I’d volunteer for this.
- skybrian 6y ago
  Why not volunteer? One dose is apparently quite protective already. Most likely, there will be little difference which arm of the trial you end up on.
- astura 6y ago
  I would.
- Rebelgecko 6y ago
  It could be beneficial for people that are further down the priority list and want to get vaccinated sooner. Especially since the people further down the list are less likely to die if they do get covid
- xboxnolifes 6y ago
  The same kind of people who already enroll in any other kind of drug trial. "Who would volunteer for that study" doesn't make much sense of a question considering people are willing to do phase 0 studies of new drugs which are theoretically far more dangerous.
stjohnswarts 6y ago
Seems like it might be better to split one dose in half and give one now and the second half in a month as a booster.
- mlyle 6y ago
  We at least know for sure that 1 dose is highly effective against actual COVID-19 before the second dose. We have indications from titrating antibody responses that a lower dose might be useful, but that's not quite the same thing. Just delaying second doses for a month would drastically change our posture against the disease, and it's an easier thing to try (same materials, we have lots of people halfway done with the trial condition, etc).
  - yyyk 6y ago
    We do not know for sure the 1 dose is highly effective. There's significant real-world data from Israel suggesting the reverse for the Pfizer vaccine (linked to some in my other comment in this topic), and since it's very similar to Moderna's the results may well transfer.
    - mlyle 6y ago
      I strongly disagree. e.g. in the Pfizer trial, during the entire time period from dose 1 to dose 2 VE was 52.4% (95% CI 29.5, 68.4) and almost the entirety of infections happened in the first 10 days; maximum likelihood efficacy rises to 90% if you look at days 10..21. And, of course, there's figure 13. https://i.imgur.com/wEcClPr.png https://i.imgur.com/wEcClPr.png I think the Israel data is being misinterpreted. Your likelihood of being hospitalized 15 days after the vaccine is not affected much, because you were probably exposed between a few days before to a few days after the first dose. And as pointed out-- there's an obvious confound: people may rush out and partay after getting their first dose in the days before protection starts to kick in.
      - yyyk 6y ago
        [EDIT: this was written before I saw the OP's edit] There's a trial and there's real world data, and real-world data is eventually more important. Current real-world data in Israel does not indicate good 1st dose efficiency [0]. It's possible the detailed release of the Clalit data [1] will change our 1st dose picture, but judging by the fact they still demand a 2 dose regiment, I suspect that Clalit data shows the same result. A theory is that the Pfizer data was accurate for the 'vanilla' virus, but 1st dose isn't enough for the B117 variant [2], and that's why the 1st dose efficiency was disappointing. [0] https://twitter.com/dvir_a/status/1359603522581454856 https://twitter.com/dvir_a/status/1359603522581454856 [1] https://www.jpost.com/health-science/clalit-data-pfizer-vaccine-reduces-risk-of-serious-covid-19-658959 https://www.jpost.com/health-science/clalit-data-pfizer-vacc... [2] https://twitter.com/AArgoetti/status/1359994165979983873 https://twitter.com/AArgoetti/status/1359994165979983873 [EDIT following OP's edit: Well, it's possible the data was misinterpreted, but there was a statistical attempt to attune for these effects, and antibody tests seem to give a plausible theory for why 1st dose was effective in trials but not real world. Even if you disagree, it's enough of a substantial objection that we can't say we know for sure 1st dose is enough.]

BurningFrog 6y ago

But it's not "blindly". We know a lot about how vaccines and the human immune system works without going through the ritual of a full scale trial for every parameter tweak. That knowledge strongly indicates that half doses will work just as well as the dose that happened to be chosen for the first trial. Waiting several months for these studies have the major downsides that thousands of people die each day we wait. To make a rational decision, that potential benefit needs to be weighed against the potential risk, but that is usually left out of these arguments.