8 ms·

Anyone knows why they insist on both doses given the limited supply of the vaccine and the marginal increase in effectiveness with the second dose? I would imag

Anyone knows why they insist on both doses given the limited supply of the vaccine and the marginal increase in effectiveness with the second dose? I would imagine every single day counts. https://www.lesswrong.com/posts/Rvzdi8RS9Bda5aLt2/covid-12-17-the-first-dose https://www.lesswrong.com/posts/Rvzdi8RS9Bda5aLt2/covid-12-1...

cameldrv 6y ago
If every single day counted, they would have done challenge trials. What counts is following the FDA's process, and the FDA's process says that you have to administer it in the same way as the trial. No one at the FDA is going to go out on a limb just to save a few thousand lives.
- CyanLite4 6y ago
  Challenge trials don’t work when 40% of infected are asymptomatic. And challenge trials especially don’t work when 15% of cases require hospitalization and ICU beds are already maxed out.
  - cameldrv 6y ago
    I don't see how the asymptomatic fraction makes a normal trial superior to a challenge trial. As for the hospitalization and ICU, those numbers are inflated, but regardless, in order to pass the trial, the same number of people need to be infected in the trial. The only difference is that while you're waiting for a few dozen people to be infected naturally because you gave them a placebo, millions are being infected and thousands are dying daily.
    - nojito 6y ago
      I work in healthcare. Where’s your source on them being inflated?
  - cwhiz 6y ago
    Citation needed for that 15% number. Even if it’s true, it absolutely isn’t true for all age groups. Give to 20-29 year volunteers. There were hundreds of thousands who volunteered.
    - rimliu 6y ago
      What our (Lithuania) officials say is that about 5% of the cases are hospitalized. We are close to the top by the number of new infections per 100000 pop.
  - bawolff 6y ago
    What doesn't work about it? Being ethical and getting results are not the same thing.
    - xyzzyz 6y ago
      Being ethical and being “ethical” according to professional expert ethicists is also not the same thing. If I learned anything this year, it’s that opinion of professional experts at ethics should not be considered when deciding who gets last piece of cake, much less in life and death scenarios.
  - MrAlex94 6y ago
    > Later, a vaccine candidate that has been proven safe in clinical trials could be given to a group of healthy adults in this age range, who are then exposed to the virus in a controlled environment. They would then be closely monitored by medics and researchers to see if the vaccine is successful in preventing infection, as well as identifying any side effects. > https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30518-X/fulltext https://www.thelancet.com/journals/lanres/article/PIIS2213-2... I imagine they will do what they did for the vaccine candidate ChAdOx1 nCoV-2019 and swab at least every week to test for infection. Do you have any source to back up your claim that a challenge trial wouldn’t work for SARS-CoV-2?
    - CyanLite4 6y ago
      When the asymptomatic rate is high, it’s hard to determine if the vaccine is truly works, and to what degree. If 40% of people are asymptomatic then that would theoretically mean that 40% of challenge trial participants won’t show symptoms. Does that mean the vaccine is working? Who knows. It could be working, it may also not work. The only way to do it and get real results is to use a challenge trial only on the elderly population where the asymptomatic rate is low and where the symptoms are exaggerated. This would mean though that if the vaccine didn’t work you would overwhelm the hospital system with a lot of sick elderly people who require the most care, when the healthcare system is already overwhelmed.
- BurningFrog 6y ago
  Are challenge trials for dearly diseases even legal?
snowmaker 6y ago
It's not an unreasonable suggestion (and a lot of people are making it now), but the risk with a single dose is low persistence. We know that the first dose has high effectiveness in the first month, but it may trail off sharply. Or it might not. Since we haven't tried a single dose, we don't know. In animal studies, the second dose was required for a durable response, that's why Pfizer decided to go with it in their trial.
tyre 6y ago
From the linked article[0]: “Yes, Moderna’s vaccine prevents transmission. One dose is good for reducing infection by 63%, two by over 90%.” The number of people you need to vaccinate with a 63% effective vaccine versus a 90% effective vaccine is a huge gap. There are two issues with vaccines that staring at these numbers won’t tell you: 1. Not everyone is going to get vaccinated. 2. The number of people who will get vaccinated is directly correlated with public trust. If you release a vaccine that is 63% effective, the “this vaccine doesn’t work crowd” and their hugely amplified voices on YouTube and social media will be exponentially worse. That snowballs into fewer people being vaccinated. Unlikely for us, with a less effective vaccine we need far more people being vaccinated. So you want a more effective vaccine because fewer people need to get vaccinated, more people will trust the vaccine, and more people will get vaccinated. (To pre-empt the bad-faith replies, this does _not_ mean we would sacrifice another six months to get a 98% effective vaccine (if it were possible) versus starting now. It’s a balance, of course.) Also very important is that a second dose isn’t just for effectiveness, it’s to boost the immune system’s response so that the conferred immunity lasts significantly longer. [0]: I struggled through this article. I find this self-congratulating “I’m smarter than everyone and I told you so in this other blog post” writing insufferable.
- dwaltrip 6y ago
  The lesswrong quote seems to be misleading. It links to an article that says the vaccine may prevent / reduce transmission but that it hasn't been proven yet. Did I miss something?
  - brobdingnagians 6y ago
    The British Medical Journal has an article that makes the point, including quotes from Tal Zaks of Moderna, that the studies aren't designed to be statistically significant indicators of disrupting transmission, preventing hospitalisation, or even preventing death: https://www.bmj.com/content/371/bmj.m4037 https://www.bmj.com/content/371/bmj.m4037 So, from what I can tell. It isn't proven to disrupt transmission or reduce hospitalisation/death. It would require much larger or longer studies, which they have opted not to do.
  - 6y ago
Imnimo 6y ago
I'm not an expert, but my understanding is that the error bars on efficacy for the single dose are quite large, just because of how the studies are conducted. Moderna's lower bound was below 70% with a single dose, and Pfizer's is below 30%. That's not to say that a single does is definitely not effective, just that there's a lot more uncertainty, and so the bounds are much looser. We also don't know whether giving a second dose a few months later rather than a few weeks later would work as well. Depending on supply forecasts, it might be worth running a new trial to get a better handle on the efficacy of a single dose, but going that route now would definitely be a gamble. Especially since we're formulating this single dose hypothesis after having run the experiment and seen the results, which is always a dangerous approach. Still, the data do seem to suggest that it's very plausible that a single dose would be sufficient. If things get bad enough, or supply is low enough, maybe that's a gamble worth taking.
IfOnlyYouKnew 6y ago
They played it save when designing the protocol. Better to err on that side, than to risk failure because you chose a dose that's too low. Given that's what they trialled, there really isn't a mechanism that would allow either them or the FDA to change the protocol from what was tested. Yes, this is annoying. You can make that educated guess and not show up for your second shot and you'll probably help someone. But medicine has a long history of people being rather convinced of theories that made an awful lot of sense and killed an awful lot of people. At some point, they noticed. The double-blind trial became not just the preferred method or something like that. It became absolute gospel. Anything else is considered the GOTO of injecting people with... stuff: Even if it's exactly what you believe is needed right now, it's just not going to happen. See also: "masks don't work" ( = "even though it sounds like a good idea, there is just as much actual evidence for their usefulness in preventing viral diseases right now, January 2020, as there is for crystal healing. Give us a month and we'll have data")
- brobdingnagians 6y ago
  "But medicine has a long history of people being rather convinced of theories that made an awful lot of sense and killed an awful lot of people." That works for both sides, both the true believers and the skeptics. Both sides are absolutely convinced that they are right and the other side's belief will kill people. At least one side is wrong. Both have their reasons, both appeal to history, both appeal to science. It is a confusing time to live.
- Erlich_Bachman 6y ago
  There is a lot of real evidence that masks do work https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31142-9/fulltext?#.XxRifFxeF38.facebook https://www.thelancet.com/journals/lancet/article/PIIS0140-6...
  - giantDinosaur 6y ago
    My impression is that the consensus is reasonably strong that masks work in and of themselves, that is - they do act as a physical barrier against transmission, but, most infections are happening at e.g. family gatherings and in households, so the actual effects of masks writ large are more muted than proponents argue. Basically, it's like saying seat-belts work, which is obviously very true, but regarding them in a kind of isolation that forgets about setting speed limits.
lultimouomo 6y ago
One thing to consider is that vaccine production is going to scale up in time; since the second dose is a month after the first, giving two doses instead of one will not mean that half the number of people will be vaccinated. Assuming, for the sake of the argument, that vaccine production doubles every month, at any given point after the first month the amount of people that have received at least one does will be a bout 2/3rds of the single dose protocol.
hannob 6y ago
Noone has tested single-dose. In this case it may sound like too much nitpicking, but the general principle is that you don't roll out something you haven't tested in a trial. In general this is a good principle. I hope they'll do trials comparing single to double-dose soon.

cameldrv 6y ago

If every single day counted, they would have done challenge trials. What counts is following the FDA's process, and the FDA's process says that you have to administer it in the same way as the trial. No one at the FDA is going to go out on a limb just to save a few thousand lives.

CyanLite4 6y ago
Challenge trials don’t work when 40% of infected are asymptomatic. And challenge trials especially don’t work when 15% of cases require hospitalization and ICU beds are already maxed out.
- cameldrv 6y ago
  I don't see how the asymptomatic fraction makes a normal trial superior to a challenge trial. As for the hospitalization and ICU, those numbers are inflated, but regardless, in order to pass the trial, the same number of people need to be infected in the trial. The only difference is that while you're waiting for a few dozen people to be infected naturally because you gave them a placebo, millions are being infected and thousands are dying daily.
  - nojito 6y ago
    I work in healthcare. Where’s your source on them being inflated?
- cwhiz 6y ago
  Citation needed for that 15% number. Even if it’s true, it absolutely isn’t true for all age groups. Give to 20-29 year volunteers. There were hundreds of thousands who volunteered.
  - rimliu 6y ago
    What our (Lithuania) officials say is that about 5% of the cases are hospitalized. We are close to the top by the number of new infections per 100000 pop.
- bawolff 6y ago
  What doesn't work about it? Being ethical and getting results are not the same thing.
  - xyzzyz 6y ago
    Being ethical and being “ethical” according to professional expert ethicists is also not the same thing. If I learned anything this year, it’s that opinion of professional experts at ethics should not be considered when deciding who gets last piece of cake, much less in life and death scenarios.
- MrAlex94 6y ago
  > Later, a vaccine candidate that has been proven safe in clinical trials could be given to a group of healthy adults in this age range, who are then exposed to the virus in a controlled environment. They would then be closely monitored by medics and researchers to see if the vaccine is successful in preventing infection, as well as identifying any side effects. > https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30518-X/fulltext https://www.thelancet.com/journals/lanres/article/PIIS2213-2... I imagine they will do what they did for the vaccine candidate ChAdOx1 nCoV-2019 and swab at least every week to test for infection. Do you have any source to back up your claim that a challenge trial wouldn’t work for SARS-CoV-2?
  - CyanLite4 6y ago
    When the asymptomatic rate is high, it’s hard to determine if the vaccine is truly works, and to what degree. If 40% of people are asymptomatic then that would theoretically mean that 40% of challenge trial participants won’t show symptoms. Does that mean the vaccine is working? Who knows. It could be working, it may also not work. The only way to do it and get real results is to use a challenge trial only on the elderly population where the asymptomatic rate is low and where the symptoms are exaggerated. This would mean though that if the vaccine didn’t work you would overwhelm the hospital system with a lot of sick elderly people who require the most care, when the healthcare system is already overwhelmed.
BurningFrog 6y ago
Are challenge trials for dearly diseases even legal?

snowmaker 6y ago

It's not an unreasonable suggestion (and a lot of people are making it now), but the risk with a single dose is low persistence. We know that the first dose has high effectiveness in the first month, but it may trail off sharply. Or it might not. Since we haven't tried a single dose, we don't know. In animal studies, the second dose was required for a durable response, that's why Pfizer decided to go with it in their trial.

tyre 6y ago

From the linked article[0]: “Yes, Moderna’s vaccine prevents transmission. One dose is good for reducing infection by 63%, two by over 90%.” The number of people you need to vaccinate with a 63% effective vaccine versus a 90% effective vaccine is a huge gap. There are two issues with vaccines that staring at these numbers won’t tell you: 1. Not everyone is going to get vaccinated. 2. The number of people who will get vaccinated is directly correlated with public trust. If you release a vaccine that is 63% effective, the “this vaccine doesn’t work crowd” and their hugely amplified voices on YouTube and social media will be exponentially worse. That snowballs into fewer people being vaccinated. Unlikely for us, with a less effective vaccine we need far more people being vaccinated. So you want a more effective vaccine because fewer people need to get vaccinated, more people will trust the vaccine, and more people will get vaccinated. (To pre-empt the bad-faith replies, this does _not_ mean we would sacrifice another six months to get a 98% effective vaccine (if it were possible) versus starting now. It’s a balance, of course.) Also very important is that a second dose isn’t just for effectiveness, it’s to boost the immune system’s response so that the conferred immunity lasts significantly longer. [0]: I struggled through this article. I find this self-congratulating “I’m smarter than everyone and I told you so in this other blog post” writing insufferable.

dwaltrip 6y ago
The lesswrong quote seems to be misleading. It links to an article that says the vaccine may prevent / reduce transmission but that it hasn't been proven yet. Did I miss something?
- brobdingnagians 6y ago
  The British Medical Journal has an article that makes the point, including quotes from Tal Zaks of Moderna, that the studies aren't designed to be statistically significant indicators of disrupting transmission, preventing hospitalisation, or even preventing death: https://www.bmj.com/content/371/bmj.m4037 https://www.bmj.com/content/371/bmj.m4037 So, from what I can tell. It isn't proven to disrupt transmission or reduce hospitalisation/death. It would require much larger or longer studies, which they have opted not to do.
- 6y ago

Imnimo 6y ago

I'm not an expert, but my understanding is that the error bars on efficacy for the single dose are quite large, just because of how the studies are conducted. Moderna's lower bound was below 70% with a single dose, and Pfizer's is below 30%. That's not to say that a single does is definitely not effective, just that there's a lot more uncertainty, and so the bounds are much looser. We also don't know whether giving a second dose a few months later rather than a few weeks later would work as well. Depending on supply forecasts, it might be worth running a new trial to get a better handle on the efficacy of a single dose, but going that route now would definitely be a gamble. Especially since we're formulating this single dose hypothesis after having run the experiment and seen the results, which is always a dangerous approach. Still, the data do seem to suggest that it's very plausible that a single dose would be sufficient. If things get bad enough, or supply is low enough, maybe that's a gamble worth taking.

IfOnlyYouKnew 6y ago

They played it save when designing the protocol. Better to err on that side, than to risk failure because you chose a dose that's too low. Given that's what they trialled, there really isn't a mechanism that would allow either them or the FDA to change the protocol from what was tested. Yes, this is annoying. You can make that educated guess and not show up for your second shot and you'll probably help someone. But medicine has a long history of people being rather convinced of theories that made an awful lot of sense and killed an awful lot of people. At some point, they noticed. The double-blind trial became not just the preferred method or something like that. It became absolute gospel. Anything else is considered the GOTO of injecting people with... stuff: Even if it's exactly what you believe is needed right now, it's just not going to happen. See also: "masks don't work" ( = "even though it sounds like a good idea, there is just as much actual evidence for their usefulness in preventing viral diseases right now, January 2020, as there is for crystal healing. Give us a month and we'll have data")

brobdingnagians 6y ago
"But medicine has a long history of people being rather convinced of theories that made an awful lot of sense and killed an awful lot of people." That works for both sides, both the true believers and the skeptics. Both sides are absolutely convinced that they are right and the other side's belief will kill people. At least one side is wrong. Both have their reasons, both appeal to history, both appeal to science. It is a confusing time to live.
Erlich_Bachman 6y ago
There is a lot of real evidence that masks do work https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31142-9/fulltext?#.XxRifFxeF38.facebook https://www.thelancet.com/journals/lancet/article/PIIS0140-6...
- giantDinosaur 6y ago
  My impression is that the consensus is reasonably strong that masks work in and of themselves, that is - they do act as a physical barrier against transmission, but, most infections are happening at e.g. family gatherings and in households, so the actual effects of masks writ large are more muted than proponents argue. Basically, it's like saying seat-belts work, which is obviously very true, but regarding them in a kind of isolation that forgets about setting speed limits.

lultimouomo 6y ago

One thing to consider is that vaccine production is going to scale up in time; since the second dose is a month after the first, giving two doses instead of one will not mean that half the number of people will be vaccinated. Assuming, for the sake of the argument, that vaccine production doubles every month, at any given point after the first month the amount of people that have received at least one does will be a bout 2/3rds of the single dose protocol.

hannob 6y ago

Noone has tested single-dose. In this case it may sound like too much nitpicking, but the general principle is that you don't roll out something you haven't tested in a trial. In general this is a good principle. I hope they'll do trials comparing single to double-dose soon.