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.
Usually you have a longer pause, which gives somewhat better results.
Now those numbers are treated as sacred by so many.
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
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.
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.
It would be horribly unethical to give people a placebo who didn't volunteer.
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.
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).
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.
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
[1] https://www.jpost.com/health-science/clalit-data-pfizer-vacc...
[2] 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.]
Can you please explain how the statistical attempt to adjust for latency of "hospitalization" at days 14-21 post-vaccination would have taken place? I believe almost all people hospitalized at days 14-21 would have been infected at times we don't expect the vaccine to be effective from the trial data-- so seeing efficacy near 0 against hospitalization at days 14-21 is indeed exactly what we'd expect.
Surely if the vaccine is preventing hospitalization right after the second dose, it prevented infection some time before that, right??
Edit: Observational data is always a mess. This looks particularly bad. Efficacy is higher in the old than in the young?? This is opposite of what we saw in the RCTs. Evidence of massive betas even right after vaccination when we expect efficacy to be 0?? This effectively says the vaccinated group is nothing like the unvaccinated group.
I'm not saying the analysis is right (I lack the credentials to say that) but I can tell you Israeli HMOs have been disappointed by 1st dose efficiency and have been vocal about it in media.
Soon there'll be a published preprint by Clalit alongside Miguel Hernán and Marc Lipsitch (so not some Israeli-only effort, there's external review), and that is likely to be definitive. For now, Clalit is keeping a 2 dose regiment and applying no pressure to change it.
I'm reading the methodology PDF and there appears to be no effort to correct for infection date.
edit: Examining the MOH data-- the date of first positive test result is used for infections, and the date of hospitalization is used for hospitalization.
The methodological assumption of inferring beta from the first few days implies, looking at the infection data, that people receiving the vaccine are significantly more careful/less susceptible to the virus than those not.
But looking at hospitalization, it implies that they are WAY WAY WAY more susceptible.
last edit, for real: I looked at the preliminary Cialit findings. This is much more sane: a case control study. They find benefit-- about 33% efficacy-- post day 14, unlike the data you've been showing.
It's not blinded, so it is potentially wholly consistent with the Pfizer data if those vaccinated are taking 2-2.5x the risk of the control cases. To me, this seems pretty likely.
And if not, it is a different subpopulation--- we don't know what the data would look like for a similar demographic in the Pfizer study.
And, of course, I don't mean that we positively know that 1 dose is super effective in the real world for a longer stretch. But, it's something that's extremely likely to be shown in a blinded RCT based on the data we have so far.
>I looked at the preliminary Cialit findings. This is much more sane: a case control study. They find benefit-- about 33% efficacy-- post day 14, unlike the data you've been showing.
I suspect you're talking about a different analysis then the preprint I'm talking about. IIRC, the preliminary analysis you're talking about was released earlier and without external verification.
Anyway, I don't see how your criteria can be falsified. If the data were to show 16% 1st dose efficiency, it would have been possible to claim the vaccinated are taking 4-5x risk. But how can you separate that from the possibility 1st dose is 4-5x less efficient than in the trials? Same thing for the reported 33% efficiency, it could be vaccinated are merely 1.25x less careful.
If so, there's a reasonable chance 1st dose isn't enough for Pfizer and by implication Moderna.
It can't be. This is why you can't really trust case control trials, especially when the participants are likely to behave differently between the groups. This is why, if you have a choice between a CCT and a RCT, you take the RCT data.
And we have a RCT, so...
And the difference between the RCT and CCT is in the direction we'd expect... and the magnitude isn't crazy high, so...
edit: and now you're editing under me. ;)
[0] https://www.researchsquare.com/article/rs-226857/v1
Earlier I linked to a short twitter thread explaining the article.
Yes, but in this case generally in the direction towards less efficacy too. People are unblinded inadvertently by their side effects and then act more recklessly, etc.
And this is immaterial: yes, RCTs can be fucked up, but CCTs are almost always fucked up.
> Also remember we're not talking about the same virus - the trials were on 'vanilla' virus while by the time Pfizer arrived to Israel en mass B117 was prevalent. It could be the 1st dose is less efficient with B117. That's close to what the other link I provided earlier[0] argued.
It could be. Anything could be. The question is the likelihood. But the other source arguing negative efficacy when even shitty case control data is showing positive efficacy is a little dubious.
Indeed, the hwole core assumption on that time series data is so bad-- assuming that people will behave the same from days 0-7 and from 7 on, when they've been cautioned that the vaccine is not immediately effective... Seriously, smh.
> Can decision makers really take that risk?
To do what I suggested? Yes. I suggested to run a trial. Don't pretend that I suggested anything different to strengthen your case.
It's a trial exceptionally likely to yield positive results for delaying the second dose.
There were suggestions earlier that 1st dose was "for sure" more effective, and judging by UK response some countries are desperate enough to try this without a trial. You didn't mean it, but it's possible some places will go for it. I'm just asking people to look before they leap, it's not a sure thing.
>Indeed, the whole core assumption on that time series data is so bad-- assuming that people will behave the same from days 0-7 and from 7 on, when they've been cautioned that the vaccine is not immediately effective... Seriously, smh.
Well, according to his github explanation[0] there was an attempt to account for that:
"It is assumed that on the days following the vaccination, there is increased caution to avoid social encounters."
Your assertions are hard to reconcile with e.g. https://pbs.twimg.com/media/Et4moRCXAAAZ18o?format=jpg&name=...
Note that most of the people positive at 21-27 days would have been exposed before the 2nd dose... Yes, it's crappy time series data, but...
As for your link, according to the original PDF[0] this is raw data before any statistical corrections, which makes it not very useful. The person you're quoting has been noted as a relative pessimist, assumes that 1st dose effect is very small due to behavioural changes[1], and that a lot of the effect is due to the lockdown. (IMHO, he's too pessimistic, but again I'm far from an expert).
[0] https://kinstitute.org.il/wp-content/uploads/2021/02/covid_1...
[1] https://twitter.com/KalksteinNir/status/1358735186637299715
RCT > CCT > Time series.
So we've got RCTs for each Pfizer and Moderna that show similar first dose efficacy. We've got prelim CCT data that seems to show Pfizer efficacy but a bit lower than we'd like, confounded by possible behavioral changes. And we have time series data that seems to show first dose efficacy.
And then we have the very-confused-seeming over-tweaked analysis of time series data that you keep linking, too, comparing to base population rates without any effort at case control, which shows negative efficacy.
Anecdote: the people that I know who received their first dose decidedly did not become less active, either in the near term (actuality: slightly more active) or the longer term (actuality: considerably more active).
IMHO, Judging by what happened in Israel at the time (a rise in cases), I for one wouldn't recommend a one dose regimen. So I don't consider what I'm saying supported by only one analysis, but by all of the Israeli CCTs so far. Judging by the consensus of Israeli HMOs, they probably feel the same.
[EDIT: Basically, I don't consider a low efficiency all that different from '1st dose isn't efficient'. So we give people the 1st dose, they party, and we come up even.]
* Yes, people probably became more active, but remember there was a lockdown too, and a different variant than in the original RCTs. There's justification for a lowered efficiency beyond bias in the RCT.
There's not just one figure of merit. The most important one is the ratio between (efficacy during the second month) with the delayed dose vs. with the on-time dose. If that's 0.5 or more, it's a slam dunk: you delay.
But post-dose 2 efficacy and immune titers and side effect profile matter, too. It's likely the long term efficacy is higher with delayed dose 2. This is what we see in most vaccines and 21 days is very, very early for a booster.
> remember there was a lockdown too,
Lockdown shouldn't affect anything in the CCT data. It's case controlled?? Presumably lockdown affects people in the two groups similarly, unless you're suggesting it reduces activity more in people who are vaccinated somehow..
So you're suggesting people with 1st dose keeping increasing the protection despite no booster in the delayed dose scenario. Possible, but important to point out that's not supported by the original RCT which takes no position on the matter.
>This is what we see in most vaccines and 21 days is very, very early for a booster.
True, but MRNA vaccines are new. 21 to 28 days could be the right period there.
>Presumably lockdown affects people in the two groups similarly, unless you're suggesting it reduces activity more in people who are vaccinated somehow..
No, but it dampens the 'people who get vaccine are partying' effect. I'm suggesting lockdown could prevent an effect you'd be seeing in the real world if we did this with no lockdown.
[EDIT: I'll respond to your other post here since this thread is already too sprawling.
>The only CCT preliminary data that I've seen suggests that one dose is protective. You have more CCTs?
My argument is that a low enough protection isn't so different from no protection. Lets say we give a delayed shot, people party for a longer time, the end result balances itself or could even be negative. ]
No?
I'm suggesting we compare e.g. cases from day 21 to 42, when A) second dose is given on day 21, and B) second dose is given on day 42. (And people are blinded).
If efficacy B is at least half of efficacy A, then it makes sense to follow plan B.
Anyhow, it's important to note that the original RCT takes no position on what the result [month 1 / month 2] would be. It's a worthy thing to check, but it's not supported by the RCTs or CCTs.
But one would expect that protection from days 21-41 without a second dose is comparable to protection from days 14-21.
We do also have some indication of durability of a single dose from the phase 2 safety trials (looking at titers).
I'm not sure that's enough for two reasons.
First, There's a study I linked to earlier, suggesting the 1st dose antibodies aren't good against the variants[0]. That would mean we need the booster ASAP.
Second, if the original efficiency is low, we're putting people at risk longer even if it stays about the same in 21-41. Imagine the 33% figure is correct. I don't think FDA would have approved the vaccine if efficiency < 50%, so should we keep people with such a low protection for another 20 days?
It suggested the neutralization titers were worse, not that they were ineffective.
> so should we keep people with such a low protection for another 20 days?
We compare the ratio between people delayed and not delayed.
If a delayed person keeps, say, 50% efficacy, and the person with the second dose has 95% efficacy, giving two people 50% efficacy is better than giving one person 95% efficacy. That's why I suggested the specific figure of merit that I did.
(That is, imagine you produce 1 dose per 21 days, and there's two people in the world. You could give, in successive 21 day periods:
A 50% protection, B 50% protection, A 95% protection, B 95% protection.... (population efficacy 25%, 50%, 72.5%, 95%)
or you could give A 50% protection, A 95% protection, B 50% protection, C 95% protection). (population efficacy 25%, 47.5%, 72.5%, 95%).
See figure B here taken from the study. That's a large difference to my completely untrained eye.
https://twitter.com/AArgoetti/status/1359994177409478656
>If a delayed person keeps, say, 50% efficacy, and the person with the second dose has 95% efficacy, giving two people 50% efficacy is better than giving one person 95% efficacy.
That logic breaks down when the divided efficacy is too low, even if it's formally half of the original. Say efficiency is 33% (and lets pretend the original is 66%). The people who got the 33% efficient vaccine go out and party, balancing out the effect. People think the vaccine doesn't help. Eventually nobody trusts your vaccine, and nobody shows up to get the second dose. I'm not sure 50% is high enough. Maybe it is, but just barely.
So, LoQ means limit of quantification, aka the threshold below which things can't be measured in their assay technique. I know it's a log scale, but...
The study was barely able to detect the response to the baseline variant, so it doesn't take all that much of a drop to escape the study's quantification limit.
It's extremely misleading to plot the line all the way down to the bottom of the graph, when all you know is that it is (probably) less than the LoQ line. I say "probably" because this assumes the authors have accurately determined the LoQ, which is easy to mess up.
> That logic breaks down when the divided efficacy is too low, even if it's formally half of the original. Say efficiency is 33% (and lets pretend the original is 66%). The people who got the 33% efficient vaccine go out and party, balancing out the effect. People think the vaccine doesn't help. Eventually nobody trusts your vaccine, and nobody shows up to get the second dose. I'm not sure even 50% is high enough
I disagree.
In any case, it's 2:56AM. I'm going to sleep :P
I'm a bit confused by what this means.
> So I don't consider what I'm saying supported by only one analysis, but by all of the Israeli CCTs so far.
The only CCT preliminary data that I've seen suggests that one dose is protective. You have more CCTs?
>Well, according to his github explanation[0] there was an attempt to account for that:
> "It is assumed that on the days following the vaccination, there is increased caution to avoid social encounters."
Yes. He fudges beta by 0.25, when it has values >3. Uhh..
Edit: unless you actually propose that the vaccine is increasing risk of infection beyond changes in behavior, there's clearly something very big methodologically wrong here. And even that can't explain the drastically different betas assumed between the hospitalization series and the infection series. (I mean, they're on OPPOSITE SIDES OF 1 AND FAR AWAY FROM IT)
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.
Rushing through things like KN-95 has consequences. My brother is a firefighter paramedic and found out that 90% of the kn95 masks issued to him were completely defective.
They did have vaccine variants that failed: We abandoned those in trials. We just don't give them to the general public without this. Some failure is expected when developing drugs, actually - some simply fail and this is part of r&d costs. If someone fabricates data to say it works, well, that is another matter entirely.
And yes, government gets reprimanded as well. Civil servants can lose their jobs, politicians get voted out. Unfortunately, the average person isn't always the best person to say that something was handled poorly and react badly when folks change their minds due to changed information.
wherefore art thou rational?
Deny thy prior and refuse thy game
Or if trials not, warranty void of
And I’ll no longer make a captious bet.
Of all the failures in the system that could have prevented lives, this seems like the least egregious.
What people need to realize is politically inclined or no, restricting political involvement to an election every 2-4 years, letting it optimize for fiscal efficiency, not resiliency and reliability, has killed a whole lot more people than extra caution over dosage.
None of the general public control drug companies. They could control the government.
I’m all in on being a big corp sycophant because the general public are clearly incompetent political agents by enabling a bigger mess than necessary in the first place.
I don't think anyone is arguing that IF the booster is not needed, then we shouldn't double the vaccine supply. Consider the following risk however: There is such a thing called vaccine resistance. A weakly immunized patient becomes a training ground for novel variants of the virus that then starts spreading & vaccine doesn't work.
All of these things are trade offs anyway - a weaker immunised patient might become a training ground for a variant, but a weakly immunised patient might also have a reduced risk of spreading which results in fewer cases and fewer chances for mutations.
Yes, you are allowed to ask questions, but why do you assume that all the involved experts at the pharmaceutical companies didn't ask those questions? And as far as I am aware, they did investigate different dosages.
So what we got now is their best effort given the many competing requirements. And yes, they might have a bit generous, but only a bit, as higher doses do create stronger side effects. And I am very happy they did, considering the mutations appeared in the meantime and the vaccines are still effective.
I am sure, the vaccines are going to be further optimized as more time goes by and especially more data becomes available.
Because they have a financial incentive not to ask those.
Pharmaceutical company employees have no power over FDA decisions.
> And as far as I am aware, they did investigate different dosages.
They did, and the result was that half doses produce as strong an immune response as full doses.
This is the basis for this "let's do half doses" argument!
The study was done with the bigger dose, and showed 95% protection.
So we know that (1) dose A has the same effect as dose B, and (2) dose B provides 95% protection.
Obviously (1)+(2) logically implies that using dose A would give twice as many people the same immunity. But logic is not part of the FDA regulatory framework. You have to blindly repeat the protocol of the study, whether it makes sense or not. Whether thousands die or not.
This is just an observation, not a criticism, because I don't have a better suggestion for what they can do, nor do I particularly believe there is a much better suggestion necessarily. You have to start somewhere. My point is just that you shouldn't overestimate the exact numbers and how much effort was put into exploring all the details. Obviously some things are deeply studied, but most things won't be.
This implies that, statistically speaking, there very likely are drugs that were formulated, created, and put into a testing regime that they failed that actually work great, but were just dosed out to the study participants such that the good effects didn't emerge yet, or were dosed on a poor schedule, etc. (Or would have worked great if paired with a hit of grapefruit. [1]) I also wonder how that compares to the number of drugs that were never tested on humans because they failed animal testing, but it turns out that in reality they would have been fine in humans. Just idle musings on life.
That's a serious question. Last time I looked at expensive vacuums, e.g. Dyson discontinued parts after 10 years. It might not break, but you can't buy a roller for 10-year-old models. Shark was way shorter. I found no long-term brands.
If you e.g. produce 1 dose per month, you're way better off giving the doses to ABCDEFABCDEF than AABBCCDDEEFF. Six people are 80% protected after 6 months, instead of 3 people 95% protected after 6 months... assuming that everyone ends up at the same efficacy at the end (which we don't know).
But... we know this is probably effective-- probably even more effective after the delayed second dose.. which isn't the same as showing that it's effective in a study.