Half Doses of Moderna Vaccine Produce Neutralizing Antibodies | Hacker News Reader

Half Doses of Moderna Vaccine Produce Neutralizing Antibodies

marginalrevolution.com

339 pointselsewhen391 comments

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

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...

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

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.

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.

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

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.

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

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.

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.

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

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.

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.

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.

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.

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.

> Even for younger adults, chances of dying if infected with Covid are much higher than that.

For a healthy young adult, chances of dying from Covid are in the same ballpark.

The above is ~1/100,000. IFR (which is compatible with what I said) for 19 and younger is 3/100,000, but that includes younger people that are even less impacted.

So it is sort of the same ballpark for the very youngest adults, but a factor of 3 isn't nothing. It's higher for people in their 20s already. We can be talking about different things though, as it isn't 100% likely a given person will be infected.

It's likely pretty close to the same. 2-4x the rate if infected; about a 1/2-1/4th chance of becoming infected eventually if no vaccine.

Thing is, the "not healthy" group is bigger than most people think. Anaphylaxis is a very controllable situation, whereas severe COVID is not. Non of the reacting subjects hasn't had a history of anaphylaxis AFAIK.

Nothing in the mRNA vaccines was chosen to enhance immune response, nothing is an adjuvant as with other vaccines. On the contrary, the polymers and co are there to protect the mRNA from immune system clearance (and are used in other non-vaccine medications too). It's worth noting, an allergic reaction is mediated by a completely different branch of the immune system. Non of the "adjuvants" aren't to be found in common household items, food and cosmetics, which is probably why the allergic people reacted in the first place.

Very few, very allergic people, seem to react to these. If so, you treat them with an antihistamine and similar.

> Nothing in the mRNA vaccines was chosen to enhance immune response, nothing is an adjuvant as with other vaccines.

This isn't -exactly- true. There's no traditional adjuvant added, but... the fact that the formulation caused adjuvant-like effects was seen as a feature, not a bug. Added care to minimize immune response has been used in the development of mRNA drug platforms

> Non of the "adjuvants" aren't to be found in common household items, food and cosmetics

You can find PEG in lots of things, but PEGylated large molecules aren't exactly common items around the home.

> but... the fact that the formulation caused adjuvant-like effects was seen as a feature, not a bug.

> Added care to minimize immune response has been used in the development of mRNA drug platforms

I don't get it. Either they want the immune response or not. Do you have a link to source your claim, they favored "adjuvant-like effects"?

> I don't get it. Either they want the immune response or not.

When mRNA is used in typical drug platforms-- you don't want the immune response.

mRNA vaccine platforms-- you do want the vaccine response.

So, e.g. Moderna has an "N1GL" formulation intended, in part, to tamp down reactogenicity that it is using for its drugs in development, and "V1GL" formulation intended for vaccines where they don't care so much. N1GL both more completely envelops the mRNA and consists of components that themselves are less "adjuvant".

(And N1GL is probably not quite good enough, yet...)

edit: Now it seems there's N2GL where they claim causes much less reactogenicity/toxicity on repeated administration and produces less anti-PEG IgM e.g. https://zerista.s3.amazonaws.com/item_files/f228/attachments... slides 19-20

But the mRNA vaccine isn't what the immune system is responding to directly, but the spike protein produced by the cells, which got infused with the mRNA. Anything that makes the immune system attack the vaccine, prevents the delivery of the mRNA. Sorry, I don't think your reasoning is sound and very based.

I don't know how my reasoning could be more "based", but here--- listen to some pharmaceutical and vaccine experts and see what you think.

Here's what Derek Lowe had to say: https://blogs.sciencemag.org/pipeline/archives/2021/01/21/mr... So to get a good RNA vaccine, you frankly have to make it work like a particularly stealthy virus, and not trip every single alarm before your payload gets a chance to enter the cells. But as mentioned, some activation of the innate system is needed to get the adjuvant boost. A lot of that work has to be done empirically, which is why we’ve seen so many RNA and DNA formulation ideas over the years. None of these have been stupid ideas (far from it) but some of them work better than others, and the current lipid nanoparticle ones are the current state of the art – the LNPs themselves activate the innate immune system, but in a way that doesn’t seem to trigger too much of a self-defeating cytokine response. It’s a useful enough effect that they’re being proposed as adjuvant additions to other, more traditional vaccines for that effect alone.

Me: Both the LNPs and the mRNA itself stimulate the immune system. Basically the vast majority of work in mRNA drugs for the last decade has been to try to reduce that-- and associated toxicity and unpredictable clearance. Meanwhile, the (right amount of) immunogenicity has been accepted as a feature in vaccine candidates.

And in a series of journal articles e.g. in Frontiers in Immunology: https://www.frontiersin.org/articles/10.3389/fimmu.2018.0222... "This was observed in the case of administration of empty PEGylated liposomes, which were able to elicit IgM response in an in-vivo model. (27, 28). Besides their potential to deliver various immune stimulators to the specific sites as well as into the deep tissues where vaccine molecules alone may not able to reach, these NPs have also been exploited as adjuvants to augment immunogenicity of vaccine candidates."

Nature / npj Vaccines: https://www.nature.com/articles/s41541-020-0159-8 "Thus, multi-antigen candidates necessitate a significant amount of LNP for a given dose. LNPs are known to have inherent adjuvant properties."

Nature / npj vaccines: https://www.nature.com/articles/nrd.2017.243 "Exogenous mRNA is inherently immunostimulatory, as it is recognized by a variety of cell surface, endosomal and cytosolic innate immune receptors (Fig. 1) (reviewed in Ref. 35). Depending on the therapeutic application, this feature of mRNA could be beneficial or detrimental. It is potentially advantageous for vaccination because in some cases it may provide adjuvant activity to drive dendritic cell (DC) maturation and thus elicit robust T and B cell immune responses. ... The immunostimulatory properties of mRNA can conversely be increased by the inclusion of an adjuvant to increase the potency of some mRNA vaccine formats. These include traditional adjuvants as well as novel approaches that take advantage of the intrinsic immunogenicity of mRNA"

I believe that is what the British are doing.

Nah, the British are just delaying the doses, without any kind of trial in play (other than population-level observation).

There has been a study now, it's just not gone through peer review yet.

https://www.ft.com/content/de00fe75-9ba1-4be7-8cf1-6e9fa55f0...

Additionally the advice to delay the second dose is now also part of the WHO recommendations.

Note that this is the AZ vaccine. They're also stretching second doses of the Moderna vaccine, which is what we were talking about trialing here.

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.

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

Given HN propensity to bash corporations I'm surprised this is not seen as a way to double or triple profits :)

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.

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.

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.

Who would volunteer for that study?

It would be horribly unethical to give people a placebo who didn't volunteer.

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.

I’d volunteer for a challenge trial, so obviously I’d volunteer for this.

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.

I would.

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

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.

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.

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).

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.

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

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.

[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

[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.]

> but there was a statistical attempt to attune for these effects

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 believe estimate of infection date is by MOH data, which tries to estimate infection date in patients by clinical data. As for other effects, the idea is to "present the full range of reasonable scenarios and show how they affect the estimation of effectiveness."[0].

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.

[0] https://twitter.com/dvir_a/status/1357653038354292737

> I believe estimate of infection date is by MOH data, which tries to estimate infection date in patients by clinical data.

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.

Seriously.. I'm going to drop this now, but this data is a mess.

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 lack the ability to defend that analysis, but as I mentioned, it's not the only analysis showing reduced 1st dose efficiency. AFAICT, there's a consensus with Israeli HMO researches it's not as good as the Pfizer trials.

>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.

> Anyway, I don't see how your criteria can be falsified. If the data were to show 16% 1st dose efficiency, it can be claimed the vaccinated are taking 4-5x risk. But how can you separate that from the 1st dose being 4-5x less efficient than in the trials?

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. ;)

Yes, but there are also plenty of ways bias can creep into an RCT. 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. Can decision makers really take that risk?

[0] https://www.researchsquare.com/article/rs-226857/v1

Earlier I linked to a short twitter thread explaining the article.

> but there are also plenty of ways bias can creep into an RCT.

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.

[EDIT: Removed an irrelevant paragraph.]

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."

[0] https://github.com/dviraran/covid_analyses

Well, you're trying my patience by putting words in my mouth that I didn't say: I didn't suggest decisionmakers immediately give everyone one dose. Are you making a dishonest argument, or did you just fail to read what I originally said.

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...

I didn't mean to put anything in your mouth you did not say. If I accidentally offended you please accept my apology. Lets keep this to the science, as far as my limited ability allows me to engage, OK?

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

It's time series data. Yes, it's not case controlled. I said this already.

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).

Assume that we do the RCTs etc. and discover the 'bit lower than we'd like efficiency' (33% vs the original 80%) the CCT you quoted argued, is the actual efficiency* , what then?

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.

> Assume that we do the RCTs etc. and discover the 'bit lower than we'd like efficiency' the CCT you quoted shows is the actual efficiency* , what then?

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..

>There's not just one figure of merit. The most important one is the ratio between (month 1 to month 2 efficacy) with the delayed dose vs. with the on-time dose. If that's 0.5 or more, it's a slam dunk: you delay.

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. ]

> 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.

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.

Sorry I misunderstood. Your original phrasing implied a case when the protection increases (If month 1 / month 2 = 0.5 then month 2 is twice month 1).

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.

The original RCT doesn't measure the exact same thing, which is why we need to actually try to measure it and confirm protection is durable...

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).

>But one would expect that protection from days 21-41 without a second dose is comparable to protection from days 14-21.

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?

[0] https://www.researchsquare.com/article/rs-226857/v1

> First, There's a study I linked to earlier, suggesting the 1st dose antibodies aren't good against the variants.

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%).

>It suggested the neutralization titers were higher, not that they were ineffective.

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.

> See figure B here taken from the study. That's a large difference to my completely untrained eye.

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

C'ya around. You'll make a fine educator - sure taught me a few things this time.

Err.. Just to be clear, I never meant to suggesty ou'd take the ratio between month 1 and month 2. I tried to use parens to indicate the parameter that would be compared between the two groups (delayed and not delayed). Anything else wouldn't be an RCT, but just gawking at time series data...

> [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.]

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?

Since you edited this in:

>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)

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.

Why is the development “this can’t fail” but the distribution isn’t? If we cut corners on distribution (and compound that with the real world flaws in the process) and you screw up, it would be a huge disaster. You would complete undermine the public’s faith in vaccines and lockdowns.

It's a gamble the British government are already taking, they decided to extend the time between doses to give me people the first dose sooner. We'll start to see in 8 weeks or so if it was worth it.

If the vaccine developers fail their companies lose lots of money and their bosses are mad at them. There’s a tiny possibility they might lose their jobs and it certainly won’t look good for promotion purposes. Also, developing vaccines is something they actually know how to do. If civil servants fuck up in ways that delay or prevent progress in fighting COVID there are no consequences. No one gets fired or reprimanded, whether for what they said about masks, preventing home testing, telling the Seattle Flu Study they couldn’t test for COVID in February, fining distillers for making hand sanitizer... And note the US FDA and CDC are at worst only a little worse than the European Medical Authority. Slower at approving more or less everything, like KN95s or the J&J vaccine, but they’re not actively trying to kill people. They’re just making sure they can’t be blamed for approving something unsafe. The people who die as a result of that delay are not their problem.

That’s nonsense government griping. In fact, we had an election and fired all of those decision makers.

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.

That's scary. How did he find out? And were the masks manufactured after last year's shortage, or before?

I'm not sure about this.

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.

The people developing the vaccine have no control over how individual countries distribute it. They were tasked with "this can't fail", and understandably so. They did their job, why some countries can't handle distributing it is a whole different can of worms that would require a discussion country by country.

O Rational, rational,

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.

I'd be first in line to get a vaccine even if it was less than 10% effective.

“Hindsight is 20/20.”

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.

Maybe because HN is rational, and thus doesn't like the factual inaccuracies in your post? 1) There were no adjuvants used 2) Antibody response doesn't linearly correlate with protection. Many vaccines provoke a higher antibody response but much less efficacy compared to the Moderna and Pfizer/BioNTech vaccine. 3) mRNA is an entirely new modality, it's not like people knew before-hand what would work, given point 2.

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.

I don’t think OP claimed any of this, at least in my reading.

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.

We can save those experiments for when there isn't 450,000 Americans dead from covid. I prefer the go early go hard approach. There will be a second round of Covid-21, the South African mutated version is proving that.

Well, this really can't fail. The challenge was to develop a ready-to market vaccine in the shortest possible time and several companies managed this task. That is why millions are already vaccinated.

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.

> but why do you assume that all the involved experts at the pharmaceutical companies didn't ask those questions?

Because they have a financial incentive not to ask those.

> why do you assume that all the involved experts at the pharmaceutical companies didn't ask those questions?

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.

Interesting, I hadn't known that. I imagine the short booster dose time also helps in implementation, because an individual gets maximum immunity 6 weeks after the first dose (4 weeks pause + 2 weeks) rather than 28 weeks (6 month pause + 2 weeks) for a longer pause. Having a longer pause to maximize individual immunity might not be the fastest way to maximize population immunity during an ongoing pandemic.

I'm not sure about that. Here in the UK we've gone with a 12 week gap precisely because it allows us to vaccinate more of the population more quickly.

First dose gets you to 80% efficacy after about 10 days.

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.

Good point, I hadn't been aware that the first dose was that effective without the booster.

Without specifically criticizing this vaccine process, I would add that if you start digging into medical research, you will find this is the rule rather than the exception. I've had my own semi-obscure issues I've gone trolling through the literature for assistance with, and one of the things I've found is that you'll find something that is tested; for a specific example, I found some examination of taurine supplementation for heart arrhythmia issues. There were multiple papers that all studied the exact same dosing schedule. This strongly suggests to me that the initial schedule was basically someone thinking for a moment and giving an informed guess about what might work.

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.

[1]: https://news.ycombinator.com/item?id=24705855

I think a lot of software developers have swallowed the "be lean all the time" that the projects managers are selling :) . "Good enough is good enough" is another one I hear a lot from PM. Anyway there's something to be said for paying $1000 for that vacuum cleaner that you won't have to replace for 30 years.

Which one?

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.

They should be sacred until we have completed studies with other regimens. What we have is a theory but we need to collect data to correctly identify the best timing.

Well, these are the numbers we have and which have been confirmed by the proper trials. I am sure, there is more research getting performed to optimize the vaccines, but we fortunately can vaccinate with good results based on these numbers.

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).

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.

> 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?

>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://twitter.com/dvir_a/status/1359603522581454856 (done on the Pfizer vaccine, but it's very similar to Moderna)

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)!

I mean we have over 1 million cases now how much more of a sample size do you need?

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.

Isn’t the Moderna vaccine dose larger?

True, but I am not sure that changes things. It's possible that the dose increase doesn't lead to a relevant clinical difference.

Ultimately, someone will have to do real world analysis and get conclusions from that. Right now, IMHO, there's better reason to think that a smaller Moderna dose is fine than to trust a single shot Moderna vaccine regiment.

Didn’t Israel test antibody levels post-1st dose, and come out with results that it’s around 50% by week 2 and 90% by week 3, before taking the second shot?

If I’m not mistaken the claims that the levels are low (and efficacy only 50%) were because some sources took average of days 1-21 instead of 14-21.

I'm not sure what your 50% and 90% refer to. 50,90 percent of what? There were tests showing an order of magnitude more antibodies a week following 2nd shot (e.g. [0]).

The efficacy claims were because disease levels took more time to drop off than what one would expect following lockdown+start date of 1st shot vaccination if 1st shot were effective. I lack the qualifications to evaluate these claims, but I can tell you all Israeli HMOs prefer the 2 shots regimen.

[0] https://twitter.com/ArielMunitz/status/1356683799568990216

Those percentages are percent of vaccinated people who have not been observed with symptoms

How closely related are SARS 1/2 and Mers to the four coronaviruses that cause (a small minority of) the common cold, could we be gaining partial protection from them too?

2020 called and wants her easy questions back! ;)

Immunity to cold viruses is so prevalent, there is no chance the effect is pronounced, by now. It has been researched tho, so you may find some studies discussing the issue.

I think you misunderstood their question. Obviously immune response to common cold isn't effective against rona. But if this vaccine is effective against a wide range of coronaviruses, could it also be effective against the one that causes the common cold?

Ah. Thanks for clearing that up! That makes a lot more sense in hindsight.

On the other hand, the cross-immunization to SARS1 and MERS is not surprising, since the mRNA vaccines were developed for these and modified for SARS2. (It is not a completely novel vaccine and "rapid development" was only possible, because a lot of basic research was already done on SARS1/MERS. Would have taken a lot longer to identify a molecular target otherwise.)

>Obviously immune response to common cold isn't effective against rona.

Actually...according to some studies it is.

https://www.nih.gov/news-events/nih-research-matters/immune-...

Pfizer-BioNTech (it's the GNU/Linux of vaccines)

Any idea what does the "beta" dimension mean in the graphs in the Twitter thread?

He explains this at his github repo, it's a statistical parameter to try to adjust for lack of proper control group (this is based on real-world data and not on an experiment):

https://github.com/dviraran/covid_analyses

"However, an underlying assumption here is that the incidence rates of those that were vaccinated early are similar to the general population. Previous analyses have shown that this is not the case as older populations have lower incidence and lower socio-economic groups have higher incidence.4 Therefore, we perform a sensitivity analysis by adjusting incidence rates using different levels of beta values (Figure 1)..."

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.

Iirc they also did that in germany and the result wasn't 20% more shots, but less bottles supplied ;-)

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.

> 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/S147...

> 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?

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

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

> 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

So many people in the comments are just certain that more money wouldn't have made any difference to vaccine production, and that economic considerations had nothing to do with it. The arguments they make fail to simple comparison tests:

"If we paid Tesla 2x as much per car, could they really not produce more cars?"

They also fail to privileging the status quo - "If we paid Tesla half as much money, would they produce fewer cars?"

Obviously, they would. Money influences how easily they can produce cars. At the margin there must be decisions related to turning money into efficiency every day. And the same thing must apply for vaccines. The best vaccine expert in the world asked for a yearly sabbatical - 200k wasn't enough to keep them. Double that to 400k? Oh actually it can wait til next year.

The question for people who deny money's ability to produce more vaccines is: why do you admit that any lower price for a vaccine would reduce supply - but you deny that any higher price would increase supply. What magic is this?

Money works well to speed things up until your project hits the the grindingly slow beast known as the federal bureaucracy. Then money potentially still works, but in ways that produce many negative externalities.

They've probably underpriced vaccine really. I guess we're spending $5-$40 per head and the value to the economy of getting back to normal a couple of months earlier is likely over $1000.

From what I understand, the problem with scaling the Moderna/Pfizer vaccines is that they use a novel process that hasn't been used for producing a vaccine at scale previously. They're having to build out entirely new factories and supply chains. This sort of work normally takes years.

Would throwing more money at the problem ease some bottlenecks in increasing production? maybe? Would it cut months off the time to complete the roll out? Plausibly. However, I don't think it'd make a huge difference to the speed of the roll out over the next six months or so. Some things just take time to ramp up.

More money per dose might have increased the efforts of the vaccine producers to speed up production and given them more financial means to do so. However, this still would not have been the optimal solution.

This is a case, where governments should have directly funded the build-up of production capacity. We need production capacities at a level which is economically infeasibly from a vendors perspective. Internationally, we need to produce like 14 billion doses per year. This would mean that whole humanity could be vaccinated within a year. Which is what we need, if we want to erradicate Sars-cov-2. But if we manage to do that, most of those new plants would become redundant and thats exactly why the government needs to pay for them.

What I don't get is why the EU doesn't buy the vaccine patents from e.g. Pfizer (or failing that, buy Pfizer outright - it would still only cost a fraction of what the lockdowns and aid packages have cost) and release the patents into public domain, so all companies with the capability can produce the vaccine. If it could hasten the reopenings by just one month, it would still be a terrific ROI.

Because there are no companies around which can produce mRNA vaccine. The production process is very specific. Opening up the patents wouldn't help. There are cooperations with those production steps which are generic, like botteling of the vaccines. Fortunately, another factory for BioNTech (which are the people who are making the vaccine, Pfizer is just the large partner) opened up in Germany recently and is going to produce a significant amount of doses. But instead of 1 more like 10 of these factories should have been built.

> They also fail to privileging the status quo - "If we paid Tesla half as much money, would they produce fewer cars?"

They would quite certainly produce no car at all - the economics would not work out. But Teslas, and vaccines, are being produced, so you analogy seems pointless.

Right. So continue your reasoning: you are arguing that if we pay the minimum required to produce an item, from that point onwards, more money doesn't unlock additional production? I agree you need to be able to charge enough to cover costs; the question is what happens after that. Why does it require proof to suggest that paying someone slightly more than the absolute minimum they'd ask to do something will increase their willingness and ability to do it?

At 20/dose, companies could produce N. At 30/dose they could probably find a way to produce more (perhaps by spending money to retrofit an old machine, which at 20/dose wouldn't have been worth it). And at 100/dose they can afford to fly the device manufacturer out to personally oversee sped-up installation.

The results in Figure 3 are certainly promising. Has anyone been able to find the mentioned supplementary material though?

> A post-hoc exploratory analysis of immunogenicity in subgroups of participants aged ≥55-<65, ≥65-74 and ≥75 years was performed (Tables S6 and S7). Increases in levels of anti-SARS-CoV-2-spike bAb and nAb at days 29 and post-second vaccination at both the 50 and 100 ug doses were generally comparable across the age subgroups and with those observed in the younger (18-55 years) study participants. Seroconversion rates were also comparable across the age groups and with those in the younger participants. It should be noted that the small size of the ≥75 year-old subgroup (n=22) precludes definitive conclusions to be made.

There doesn't seem to be any link to supplementary material at either the Elsevier page [1] nor the NIH page [2]. The clinical trial registration [3] suggests that there was an update just a few days ago, so perhaps they're just waiting to upload a new PDF?

[1] https://www.sciencedirect.com/science/article/pii/S0264410X2...

[2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871769/

[3] https://clinicaltrials.gov/ct2/show/study/NCT04405076

Probably not available as part of the journal's "pre-proof" process. You'll likely have to wait until the formal publication date.

> These versions will undergo additional copyediting, typesetting and review, and may not yet have full ScienceDirect functionality. For example, supplementary files may still need to be added, links to references may not resolve yet, etc. The text could still change before final publication.

https://service.elsevier.com/app/answers/detail/a_id/22799/s...

Is the title confusing?

On first read, I thought it was something that neutralizes antibodies, rather than antibodies that neutralize the virus.

My layman's assumption was that the antibodies would always neturalize, so adding the adjectives threw me off the meaning.

Not all antibodies neutralize the (or any) virus. Some just mark virions for immune cells to acttack, but won't stop the infection process.

(Summarizing things I've picked up from reading Derek Lowe's blog [0])

Not all antibodies are neutralizing. Antibodies can only bind to a certain part of pathogens, but if an antibody binds to something it might not disrupt what that thing needs to do to infect the body. Relating this to SARS-CoV-2, it looks like if an antibody bind to something other than the spike protein, the virus can still infect cells. As another example, most people have been exposed to at least some other coronaviruses, and of that group, some of those people have developed antibodies that react to SARS-CoV-2. A recent paper [1] looked at if these "cross-reactive" antibodies were helpful in preventing COVID, but it looks like they're non-neutralizing as they couldn't see any effect.

0: https://blogs.sciencemag.org/pipeline/

1: https://blogs.sciencemag.org/pipeline/archives/2021/02/10/do...

"Neutralizing antibodies" is the standard technical term amongst immunologists.

The Moderna dose is already more than 3x the dosage of the Pfizer ones. 100mcg vs 30mcg. Would be great if they could cut that down and still be effective.

So... if that plays out, perhaps split the doses in half, cover twice the people, so we can all go back to our normal pre-COVID life (or what's left of it).

Of course this won't double the number of people vaccinated since Moderna doesn't cover 100%. But every little helps.

We're not going back to pre covid lives period. Even if everyone was vaxxed there would still be more moderate cases that our hospitals can handle. And then that allows the virus millions of chances to mutate and then, just like we're seeing with the UK and South Africa strains. Which as we're seeing all but nullifies the vaccine. The vaccines we're seeing are only 10% effective against the SA strain. Statistically >5% is great, but that's not a risk the vast majority of people want to run with.

The vaccines we're seeing are only 10% effective against the SA strain.

This is not accurate.

The AZ vaccine was only 10% effective in a study in SA. That's the only one that was shown to be vastly less effective.

The Pfizer vaccine is believed to be effective against the SA variant (though I think it used In Vitro studies) and there are lots of other vaccines on the way. We will get this under control but it will be a long slow process over several years.

So far it is the only one.

I believe Moderna was also shown to be effective.

Astrazeneca is not an mRNA vaccine so there’s that

> We're not going back to pre covid lives period.

We are. Most people, myself included, won't accept living like this forever. If vaccination fails and no treatment will be found, we'll expand healthcare capacity and accept that people will die.

Didn’t we move this way with the flu?

People couldn't behave back then for real reasons, most people that are the problem today are just spoiled brats. Back then they didn't have the century of epidemiology knowledge that was outright ignored and trivialized.

We're already taxing our medical system. Personnel will wear down.

Hence I said to expand healthcare capacity. If there's not enough personnel, we should educate and hire more personnel. I'm not saying this is something we should do tomorrow -- only in the hypothetical case that we haven't found an effective prevention and/or cure in 5 years or so.

Pausing the entire global economy for 5 weeks would be vastly less costly than training personnel while we deal with it for 5 years.

I do get that it would never happen, because people would refuse to do it (their belief that it wouldn't work would, in a sublime irony, prevent it from working).

Can you put a figure on 'pausing the global economy for 5 weeks'? How do you know it would be less expensive? The global economy is massive so you'll have to provide some well reasoned figures to support such a claim. Such a pause could easily trigger much larger problems, how do you know it wouldn't? And why did you pick five weeks? The disease won't be eliminated in five weeks of everyone doing nothing; plus a lot of the global economy is essential to human civilisation.

The net cost would be very small. There would be a planned period of increased activity prior and a period of make up after. And then you'd have 5 years of the economy running without a pandemic to make up any loss.

Substitute some other plan of coordinated action for the five weeks if you want. I don't care to argue about it, it's clear from New Zealand and Taiwan and so on that coordinated action works very well, if it is made to happen. It's also reasonably clear that it's cheaper than dealing with a raging pandemic.

You said 'pause the global economy', and now wish for me to substitute in any other effective plan, which kind of begs the question, doesn't it?

Right, I was just suggesting a severe coordinated action for the sake of making the comment. I don't care about convincing you.

So not only do you admit it would never happen, you cannot even provide any actual figures to support your claim. New Zealand and Taiwan have had success because they effectively eliminated the disease at the start of the pandemic, they didn't shut down with 30% of their population infected and millions of current infections, which is why that particular comparison is poor.

It isn't unreasonable to ask for justification of your claim that it'd be so much cheaper to shut down the global economy or take 'severe' action at this time. So, thanks for providing absolutely nothing beyond some vague claims about ideal actions that won't happen?

Yeah, you should probably discount my comment if those are problems for you.

It may be helpful to look at HN comments more as a discussion forum than a peer reviewed journal with documented justification for claims and so on.

The efficacy number is about preventing cases of Covid-19, but in fact, even the "low" efficacy vaccines are extremely good at preventing severe illness and death. Once we get everyone vaccinated, we should be good.

https://www.vox.com/22273502/covid-vaccines-pfizer-moderna-j...

If we vaccinate enough people to get the fatally rate well below the flu there is absolutely no reason not to go back to the old way. There is no 100% safe but there is a level at which hospitals are not overwhelmed and people are accepting the risk of being alive.

Wow. You’ve really been hitting the doomer echo chambers hard, huh? Literally nothing in your post is accurate.

There's no point in sending people with Covid to the hospital. We can't cure viral infections anyways, all it does is just facilitate spread.

Eventually we'll just figure out prophylactic measures for those groups most at risk and leave it at that. It's what we do already with the "common cold", even though the cold can be very dangerous and deadly to some people.

You don't send everyone with covid (or a cold) to the hospital, but if they're having trouble breathing you certainly do, and of course there are things that can be done there to help. Even at the beginning of the pandemic before the disease was well understood mortality was several times higher without access to hospital. Now as more has been learned the standard of care has improved further. Just because they can't wave a wand and cure the virus doesn't mean they can't do anything.

They're not the same formulation, so you can't compare the dosing, it's Apples vs. Walnuts

The problem with the 50mcg dose is that there is justifiable concern that if you error on the side of low-dosing that the mass vaccination won't work and the public sentiment will turn against it. We'd rather see 95% efficacy with the 100mcg than risk the POSSIBILITY of 60% efficacy with the 50mcg dose. We literally have one shot (or two, pun intended) to get it right the first time. Only 4 months ago, most of the world hadn't even heard of mRNA vaccines or somehow believed it was micro-chipped by Bill Gates. Much of that nonsense has gone away because they're getting unbelievable efficacy that's higher than the traditionally-made vaccines from Astra-Zeneca and JnJ.

Just use your pun - no need to point it out every time.

Yeah. And a dose of vitamin C at 3000 mg is 30,000 larger than Moderna’s. You are comparing apples and cheese. Simply weighing them won’t tell you anything.

They are both messenger RNA vaccines, so it's more like comparing two types of apples. But thank you for your sarcastic response, very helpful.

The issue is that mRNA is only a tiny fraction of the vaccine by weight. The rest is made up of the lipids that hold it, plus stabilizers and such. The ratio of those to the mRNA core varies between the two vaccines. So comparing their weights is meaningless. The fact that Moderna's dose is several times larger doesn't mean you're getting several times as much mRNA. Hence, it's like comparing the weights of two different foods with different calorie densities - ie, apples and cheese.

The microgram dose refers only to the mRNA, not the lipids, stabilizers, and such. You're right that is is only a tiny fraction of the vaccine by weight, but the dose mass refers only to the mRNA amount. So you are getting 3.33x more mRNA in the Moderna vaccines compared to the Pfizer/BioNTech vaccine.

Ah, thank you for that correction. In retrospect I should have realized that since 100mcg is a tiny amount.

I gotta say that the dose really is a pain in the arm. We ended up on the list at work and the first dose hurt for a good four days. Others had a similar outcome. My father got the first Pfizer and he reported no issues with his arm hurting. I doubt he was not telling the truth on that one.

Got Pfizer. Zero arm pain. Same for my wife.

Moderna is well known to have more injection site pain and greater immune response for the second dose but it's showing vastly greater efficacy percentages than all other manufacturers

More than Pfizer?

This could be because of the manufacturer, or it could be because your father is older than you. There's a small amount of actual data (https://www.cdc.gov/vaccines/covid-19/info-by-product/pfizer..., which just talks about injection site pain) and anecdata/implied wisdom (https://www.aarp.org/health/conditions-treatments/info-2020/...) that says that older recipients are dealing with fewer side effects than younger recipients.

Well, I'm the youngest of our group that got it and I'm 50. The older folks all had arm pain for days. We had a lot of grumpy folks on a video call three days later.

Nocebo effect is proven for vaccines. Even if we inject salted water: many will develop fevers, arm pain, headaches, nausea, ... (because they expect such symptoms). In some cases, as many as 90% of observed side effects are nocebo. i.e. if 100 people get the real vaccine and 100 people get salted water, 10 will get side effects on the first group, 9 will get the same side effects on the control group.

It hurt a bit for two days, then subsided. No other side-effects aside from better 5G reception /jk .

I'm surprised some poorer nations haven't taken their ~million vaccine doses, split each one into 20 fractional-doses and inoculated 20 million people.

Sure, the vaccine efficiency probably drops from 93% to 15%, but it's still better to have a population of 15% resistant people than a population where 1 million get 93% protection and 19 million get 0%.

As more doses come in, the country can similarly divide them and give them as 2nd, 3rd and 4th 'boosters'. They'd probably get up to herd immunity levels with far less total vaccine...

I wonder if perhaps the contracts with vaccine producers stop them doing this? (since it might hurt the vaccines reputation)

One of the many problems in poorer nations is the cost to get people to the vaccination centers. Multiplying that cost 3-4 times does not help.I don't know if mobile vaccination teams are really possible for Moderna and Pfizer, due to temperature requirements.

My understanding is that insufficient dosing could theoretically breed vaccine-resistant variants of the virus, but there's not a lot of data on this, so it's not known how great a risk it is.

While this is interesting, I'd still like to see a link to a doctor's opinion, not an article by an economist.

A doctor's opinion really isn't worth much. Maybe a virologist.

I wonder if they, like Pfizer, will take the opportunity to declare that they have shipped 2x as many doses retroactively (in Pfizer’s case it was an extra dose in every vial).

Hundreds of millions of people would pay 5x the current price to get the vaccine faster. I feel like the policy of governments getting a monopoly on vaccine distribution is stopping companies in competing for speed of vaccine production and building more factories.

Yeah but for that reason I’m very thankful that the government DOES have a monopoly on this process. That’ll ensure the vaccine goes to the people that need it the most first, not just the people that can be gouged the most.

Edited to add: I'm not sure what's controversial about this? What did I mess up here? People seem to disagree but aren't, as of about an hour after I replied, saying why.

In a way, we're seeing this happen at the national/country scale already. Countries that can afford it ("that can be gouged the most") are buying hundreds of millions of doses and the systems that are supposed to be getting doses to countries that can't afford it appear to be going wanting.

That's the problem with health care as a capitalistic market. There's no upper bound on what someone would want to pay to preserve either their life or the life of someone they care about. The only limit is on the resources that person has access to, and people will make some screamingly bad long-term decisions in order to satisfy that short-term need for cash.

If we did as the grandparent proposed and opened something like a bidding market for vaccines, you'd absolutely have GoFundMe and whatever the digital equivalent of yard sales are for people who are desperate to get the vaccine but don't have the money. Hell, I already see "please venmo me some cash so I can shelter-in-place away from my relative who has COVID because I can't afford to catch it myself as I'm the only person who makes money for my household."

Your words anger me.

I would normally argue this case, but "factories" is sort of hand-wavy here. The factories dumping out the feedstock are all producing enough to meet a higher level of production. The mixing step is the bottle neck, and is a really hard, expensive process to scale up. Demand for the vaccine is likely to dry up in a year or two, and companies don't want to drastically over shoot building out expensive single purpose tooling.

> Demand for the vaccine is likely to dry up in a year or two

Aren't many scientific advisors saying that 1) it will take years to vaccinate the developing world, and 2) risk groups may need annual booster shots in perpetuity to deal with mutations?

Potentially but that's not definite. No company will risk profits to invest in an unknown short term demand. They're fine letting people languish so they can ensure maximum profit.

You’re simplifying this thing beyond reasonable.

Several counterpoints:

(1) “profit” is just another way of saying “effort”. Would you try and work hard and risk your own money if you knew you weren’t getting paid for it? If you say “yes”, do you actually do that?

(2) they’re probably used to it in this industry, but these pharma companies are really getting more hate than praise these days. “Damned if you do, damned if you don’t.” Except that they’re not actually damned if they don’t, they wouldn’t be in the news at all!

(3) same argument as above, except r/pharma/West. People here developed an amazing technological post-industrial civilisation over centuries, and now we can use this technology to rapidly produce vaccines... yet we’re getting all the hate for not producing, manufacturing, distributing it fast enough.

A bit unfair, don’t you think?

Profit is not equivalent to effort, that's naive. Profit occurs as much from inaction as it does action.

Profit is exploitation of needs or wants, which isn't necessarily evil. Evil is having the power to stop suffering easily without harming yourself but choosing to seek profits instead (e.g. insulin prices).

Just as we have regulations (e.g. patents) to protect business's profitability, we should have equal regulations to protect the public need.

And that's why we have the Defense Production Act. Don't give them a choice.

Well yes, but you still don't want to overbuild capacity.

This may be true, but isn't vaccine fundamentally a delivery mechanism for a custom mRNA strand?

If you build up the infrastructure you could quickly deliver a vaccine for another disease or practically any genetic therapy that could be delivered the same way. Moderna also has an advantage in that the logistics required are simpler.

The mixing step ins't transferable. I'm not super familiar with micro fluid mixing, but it happens on specially created glass plates with channels as narrow as a molecule wide. They's essentially single purpose physical process microchips. Constructing them is a (maybe the) bottle neck. Apparently you can count on both hands the number of people who know how to build these things.

Interesting. Are these channels related to length (in bases) of certain components?

What is the basis for saying the vaccine were developed "in a day" if this crucial, specific step was required?

Are there good sources with details on those steps and microfluidic chips?

Is there any evidence that paying 5x the price would actually result in a faster rollout of the vaccine? At a certain scale and timeline you can't throw money at the problem anymore there's a finite limit to how fast our global infrastructure can operate.

The only thing it would result in is a faster rollout of the vaccine to low-risk individuals with money to spend. Distribution is currently [/supposedly] roughly correlated to risk and public exposure in the early phases. High-risk people with money would just have to spend money they otherwise wouldn't. So this type of plan would come at the expense of high-risk people without money.

This proposal is literally about putting high-risk people at greater risk - and by extension, killing them - so low-risk people with money can feel a little better about eating at a restaurant and drinking at a bar on a Friday night.

Do you feel the same way about Tesla? ”These selfish rich people just wanna feel better about themselves driving their EV vehicles that noone else can afford!” Yet the end result is, that more people can now afford EVs than otherwise could.

I know it’s a bit different with Covid vaccines (AFAIK they were largely sponsored by governments), but the underlying principle of your argument is just wrong - it’s good that rich investors sponsor new technology (even for selfish reasons!) because that makes technology available to everyone, sooner!

I think comparing driving a Tesla when plenty of other cheaper forms of transport exist, with a vaccine to a currently ongoing pandemic that is literally killing people and to which there is no other available vaccine option, is a tad on the ridiculous side.

It's almost as if luxury vehicles and life-saving vaccines are different, and should be treated differently.

Free market ignores need and just exploits want.

Regulation ensures those in need receive it.

Scarcity ensures demand, supply erodes price.

The ability for companies to charge what they want for the vaccine would ensure only those that could afford it would receive it, and there wouldn't be additional capital investment because that would dilute profits.

Regulations price lives of old people at about $500 right now (vaccine price / death rate).

The only government that didn't try to get the cheapest price for the vaccine is Israel, and we see the impressive results already.

This is true, but also misleading. There would not be more vaccines made if every country were overbidding, Israel is just moving ahead in the queue. It can do this because it is rich and is really tiny.

The Israel strategy would only work for a few select countries in the world.

Needs are wants with greater urgency. Demand is ensured by the ongoing widespread death associated with the virus. Government should stand ready to pay a large price to ensure supply and provide subsidy for those with less means. Regulation, in this case, introduces inefficiency. Inefficiency, in this case, costs lives.

> Needs are wants with greater urgency.

You don't always want needs. Want is desire. Need is requirement.

People are notorious for trying to satisfy their needs with desires and left feeling unfulfilled.

I don’t always want my wants either. The point is that needs usually produce greater motivation. The alcoholic who really wants that drink describes it as a need and works to satisfy it as if it is.

Alcoholism is a disease and addiction. They feel physical withdrawal so alcohol is a need to an alcoholic.

It's sometimes hard to see that because alcoholism is a spectrum and people joke about being alcoholics. Dismissing alcohol as a vice is not unlike dismissing an autistic as overly sensitive.

> Free market ignores need and just exploits want.

No, free market relies on the person with the need/want to decide which is which. And the person then takes the consequences of their choice.

> Regulation ensures those in need receive it.

No, regulation ensures that the people making life and death decisions about what is a "need" and what is just a "want" are unelected bureaucrats with no personal stake in the outcome, instead of the people who will actually suffer the consequences.

> free market relies on the person with the need/want to decide which is which.

That's your fatal misunderstanding. There isn't a choice.

> There isn't a choice.

What do you mean? That individual people aren't capable of deciding what they need vs. what they want and prioritize accordingly? Even if that were true (and I don't think it is), it would not imply that unelected bureaucrats with no stake in the outcome could do any better.

Or do you mean that you refuse to accept any structure of society that allows people to make such decisions for themselves?

No, I mean that no one gets to decide what is a need or a want.

Things are intrinsically a need or they aren't. A need can also be a want, and people can choose to want things but you don't get to decide if something is a need. Calling something that isn't a need, doesn't magically make it need.

You also can't arbitrarily decide you no longer need something. If you can then it was never a need.

> I mean that no one gets to decide what is a need or a want.

If you mean that, for example, no one can "decide" that they don't need food, yes, I agree. But that sense of "need" is irrelevant to the question of how food gets allocated to people, which was the original subject of this subthread. The fact that food is a need, not a want, does not mean a free market in food is not possible or that it does not allocate food better than regulation would. Many countries over the course of human history have run the experiment of having a central authority regulate food allocation instead of letting a free market do it. All of those experiments failed--they resulted in famine, mass starvation and death.

Some people confuse a free market in food with subsidizing food purchases for the poor, as, for example, food stamps do in the US. They're not the same thing. People on food stamps effectively get a certain amount of money each month that they can spend on food. It's true that "food" is, strictly speaking, a regulation of a sort, since, for example, gas stations or car repair shops or drugstores don't accept food stamps, so they're not exactly equivalent to money. But it still leaves a very wide scope for free choice; people on food stamps are purchasing food in a free market, even though their purchases are being subsidized by the government. They are able to choose what items they buy at the grocery store and thereby are sending price signals into the market about their preferences, just like everyone else.

You argue that allowing free markets for vital needs leads to exploitation.

But look at food - capitalist economies have been much more successful at feeding their people than socialist/other highly regulated ones. (Not that they're perfect, no system is). But I think your story of "people trying to make money leads to exploitation" needs some refinement, because it implies outcomes we don't see in reality.

Just compare HK & Singapore to China in the 1960s - free market countries did fine, while communist economies starved their people. The difference is, if you let people do things they want to improve their lives or offer valuable services to others, they will do it. If you make it tough and complex to do this, or prevent them from profiting by their labor, they won't do as much.

The ability to charge what they want and have a monopoly would be bad - but I don't think that's what is being suggested.

The jump from "letting people make things other people want, and charge prices for them" to "let sellers restrict supply of competing goods, and / or force people to buy items at high prices" is a big one - it's the difference between successful capitalist countries which provide cheap goods for their people, and horrible states. The US and Europe still resemble the former, more than the latter, which is why millions of people still try to emigrate here annually.

Food is highly regulated by the government. All those farm subsidies paid for by taxpayer money are essentially a form of socialism for farmers.

The OP doesn't actually propose giving the money as profit. An alternative interpretation of his proposal to "let people pay more" would be for the government to offer a prize to companies for producing X number of additional vaccines by a certain day, offering to buy them from the company for say 3x the current price - then selling a portion of those at 5x and giving the rest away for free to need people, to balance out the cost.

This would be a truer test of "Do companies really, really not have any extra capacity? Or are they just allocating resources according to profit maximization, not to maximum effort?"

This is what normal markets ARE - companies take risks and investments for a chance at profit. The government could fake the system by offering high rewards... or we could just let companies do reasonable things like sell 20% of their output at market price.

This reminds me of the CCP in the 1950s where most private land was socialized... and farmers ended up putting all their effort into their private plots, because that was the only work they could do that they'd actually get to keep.

5 times 0 is still zero. Also I hate everything your comment represents. From top to bottom. Nothing against yourself personally of course.

There's absolutely no evidence that this is the case. Money can't buy things instantly, the vaccine ramp is progressing very well as it is, and if you want to claim that a giant check would somehow produce more shots in arms you need to make that case with data. There are only so many units of the nanolipid production equipment available, and only so many factories that can make more, and only so many engineers who know how to operate those factories.

A gaint check could make a difference in the rate six months from now. Though with other vaccines in development that use different processes it is questionable if those would be shots in the arm vs shots made and discarded because we don't need them. Your guess is as good as mine as to which vaccines will work.

> A gaint check could make a difference in the rate six months from now.

Six months from now, assuming no further ramp in vaccine production (which seems extremely conservative given that it reflects only Pfizer and Moderna production), the US will have fully vaccinated almost 60% of the population, which is likely close to a herd immunity threshold.

Increased production beyond that would be wasted money, as the pandemic will be controlled.

There is the rest of the world. Your point still stands though.

Please do not bring the American healthcare mentality to a product that is needed by literally everyone. The minute people can spend 5x to get the vaccine means that people will need to spend 5x to get the vaccine.

I don’t want to live in your world.

No, that's preposterous, paying 5x more won't increase production capacity any more.

There's already massive incentive to ship first, since there are competing vaccines. If an additional $10B-$100B could result in additional production of mRNA vaccine, it would have been delivered by governments if not by investors.

This is simply a new tech with new techniques. Throwing extra money at a problem when there isn't a chance of increasing production capacity only causes inflation of prices, and rentierism. There is no benefit.

It's a huge claim to say that $100B extra couldn't have resulted in a speed up.

What makes you so sure of that? What's the manufacturing bottleneck that an extra $100B up front couldn't parallelize?

I just have trouble believing that without some evidence?

For mRNA vaccines, this is the first time they've ever been produced at all, and it's for the biggest vaccination campaign in history.

So I can see how that can't go much faster.

For regular tech vaccines, you're probably right.

OK, but conversely there were literally no mRNA vaccines mass produced a year ago, and now they are delivering hundreds of millions of doses this year - so they've clearly being able to scale production quite quickly.

Its a big claim to say another $100B wouldn't have scaled it faster. I'm sure they still have bottlenecks, and financial risks they weren't willing to take.

$100B is a lot of resources - but a justified amount given the economic costs, which is the point.

If you're writing software, and want the project to be completed faster, does throwing another $100B at a project make it go faster? Usually, this will slow it down, not make it go faster. A classic of the software engineering industry, The Mythical Man Month, is all about this process.

This is a similar sort of process. There's extremely specialized knowledge held by only a tiny number of people, and though there is a plan to vastly expand production, it's never been done before.

The bottleneck is not money, the bottleneck is people. People who have undoubtedly been working themselves to the bone to get this done as quickly as possible.

>If you're writing software

Yes, 100% yes.

Adding substantial resources can hugely speed up a project.

I will requisition the very best engineers, the best support staff, remove all financial bottlenecks, dedicate shadowing teams to work in isolation in parallel on the critical sections, etc.

> A classic of the software engineering industry, The Mythical Man Month, is all about this process.

First off, if i recall correctly, and it's probably been 20 years since I read it, that mostly applies to late projects that have already gone off the rails.

The broader point isn't true anyway. We're way better at writing software than we used to be.

I've personally been on quite a few software projects where they became more strategic or promising than they initially seemed, and we threw more engineers at them to speed them up, and they sped up excellently.

They're not writing software. Insofar as the vaccine is like software, they wrote the software in about a week. The problem is deploying the software.

This is a mechanical problem. It involves setting up assembly lines. These lines consist of expensive medical equipment, highly skilled installation experts, and skilled operators.

$100 billion could definitely buy or lease more equipment, get it installed, get it inspected, and pay more operators to operate the equipment. It could pay for for scientists and technicians working in related med-tech fields. It could pay their current employers to lend them from their current jobs, guaranteeing their positions upon return. The money could likewise supply any needed training, and if necessary, it could pay them extra money and extra vacation to compensate for the disruption in their lives from working third-shift, so that the machines run overnight.

Money to the tune of billions and hiring lots of the best people is specifically what makes it so people don't have to "[work] themselves to the bone".

Money and time. You can't make the assembly lines overnight, but enough money could make them in a few months. Just copy the designs for the machines they already have. There is probably opportunity to make more efficient machines as well, there almost always is, but that takes longer than a blind copy. Better in the long run, but takes longer to work out the bugs in the new design.

This is very different than software. We have plants producing this, we only need to replicate them, all the machines in those plants have drawings, the plants have drawings, the process is documented. It's not like some Ph.D. dude is mixing up liquids in a test tube.

Now granted any money in the world won't have the plant replicated by tomorrow, but enough money will have it replicated much faster. And the process could have been started months ago. Pretty much any vendor will do things faster if you pay them more money and I'm sure this is true for Pfizer's various vendors here. You can order some machine part produced in 3 months or in 3 days (with the latter being like x20 the price, but who cares now).

Yet you presume that the current price is magically the correct one - even though that price is different by region.

What would you say the effect of the government offering half as much would be? 1/10th? At one point does economics matter? I think once you admit money matters on the downside, you have a hard time proving that the point it zeros out of effect as it increases exactly matches the arbitrary point it was actually set at.

A tech comparison would be 4 or maybe 3 nm chips. Imagine everybody in the world would fork over 200B and order 7 billion chips this year... your constraint in that case is the manufacturing equipment and there are only so many experts in that area. The vaccine technologies we are using are scaled for the first time so you don’t have a big pool of experts or companies. The Chinese vaccine is probably the one best suited for scaling up and they are doing that rapidly.

It's a far more remarkable claim that $100B would improve production capacity, since that's a tiny tiny fraction of the costs of delay.

But if you think that producers are intentionally holding back, and don't understand mRNA vaccine differences from adenovirus vaccines that have been used forever, this might help:

https://blogs.sciencemag.org/pipeline/archives/2021/02/02/my...

> If an additional $10B-$100B could result in additional production of mRNA vaccine, it would have been delivered by governments if not by investors.

No. No. No.

Not only is there no guarantee that it would have been delivered by governments, there is a major counterexample affecting hundreds of millions of people: the European Union.

The EU tasked a specific body, the European Commission, to negotiate vaccine purchases for the entire bloc at once. The commission approached vaccine negotiations like a trade deal, because they usually negotiate trade deals, and ended up extracting terms that would have been good for a trade deal. They refused to go easy on the manufacturers, and thus "saved" themselves many billions — billions that they would have been much better off sacrificing (to make the negotiations faster, instead of taking months) or outright spending (to speed up production).

https://www.economist.com/europe/2021/02/03/how-europe-dodge...

https://www.wsj.com/articles/how-europe-tripped-in-covid-19-...

https://www.politico.eu/article/europe-coronavirus-vaccine-s...

Now they are tripping over themselves in an attempt to salvage the mess they made, issuing ill-considered threats to seize production that has been pledged abroad, rather than trying to speed things up.

https://www.economist.com/graphic-detail/2021/02/01/vaccine-...

Please note that the EU is the _only_ Western country that is currently exporting vaccines to the world. It is the US + UK that are blocking all exports. Even Canada gets its vaccines from the EU, since the US is not sending them any.

So yes, clearly the EU has made mistakes (fully agree with the 1st part of your post), but they had good intentions and it is not as bad as you make it sound.

> It is the US + UK that are blocking all exports

No. The UK government publishes a list of medicines blocked for export[1] and the vaccine isn’t on the list. The EU is solely to blame for being at the back of the queue and are the only state I know of to threaten blocking exports.

[1] https://assets.publishing.service.gov.uk/government/uploads/...

Not much difference between using 100% of the locally produced doses locally and blocking it for export. Let's rephrase the question: which countries are the US and UK currently exporting vaccine to and in which quantities?

Every country they promised to, which is the core of the matter.

It's one thing to be upfront from the start about how you're going to independently produce vaccine for yourself first, ensuring nobody plans on receiving your production.

It's another entirely to promise to export and then later threaten to hold back.

Ok, and what is the list of those countries and the quantities that they're getting?

Because from your second sentence it read like an awfully short list if nobody's expecting on receiving vaccine.

> It's one thing to be upfront from the start about how you're going to independently produce vaccine for yourself first

It's not even that, it's being up front about paying all the local manufacturers to make vaccines for you first.

AZ was/is shipping vaccine from the EU to the UK. That's what the EU considered stopping.

The EU's local manufacturers were supplying non-locally because they had a contract to do that and the EU hadn't set up such a contract, or a contract at all. Usually, if you've not got a contract then you don't get a say, and usually, if other people set up a contract first, they get supplied first, which is why the EU tried to use other means, and because that jeopardises the most fundamental part of all trade - contracts - everyone condemned them. Quite rightly.

Perhaps you were referring to something else?

There’s a huge difference.

If you buy up all a local farmer’s apples for your cider business that is not protectionism. If you arrange for him to effectively become your sole supplier during your busy period that is not protectionism. It’s free trade, that well known opposite.

Hard enough to defend the EU’s protectionism and disorganisation when it’s just food, didn’t think I’d see anyone lining up to do it over vaccines.

That's literally apples and vaccines. In the future you might as well not bother with such pointless digressions.

Back on topic: recently read on CNN that the UK contract's exactly the same as the EU one (best effort) and it was signed later than the EU one even if it was negotiated earlier.

If we combine that with the fact that the UK is not exporting any vaccine and the EU is, including to the UK, it seems to me that the EU was right to be upset with AZ and put pressure on them.

The UK is being selfish and trying to make the EU look like the bad guy.

If you're unwilling to be civil and also unwilling to engage in the argument presented to you - even when made clear via analogy - then I'm not sure why you think anyone will bother to listen to you.

> it seems to me that

You've busted that flush.

The UK is currently not exporting vaccines and there are no countries which are receiving vaccines from the UK.

This is what OP claimed and there is only one argument that can be made against that: a list of countries where the UK or the US is exporting vaccines. By now it should be clear to anyone reading this far that you can't provide that.

> This is what OP claimed

No, this is what the OP claimed:

> It is the US + UK that are blocking all exports

As to this:

> there is only one argument that can be made against that

Again - no, there are other arguments against that, the best being that black and white thinking is a terrible way to analyse reality, the second best being that a list was provided above of medicines blocked for export by the UK and no SARS-COV-2 vaccines are on it.

If the logic evades you further it may help to ask a question: which vaccines are you exporting and is it because you are blocking exports?

That should make it clear that there are more possible reasons for exports not to happen than their being intentionally blocked.

Human beings are able to move past the narrow meaning of specific words and look at the bigger picture, which is that vaccines are neither leaving the UK, nor reaching other countries.

This is the measure that will be used to judge the UK. Whether the vaccine is on some list may be an aggravating factor, but it's otherwise immaterial.

> Human beings are able to move past the narrow meaning of specific words

How convenient. Considering you claimed one thing that was false and are now claiming another thing that is also false but would help make your original claim true because you say so, I think I'll stick with the "narrow" form of interpretation that humans have managed so well with up till now.

> This is the measure that will be used to judge the UK.

Only by those with such strong prejudices that it requires a reimagining of the English language and of logic to help protect them from having to re-examine their notions.

> Whether the vaccine is on some list may be an aggravating factor, but it's otherwise immaterial.

Unless you have evidence of the vaccine being blocked then it is material indeed, however inconvenient that is for you. Feel free to supply actual evidence of the vaccine being blocked that goes beyond "because I say so" and doesn't require pushing words beyond their actual meaning.

Vaccines are neither leaving the UK, nor reaching other countries.

I’m also not going to or leaving the UK and there’s no blocking going on.

Have you noticed the lack of logical necessity in your argument yet?

Yes, and if someone were to wait for you and need you outside the UK you would not be there for them. Just like the vaccine.

Because of prior arrangements, not because of blocking.

I'm glad that you now acknowledge that "there is only one argument" is not so, that is definitely progress.

I've been trying to say for quite a while now that it doesn't matter why something/someone is not present where they should be, if the consequence is people will die. How hard can it be to understand that? :)

Those people are still dead.

I agree that they shouldn't have tried to squeeze the last cent out of it, while the pandemic is costing much more.

But would it really have changed things if they didn't?

There wouldn't magically have been more factory capacity and it's not like the UK/US would allow for a substantial part of their capacity to be exported.

Then there was also the unfortunate failure of the Sanofi vaccin and the late arrival of the Jannsen vaccin which was just really bad luck for the EU.

And some of other hundreds of millions won’t be able to pay for vaccine. Are you sure you want to decide on health outcomes based on income / wealth?

I mean, gestures at health outcomes in America, we do that today.

The cost is in ramping up production, actually after it is ramped up, it's generally cheaper to produce an additional vaccine (Wright's law). With the current pace people in most countries need to wear masks for years to come.

If this were purely a logistics problem then I would sort of agree with this, at least in the sense of being an avenue worth trying - but as far as I can tell the current problems with the vaccine are mainly in the nitty-gritty details of actually making it in the first place. Right now the companies doing that can basically write their price.

In the case of mRNA vaccines, according to what I've read the limiting factor is that they depend on specialized precursors that very few companies can make.

Before the COVID-19 mRNA vaccine all mRNA vaccines that had been developed for humans didn't make it past testing. There was no need to have the ability to make them beyond what was needed for research and testing.

And if one of the prior human mRNA vaccines had looked good in the middle of the phase III trial, the low manufacturing capacity would not have mattered. A normal phase III trial takes years, and the diseases the vaccines were for were not pandemics. So even if it takes a couple years to get up to the needed capacity, that would be fast enough.

With COVID-19 mRNA vaccines, we've got (1) an emergency use authorization rather than a normal approval, so a much shorter time between finding out that the thing works and the start of consumer distribution, and (2) it's a pandemic so the number of doses needed is very very high. That's the worst possible combination.

I read that the precursor was using an animal and there is a way to make it artificially (which was not approved by the FDA so far).

I just wish governments were focusing on helping in ramping up manufacturing instead of using the current crisis for stealing as much money as possible (which is happening in my country).

The critical path is microfluidics and machines to make lipid nanoparticles. It's likely these paths are ramping as quickly as possible.

There's no use of intact animals to make these vaccines. I don't think there are any use of animal cell cultures in any of the mainline vaccine paths (though there are some human cell lines used in the adenovirus, etc, vaccines that many people consider problematic).

I imagine they are referring to endotoxin testing.

(and then horseshoe crabs and recombinant factor C)

The FDA should figure out if fFC works and then mandate use of it if it works.

Oh, well, sure. But the COVID vaccines even at peak production will likely only be using a single digit percentage of the endotoxin tests done in the US in a typical year. In no way can this be considered limiting.

About 60k doses/lot, figure 30 endotoxin tests per lot, that's 1 test per 2k doses =~ 300k endotoxin tests to vaccinate the US.

I guess I can't say I've read them closely, but I don't recall any of the recent articles about the crabs having figures like that (which it is good that it isn't a problem, I'm referring to the articles not getting to the important bit about it not being an issue).

https://www.baltimoresun.com/coronavirus/bs-md-coronavirus-h...

"For now, the industry says it has plenty of horseshoe crab blood to screen coronavirus vaccines. Pharmaceutical companies test a sample from a batch of vaccines, not every dose. And that sample size, say three vials, doesn’t change whether the batch contains 100,000 doses or 1 million, says Allen Burgenson of Lonza.

In fact, Burgenson says, the industry produces enough tests in one day to screen 5 billion doses of coronavirus vaccine."

(I think this is unduly optimistic, because mfrs are likely to screen at multiple steps during production, since the latency of batches is ~100 days, and because lot sizes aren't so large yet. So divide 5 billion by a small integer).

There aren't many people with the expertise to produce the vaccine, and they're all already working on the existing production lines. The lead times are just inherently long here; takes months to start up a production line.

You seem to imply that that's somehow a trick or a bad thing, but the only valid purpose to counting number of vaccines shipped[1] is as a proxy for the number of vaccines delivered. The extra doses in a vial were a happy accident, not a trick. And the number we actually want to know is the one we're being given now.

If a vaccine vial was shipped in December and was given wholly to one person, that’s one dose. You can’t claim it was two back then because it couldn’t have been used as two.

The real problem I see is that we count vaccine doses as one shot. For Pfizer and Moderna two shots = one dose. It is misleading to show a two vial dose as two doses.

the vials hold 5 shots and then they were approved to hold 6 shots. this was good because the packaging of the vaccine was one factor in slowing down the spread of the vaccines.

But you can’t count that retroactively for vials where 5 shots were administered and at that point the vial was empty. You can only count that for unopened vials.

Right, but this is a dispute over something they didn't do.

You can count 6 shots if 6 shots were given. That's what's happening.

Correct, but nobody tried to do that.

I didn’t think that was the case. I thought that the vials held the same volume regardless. But each vial has some “extra” to account for lost volume in extraction. Let’s say it had 5% extra per dose. That’s almost enough for a complete 6th dose, but not quite. But, if you use a more efficient syringe, then you might save an additional 1% per dose. So now, your 5 dose vial has enough “extra” volume for a complete 6th dose. And the manufacturing doesn’t need to change.

That’s the benefit.

Note: this was always accounted for as “extra” doses. It was part of the plan that there would be extra volume for each vial that could be pooled together for extra full doses. But because they are “extra”, you couldn’t plan on there always being that extra dose (or over the course of a day how many extra doses).

You do need a specific type of syringe in order to extract the 6th dose correctly and it was not the case that 100% of the distribution was set up with that particular syringe in mind.

Yes. You need vaccines and needles with low dead space. They could comfortably extract 6 and even in some cases 7 doses from vials.

Initially some doses were wasted because it was unclear whether that was a legitimate thing to do.

Then, after explicit guidance, they said "OK, these count as 6 doses, then, for the purpose of our Federal contract!"

Then, Feds scrambled to ship supplies to ensure low-dead-space syringes were being used everywhere.

Also, at least in some places there was a policy that you can't mix the leftover from two vials. So you could have three vials that each have only 0.8 doses in them, you have 0 extra doses, not 2.

That feels like one of the points where bureaucracy is stupidly killing people.

Nah. That's a good rule. Pooling of vials has caused contamination and severe consequences to patients in the past, and it also compromises traceability.

Having bad outcomes from pooling and not knowing whether it came from the combining practice, a certain vial, an entire lot, or even worse-- the fundamental vaccine-- could take the entire vaccination program off the rails. That's not worth it to stretch supplies a few percent.

Just to make sure it's clear to everyone, you need to extract every dose with the special syringes - not just the 6th one. If you use the low dead space syringes for the first 5 doses, the efficiencies add up to enough solution left over for a guaranteed 6th one.

Not retroactively since it would need the ok from the regulator (and then start dispensing the half doses)

I think Pfizer could only start counting the 6th doses after the agencies Ok'd it (and the special syringes were procured)

Do you have any source or proof regarding that "retroactively" claim?

Because AFAIK they only started to bill customers for 6 doses per vial when they received official regulatory approval for the 6th dose. Vials delivered earlier were not affected, so any 6th dose gathered from them was effectively free.

You are correct, it was not applied retroactively:

> Gottlieb, the former head of the FDA, clarified that the change is not going to be applied retroactively, meaning that all vials previously shipped out are counted as containing five doses.

https://www.cnbc.com/2021/01/25/pfizer-board-member-gottlieb...

Can you edit your original comment to reflect this? It is false and misleading.

No, unfortunately, it is past the point where I can edit it. Feel free to flag it - I’m not sure how else to moderate the comment at this point.

Very understandable, thank you.

"Premature optimization is the root of all evil" --Knuth (b. 1938)

So does getting the disease.

Let's hope that half half doses works too

Homeopathy? Homeopathy!

Stirred, not shaken!

Take a bit of blue Ford Mondeo...

My God man, do you want people to overdose?!

Which retail job can I get to bump me up the list on vaccination, but doesn't actually increase my exposure possibility?

I would just stick with trying to follow rumors of thawed vaccines about to be thrown out for the day, but all of my group chats are jetsetters and they're often easily swayed by conspiracies or are just Republican and I don't have energy to ask about being vaccinated there.

edit: well its nice that I was able to crowdsource a discussion here! as you see, the energy of doing this in a sequential chat is much greater than a nested thread chat. really great insight into how to get it, thanks lifehackernews!

What makes you think that you are somehow entitled to faster vaccination?

There is an argument that the rationing/prioritization scheme that is currently in use is inherently unjust, and that no one is entitled to faster vaccination than anyone else.

What is the argument against prioritizing those who are at significantly higher risk of death?

Doses that go to waste because the prioritization system ignores logistics. Utilization should be optimized for.

The “all or nothing” approach many states has built is extremely foolish, yes, but that isn’t inherently part of an approach based on prioritization.

You can prioritize for the sickest while simultaneously optimizing for all doses being used.

(Removed redundant commentary, leaving citations)

https://thehill.com/policy/healthcare/533364-fda-chief-urges... ("FDA chief urges states to allow COVID-19 vaccinations of lower-priority groups")

https://www.nbcnews.com/news/us-news/thousands-covid-19-vacc... ("Thousands of Covid-19 vaccines wind up in the garbage because of fed, state guidelines")

https://www.npr.org/2021/01/28/961722489/why-are-health-care... ("They're A Precious Commodity, So Why Are Some COVID-19 Vaccines Going To Waste?")

https://www.propublica.org/article/covid-vaccine-wastage ("How Many Vaccine Shots Go to Waste? Several States Aren’t Counting.")

https://www.medpagetoday.com/special-reports/exclusives/9093... ("There are vaccines that are being wasted and that is a travesty," Terry Fulmer, president of the John A. Hartford Foundation, told ABC News. "Even one dose wasted is too many.")

> The “all or nothing” approach many states has built is extremely foolish, yes, but that isn’t inherently part of an approach based on prioritization.

You're agreeing with me.

Seems like a false dichotomy. You can have a policy of prioritisation while also allowing vaccination of non-prioritised people if/when there are excess doses available that are approaching expiration. This is the approach currently being taken here in the UK.

https://www.bbc.co.uk/news/world-55841017

same in US except its not a policy just a reality

What is the argument for it that entitles anyone to cut the line?

If you start from the assumption that a successful Covid vaccination rollout protects the most people from serious illness and death, it follows pretty quickly. My parents are significantly more likely than I am to be hospitalized and/or die from Covid than I am. My grandparents as well, but their risk is even an order of magnitude higher than my parents face.[1]

A successful vaccination program, then, would aggressively work through the most vulnerable populations first.

[1]: https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investi...

Yes, that seems to be the consensus, although I don't share it.

I was answering the question posed by someone asking why someone felt entitled to faster vaccination.

> Yes, that seems to be the consensus, although I don't share it.

I know, you said:

>> There is an argument that the rationing/prioritization scheme that is currently in use is inherently unjust, and that no one is entitled to faster vaccination than anyone else.

I'm curious what that argument is.

This isn't my stance, but I'll steelman it anyway:

Those at highest risk of death are the 70+. Coincidentally, people 70+ also have already led long lives / have the least utility left to give back to the society that is doing the prioritization. It is therefore more important to give doses to young people first, as someone needlessly dying with 60 years left on their clock is significantly worse than someone who has already had the opportunity to live a full life and statistically would've died within the next 10 years anyway.

I’ll bite. There is actually a very simple argument to be made as long as you accept the premise that 1. Death is a natural part of life, and 2. It’s not years of life that should be saved, but _quality_ years of life.

I find it unethical to take away all quality of life for hundreds of millions of young people in the prime of their lives, as well as destroying thousands of small businesses, so that bed ridden 90 year olds can be bed ridden for a couple more years, at best. Yet this is exactly what is happening, at least in Europe, with draconian lockdowns and curfews in place while vaccinating groups that didn’t leave their houses pre-COVID either.

With how things are going currently in my country my peers and I will be lucky if we can be vaccinated in 2021.

If we are going all in on “project cull the old”, we’re missing a few big things.

One that jumps out is a blanket, age-based DNR. A 70 year old who has been refused the shot but subsequently develops Covid is significantly more likely to be hospitalized than your “prime of their life young person”, for whom Covid isn’t nearly as likely to be severe.

This means they’re going to be an overall resource strain on the system. It wouldn’t be logical to refuse vaccinations for those most likely to be seriously sickened by the disease but then to try to provide advanced life support when they need it.

We will need to convert some percentage of hospital staff into “Covid hospice workers” to allow those who are sick to die as peacefully as one can when their lungs are shutting down.

I get that. I don’t think you get my point though. The reason I want young people to get vaccinated is not due to COVID, since they’re very unlikely to have severe complications anyway. In fact, the actual vaccination is not the point at all.

The reason I’d like them to be vaccinated is so that normal life can resume to some degree. All public places save for grocery stores and pharmacies have been closed here since early December. There’s been a 9PM curfew in place for a month with no end in sight. People’s mental health is rapidly deteriorating. I would not be making this argument if we were simply required to wear masks and could go about our business as is the situation in many places around the world. But that is not the case at all here.

That's kind of why I want the vaccine early, because there are a lot of underground things that are happening anyway that I'm avoiding. When I could be socially and having fun.

I don't think just swapping priority from elderly to prime age is a solution. As elderly will still be the ones bogging down emergency services, making relatively benign injuries a huge massive problem for everyone else. When returning to the normal distribution of emergencies after opening everything up, this is still a disaster for the hospitals.

Yes; however, prioritization lets us speed up the effects of population-scale vaccination by either...

1. Vaccinating people who are the most likely to get sick

2. Vaccinating people who are the most likely to spread the virus

Option 1 makes the death and hospitalization rates fall quicker, so that anyone we miss is more likely to still have a hospital bed to get treated in. Option 2 reduces the total number of people exposed to the virus.

The whole point of vaccination is to keep people from having to go to the hospital or dying - protecting the weakest first achieves that better than random vaccinations. Someone like me who basically lives in his room and works remotely can afford to wait for shots - someone who works in retail and has 1000s of exposures per day needs their shots yesterday.

It’s arguable the point of the vaccine is secondarily about protecting individuals due to the immunity it confers, and primarily about accelerating herd immunity to kill the virus off, which would counterfactually save thousands of lives per day in perpetuity. (It’s in either case very close between the two.) Given this, it makes prioritization pretty tricky under a supply constraint after you’ve immunized people who are objectively in a revere risk pool. For example, if we knew someone would be a super spreader, but would be at a low risk of severe covid, the margin of lives saved by prioritizing them over others that are at more risk of severe covid may be much higher. (Fwiw, I am skeptical the current prioritization regimes are designed around this optimization problem.)

> Someone like me who basically lives in his room and works remotely can afford to wait for shots - someone who works in retail and has 1000s of exposures per day needs their shots yesterday.

I think this is an oversimplification. We are living in our rooms because we choose to; many who don't work in retail that could be living in their rooms are not, and are voluntarily engaging in 1000s of exposures per day. If those people are young and not in healthcare (mostly true), such potential superspreaders are not priorities for vaccination due to this convoluted priority system.

Vaccine trials have shown that approved vaccines reduce moderate to severe illness and death. There is no trial-based evidence that they prevent people from catching the virus and spreading it [1]. It's even possible that people who are vaccinated are more likely to be asymptomatic and more likely to unknowingly pass it on.

So "vaccinating people who are the most likely to get sick" is the only option supported by the evidence. Or preferably vaccinate people most likely to become moderately to severey ill, or die.

At this time we should not be "vaccinating people who are the most likely to spread the virus". We don't know if approved vaccines will help with this.

[1] https://www.bbc.com/future/article/20210203-why-vaccinated-p...

That’s a consumer argument. The public health argument while vaccination is still constrained is that you prioritize vaccination for populations where they are most likely to be hospitalized.

What we’ve seen is that if hospitals aren’t overloaded, they are effectively able to treat people.

In a few weeks, as production ramps, the priority will shift to mass vaccination to everyone. You’ll literally have vans driving around setting up pop up events.

I interpreted his question as how to become entitled to it more quickly.

It’s a generous interpretation, but using prioritization to determine how best to help feels at least roughly accurate. We are, as a society right now, being pretty explicit about who we think is most valuable.

How else could it be interpreted?

Oh, I guess they could have meant as a way to pretend to be more valuable than they intended on being.

Signing up as a rideshare driver but offering no real rides, for example.

OP here, thats an odd interpretation

The plan is to actually have the job and its duties and fit in the classification. I dont want it to be counterproductive if I can also just wait. So there exists some essential worker jobs that dont really include being surrounded by aerosol spores all day.

I was asked what other interpretations could be and provided one. I wasn’t suggesting this was your intention, in fact I explained how it probably wasn’t in my comment directly prior.

> Which retail job can I get to bump me up the list on vaccination, but doesn't actually increase my exposure possibility?

Clearly the objective is getting the vaccine and not doing something for the greater good.

why don’t you think those are mutually inclusive?

there exists retail [essential worker] jobs that don’t currently expose you to alot of people

and would fit the categorizations created by the state

the same goes for health care professionals or education workers

surprising to see how much the consensus here is grasping. newsflash remote tech workers, you dont have to keep the same job or only one job and your circumstance may not actually be privileged

> why don’t you think those are mutually inclusive?

Because the question is not “Which retail job can I get to help things going on, but doesn't actually increase my exposure possibility?”.

It seems to me the motivation is only getting the vaccine, OP doesn't mention the will/objective to help.

OP didn't say "I want to help retail, how do I do it without getting exposed ?” ?

His objective is to get bumped on the vaccine list by going retail with the least exposure. That's literally his statement.

I just read the question again and I still can't interpret it any differently than someone trying to find out how they can cut the line.

I have heard signing up as a rideshare driver if your state is prioritizing them as essential workers has worked.

I’ve been thinking about outdoor valet driver in hospitality sector, at a hotel.

I’ll look into the ride share thing I hadn't considered scouring each states “what is an essential worker” list. Or as another person wrote: writing bots to check some appointment list.

Aside from the ethical questions, if I could help it I wouldn’t want my job to be spending all day getting into enclosed spaces only recently vacated by a series of probably unmasked people, as a valet job likely consists of. (Sure you can open the windows so it’s better than say cleaning a capsule hotel.)

Not sure how formal they are at checking employment or pre existing conditions.. Would depend state by state

Hadn't considered that, I’m just watching every state mess up their own “phases” and dissatisfied at the federal apportioning

I can get a job, at least then I wouldn’t be pretending that “we’re all in this together” right?

Pennsylvania (at least at the pharmacies) doesn't verify anything. It's all self certification. You say that you qualify for 1A to make the appointment, and they don't ask you anything when you show up. But Pennsylvania's criteria for 1A is pretty broad, potentially representing 40-60% of the population. So tons of people qualify, but appointments are really hard to come by.

In Texas, they check nothing. You decide yourself if you meet the criteria. I have no problem with this. Each of us knows our circumstances best. (not saying jumping the line is acceptable..)

The risk of dying for the 70+ crowd is significant and much, much higher than for regular influenza. The risk of dying for the below 50 crowd is negligible and on par with regular influenza.

Prioritizing the elderly literally saves lives.

Jumping the queue if you belong to a group that is not at risk is incredibly selfish and immoral. You can wait a couple of months, it won't kill you.

Morality is not as objective as you're making it out to be.

If a 70+ that otherwise would not have died from COVID gets vaccinated but on account of not getting vaccinated the OC dies from COVID, is that moral?

Utilitarian maximalism (via statistical predictions) is an approach to morality, not the approach.

Go ahead, find an approach to morality that leads to a healthy 30yo getting vaccinated while a 70+ does not. I’ll wait.

The length to which people with no morals will go to convince themselves they are good never ceases to amaze me.

Only if they will save more lives by being vaccinated than if the 70 year old was. We should be focusing on people who are higher risk of being transmission vectors, such as grocery store employees etc, at the same time as vaccinating the weak.

Again if the OC was a frontline worker we wouldn’t be having this conversation.

If the 30 yo works at a nursing home for the elderly while the 70 yo lives alone in a cabin in the woods

If the OC was working in a nursing home, we wouldn’t be having this conversation...

OC has nothing to do with the question you posed an I answered

Why are we trying to maximize human lives saved as opposed to human life-years saved?

Generously assuming people live to 90, saving a 30yo who would have died of covid saves 60 life-years, while saving a 70yo saves 20 life-years, i.e. 3x more.

But the risk of dying is around 50x higher[1] for a 70yo compared to a 30y, which means you have to vaccinate ~15x as many 30yos as 70yos to save the same amount of life-years.

So vaccinating the elderly first both saves lives and more life-years.

[1] https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investi...

> Generously assuming people live to 90, saving a 30yo who would have died of covid saves 60 life-years, while saving a 70yo saves 20 life-years, i.e. 3x more.

This makes the fallacious assumption that if life expectance at age X is n years, life expectancy at age X+k is n-k years.

This is very much not true. See, e.g., https://www.ssa.gov/oact/STATS/table4c6.html

Using actual life expectancy by age makes the number of life years saved at age 70 much closer to that at age 30.

Overall good point. Much closer but still significantly different. The life expectancy is 14 years vs 48

> The life expectancy is 14 years vs 48

...which is still a factor of ~3x, which means my napkin math wasn't too shabby, which means this tangent was completely irrelevant, because my main point is unchanged.

But you're giving equal weight to a year lived in the prime of someone's life vs. a year lived in a care home, which might not be a reasonable way to calculate it.

fair enough. "closer" but still significantly different is a support for your position.

> Go ahead, find an approach to morality that leads to a healthy 30yo getting vaccinated while a 70+ does not

If the 30 year old is employed in a position with many unavoidable close contacts, the expected number of lives, life-years, or QALYs saved by vaccinating them can be much higher than the 70 year old, if the latter has few unavoidable close contacts.

Of course with a highly transmissible virus the opportunity cost between vaccinating an isolated 70+ person and a young person who comes in contact with many 70+ people is tricky to ascertain. That said, I don’t think here in CA the tiering system is attempting to minimize deaths by accounting for expected transmissions.

I know people who are in their 30s with no pre existing conditions who have already been vaccinated because:

* they work for a hospital system (in IT) * they work at a university (doing research) * their family member has a pre existing condition (but somehow that family member is not the only one to get a vaccine)

In addition to this, smokers and those /who have already recovered from covid/ are lined up to get first /and second/ doses before I get a single dose. I think it's fair to think of the system the politicians have decided on as flawed; to use your rhetoric, it literally ends lives to waste 2 doses on those who have already recovered from the illness. If gp wishes to apply his own sense of rationality to the process, I don't blame him.

I agree that the priority system is screwed up in many places and that as a result a lot of people were vaccinated who really shouldn't have been at this stage.

But that's the moral choice of the people who designed those systems, and the people who didn't decline even though that was the right choice.

But two wrongs don't make a right. It's still wrong for you to jump the queue, regardless of what everyone else is doing.

You've fallen for the fallacy of believing that sick/vulnerable people are less deserving, and also failed to understand that preventing these people from being sick in hospitals make hospitals more available to you and your family if you should need them, for urgent or non-urgent care. The priority is to prevent system collapse first, then prevent deaths, then disability, and finally overall risk reduction.

Also, people who work in IT in hospitals have significantly higher risk just because if their workplace, and reducing the likelihood of them being carriers protects other patients (some of whom cannot be vaccinated) and their staff. The same applies for family members of vulnerable people.

This is not hard, you're just not trying.

This is less clear-cut than it seems because nearly everyone that's highest risk is retired and doesn't really need to leave the house. Is it better to tell a dozen pensioners that leave the house once a week for grocies to stay home so younger people can get vaccinated and go back to work? Possibly, depending on who you're asking.

Younger people are far more mobile and so contribute greatly to the spread of the virus. The old and sick don't go out much so aren't the ones spreading the virus.

Is it more important to stop the spread as quickly as possible or directly vaccine the more vulnerable? It's hard to know, and it probably depends on how much vaccine you have. Countries like the US with lots of vaccine may be better off vaccinating the most mobile members of society first to drop total infections ASAP. Countries with less are better off focusing on the vulnerable because they're a long way from herd immunity.

If you have enough vaccine supply you will minimize deaths by eliminating transmission quickest which implies vaccinating the most exposed, not the most vulnerable.

Throwing more variables at a question we already have an answer to is a waste of time. We know that older people get it more, die more, and are more at risk under all circumstances.

Less of them may die if we can get R0 under 1.0 faster by vaccinating those spreading the virus. It's absolutely still an open question IMO.

You are wrong about the first part. There are way more under 65 infected than over. And I've seen some preliminary studies that they do 80%+ of the viral spreading.

It is also infinitely easier to find old people than it is to find uninfected super-spreaders, we'll have vaccinated all the elderly long before anyone could develop a system to find the biggest potential spreaders.

Also, with vaccine production ramping up, a lot of countries project that they'll have vaccinated everyone by summer. Who cares if there's a better model? Elderly + frontline healthcare workers is a good enough model, go go go!

"uninfected super-spreaders" That's not a thing.

I have seen this stated before. What is your source please? This is false: SARS-CoV-2 is significantly more lethal than seasonal influenza for all ages past puberty. In fact, at 50 it is almost 15 times more lethal. https://github.com/mbevand/covid19-age-stratified-ifr

If you are below 50, risk factors play a significant role in determining your actual IFR, while if you're above 70, your age is the primary risk factor.

I don't think your graph adjusts for that, and I think the difference in IFR between covid and the flu for healthy people under 50 is smaller. We're already at pretty small risks for those ages, and even if the difference is still 10x, it is - to use a highly scientific term - whatevs.

So if you are healthy and under 50, you won't die from covid, and you shouldn't jump the queue. Better?

Long Covid appears to be fairly common. Mortality isn’t the only relevant metric.

Sure, but that doesn't change the argument. I napkin-mathed the QALY difference between vaccinating a 30yo compared to a 70yo elsewhere in the thread, feel free to continue that by adding long covid into the mix.

If anything, I bet it will strengthen my case, because older people are more likely to get sick from the virus, and therefore more likely to develop long covid than younger people, which means the "QALY utility" of vaccinating an older person becomes even greater, which makes GP an even bigger immoral asshole for skipping the line.

You're moving the goal posts. I'm not saying it's okay to jump the queue, but it's not "old people", it's "old people and people with other health issues that are risk factors".

Getting a retail job or getting a thawed vaccine about to be thrown out does neither of those things

Save that copypasta for something you understand

The state handles the prioritization and they already prioritize the elderly. When their infrastructure fails at making appointments, a vaccine dose will be destroyed so there is greater utility for someone outside of the queue to use it at that point

> “Prioritizing the elderly literally saves lives.”

that’s true, but a bit naive. the utility function shouldn’t simply be a function of age, as that would ignore important other factors, like transmissibility, that affect overall population-level outcomes. QALYs[0], while not impervious to critique, would be a better target for maximization.

but the problem with that, again, is political, not technological or even psycho-social. that prioritization metric would be perceived as too complicated (harder for most politicians to explain without potentially exposing their own ignorance), but moreover, doesn’t serve the interests of the largest political donors.

[0] https://en.wikipedia.org/wiki/Quality-adjusted_life_year

Do the napkin-math calculation of QALYs saved per vaccinated 30yo compared to 70yos.

Hint: The IFR difference between a 30yo and a 70yo is at least 50x.

Wouldn't you also have to add in the second-order effects of the long-term impact on society of that 30yo being able to return to the workforce in a more full capacity? I have no dog in this fight and don't really care who gets vaccinated soon. Just trying to sharpen up your analysis.

that may (or may not) be true, but it likely doesn't matter. you're thinking of the system as essentially static, so you're only solving for a portion of the problem (the naive solution). dynamic systems like pandemics have intertwined higher-order effects, which can often drown out the more obvious direct effects in unintuitive ways.

for instance, you're ignoring the limited flow rate of vaccine production and the significant friction of wide distribution, which at least means there's an inflection point before which it makes more sense to target "superspreaders" first.

the optimal answer to a dynamic system is rarely the static one.

> Jumping the queue if you belong to a group that is not at risk is incredibly selfish and immoral. You can wait a couple of months, it won't kill you.

Per the NYTimes, medical ethicists disagree with this viewpoint.

1. People often are bad at measuring their risk level.

2. If you turn down the chance to get vaccinated, someone even less at risk than you might get it instead.

3. Active folks who are out and about might spread the disease to hundreds of people, many of them at high risk. As we now know that the vaccines do in fact influence spread, prioritizing vaccinations to active individuals can and will save many lives.

4. I care for you and hope you and your loved ones can get vaccinated soon.

"If You’re Offered a Vaccine, Take It", from the NYTimes:

> If you turn down a vaccination based on the belief that you’re not particularly high risk, you might also be fooling yourself. It’s difficult for people to accurately measure their own risk level; research has shown that people underestimate their risk in all kinds of situations. These optimistic biases, as they are called, often lead people to perceive, wrongly, that public health campaigns are more relevant to others than to themselves.

> In other words, the notion that other people need vaccination more than you do may simply be a product of irrationally optimistic thinking. After all, the science on Covid-19 is not yet fully understood, and it is evolving rapidly, especially given the emergence of variants of the virus.

> When you get a vaccination, you’re not the only person who benefits, either. Scientists aren’t yet sure how much vaccination thwarts the transmission of Covid-19, but preliminary data suggests that it reduces spread to a degree. When you get the shot, then, you’re not only protecting your own health; you’re also likely slowing the spread of infection in your community and reducing the chance of overwhelming hospitals. In addition, if you are inoculated and friends or family members fall ill with Covid-19, you are better able to care for them, since you probably won’t get sick.

> Still, people may yell at you for getting a shot when you’re eligible if they feel you don’t deserve it as much as they or their loved ones do. And you may not be able to appease them with rational answers. Deep down, individuals who are angry about unfair vaccine allocation are upset at the system, and understandably so. In that situation, you’re just an easy scapegoat. “I think the best thing to do in a situation like that would be to say that you care for that person and hope they get the chance soon, too,” Dr. Ferguson said.

Source: https://www.nytimes.com/2021/01/21/opinion/covid-vaccine-eth...

> the risk of dying for the below 50 crowd is negligible and on par with regular influenza.

This is indeed a fact yet, many people I know that pride themselves in being informed and progressiv act like they're going to die immediately if they come into contact with the virus. Imagine if these people knew how many viruses and bacteria are all around them, even inside them. People can be really dumb when they are needlessly afraid.

My anecdote is that at my local grocery store the main people not wearing masks are the older folks and teenagers.

Two points:

a) Age is just a confounding variable. Covid seems to be a "cardiovascular" viral disease rather than a "respiratory" one. For the vast majority of people Covid is unpleasant but not at all dangerous. Figuring out the real factors that make Covid dangerous should have been top priority, but unfortunately it isn't.

b) Flu and "common cold" is, in fact, very dangerous and deadly. We just classify those deaths differently, e.g., as deaths from stroke even though strokes can be caused directly by the "common cold".

Lol wish I had any jetsetters in my social circles. I would probably have a lot more money.

Anyways, how I did it was have a pre existing condition and act like a scalper. Appointments get taken within seconds of opening up, I assume many are writing their own bots.

I wrote something to notify me when a slot opened up and clicked links many times over a period of a week until a managed to get a spot.

I am in group 1B which is getting vaccinated here so I didn't feel it was unethical.

If you don't have a pre existing conditions that raises your risk (and you're rich) I suppose you could look up the US territories and zip codes with highest adminstration rates and travel there. Some are approaching 35% so they will be opening general doses for anyone soon

> I suppose you could look up the US territories and zip codes with highest adminstration rates and travel there

yeah by default I’m very low on the list if I dont get crafty

I could do that, I already travelled to a low covid area and quarantined and didnt bring it with me

I met some ppl that got it through their tribe, so I contacted mine across the country but in that state they arent doing anything for indigenous.

Its a little weird how vaccines are aiming to be apportioned across all states at the same time. When really there is some lower hanging fruit than others. Like in one week you can send a freezer full to Wyoming or Hawaii and be done with those states, and only have temporarily reduced a 6 million allocation for California by 2 million!

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