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
Imagine the blowback on mRNA vaccines in general if they went with the low-dose version and got lowered efficacy...
Nope. There's data indicating we must have the second shot for T-cell response, or the vaccine will fail against mutations:
(done on the Pfizer vaccine, but it's very similar to Moderna)
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)!
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.
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.)
Actually...according to some studies it is.
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.
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.
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.
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.
"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)..."
Usually you have a longer pause, which gives somewhat better results.
Now those numbers are treated as sacred by so many.
I've been following the vaccine development pretty closely and everything looks like a "this can't fail" mentality.
People need to realize that it's rational to ask if we really need the dose this high and really need a booster because if we find out we don't, it could double or even quadruple our vaccine supply. That could save half a million lives.
It's good to ask questions like this especially when there's a massive worldwide vaccine shortage
I don't think anyone is arguing that IF the booster is not needed, then we shouldn't double the vaccine supply. Consider the following risk however: There is such a thing called vaccine resistance. A weakly immunized patient becomes a training ground for novel variants of the virus that then starts spreading & vaccine doesn't work.
All of these things are trade offs anyway - a weaker immunised patient might become a training ground for a variant, but a weakly immunised patient might also have a reduced risk of spreading which results in fewer cases and fewer chances for mutations.
When those are proven out (or not) changes in the protocols can be applied then.
Blindly changing the protocols without proper controls/studies done in widescale deployment and hoping for the best is a great way to screw things up.
Give half of them dose 2 and half placebo at the normal interval; then at double interval give those that hadn't gotten dose 2 yet their second dose.
This can cut a month off the trial. I also think you don't need a full 4 months of data for this-- just enough to show not-gross-inferiority.
It would be horribly unethical to give people a placebo who didn't volunteer.
If my second dose was delayed, odds are I'd end up with better long term immunity, too, even though my risk in the intermediate period would be higher.
> It would be horribly unethical to give people a placebo who didn't volunteer.
No shit. That's why I said "enroll" -- this includes getting consent. I suspect finding 20k people to volunteer out of the ~10M dosed per week wouldn't be that hard.
Just delaying second doses for a month would drastically change our posture against the disease, and it's an easier thing to try (same materials, we have lots of people halfway done with the trial condition, etc).
I think the Israel data is being misinterpreted. Your likelihood of being hospitalized 15 days after the vaccine is not affected much, because you were probably exposed between a few days before to a few days after the first dose. And as pointed out-- there's an obvious confound: people may rush out and partay after getting their first dose in the days before protection starts to kick in.
There's a trial and there's real world data, and real-world data is eventually more important. Current real-world data in Israel does not indicate good 1st dose efficiency . It's possible the detailed release of the Clalit data  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 , and that's why the 1st dose efficiency was disappointing.
[EDIT following OP's edit: Well, it's possible the data was misinterpreted, but there was a statistical attempt to attune for these effects, and antibody tests seem to give a plausible theory for why 1st dose was effective in trials but not real world. Even if you disagree, it's enough of a substantial objection that we can't say we know for sure 1st dose is enough.]
Can you please explain how the statistical attempt to adjust for latency of "hospitalization" at days 14-21 post-vaccination would have taken place? I believe almost all people hospitalized at days 14-21 would have been infected at times we don't expect the vaccine to be effective from the trial data-- so seeing efficacy near 0 against hospitalization at days 14-21 is indeed exactly what we'd expect.
Surely if the vaccine is preventing hospitalization right after the second dose, it prevented infection some time before that, right??
Edit: Observational data is always a mess. This looks particularly bad. Efficacy is higher in the old than in the young?? This is opposite of what we saw in the RCTs. Evidence of massive betas even right after vaccination when we expect efficacy to be 0?? This effectively says the vaccinated group is nothing like the unvaccinated group.
I'm not saying the analysis is right (I lack the credentials to say that) but I can tell you Israeli HMOs have been disappointed by 1st dose efficiency and have been vocal about it in media.
Soon there'll be a published preprint by Clalit alongside Miguel Hernán and Marc Lipsitch (so not some Israeli-only effort, there's external review), and that is likely to be definitive. For now, Clalit is keeping a 2 dose regiment and applying no pressure to change it.
The methodological assumption of inferring beta from the first few days implies, looking at the infection data, that people receiving the vaccine are significantly more careful/less susceptible to the virus than those not.
But looking at hospitalization, it implies that they are WAY WAY WAY more susceptible.
last edit, for real: I looked at the preliminary Cialit findings. This is much more sane: a case control study. They find benefit-- about 33% efficacy-- post day 14, unlike the data you've been showing.
It's not blinded, so it is potentially wholly consistent with the Pfizer data if those vaccinated are taking 2-2.5x the risk of the control cases. To me, this seems pretty likely.
And if not, it is a different subpopulation--- we don't know what the data would look like for a similar demographic in the Pfizer study.
And, of course, I don't mean that we positively know that 1 dose is super effective in the real world for a longer stretch. But, it's something that's extremely likely to be shown in a blinded RCT based on the data we have so far.
>I looked at the preliminary Cialit findings. This is much more sane: a case control study. They find benefit-- about 33% efficacy-- post day 14, unlike the data you've been showing.
I suspect you're talking about a different analysis then the preprint I'm talking about. IIRC, the preliminary analysis you're talking about was released earlier and without external verification.
Anyway, I don't see how your criteria can be falsified. If the data were to show 16% 1st dose efficiency, it would have been possible to claim the vaccinated are taking 4-5x risk. But how can you separate that from the possibility 1st dose is 4-5x less efficient than in the trials? Same thing for the reported 33% efficiency, it could be vaccinated are merely 1.25x less careful.
If so, there's a reasonable chance 1st dose isn't enough for Pfizer and by implication Moderna.
It can't be. This is why you can't really trust case control trials, especially when the participants are likely to behave differently between the groups. This is why, if you have a choice between a CCT and a RCT, you take the RCT data.
And we have a RCT, so...
And the difference between the RCT and CCT is in the direction we'd expect... and the magnitude isn't crazy high, so...
edit: and now you're editing under me. ;)
Earlier I linked to a short twitter thread explaining the article.
Yes, but in this case generally in the direction towards less efficacy too. People are unblinded inadvertently by their side effects and then act more recklessly, etc.
And this is immaterial: yes, RCTs can be fucked up, but CCTs are almost always fucked up.
> Also remember we're not talking about the same virus - the trials were on 'vanilla' virus while by the time Pfizer arrived to Israel en mass B117 was prevalent. It could be the 1st dose is less efficient with B117. That's close to what the other link I provided earlier argued.
It could be. Anything could be. The question is the likelihood. But the other source arguing negative efficacy when even shitty case control data is showing positive efficacy is a little dubious.
Indeed, the hwole core assumption on that time series data is so bad-- assuming that people will behave the same from days 0-7 and from 7 on, when they've been cautioned that the vaccine is not immediately effective... Seriously, smh.
> Can decision makers really take that risk?
To do what I suggested? Yes. I suggested to run a trial. Don't pretend that I suggested anything different to strengthen your case.
It's a trial exceptionally likely to yield positive results for delaying the second dose.
There were suggestions earlier that 1st dose was "for sure" more effective, and judging by UK response some countries are desperate enough to try this without a trial. You didn't mean it, but it's possible some places will go for it. I'm just asking people to look before they leap, it's not a sure thing.
>Indeed, the whole core assumption on that time series data is so bad-- assuming that people will behave the same from days 0-7 and from 7 on, when they've been cautioned that the vaccine is not immediately effective... Seriously, smh.
Well, according to his github explanation 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."
>Well, according to his github explanation 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)
Your assertions are hard to reconcile with e.g. https://pbs.twimg.com/media/Et4moRCXAAAZ18o?format=jpg&name=...
Note that most of the people positive at 21-27 days would have been exposed before the 2nd dose... Yes, it's crappy time series data, but...
As for your link, according to the original PDF 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, 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).
RCT > CCT > Time series.
So we've got RCTs for each Pfizer and Moderna that show similar first dose efficacy. We've got prelim CCT data that seems to show Pfizer efficacy but a bit lower than we'd like, confounded by possible behavioral changes. And we have time series data that seems to show first dose efficacy.
And then we have the very-confused-seeming over-tweaked analysis of time series data that you keep linking, too, comparing to base population rates without any effort at case control, which shows negative efficacy.
Anecdote: the people that I know who received their first dose decidedly did not become less active, either in the near term (actuality: slightly more active) or the longer term (actuality: considerably more active).
IMHO, Judging by what happened in Israel at the time (a rise in cases), I for one wouldn't recommend a one dose regimen. So I don't consider what I'm saying supported by only one analysis, but by all of the Israeli CCTs so far. Judging by the consensus of Israeli HMOs, they probably feel the same.
[EDIT: Basically, I don't consider a low efficiency all that different from '1st dose isn't efficient'. So we give people the 1st dose, they party, and we come up even.]
* Yes, people probably became more active, but remember there was a lockdown too, and a different variant than in the original RCTs. There's justification for a lowered efficiency beyond bias in the RCT.
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.
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.
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.
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.
Because they have a financial incentive not to ask those.
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.
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.
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.
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.
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. ) I also wonder how that compares to the number of drugs that were never tested on humans because they failed animal testing, but it turns out that in reality they would have been fine in humans. Just idle musings on life.
That's a serious question. Last time I looked at expensive vacuums, e.g. Dyson discontinued parts after 10 years. It might not break, but you can't buy a roller for 10-year-old models. Shark was way shorter. I found no long-term brands.
If you e.g. produce 1 dose per month, you're way better off giving the doses to ABCDEFABCDEF than AABBCCDDEEFF. Six people are 80% protected after 6 months, instead of 3 people 95% protected after 6 months... assuming that everyone ends up at the same efficacy at the end (which we don't know).
But... we know this is probably effective-- probably even more effective after the delayed second dose.. which isn't the same as showing that it's effective in a study.
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
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.
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.
Even for younger adults, chances of dying if infected with Covid are much higher than that.
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.
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.
For a healthy young adult, chances of dying from Covid are in the same ballpark.
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.
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.
> 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"?
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
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"
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.
But dying is slightly more severe than a couple hours being treated for a moderate anaphylaxis reaction. We're also ignoring any risk of morbidity from COVID.
Additionally the advice to delay the second dose is now also part of the WHO recommendations.
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
Traditionally, mRNA vaccines were not very effective. There's definitely some magic "trade secret" sauce in these vaccines.
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.
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...
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.
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?
Tell that the to the 400,000 dead, buddy. They made the vaccine in January 2020. GOVERNMENT rules mean I STILL have not gotten it well over a year later. My NINETY year old Grandma doesn't have it yet. Nice effort though. How does that leather boot taste?
We've warned you several times before. If you keep posting flamewar comments to HN we will have to ban you. I don't want to ban you, so please review https://news.ycombinator.com/newsguidelines.html and use HN in the intended spirit—thoughtful, curious conversation—from now on.
For more of the intended spirit, here's an extra guideline on my list that hasn't made the official list yet: If you're hot under the collar, please cool down before posting.
At first, it wasn't clear we needed to use them. It wasn't just Fauci. Not only that, but we didn't have enough production for everyone to have them and it was more important that certain population groups had them. The message changed when it was more clear they were necessary and we started to get enough production that we could have the general public wear them.
When were numbers made up? Can you give specifics that aren't due to learning new facts?
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.
Source? I've never seen anything that suggests that, and can't even think of a rationale why it would ever be true?
"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?
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.
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.
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.
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.
> 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  nor the NIH page . The clinical trial registration  suggests that there was an update just a few days ago, so perhaps they're just waiting to upload a new PDF?
> 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.
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 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  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.
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.
Of course this won't double the number of people vaccinated since Moderna doesn't cover 100%. But every little helps.
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.
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.
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).
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.
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?
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.
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)
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.
> 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.
I think Pfizer could only start counting the 6th doses after the agencies Ok'd it (and the special syringes were procured)
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.
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).
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.
That feels like one of the points where bureaucracy is stupidly killing people.
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.
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.
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).
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.
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.
No. The UK government publishes a list of medicines blocked for export 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.
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.
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.
> it seems to me that
You've busted that flush.
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.
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.
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.
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.
Have you noticed the lack of logical necessity in your argument yet?
I'm glad that you now acknowledge that "there is only one argument" is not so, that is definitely progress.
Those people are still dead.
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.
It's not even that, it's being up front about paying all the local manufacturers to make vaccines for you first.
Perhaps you were referring to something else?
Because from your second sentence it read like an awfully short list if nobody's expecting on receiving vaccine.
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.
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?
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:
So I can see how that can't go much faster.
For regular tech vaccines, you're probably right.
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.
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.
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".
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.
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).
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.
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.
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.
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.
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.
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.
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.
That's your fatal misunderstanding. 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?
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.
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.
The only government that didn't try to get the cheapest price for the vaccine is Israel, and we see the impressive results already.
The Israel strategy would only work for a few select countries in the world.
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 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).
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).
(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.
About 60k doses/lot, figure 30 endotoxin tests per lot, that's 1 test per 2k doses =~ 300k endotoxin tests to vaccinate the US.
"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).
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.
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?
(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 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.
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.
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?
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.
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!
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."