“As is now generally known, a working Covid vaccine was on the ground in late February; “
That was no working vaccine. There were preliminary mRNA designs based on the sequence of the sars-cov2 but there were alterations to the sequence for various technical reasons, and there still needed to be trials to determine the best sequence and the most effective dosage if in fact there was an effective dosage and also to determine associated adjuvants and other material to be included with the mRNA. Also the stability of vaccine for storage had to be determined.
I will concede that by August when the final production specifications were fixed assuming the stage trials were successful that risk/reward ratio favored allowing high risk groups access to the vaccine.
Is that so, though? I'm willing to see sources on this, but everything I can find is either like this:
"You may be surprised to learn that of the trio of long-awaited coronavirus vaccines, the most promising, Moderna’s mRNA-1273, which reported a 94.5 percent efficacy rate on November 16, had been designed by January 13. This was just two days after the genetic sequence had been made public in an act of scientific and humanitarian generosity that resulted in China’s Yong-Zhen Zhang’s being temporarily forced out of his lab. In Massachusetts, the Moderna vaccine design took all of one weekend. It was completed before China had even acknowledged that the disease could be transmitted from human to human, more than a week before the first confirmed coronavirus case in the United States. By the time the first American death was announced a month later, the vaccine had already been manufactured and shipped to the National Institutes of Health for the beginning of its Phase I clinical trial. This is — as the country and the world are rightly celebrating — the fastest timeline of development in the history of vaccines. It also means that for the entire span of the pandemic in this country, which has already killed more than 250,000 Americans, we had the tools we needed to prevent it." (https://archive.is/37YtH#selection-1281.0-1285.1024)
Or like this:
"Forty-two days after the genetic code was released, Moderna’s CEO Bancel opened an email on Feb. 24 on his cellphone and smiled, as he recalled to the Globe. Up popped a photograph of a box placed inside a refrigerated truck at the Norwood plant and bound for the National Institute of Allergy and Infectious Diseases in Bethesda, Md. The package held a few hundred vials, each containing the experimental vaccine.
Moderna was the first drug maker to deliver a potential vaccine for clinical trials. Soon, its vaccine became the first to undergo testing on humans, in a small early-stage trial. And on July 28, it became the first to start getting tested in a late-stage trial in a scene that reflected the firm’s receptiveness to press coverage."
If I'm wrong I'd like to know, it's just not the narrative I've seen anywhere that covers the history of these vaccines. Granted these are articles aimed at laymen; what's a good source that shows me what I'm being told I'm missing?
As far as August goes, I doubt I'd be writing this article if we had got it - I'm not sure exactly where my "fast enough" cut-off lies, but there's at least a point where I wouldn't bother to write about it and that's probably July/August for me. I might think May is possible/doable, but at some point it gets into reasonable-discussion territory about tradeoffs as opposed to "no, you don't understand, we really like paperwork" stuff.
As noted in the second quoted article what was delivered at the end of February was experimental as it wasn't tried out yet in humans and safety and efficient dose characteristics still had to be determined before it becomes a working vaccine. If you are treating a person for a disease you can adjust the dosage of a drug, but for mass inoculation you don't want too high a dose that puts half the healthy recipients in bed with a fever for 3 days and you don't want too low a dose and have no protection or keep having to measure immune response giving them additional doses until the immune response is satisfactory. Also even if the dosage was know scaling up manufacturing was still ongoing.
Here is the situation around the end of April
“Moderna’s mRNA1273
This is another one that’s progressing rapidly in the clinic, and if you’re keeping score, is the most advanced vaccine candidate from a US company. Moderna’s expertise is in messenger RNA-based therapies, and this one is indeed an mRNA vaccine, developed in collaboration with the NIH. The hope is that this engineered RNA will enter cells and make them produce coronavirus spike proteins, which will then set off an immune response. As mentioned in the background post, this is a relatively new vaccine technology, and no vaccines have been approved yet using it. It has the advantage of being fast, though, which is why this candidate is in the position it is.
Volunteers have already been given a low dose of the vaccine in a 45-patient Phase I trial in Seattle, and a larger one is enrolling at Emory, dosing 25, 100, and 250 micrograms of the mRNA in various age groups. That will set up the dosing protocols for the first Phase II trials, which Moderna’s management has been saying could begin in the spring. Of course, “spring” is a flexible concept! This is a big bet on a new technology – the company has set up to receive as much as $483 million from HHS’s BARDA to ramp up clinical work and manufacturing in an effort to not miss a beat should the vaccine show promising data.
Update, 4/28: five days after starting the second Phase I doses, Moderna filed for an IND to go on into the Phase II trial mentioned above. It will have 600 patients, divided in to 50 microgram, 250 microgram, and placebo groups. As soon as the safety signals read out from the current dosing, they’ll take off, starting in May. And they’re already planning for a rapid Phase III later in the year.
Update, 5/1: Moderna has just signed a worldwide development agreement with Lonza, which could allow for scaleup of a 50-microgram vaccine dose to 1 billion doses per year. Moderna’s own production facility in Massachusetts is already heading to a 24-hour production schedule, using that BARDA funding mentioned above.
BioNTech and Pfizer
More mRNA candidates are moving along briskly as well. BioNTech has a deal with Fudan to work on such coronavirus vaccines in China, and they signed up last month with Pfizer for the rest of the world. (The companies had already been working on an mRNA influenza vaccine). Word has just come that the companies have received clearance from German regulatory authorities to start a Phase I/II trial. They’re spreading out the risk by adding to the work, taking four different candidates into the clinic more or less simultaneously.
They’re varying both the payload and the method of delivering it. Two of the candidates use mRNAs with naturally occurring (but less common) modified nucleoside bases in them (presumably things like pseudouridine), a trick that’s been tried over the years to increase stability and to cut down on the problem of developing antibodies to the mRNA vaccine itself (rather than to the protein it eventually produces!) The third has another modification, uridine-containing mRNA (presumably an extra tail of U residues?), which has been shown in some cases to increase the immune response to the protein product. And the fourth is a so-called “self-amplifying” mRNA, which has a sequence for a replicase enzyme in it as well. When this gets translated into protein, the replicase goes to work making more copies of the mRNA, including some double-stranded species that prime the immune system even more. As for the payload, two of these have the Spike protein (a popular choice, and for good reason), while the other two have just the receptor-binding domain from the spike (which came up in a recent post on coronavirus mutations here as well).
The trial will be dose-escalation design (1 to 100 micrograms), doing the usual range-finding for the later trials in up to 200 volunteers. They’re also going to look at the effect of repeat vaccinations and will try some cohorts of higher-risk patients as well. This is an ambitious program indeed.
Update, 4/28: Pfizer has said that they are going into human dosing next week, and say that they could be ready for emergency use “in the fall”, which is getting pretty lively even by the current standards (!)
Update, 5/1: the first cohort of 12 patients has been dosed by BioNTech in Germany, and Pfizer says that they are expected approval any day now to start similar trials in the US and move on to dose-escalation, etc. The first three candidates mentioned above will be dosed twice in patients, while the self-amplifying one will be a single dose."
Could be wrong, but I don't think used cars got expensive because of deaths. They got expensive (at least in part) because of travel restrictions. Rental cars weren't being used, so rental car companies sold their fleets. Cars weren't being produced because rental car companies weren't buying (and because there is a global microchip shortage). As things started reopening, rental car companies had to scramble to buy fleets. High demand plus low supply = higher price.
I've heard a lot of explanations for this - supply lines disrupt chip production, etc. - and I'm not sure I fully buy any of them. I think it's just complex; less people worked, there was a lot of uncertainty that you might argue made people feel less safe buying full-price new cars, supply lines were disrupted, and what you've mentioned about rental cars.
I'd buy any or all of those, frankly. Part of why I'm reluctant to pin it down to just one (say, microchips) is that from what I've seen the prices of a lot of craigslisty-type goods have raised on a pretty broad spectrum of products (musical instruments, cookware). I could make a just-so story to explain my anecdotal experience on that, but I'm not confident it would be right; I'm pretty content to settle for "it's probably a lot of things" on this one.
At the top of the "lot of things" list, I believe a major drop (and sustained drop at that) in mass transit ridership fueled demand for safe transport thus the used car price increases.
Interesting. Do you have any quick links to ridership stats? As a non-urbanite, I don't know how much of total transit is typically done via mass transit (nor do I know how much mass transit has gone down during covid)
Can you concretely state why the FDA has not approved the vaccines yet? Not the blatantly hyperbolic stuff like "to cover their asses", but actually steelman their rationale? Can you then identify the costs and benefits of the FDA's current rationale? What are the long-term benefits of their current strategy? How does that compare to the long-term cost?
It's obvious that there's benefits to immediately fully approving the vaccines tomorrow, rules be damned. And it's obvious that there's benefits to dismantling the entire approval structure of the modern pharmaceutical industry and existing in a libertarian utopia. But there are costs, too!
Will your vaccine-skeptical coworker really change their tune tomorrow if the FDA announced an expedited full approval? O would they be right back to, "the vaccines weren't fully evaluated, after all they were expedited and didn't go through full review"?
I'm answering both of your comments separately just to keep stuff straight in my head.
I think we think about this a lot differently, but let me try to break down where I think the conflict between our viewpoints is.
I hear a lot of an argument that the FDA has to do things to augment trust in it - that trust is an all-important standard and that any compromise on anything, at any point, is tantamount to burning the whole thing down and nothing should be changed, ever. That's obviously the extreme version of it, but there's a lot of people pretty close to that viewpoint even if they aren't that extreme, or are saying the same thing in a less hyperbolic way.
Looking at the situation on the ground, I think it's reasonable to narrow this down to that idea of trust. The FDA explicitly thinks the drug is safe enough for unlimited people to use. They encourage people to use it, and continue to do so after seeing what data has come over 10 months of use:
"The FDA evaluated data from clinical studies that included tens of thousands of people for each COVID-19 vaccine. The FDA authorized the vaccines because the data from these studies clearly showed that the known and potential benefits of the FDA-authorized COVID-19 vaccines outweighed the known and potential risks.
Over 300 million doses of COVID-19 vaccines have been administered in the U.S. and the ongoing post-authorization safety monitoring tells us that the known and potential benefits continue to outweigh the known and potential risks. The chance of developing a serious adverse event following vaccination is very low." (https://www.fda.gov/consumers/consumer-updates/learn-more-about-covid-19-vaccines-fda - apparently written during the "emergency authorization" period, not after)
So we know to a reasonable level of certainty it's not a safety thing - common sense says the use of the two "good" vaccines outweighs the danger of not using them, and there's no significant data that seems to have come out of the testing or >300 million doses that contradicts it.
We also know it's nothing like "once they approve a drug it's on the market forever"; the FDA can and does pull drug authorizations; if something comes out that's better/safer/faster/nicer than Pfizer or Moderna, they can pretty easily force the issue and switch over to those, outlawing the drugs we have now.
We get left with a situation where pretty much everybody except your hardcore anti-vax people agrees that our best course of action is to jab as many arms as we possibly can, at least in the "older than 12" demo. That's just by and large where virtually everyone outside of the snake-oil and "gumment coming to get me" contingent is.
I think that pretty reasonably narrows this down to what I call the FDA covering it's ass and what some people think of as the FDA maintaining that all-important trust. The FDA can't say "get this as soon as possible, we've done all the risk analysis and it's great; let's put this in as many people as possible" and then claim it's about anything but optics in the long term.
I now have to zig-zag into the hypothetical anti-vax friend, because this is where I think we get into isolated demand for vigor territory. On one hand, FDA-trust theory says "the FDA can't possibly rush into approving things; there's huge costs. A slight misstep here means people never trust the FDA again the same way; it sets public health back decades and decades. It's a huge, huge dangerous deal". But then it turns around and says "But, just so you know, this authorization means exactly nothing; it won't convince anybody and nobody is even paying attention to it".
I think that's a lot of me to swallow as an argument without pushing back on it. Like, yes, of course if there's no upside at all to approval we shouldn't approve just because the cost of paper is probably pretty high right now. But while "I won't be convinced by anything" anti-vaxxers certainly exist, I'm not at all sure they make up the vast majority of everybody. My mom, for instance, was never anti-vaccine but has anti-vaccine people she knows who were feeding her a lot of questionable information about why she wouldn't get it (her sister told her she'd be dead within three months). She had to be talked into it, but she absolutely could be talked into it; something like this would have helped a lot in that process.
The flip side of me being asked to imagine every person who hasn't been vaccinated as an unreachable, entrenched holdout is that I'm also being asked to imagine that everyone else (a whole normal vax "reasonable" side of the population) is supremely sensitive to the difference between emergency authorization and full approval in a way where problems that might occur because of the vaccinations in either scenario would result in significant differences in their trust in the FDA, differences big enough that it would absolutely outweigh the benefits on the other side.
The reason why I come down really, really hard on the side of the FDA not having a good reason to do this is just because of who they are. They take forever on everything; they go as slow as they possibly can within the reasonable bounds of their politics. There's a good article on this here: https://astralcodexten.substack.com/p/adumbrations-of-aducanumab. Scott is a lot more gentle/reasonable than me (you should of course read him if you already aren't), but he's basically talking about the same problem one step removed, putting the blame basically on congress and politics rather than the FDA.
So I'm left with an agency who is chronically slow/overcautious on all things, and has been throughout my lifetime, being apparently slow and overcautious here at a loss of what I think is reasonably thousands of lives a day (with me thinking people are more convincible than you) and with very little to risk besides having a political "they made us do it" out (with me thinking the of the disaster of FDA trust being undermined is taken as much too much of a given with very little justification as to why it would be a huge effect in this situation). And, being a guy who thinks the FDA is always doing stuff like this to CYA (see: not wanting to do challenge trials while pretty much having to know it was very likely a horrific tradeoff in terms of deaths), I come to what I think (but what you don't think) is a reasonable conclusion: the FDA will let people die in any situation where going slower might give them some level of additional political cover, no matter how small.
I know this is super over-long and jumbled; my apologies. It's been a fairly long week for me, but I didn't want to not reply to you at all. As always, I appreciate the pushback and you reading my stuff.
I would really like help on reading this, at least before we get into the weeds on it. From what I read their arguments as being, it's something like:
"Despite being the best treatments available, effectiveness of the vaccines is falling to ~50%, as opposed to nothing; in dealing with a mutation the drugs weren't designed for, it's perhaps as low as ~35%."
I know there's more to this, but that alone gave me pause; I don't see them claiming anything like "people are dying from using this vaccine in a way that we have to weigh against the amount of people who are living from using it" - they don't seem to claim any evidence of danger at all, with the vaccine having been in absurdly wide usage for nearly a year.
I'm legitimately confused here - are you or the authors arguing something that would negate "the vaccine should be used by as many people as possible, as soon as possible, to save as many lives as possible"? Because if you aren't, this just loops into what I said above - I think the FDA delaying anymore would just be meaningless CYA that would minimize use. If they are arguing something different, and I suspect they might be, then that's something different to talk about entirely. But I'm not in a good headspace for picking up that nuance RN.
Forget about Epsilon; what are we doing to prepare for Lambda, which is sadly quite real ? I can imagine a few useful policies:
* Stockpiling masks. Real ones that protect against COVID, not Chinese knockoff ones that protect only against dust.
* Stockpiling respirators. Ditto.
* Committing to N billion dollars in new vaccine purchases, as soon as those vaccines are developed.
* Setting up mobile emergency hospitals. Some of these were used during peak COVID, but their rollout came too little, too late.
* Announcing clear and transparent lockdown targets: "your neighbourhood will be locked down if daily COVID tests reach X, un-locked down when they fall below Y".
We don't need the FDA for any of this, AFAIK, but we are doing none of it.
To be a counter-contrarian, I'd say that focusing on the next, perhaps far worse, virus is possibly misguided, and almost certain to divert our attention and resources. It's the problem of recency bias. We just had a huge crisis with a virus. What if it happens again? And soon?
But, you know, it probably won't. It's been a hundred years since the last catastrophic pandemic. We've had scares since then, but ultimately were manageable. While we should do smart things in advance (such as really pushing research on broad scale mRNA vaccines), our efforts would better be directed elsewhere.
And by that I mean potential disasters that *haven't* happened yet, and that we so far turn a blind eye to. Catastrophic earthquakes on the West Coast. Heck, a repeat of the 8.0 New Madrid earthquake of 1811. Massive hacking of our electrical grid. An asteroid heading our way!
I'd say none of these is less a worrisome problem than Epsilon, which we tend to focus on because of how burned we feel by COVID. But they would be as bad or worse than COVID and I guarantee you, they receive an infinitesimal amount of attention and resources in comparison.
> We should absolutely be doing more than this. We should be demanding some sort of stated plan for expediting vaccines in emergency situations, something better than “whenever we get to it - this is how it’s always been done”.
What good would that do? The UK had a plan. The mob listened to it, said fuck you, and demanded a bunch of stupid bullshit instead. What we should be demanding is that the FDA be burnt to the ground, and site of its HQ turned into a monument to covid victims. then a new institution set up with a very different mandate and a culture that starts with "Never forget that drugs save lives".
Most of this stuff is mob-agnostic - like, whatever the mob does, it's probably helpful if it has options sooner; having all the people who are going to get vaccinated vaccinated in August-November instead of December-April or something like that gives the "let us out of fucking houses, assholes" contingent more ammo ooner and legit saves lives when people who take vaccines take them sooner. Detecting viruses that might pose a big threat and getting the wheels turning sooner makes things happen sooner. There's lots of stuff that works "despite the mob" even if a lot of the mob is dumb.
More on the point, I'm not sure the mob is down for another round of this. Even a bunch of your dyed-in-the-wool government-is-always-good types pushed back on the CDC when it said "hey, good, you are vaccinated! change nothing, keep all restrictions in place". They might be down for another lock-down in a few years, but I'm not sure that's certain.
I 100% guarantee that the FDA will come up with a plan for the next pandemic. Dozens of committees will spend thousands of hours and millions of dollars on it. The result will be a plan for a vaccine out in a year, because that's what the current system requires. The only way to fix that is to fix the system. It will never fix itself because it is shaped by the incentives that it faces, and those haven't changed. So if you want it to change, you're going to have to force it to change, and the only way to do that in the long run is to change the incentives it faces.
You could, for example, force the FDA to do calculations about how many QALY's will be lost from inaction when laying out the approval schedule and designing trials regimes, and adjust them accordingly. A new treatment for baldness? Take your time. Slight modification of a vaccine for a raging pandemic? Get to work ASAP.
But even that's not a solution. For one, it adds another step to the process, so you have to make sure it has teeth or it's a net negative. And given the existing culture and incentives, they're very likely to lowball the costs and hype up the benefits of delay. So to make it happen you need an FDA administrator that wants to force their hand, knows enough to make sure they aren't logrolling him, and who is around enough to make it stick. It's not easy, but if you do that, you've changed the system. And it's not the sort of thing you will ever get people marching for.
That may be, but I'm not really the "assume defeat and do nothing" type. I don't actually *expect* that this article will cause people to get off their asses and complain in a way that gets us a 3-6 month vaccine, but I'd at least like to live in a world where that's slightly more likely.
As for the plan being a year: That's sort of like a guy's "stop beating my wife" plan to be only to hit her once a day instead of 10 times. I know you know this, but that's not good enough. Moreover the plan for other types of vaccines is still "10-15 years for no reason at all, haha, it's funny when people die, right?", which is less noticeably bad but probably just as bad overall.
I'm not saying assume defeat and do nothing. I'm saying you're solving the wrong problem. If you're going to have a call for action, call for an action that would actually help. "Get a vaccine plan!" will not change things, "Force the FDA to consider the cost of delaying drug approval!" might.
I'm not sure I buy the mechanics here - part of your premise is that it's basically out-of-reach to get the FDA to make a vaccine plan, that we can't get the political pressure for that. But "we need vaccines for pandemics much faster, because you don't like lock-downs and mass death" is a much more generally digestible idea than "The FDA takes literally 20-30 times to long to approve every drug it approves, let's change everything about that", if for no other reason than the effects of bad pandemic vaccine policy are a lot more visible right now.
It's not that I disagree - I would gladly piss on the ashes of a completely destroyed FDA. I just don't know that we can get the hard-mode version of what I want if we can't get the easy-mode version.
I don't disagree that "we need vaccines for pandemics much faster, because you don't like lock-downs and mass death" is a decent rallying cry. I object to what you're adding afterwards, which is "so let's make the same chucklefucks who took a year the first time come up with plan to do better the next time." Because they won't. If the stars align they'll come up with a plan that takes a month less, tops.
My plan is to use the present crisis to do something that will actually make a difference. Your plan, even if it works won't. He'll, there's a decent chance you'll make things worse because now we actually have a plan, which means we have to follow it, even if some of the steps end up not making sense in the context of actual events.
You are thinking about this like the agency is a person that can make rational decisions. It isn't, it's a government agency that works far more like a computer program than a human. If you want it to do better, telling it "think about how to do better" will never, ever work. You need to embed the heuristic you want in its code, set because it is incapable of thinking itself out of the box it's made.
Russia has no FDA, so their vaccine rollout went much more smoothly. On paper.
To this day, most people are waiting in line to get Pfizer or Moderna, because they are convinced that Sputnik-V is just government propaganda. There are ten thousand charlatans selling miracle cures; Russian congresspeople are seen wearing little plastic badges with magic COVID-deflecting electromagnetic doohickeys inside. Most people self-medicate with vodka and garlic. Hooray for no FDA !
I'm not sure you are wrong on this, but it almost definitely has to be more complex than you are putting it forward as being. I'd be absolutely shocked if the average Russian has anything like the same baseline regard and mindset for the government at large that the average US citizen has, FDA/russian drug approval specifics aside.
That doesn't mean that "FDA approves things faster and we are immediately as bad as Russia in terms of the populace's reaction to government drug approvals" is absolutely wrong, but it's not clearly right to me. What's more it seems like assuming it's clearly right is an effective full argument for any improvements at all with the FDA - if all we consider are "US > Russia" and "FDA takes longer than Russia", then there's no discussion of "FDA could be better" to be had in the first place.
No one is arguing that making the FDA *faster* is a bad idea (well, at least, I'm not). However, all the proposals I see for making this happen are along the lines of "abolish the FDA" or "allow the FDA to approve drugs based solely on lack of harm and not efficacy" or "don't run human clinical trials at all", etc.
But I would argue that the lives lost due to the FDA's slow response to COVID would've been more than offset by the lives lost if the FDA were abolished or reduced to a rubber-stamping agency. There would be loss of life due to charlatan miracle cures, untested drugs that fail to work (or end up being harmful), and general loss of public confidence in vaccines (a justifiable loss, in that scenario).
There's a reason why many people in Russia -- rich ones, anyway -- prefer to import American or European drugs. It's because they have zero faith in the government, and relying on word of mouth to determine which drugs are safe and effective is simply untenable. But when you buy an FDA-approved drug, you *know* that it works. That level of confidence is worth a lot more than people give it credit for.
Minor typos: In the first sentence you have "are document". In the second paragraph of the second section you have a trailing "I". Otherwise an excellent, chilling article. We must reform the FDA, allow challenge trials, speed up both emergency auth and full auth of vaccines.
“As is now generally known, a working Covid vaccine was on the ground in late February; “
That was no working vaccine. There were preliminary mRNA designs based on the sequence of the sars-cov2 but there were alterations to the sequence for various technical reasons, and there still needed to be trials to determine the best sequence and the most effective dosage if in fact there was an effective dosage and also to determine associated adjuvants and other material to be included with the mRNA. Also the stability of vaccine for storage had to be determined.
I will concede that by August when the final production specifications were fixed assuming the stage trials were successful that risk/reward ratio favored allowing high risk groups access to the vaccine.
Is that so, though? I'm willing to see sources on this, but everything I can find is either like this:
"You may be surprised to learn that of the trio of long-awaited coronavirus vaccines, the most promising, Moderna’s mRNA-1273, which reported a 94.5 percent efficacy rate on November 16, had been designed by January 13. This was just two days after the genetic sequence had been made public in an act of scientific and humanitarian generosity that resulted in China’s Yong-Zhen Zhang’s being temporarily forced out of his lab. In Massachusetts, the Moderna vaccine design took all of one weekend. It was completed before China had even acknowledged that the disease could be transmitted from human to human, more than a week before the first confirmed coronavirus case in the United States. By the time the first American death was announced a month later, the vaccine had already been manufactured and shipped to the National Institutes of Health for the beginning of its Phase I clinical trial. This is — as the country and the world are rightly celebrating — the fastest timeline of development in the history of vaccines. It also means that for the entire span of the pandemic in this country, which has already killed more than 250,000 Americans, we had the tools we needed to prevent it." (https://archive.is/37YtH#selection-1281.0-1285.1024)
Or like this:
"Forty-two days after the genetic code was released, Moderna’s CEO Bancel opened an email on Feb. 24 on his cellphone and smiled, as he recalled to the Globe. Up popped a photograph of a box placed inside a refrigerated truck at the Norwood plant and bound for the National Institute of Allergy and Infectious Diseases in Bethesda, Md. The package held a few hundred vials, each containing the experimental vaccine.
Moderna was the first drug maker to deliver a potential vaccine for clinical trials. Soon, its vaccine became the first to undergo testing on humans, in a small early-stage trial. And on July 28, it became the first to start getting tested in a late-stage trial in a scene that reflected the firm’s receptiveness to press coverage."
If I'm wrong I'd like to know, it's just not the narrative I've seen anywhere that covers the history of these vaccines. Granted these are articles aimed at laymen; what's a good source that shows me what I'm being told I'm missing?
As far as August goes, I doubt I'd be writing this article if we had got it - I'm not sure exactly where my "fast enough" cut-off lies, but there's at least a point where I wouldn't bother to write about it and that's probably July/August for me. I might think May is possible/doable, but at some point it gets into reasonable-discussion territory about tradeoffs as opposed to "no, you don't understand, we really like paperwork" stuff.
Second quote link (https://www.statnews.com/2020/11/10/the-story-of-mrna-how-a-once-dismissed-idea-became-a-leading-technology-in-the-covid-vaccine-race/)
As noted in the second quoted article what was delivered at the end of February was experimental as it wasn't tried out yet in humans and safety and efficient dose characteristics still had to be determined before it becomes a working vaccine. If you are treating a person for a disease you can adjust the dosage of a drug, but for mass inoculation you don't want too high a dose that puts half the healthy recipients in bed with a fever for 3 days and you don't want too low a dose and have no protection or keep having to measure immune response giving them additional doses until the immune response is satisfactory. Also even if the dosage was know scaling up manufacturing was still ongoing.
Here is the situation around the end of April
“Moderna’s mRNA1273
This is another one that’s progressing rapidly in the clinic, and if you’re keeping score, is the most advanced vaccine candidate from a US company. Moderna’s expertise is in messenger RNA-based therapies, and this one is indeed an mRNA vaccine, developed in collaboration with the NIH. The hope is that this engineered RNA will enter cells and make them produce coronavirus spike proteins, which will then set off an immune response. As mentioned in the background post, this is a relatively new vaccine technology, and no vaccines have been approved yet using it. It has the advantage of being fast, though, which is why this candidate is in the position it is.
Volunteers have already been given a low dose of the vaccine in a 45-patient Phase I trial in Seattle, and a larger one is enrolling at Emory, dosing 25, 100, and 250 micrograms of the mRNA in various age groups. That will set up the dosing protocols for the first Phase II trials, which Moderna’s management has been saying could begin in the spring. Of course, “spring” is a flexible concept! This is a big bet on a new technology – the company has set up to receive as much as $483 million from HHS’s BARDA to ramp up clinical work and manufacturing in an effort to not miss a beat should the vaccine show promising data.
Update, 4/28: five days after starting the second Phase I doses, Moderna filed for an IND to go on into the Phase II trial mentioned above. It will have 600 patients, divided in to 50 microgram, 250 microgram, and placebo groups. As soon as the safety signals read out from the current dosing, they’ll take off, starting in May. And they’re already planning for a rapid Phase III later in the year.
Update, 5/1: Moderna has just signed a worldwide development agreement with Lonza, which could allow for scaleup of a 50-microgram vaccine dose to 1 billion doses per year. Moderna’s own production facility in Massachusetts is already heading to a 24-hour production schedule, using that BARDA funding mentioned above.
BioNTech and Pfizer
More mRNA candidates are moving along briskly as well. BioNTech has a deal with Fudan to work on such coronavirus vaccines in China, and they signed up last month with Pfizer for the rest of the world. (The companies had already been working on an mRNA influenza vaccine). Word has just come that the companies have received clearance from German regulatory authorities to start a Phase I/II trial. They’re spreading out the risk by adding to the work, taking four different candidates into the clinic more or less simultaneously.
They’re varying both the payload and the method of delivering it. Two of the candidates use mRNAs with naturally occurring (but less common) modified nucleoside bases in them (presumably things like pseudouridine), a trick that’s been tried over the years to increase stability and to cut down on the problem of developing antibodies to the mRNA vaccine itself (rather than to the protein it eventually produces!) The third has another modification, uridine-containing mRNA (presumably an extra tail of U residues?), which has been shown in some cases to increase the immune response to the protein product. And the fourth is a so-called “self-amplifying” mRNA, which has a sequence for a replicase enzyme in it as well. When this gets translated into protein, the replicase goes to work making more copies of the mRNA, including some double-stranded species that prime the immune system even more. As for the payload, two of these have the Spike protein (a popular choice, and for good reason), while the other two have just the receptor-binding domain from the spike (which came up in a recent post on coronavirus mutations here as well).
The trial will be dose-escalation design (1 to 100 micrograms), doing the usual range-finding for the later trials in up to 200 volunteers. They’re also going to look at the effect of repeat vaccinations and will try some cohorts of higher-risk patients as well. This is an ambitious program indeed.
Update, 4/28: Pfizer has said that they are going into human dosing next week, and say that they could be ready for emergency use “in the fall”, which is getting pretty lively even by the current standards (!)
Update, 5/1: the first cohort of 12 patients has been dosed by BioNTech in Germany, and Pfizer says that they are expected approval any day now to start similar trials in the US and move on to dose-escalation, etc. The first three candidates mentioned above will be dosed twice in patients, while the self-amplifying one will be a single dose."
https://blogs.sciencemag.org/pipeline/archives/2020/04/23/a-close-look-at-the-frontrunning-coronavirus-vaccines-as-of-april-23
Could be wrong, but I don't think used cars got expensive because of deaths. They got expensive (at least in part) because of travel restrictions. Rental cars weren't being used, so rental car companies sold their fleets. Cars weren't being produced because rental car companies weren't buying (and because there is a global microchip shortage). As things started reopening, rental car companies had to scramble to buy fleets. High demand plus low supply = higher price.
I've heard a lot of explanations for this - supply lines disrupt chip production, etc. - and I'm not sure I fully buy any of them. I think it's just complex; less people worked, there was a lot of uncertainty that you might argue made people feel less safe buying full-price new cars, supply lines were disrupted, and what you've mentioned about rental cars.
I'd buy any or all of those, frankly. Part of why I'm reluctant to pin it down to just one (say, microchips) is that from what I've seen the prices of a lot of craigslisty-type goods have raised on a pretty broad spectrum of products (musical instruments, cookware). I could make a just-so story to explain my anecdotal experience on that, but I'm not confident it would be right; I'm pretty content to settle for "it's probably a lot of things" on this one.
I am inclined to agree with you that "it's probably a lot of things."
At the top of the "lot of things" list, I believe a major drop (and sustained drop at that) in mass transit ridership fueled demand for safe transport thus the used car price increases.
Interesting. Do you have any quick links to ridership stats? As a non-urbanite, I don't know how much of total transit is typically done via mass transit (nor do I know how much mass transit has gone down during covid)
https://transitapp.com/APTA
FYI, we do already have a named Epsilon variant:
https://ourworldindata.org/grapher/covid-variants-area?country=~GBR
Can you concretely state why the FDA has not approved the vaccines yet? Not the blatantly hyperbolic stuff like "to cover their asses", but actually steelman their rationale? Can you then identify the costs and benefits of the FDA's current rationale? What are the long-term benefits of their current strategy? How does that compare to the long-term cost?
It's obvious that there's benefits to immediately fully approving the vaccines tomorrow, rules be damned. And it's obvious that there's benefits to dismantling the entire approval structure of the modern pharmaceutical industry and existing in a libertarian utopia. But there are costs, too!
Will your vaccine-skeptical coworker really change their tune tomorrow if the FDA announced an expedited full approval? O would they be right back to, "the vaccines weren't fully evaluated, after all they were expedited and didn't go through full review"?
I'm answering both of your comments separately just to keep stuff straight in my head.
I think we think about this a lot differently, but let me try to break down where I think the conflict between our viewpoints is.
I hear a lot of an argument that the FDA has to do things to augment trust in it - that trust is an all-important standard and that any compromise on anything, at any point, is tantamount to burning the whole thing down and nothing should be changed, ever. That's obviously the extreme version of it, but there's a lot of people pretty close to that viewpoint even if they aren't that extreme, or are saying the same thing in a less hyperbolic way.
Looking at the situation on the ground, I think it's reasonable to narrow this down to that idea of trust. The FDA explicitly thinks the drug is safe enough for unlimited people to use. They encourage people to use it, and continue to do so after seeing what data has come over 10 months of use:
"The FDA evaluated data from clinical studies that included tens of thousands of people for each COVID-19 vaccine. The FDA authorized the vaccines because the data from these studies clearly showed that the known and potential benefits of the FDA-authorized COVID-19 vaccines outweighed the known and potential risks.
Over 300 million doses of COVID-19 vaccines have been administered in the U.S. and the ongoing post-authorization safety monitoring tells us that the known and potential benefits continue to outweigh the known and potential risks. The chance of developing a serious adverse event following vaccination is very low." (https://www.fda.gov/consumers/consumer-updates/learn-more-about-covid-19-vaccines-fda - apparently written during the "emergency authorization" period, not after)
So we know to a reasonable level of certainty it's not a safety thing - common sense says the use of the two "good" vaccines outweighs the danger of not using them, and there's no significant data that seems to have come out of the testing or >300 million doses that contradicts it.
We also know it's nothing like "once they approve a drug it's on the market forever"; the FDA can and does pull drug authorizations; if something comes out that's better/safer/faster/nicer than Pfizer or Moderna, they can pretty easily force the issue and switch over to those, outlawing the drugs we have now.
We get left with a situation where pretty much everybody except your hardcore anti-vax people agrees that our best course of action is to jab as many arms as we possibly can, at least in the "older than 12" demo. That's just by and large where virtually everyone outside of the snake-oil and "gumment coming to get me" contingent is.
I think that pretty reasonably narrows this down to what I call the FDA covering it's ass and what some people think of as the FDA maintaining that all-important trust. The FDA can't say "get this as soon as possible, we've done all the risk analysis and it's great; let's put this in as many people as possible" and then claim it's about anything but optics in the long term.
I now have to zig-zag into the hypothetical anti-vax friend, because this is where I think we get into isolated demand for vigor territory. On one hand, FDA-trust theory says "the FDA can't possibly rush into approving things; there's huge costs. A slight misstep here means people never trust the FDA again the same way; it sets public health back decades and decades. It's a huge, huge dangerous deal". But then it turns around and says "But, just so you know, this authorization means exactly nothing; it won't convince anybody and nobody is even paying attention to it".
I think that's a lot of me to swallow as an argument without pushing back on it. Like, yes, of course if there's no upside at all to approval we shouldn't approve just because the cost of paper is probably pretty high right now. But while "I won't be convinced by anything" anti-vaxxers certainly exist, I'm not at all sure they make up the vast majority of everybody. My mom, for instance, was never anti-vaccine but has anti-vaccine people she knows who were feeding her a lot of questionable information about why she wouldn't get it (her sister told her she'd be dead within three months). She had to be talked into it, but she absolutely could be talked into it; something like this would have helped a lot in that process.
The flip side of me being asked to imagine every person who hasn't been vaccinated as an unreachable, entrenched holdout is that I'm also being asked to imagine that everyone else (a whole normal vax "reasonable" side of the population) is supremely sensitive to the difference between emergency authorization and full approval in a way where problems that might occur because of the vaccinations in either scenario would result in significant differences in their trust in the FDA, differences big enough that it would absolutely outweigh the benefits on the other side.
The reason why I come down really, really hard on the side of the FDA not having a good reason to do this is just because of who they are. They take forever on everything; they go as slow as they possibly can within the reasonable bounds of their politics. There's a good article on this here: https://astralcodexten.substack.com/p/adumbrations-of-aducanumab. Scott is a lot more gentle/reasonable than me (you should of course read him if you already aren't), but he's basically talking about the same problem one step removed, putting the blame basically on congress and politics rather than the FDA.
So I'm left with an agency who is chronically slow/overcautious on all things, and has been throughout my lifetime, being apparently slow and overcautious here at a loss of what I think is reasonably thousands of lives a day (with me thinking people are more convincible than you) and with very little to risk besides having a political "they made us do it" out (with me thinking the of the disaster of FDA trust being undermined is taken as much too much of a given with very little justification as to why it would be a huge effect in this situation). And, being a guy who thinks the FDA is always doing stuff like this to CYA (see: not wanting to do challenge trials while pretty much having to know it was very likely a horrific tradeoff in terms of deaths), I come to what I think (but what you don't think) is a reasonable conclusion: the FDA will let people die in any situation where going slower might give them some level of additional political cover, no matter how small.
I know this is super over-long and jumbled; my apologies. It's been a fairly long week for me, but I didn't want to not reply to you at all. As always, I appreciate the pushback and you reading my stuff.
As a follow-up, there are very, very good reasons to be unhappy with the FDA's recent decision to approve the Pfizer-BioNTech vaccine.
https://blogs.bmj.com/bmj/2021/08/23/does-the-fda-think-these-data-justify-the-first-full-approval-of-a-covid-19-vaccine/
Tackling this separately:
I would really like help on reading this, at least before we get into the weeds on it. From what I read their arguments as being, it's something like:
"Despite being the best treatments available, effectiveness of the vaccines is falling to ~50%, as opposed to nothing; in dealing with a mutation the drugs weren't designed for, it's perhaps as low as ~35%."
I know there's more to this, but that alone gave me pause; I don't see them claiming anything like "people are dying from using this vaccine in a way that we have to weigh against the amount of people who are living from using it" - they don't seem to claim any evidence of danger at all, with the vaccine having been in absurdly wide usage for nearly a year.
I'm legitimately confused here - are you or the authors arguing something that would negate "the vaccine should be used by as many people as possible, as soon as possible, to save as many lives as possible"? Because if you aren't, this just loops into what I said above - I think the FDA delaying anymore would just be meaningless CYA that would minimize use. If they are arguing something different, and I suspect they might be, then that's something different to talk about entirely. But I'm not in a good headspace for picking up that nuance RN.
Forget about Epsilon; what are we doing to prepare for Lambda, which is sadly quite real ? I can imagine a few useful policies:
* Stockpiling masks. Real ones that protect against COVID, not Chinese knockoff ones that protect only against dust.
* Stockpiling respirators. Ditto.
* Committing to N billion dollars in new vaccine purchases, as soon as those vaccines are developed.
* Setting up mobile emergency hospitals. Some of these were used during peak COVID, but their rollout came too little, too late.
* Announcing clear and transparent lockdown targets: "your neighbourhood will be locked down if daily COVID tests reach X, un-locked down when they fall below Y".
We don't need the FDA for any of this, AFAIK, but we are doing none of it.
To be a counter-contrarian, I'd say that focusing on the next, perhaps far worse, virus is possibly misguided, and almost certain to divert our attention and resources. It's the problem of recency bias. We just had a huge crisis with a virus. What if it happens again? And soon?
But, you know, it probably won't. It's been a hundred years since the last catastrophic pandemic. We've had scares since then, but ultimately were manageable. While we should do smart things in advance (such as really pushing research on broad scale mRNA vaccines), our efforts would better be directed elsewhere.
And by that I mean potential disasters that *haven't* happened yet, and that we so far turn a blind eye to. Catastrophic earthquakes on the West Coast. Heck, a repeat of the 8.0 New Madrid earthquake of 1811. Massive hacking of our electrical grid. An asteroid heading our way!
I'd say none of these is less a worrisome problem than Epsilon, which we tend to focus on because of how burned we feel by COVID. But they would be as bad or worse than COVID and I guarantee you, they receive an infinitesimal amount of attention and resources in comparison.
> We should absolutely be doing more than this. We should be demanding some sort of stated plan for expediting vaccines in emergency situations, something better than “whenever we get to it - this is how it’s always been done”.
What good would that do? The UK had a plan. The mob listened to it, said fuck you, and demanded a bunch of stupid bullshit instead. What we should be demanding is that the FDA be burnt to the ground, and site of its HQ turned into a monument to covid victims. then a new institution set up with a very different mandate and a culture that starts with "Never forget that drugs save lives".
Most of this stuff is mob-agnostic - like, whatever the mob does, it's probably helpful if it has options sooner; having all the people who are going to get vaccinated vaccinated in August-November instead of December-April or something like that gives the "let us out of fucking houses, assholes" contingent more ammo ooner and legit saves lives when people who take vaccines take them sooner. Detecting viruses that might pose a big threat and getting the wheels turning sooner makes things happen sooner. There's lots of stuff that works "despite the mob" even if a lot of the mob is dumb.
More on the point, I'm not sure the mob is down for another round of this. Even a bunch of your dyed-in-the-wool government-is-always-good types pushed back on the CDC when it said "hey, good, you are vaccinated! change nothing, keep all restrictions in place". They might be down for another lock-down in a few years, but I'm not sure that's certain.
I 100% guarantee that the FDA will come up with a plan for the next pandemic. Dozens of committees will spend thousands of hours and millions of dollars on it. The result will be a plan for a vaccine out in a year, because that's what the current system requires. The only way to fix that is to fix the system. It will never fix itself because it is shaped by the incentives that it faces, and those haven't changed. So if you want it to change, you're going to have to force it to change, and the only way to do that in the long run is to change the incentives it faces.
You could, for example, force the FDA to do calculations about how many QALY's will be lost from inaction when laying out the approval schedule and designing trials regimes, and adjust them accordingly. A new treatment for baldness? Take your time. Slight modification of a vaccine for a raging pandemic? Get to work ASAP.
But even that's not a solution. For one, it adds another step to the process, so you have to make sure it has teeth or it's a net negative. And given the existing culture and incentives, they're very likely to lowball the costs and hype up the benefits of delay. So to make it happen you need an FDA administrator that wants to force their hand, knows enough to make sure they aren't logrolling him, and who is around enough to make it stick. It's not easy, but if you do that, you've changed the system. And it's not the sort of thing you will ever get people marching for.
That may be, but I'm not really the "assume defeat and do nothing" type. I don't actually *expect* that this article will cause people to get off their asses and complain in a way that gets us a 3-6 month vaccine, but I'd at least like to live in a world where that's slightly more likely.
As for the plan being a year: That's sort of like a guy's "stop beating my wife" plan to be only to hit her once a day instead of 10 times. I know you know this, but that's not good enough. Moreover the plan for other types of vaccines is still "10-15 years for no reason at all, haha, it's funny when people die, right?", which is less noticeably bad but probably just as bad overall.
I'm not saying assume defeat and do nothing. I'm saying you're solving the wrong problem. If you're going to have a call for action, call for an action that would actually help. "Get a vaccine plan!" will not change things, "Force the FDA to consider the cost of delaying drug approval!" might.
I'm not sure I buy the mechanics here - part of your premise is that it's basically out-of-reach to get the FDA to make a vaccine plan, that we can't get the political pressure for that. But "we need vaccines for pandemics much faster, because you don't like lock-downs and mass death" is a much more generally digestible idea than "The FDA takes literally 20-30 times to long to approve every drug it approves, let's change everything about that", if for no other reason than the effects of bad pandemic vaccine policy are a lot more visible right now.
It's not that I disagree - I would gladly piss on the ashes of a completely destroyed FDA. I just don't know that we can get the hard-mode version of what I want if we can't get the easy-mode version.
I don't disagree that "we need vaccines for pandemics much faster, because you don't like lock-downs and mass death" is a decent rallying cry. I object to what you're adding afterwards, which is "so let's make the same chucklefucks who took a year the first time come up with plan to do better the next time." Because they won't. If the stars align they'll come up with a plan that takes a month less, tops.
My plan is to use the present crisis to do something that will actually make a difference. Your plan, even if it works won't. He'll, there's a decent chance you'll make things worse because now we actually have a plan, which means we have to follow it, even if some of the steps end up not making sense in the context of actual events.
You are thinking about this like the agency is a person that can make rational decisions. It isn't, it's a government agency that works far more like a computer program than a human. If you want it to do better, telling it "think about how to do better" will never, ever work. You need to embed the heuristic you want in its code, set because it is incapable of thinking itself out of the box it's made.
Russia has no FDA, so their vaccine rollout went much more smoothly. On paper.
To this day, most people are waiting in line to get Pfizer or Moderna, because they are convinced that Sputnik-V is just government propaganda. There are ten thousand charlatans selling miracle cures; Russian congresspeople are seen wearing little plastic badges with magic COVID-deflecting electromagnetic doohickeys inside. Most people self-medicate with vodka and garlic. Hooray for no FDA !
I'm not sure you are wrong on this, but it almost definitely has to be more complex than you are putting it forward as being. I'd be absolutely shocked if the average Russian has anything like the same baseline regard and mindset for the government at large that the average US citizen has, FDA/russian drug approval specifics aside.
That doesn't mean that "FDA approves things faster and we are immediately as bad as Russia in terms of the populace's reaction to government drug approvals" is absolutely wrong, but it's not clearly right to me. What's more it seems like assuming it's clearly right is an effective full argument for any improvements at all with the FDA - if all we consider are "US > Russia" and "FDA takes longer than Russia", then there's no discussion of "FDA could be better" to be had in the first place.
No one is arguing that making the FDA *faster* is a bad idea (well, at least, I'm not). However, all the proposals I see for making this happen are along the lines of "abolish the FDA" or "allow the FDA to approve drugs based solely on lack of harm and not efficacy" or "don't run human clinical trials at all", etc.
But I would argue that the lives lost due to the FDA's slow response to COVID would've been more than offset by the lives lost if the FDA were abolished or reduced to a rubber-stamping agency. There would be loss of life due to charlatan miracle cures, untested drugs that fail to work (or end up being harmful), and general loss of public confidence in vaccines (a justifiable loss, in that scenario).
There's a reason why many people in Russia -- rich ones, anyway -- prefer to import American or European drugs. It's because they have zero faith in the government, and relying on word of mouth to determine which drugs are safe and effective is simply untenable. But when you buy an FDA-approved drug, you *know* that it works. That level of confidence is worth a lot more than people give it credit for.
Minor typos: In the first sentence you have "are document". In the second paragraph of the second section you have a trailing "I". Otherwise an excellent, chilling article. We must reform the FDA, allow challenge trials, speed up both emergency auth and full auth of vaccines.
Fixed! Thank you!