The testing is so maddening. The FDA could say: “we are going to provisionally authorize for sale any test that has been approved by the EU, UK, Japanese or South Korean authorities.” This isn’t thalidomide- the worst possible outcome is somewhat higher error rates. Big deal.
The Biden administration’s passivity on COVID has been so frustrating. There are so many things they could be doing - none of which require approval from Republicans and/or Sinema/Manchin. To pull in another stream from “the discourse” - this would be a perfect job for Kamala Harris. She could be the COVID czar- running around and pushing end runs around these dumb regulatory barriers. It would be great the country and even better for her!
Imagine it- here’s Harris at the FDA announcing that they are now authorizing foreign rapid tests, with the expectation that they will be significantly cheaper. Two weeks later - here’s Harris again at a Walmart, where they have started putting foreign tests on the shelves and they’ll cost $3 each. Here’s Harris at a big research university where they are beginning human challenge trials of a new super-targeted Omicron booster (check out the footage of the super wholesome photogenic young volunteers). Here’s Harris at a Moderna manufacturing plant, 3 weeks later the day after the successful completion of the trial where they are starting up production of the new Omicron booster. Here’s Harris at an airport - at a new TSA lane where travelers can voluntarily prove their vax status and take a rapid test - but then they get a tamper proof bracelet that lets them fly that day without a mask.
There so much they could be doing - every two weeks or so we could see Harris on TV and we’d love seeing her because each time she’d be doing something that is making the pandemic just a little bit easier to deal with.
Yeah it’s frustrating because it’s actually hard to point to anything Biden has done that has actually been better than the Trump administration on COVID. At least he’s not saying stupid stuff at press conferences, but all the smart ideas that were floating around in the early days of the administration (they were talking about using rapid tests to open schools, I definitely remember it!) seem to have vanished under the weight of the regulatory establishment and Biden seemingly has no appetite for challenging it.
Unfortunately, in our inept political reporting environment, if I register my modest disapproval with the Biden Administration so far, that maps 1:1 onto "ooooo look at this totally gettable moderate who might flip Trump in 2024!". And because reporting and real life has a nasty feedback loop, I need to rah-rah go blue rather than simply say they're not doing a very good job and risk feeding the news cycle.
I think you're overestimating your personal impact on the new cycle.
Radical idea: what if people try to express what they actually think, in as nuanced a manner as they can? And leave tactical positioning to actual public figures?
The Biden admin has been so bad on Covid, mostly because it got rolled by nitwit staffers at the FDA and CDC. We've already lost thousands of lives because the FDA/CDC delayed boosters for all adults. Now it's slow walking the Merck and Pfizer pills. I know that there are legit concerns about the Merck pill (which Matt lays out above), but how is that we're staring down a potentially catastrophic variant but we haven't even scheduled a review panel for Pfizer?
"Thousands of lives"? I seriously doubt very many lives have been lost because low-risk vaccinated individuals (like me!) were denied the ability to get a booster for a couple months.
It was a bad, overly-conservative, needlessly complicating decision, for sure. But I don't think you can pin very many deaths on it. The people dying are the ones who aren't getting vaccinated in the first place, or very-high-risk folks that had boosters approved for them.
The confusing messages left many vulnerable people unsure of what to do. I don't think it's a stretch to say that a clearer message of "everyone get a booster after 6 months" would have encouraged more boosting among the vulnerable. And even if that weren't the case, there's also the fact that a more robust booster rollout would have slowed the spread considerably during the ongoing Delta wave. Honestly, "thousands" is conservative.
In any event, I think delaying approval of therapeutics is going to be much worse in terms of harm unless Omicron is a lot less pathogenic than Delta. If it causes severe disease at the same rate as Delta, we're going to see people dying in hospital hallways.
“…this would be a perfect job for Kamala Harris. She could be the COVID czar- running around and pushing end runs around these dumb regulatory barriers.”
The woman whose staff says “refuses to wade into briefing materials prepared by staff members”? I mean, really, is she good for anything at all?
Ah, so when you wrote that she could be “running around and pushing end runs around these dumb regulatory barriers” and that “It would be great the country” you were just kidding?
The CDC seems to have a weird inverted pyramid of evidence where “any study conducted by the CDC” is at the top, “double blind study conducted by a fancy drug company” appears somewhere in the middle, and “anything out of Israel or Great Britain” is at the bottom. That’s how we end up with essentially all guidance determined by a couple observational studies of Provincetown Bear Week and some incident in a Marin county school while the high quality studies conducted by nationalised health care systems go seemingly ignored.
It is apparent that large factions of the CDC view themselves as belonging to a disease research organization, not an operational public health organization. There's nothing wrong with having a former, but we have witnessed the consequences of lacking the latter.
There really is something very concerning about how the CDC ranks the quality of evidence. Sometimes I wonder if they are now a marketing agency rather than a scientific organization
There's a really fascinating how-the-other-side-lives angle to this article, somewhat orthogonal to its main thrust.
Away from the Coastal Elites (TM), in my lefty, 85%-of-adults-vaccinated MSA, I've gotten one covid test ever (got violently sick from some bad chicken--practice safe refrigeration, folks!). Regular testing as policy, beyond definite exposure to someone who is confirmed positive, isn't a culture-war flashpoint--it's unheard-of, not discussed as even a theory. Aside from pretending masks matter when we're standing in the restaurant and not when we're sitting, the 'rona is over, and our death rate last month was about 1/100,000.
¯\_(ツ)_/¯
I'm not yet bought into the idea that there's a segment of the population that adopted the pandemic as a part of their identity and refuses to let it go, but I'm no longer able to casually dismiss that idea. The local paper sure has figured out what types of coronavirus get clicks, though. The vaccines "may" offer "somewhat less" protection against a new variant, and other technically-correct weasel language of that nature.
Even among the Coastal Elites (I live within eyesight of a DC Metro station) I've been tested exactly once, and that was just because I was headed to a Thanksgiving event with a lot of old people.
At this point Covid affects my life in that I wear a mask on the Metro and in movie theaters, and that's about it.
My wife is anxious by nature and doesn't feel right going through her day without something to be afraid of. The count of times she has become convinced she has COVID is well into double digits now. At-home tests have been great for us, they've reduced the consequences of psychosomatic COVID from "potential daylong freakout" to "10 minutes and some grumbling about test accuracy."
We've used about 5 at home test kits at this point (might have used more but price and availability is definitely a factor)
3/5 cases:
Kid has sniffles. Almost positive it's not Covid, test anyway. Negative. When one of us then came down with the same thing we didn't bother to test - assumed still not Covid.
1/5 cases:
I came back from a 1500 person indoor convention where everyone signed an affidavit saying they were vaxxed/tested negative and I (other than some dining) always wore a mask and stayed around other masked people - but I was about to visit my family for thanksgiving so I tested myself after I got back. Not perfect timing - if I had caught it at the end of the convention I might not test positive until already at thanksgiving, but I was working with what I had (and everyone at thanksgiving who should be boosted was). Had I tested positive I was going to confirm with the more accurate PCR.
1/5 cases:
My husband felt a bit sick and tested himself as well - similar to kid sniffles.
The tests are tolerable but unpleasant.
If the tests magically dropped on my doorstep every week that's probably how we'd use them - testing it after exposure, or when I did something _particularly_ risky (fly, go to a convention) but testing weekly? Only if everyone else were doing it.
I have free saliva-based tests at work any time I want one. I have taken precisely two since getting vaccinated in April (both negative). I hosted a large Thanksgiving gathering, which included my older parents, and no one got tested beforehand (everyone is vaccinated plus boosted). I agree that broader availability of cheaper (or even free) tests would have been *very* desirable a year ago, but at this point in the pandemic, I agree with Psaki that it's probably a waste of money.
The point Matt is making though is that the market price of tests would be super cheap if more were authorized, so it wouldn't cost the government anything at all.
I curious where you live that the death rate is an order of magnitude lower than for the rest of the United States. According to Our World in Data, there were 34,240 COVID deaths Nov. 7 to Dec. 6. Dividing by the US population of 330 million, that's 10.4 deaths per 100,000.
I took exactly one test voluntarily in extremely Blue Illinois after getting a runny nose the day after seeing a friend is a trainer (would have had huge impact on her business).
I have been tested a bunch of other times though since the pandemic is over for me and I've been traveling a fair amount and various governments are requiring tests to fly.
Having kids is where tests-in-every-home would help. Even wearing masks in school, they occasionally catch a cold and we've been going to get them tested. Seeing MY mention that antigen tests are easily obtained on Amazon, I picked some up (but most folks won't do that since they're $10/test).
I live in a NE sapphire-blue metro and there are definitely some of those types. Unfortunately, they’re loud, like the NIMBYs, and that makes it seem like there are a lot of them.
Chickens always come home to roost. As an old guy I well remember when governments had a hard time finding manufacturers of vaccines at all. The margins were low, even the best produced rare serious and occasionally lethal side effects so the absolutely insane American tort laws made this a very risky business to do. The intelligent thing was done and a kind of insurance pool was created to assist people with the consequences of rare adverse side effects and legal recourse was limited. I note that this was universally excoriated on the left, as was all product liability tort reform. They wanted vaccines but also the power to sue the vaccine manufacturers out of existence.
I will add, as an interesting side point, that before Covid exploded into our world, the largest manufacturer of N95 masks in the United States, 3M, was successfully sued by exactly two coal miners for about thirty million dollars. The theory here being that defective masks resulted in their getting black lung. Do I believe this? Nope. But a jury did.
With regard to test kits for Covid one has to ask, why would any sane manufacturer rush to invest in making tests of dubious reliability (thereby creating a low margin high risk business model) when they are virtually certain to face class action suits related to false positives or false negatives. Is someone planning on addressing this issue? I can't find anyone doing so. And I am willing to bet that various members of the ABA are salivating at the prospects.
Great comment. Also a great example of how America's ancient, creaking constitutional order holds the country back. The US is the only developed country that still does civil trials with a jury deciding the verdict- every other country uses a judge. And why are we the only ones? The 7th Amendment:
"In Suits at common law, where the value in controversy shall exceed twenty dollars, the right of trial by jury shall be preserved, and no fact tried by a jury, shall be otherwise re-examined in any Court of the United States, than according to the rules of the common law."
And we also have the single most difficult-to-alter constitution of almost any democracy, regardless of wealth. Good luck fixing that one!
Are there any good articles or definitive explanation about why the FDA has been so slow to approve covid tests that Europe has? Is it regulatory capture by incumbents who want to jack up prices? Slow bureaucracy, somehow less efficient than European states?
According to former FDA commissioner Scott Gottlieb, it has to do with how self-tests are categorized and the lack of a process to recategorize them. In the American system, they end up stuck in a regulatory slow-lane with attendant costs. Most European countries were able to recategorize them into the "mostly harmless" regulatory bucket, which is why they are cheaper and more available there.
"But is it actually true that the Moderna vaccine is “more effective,” or are they just giving you triple the dose? An ibuprofen gel tab is no more effective than a normal ibuprofen pill, but if you take 3x the dosage of the gel tab that will have a stronger effect."
This is a terrible analogy! It's like observing that pressing down on the gas peddle makes your car go faster, so logically, pouring gasoline all over the engine and lighting on fire will make it go even faster.
Ibuprofen circulates in the bloodstream. It binds receptors (on cyclo-oxygenase) antagonistically, meaning it is inhibitory. The higher the concentration of ibuprofen, the further the equilibrium shifts towards bound ligand-protein, i.e., the greater the effect. Fluvoxamine is an agonist towards a receptor that leads to the up-regulation of a an anti-inflammatory. In both cases, higher doses lead to higher concentrations in the bloodstream, which lead to greater (side)effects.
The Pfizer and Moderna vaccines are suspensions of lipid nanoparticles containing messenger RNA. They are injected locally in to muscle tissue specifically so that they do not enter the blood stream. Their efficacy is unrelated to binding constants; once a strand of m-RNA makes it into the cytoplasm, it is actively transported into the ribosome where its sequence is transcribed into a protein. That protein is then released, but since it is exogenous, the immune system identifies it as such, generates antibodies to attack it and then retains a record of the antibodies for later use. Higher doses may elicit stronger immune responses by producing proteins in more cells (with the upper-bounds being full-blown COVID-19 symptoms), but they might also cause necrosis.
Moreover, the Moderna and Pfizer vaccines encode different sequences, so they are not even producing the same proteins. It could just as easily be the case that higher Pfizer doses would lead to worse immune responses because they interact with antibodies differently from the Moderna-instantiated proteins.
It's easy to armchair quarterback vaccine development and testing with bad analogies, easier still to assume a profit motive behind Pfizer's vaccine schedule. But the reality is that these things are not arbitrary and people far more knowledgeable about mRNA vaccines, epidemiology and clinical trials than any of us were intimately involved in planning and executing the vaccine trials.
I'm not arguing against more testing, but I see stupid analogies like this everywhere, usually in the context of trying to make the CDC or FDA or scientists look lazy or stupid. Worse, this is the same faulty reasoning that is used to attack epidemiology; it is common sense that higher doses work better than lower doses, so clearly there is a conspiracy theory and/or these hacks with their fancy degrees do not know what they are doing.
The pfizer vaccine did in fact show a dose-response between 10 and 20 ug doses, possibly leveling out at 30 ug. They did test 10, 20, and 30 ug doses in a phase I study. Fine, maybe the ibuprofen analogy oversimplifies a bit, but it’s basically true that the vaccines show a dose-response and it’s not unthinkable that the higher dose used in the Moderna vaccine could contribute to its higher efficacy. Also, the regulatory authorities are wrong about the dose-schedule and lots of people pointed this out in real time, so it’s not hindsight.
Yes, but that is what I am saying; you need to study a vaccine to establish a dose-reponse curve, not assume that one exists. Likewise, you cannot base assumptions on "vaccines" because there are many different types with many different methods of action. You cannot base the dose of an mRNA vaccine on that of an attenuated virus. That is why the ibuprofen analogy is just plain wrong. Post-hoc rationalizations based on bad analogies is not how science is done.
"Post-hoc rationalizations based on bad analogies is not how science is done."
No - but its often how science is explained to laypeople. How many classes in school did you take to learn the basics and then get to the higher level class where they tell you that while the previous explanation gave an overall idea of how things work, its actually all wrong in the details.
That is the nut of my beef—simple analogies to help students understand difficult concepts are one thing, but in the specific context of vaccines, they are proliferating on the Internet with high salience.
We are all familiar with the bad-faith version of this phenomenon. But the good-faith efforts to understand and to question—like this post—also contribute to anti-elitism and the denigration of institutions like the CDC that, I think, is ultimately not constructive.
Maybe. Here's the challenge I see: There are numerous things that generalists like Matt and others here/elsewhere think that the FDA/CDC/etc. could be doing better. Unfortunately, I see very little good faith response to those criticisms about why they are wrong, or why the above institutions are focused on other more important priorities. Instead, more often than not there is a retreat behind the curtain of expertise/credentialism. I would hope that most people are open to being informed by experts, but that actually requires experts explaining their actions (and possibly using their very own crummy analogies to do so).
I fully agree that they could have done better, could do better and should improve. But if we are going to criticize them, we need to do so thoughtfully. The reason that analogy irked me is that it is inaccurate and gives a sense that these are easy problems with common sense solutions. That thinking has taken root amongst bad-faith actors and, increasingly, good-faith skeptics and contrarians. The underlying issues are much more complex than “more ibuprofen works better than less” and using logically faulty analogies does nothing to help people understand that complexity. It also feeds the narrative that experts are full of it and any random idiot could do better… that was a successful presidential campaign and I fear that the same mentality is infecting the public perception of science.
I don't think Matt is denying that there could be a relevant difference between Moderna and Pfizer/BioNTech beyond just the dose size. But his point is that there have been precisely 0 studies discussed in any public arena investigating this. If Moderna has studies showing that 50 micrograms is less effective than 100, they should show it! Or even better if they have studies showing that it's equally effective, so that we get twice as many doses! If Pfizer or BioNTech have studies showing that their vaccine won't do any better at 100 micrograms, let them show it!
It's just one person's opinion, so I don't want to put much stock in the question of "right" or "wrong", but it at least shows a fraction of the many key decisions that had to be made with limited support. (as an aside: I was looking to see if anyone's done proteomics to check these questions but didn't find anything yet.)
I know your point is mainly about Matt's use of the analogy, but just to continue your metaphor, if not armchair QB, it's not so crazy to Monday-morning QB a bit and at least ask if there's still more room to optimize some of the decisions made previously, like dosing and spacing.
Hey, I am all for optimization and improvement. But let me play devil's advocate for a moment.
Matt has been a vocal critic of CDC policy that tries to engineer behavior, like saying not to wear masks to head off a run on surgical masks needed by medical professionals. Although it's pretty clear that was a dumb decision, if the CDC starts changing the spacing and/or size of doses, I could see two bad things happening.
First, it would take time for the policy to trickle down to pop-up vaccine clinics and such, so you'd have people on social media saying "hey, look over here, they're spacing my doses differently than yours", which will lead to a deluge of speculation and all the social media bullshit that entails. There is no way that does anything but further polarize people around the "trust the science" issue. Second, and worse, bad-faith opportunists would hold it up as proof that the CDC doesn't know what it is doing because the facile perception that "they would have gotten it right the first time if they actually knew what they were doing" is pervasive.
Now, let's say that the benefits of spacing the Pfizer doses at eight weeks instead of three is a 99% chance in the decrease in the rate of hospitalization; i.e., the effect is very significant. But let's say that the decrease is only 1%; i.e., the effect-size is rather small. At the global population level, that will make a huge difference, but it is trivial at the personal/local level.
If I were a policy-maker at the CDC, would I want to expend resources and risk credibility for a tiny effect on the rate of hospitalization? Or would I rather those resources go towards getting more people vaccinated? The Oxford study Matt linked to is a pre-print, meaning it hasn't even been peer-reviewed. And the Reuters article only discusses antibody levels, which is probably not a great metric for the CDC; they should be concerned about real-world outcomes, not updating their guidelines every time Reuters picks up a story about a preprint. (BTW that is the main reason the CDC trusts their own data more than anything else; they are measuring very specific outcomes in the American population/system.)
Fair points! But a lot hinges on where the improvement falls between 99% and 1%. And I'm not entirely convinced that their credibility is best protected by never deviating from any decision.
I fully agree. The CDC and FDA need some structural reforms to enable them to be more nimble during an emergency, particularly with respect to how they injest and react to emerging data from external sources. But I do think they have to be extremely careful not to seem capricious. It is a sad truth that one of the two major political parties has decided the CDC, FDA and science, in general, are political enemies. There is an entire media ecosystem that will pounce on and amplify any perceived inconsistency as proof of a secret, malicious agenda.
There are probably already snippets of Matt's post, taken out of context, circulating on right-wing social media circles as proof that even the libs think the CDC is incompetent and mendacious. My dad occasionally forwards that stuff to me to debunk when he thinks there is merit to the claims. They do a great job at cherry-picking from legitimate sources and using technical terms (incorrectly) to sound authoritative.
"For example, the folks at Pfizer decided they wanted to test a 30-microgram dose, while Moderna scientists decided to test a 100-microgram dose. We learned from those experiments that 30-micrograms of Pfizer work but 100-micrograms of Moderna work better. But is it actually true that the Moderna vaccine is “more effective,” or are they just giving you triple the dose?"
That's not an apples-to-apples comparison though; they're different vaccines. Drug makers do a lot of calculations to try to predict the proper human dose and then adjust as they start running the trials. For example, you wouldn't assume to take the same amount of acetaminophen or ibuprofen to treat a headache, even though people use those for similar purposes.
For at home rapid testing, I agree in principle that we should be doing for more of that, but this article in the Atlantic gave me pause: https://www.theatlantic.com/health/archive/2021/12/jen-psaki-free-rapid-covid-testing-sarcastic/620925/. Germany and the UK have been doing widespread rapid testing and have still faced large numbers of COVID cases lately. The article does note the objection that perhaps we should be doing even higher levels of testing than they're already doing but then glosses over it without really addressing whether that would make a difference, so I'm not 100% convinced either way on this.
As for molnupiravir, I saw Zeynep Tufecki flagged the potential for viral mutations from non-compliance the other day... not sure how much of concern that is, but it's certainly not zero. But the bigger thing is, Pfizer already demonstrated that Paxlovid is far more effective! It's a protease inhibitor and the mechanism of action (MoA) is such that it should attack all variants of COVID. So there's no need to take the risk on molnupiravir unless someone is going to run a trial for a combination therapy (but molnupiravir is a Merck drug, so the companies would have to iron out the legal details with that).
At some point, as long as people aren't getting sick enough to incur grievous medical costs or die, I won't care what the declared case numbers are. Nobody seems to be articulating an endgame other than "you either got vaccinated or you got sick, and better the former than the latter"--frankly, few seem to be articulating an endgame at all.
If large numbers of people are still getting sick then you are breeding variants. If those people are intermixing with vaccinated people then you are selecting for variants that can pierce vaccines. (There is reason to care if people are getting sick...)
The very nature of coronavirus immunity in humans likely means that we're never getting a vaccine that produces durable sterilizing immunity.
Vaccines aren't the endgame, they just make getting there less painful.
The likely endgame is that *everyone on earth* gets COVID enough times that they develop durable immune memory to the whole constellation of variants and strains, as we see with common colds. We simply don't know what a common cold virus would do to people who have no prior exposure and no inherited or epigenetic immune responses, but at this point it seems someone justifiable to suggest that it would look a lot like COVID.
There are only two reasons why long-established cold viruses would be less dangerous to humans: either the viruses have faced evolutionary pressure to become less virulent/lethal (unlikely) or humans have adapted in some manner to them. Given the length of a human generation and lack of selection pressures, the latter cannot be explained by evolution, only by innate immune responses and epigenetics.
If this hodgepodge of ideas cribbed from various papers is right, then we're going to see the CFR for even new variants go down after a time with no real causal mechanism mooted. But that might take a number of years.
In the meantime, vaccination and preventing local hospital systems from collapse are about it. Other than that, all interventions are pointless if not harmful. Short of the increase in CFR that would come from insufficient ICU capacity, any other move to suppress transmission is just shuffling death around, not stopping it.
The only other option is an eliminationist strategy, which has already failed everywhere except for China. That was always a mirage, IMO, as the developing world lacks the ability to do it even if China and the developed world did, and as China has found, no wall is high enough to avoid regular internal clampdowns when a new strain jumps over it. Even China will have to give up eventually.
I do not believe that we have enough knowledge to _confidently_ declare, "The...nature of coronavirus immunity in humans likely means that we're never getting a vaccine that produces durable sterilizing immunity." If you change "nature of coronavirus immunity" to "politics of human nature," I am fully on board.
On the other hand, I agree fully that your proposed endgame is far and away the most likely scenario and I agree with everything else in your post wholeheartedly as well.
My understanding is that Pfizer and Moderna are really similar enough that it's a valid comparison.
Also, Pfizer has been pretty explicit that they chose a low dose in hopes to minimize side effects, so you're right that they did try to predict what a good dose is --- but they optimized for short-term rather than long term benefit.
There's the additional issue that Pfizer may have chose the dose size for a different vaccine than the one they eventually used. They originally planned to only produce a fragment of the spike protein rather than the whole thing. When they changed course on that, they didn't update the dosage and
"Because the full-length spike’s gene sequence was about five times as long as the fragment’s, each microgram of vaccine contained one-fifth the number of copies. It was immediately obvious that the side effects were less intense as a result, but the antibody response might end up being smaller too. That would take several weeks to assess—and the clock was ticking... Dolsten and Pfizer’s CEO, Albert Bourla, had persuaded the vaccine team to follow Moderna’s lead and advance the full-length sequence, but at Pfizer’s lower dose of 30 micrograms. That would likely give Pfizer’s vaccine a safer profile in terms of side effects. It would also be cheaper and easier to manufacture, though Dolsten said the scientific team didn’t weigh that in its decision."
They are similar in that they both encode parts of the spike protein into messenger RNA. But consider that single-site mutations (which changes a single amino acid in a protein) are responsible for all kinds of horrible diseases, including many forms of cancer.
A less accurate, but more fun analogy is enantiomers that smell completely different from each other. For example, carvone (https://en.wikipedia.org/wiki/Carvone). R-carvone smells like carroway, while L-carvone smells like spearmint. They are compositionally identical; same chemical formula, same connectivity, they just differ on which plane a hydrogen atom sits. They are as identical as two molecules can get without being identical, yet trigger completely different olfactory responses.
Whatever their internal reasoning for choosing a lower dose, I do not think it is productive to second-guess Pfizer's approach to testing a rushed vaccine that billions of people will take within the span of a year. Not to get all slippery-slope, but the end point here is crowd-sourcing optimal vaccine doses with Twitter polls.
"They are similar in that they both encode parts of the spike protein into messenger RNA."
My understanding is that they encode exactly the same part of the spike protein (i.e. the whole thing).
"But consider that single-site mutations..."
Why? They both used the genome provided by the Chinese at the start of the pandemic. They are encoding exactly the same spike protein! That's why they are reasonably comparable!
That's not to say that the vaccines are identical; they're not. But all this talk about how they can't be compared relies mostly on FUD --- not on their actual differences.
"I do not think it is productive to second-guess Pfizer's approach to testing a rushed vaccine that billions of people will take within the span of a year."
So we should just accept their original decision as gospel and not change anything? The fact that they made a rushed decision is all the more reason to reevaluate it it!
They acted fast in 2020, and that's totally understandable, but there's absolutely no way they made an optimal choice. However, we haven't changed anything since then. That's bad. End of story.
Neither vaccine encodes the whole spike protein nor uses the exact sequence. They altered (at least) two amino acids to increase the stability of the folded structure. But that is beside the point. There is a lot of cruft in the mRNA sequence that affects uptake and trasnscription and virtually all of that differs between them. In fact, one key difference is in the region that controls translation initiation. That means that the correlation between dose and the rate of transcription will be different for the two vaccines. Assuming that upping the Pfizer dose to that of Moderna would yield the same effect is like assuming that drinking the same volume of tequilia and beer will get you equally drunk.
The dosing and scheduling was determined in a rushed process and it should be optimized, eventually. But that optimization should be slow, deliberate and conservative because of the simple fact that, after billions of doses, we know that it works and has minimal side-effects. When a new consensus emerges after long-term studies are published and deliberated, the guidelines should shift to that consensus. It is a terrible idea to go monkeying around with the vaccination process to chase every little potential gain because 1) the effect-sizes of these studies are often very small and/or are based on indirect measures like antibody levels and 2) The Law Of Unintended Consequences scales with the population size.
"I do not think it is productive to second-guess Pfizer's approach to testing"
"trust the elites, they know what they're doing" is a very interesting way of operating in the context of these decisions having been made somewhat arbitrarily
That is second-guessing the experts and is what I mean by people "doing their own research". Either you accept that the experts are doing their best and listen to them or you don't. By being irritated that they are not doing things the way you think they should be done, you are implicitly rejecting the very notion of expertise.
I'm not trying to be a jerk or pigeonhole you, but I think that your response typifies a pattern of anti-elitism that is emerging amongst smart, skeptical independent-thinkers. It is a sophisticated mirror-image of the dumb, obtuse Trumpy version.
Matt demonstrated a clear, fundamental lack of understanding of the science of (particularly mRNA) vaccines and pharmacology with his terrible analogy about Ibuprofen. He went on to criticize the CDC for what he sees as their inability to adapt to emerging data and cited a Reuters article about a preprint that is silent on rates of hospitalization to support his assertion. That kind of reckless armchair quarterbacking is not functionally different from those idiot members of Congress comparing Fauci to Nazi scientists.
The government healthcare community picked sides in the culture wars. Once they did that conservatives shut them out. The scientist need to say “I don’t do culture wars, I just do science. I follow facts wherever they lead”. Fauci should step down and Biden should appoint someone who takes this approach. That would be better for the country. Fair or not fair, Fauci is viewed as a partisan.
I don't know if it's fair to Fauci, but that's a good point. I'm not on conservative media but I can easily imagine that "Everybody social distance unless you're protesting for social justice" was credibility killing for many on the right
ANd of course, it turned out that under pre-delta conditions it was entirely possible to do just about anything safely outdoors, and there was plenty of modeling that let us know what the ventilation requirements to approximate those conditions indoors were.
Even after making that massive misstep, they could have redeemed themselves by saying "We were wrong about outdoor activity, so protests and other outdoor events are fine... and also, here's how we learned from the experience and will get schools open in person before January 2021."
Instead, we just got "It turns out we were right about the protests being ok, so fuck off with your criticism."
Can't imagine why that latter messaging was problematic.
I think that also created a feedback loop. The CDC and Fauci started endorsing policies that weren’t supported by science (closing schools for over a year) but were the opposite of what conservatives were pushing for. It has not been good for science
Right. If FDA and CDC read this article today, and are persuaded to immediately adopt its recommendations, is that going to move the needle in the real world, where public officials are actively undermining even a basic vaccination campaign? Even assuming it is correct, this article seems to be straining after fruit at the top of the tree when there's a whole lot at ground level still waiting to be picked. And the reason it hasn't been picked is why this article is kind of beside the point.
If you’re saying that “things at ground level waiting to be picked” is the public officials undermining a vaccine campaign (which at risk of engaging in mud slinging, I think they generally are opposing a mandate), or a portion of the population’s overall reluctance to be vaccinated I would challenge that Matt’s points are actually easier fruit to pick.
I read Matt’s post as “if we isolate on how we can use the population who is willing to do things for the pandemic to help with the pandemic, here’s what the government/ public health agencies can do to help.”
Separate out two things: one, slowing the contagion, ie, preventing more people from getting covid; and two, effectively treating people that did get infected. The first is the only one that's dependent on public behavior, and mass vaccination is overwhelmingly the most effective measure, and the only one that will get us back to normalcy. Tweaking FDA/CDC guidelines a little this way or that isn't the key to solving that problem to the extent it's become a culture war issue (it may not be solvable). On the second, treatment, skilled clinicians don't need FDA or CDC to tell them how to treat patients because they have direct access to the best, most current evidence and treatment protocols; off-label use of FDA approved products is common when there's evidence to support it that for whatever reason hasn't been endorsed by FDA.
"So everyone is following procedure and doing things by the book."
Of course they are. Because if the school does one thing that hasn't been government approved and one child gets sick, they are going to get sued. Until the longer dosing regime is approved by the government, no school or other entity is even going to entertain the thought of doing it differently.
Even if they really, really wanted to go with the best evidence and change the dose timing, their lawyers would advise them not to and get signed statements saying this was our advise and they are acting against our advise.
If you read the SEC filings, earnings conference calls, etc. from Quidel, maker of the QuickVue rapid test and a smaller competitor to Abbott, it is absolutely clear that the limiting factor in Quidel rolling out more tests is production capacity. And on top of that, the US government itself has tied up a lot of Quidel's output with a large DoD contract to buy QuickVue tests. But nowhere is the government subsidizing increases to the production capacity.
Meanwhile, a company like Quidel is beholden to shareholders and cannot reasonably justify building out crisis-level capacity when it may not be needed in 2 or 5 years. At the same time, such capacity - if created with government help - could be an element of a government-led quick-response program for future pandemics.
The contracts specify a one-year period to supply the tests so Quidel needs to have at least that level of annual capacity and could obtain financing for that based on the DoD contract. That capacity would remain once the contract ends. The DoD contract is government help in creating capacity. Whether that capacity is shut down after the contract ends is a different matter
That is fair but it seems short-sighted. Because then the only way to expand the capacity is to tie up that capacity for the first year which is exactly when it's needed most.
I suspect that DoD will not be hoarding its tests to a large degree. if they don't need them for their own personnel, they will distribute them outside DoD, much like PPE and ventilators
Also on masking. LA Public health is still handing out CLOTH masks at vaccine centers, with public health logos on them. This suggests that LA Public Health thinks cloth is just as good as N95 (which is widely available in Los Angeles), which is clearly not the case.
The challenge for the intelligent generalist pundit, like Matt, is to be read up enough on a subject and fast enough to be able to say something interesting and meaningful. The problem is that you don't know as much as the people on the inside and often don't really have the professional background to discern what is a screwup and what is driven by concrete obstacles.
For all I know, the FDA and the CDC have been and continue to screw up in unforgiveable ways (Scott Gottlieb's new book, "Uncontrolled Spread" is very good on this, though I note that he's a lot more unforgiving to the CDC than the FDA, which he had headed). But what I also know from professional experience is that it's often the things you don't know that are really meaningful and can refute what you think is the truth and the path forward. Life is complicated.
An example of this is congestion at the LA/Long Beach port. Bad problem, and people who know very little instantly opined on how to fix it. But as you dig deeper into the details, you realize that we're facing a series of bottlenecks, and each one needs to be resolved sequentially, after doing due diligence. It's usually never "one weird trick."
So Matt may be way off base here -- though none of us is expert or informed enough to know. That said, we need people like Matt out there asking interesting questions and trying to inform the public, even when he doesn't know enough to give us the full truth.
If the people on the inside are consistently incapable of explaining things to intelligent people like Matt then the fault is clearly with them.
The people on the inside have also been saying things that turned out to be wrong/lies all throughout the pandemic, making things even moreso their fault
Well, organizations should always do a better job explaining themselves, but I don't really want them to sit down with every Substacker with 13,000 subscribers to explain in detail what they're doing.
Another issue is with respect to quarantines. It does not seem that the PHA at large have adjusted their quarantine requirement other than to reduce it from 14 to 10 days. Most of this guidance preceded the onset of vaccines.
Here in Ohio, I'm able to stop by the local rec center and pick up a free Binax Now test. They have a weird layer of bureaucracy where the box doesn't include instructions and they want you to use an online proctor, but apparently that is just so that the results can be "officially" used for school, travel, etc. https://coronavirus.ohio.gov/wps/portal/gov/covid-19/resources/general-resources/rapid-covid-19-test
The testing is so maddening. The FDA could say: “we are going to provisionally authorize for sale any test that has been approved by the EU, UK, Japanese or South Korean authorities.” This isn’t thalidomide- the worst possible outcome is somewhat higher error rates. Big deal.
The Biden administration’s passivity on COVID has been so frustrating. There are so many things they could be doing - none of which require approval from Republicans and/or Sinema/Manchin. To pull in another stream from “the discourse” - this would be a perfect job for Kamala Harris. She could be the COVID czar- running around and pushing end runs around these dumb regulatory barriers. It would be great the country and even better for her!
Imagine it- here’s Harris at the FDA announcing that they are now authorizing foreign rapid tests, with the expectation that they will be significantly cheaper. Two weeks later - here’s Harris again at a Walmart, where they have started putting foreign tests on the shelves and they’ll cost $3 each. Here’s Harris at a big research university where they are beginning human challenge trials of a new super-targeted Omicron booster (check out the footage of the super wholesome photogenic young volunteers). Here’s Harris at a Moderna manufacturing plant, 3 weeks later the day after the successful completion of the trial where they are starting up production of the new Omicron booster. Here’s Harris at an airport - at a new TSA lane where travelers can voluntarily prove their vax status and take a rapid test - but then they get a tamper proof bracelet that lets them fly that day without a mask.
There so much they could be doing - every two weeks or so we could see Harris on TV and we’d love seeing her because each time she’d be doing something that is making the pandemic just a little bit easier to deal with.
<sigh> I’ll go back to dreaming again.
Yeah it’s frustrating because it’s actually hard to point to anything Biden has done that has actually been better than the Trump administration on COVID. At least he’s not saying stupid stuff at press conferences, but all the smart ideas that were floating around in the early days of the administration (they were talking about using rapid tests to open schools, I definitely remember it!) seem to have vanished under the weight of the regulatory establishment and Biden seemingly has no appetite for challenging it.
Biden's big announcement thing last week included something about test-to-stay, so maybe that'll get implemented nation-wide eventually
https://www.whitehouse.gov/briefing-room/statements-releases/2021/12/02/fact-sheet-president-biden-announces-new-actions-to-protect-americans-against-the-delta-and-omicron-variants-as-we-battle-covid-19-this-winter/
What? Being unabashedly pro-vaccine was a pretty big difference.
the Dems being competent is less likely than a C list comedian becoming a famous TV dad
no need to run for office. All I need is BBB cutting my taxes with increasing SALT cap
Unfortunately, in our inept political reporting environment, if I register my modest disapproval with the Biden Administration so far, that maps 1:1 onto "ooooo look at this totally gettable moderate who might flip Trump in 2024!". And because reporting and real life has a nasty feedback loop, I need to rah-rah go blue rather than simply say they're not doing a very good job and risk feeding the news cycle.
I think you're overestimating your personal impact on the new cycle.
Radical idea: what if people try to express what they actually think, in as nuanced a manner as they can? And leave tactical positioning to actual public figures?
The Biden admin has been so bad on Covid, mostly because it got rolled by nitwit staffers at the FDA and CDC. We've already lost thousands of lives because the FDA/CDC delayed boosters for all adults. Now it's slow walking the Merck and Pfizer pills. I know that there are legit concerns about the Merck pill (which Matt lays out above), but how is that we're staring down a potentially catastrophic variant but we haven't even scheduled a review panel for Pfizer?
"Thousands of lives"? I seriously doubt very many lives have been lost because low-risk vaccinated individuals (like me!) were denied the ability to get a booster for a couple months.
It was a bad, overly-conservative, needlessly complicating decision, for sure. But I don't think you can pin very many deaths on it. The people dying are the ones who aren't getting vaccinated in the first place, or very-high-risk folks that had boosters approved for them.
The confusing messages left many vulnerable people unsure of what to do. I don't think it's a stretch to say that a clearer message of "everyone get a booster after 6 months" would have encouraged more boosting among the vulnerable. And even if that weren't the case, there's also the fact that a more robust booster rollout would have slowed the spread considerably during the ongoing Delta wave. Honestly, "thousands" is conservative.
In any event, I think delaying approval of therapeutics is going to be much worse in terms of harm unless Omicron is a lot less pathogenic than Delta. If it causes severe disease at the same rate as Delta, we're going to see people dying in hospital hallways.
“…this would be a perfect job for Kamala Harris. She could be the COVID czar- running around and pushing end runs around these dumb regulatory barriers.”
The woman whose staff says “refuses to wade into briefing materials prepared by staff members”? I mean, really, is she good for anything at all?
All she would have to do is stay out of her staff’s way and show up for the photo ops. Hopefully she could pull that off?
Ah, so when you wrote that she could be “running around and pushing end runs around these dumb regulatory barriers” and that “It would be great the country” you were just kidding?
Ken, be polite to your next president now. \s
I treat her with more respect than she has earned.
I just really wanted to see the smoke coming out of your ears. :)
Kamala and/or the White House should hire you
The CDC seems to have a weird inverted pyramid of evidence where “any study conducted by the CDC” is at the top, “double blind study conducted by a fancy drug company” appears somewhere in the middle, and “anything out of Israel or Great Britain” is at the bottom. That’s how we end up with essentially all guidance determined by a couple observational studies of Provincetown Bear Week and some incident in a Marin county school while the high quality studies conducted by nationalised health care systems go seemingly ignored.
It is apparent that large factions of the CDC view themselves as belonging to a disease research organization, not an operational public health organization. There's nothing wrong with having a former, but we have witnessed the consequences of lacking the latter.
There really is something very concerning about how the CDC ranks the quality of evidence. Sometimes I wonder if they are now a marketing agency rather than a scientific organization
There's a really fascinating how-the-other-side-lives angle to this article, somewhat orthogonal to its main thrust.
Away from the Coastal Elites (TM), in my lefty, 85%-of-adults-vaccinated MSA, I've gotten one covid test ever (got violently sick from some bad chicken--practice safe refrigeration, folks!). Regular testing as policy, beyond definite exposure to someone who is confirmed positive, isn't a culture-war flashpoint--it's unheard-of, not discussed as even a theory. Aside from pretending masks matter when we're standing in the restaurant and not when we're sitting, the 'rona is over, and our death rate last month was about 1/100,000.
¯\_(ツ)_/¯
I'm not yet bought into the idea that there's a segment of the population that adopted the pandemic as a part of their identity and refuses to let it go, but I'm no longer able to casually dismiss that idea. The local paper sure has figured out what types of coronavirus get clicks, though. The vaccines "may" offer "somewhat less" protection against a new variant, and other technically-correct weasel language of that nature.
Even among the Coastal Elites (I live within eyesight of a DC Metro station) I've been tested exactly once, and that was just because I was headed to a Thanksgiving event with a lot of old people.
At this point Covid affects my life in that I wear a mask on the Metro and in movie theaters, and that's about it.
Also, to be clear, there's approximately zero enforcement regarding masks on the Metro and in movie theaters.
My wife is anxious by nature and doesn't feel right going through her day without something to be afraid of. The count of times she has become convinced she has COVID is well into double digits now. At-home tests have been great for us, they've reduced the consequences of psychosomatic COVID from "potential daylong freakout" to "10 minutes and some grumbling about test accuracy."
We've used about 5 at home test kits at this point (might have used more but price and availability is definitely a factor)
3/5 cases:
Kid has sniffles. Almost positive it's not Covid, test anyway. Negative. When one of us then came down with the same thing we didn't bother to test - assumed still not Covid.
1/5 cases:
I came back from a 1500 person indoor convention where everyone signed an affidavit saying they were vaxxed/tested negative and I (other than some dining) always wore a mask and stayed around other masked people - but I was about to visit my family for thanksgiving so I tested myself after I got back. Not perfect timing - if I had caught it at the end of the convention I might not test positive until already at thanksgiving, but I was working with what I had (and everyone at thanksgiving who should be boosted was). Had I tested positive I was going to confirm with the more accurate PCR.
1/5 cases:
My husband felt a bit sick and tested himself as well - similar to kid sniffles.
The tests are tolerable but unpleasant.
If the tests magically dropped on my doorstep every week that's probably how we'd use them - testing it after exposure, or when I did something _particularly_ risky (fly, go to a convention) but testing weekly? Only if everyone else were doing it.
I have free saliva-based tests at work any time I want one. I have taken precisely two since getting vaccinated in April (both negative). I hosted a large Thanksgiving gathering, which included my older parents, and no one got tested beforehand (everyone is vaccinated plus boosted). I agree that broader availability of cheaper (or even free) tests would have been *very* desirable a year ago, but at this point in the pandemic, I agree with Psaki that it's probably a waste of money.
The point Matt is making though is that the market price of tests would be super cheap if more were authorized, so it wouldn't cost the government anything at all.
I curious where you live that the death rate is an order of magnitude lower than for the rest of the United States. According to Our World in Data, there were 34,240 COVID deaths Nov. 7 to Dec. 6. Dividing by the US population of 330 million, that's 10.4 deaths per 100,000.
I live in the land of not-enough-coffee-to-comment-yet.
With reporting delays (related: WTF?), Dane County, WI is up to 11 November deaths on a population about 560,000. Last I'd looked, I think it was 7.
https://publichealthmdc.com/coronavirus/dashboard
We have to divide the US into two countries: one vaccinated (Dane County being a rough approximation) and one unvaccinated.
Nope, not enough data, according to the CDC.
Our breakthrough infection reporting is... two months? behind at this point?
Can't do it.
I took exactly one test voluntarily in extremely Blue Illinois after getting a runny nose the day after seeing a friend is a trainer (would have had huge impact on her business).
I have been tested a bunch of other times though since the pandemic is over for me and I've been traveling a fair amount and various governments are requiring tests to fly.
Ooops - make that voluntarily twice. I took the Abbott test that time I caught COVID attending a wedding after being double vaxxed.
Having kids is where tests-in-every-home would help. Even wearing masks in school, they occasionally catch a cold and we've been going to get them tested. Seeing MY mention that antigen tests are easily obtained on Amazon, I picked some up (but most folks won't do that since they're $10/test).
I live in a NE sapphire-blue metro and there are definitely some of those types. Unfortunately, they’re loud, like the NIMBYs, and that makes it seem like there are a lot of them.
Chickens always come home to roost. As an old guy I well remember when governments had a hard time finding manufacturers of vaccines at all. The margins were low, even the best produced rare serious and occasionally lethal side effects so the absolutely insane American tort laws made this a very risky business to do. The intelligent thing was done and a kind of insurance pool was created to assist people with the consequences of rare adverse side effects and legal recourse was limited. I note that this was universally excoriated on the left, as was all product liability tort reform. They wanted vaccines but also the power to sue the vaccine manufacturers out of existence.
I will add, as an interesting side point, that before Covid exploded into our world, the largest manufacturer of N95 masks in the United States, 3M, was successfully sued by exactly two coal miners for about thirty million dollars. The theory here being that defective masks resulted in their getting black lung. Do I believe this? Nope. But a jury did.
With regard to test kits for Covid one has to ask, why would any sane manufacturer rush to invest in making tests of dubious reliability (thereby creating a low margin high risk business model) when they are virtually certain to face class action suits related to false positives or false negatives. Is someone planning on addressing this issue? I can't find anyone doing so. And I am willing to bet that various members of the ABA are salivating at the prospects.
Great comment. Also a great example of how America's ancient, creaking constitutional order holds the country back. The US is the only developed country that still does civil trials with a jury deciding the verdict- every other country uses a judge. And why are we the only ones? The 7th Amendment:
"In Suits at common law, where the value in controversy shall exceed twenty dollars, the right of trial by jury shall be preserved, and no fact tried by a jury, shall be otherwise re-examined in any Court of the United States, than according to the rules of the common law."
And we also have the single most difficult-to-alter constitution of almost any democracy, regardless of wealth. Good luck fixing that one!
Are there any good articles or definitive explanation about why the FDA has been so slow to approve covid tests that Europe has? Is it regulatory capture by incumbents who want to jack up prices? Slow bureaucracy, somehow less efficient than European states?
According to former FDA commissioner Scott Gottlieb, it has to do with how self-tests are categorized and the lack of a process to recategorize them. In the American system, they end up stuck in a regulatory slow-lane with attendant costs. Most European countries were able to recategorize them into the "mostly harmless" regulatory bucket, which is why they are cheaper and more available there.
He explained it in on a podcast:
https://www.kcrw.com/news/shows/left-right-center/uncontrolled-spread
"But is it actually true that the Moderna vaccine is “more effective,” or are they just giving you triple the dose? An ibuprofen gel tab is no more effective than a normal ibuprofen pill, but if you take 3x the dosage of the gel tab that will have a stronger effect."
This is a terrible analogy! It's like observing that pressing down on the gas peddle makes your car go faster, so logically, pouring gasoline all over the engine and lighting on fire will make it go even faster.
Ibuprofen circulates in the bloodstream. It binds receptors (on cyclo-oxygenase) antagonistically, meaning it is inhibitory. The higher the concentration of ibuprofen, the further the equilibrium shifts towards bound ligand-protein, i.e., the greater the effect. Fluvoxamine is an agonist towards a receptor that leads to the up-regulation of a an anti-inflammatory. In both cases, higher doses lead to higher concentrations in the bloodstream, which lead to greater (side)effects.
The Pfizer and Moderna vaccines are suspensions of lipid nanoparticles containing messenger RNA. They are injected locally in to muscle tissue specifically so that they do not enter the blood stream. Their efficacy is unrelated to binding constants; once a strand of m-RNA makes it into the cytoplasm, it is actively transported into the ribosome where its sequence is transcribed into a protein. That protein is then released, but since it is exogenous, the immune system identifies it as such, generates antibodies to attack it and then retains a record of the antibodies for later use. Higher doses may elicit stronger immune responses by producing proteins in more cells (with the upper-bounds being full-blown COVID-19 symptoms), but they might also cause necrosis.
Moreover, the Moderna and Pfizer vaccines encode different sequences, so they are not even producing the same proteins. It could just as easily be the case that higher Pfizer doses would lead to worse immune responses because they interact with antibodies differently from the Moderna-instantiated proteins.
It's easy to armchair quarterback vaccine development and testing with bad analogies, easier still to assume a profit motive behind Pfizer's vaccine schedule. But the reality is that these things are not arbitrary and people far more knowledgeable about mRNA vaccines, epidemiology and clinical trials than any of us were intimately involved in planning and executing the vaccine trials.
I'm not arguing against more testing, but I see stupid analogies like this everywhere, usually in the context of trying to make the CDC or FDA or scientists look lazy or stupid. Worse, this is the same faulty reasoning that is used to attack epidemiology; it is common sense that higher doses work better than lower doses, so clearly there is a conspiracy theory and/or these hacks with their fancy degrees do not know what they are doing.
The pfizer vaccine did in fact show a dose-response between 10 and 20 ug doses, possibly leveling out at 30 ug. They did test 10, 20, and 30 ug doses in a phase I study. Fine, maybe the ibuprofen analogy oversimplifies a bit, but it’s basically true that the vaccines show a dose-response and it’s not unthinkable that the higher dose used in the Moderna vaccine could contribute to its higher efficacy. Also, the regulatory authorities are wrong about the dose-schedule and lots of people pointed this out in real time, so it’s not hindsight.
Reference:
https://www.medrxiv.org/content/10.1101/2020.08.17.20176651v2.full-text
Yes, but that is what I am saying; you need to study a vaccine to establish a dose-reponse curve, not assume that one exists. Likewise, you cannot base assumptions on "vaccines" because there are many different types with many different methods of action. You cannot base the dose of an mRNA vaccine on that of an attenuated virus. That is why the ibuprofen analogy is just plain wrong. Post-hoc rationalizations based on bad analogies is not how science is done.
"Post-hoc rationalizations based on bad analogies is not how science is done."
No - but its often how science is explained to laypeople. How many classes in school did you take to learn the basics and then get to the higher level class where they tell you that while the previous explanation gave an overall idea of how things work, its actually all wrong in the details.
That is the nut of my beef—simple analogies to help students understand difficult concepts are one thing, but in the specific context of vaccines, they are proliferating on the Internet with high salience.
We are all familiar with the bad-faith version of this phenomenon. But the good-faith efforts to understand and to question—like this post—also contribute to anti-elitism and the denigration of institutions like the CDC that, I think, is ultimately not constructive.
Maybe. Here's the challenge I see: There are numerous things that generalists like Matt and others here/elsewhere think that the FDA/CDC/etc. could be doing better. Unfortunately, I see very little good faith response to those criticisms about why they are wrong, or why the above institutions are focused on other more important priorities. Instead, more often than not there is a retreat behind the curtain of expertise/credentialism. I would hope that most people are open to being informed by experts, but that actually requires experts explaining their actions (and possibly using their very own crummy analogies to do so).
I fully agree that they could have done better, could do better and should improve. But if we are going to criticize them, we need to do so thoughtfully. The reason that analogy irked me is that it is inaccurate and gives a sense that these are easy problems with common sense solutions. That thinking has taken root amongst bad-faith actors and, increasingly, good-faith skeptics and contrarians. The underlying issues are much more complex than “more ibuprofen works better than less” and using logically faulty analogies does nothing to help people understand that complexity. It also feeds the narrative that experts are full of it and any random idiot could do better… that was a successful presidential campaign and I fear that the same mentality is infecting the public perception of science.
I don't think Matt is denying that there could be a relevant difference between Moderna and Pfizer/BioNTech beyond just the dose size. But his point is that there have been precisely 0 studies discussed in any public arena investigating this. If Moderna has studies showing that 50 micrograms is less effective than 100, they should show it! Or even better if they have studies showing that it's equally effective, so that we get twice as many doses! If Pfizer or BioNTech have studies showing that their vaccine won't do any better at 100 micrograms, let them show it!
I think it was Ken in MIA who posted this interesting paper last week (apologies if I misremembered): https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310186/
It's just one person's opinion, so I don't want to put much stock in the question of "right" or "wrong", but it at least shows a fraction of the many key decisions that had to be made with limited support. (as an aside: I was looking to see if anyone's done proteomics to check these questions but didn't find anything yet.)
I know your point is mainly about Matt's use of the analogy, but just to continue your metaphor, if not armchair QB, it's not so crazy to Monday-morning QB a bit and at least ask if there's still more room to optimize some of the decisions made previously, like dosing and spacing.
Hey, I am all for optimization and improvement. But let me play devil's advocate for a moment.
Matt has been a vocal critic of CDC policy that tries to engineer behavior, like saying not to wear masks to head off a run on surgical masks needed by medical professionals. Although it's pretty clear that was a dumb decision, if the CDC starts changing the spacing and/or size of doses, I could see two bad things happening.
First, it would take time for the policy to trickle down to pop-up vaccine clinics and such, so you'd have people on social media saying "hey, look over here, they're spacing my doses differently than yours", which will lead to a deluge of speculation and all the social media bullshit that entails. There is no way that does anything but further polarize people around the "trust the science" issue. Second, and worse, bad-faith opportunists would hold it up as proof that the CDC doesn't know what it is doing because the facile perception that "they would have gotten it right the first time if they actually knew what they were doing" is pervasive.
Now, let's say that the benefits of spacing the Pfizer doses at eight weeks instead of three is a 99% chance in the decrease in the rate of hospitalization; i.e., the effect is very significant. But let's say that the decrease is only 1%; i.e., the effect-size is rather small. At the global population level, that will make a huge difference, but it is trivial at the personal/local level.
If I were a policy-maker at the CDC, would I want to expend resources and risk credibility for a tiny effect on the rate of hospitalization? Or would I rather those resources go towards getting more people vaccinated? The Oxford study Matt linked to is a pre-print, meaning it hasn't even been peer-reviewed. And the Reuters article only discusses antibody levels, which is probably not a great metric for the CDC; they should be concerned about real-world outcomes, not updating their guidelines every time Reuters picks up a story about a preprint. (BTW that is the main reason the CDC trusts their own data more than anything else; they are measuring very specific outcomes in the American population/system.)
Fair points! But a lot hinges on where the improvement falls between 99% and 1%. And I'm not entirely convinced that their credibility is best protected by never deviating from any decision.
I fully agree. The CDC and FDA need some structural reforms to enable them to be more nimble during an emergency, particularly with respect to how they injest and react to emerging data from external sources. But I do think they have to be extremely careful not to seem capricious. It is a sad truth that one of the two major political parties has decided the CDC, FDA and science, in general, are political enemies. There is an entire media ecosystem that will pounce on and amplify any perceived inconsistency as proof of a secret, malicious agenda.
There are probably already snippets of Matt's post, taken out of context, circulating on right-wing social media circles as proof that even the libs think the CDC is incompetent and mendacious. My dad occasionally forwards that stuff to me to debunk when he thinks there is merit to the claims. They do a great job at cherry-picking from legitimate sources and using technical terms (incorrectly) to sound authoritative.
"For example, the folks at Pfizer decided they wanted to test a 30-microgram dose, while Moderna scientists decided to test a 100-microgram dose. We learned from those experiments that 30-micrograms of Pfizer work but 100-micrograms of Moderna work better. But is it actually true that the Moderna vaccine is “more effective,” or are they just giving you triple the dose?"
That's not an apples-to-apples comparison though; they're different vaccines. Drug makers do a lot of calculations to try to predict the proper human dose and then adjust as they start running the trials. For example, you wouldn't assume to take the same amount of acetaminophen or ibuprofen to treat a headache, even though people use those for similar purposes.
For at home rapid testing, I agree in principle that we should be doing for more of that, but this article in the Atlantic gave me pause: https://www.theatlantic.com/health/archive/2021/12/jen-psaki-free-rapid-covid-testing-sarcastic/620925/. Germany and the UK have been doing widespread rapid testing and have still faced large numbers of COVID cases lately. The article does note the objection that perhaps we should be doing even higher levels of testing than they're already doing but then glosses over it without really addressing whether that would make a difference, so I'm not 100% convinced either way on this.
As for molnupiravir, I saw Zeynep Tufecki flagged the potential for viral mutations from non-compliance the other day... not sure how much of concern that is, but it's certainly not zero. But the bigger thing is, Pfizer already demonstrated that Paxlovid is far more effective! It's a protease inhibitor and the mechanism of action (MoA) is such that it should attack all variants of COVID. So there's no need to take the risk on molnupiravir unless someone is going to run a trial for a combination therapy (but molnupiravir is a Merck drug, so the companies would have to iron out the legal details with that).
At some point, as long as people aren't getting sick enough to incur grievous medical costs or die, I won't care what the declared case numbers are. Nobody seems to be articulating an endgame other than "you either got vaccinated or you got sick, and better the former than the latter"--frankly, few seem to be articulating an endgame at all.
If large numbers of people are still getting sick then you are breeding variants. If those people are intermixing with vaccinated people then you are selecting for variants that can pierce vaccines. (There is reason to care if people are getting sick...)
The very nature of coronavirus immunity in humans likely means that we're never getting a vaccine that produces durable sterilizing immunity.
Vaccines aren't the endgame, they just make getting there less painful.
The likely endgame is that *everyone on earth* gets COVID enough times that they develop durable immune memory to the whole constellation of variants and strains, as we see with common colds. We simply don't know what a common cold virus would do to people who have no prior exposure and no inherited or epigenetic immune responses, but at this point it seems someone justifiable to suggest that it would look a lot like COVID.
There are only two reasons why long-established cold viruses would be less dangerous to humans: either the viruses have faced evolutionary pressure to become less virulent/lethal (unlikely) or humans have adapted in some manner to them. Given the length of a human generation and lack of selection pressures, the latter cannot be explained by evolution, only by innate immune responses and epigenetics.
If this hodgepodge of ideas cribbed from various papers is right, then we're going to see the CFR for even new variants go down after a time with no real causal mechanism mooted. But that might take a number of years.
In the meantime, vaccination and preventing local hospital systems from collapse are about it. Other than that, all interventions are pointless if not harmful. Short of the increase in CFR that would come from insufficient ICU capacity, any other move to suppress transmission is just shuffling death around, not stopping it.
The only other option is an eliminationist strategy, which has already failed everywhere except for China. That was always a mirage, IMO, as the developing world lacks the ability to do it even if China and the developed world did, and as China has found, no wall is high enough to avoid regular internal clampdowns when a new strain jumps over it. Even China will have to give up eventually.
I do not believe that we have enough knowledge to _confidently_ declare, "The...nature of coronavirus immunity in humans likely means that we're never getting a vaccine that produces durable sterilizing immunity." If you change "nature of coronavirus immunity" to "politics of human nature," I am fully on board.
On the other hand, I agree fully that your proposed endgame is far and away the most likely scenario and I agree with everything else in your post wholeheartedly as well.
True, a bit bold.
"Our current understanding of coronavirus immunity in humans" perhaps.
My understanding is that Pfizer and Moderna are really similar enough that it's a valid comparison.
Also, Pfizer has been pretty explicit that they chose a low dose in hopes to minimize side effects, so you're right that they did try to predict what a good dose is --- but they optimized for short-term rather than long term benefit.
https://www.businessinsider.com/pfizer-lower-dose-moderna-covid-19-vaccine-fewer-side-effects-2021-9
There's the additional issue that Pfizer may have chose the dose size for a different vaccine than the one they eventually used. They originally planned to only produce a fragment of the spike protein rather than the whole thing. When they changed course on that, they didn't update the dosage and
"Because the full-length spike’s gene sequence was about five times as long as the fragment’s, each microgram of vaccine contained one-fifth the number of copies. It was immediately obvious that the side effects were less intense as a result, but the antibody response might end up being smaller too. That would take several weeks to assess—and the clock was ticking... Dolsten and Pfizer’s CEO, Albert Bourla, had persuaded the vaccine team to follow Moderna’s lead and advance the full-length sequence, but at Pfizer’s lower dose of 30 micrograms. That would likely give Pfizer’s vaccine a safer profile in terms of side effects. It would also be cheaper and easier to manufacture, though Dolsten said the scientific team didn’t weigh that in its decision."
https://www.theatlantic.com/health/archive/2021/10/pfizer-won-vaccine-race-was-there-downside/620276/
In other words, there is a good case to be made that Pfizer skimped on the dose size and the reduced efficiency is due to that.
They are similar in that they both encode parts of the spike protein into messenger RNA. But consider that single-site mutations (which changes a single amino acid in a protein) are responsible for all kinds of horrible diseases, including many forms of cancer.
A less accurate, but more fun analogy is enantiomers that smell completely different from each other. For example, carvone (https://en.wikipedia.org/wiki/Carvone). R-carvone smells like carroway, while L-carvone smells like spearmint. They are compositionally identical; same chemical formula, same connectivity, they just differ on which plane a hydrogen atom sits. They are as identical as two molecules can get without being identical, yet trigger completely different olfactory responses.
Whatever their internal reasoning for choosing a lower dose, I do not think it is productive to second-guess Pfizer's approach to testing a rushed vaccine that billions of people will take within the span of a year. Not to get all slippery-slope, but the end point here is crowd-sourcing optimal vaccine doses with Twitter polls.
"They are similar in that they both encode parts of the spike protein into messenger RNA."
My understanding is that they encode exactly the same part of the spike protein (i.e. the whole thing).
"But consider that single-site mutations..."
Why? They both used the genome provided by the Chinese at the start of the pandemic. They are encoding exactly the same spike protein! That's why they are reasonably comparable!
That's not to say that the vaccines are identical; they're not. But all this talk about how they can't be compared relies mostly on FUD --- not on their actual differences.
"I do not think it is productive to second-guess Pfizer's approach to testing a rushed vaccine that billions of people will take within the span of a year."
So we should just accept their original decision as gospel and not change anything? The fact that they made a rushed decision is all the more reason to reevaluate it it!
They acted fast in 2020, and that's totally understandable, but there's absolutely no way they made an optimal choice. However, we haven't changed anything since then. That's bad. End of story.
Neither vaccine encodes the whole spike protein nor uses the exact sequence. They altered (at least) two amino acids to increase the stability of the folded structure. But that is beside the point. There is a lot of cruft in the mRNA sequence that affects uptake and trasnscription and virtually all of that differs between them. In fact, one key difference is in the region that controls translation initiation. That means that the correlation between dose and the rate of transcription will be different for the two vaccines. Assuming that upping the Pfizer dose to that of Moderna would yield the same effect is like assuming that drinking the same volume of tequilia and beer will get you equally drunk.
The dosing and scheduling was determined in a rushed process and it should be optimized, eventually. But that optimization should be slow, deliberate and conservative because of the simple fact that, after billions of doses, we know that it works and has minimal side-effects. When a new consensus emerges after long-term studies are published and deliberated, the guidelines should shift to that consensus. It is a terrible idea to go monkeying around with the vaccination process to chase every little potential gain because 1) the effect-sizes of these studies are often very small and/or are based on indirect measures like antibody levels and 2) The Law Of Unintended Consequences scales with the population size.
"I do not think it is productive to second-guess Pfizer's approach to testing"
"trust the elites, they know what they're doing" is a very interesting way of operating in the context of these decisions having been made somewhat arbitrarily
…by experts forced to do so in response to an emergency.
What’s the alternative? Let people “do their own research”? Have Congress vote on it? Ask your favorite social media influencer?
I'm not faulting them for making arbitrary decisions. I'm faulting them for being slow to adjust guidance when new information becomes available.
That is second-guessing the experts and is what I mean by people "doing their own research". Either you accept that the experts are doing their best and listen to them or you don't. By being irritated that they are not doing things the way you think they should be done, you are implicitly rejecting the very notion of expertise.
I'm not trying to be a jerk or pigeonhole you, but I think that your response typifies a pattern of anti-elitism that is emerging amongst smart, skeptical independent-thinkers. It is a sophisticated mirror-image of the dumb, obtuse Trumpy version.
Matt demonstrated a clear, fundamental lack of understanding of the science of (particularly mRNA) vaccines and pharmacology with his terrible analogy about Ibuprofen. He went on to criticize the CDC for what he sees as their inability to adapt to emerging data and cited a Reuters article about a preprint that is silent on rates of hospitalization to support his assertion. That kind of reckless armchair quarterbacking is not functionally different from those idiot members of Congress comparing Fauci to Nazi scientists.
The government healthcare community picked sides in the culture wars. Once they did that conservatives shut them out. The scientist need to say “I don’t do culture wars, I just do science. I follow facts wherever they lead”. Fauci should step down and Biden should appoint someone who takes this approach. That would be better for the country. Fair or not fair, Fauci is viewed as a partisan.
I don't know if it's fair to Fauci, but that's a good point. I'm not on conservative media but I can easily imagine that "Everybody social distance unless you're protesting for social justice" was credibility killing for many on the right
ANd of course, it turned out that under pre-delta conditions it was entirely possible to do just about anything safely outdoors, and there was plenty of modeling that let us know what the ventilation requirements to approximate those conditions indoors were.
Even after making that massive misstep, they could have redeemed themselves by saying "We were wrong about outdoor activity, so protests and other outdoor events are fine... and also, here's how we learned from the experience and will get schools open in person before January 2021."
Instead, we just got "It turns out we were right about the protests being ok, so fuck off with your criticism."
Can't imagine why that latter messaging was problematic.
I think that also created a feedback loop. The CDC and Fauci started endorsing policies that weren’t supported by science (closing schools for over a year) but were the opposite of what conservatives were pushing for. It has not been good for science
Welcome to American public "discourse:"
All culture war, all the time. Every facet of life is a new front in the culture war.
Right. If FDA and CDC read this article today, and are persuaded to immediately adopt its recommendations, is that going to move the needle in the real world, where public officials are actively undermining even a basic vaccination campaign? Even assuming it is correct, this article seems to be straining after fruit at the top of the tree when there's a whole lot at ground level still waiting to be picked. And the reason it hasn't been picked is why this article is kind of beside the point.
If you’re saying that “things at ground level waiting to be picked” is the public officials undermining a vaccine campaign (which at risk of engaging in mud slinging, I think they generally are opposing a mandate), or a portion of the population’s overall reluctance to be vaccinated I would challenge that Matt’s points are actually easier fruit to pick.
I read Matt’s post as “if we isolate on how we can use the population who is willing to do things for the pandemic to help with the pandemic, here’s what the government/ public health agencies can do to help.”
Separate out two things: one, slowing the contagion, ie, preventing more people from getting covid; and two, effectively treating people that did get infected. The first is the only one that's dependent on public behavior, and mass vaccination is overwhelmingly the most effective measure, and the only one that will get us back to normalcy. Tweaking FDA/CDC guidelines a little this way or that isn't the key to solving that problem to the extent it's become a culture war issue (it may not be solvable). On the second, treatment, skilled clinicians don't need FDA or CDC to tell them how to treat patients because they have direct access to the best, most current evidence and treatment protocols; off-label use of FDA approved products is common when there's evidence to support it that for whatever reason hasn't been endorsed by FDA.
What are some of those things at ground level waiting to be picked?
Are you suggesting it'd be easy to get public officials to stop undermining the vaccination campaign?
"So everyone is following procedure and doing things by the book."
Of course they are. Because if the school does one thing that hasn't been government approved and one child gets sick, they are going to get sued. Until the longer dosing regime is approved by the government, no school or other entity is even going to entertain the thought of doing it differently.
Even if they really, really wanted to go with the best evidence and change the dose timing, their lawyers would advise them not to and get signed statements saying this was our advise and they are acting against our advise.
It is a giant CYA.
If you read the SEC filings, earnings conference calls, etc. from Quidel, maker of the QuickVue rapid test and a smaller competitor to Abbott, it is absolutely clear that the limiting factor in Quidel rolling out more tests is production capacity. And on top of that, the US government itself has tied up a lot of Quidel's output with a large DoD contract to buy QuickVue tests. But nowhere is the government subsidizing increases to the production capacity.
Meanwhile, a company like Quidel is beholden to shareholders and cannot reasonably justify building out crisis-level capacity when it may not be needed in 2 or 5 years. At the same time, such capacity - if created with government help - could be an element of a government-led quick-response program for future pandemics.
Here's some detail on the DoD contracts: https://www.nsmedicaldevices.com/news/four-firms-win-647m-contracts-from-us-dod-to-supply-covid-19-test-kits/
The contracts specify a one-year period to supply the tests so Quidel needs to have at least that level of annual capacity and could obtain financing for that based on the DoD contract. That capacity would remain once the contract ends. The DoD contract is government help in creating capacity. Whether that capacity is shut down after the contract ends is a different matter
That is fair but it seems short-sighted. Because then the only way to expand the capacity is to tie up that capacity for the first year which is exactly when it's needed most.
I suspect that DoD will not be hoarding its tests to a large degree. if they don't need them for their own personnel, they will distribute them outside DoD, much like PPE and ventilators
It's SOP for the military to hoard stuff
Also on masking. LA Public health is still handing out CLOTH masks at vaccine centers, with public health logos on them. This suggests that LA Public Health thinks cloth is just as good as N95 (which is widely available in Los Angeles), which is clearly not the case.
The challenge for the intelligent generalist pundit, like Matt, is to be read up enough on a subject and fast enough to be able to say something interesting and meaningful. The problem is that you don't know as much as the people on the inside and often don't really have the professional background to discern what is a screwup and what is driven by concrete obstacles.
For all I know, the FDA and the CDC have been and continue to screw up in unforgiveable ways (Scott Gottlieb's new book, "Uncontrolled Spread" is very good on this, though I note that he's a lot more unforgiving to the CDC than the FDA, which he had headed). But what I also know from professional experience is that it's often the things you don't know that are really meaningful and can refute what you think is the truth and the path forward. Life is complicated.
An example of this is congestion at the LA/Long Beach port. Bad problem, and people who know very little instantly opined on how to fix it. But as you dig deeper into the details, you realize that we're facing a series of bottlenecks, and each one needs to be resolved sequentially, after doing due diligence. It's usually never "one weird trick."
So Matt may be way off base here -- though none of us is expert or informed enough to know. That said, we need people like Matt out there asking interesting questions and trying to inform the public, even when he doesn't know enough to give us the full truth.
If the people on the inside are consistently incapable of explaining things to intelligent people like Matt then the fault is clearly with them.
The people on the inside have also been saying things that turned out to be wrong/lies all throughout the pandemic, making things even moreso their fault
Well, organizations should always do a better job explaining themselves, but I don't really want them to sit down with every Substacker with 13,000 subscribers to explain in detail what they're doing.
No offense to Matt, of course.
Looking at Publix discourse at this point, I’m unsure whether we’re supposed to follow the science, or Follow The Science (TM).
These are two very different things.
Another issue is with respect to quarantines. It does not seem that the PHA at large have adjusted their quarantine requirement other than to reduce it from 14 to 10 days. Most of this guidance preceded the onset of vaccines.
https://www.theatlantic.com/science/archive/2021/12/fully-vaccinated-covid-isolation-breakthrough-transmission/620919/
Here in Ohio, I'm able to stop by the local rec center and pick up a free Binax Now test. They have a weird layer of bureaucracy where the box doesn't include instructions and they want you to use an online proctor, but apparently that is just so that the results can be "officially" used for school, travel, etc. https://coronavirus.ohio.gov/wps/portal/gov/covid-19/resources/general-resources/rapid-covid-19-test