In this thread, none of the comments seem to note a key issue here as stated in the FDA post: "Those participants who did not receive two vaccine doses at either a three-or four-week interval were generally only followed for a short period of time, such that we cannot conclude anything definitive about the depth or duration of protection after a single dose of vaccine from the single dose percentages reported by the companies. "
In other words, we basically have NO DATA on single dose schedules for Moderna/Pfizer vaccines. There's too few of them anyway to gain any statistically meaningful insight even if we did follow up on these study participant washouts. This is hydroxychloroquine all over again. When you are looking at inadequate data, you can find all sorts of patterns. It is very rare that such patterns turn out to be real. The most reasonable approach is to assume that there is little to no durable protection from a single dose, just like most prime/boost vaccines.
"No data" is wildly incorrect. We have priors from other vaccines and vaccine candidates, and the data from these trials. All data about the first dose suggests strongly that 1 dose provides very strong protection against severe disease, and solid protection against mild disease.
Most vaccines have increased efficacy when spreading out the doses, so the same is likely true here, which means this is most likely to increase efficacy.
We don't have data on lots of things, like what if we vaccinated people in cars instead of indoors? We can't run RCTs for everything in this world.
People are also not advocating for 1 dose only, rather spreading the doses out more to get more people vaccinated faster.
1 dose first, followed by another 12 weeks later is almost certainly going to be highly effective and it's almost certainly going to be safe.
This is also not a binary decision. To let you to 10M people try this regime while watching the data has as close to "only upside" as you can get in medicine.
If the FDA approved Astrazeneca now, and the states focused on getting first doses, we could be done with this pandemic in like 45 days. It's worth taking a tiny amount of risk that this group of 10M might not have effective immunity and need to be revaccinated.
EUA means Emergency Use Authorization. Emergency, yes, that's what Covid is. As such, leadership means taking some calculated risks. What FDA essentially does is "you can't get fired for buying IBM". They stick to "we don't have any data for this and that", "this is what the science shows", and people out there are dying. A perfect demonstration of lack of leadership.
It does provide protection, but what we don't know is:
1) For how long
2) How it impacts future vaccination efforts
(As well as a slew of other things)
If it was just #1, I'd be with you. If we give a big chunk of the population a vaccine which lasts 6 months and makes them unimmunizable, we've changed a serious problem into a serious, serious problem.
One mechanism: If you have a vaccine designed to deliver a spike protein (without a virus) surrounded by a carrier. The body learns to destroy the carrier. On future doses, the body recognizes the carrier, and the vaccine is destroyed before the body can react.
Of course, a vaccine with a different carrier won't be affected by this mechanisms, but there are many other mechanisms as well. I'm not an expert, and I don't know all of them. I'm not sure science knows all of them either, for that matter.
There have even been instances of vaccines making diseases worse too (actually, viruses not too dissimilar to COVID19). And there are a bunch of other possibilities.
I'd buy the basic premise of giving each person one dose for giving everyone imperfect immunity if not for these sorts of complications. I'd rather just wait a few more months than risk a small (but definitely non-zero) chance of something really, really bad.
> The most reasonable approach is to assume that there is little to no durable protection from a single dose
How is that the most reasonable approach? Virtually every vaccine ever discovered provides more immunity on first dose, than the incremental gain on subsequent boosters.
You certainly can't be sure of this, but pre-existing evidence would strongly suggest that this vaccine is subject to the law of diminishing returns. At the end of the day, we're just trying to maximize infections prevented. If the two-dose schedule confers 95% immunity, then as long as we expect over 50% immunity from a single dose, then First Dose First is best policy.
We have no data for mRNA vaccines except those trials. We don't know if the historical data on traditional vaccines are applicable here. As such, it is also possible that a single dose isn't good enough or a single dose is good enough but only for a couple months. We just don't know and it would be way worse if it turns out we have to re-vaccinate everyone because we were impatient.
> We have no data for mRNA vaccines except those trials. We don't know if the historical data on traditional vaccines are applicable here.
This is not how decision making under uncertainty works. When you don't have rigorous proof of whether something works or doesn't work you have to make educated guesses based on various priors and make the percentage play. You can't refuse to incorporate priors into your decision making just because you don't have a peer reviewed p<0.05 study validating it.
Uncertainty about the result cuts both ways. You can't claim that we can't do X over Y because we don't have rigorous proof that X is better than Y, when we don't have rigorous proof that Y is better than X either. Regardless of what you do you're taking a leap of faith.
> We just don't know and it would be way worse if it turns out we have to re-vaccinate everyone because we were impatient.
If there's probability p that it doesn't work and we have to spend X extra months re-vaccinating everyone that's an expected delay of p * X. But if it does work then not pursuing the single dose strategy will delay the vaccination schedule by X' months also.
If p * X < (1-p) * X' then the former is a perfectly acceptable risk.
I personally try to make decisions using probability. I understand where you are coming from but there is one factor missing in your analysis: this situation is literally life and death. That changes the math a bit to something more akin to "better safe than sorry" in my opinion. We have found a guaranteed path out of this mess. There may be other faster paths that save more lives, but it could also end up killing millions more too. I'm all for experimenting but I take issue with making the experiment the policy when lives are on the line.
We DO have a good understanding of the human immune system, and how the mRNA vaccines interact with it. The effectiveness shown in the trials confirm those theories.
Sure, there could be some odd unforeseen effect. If so we'd learn as we go.
> it would be way worse if it turns out we have to re-vaccinate everyone
Worse than 3000 people dying every day? Because of the extra expense of making more doses?
> We DO have a good understanding of the human immune system...
As someone who is an active researcher in this field, I can tell you that this is just not true. The immune system is VERY complex and we know very little about it. We have only had the tools to begin to systematically probe it for a few years.
I know what you're getting at in this context, but in reality when you start digging into how the immune system works it's shocking how little is understood about it.
"There’s a joke about immunology, which Jessica Metcalf of Princeton recently told me. An immunologist and a cardiologist are kidnapped. The kidnappers threaten to shoot one of them, but promise to spare whoever has made the greater contribution to humanity.
The cardiologist says, “Well, I’ve identified drugs that have saved the lives of millions of people.” Impressed, the kidnappers turn to the immunologist. “What have you done?” they ask.
The immunologist says, “The thing is, the immune system is very complicated …”
Propose to the companies to conduct a trial to test your hypothesis on the effectiveness of a single dose? Until then the FDA policy is clearly data based and they are saying to follow the tested dose schedule from the clinical trial and not to deviate.
Hypothetical question. Imagine if for some reason everyone in the trial received the vaccine on a rainy day (maybe it occured in Seattle during a bad patch of weather). The vaccine shows immunity, but we can only be sure for a population that got it on a rainy day.
Now we're distributing the vaccine, but the bottleneck is that we have to keep waiting for rainy days. It's especially bad in Arizona and Nevada. Is your contention that we keep the rainy day requirement? Even when all are scientific and empirical priors tell us that the effect is de minims.
The example is kind of silly, but it makes my point. There's literally countless number of factors that go into any trial. There's no possible way that the way treatment is deployed in the field will exactly match the way it was tested. Yet doctors, scientists and public health experts use judgement and empirical priors to determine when and where we can relax the requirements.
> Yet doctors, scientists and public health experts use judgement and empirical priors to determine when and where we can relax the requirements.
They certainly do. And the FDA, a collection of the leading doctors, scientists, and public health experts, just told you that two doses is the regimen. Is there something that you know that these experts don't?
There is nothing special with these two dose regimens. It's just what was decided to try for the first studies.
3-4 weeks are quite short intervals for booster shots, picked because of the urgency of getting results, not because it's optimal from a medical standpoint.
> FDA, a collection of the leading doctors, scientists, and public health experts
FDA is primarily a regulatory bureaucracy, tasked with enforcing federal law in this area. The incentives it is under do not always align with optimizing public health.
Considering that the FDA let thousands of Americans needlessly die because they delayed the approval hearing to enjoy a relaxing Thanksgiving weekend... Yes, I don’t trust their judgement.
As for more general critiques, there’s mountains of evidence that the FDA is too risk averse, even before Covid.
Setting aside my deep visceral reaction to what you're suggesting, how is it safe or productive to conduct a review on a Friday evening at the end of a long week and not sleep or eat until it is done? Do you have any reason to believe they would make more or fewer mistakes doing so? And what's your personal policy on making really important decisions while sleep deprived? Would you, for example, get some sleep before signing a contract on a house?
If anyone only ever made decisions while they were perfectly fed and rested, this would be a sad, slow, boring world, because nothing would ever get done or decided. There is such a thing as urgency, and people do work beyond a 35 hour work week with evenly spaced meals, and especially during a global pandemic.
Specific to this instance, this FDA meeting was a formality -- they had already had the data for two weeks to review. The efficacy was well-known. They chose to take a 4-day holiday (Thursday, Friday, Saturday, Sunday).
People don't all of a sudden sign house contracts. They've germinated the idea, spent weeks or months working through the pros and cons, talking to their life partners and family and agent and mortgage broker. The decision is made well in advance of the actual contract signing, and all the red lines are done before you get to the actual meeting to sign on the line. Similarly with the FDA regulators, they weren't meeting to review the data for the first time and come up with a decision on the spot. This was one final step in a very long process.
The application was submitted on November 22 and the review meeting was not scheduled until December 10. The UK, not exactly a country known for taking reckless medical risks, approved the Pfizer vaccine eight days earlier than the US despite receiving the application at the same time.
While nearly ten thousand Americans died, I guess the FDA was “catching up on its sleep”. Eight long days of glorious sleep!
And yet, regardless of your own personal feelings and beliefs, here we sit, locked in our little worlds which have been shrunk down to the space inside the walls of our homes, with a government mandated two dose regimen as you scream helplessly into the wind like an obese turtle on its back screeching for help. Because we're going to Follow the Science that the government and experts have decided is Correct. So stop complaining, stay the fuck inside, and quit questioning the science because you half-dosers are really starting to sound like antivaxxers and antimaskers all of a sudden.
A lot of ad hominem and hysterics, for someone who continuously dances around the very simple question. What is your prediction for the effectiveness of a single dose regime?
Because if it's over 50%, then the math is very simple. First doses must go first. Here's my simple proposal: I bet you $500 that the first peer-reviewed study to specifically test one-dose mRNA Covid-19 vaccines finds at least 50% effectiveness.
Talk is cheap, and I'm sure you get a lot of upvotes on Reddit and Twitter by sprouting some "Follow the Science" hashtag. But actual people's lives are on the line, so if you won't even risk a little bit of money on your beliefs, stop risking people's lives.
Your proposal is highly unspecified. I suggest that you should add a durability term or the 50% effectiveness is meaningless. That is, for how long do you suspect there to be at least 50% effectiveness?
Are they "leading" because they lead in expertise or because they control the reigns of regulation?
I'm not sure I would describe the FDA as optimistically as you do - they are a collection of federal employees, leaning heavily on private industry expertise to navigate the demands of politicians, the expectations of the public, and needs of businesses.
737 MAX is a debacle all right, but FAA actually has a stellar track record as far as government agencies go, and is respected worldwide. Or replace FAA with NTSB.
I think the analogy to your example is to have conducted a larger trial where the dose was given under different weather conditions, or in the case of the real vaccine vary the timing of the 2nd dose. I agree, if experts agree the likelihood that 1 dose is effective and the likelihood of it being ineffective is low, we should do what will save the most lives. This is an emergency.
It's not only about minimizing total infections. If it were, priority would be given based on social sphere sizes, eg priests and postmen before old people.
It's also about giving people a vaccine they can believe in, which allows them to return to some of their normal activities. If everyone is 50% safe, no one has any real expectation that they can take any risks without being infected. If half the people are 95% safe, that half can do more things (travel long distances, go to school) while the unvacccinated half can continue to avoid risks until more vaccine is available.
> It's not only about minimizing total infections. If it were, priority would be given based on social sphere sizes, eg priests and postmen before old people.
Exactly how it is rolled out here in Moscow. It has never occurred to me that it's not the one and obvious way.
But yes, the "Sputnik" vaccine has huge problems with giving people something they can believe in. Rolling it out in a "rational" order, as if they actually believe it works, is probably the most city government can do to raise confidence.
> A false sense of security is worse than no security at all.
True. But that isn't what is happening here.
This is more "some level of security which is less than absolute, and unclear what sense of security people will assume they have"
We've seen "false sense of security" arguments used time and time again to oppose partial, imperfect safety interventions (seat belts in cars is a great example).
It’s not just a question of 95% immunity vs. 50% immunity (even if we were to take your arbitrary 50% number at face value). It’s also a question of how long we expect the immunity to last for two-dose vs. one-dose, and where we expect to be in terms of virus spread and vaccine manufacturing and vaccination rates when that initial immunity runs out. These are complicated questions.
> we basically have NO DATA on single dose schedules for Moderna/Pfizer vaccines
I wonder if anything can be deduced given knowledge of the mechanisms these vaccines use compared to other vaccines against other viruses.
I know there are vaccines like for HEP-A that confer immunity for at least 10 years given a single shot, and a 20+ years of immunity if a booster is given in six months.
It appears that the FDA doesn't want to offer any information outside of the studies. This cut in half the number of people who can be protected during this winter's covid season.
Agreed. Taking a conservative approach to something you don't yet understand is the best approach on a mass scale. There isn't any significant data for the one dose approach. These vaccines are only authorized on an EUA on a specific way to apply the dosage and it would be foolhardly to experiment now with different approaches on health care workers who are high risk on the front line.
Definitely need more data on the single dose approach and if that proves safe enough then providers can go that route. Playing with people's health because we want to go cowboy and extract many doses as possible is irresponsible.
What happens if the single dose approach doesn't work as well as hoped? I wouldn't want to be that guinea pig who thought "I'm protected". How long will it be that all hospitals get the information to go back to the two dose approach. Consistent messaging is key during this pandemic. That alone has been hard enough.
Letting a few hundred thousand extra people die because of a slow vaccine rollout is not the conservative approach.
If you give more people a single dose you may be gambling that those people receive sufficient uncertainty, but if you give fewer people two doses you are ALSO GAMBLING with the lives of people who do not receive a vaccine. There is no "safe" option here. You just have to make educated guesses about the probabilities and risks involved instead of pretending that one approach is the "safe, conservative" one.
This will happen under any dosing schedule, because we already know the vaccine doesn't become effective until some time after the first dose. (Which is also one of the reasons it's hard to tell exactly how much benefit the second dose gives.)
"NO DATA" is an epistemologically bankrupt cop-out. We don't have RCTs that prove that jumping out of an airplane with a parachute is safer than jumping out of a plane without one. And yet everyone packs a chute when jumping out of a plane. Why is that so? Because we have priors based on our understanding of physics and biology that hitting the ground slowly is less likely to kill you than hitting the ground fast.
The same is true for vaccines; we have lots of them and we can make an educated guesses about how new ones work, even if new vaccines may not always behave the same as old ones. When you have to make decisions under uncertainty you can't refuse to incorporate educated guesses just because you don't have rigorous p<0.05 peer-reviewed proof confirming those hypotheses.
It's simply pathological to claim that we have NO DATA just because a large scale RCT wasn't performed.
For starters, we have profound differences in the attack curves between treatment and control group, starting about 14 days after administration of the first dose [1]. I don't have the numbers in front of me, but I'm going to guess the trial size is more than adequately powered to detect differences 27 days out.
All this is exactly as theory would predict. Seroconversion typically takes about two weeks. Once seroconversion happens, immunity lasts years (if not decades), which is why most booster doses are given years apart [2]. And any talk of "full efficacy" is confusing population statistics with individual outcomes. To say that Moderna is ~85% effective after one dose, as it appears to be, is to say that 85% of the population will produce antibodies after a single dose. There is no "partial immunity"--you're immune or you're not.
There is no "partial immunity"--you're immune or you're not.
Is that true? (I'm not an immunologist; I genuinely have no idea.)
I'd have thought that it was all a statistics game: how many antibodies you have and how fast your white cells can respond to the threat before the virus got a foothold. In that model there is partial immunity: some people would win that race, and some wouldn't.
If I'm wrong about that I'd appreciate a better model. Thanks.
The OP's categorical statement on partial immunity is entirely false. Look at the Astrazeneca data in the Lancet. No hospitalizations in the treatment arm. That is evidence of "partial immunity."
Presumably, that some people did get sick but not sick enough to be hospitalized. The vaccine was rated at ~90% effective, not 100%, so some people did get sick. But if they got lighter symptoms, that would qualify as "partial immunity".
90% efficacy does not mean that 100% of the population is 90% able to fight off the disease. It means that 90% of the vaccine recipients are ~100% immune, while 10% are ~0% immune. This has a biological basis: did they seroconvert or not.
It simply isn't workable to reason from lighter symptoms to "partial immunity." Let's pretend the vaccine didn't exist. Take someone with a mild case of covid. Would you say this person is partially immune? Or consider someone with no symptoms at all--are they completely immune? Since the vast majority of cases are mild or asymptomatic, are you prepared to argue that "immunity" is actually very widespread?
Again, your "some people win the race, some lose" analogy is on the mark. It's pointless to talk about "partial victory"
> some people would win that race, and some wouldn't.
You've basically answered your own question. At the population level, immunity is probabilistic. At the individual level, it's ~deterministic. Those who are challenged but stay healthy are immune. Those who are challenged but get sick are not immune. If we were to repeat the experiment, the individuals who stay healthy/get sick would largely remain the same. In this ex-post view of things, there's no "in-between." You got sick or you didn't, you're immune or you're not.
From an ex-ante perspective, we would instead try to predict whether a person will get sick or not. The answer to this largely depends on whether the body can generate a response to previously recognized antigens. This again is binary. You have memory B-cells due to primary response or you don't; you're immune or you're not.
Your cells will take up the mRNA and manufacture spike protein, which is the antigen of interest. We should expect this to be pretty similar to just injecting the antigen directly, as the other vaccines do.
> However, making such changes that are not supported by adequate scientific evidence may ultimately be counterproductive to public health.
I remain sympathetic to the argument that we're maintaining too high of a standard of evidence during a rapidly moving pandemic. The question isn't whether this "may be" a harmful decision (of course it might); it is whether it is likely to be. The FDA's memo fails to convince me the expectation is worse taking the single dose strategy.
This reads like a letter by someone who keeps all their money in CDs rather than stocks, because they might lose money.
> The question isn't whether this "may be" a harmful decision (of course it might); it is whether it is likely to be.
The statement said there was insufficient data to make that calculation definitively. If you want to take a course of action not borne out by the study, the FDA doesn’t go after you or your doctor for off label use. The FDA is clarifying that the unproven route is, well, unproven.
The FDA is all about medical risk vs provable results. They can’t intelligently comment on the uncontrolled unknown beyond saying that that you’re entering that territory. If you want odds on rolling the dice outside that space, they’re irrelevant to you. So stop looking there.
edit: what you want is a politician with the balls to say whether we should do it anyway and convince other politicians that they should own making that decision even if they turn out to be wrong. But Washington is full of cowards too cowardly to even go to bat for sticking to the studied regime beyond milktoast deference to science so you’re here expecting the FDA to start exceeding their role.
It is not about who has "balls." You seem to think this is just a balancing of risks. It is not. It is a balancing of "what do we actually have data to support" versus "what do we hope to be the case but have no actual evidence to suggest it is so."
Sure, but we do have prior probabilities based on other vaccination campaigns and studies. We also have some understanding of the causal mechanism of this vaccine, so there is other evidence. It’s just not a direct randomized control. People fixate on statistical testing under randomized control, but there’s a lot more information out there that can be used to assess probabilities.
> You seem to think this is just a balancing of risks.
No I don’t. I was saying that the kind of balancing you mention is out of scope for FDA to answer. The fact you can’t find anyone to answer the question you want answered is not the FDA’s problem.
I said go off-label if you want to (although off-label might be slightly the wrong word in this case). Good luck finding a politician that wants to tie themselves to recommending that, in case it turns out wrong.
I wish that these decisions wouldn't need to be deferred to politicians. So many of them are selfish idiots.
I'd more trust the vote of relevant medical specialists. I'd rather that these specialist provide the public the best/concise information they have and let people make informed decisions for themselves, or even have a referendum on one dose versus two, and prioritizing.
Politicians have already turned the world upside down for something that looks like it will kill two out of a thousand people when all is said and done, mostly older. Half the population is dumbfounded by their lack of perspective, the other half is scared shitless.
This is why I am frustrated by the FDA. It seems like all they are willing to do is read statistics produced by others.
The suggested dosing is obviously unproven because it has not had a nice large scale study done. Shouldn't this be where they conduct a few rapid small scale experiments?
That data, the existing trials, along with a deep bench of knowledge should be enough to make a well justified determination.
FDA is doing exactly what’s in their statutory responsibility and authority. ie: what congress told them to do. (See my edited addendum to the parent comment.)
When someone observes that a government agency which seems to be doing something nonsensical is actually just following the law perfectly, it always brings to mind H. L. Mencken: "Democracy is the theory that the common people know what they want, and deserve to get it good and hard."
2) Trials must be large to see results because Covid is rare. The Moderna trial took 30,000 patients 3 months to get to 90 covid cases.
3) This could be a an interesting opportunity for challenge trials, but unfortunately, the key metric for vaccines is reduction in severe cases. Subjecting people likely to have a severe case is unethical when there chance of normally catching it is very low.
Why not look for key indicators of immunity in the authorized dosage group, then compare against indicators in the reduced dosage group?
This is part of my complaint. Why is a large trial, or even a challenge trial (which I also support), the only way to get results here?
There is more to science than reading statistics from trials. They should be able to ask and answer very specific questions based on the working model proven far. Then scale those results to the broader problem.
> We find that under most plausible scenarios, a more balanced approach that withholds fewer doses during early distribution in order to vaccinate more people as soon as possible could substantially increase the benefits of vaccines, while enabling most recipients to receive second doses on schedule.
I've only read the abstract, but this is an example of the kind of analysis you want to see behind a decision, as opposed to "we cannot conclude anything definitive" which is true but a deflection from actual decision-making.
I think this is part of the overall issue with the handling of this pandemic. No one wants to take responsibility.
The FDA's job is not to decide which lives are more valuable than others, or what our society's risk tolerance is. Their job is to keep people safe and to present the data and the options to political leaders.
The FDA clearly has a goal of not tarnishing their reputation. If they make the wrong decision here, then they lose credibility with approvals for future drugs that come out to treat Alzheimer's or diabetes or whatever else.
Ultimately, I think we look to our scientists to make many decisions that aren't really their place to decide. A scientist can tell me that vaccine X is this effective based on their data. Or even that they have a hunch that treatment X will do Y. But ultimately, I think it's on our elected leaders' shoulders to hear the scientists out about what the various risks are and then make a decision. Unfortunately, I don't have faith that our current elected leaders can adequately listen to our scientists counsel and then make wise decisions accordingly.
> This reads like a letter by someone who keeps all their money in CDs rather than stocks, because they might lose money
If there were a clear delta in expected value, then we'd do it. But you can't compare a speculative change to requirements with asymmetrical costs/rewards in a policy context during a pandemic to CDs vs stocks.
Don't give in to the temptation to be like the business guys who change requirements the day of launch. We have a path to end the pandemic. Let's take it.
Following the status quo path will likely result in significantly more people dying. It's a gamble either way, and if you want to argue that the risk of a first-doses-first approach is not worth the risk, then quantify your reasoning and explain exactly how many extra deaths you're willing to accept instead of these platitudes about paths.
No. But we can ask the FDA to justify its reasoning by sharing their modeling of the expected value of QALY for different courses of actions. It's ridiculous for them to spit out a proclamation like this without providing a framework for the decision other than "has not been tested".
I hear you about the path to end the pandemic, but there's also that scary thing about the virus mutating enough to render the current vaccines useless. That feels like a very compelling reason to at least consider whether a single dose or smaller doses might get more of us immunity more quickly.
Sure, Moderna and Pfizer could whip up a new vaccine to tackle this ... but how much does the new variant spread and further mutate while we're testing new vaccines?
News is generally trustworthy, but it is in their interest to always make everything sound as dramatic as possible. "Potential new strain which may result in mild reduction in vaccine effectiveness" is not a headline you will ever read. It's a very boring headline. It's in the interest of an advertisement supported company to make the most inflammatory headlines possible.
Let the science do it's work, don't try to be clever and cheat the system.
It reads to me like a letter by someone who invests in target date retirement funds and index etfs by dollar cost averaging on an automated schedule, and avoids investing in tulip bulbs, because the available data shows that this is the most prudent approach.
Unlike stocks the risk here is vastly larger than the reward.
COVID vaccines aren’t believed to be indefinitely effective, so it’s very possible that less effective large scale vaccination effort would cycle through and fail to stop the spread long term. However, a sufficient vaccination effort could completely eliminate the disease globally.
On what basis do you say that? Stocks could potentially involve you losing everything, and the "reward" of cutting the number of necessary doses in half is that we could potentially reach herd immunity much faster.
Bear in mind that the expectation is only about 1.9 billion doses total will be produced in 2021 - so we are talking about the difference between maybe 1/3 or 1/2 of the first world being immunized, and hitting herd immunity this year.
I'm not saying we should, the FDA is probably correct that we should follow the dosing schedule we know works rather than throwing away a whole year of vaccination efforts, but it's obviously desirable.
(it's unfair but I'm sure that most of the doses are going to end up in the US, Europe, and other western-aligned countries first, then China and Southeast Asia, and the developing world is going to get the shit end of the stick, the developed world is going to hit herd immunity long before let's say India or Africa.)
Why don't we start playing options? Everyone gets a tenth of a dose so we can get it done next week. Just start a whole new study, made up of everyone.
Vaccines generally do not eliminate a pathogen and they are not expected to eliminate this Coronavirus. Smallpox is the only human disease to ever be successfully eliminated.
Relatively few vaccines exist, and even fewer old ones, but on the whole they have been quite effective. https://www.vaccines.gov/diseases In total both Smallpox (human) and Rinderpest(cattle) have been eliminated in the wild. Seasonal flu is kind of an interesting case as each year is arguably a different disease with the old one having been eradicated. That’s hopefully a model which will work for covid-19.
Polio is very close to being eliminated, with only 125 known cases in 2019, which was a spike. Rubella dropped from 670 thousand in 2000 to under 15 thousand in 2018.
Ovine rinderpest elimination is considered a reasonable goal, but still 15+ years off.
We don’t have specific data on covid, but it’s closely related to other diseases where immunity from contacting the disease tapered over time.
The best estimate we can make on the vaccine is. "From what we know of the duration thus far of immunity, I would be surprised if it turns out to be a 20-year duration, but I would also be surprised if it was less than a year,"
We don’t have the capacity to make enough vaccines for global herd immunity in under a year. Which is why reduced long term efficiency is a significant concern over a faster rollout schedule.
So you're making a super strong statement that's not very justifiable.
> but it’s closely related to other diseases where immunity from contacting the disease tapered over time.
I mean, maybe? Let me know when there's more then extremely minimal evidence of reinfection. We are at the point now where we are coming up on a year of significant spread and it's still missing. Additionally, have we ever seen an mRNA vaccine for a coronavirus? Nope. Evidence here is at best uncertain.
> We don’t have the capacity to make enough vaccines for global herd immunity in under a year. Which is why reduced long term efficiency is a significant concern over a faster rollout schedule.
Would we have enough if we split doses? Why does the US need global herd immunity?
> So you’re making a super strong statement that’s not very justifiable
We don’t think of each annual flu as it’s own disease, but they are caused by closely related strains not a single virus. Similarly, COVID-19 was originally named SARS-Cov-2 due to it’s close relationship with SARS-CoV also known as SARS. https://www.cdc.gov/coronavirus/types.html
Which is why the vaccine could both be developed so quickly in the first place and we can make reasonable predictions about the vaccine. They didn’t create a successful vaccine in under a week from scratch without a lot of knowledge of closely related diseases. It’s that same knowledge which is behind the dosing schedule, and why it was tested like that.
> Why does the US need global herd immunity?
Ending the vast social and economic harm from social distancing efforts. With local herd immunity things go back to normal even if the rest of the world is dealing with the disease.
PS: The demographics of the developing world even support a staggered approach. First a focus on vaccinations for the elderly and medical workers globally then local herd immunity based on population demographics. Local herd immunity protects those who the vaccine can’t, but evenly spreading out vaccinations to the younger population accomplishes little.
> They didn’t create a successful vaccine in under a week from scratch without a lot of knowledge of closely related diseases. It’s that same knowledge which is behind the dosing schedule, and why it was tested like that.
Was there a SARS vaccine? What same knowledge would give the current dosing schedule then? Why does it trump the new knowledge gained from an actual RCT of the vaccines?
> With local herd immunity things go back to normal even if the rest of the world is dealing with the disease.
Huh? So then the US doesn't need the global herd immunity like I was suggesting?
> PS: The demographics of the developing world even support a staggered approach. First a focus on vaccinations for the elderly and medical workers globally then local herd immunity based on population demographics. Local herd immunity protects those who the vaccine can’t, but evenly spreading out vaccinations to the younger population accomplishes little.
Okay, how is this relevant to whether or not there should be a longer time between initial dose and booster? It's totally irrelevant.
> Similarly, COVID-19 was originally named SARS-Cov-2
No, it wasn't. The disease and the virus that causes it were originally referred to as “the 2019 novel coronavirus” (or, 2019-nCoV for short.)
SARS-CoV-2 was announced as the name of the virus by the International Committee on Taxonomy of Viruses on 11 February 2020; COVID-19 was announced as the name of the disease by WHO also on 11 February 2020.
I am specifically referring to the virus, which I hoped was obvious. To avoid confusion with the disease SARS, the WHO sometimes refers to SARS-CoV-2 as "the COVID-19 virus" in public health communications. And from there it’s entered the popular press.
But yes, the disease was named COVID-19 thus the overlap, and current confusion over the viruses name.
We have a known vaccine that works with 2 doses. We don’t know if 1 dose will work. We have single-dose vaccines with higher temperature tolerance from AstraZeneca and J&J ready to be approved.
Let’s not snatch defeat from the Jaws of victory. Let’s let the 2 dose vaccines goes to those who need it the most and the most at risk. They need more care and monitoring to entire they get both doses.
In a few months when the other vaccines come online then we have unimaginable more flexiblity.
Now is not the time to confuse Americans who apparently are easily confused. Take two doses now. Splitting them up and then some getting Moderna and some getting Pfizer is just a clusterfuck.
How much uncertainty we accept depends a lot on the potential downsides. For example there isn't much of a downside to wearing masks, so that is a measure you could defend on rather flimsy data if you had to.
The potential downside here is very large, it could mean that the vaccine loses a lot of efficacy if the delay to the second dose is too large. It also could create circumstances that favor mutations that escape the vaccine, because you have a lot of people with a weaker vaccination response while the virus is circulating widely.
>This reads like a letter by someone who keeps all their money in CDs rather than stocks, because they might lose money.
That's a good thing in medicine and science- it's called the "precautionary principle". We have what we know (two does in the trials) working, so trying something new like a one dose regimen is risky.
I think the FDA is dodging the obvious since the US doesn't want to alienate the UK:
R-Value with UK mutation:
3?
Effectiveness with 1 dose:
66%?
Probability of breeding a new mutation if you gradually vaccinate everyone in the UK up to only 1 dose:
99.9%?
Once 2/3 of people have 1 dose, mutations that make the vaccines worthless should dominate given the available pool, and then the available pool is back to everyone again.
From what I recall from Dr. John Campbell’s excellent daily videos, the UK strategy was not to give only one dose, but to simply delay the second dose a few weeks so that more people could get their first injection from the initial supply(presumably supply will increase over time). That sounds much lower risk. I think the single dose proposal was a US thing.
All of the mRNA vaccines target the spike protein. Coronavirus spike protein mutations have only ever been observed to occur in bats- never humans. Therefore the number of vaccinated people will almost assuredly not increase the likelihood of a resistant strain.
I would accept a similar kind of reasoning in an argument towards caution, but not in an argument for seeing what happens with prolonged partial but insufficient immunity. Aside from near certainty that a change to the target protein is game over, we have no idea what other mutations could render immune responses triggered by the vaccines worthless, and I don't see the ethics in an experiment to find these mutations.
These vaccines were invented a year ago. Especially given the emergency this virus has created, I can't help but wonder how life would have been different if the trials were open to anyone who wanted one.
"This vaccine probably works. We won't know for sure until December. If you want to try it anyway, come get one. Otherwise, we'll let you know when the trials are completed."
It's heartbreaking to think about all of the irreplaceable experiences people missed this year, especially for those who didn't live to see the end of this pandemic. Of course I'm glad for all the people who didn't catch the virus, but the costs are too infrequently considered. Our regulatory bureaucracy was insanely expensive this year in terms of our most valuable resource: quality time. Nobody even questions it; we just accept that this is how it's supposed to work, because it's all we've ever experienced.
There are real safety risks to testing unknown drugs and the public literally isn’t smart enough to assess the risk to themselves. Everyone would sign up for the test vaccine to get a chance at escaping quarantine without understanding the risk. And if we offered this on a regular basis it is inevitable that a candidate drug would have adverse effects on a large group and people would be out for blood because nobody actually read the fine print.
Here’s a list of examples that shows why the FDA must be deliberate in their testing. People can die or be permanently crippled when we screw it up. Just imagine if we rushed a coronavirus vaccine with a similar safety concern and ended up hurting millions of people before we realized it: https://www.cdc.gov/vaccinesafety/concerns/concerns-history....
The FDA already does have compassionate use exemptions for people that are on death’s door and there are no downsides to taking an experimental drug- they’re dying anyway if it doesn’t work out. I think that’s about the right level threshold for deciding whether to give people unproven drugs and we should not have rushed the vaccines any faster- hindsight may show us that the vaccines are safe but we couldn’t have known that a few months ago. We have to do the testing.
a chance at escaping quarantine without understanding the risk.
Yet it appears that the FDA makes no attempt to understand the downside risk associated with NOT taking the vaccine. I don't see them talking to economists trying to understand what damage will be done to our businesses, and how people will suffer as a result of that; or even of what lockdowns are doing to our mental health. The ONLY risks they're considering are on the side of taking the vaccination.
And this is always how it works for them, both in normal times and during the pandemic. Consider last March, when the CDC's covid-19 test was defective. Despite the fact that the assay is a simple matter that any decent hospital can do in their own lab, the FDA would not allow anyone to do it. That set America's pandemic fight back by a couple of weeks. If we could shift the spread backwards by two weeks, how many thousands of lives would we be saving? The FDA's hidebound refusal to look at both sides is responsible for this.
This probably isn't a situation you want to take a purely economic outlook towards the problem. When the largest at-risk group is the elderly you're not going to see a lot of financial disruption in sectors that keep the wheels moving.
I'm not looking for a purely economic outlook. I'm complaining that the FDA is at the far extreme, with a purely medical outlook, giving no consideration for other factors.
(I should amend that a bit. They've clearly done a lot to streamline their processes for this. But as far as I can tell, they haven't done anything to balance different kinds of risk in their standards.)
Back in the summer, supplies were much smaller than the current shortage. So it wouldn't have made much difference.
That said, I support drug legalization of all kinds.
mRNA vaccines should become very fast to ramp up production of, since it's an industrial process, not a biological one, but this is the very first time it's done.
A single scientist at Pfizer created 10 vaccine candidates in a day. Most worked, but some were less 'tolerated' than others. It's ok to do that in a lab setting, with health care standing by. There are limited resources for trials, you can't easily scale to millions.
Huh? Anyone could sign up for the trial, even after I participated in one I still got calls from countless trial recruiters from other manufacturers. It was quite easy to participate
I'm thinking more broadly than a binary choice in the spring for someone who happens to live near a research lab and have clicked the right Facebook ad.
What if, at any time, you could walk into your doctor's office and say "I'm ready for that experimental vaccine?" You could contribute your data to the pool that increases our confidence in its efficacy. As confidence gets stronger, more people volunteer. Eventually, third party labs (maybe regulators like the FDA - maybe NGOs like the UL) certify that they believe a vaccine is safe and effective, which makes even more people comfortable getting it.
If we had done that, how would life be different now? Could we have closed fewer things? Would more people have led a more normal/less stressful lives? Would we be closer to being done with this mess? How many fewer long-term ramifications (health, financial, social, developmental, psychological, mortal) would people have to deal with?
We reconsidered, reenvisioned, and reinvented so many things this year. Why can't we apply that same mindset here too?
I mean, take the flu shot. The times I've gotten it I've not had any reaction or one so mild I don't remember. Maybe a sore arm? Slightly tired, though that could have been work. I wouldn't personally know until they do blood tests.
Even if you have side effects - outside of a possible sore arm, you wouldn't know it was the vaccine or just unfortunate timing for a virus or something.
A friend of mine did the Pfizer trial, and he strongly suspected he had the real thing because he had some pretty strong reactions to it, with flu-like symptoms making him feel awful for a day. He later got an antibody test, and it was confirmed.
I don't know what the poster above was talking about, getting calls to participate in a study. Nobody contacted my wife or I with such offers. I suspect that the poster was lucky to live right in a city where the test was being conducted; those outside of major cities are probably not included in his claim that anyone could participate in the trials.
I know some folks have reactions to vaccines: not everyone does, though. And weirdly, when folks don't know, sometimes the placebo gives them reaction. Pretty much, side effects have to happen more often in the real thing than they do a placebo.
Sometimes it just doesn't work to have double blind: LSD trials, for example, make things pretty obvious. It isn't the case for the flue, though.
You are correct on the trials: most folks don't get called. That said, living outside the city doesn't exclude you from trials in general because they generally need participants with x and/or y. Often, they will pay for expenses to travel, especially if your disease is uncommon or they have trouble finding participants.
that's interesting i didn't think about that! would taking an antibody test be banned for participants? because those who confirm that they received the real shot could change their behavior?
Oh, give me a break. The issue here were the fact that people were willing to break the lockdown, and not wear masks and social distance. All the countries that followed the protocol (larger countries and denser countries) were able to deal with the problem with minimal casualty. That was the real issue. Not this BS “taking too long to approve a vaccine”
While I admit that this is a tough call, and I can see coherent arguments for either one, if the FDA was _trying_ to infuriate people who disagree with them, they could hardly have done a better job than this.
It essentially implies that other nations, most prominently the U.K., that decide to gamble the other way, are foolish or unaware that there are risks. This is manifestly not the case. It is a gamble, and there are certainly risks, but no one who is advocating changing the dose regimen on the fly is suggesting otherwise, that I know of.
The motivation for going with one dose for twice as many people (in a given period of time), is that currently we seem on track to have the vaccine show up just barely too late to do much good. The virus is getting better at spreading all the time, and at the current rate of production, even if everything were distributed more or less instantly (which it isn't), we won't get a vaccine to most people before they get exposed to the virus anyway.
Now, there are still certainly arguments to be made that sticking with the tested regimen is the least bad option. None of them were present in this statement, which more or less attacks a straw-man argument that changing the dose regimen is without risk. If they were trying to make people angry with them, they could hardly have done a better job.
As a medical researcher, I received my first Moderna vaccine dose yesterday. I feel incredibly lucky, but also, a tiny bit guilty. I have very minimal patient contact, and I could not help but wonder if by taking the vaccine, I was depriving someone more needy of the vaccine. In the end, I decided that due to inevitable bureaucratic/managerial inefficiencies, any action I take would not materially affect when non-hospital employees begin to get vaccinated, and that by getting vaccinated could potentially prevent me from spreading the virus in the future. Who knows whether I made the most ethical choice, but at least, I tell myself, I considered the question.
edit: I would add that telling friends and family that I got vaccinated actually uplifted their spirits: It seemed to give them hope that this would all end. Its different when people you know get it, versus hearing about it on the news.
You know what? Congrats. You got your first injection. This does make you less likely to be a vector for this particular virus, and more importantly, makes it less likely that you’re going to die or suffer long term effects from COVID.
You shouldn’t discount that.
Sincerely, a member of the public.
EDIT: the type of typo that is the exact opposite of what I meant to say. Goddamnit.
Yeah, I'm at a medical university and in a similar situation. However, I am hearing that far fewer eligible people are electing to receive the vaccine than hoped. The line to get the vaccine is far shorter than it was supposed to be. We need people to take the vaccine to make this go away, so I suppose anyone in line should just take the vaccine and not feel guilty.
This depends on where you are. Some places are managing it well, some aren't.
There was a huge mess in Chattanooga with people waiting in line for 6h, being told there weren't enough doses and to leave, and then there being plenty so they gave them to friends and family.
You did the right thing, in my opinion. I am in a cohort that has no hope of getting the vaccine before May... from where I’m sitting, it’s very frustrating seeing vaccine doses just sitting there, not being taken because of bureaucratic inefficiency. I’d infinitely rather the vaccines went to some of the “wrong” people than sit unused. In fairly short order, I think the main problem is going to be people refusing to take the vaccine, making it difficult to achieve herd immunity.
I've felt the same about a friend (he works in a hospital). Rather than feeling jelaous, we all felt something good is happening, lots of folks are still afraid to take it, so this taken by medical personnel is uplifting.
How did they originally decide to do 2 doses, instead of 1 or 3? How did they originally decide to do 21 days, instead of 42 or 3?
Presumably these choices weren't picked out of thin air, or made up by some businessperson based on business considerations -- "We think we can get paid twice if we put it in two doses, but if we try to go to three doses it'll be impossible to market" -- hopefully that's not what happened.
Hopefully instead this decision was made based on actual data -- for example in animals or a small group in Phase I or for some similar vaccine, they did actually try N-day dose separations for all 1 < N < 50 and then made some actual measurements of how fast white blood cells attacked the COVID virus in a lab dish or whatever. The lab test maybe wouldn't be as ironclad as the Phase 2 which actually sends the subjects back into the wild and sees how many got COVID in the next 3 months, but it's some concrete data.
Where is that data? Couldn't you use whatever data was used to decide on the dosing schedule in the first place to quantifiably answer how much worse were the alternative dosing schedules that weren't chosen?
Two (or more) doses are fairly standard for vaccines. The first to trigger seroconversion, the subsequent ones to exercise the secondary immune response (and for those relative few individuals who did not seroconvert after the first jab). The interval between them is typically quite long, often on the order of years [1]. From that pov, the 3-4 week booster interval for the COVID vaccines is tiny. It's likely the minimum possible interval given that seroconversion takes >= 14 days (I'd guess the short interval was chosen to get trial results as soon as possible). There are many reasons to think that alternative dosing schedules would be not only viable but better than the current default.
How did they decide on this years-apart schedule though? Presumably they had some data to say "we tried giving group A a booster after 90 days, group B after 365 days, group C after 2 years, group D after 3 years, group E after 7 years, and group D did best in terms of not catching the disease"?
Or maybe they said "we measured secondary immune response with a lab test, and group D had the highest number"?
If these weren't done for the COVID vaccine specifically, but some other vaccine, couldn't you still put some rough ballpark quantitative guesses on the COVID vaccine to help guide public policy better than "shrug, we have no clue what will happen if you do anything other than 21 days"?
Something like "We think 40% will be protected with one shot, 90% will be protected with two separated by 21 days, and we can fit a curve to these two data points which has the same shape as curves for other decades-old vaccines that have tons of data and is supported by biological theory [paper1] [paper2] [paper3] [paper4] [paper5], and that curve continues to monotonically increase, so waiting 5 weeks instead of 3 should be no problem, in fact we think you'd be 91% immune instead of only 90% immune (provided you don't actually get the disease in the extra intervening 2 weeks), r^2 = whatever, but waiting 1 week instead of 3 is probably super bad, you only get up to 50% based on the shape of the curve and what's known from other vaccines, [paper6] [paper7] r^2 = whatever.
Disclaimer: This assumes COVID-19 vaccine acts like the vaccines in [paper8] [paper9] [paper10] which collectively cover 80% of known vaccines, but it's always possible since it's MRNA the curve will be something super weird and there's absolutely no reason to think it'll be like that, but it'll take us 10 years to definitively rule it out, but if you need to make public policy and you don't have 10 years to wait, a policy based on a tentative analysis with a 20% chance of being wrong, which 20% we got by polling experts' Bayesian priors of the probability that a new vaccine will have a totally different curve, is probably better than a policy based on a completely random guess [paper11] [paper12] [paper13]."
Based on that you could do an expected-value calculation of how many less people will get sick under policies of holding back various percentages of vaccine for second doses (the factor you control), vs some distribution of possible random future production hiccups (the factor you don't). You might find it's better to get shots in arms now to have as many people as possible 50% protected as long as possible if you know it's implausible that it's going to be a disaster if those people wait 5 weeks instead of 3 for the second shot due to a manufacturing hiccup.
> If these weren't done for the COVID vaccine specifically, but some other vaccine, couldn't you still put some rough ballpark quantitative guesses on the COVID vaccine to help guide public policy better than "shrug, we have no clue what will happen if you do anything other than 21 days"?
You definitely could (and this is exactly what many people are trying to do!) But this approach relies on many assumptions, and the FDA is hesitant to let assumptions (no matter how well-grounded) enter into its evaluations. Thus its near exclusive reliance on RCTs. This is mostly reasonable, but it causes confusion amongst people who don't understand evidentiary standards. Thus all the braying about "no data" or "no evidence."
The underlying data is available [0] As I understand it, Phase 2 of the trials was when they determined this by looking at the immune system response. Phase 3 then looked at actual disease outcomes. (Phase 1 was safety/side effects)
It's very important to note that Phase 3 was about COVID19 disease and less about Sars-Cov2 infection. They do have some infection information, but the vaccine is licensed to prevent disease, not infection.
If there was more time, there would be more answers, but you can only run so many trials when people are dying from a pandemic.
For the people that is arguing for a delayed dose. The issue at hand is we have 80% of the stock pile unused, there is currently no point in even applying this tactic and taking unnecessary risk.
Yes, this false choice is confusing the issue. The rules for who gets the vaccine and when are poorly thought out and are leading to us using 1/6 of the available doses.
That's a separate problem that needs to be debugged. [It sounds like there's distribution problems that may be temporary or may require vastly simplifying our distribution rules - e.g. just set up drive-thrus and tell any elderly person they can come because rules restricting access slow down vaccinations -- fwiw, we discovered the similar problems when we initially tried to restrict testing]
However, once we fix that, we still have a problem of insufficient vaccine.
Should we eventually reach the point where there is a shortage of vaccine stocks it might make sense to revisit. As things are going it doesn’t seem likely though.
While I think Trump botched the initial response to covid, it was so new and we had so little information that I'm not convinced Biden (or anyone else) would have done much better.
Vaccine distribution is another matter. We knew this was coming, we knew we'd need cold storage, and there were only a few reasonable scenarios for who would be prioritized. Not getting out doses is the real failure, and not just Trump's; governors aren't doing great, either.
The other failure was not preparing for a winter surge.
How is it at all Trump's failure? The states have these doses, and it is the state health departments which are just refusing to give the vaccines to people out of "fairness".
In my state, Arizona, the injection sites are open from 8-5 every day, and were closed on New Years Day.
This is so far past frustrating to me that I don't have words for it. Get the fucking vaccines into people's arms YESTERDAY. Don't take one minute of rest until you have to as you wait to get resupplied.
We were giving 400,000 vaccine doses. So far we have used 1/4 of them. 75% of our supply is sitting on a shelf while people go home every day at 5:00, or take a day off to celebrate the new year.
Not acceptable.
I just absolutely do not understand why these state health departments won't get going. For the love of god this is NOT the time to be taking vacation days. I just cannot even wrap my head around that. This pandemic is so awful that we are locking people in their homes, doing who knows what sort of damage to an entire generation of children, locking the elderly in nursing homes isolated from the world, destroying businesses, neglecting cancer treatments and screenings, and sprinting as fast as we can towards a collapsing economy.
We have the solution sitting in a freezer. Instead of putting it into practice, people are going on vacation.
Is this a catastrophic global pandemic or not? Why are people seriously taking VACATION time during something which is causing the collapse of our society?
Here's a story from 5 days ago where a New Mexico man has had to sue for the ability to touch his wife (https://www.fox19.com/2020/12/31/husband-sues-right-touch-wi...). And people are going on vacation instead of solving this? They're going home at 5:00?
States need money to establish and run a new and fast operation, money that was finally approved by Congress long after it should have been. Trump wasn't even involved in negotiations (too busy contesting the election with no evidence and/or golfing) and then he refused to sign the bill for several days because of surprise, last minute demands he decided to make (and then go back on, gaining nothing but losing us all time). A competent leader would have been all-in on the entire process.
EDIT: It's also worth noting that these healthcare professionals you are attacking have been working under difficult conditions and at significant risk for most of a year and probably deserve either a) a bunch of extra pay that states cant afford on their own or b) some damn time off.
Thank you so much for saying this! I am beyond upset at my state for fucking this up so badly. We can't open schools but we can take time off and worry about equity over expediency?
This is how my state views the vaccine: "OHA considers the planningfor COVID-19 vaccine to be an opportunity to reimagine how the agency engages communities in co-creating the work of public health. This vaccine plan, as mentioned above, is a starting point for this journey."
Fuck this all. Get shots in the arms right fucking now
Well, it was effortlessly within his power to squash the anti-mask nonsense, instead he defended it for political reasons and I don't think any other president of any party would have done that.
Throughout this pandemic my impression is that nations generally failed on two fronts: 1. data sharing, and 2. scaling. You can't optimize what isn't measured and the vaccination programs that I know of are not sharing basic logistics data. In absence of hard data, people try to optimize systems based on hypothetical problems.
The U.S. seems unable to distribute their existing supply, Canada seems unable to acquire enough supply, the EU was slow to approve, and Israel seems to be firing on all cylinders. If we had better data perhaps we could do more than speculate about the emergent bottlenecks and best practices of each process chain.
Let’s take the Moderna trial for example, which doses on Day 1 and Day 29. I can’t find specific published data, but safe to assume that “Day 29” is not absolutely 28 days later in every case, but on average 28 days later.
So the “fail safe” method would be to have a 100% reserve of second doses at all times. No first dose can be given if a second dose is not reserved.
Alternatively, you give out all your doses as fast as they come in, and you have a separate queue for 2nd-dosers who get priority when they schedule their time slot. Some days your whole supply could go to 2nd shots.
But unless you’re willing to actually delay the second dose for several months, the total number of people vaccinated in the first 3 months doesn’t really change all that much between the two scenarios.
In either case you shouldn’t literally be locking up doses for 30 days. The smart thing to do logistically is you have tracking on doses throughout the delivery pipeline, probably knowing your specific scheduled deliveries at least 14 days out. The second dose for a person dosed today doesn’t have to sit in the freezer from Day 1, it just needs to be reserved from the delivery expected on Day 24.
If a shipment gets behind and someone gets their second shot on Day 30 or 31, obviously this is perfectly fine. The only issue with getting ahead of yourself would be a major unexpected supply chain interruption that could leave people waiting a couple weeks longer, but then we have much bigger issues.
>If people do not truly know how protective a vaccine is, there is the potential for harm because they may assume that they are fully protected when they are not, and accordingly, alter their behavior to take unnecessary risks.
Amazing, this statement could equally apply to recommending mask wearing. Seems like the prudent answer in both cases is "public education" on risk.
Public education fails against people's psychological biases and social dynamics. Its part of the solution but not a replacement for other top down policies.
I got downvoted in another thread for this opinion, but given the very obvious efficacy BEFORE the second dose (in fact the effect of the second dose is not observable at all in the incidence rate data), I find it ethically very challenging to accept thousands of additional, preventable deaths just to stick to the protocol and because nobody wants to take responsibility for a unprecedented decision.
Efficacy, like stock prices, can go down as well as up. We don't know what would happen to that chart if the second dose wasn't given. It could look like a bell curve for all we know.
They took essentially the approach most likely to be effective and deliver results as fast as possible. If you choose the overly conservative choice on dosage you might possibly end up with not meeting your efficacy goals and end up either having to rerun phase III.
The duration between doses was chosen because it was the minimum plausible time that the second dose was likely to provide significant additional benefit, and therefore the fastest to test. It's entirely plausible given what we know about other vaccines, that delaying the second dose 8-12 weeks may actually have been more effective long-term, but if they'd done that the end of the testing (and therefore approval) would have been delayed another 4-8 weeks.
It's strange to me that they couldn't test several dosing regimens in parallel.
Surely this would present no more moral dilemma than having a control group in the first place. It's just a question of numbers and resources, and if there's ever been a vaccine trial in history that could afford to throw numbers and resources at the problem, this is it.
Was there some legal or regulatory reason not to do this obvious thing?
The phase 3 trials were already large: the Pfizer trial had over 40,000 enrolled patients.
However, they were still optimizing for speed: they presented results to regulatory agencies as soon as they reached a threshold number of covid infections in the group, which allowed them to demonstrate efficacy.
If instead they ran a split-dose trial, the results from each arm would have less statistical power, so the trial could not conclude until it sees more covid patients, taking longer overall.
I think the idea is to run multiple trials, each _still_ with 40,000 patients. That way we could have approved a 2-week dosing schedule and started giving out the first doses, and by the time the first patients are ready for their 2-week dose, the results of the 4-week dosing schedule would be ready, etc, etc. So we could push back the 2nd dose "indefinitely", preventing this issue in the first place. (Assuming by the time the 2nd dose is really worth getting, we have already made enough vaccines that the scheduling details are less important)
You're neglecting the time it takes to recruit 40,000 patients. It's not fast or easy to identify those folks, as a significant number of people have disqualifiers (like comorbidities e.g., obesity). Once they're identified as candidates, you still need to go through the task of recruiting them, likely through their healthcare network. You can't just use automated calls for that because nobody's going to trust a recording that promises "Free Vaccine Fast, Act Now!"
They likely ran the trial with 40,000 patients because that was all the qualified patients they were able to quickly contact reliably enough to include them in the study (otherwise you have study dropouts, as mentioned in other comments above).
You're really missing that these prescribed regimes aren't some long-tested, optimized plan. The vaccine manufacturers literally had one chance to guess what the right application schedule was, and had one chance to do clinical trials on them.
Because they NEEDED the vaccine to work, they chose very conservative numbers. Multiple doses, high loads, super cold temperatures, etc. Those trials have produced a lot of strong corollary evidence that partial vaccinations work, but it will take a very long time to do a full set of clinical trials on those doses.
And in the interim, a lot of people will die, who probably would have lived had we proceeded with 1-shot vaccinations. There's a lot of risk here either way, and choosing and never modifying the original dose schedule is not "safer" -- it's just a bias towards inaction.
I’m not missing any point. They picked what they could initially prove and the FDA expands on this to say that yes, we could try some other variables in further clinical trials.
It’s time to start injecting people, and to stop bullshitting around it. The vaccine is not effective immediately, we’re still going to have to continue social distancing and practicing better than usual hygiene and masking for most of us. You want to save lives? Be responsible instead of advocating for reckless changes to vaccine dosages. Continue to wear your mask, continue to practice good hygiene, continue to keep your distance until such a time as herd immunity is achieved. These aren’t even the only vaccines in the pipeline, just the two authorized by the FDA thus far and Pfizer, Moderna and FDA can continue clinical trials to see if they can lighten up on the dosage requirements down the line.
> The vaccine manufacturers literally had one chance to guess what the right application schedule was, and had one chance to do clinical trials on them.
Couldn't they have done additional arms in the trial? Moderna could have had a trial arm with 1 mcg doses.
This is what I don't understand... why didn't we run several parallel studies for different dosages and time frames? I highly doubt there was a shortage in the pool of people willing to sacrifice themselves.
In other words, we basically have NO DATA on single dose schedules for Moderna/Pfizer vaccines. There's too few of them anyway to gain any statistically meaningful insight even if we did follow up on these study participant washouts. This is hydroxychloroquine all over again. When you are looking at inadequate data, you can find all sorts of patterns. It is very rare that such patterns turn out to be real. The most reasonable approach is to assume that there is little to no durable protection from a single dose, just like most prime/boost vaccines.