- This isn't really the reason why mRNA is attractive here (see my other comment above). (Though, ability to iterate/try many protein combinations quickly in animal models was helpful).
- Almost no drugs or treatments do we really know the long term picture of. Running studies in a way that lets you detect effects far later in life isn't practical.
- When we're talking about treatments to prevent severe disease, bounding the consequences to be very, very likely to be well below the consequences of the virus times the likely infection chance is "good enough".
Vaccine are building an immune response, they're not drugs that try to cope the symptoms (eg. Panadol) and they are the safest drugs out there.
Is so interesting how people eat Panadol and many other drugs like candies (without reading the KNOWN side effects - which are also nasty), while they focus so much on things they know nothing about thinking that has mysterious "long term effects"
I strongly doubt that Acetaminophen would be approved as an OTC drug if proposed today.
> He died at a hospital in Seattle. His wife, Cindy Engstrom, said he had injured one of his feet in October, accidentally took too much Tylenol for pain relief and suffered liver damage.
Once I realise that the Flu (or whatever) is inducing enough pain that I can't ignore it, or I start to run a serious fever, I take paracetamol to get on top of that, usually in the form of Lemsip because I'm bad at taking pills, Lemsip is cheap, and none of the other ingredients in ordinary Lemsip these days really do anything much, just the paracetamol.
I find maybe 1 or at most 2 of the "maximum" 1g (= 1000mg) doses a day gets the job done, which is well inside the indicated limits.
None of the OTC alternatives do it for me, they're not useless but the effect from the indicated dose is far reduced so I'm glad to have paracetamol. I've had fentanyl after surgery, which was certainly effective but seems like a very bad idea to have around the house, and Entonox after a road accident which again, effective but seems like a bad idea for OTC usage.
Popping NSAIDs multiple times a week on a regular basis is definitely not good, and yet the same people who do that are often afraid of vaccines.
People are seriously clueless about relative risks.
I'm not saying Advil is dangerous, I'm saying people significantly overestimate the risks of vaccines.
If you're concerned about vaccines but not about other common drugs, you're in need of some risk calibration.
The good news is that I am not concerned about the safety and efficacy of vaccinations. I misinterpreted your comment because of the way it was worded. This is because I know some over the counter pain medications, like Tylenol, can be dangerous. So, I assumed there was a risk to Advil that I wasn't aware of and wanted to know more, given your background as a Biochemist.
Also, NSAIDs are shown to slow healing from injury in most cases.
Ibuprofen is terrifically useful but also a little scary for something we use so routinely.
e.g. some parents gave their 7 year old a motrin, and all her skin sloughed off her body and she had brain damage and lost 80% of her lung function.
https://www.cbsnews.com/news/jury-awards-63m-to-samantha-rec....
And fatal anaphylactic reactions to vaccines aren’t atypical.
My point is not that Advil is particularly dangerous, my point is that people dramatically overestimate the dangers of vaccines.
Look at Vioxx. It took 4 years on the market before anyone realized it increased the risk of heart attacks.
Advil has been around for decades. It has known risks.
I have all three vaccine doses too, I’m not saying don’t take the vaccine, I’m saying Advil has a more robust safety profile.
Other drugs don't have a better safety profile if they were tested for so long. If anything, it proves that is highly toxic for your body (similarly to many chemio treatments)
Covid has been around for 2 years. The vaccines for 1 year. We don’t know the long term effects of either.
Vaccines were trialed for dengue fever that made the disease worse. Vaccines are NOT “the safest drugs out there”.
Anyone who says “the vaccines are the safest drugs out there” is just lying or incompetent.
The risk of an autoimmune disorder may not show up for years.
Our data collection right now is garbage and it’ll take years to sort through.
"Autoimmune disorder" probably have a very low correlation and if anything vaccine have saved the life of many, more than any other drug.
This is because there generally isn't a known mechanism for vaccines to have long term effects. Not ruling out the possibility, but we understand how vaccines work pretty well. Also, most vaccines are subject to a cost/benefit analysis anyway (we don't give the rabies vaccine out to everyone) so the miniscule chance of having long term effects has to be weighed against the much more likely long term effects of the disease.
I know a lot of people believe this, but as a developer who regularly deploys code to production, this mindset blows me away.
I'm not saying that being a developer means I know anything about this. I'm well aware of my (our? I don't know what you do) peoples habit of thinking being good at our craft means we're also somehow suddenly good at others.
But if I told someone that I don't need to know the effects of v7.1.3 before patching it because I can't think of a mechanism for it going wrong, and besides, we already released all those other versions and they were fine, I'd hopefully be fired.
I get it, software and medicine are different things, and some things just aren't practical in meat space, but the mindset around testing is something that I think will always be difficult for me to understand after being in this occupation for so long.
You are missing the point. If someone told you they are worried that your code is going to turn the CPU into strawberry jelly, you would be correct if you said 'there's no known mechanism that will cause that'.
It's not quite strawberry jelly, but depending on the target you're writing for, you could destroy the actual hardware (think embedded devices).
If you presuppose that adverse effects can't happen, then sure, your quip makes sense. But pharmaceuticals having adverse effects isn't some unimaginable thing, it's expected and tested for.
Not for potential issues tens of years later, which is basically the concern people are raising about these vaccines. We instead look at known potential mechanisms that could cause harm and operate off of that.
We have studied the short term side effects of these vaccines, much we do anything else, and have looked at known potential mechanisms that could cause issues down the line, and have not identified any. This is more or less the same standard applied to just about any medical research for drugs, vaccines, other treatments, etc.
I am concerned about tens of years later, but also about just ones of years later as well. We've done the best we can so far, and it seems like a clear win for some categories of people. For others, it's not so clear (like young healthy people with a previous infection living in the age of omicron for example. This is not medical advice, go to your doctor for that).
> This is more or less the same standard applied to just about any medical research for drugs, vaccines, other treatments, etc.
Sure, but I'm not chomping at the bit to take any more of those either (already had all the usual vaccines and then some, minus flu). And those other things have been around long enough that adverse effects eventually become unmissable. You see those occasionally in class action commercials.
That reminds me of the first atomic bomb test. We weren't 100% sure that the atmosphere wasn't going to ignite with an atomic bomb, but those that knew the physics knew it was almost impossible.
> "If, after calculation, [Compton] said, it were proved that the chances were more than approximately three in one million that the earth would be vaporized by the atomic explosion, he would not proceed with the project. Calculation proved the figures slightly less -- and the project continued."
https://www.insidescience.org/manhattan-project-legacy/atmos...
Of course it can, that's what you use to write your test plan. But I never (ever) rely on those predictions alone. Everyone who has done this long enough knows that if you don't test your code well enough before you push it out, it will fail. Hell, it'll even fail sometimes when you did thoroughly test it.
If you had to push code and wait a year for feedback then how you tested and pushed code would change dramatically.
Now imagine the environment you were pushing code to was
1. Always changing in very small ways that could sometimes have huge affects due to completely random variable changes you had no control over. 2. Every host your ran your software on 'could be' different in ways that are incompatible and you have no way of testing all of them.
Welcome to the problem space of biology.
But this isn't what they're saying. They're saying that there are few to no ways for it to not have any detectable issues for 6 months and then suddenly go wrong (which I'll note is also true for software!). Canarying and staged rollouts are a good idea in software, as they are in medicine. But much like you don't think its necessary to canary v7.1.3 for a year, just in case it has a bug that makes it shut down suddenly after 200 days, its probably not necessary to wait a year to see if a vaccine causes sudden acute liver failure after 7 months, because there just isn't a biological mechanism for it to do that (the vaccine is already out of your body by that point!).
And to the extend that such issues are possible (leap days can do weird stuff), we can look specifically for those mechanisms (like say monitoring for stuff that would lead to liver damage in the weeks after vaccination).
Over the years I've become a little obsessed with imagining the ways things can fail (I'm just as fun at parties as you can probably imagine).
An example that immediately jumps to mind where that is not true for software would be something that quietly uses some resource that you didn't expect (open ports, filehandles, space on disk/memory, the space inside of however many bits you have for a field, anything like that). These are things that you don't know to test until you've seen them fail, and only then can you start to automate.
One possible analogy here is cancer or autoimmune issues. If you get diagnosed with either of those today, they almost certainly started a while ago, they just weren't detectable until today. Or maybe they would have been if you knew exactly where to look, just like if you knew to keep an eye on how many ports you had left on your live server. (Not claiming these vaccines cause these things, I'm sure some peoples blood pressure started rising as they read this).
The complexity of software is nowhere near that of the human body or populations of humans, and yet it can be incredibly hard to predict. Multiple backwards compatible versions on the client and server side, running on different hardware with different operating systems, all of these things changing over time. Unexpected behaviors can absolutely show up at any time.
Of course you can't test it all, but you do what you can, and then after that you monitor very carefully, but its way more expensive to fix the problem after it reaches prod. In humans, there's a chance that its not just expensive, it's impossible.
Some engineer creates a fix by turning off some recently added experiment responsible for the service degradation. The rollback passes all unit tests and integration tests. You know this fix is low-risk (maybe because your service was healthy for the ~1 year prior to the rollout). Even if there is some risk that this rollback breaks the service at some point in the future, in comparison to the known revenue loss the expected loss of that breakage would be minimal.
Another engineer objects to the rollback saying that "they don't know of the long term effects of such a rollback." You try to counter their claims by showing that previous rollbacks were almost always successful, and when they caused another failure that failure was not nearly as bad as the original service degradation. Also, the rollback passes all tests. That engineer then repeats "we don't know of the long term effects of this particular rollback, and I'm skeptical that the fix is good because the failing experiment and rollback was identified so quickly."
(Rollback vs. fix-forward doesn't actually matter; the point is that all available knowledge shows that the fix is low risk, historically supported, and that there is likely no mechanism for random failure in 6+ months.)
Do you think it would be correct to prefer the second engineer's claims?
But the assumptions that you use to calculate that net are where all of the disagreements stem from. In your example, you've constrained it to losing well defined revenue, and "you know this fix is low risk", so the answer is easy.
Maybe (wrongly or rightly) you don't have faith in the revenue numbers, or in the test suite or the engineers writing the tests or the fix, maybe there's office politics involved, etc.
This thread started with my reaction to these lines from op:
> Knowing long-term effects (1+ years) is not a precondition of approval for most vaccines. It just so happens that vaccines usually take a long time for approval, so we end up knowing long-term effects as a side effect. This is because there generally isn't a known mechanism for vaccines to have long term effects. Not ruling out the possibility, but we understand how vaccines work pretty well. [...]
I've seen this claim dozens of times, and it always always always makes me think of those scenarios where you find a bug in code that you or someone you trust/respect wrote from the ground up, and you wonder "how in the f*** did this ever work?". I'm not claiming I'm right to feel that way, maybe this is a defect in my character, but I just can't buy the "we understand vaccines pretty well" thing.
You seem to be taking this from the perspective that, because there are unknowns, literally anything could happen. And we don't think that's the case with my vaccines or code.
Pushing v2 of your webapp to master isn't going to cause rockets to launch. There are things that could happen and there are even very surprising things that are unlikely but could happen. But not everything is possible.
When we say "we understand how vaccines work pretty well", we mean that in the same was as "we know how our app works pretty well". That doesn't mean that we can't still be surprised, but it does mean that we have some things that we can be confident won't happen.
One such thing is sudden onset symptoms well after the thing has left your system, because there isn't a biological way for that to have an effect (to use the code analogy, you enable an experiment, it modifies database writes for a while, then you disable the experiment and delete the code. Once you've deleted the code, we know it can't do anything else, because it's not there anymore.
That's true with both vaccines and webapps.
The hard part about conversations like this are that you could have written the definitive book on this stuff, or you could be just another dummy on the internet like me. So I have to take a statement like that and do my best to evaluate it myself, since I have no idea how to value your expertise. If you're an expert of some sort, I apologize in advance.
We know for a fact that vaccines have long term effects. They wouldn't be useful otherwise. It would be nice if they could only have positive long term effects, but why would there be any guarantee of that?
Symptoms could start immediately but be undetectable until they progress far enough (think a tiny little tumor for just one example). Again, not claiming this is happening, just saying that it seems nutty to assume it can't happen.
When I read "we understand how vaccines work pretty well", I automatically translate it to "we understand pretty well what happens when we inject a substance into a human body", and then I think "really?". We have some useful models, sure, but "understanding pretty well" seems a vast overstatement of the situation, especially when its laypeople chatting on the internet.
The abstract concept of a vaccine is pretty simple. Anybody can regurgitate the picture book version of it. Any specific instantiation of one is remarkably complex, all the way from manufacturing, to transport, to administration, and then interacting with the legacy ball of spaghetti that is the human body and it's various systems.
The fact that we humans decided to name some substance the same thing that we named some other substances that we created in the past doesn't necessarily tell you how that substance is going to interact with the body. It can provide you with hypotheses, but hypotheses need to be tested.
Correct, but, and this is the important bit: the only lasting thing the vaccines do is leave your body primed to react to certain proteins (everything else they "do" leaves the body pretty quickly, you can think of this as a fairly limited api they're interacting with). This could be a bad thing, but if it is
1. Anyone who naturally caught covid would also suffer the same consequences
2. you'd expect to see the issues as soon as the immune system was primed, this takes days to weeks, not months.
So yes, there are all sorts of weird thins that could happen, but I'll reiterate: we know of know biological mechanisms that would make those things happen suddenly, without warning, months after the vaccine. We understand, very well, that such things can't really happen.
Just because you don't understand the human body very well doesn't mean the medical establishment also has equally no clue.
That is of course the goal, and assumes nothing goes wrong in the manufacturing, transport, or delivery mechanism for the payload. But if they haven't been tested for long term adverse effects, how do we know this? And again the answer ends up being because we know how vaccines work and round and round we go.
But let's leave that and assume that it actually does verifiably only prime the immune system to react to certain proteins. Is that some small thing? Immune disorders can range from annoying to horrific, and they're all from just reacting to certain proteins.
> This could be a bad thing, but if it is 1. Anyone who naturally caught covid would also suffer the same consequences
This seems to be a hypothesis. The current vaccines are based on a modified little chunk of a now extinct(?) variant of the virus plus some novel packaging. That they should have the same effect on the body as the whole current or future dominant variant (edit: entering the body via a different pathway) doesn't seem obviously true.
> you'd expect to see the issues as soon as the immune system was primed, this takes days to weeks, not months
Why? I'll use the same example again. If a tiny little tumor were formed, or would be formed over time as a result of some protein reaction that started right after being dosed, why would you expect it to be detectable immediately?
The specific mechanism isn't important, it's just the "we can't think of a way it could fail, therefore we dont need to verify this" is just impossible for me to get my head around.
Feel free to drop the conversation if this gets frustrating. I will continue to ask until I understand, and I may not get there. I'm actually enjoying this, but I know I'm weird and this drives some people nuts.
> Just because you don't understand the human body very well doesn't mean the medical establishment also has equally no clue.
Fair, but that's not my claim. I can be at 1, while the medical establishment is at 100, and actual understanding of what's going on in the body could be 10000. We do some black box testing and get some somewhat repeatable results. That's a pretty amazing feat, but still a far cry from really understanding what's going on under the hood.
Pushing webapp code to master certainly won't result in rockets launch, if only because no sane person physically connects launching platform to build server ("no biological pathway"). On the other hand, deploying build artifacts carries much more risk. This risk is usually mitigated by extensive multi-level testing and appropriate live monitoring. In addition, the target environment for software is, at least theoretically, fully tractable. I.e. it can be de-constructed and understood to the very last bit. It is also fully human-made and controllable, without random nuclear reactors hooked up to web server. If such invariants cannot be established, I think it is not ethical for a senior software engineer to approve mandatory wide-scale deployment. Under such conditions the decision must be strictly on the owner of each server.
In case of vaccine we deal with infinite number of reasonably unique "environments" - human bodies. We know that each of these "environments" are absolutely capable of developing a million of adverse things like cancers, strokes, autoimmune diseases, etc. So, the "biological pathway" exist, the "rocket launchers" are there. Our understanding of inner workings of human body is very imperfect, as demonstrated by the fact that humans still suffer and die from all sorts of diseases. Our monitoring tools are very limited, and our analytical framework is just blunt statistics. The vaccine is, basically, a clever hack into a half-understood system. So, it is certainly up to the owner of the body to decide what to "deploy" into it. And disagreement or misunderstanding, in my opinion, is exactly around the concept "who really owns one's body".
The database analogy is also interesting, in that while the experimental writing code is gone, the database remains modified. In sufficiently complex and poorly understood system how can one guarantee that modified data doesn't cause any unhandled exceptions down the track, especially given the number of vulnerable third-party clients?
I'm not against vaccines at all for the record. But this doesn't seem like a strong argument for them.
Cells multiply by themselves all the time. Triggering that effect is how you get cancer. Your heart beats constantly. Triggering that too much (or in the wrong rhythm) is not a good thing. There are probably a ton more examples.
Those are wrong analogies though. Vaccines don't trigger something too much. They trigger the exact same mechanism that will be triggered anyway when you get infected with the actual virus, but in a safe way.
However, with HIV as with COVID, there's a pretty significant installed base around the country so showing that it works isn't really a challenge.
Usually only a few thousand or tens of thousands of folks participate in basically any drug trial, btw. We very well understand the risk profile of mRNA vaccines at this point, having deployed billions of them and studied the technology for 40+ years. And having studied vaccines for upwards of 300 years.
What you define as "long term"? Because in my definition, in the "long term" we're all dead.
The "long term" effects of many pathologies is also death for example.
My wife's studio got a "everyone who takes the vaccine will die!" pamphlet pushed under the door, which gave us a good chuckle.
I ask that you please speak to some people in South Africa or Botswana where almost 20% of the population live with HIV, including children (both victims of rape - there was and still is the belief that having sex with a virgin can cure AIDS - and children of HIV-positive mothers who were born with the condition).
It's beyond inhuman, and if such a vaccine were to work it would be as impactful as the eradication of Polio (yes, I know it still exists in some places) or Smallpox.
So more likely you’ll just get over a shorter release cycle and the longer one gets deprecated, relegated to certain style of treatment that mRNA based investment and research will run laps around anyway, further pushing people to evaluate and prioritize mRNA versions.
You can try to hold out for an arbitrary threshold of “long term” for your own comfort level. Its accurate that the state wont be helping you.
mRNA is like a file for a 3D printer, telling the body what to print for. Other styles of treatments were showing the body the payload. We will definitely learn how often we can get the body to do this, but I wouldn't call it an inferior beta status. Its just as good (or bad) as the longer process for different kinds of treatment. Same efficacy, which allows me personally to not focus on that.