Are there any possible long term side effects of using such an mRNA drug that are yet unanticipated? All the short term side effects are known / will soon be. Anything beyond that, we haven't had enough experience to know?
There are people that this was tested on still hanging around with no lasting negative effects (to my knowledge).
I don't know anything about biochemistry, and I'm aware that the above is just remote speculation. It is meant as an example of food for thought. But I do wonder when a whole field of scientists state "there is no possibility of unexpected long-term side effects" to a therapeutic tool that has never been used at anything resembling this scale.
Would love to hear more experts discuss why this is considered sufficiently long-term safe to make the decision of vaccinating a billion people after nine months of testing. Am I missing something, or is it just a question of the precautionary principle in this case being considered too costly?
Edit: sorry, my comment may have sounded snarky, which was not my intention. World-wide vaccinations do carry a risk. It’s just that such a risk clearly pales in comparison to the very known downsides of the current situation. I am in no way a vaccine expert and cannot comment intelligently on why long-term risks are considered to be low.
That's not to say it isn't possible, but many things are possible but sufficiently unlikely that we take those risks. We eat, drink, and breathe many things every day that we don't fully understand the ingredients or impacts of.
For the analogy to be more accurate, the parts should explicitly not be bicycle parts.
From the responses you’d think I was talking about brain chips injected by Bill Gates, but I suppose this is the result when a layman attempts to explain something unfamiliar to other laymen.
FDA approvals aren't a black and white affair. Some drugs are approved as orphan drugs through trials designed to be much cheaper than Phase 1-3 trials when they treat diseases that wouldn't be profitable for pharma, for example, and there is a path for preliminary compassionate use approvals and accelerated development for stuff like chemo where the disease is terminal anyway. The FDA works with each company to tailor the process to their needs (although, obviously, they stick to a strict standard unless there's good justification).
Likewise, the vaccine rollout won't be all or nothing. We won't even have a billion doses for a long while and the focus will (likely) be on vaccinating those for whom the benefits outweigh the extra risk like front line medical staff and the immunocompromised or elderly. I don't expect the world to get vaccinated at gun point, although the rules for schools and other institutions will quickly accumulate to cover most of the population.
Personally, I'm not going to be taking the vaccine for a while since no one in my family is at risk and we're (mentally) preparing for several years of varying levels of isolation and other precautions. I have faith in the system for the most part since I've worked on an FDA application before (clinical diagnostics, not therapeutics), but the kind of geopolitical and economic pressure its under right now is unprecedented and should keep epidemiologists up at night (hell, it probably does). It's going to be up to each individual to balance their risks and obligations at least until we get more data.
These new vaccines have a 90% efficacy. It's probably a no-brainer to give them to someone in their 70s or 80s with a high likelihood of having an adverse covid case. But a 20-year-old?
Out of a purely selfish wish of having a more normal world, part of me wants to suppress these thoughts and think "I'm probably excessively cautious, it's a good thing that the economic pressures will probably ensure that most are vaccinated in a year or two". But I do worry that many healthy people don't have a complete view of the potential for unknown unknowns when they decide to take it.
The selfish part of me is thankful that someone else does the dirty job for ensuring that those thoughts aren's spread wider. I'm really hoping that the authorities know what they're doing, and I'd definitely be lying awake at night if I was in that role.
I probably won't take it myself - there, I said it - but rather wait and get more data, or maybe go as far as seeing when one of the protein-based vaccines are ready.
People only use the precautionary principle for things they don't want to do.
It's very good for that, since it always results in recommending not to do things.
I think, generally, it has been discussed. There's lots of research on mRNA vaccines going back decades at this point, though they haven't made it to market until now. I see people saying "it's not being discussed" often on this site, but really, anyone saying "no, this is safe" has the implicit support of all that research behind them.
"Suppose someone was infected with a retrovirus, could reverse transcriptase embed that rna into the dna? This could be especially worrisome if we're talking about a pregnant woman and fetus undergoes rapid cell division... etc.."
I would be surprised if I did not mangle up some terms & concepts in the paraphrasing above. Someone who knows more can correct me or just watch/read the fda hearing.
Another thing that was mentioned in the FDA hearing was that pfizer also tested it on HIV positive people. HIV is a retrovirus which also carries the reverse transcriptase enzyme. I don't want to draw any conclusions from this because I don't have any medical knowledge. Maybe someone here with more insight could comment.
> Moreover, mRNA vaccines induce transient antigen expression, while DNA vaccines provide a long-lasting expression, thus mimicking an acute viral infection. Although a transitory gene expression might be desirable as it minimizes potential risks of genetic transformation, this inevitably affects mRNA potency, thus necessitating a dose increase.
This means that mRNA reduce the risk of genetic transformation compared to DNA vaccines, but it comes as a price because you have to deliver a larger dose of mRNA.
This means that when circumstances say no you cant, biological entities find a work around.
as a cover your ass practice, even the smallest chance of occurence means non zero chance.
in this case an mRNA would have to be captured by a reverse transcription system most likely due to co-infection with a retro virus, that complex would have to be functional and would have to be transported into the nucleus.
this is a very remote chance but non zero, thus :
"minimizes potential risks of genetic transformation"
the RNA must interact with retroviral reverse transcriptase in a manner that makes a functional complex or it will just be snipped apart and decycled like garbage.
RNA will fold and produce 2' structure this has interesting consequence. catalytic RNA, structural RNA, stabilizing or protective RNA..
[0] https://www.youtube.com/watch?v=RYwVnzYf4V8
[1] https://pubmed.ncbi.nlm.nih.gov/20358252/
[2] https://sci-hub.st/https://doi.org/10.1007/s00018-010-0346-2 [PDF]
[3] https://www.researchgate.net/profile/Tania_Matamoros2/public... [PDF]
from the paper [3] above: "Reverse transcription initiates after binding of a cellular tRNA primer (in HIV-1, tRNA Lys,3 ), to the primer binding site (PBS). The PBS is a sequence of 18 nucleotides, located downstream of the 5’-end of the genomic RNA. The viral RNA that serves as template for reverse transcription is flanked by repeat (R) sequences at its 5 ́ and 3 ́ termini."
the vaccine mRNA does not meet these requirements.
retroviral RNA is configured to function with the reverse transcriptase. Promiscuity to include other RNA is exceptional not common.
virally infected cells also undergo changes that exclude further infection so they have the cell to themselves.
i would like to say zero chance, but life is in the business of sidestepping the rules to its advantage, however you have a much greater chance of being attacked by a shark while hiking the sahara dunes.
the situation was artificially created.
the retroviral Reverse Transcriptase must be present in the individual cells also infected with the covid virus.
Anti-vaxxers are generally tolerated until there's a critical mass of them, which start causing problems for everyone else.
At any rate, government tyranny has killed millions and millions more than viruses have. And I won't stand for it. Medical tyranny will never be tolerated. If YOU want the vaccine, you get it. That's how liberty works.
So, while I used to write comments like yours, myself, I don't bother anymore. I'd have to spend years toeing the line to build up enough karma to not get shadowbanned for it.
Anyway, I sign in here to say that I'm with you. I think it's important to show that this point of view is not the minority view in this country, and maybe even the world, despite all the media does to make it look like it is.
It looks like China's already started World War 3 in terms of "Unrestricted Warfare" (China's term, not mine): financial, biological, psychological, political. Just regarding COVID, they told the world COVID wasn't infectious between people, they held a 40,000-person potluck dinner in Wuhan while the virus was spreading and then let people travel out of the city, they threatened to turn ships around and withhold masks and medicine produced in China...how can anyone look at what China's done and not recognize their malicious intent? At the same time, they're building up their military around the world, indebting poor African nations, pushing their troops into Nepal and India (and actually killing Indian soldiers)...the list goes on and on. We have to wake up before it's too late.
[Of course, the 50 Cent Army is active on HN. Watch my comment fade away...]
Now, we have the (repeatedly) proven ability to avoid such a disaster, and you argue we should not? You really think protection from disease is not a basic human right?
We are not gods. At least with previous vaccines we just killed off the active parts and said “hey, go bull fight this” to our immune system.
Last bit: Leverage works in both ways
It depends on the function of the protein if this leads to a bad outcome.
This statement cuts both ways — if this recent pandemic was human made we need human solutions... only IF the virus is insurmountable.
As someone with direct experience with a large N, this virus is nothing to exponentially increase long term and second order risk with human “solutions” ... UNLESS the long term effects for asymptomatic cases are severe and under reported.
Again... too many variables outstanding to be certain, but highly cautious
https://www.reuters.com/article/uk-factcheck-hiv/fact-check-...
"This is a reference to trials of a vaccine being developed by the biotech company CSL and The University of Queensland which used a fragment of a HIV virus protein as a component to stabilise the vaccine (here). Production was halted after trials showed that antibodies generated in response to the protein fragment could lead to false positives on some HIV tests (here)."
https://www.modernatx.com/pipeline/modernas-mrna-clinical-tr...
A handful of studies are currently recruiting for Phase 2, so that means there was a successful Phase 1 some years ago. So those people would, I believe, be the longest-surviving patients to have received an mRNA vaccine.
They might be followed closely for a long time; but it may only be a handful of people too.
The mRNA is translated to a protein, which is the actual target your immune system then recognises as foreign, attacks, and remembers.
In a sense, it's a lot like a prodrug, which is a "traditional" small-molecule that is turned into the actual drug by some interaction with your body–your stomach acid, for example.
"mRNA" might sound scary. But it isn't going to change your genome or anything like that; it's strictly downstream from DNA. Any virus, bacteria, or salad you eat contains far more mRNA in addition to DNA or RNA, and the first of those really does come with mechanisms to insert itself into your cells' DNA and has evolved to defend itself against your defences, and to slowly take over your body in some way or other.
There are some short-term risks on the order of, say, eating lobster for the first time. Allergies, for example, which can be quite severe and even deadly. But those are exactly the risks the trials would have uncovered, and the people possibly at risks of such things would already know they are susceptible.
There is no known mechanism for any risk that would not manifest within the first day or two.
You have heard of mad cow disease? Also how misshaped proteins are pretty much impossible to destroy eh?
HOWEVER, knowing we as humans tried to replicate the exact “key card” into our cells that makes this virus so potent (aka the spikey bits with the ACE receptor end) worries me greatly. That’s not on evolutionary time scales or mutations... that sounds like IVF and diabetes.
If you think it's a risk, quantify and measure it, and compare it to the risk of not doing anything. People love to grouse about vaccines, bit they never seen keen on doing the math. (Because it consistently does not support such an argument.)
The doses have 30-100 ug. Assume 1)this is pure RNA, and 2)the molecules are about the same size as the spike protein sequence. With these assumptions, a dose gives you 10^10 RNA molecules. Average sputum samples show about 10^6 molecules/mL; max samples show 10^9/mL. I don't know how vaccines dilute when you inject it into somebody's shoulder, but it doesn't seem unreasonable to say the final conc will be between 10^6 and 10^9 RNA/mL.
So RNA is going to be in us, whether we want it or not. The question is, do you want the whole genome, or part of the genome. I'm picking the one that doesn't make more virus.
Is this way of injecting mRNA really any different from just injecting someone with a virus? Not in the sense that it makes you ill but in the sense that a virus would do the same thing just with more harmful mRNA.
If you inject with virus, presumably the virus would begin to replicate and attack your body.
You don't want the virus RNA, that would be presumably all that plus more!
The answer to your question is, it's a subset of the virus.
I'm not sure but I strongly assume yes.
The MAIN reason for this skepticism is that if it was just possible to introduce RNA such that we could have a net positive benefit against coronavirus, a virus that has existed for almost as long as mammals have, we'd have naturally evolved this ability.
The reason we haven't is because it will introduce more problems than it solves down the line.
It could very well be that with a limited understanding of human immune system, we have stumbled upon a solution to a problem that has affected us for millions of years. So, I think some people should try it. But forcing it on the masses is a terrible idea.
Also, COVID-19 has not been around "for millions of years." Other coronaviruses, such as the common cold, have. The evolutionary benefits of defense against the common cold are fairly different than benefits against COVID-19. And immunity against one coronavirus doesn't grant immunity against all other coronaviruses.
That is true. Most of them don't work, not without creating worse problems down the line. Specially, if it's something as simple as creating some proteins that the body can already produce (which is what happens when mRNA vaccine is given). If the solution was as simple, evolution would have found ways to do that.
Currently, some deadly diseases do have some treatments that work... but that comes at HUGE expense i.e. a LOT of energy has to be spent for little gain. It is only possible because there is huge inequality among people and the rich class can afford to spend enormous energy and manpower to treat those diseases. If and when the world becomes more equal, this will no longer be possible (you'd think that "robot slaves" working off of "free energy" would solve that... I don't think that's going to happen but that's a different discussion).
>Also, COVID-19 has not been "around for millions of years."
We can't know that. It could very well be that COVID-19 had infected mammals before and we naturally god rid of it in a few generations. When infections come about, "weaker" individuals die and those with stronger immunity survive and reproduce and the species of COVID-19 might have died out. Some coronaviruses continue to live with us because they don't cause major problems... but there must have been many more which caused major problems and we had had to deal with them differently... and one of them could have been very similar to COVID-19.
But yeah, it could also be that this is the first time we're encountering it. So, let's go with that. My argument doesn't change.
>immunity against one coronavirus doesn't grant immunity against all other coronaviruses
True. However, in millions of years, our immune system has encountered many species and strains of coroviruses, and trained on that data and come up with a much more generalized and long term solution. I'd rather trust that than some random know it all people who think that have a better solution with very limited knowledge of what is going on.
Having said that, I'm not against testing new solutions. It's the scale that bothers me.
We'd have naturally evolved the ability to train our immune systems against specific things it hasn't seen before? How would that POSSIBLY work?
The novelty of this particular coronavirus is sort of the problem here, since people don't already have immunity, so your "millions of years" thing is completely off base.
You seem to be arguing against the possibility of a "universal vaccine" for all viruses but that's entirely not what this is. It's very specifically targeted and the idea that we'd evolve the ability to target things specifically without actually being exposed to them in the same way is plainly nonsense.
> How would that POSSIBLY work?
Through a process called V(D)J recombination [2]. Essentially, every lymphocyte gets a different receptor of random shape, and purely by chance there will be a few lymphocytes with a receptor that matches the shape of the invading viruses (in most cases).
But the poster I was responding to was claiming that our immune system should have evolved the ability to not respond to those threats, but anticipate their specific forms without seeing them. That vaccination as a concept is hogwash because if it was useful, we'd have done it through evolution. But that's plainly nonsensical - we wouldn't need a system that functioned by random variation if we evolved the ability to know what the real targets would be, but we couldn't do that without specific knowledge, which we can't get without being exposed to the things, by which time ... it's too late to have then already built the specific defenses.
See my response to another comment. We must have dealt with countless species and strains of coronaviruses already. So, our genes have a lot of training they need. Even if we haven't trained for this particular strain or species, we will most likely fare better than the solution that has never been tried ever.
What if the children of those vaccinated turn out to be much weaker against other common antigens start dropping dead? It will set humanity back by a lot.
These are not exaggerated hypotheticals. These are VERY REAL possibilities: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5607155/ https://www.ncbi.nlm.nih.gov/books/NBK233000/
>since people don't already have immunity, so your "millions of years" thing is completely off base.
We do. Most people are completely unaffeted by the virus. It's a relatively small percentage that has severe problems. To endanger EVERYONE because a small percentage is affected is downright retarded. Having said that, I'm not at all against trying different things out. The best way to roll it out would be to do it over a VERY LONG PERIOD, spanning generations. And most importantly, keeping significant number of people completely unvaccinated. This has not been a problem until now because big enough population chose to be unvaccinated. However, the scale of current problem might mean that this could change... which is terrifying.
>> The reason we haven't is because it will introduce more problems than it solves down the line.
This is just not sound reasoning, and it's a terrible argument against the vaccine. Have you ever taken antibiotics? Or have you ever benefited long-term from anything medical that we didn't "evolve" through natural selection? Because I sure as hell have. How does this not apply to other vaccines, which have clearly saved an astonishing number of lives, and have, almost without exception, not produced the kind of long-term existential threats to humanity you seem to be hinting at.
It does apply to all vaccines. Vaccines bias the immune system, which has evolved to be general enough to deal with problems that generally come our way. This bias caused by vaccines results in better performance against those specific viruses but comparatively worse performance against most of anything else. This can also result in auto immune disorders down the line:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5607155/
Generally, this bias also happens naturally when viruses infects populations. But the tradeoff is mostly worth it when the virus is still at large... and the natural population is optimized for wide variety of attacks because the immune systems are biased in many different ways in the first place, so even after a pandemic, the resulting population will still have a varied enough immune systems.
Large scale vaccinations bias the population in a very few particular ways. When vaccines for multiple viruses are given to everyone, the immune systems become more and more similar than it would ever happen naturally. So, mass vaccinations make us more fragile as a species against future pandemics, not to mention the autoimmune disorders that also happen as a result.
Given that vaccines have unintended consequences, you probably agree that targetted vaccinations are effective i.e. what if we could vaccinate exactly those who will get infected right before they get infected? That way, we could help them fight the infections better while not affecting anyone else. Right? That is how the immune system already works. It starts the fight right after it detects the infection.
Sometimes, the immune response is not appropriate and can cause more problems than it solves. The same can happen with vaccines.
Sometimes, the immune response may be appropriate but is not sufficent to save the host. The same can happen to vaccinated individuals. It can be argued that the headstart that one gets because of early vaccination might make it worth it... but you also have to consider how many will be vaccinated even though they never really get infected and how many will be missed anyway... and there is also a cost to determining these things. So, overall, it is highly unlikely to be worth it.