Am I crazy for being nervous about taking an mRNA COVID shot?
Like all of you I’m not an expert in the field, but from what I’ve skimmed online it seems like mRNA vaccines have never been used widespread in humans before? This is making me want to take the J&J one instead.
I’m totally open to other opinions though, I haven’t made up my mind on this.
I'm not specifically an mRNA vaccine expert, but I have a biomedical science PhD, and my "generally well educated in this area" gut feeling is that mRNA vaccines are a simple, "clean" formulation with less chances for something surprising to go wrong compared to other vaccine formulations.
I got the Moderna shot and I've been totally nerding out about how cool it is. It's just mRNA, which basically falls apart when you look at it funny, with just enough lipids to hold it together until it gets into your cells. If there were going to be terrible side-effects, I would expect them to show up immediately or not at all, since the constituent ingredients are simple things that break down quickly in the body.
Same. Infectious disease epidemiologist, and I am hyped about how cool this is.
I got the Pfizer vaccine.
This is such a huge step from some of our older vaccines, which had much higher side effect rates, relatively speaking. These vaccines were tested in large clinical trials, and we're seeing very few poor outcomes. And yeah, what's in this vaccine is so much more ephemeral than "This virus is...mostly harmless?"
That claim you’ve just made is completely inconsistent with evidence showing much higher side-effect rates for mRNA over traditional formulations.
Moderna has something like an 80% incidence of fever after the second shot. That incidence of side-effect is unheard of, but in the opposite direction you claimed.
I didn't mean "statistically significant" or anything otherwise technical.
This is the data I pulled [0] (apologies to mobile users for the formatting, it's TSV):
COVID19 VACCINE (COVID19) 8,507
DIPHTHERIA AND TETANUS TOXOIDS ACELLULAR PERTUSSIS POLIOVIRUS INACTIVATED HAEMOPHILUS INFLUENZA B AND HEPATITIS B VACCINE (HEXAVAX) (6VAX-F) 29
DIPHTHERIA AND TETANUS TOXOIDS AND ACELLULAR PERTUSSIS VACCINE + HEPATITIS B + INACTIVATED POLIOVIRUS VACCINE (DTAPHEPBIP) 2,247
DIPHTHERIA/TETANUS/PERTUSSIS/HEPATITIS B (DTPHEP) 8
HEPATITIS A AND HEPATITIS B VACCINE (HEPAB) 256
HEPATITIS B VACCINE (HEP) 5,991
With the query criteria:
Serious: Yes
State / Territory: The United States/Territories/Unknown
Vaccine Products: COVID19 VACCINE (COVID19); DIPHTHERIA AND TETANUS TOXOIDS ACELLULAR PERTUSSIS POLIOVIRUS INACTIVATED HAEMOPHILUS INFLUENZA B AND HEPATITIS B VACCINE (HEXAVAX) (6VAX-F); DIPHTHERIA AND TETANUS TOXOIDS AND ACELLULAR PERTUSSIS VACCINE + HEPATITIS B + INACTIVATED POLIOVIRUS VACCINE (DTAPHEPBIP); DIPHTHERIA/TETANUS/PERTUSSIS/HEPATITIS B (DTPHEP); HEPATITIS A AND HEPATITIS B VACCINE (HEPAB); HEPATITIS B VACCINE (HEP)
Group By: Vaccine Type
Show Totals: True
Show Zero Values: True
It looks like ~130m people in the USA have received at least one dose of any Covid-19 vaccine [1]. It's hard to pin down a number of Hep B vaccinations as of 2021, but it looks like about ~70m people had been vaccinated as of 2002 [2]. 91-93% of newborns in the USA have been vaccinated for Hep B every year since then [3], and I very roughly guessed that 3.5m babies are born every year in the USA [4]; at 91% of 3.5m over 20 years, that's very very very roughly 64m people vaccinated against Hep B since 2002.
So there have (maybe) been at least as many Hep B vaccines administered as Covid vaccines, and there have been 2500 more adverse events for Covid-19 vaccines than for Hep B vaccines. The difference is smaller than I remembered, so I regret saying it's "significant".
That said, we can compute 99% confidence intervals [5] for both of these (in R):
library(binom)
(cis <- binom.confint(
x = c(8500, 6000),
n = c(130000000, 134000000),
conf.level = 0.99,
methods = "agresti-coull"
))
# method x n mean lower upper
# 1 agresti-coull 8500 1.30e+08 6.538462e-05 6.358307e-05 6.723719e-05
# 2 agresti-coull 6000 1.34e+08 4.477612e-05 4.331152e-05 4.629023e-05
So yeah, the difference between 4.5 per 100k and 6.5 per 100k is statistically significant. The two estimated distributions basically don't overlap at all (which you can confirm by looking at the percentiles).
You can add as many 9s as you want to the confidence interval size, and you will get basically the same result.
But I don't know if this is considered a medically significant effect size.
Edit: This is a back-of-the-envelope result. Please do not take it very seriously.
[0]: United States Department of Health and Human Services (DHHS), Public Health Service (PHS), Centers for Disease Control (CDC) / Food and Drug Administration (FDA), Vaccine Adverse Event Reporting System (VAERS) 1990 - 4/10/2021, CDC WONDER On-line Database. Accessed at http://wonder.cdc.gov/vaers.html on Apr 21, 2021 1:31:17 PM
One note: VAERS is a voluntary reporting system, and not anything close to a census of vaccine side effects - it's notoriously unreliable. People are watching the COVID-19 vaccines like hawks (for excellent reasons), while there's no reason to believe the standard schedule vaccines are receiving anywhere near the same level of scrutiny.
I'm replying because I can't edit my post anymore. I'd like to know if I should be counting the "combined" vaccines like DTAPHEPBIP as "Hep B" vaccines. I have no idea, but it changes the result.
There's a well established alternative for flu already? It's like asking why electric engine cars have taken so long to overtake petrol cars; there's a giant existing infrastructure and well known protocols for flu already, so the risk/reward balances aren't great for the newcomer.
Otoh having an established baseline can help understand the efficacy and cost comparison (and time to market), and with new technologies you might want to play it safe?
An emergency like Covid is the ideal environment to dismiss all concerns about efficacy and cost. The risk to losing some money on a failed vaccine is negligible compared to the cost dragging out the restrictions even just a little bit longer than necessary.
Disclaimer: no education in biotechnology or vaccines, just an observer who likes to nerd out on information and think about them.
My understanding is that mRNA vaccines need a protein to target (since mRNAs make cells produce proteins). What makes SARS-CoV-2 particularly suited for this vaccine type was their spike proteins. My understanding it that the spike proteins are very unique to that virus type, was enveloping the virus and the human biology doesn't have something similar to that, so it was an easy (!) target for this vaccine type.
At least one of those conditions above may not hold true for <insert virus name here>, which can make it difficult/unsuitable for mRNA vaccines to target.
Again, I may be wrong (please correct me and give me the correct information if so), but this is my understanding.
I'm no biologist, but mRNA is ephemeral by design - it's constantly being broken down in the body. The fact that mRNA is converted to proteins by ribosomes is one of the best understood processes in cellular biology, and synthesizing the mRNA for a new protein is not a new idea. Getting actual viral vectors injected into my arm seems much more concerning on the surface (though it's obviously also very safe).
Were that it was so simple. My understanding is the mRNA used in the vaccines was engineered to be more stable (less ephemeral). Not sure what that means in terms of half life, but AFAICT it's a mistake to assume that it will behave similarly to naturally occurring mRNA if this is true.
They put a lipid coating around the mRNA to protect it. But as soon as that coating is removed, it will be quickly be broken down in the body by various enzymes.
I'm no expert on this but the lipid coating allows it to enter the cell where the coating is removed and the reverse transcription happens. I've read that any of the mRNA that is injected will be gone within 2-3 in the body.
If it can be reverse transcribed then so can Covid which has the same mRNA as the vaccine and way way more. Plus, covid infects a million times more cells than the mRNA vaccine.
I've been thinking the same things, that there is a small likelihood there's a nasty black swan hiding in there somewhere.
But in addition to the theory, we're approaching one year of empirical data on large-scale clinical trials, soon improving by the millions every day. So I'm less and less nervous for such a "holy shit, who could have imagined that" moment for each week that passes.
That the rare AZ/J&J side effects were promptly discovered is also a good sign that the monitoring system works.
> Like all of you I’m not an expert in the field, but from what I’ve skimmed online it seems like mRNA vaccines have never been used widespread in humans before?
Moreover there haven't been any long-term studies... There is a very very small chance that something strange happens [0].
> Am I crazy for being nervous about taking an mRNA COVID shot?
You're not crazy, but you're probably being unreasonable. The "gut-feeling" likelihood of something strange happening are very very low.
[0] one mRNA-specific example, and one "new investigational drug" example: 1. the mRNA could somehow retrotranspose into your DNA, and cause problems. It's not seen in the lab but that doesn't mean it doesn't happen in vivo, it could also depend on what active retrotranspons you have inside of your cells. 2. the antigen could accidentally elicit an antibody response that activates an oncogenic receptor and increase your chances of getting cancer.
I think it's important to note that these are plausible mechanisms and are probably untested/untestable at the scales that matter when you're delivering to millions of people. But plausible does not mean significant. Every time you put something in your body, whatever it is, if it's food from the grocery or that new whiskey that hit the market, you're taking on risk. And keep in mind how convoluted a mechanism it takes to get to the point where it's something risky.
I recently came across this study which suggests it can retrotranspose into your DNA. From what I understand they weren't attempting to find that intentionally, but found it while looking into why people were testing positive for COVID many months after being infected and not currently infected.
I'm not suggesting that the vaccines could do the same, but it's not that big of a leap to wonder if the virus can retranspose, then the vaccine could as well.
Also I'm aware it's a preprint and not fully peer-reviewed yet, interesting nonetheless.
All those risks are orders of magnitude higher with Covid. Getting infected with it is like taking a 1000x dose of the vaccine, if we’re talking about the cancerogenity and reverse transcription risk.
Absent the cell already being cancerous, wouldn't it eventually die off or become targeted by the immune system (I'm not sure if the synthesized spike proteins are free-floating or if the cell becomes some kind of sacrifice for the immune system to kill and dissect)?
And the HPV vaccine before that was a virus-like particle vaccine, which was new tech as well. We've effectively run out of low hanging fruit where inactivated or live-attenuated vaccines are really amenable for use.
Lots of good responses to assuage your fears. The one thing I don't see a response to is the auto-immune angle. Let's assume that the mRNA vaccine quickly goes away, but the whole point of it is to train your immune system to attack the spike protein. How confident are we that the spike protein isn't naturally occuring in any human cell type in any population of humans on the planet? Can we say with near-certainty that the likelihood of an autoimmune issue is non-existant?
I'm not very worried about it. I just received my first dose of the Pfizer vaccine today(some soreness at the injection site and fatigue ~12h after). I just would like to hear the response to that concern in case someone tries to argue that angle with me.
We actually know the primary sequence (i.e. order of amino acids) for every gene in the body. It’s trivially easy (a senior undergrad in bioinformatics ought to be able to do it with little or no handholding) to look for genes with even a vaguely similar sequence. Protein folding is a hard problem, but the space of possible solutions is large enough that it’s unlikely that an unrelated sequence would have a similar enough structure to be recognized by the same antibodies.
Most variation between populations is not so much what genes are there, but how at what level they are expressed, point mutations, and short repeats (all of which are unlikely to create totally new structures). For there to be a population that had spike protein expressed, there would have to have been some sort of horizontal gene transfer into the germline (which is relatively protected from mutations for precisely this reason) at some point in the past. There’s reasonable atlases of human genetic variation (see, for example, the 1000 genomes project), so if there was some large population of people with any obviously new viral sequence, we’d see it.
Plus, if a person somehow, miraculously, had a protein that looked like Spike, their immune system should already be tuned to ignore it. (I have a PhD in biology, but immunology was not something I have much expertise in, so take this with a grain of NaCl).
And, that person who has a Spike protein naturally would be in pretty deep trouble if infected with Covid -- since the immune system wouldn't trigger on the spike! Though antibodies can also attack non-spike things.
Biology is messy and you can not say for certain that there will never be a group of individuals with an autoimmune issue. That is why vaccines go through several clinical trial phases. I recommend listening to this lecture about the process:
https://youtu.be/35Idb_lCU4o?t=61
Especially the part about poly-A tail. IIUC, it means that each mRNA "particle" that gets delivered into your body has an upper limit on how many times the protein will get synthesized from it, and the payload only contains info on the spike protein, so there should be no runaway synthesis of something else that would take over my entire body. Standard disclosure: IANADoctor. Also, got my first shot 3 days ago.
This is an excellent article. Thank you for sharing.
This whole pandemic I've been waiting for us to "get lucky" and find that the virus has some weakness. Like some simple off-the-shelf medicine is a cure. Or that it spreads through some simple mechanism we can beat easily. Or that it can't handle summer. Or that it would never mutate.
Nothing seemed to go our way though.
Then the mRNA vaccines came and that was finally our lucky break! Now thanks to this article I can see that the real breakthroughs came years earlier, from basic researchers. Without these breakthroughs -- which I'm sure didn't excite the public or earn anyone a Nobel prize -- we'd have only inferior vaccines out there.
One major argument is that the mRNA-part is the initial delivery vehicle that does not stay around, so if it being mRNA-vaccine would cause issues we'd very likely know by now. That said, given that the mRNA-vaccines are used for everybody there is little reason why you shouldn't be able to get J&J if you are more comfortable with that.
Since the hijacked cells expressing the spike protein are your own, presumably they still emit "friendly" signals to the immune system (eg: I am self, do not attack). I am curious how the immune system would even recognize the spike proteins as bad in this case. If the vaccine has some mechanism to attract attention to the spike, is there a risk that antibodies could develop to the cells themselves for instance?
As someone with sarcoidosis, that is my worry too. Also, for folk that already developed antibodies against those spike proteins, it seems like shotgunning a bunch of mRNA into their cells might lead to a rather severe inflammatory response, worse than re-exposure to the virus.
Anecdotally, I have a very elderly acquaintance that reacted quite poorly to the vaccine, including developing "shingles" in her eye. A nurse taking care of her then accidentally exposed her to COVID, which she subsequently tested positive for but had no symptoms.
> I wonder if some of the people having fevers and other flu-like side effects are people who were asymptomatic Covid carriers at one point!
I saw a similar claim about a week ago, that the correlation is high between people who were actually sick and then also got side-effects from a vaccine. They didn't include a reference, but if I see it again I'll definitely be poking them for one.
FYI: The J&J vaccine directly injects DNA into the cell nucleus to begin spike protein production. DNA-based vaccines have been tested before (see J&J's Ebola vaccine), and I believe the general consensus is that mRNA is a safer technology due to its inherently short lifetime.
I got J&J and am currently waiting around to see if I get a blood clot.
Hope I recognize the symptoms. I have a lot of weird aches normally so I might miss it. Hopefully can avoid a multiple-thousand dollar trip to the ER just to find out its nothing.
Yes I understand the risk is low, but its higher than the one in a million number everyone is throwing around. Potentially much higher as I suspect that cases in men haven't been reported.
I was listening to a podcast on this the other day that was really informative. The symptoms of the kind of blood clot associated with the AZ and J&J vaccines cannot be missed. You'd have abdominal pain, breathing problems, and get a headache so painful you'd want to seek medical help. They're not easily confused with symptoms of flu-like illness or everyday aches and pains.
Yes I heard that as well. My primary risk is that I'm a stubborn bone head who doesn't like to go to the doctor or especially to an ER. However I think I'm fine now.
Even if you believe Norway's numbers to be close to your average, it's ~1:20,000. So the odds are still quite safe, and it's thankfully cureable if discovered early.
Isn't there a telltale sign with miniature bruises/bleedings in the skin? I think the doctors involved in the study made a list. I'm assuming you've looked at it?
Well, now you know why Denmark and Norway suspended AZ vaccinations for everyone, and many European countries stopped them for everyone younger than 65. It wasn’t because their governments are antivaxxers.
Indeed I'm in the US. Actually its hard to tell what the cost would be. It might be just $500 if they don't admit me. But it could be thousands. No way to know without actually going.
To be clear I don't have symptoms right now that warrant it and highly unlikely its J&J related anyway. But nevertheless we do have to consider costs here before we make any decisions involving hospitals.
I'm generally more sanguine with mRNA vaccines than other sorts. The problems we've historically had with vaccines have mostly either been with live attenuated viruses that turned out to not be attenuated enough or with adjuvants. With mRNA there's no virus at all and it works via the normal cell viral infection detection pathways so no need for an adjuvant that might accidentally sensitize you to something else.
You aren't crazy of course, but all indications are they are quite safe. Additionally, a lot of the excitement around mRNA techniques in general is that it is actually a much "lighter touch" than others in various ways -- e.g. not editing genes like CRISPR, using a much simpler delivery method (lipid delivery vehicle vs adenovirus delivery as in the other vaccines), etc.
> This is making me want to take the J&J one instead.
On one hand, we have mRNA, which is self-limiting and that we know exactly what it encodes, as every single base has been put in there by us. We know what protein it encodes. And if that protein turns out to be harmful long term, guess what, the virus has it too.
On the other hand, we have a viral vector vaccine, which injects a live adenovirus which then delivers the instructions? I know we have chosen a harmless virus, but it's an entire virus nonetheless.
mRNA vaccines are seeing their first large scale deployment now, but they are based on decades of research. Humans know a lot about mRNA, which is how they even became possible.
I prefer the more precise approach mRNA vaccines provide. Mind you, they are both good for our current situation. I would have gladly taken J&J if that was the option. Ended up getting Pfizer due to the current halt and I'm very happy about that.
It's just that mRNA vaccines open up entire new treatment options. We have come a long way from having to grow viruses in chicken eggs (which is something that's still done).
You have to weigh the risk reward for your particular situation. Are you more nervous about a new vaccine or Covid? It depends on your age and comorbidities.
It doesn't depend on age or comorbidities. Covid vaccines - of any type - are orders of magnitude safer than getting infected by a "live" and constantly mutating virus.
I was also nervous. But I was reassured when I discovered the first Clinical trials were one year ago (almost to the day).
Additionally the number of shots we have given (around 200 million, probably more) is effectively the worlds largest clinical trial. If there were problems, even rare ones, we would hear about it by now.
Those two things reassured me to the point that I went and got the shot.
Long-term effects follow a bell curve, so if they took 1-2 years to show up in average, with 200M vaccinated people, we would see initial cases already.
Also, there have been no long term effects of a vaccine that didn’t begin in a first month-post vaccination, ever. There is no theory even on how would it be possible for them to manifest after more than a year if nothing happened before.
I went with Sinopharm, even though I did have the choice to take Pfizer. I prefer the idea of a traditional vaccine. I’ll see how MRNA looks after this mass beta testing is complete.
Not knowledgable in the biology area so forgive any incorrect terminologies or assumptions in advance. mRNA sounds incredible. As I understand the vaccines work by injecting an mRNA sequence which produces a certain spike protein to defend against certain viruses. In contrast, cells here are not producing the mRNA.
Do these injected mRNA eventually phase out and die out from the body? Typically what is the lifetime? Is there also some 'off' mode, or complementary vaccine to undo an injection say after learning of some serious affect?
>I think also the instability is a large component of why the vaccines must be stored at such low temperatures.
As I understand it, the low temperatures are partly required because of the liposomes the mRNA is "packed" into
As I understand the instability of mRNA in the general cell background cytoplasm is because of the presence of enzymatic molecules (produced by the cell) that attract and then break down (lyse) any mRNA that floats into their 'jaws'. Loads of different things get broken-down by this kind of background presence of some enzyme, and since mRNA is used by the cell itself, maybe not too surprising that it has a cleanup mechanism in-place already?
Edit: As noted in a comment, the half-life for the vaccine-related mRNA strands are longer, by design, so they produce more spike protein, but they remain fairly transient.
Moderna and Pfizer mRNA half life is actually 10 and 14 days. The human one is indeed hours. Which is fine but it’s indeed not clear in their communication.
For GP’s comment, what happens to vaccine components that are “broken down”? It’s not just the mRNA in there right? There are other compounds to aid in delivering and stabilizing the dose. A serious side effect known only in the future may not specifically arise from the broken down mRNA. So does the body flush out (pardon my informality/ignorance on the right terminology) all the components of the vaccine somehow?
The rest of the components are also broken down. The components are lipids (fats) meant to protect the mRNA while it's being introduced, some salts for stabilization, and sucrose.
Your body knows how to handle all of those perfectly well, and yes, most of them will be excreted.
That's how I understood so appreciate all the above responses in response to mRNA Do Not last long.
First I think it is quite incredible to have such a vaccination out so quickly. As the pandemic eases are we in a situation needing to continue booster shots say on some reoccurring basis as a preventative measure? I am not very clear on the virus itself whether it eventually gets eradicated over time. Or something a bit more reactive where it is possible to get a shot after infected or having symptoms and whether mRNA works in this way as well on a reactive basis.
> * As the pandemic eases are we in a situation needing to continue booster shots say on some reoccurring basis as a preventative measure?*
Most likely. SARS-CoV-2 is now endemic in the human population & unlikely to die out. The general impression in the scientific community is that the current set of vaccines should be protective for at least a year or two, at which point variants will have emerged that evade the vaccines developed on the Wuhan strain. Booster shots developed on these new variants would be required for the foreseeable future.
> Or something a bit more reactive where it is possible to get a shot after infected or having symptoms and whether mRNA works in this way as well on a reactive basis.
In principle this is possible - some vaccines are capable of arresting an active infection, though that is highly specific to certain pathogens. This is not something current COVID vaccines can do.
The mRNA vaccine process has been developed over the last 10 years or so. The actual spike protein was identified early, so the main work was to create the mRAN sequence for that protein. Not easy but the tools have gotten much better in recent years.
This was the first large-scale use of this kind of vaccine so it is an amazing field test of the process. Normally that would be a slower, incremental process but the risk from Covid forced them to simplify and speed up the process.
They did a great job with the mRNA vaccines, but they have been prolific in research for nearly decade. In my opinion a intersting question is whether infectious disease vaccines now matter to the "wealthy world", as infectious disease has largely been an economic backwater for Pharma/VC,etc. How mRNA vaccines play a role in that maybe interesting, as their product profile is mostly 'wealthy world friendly' at this point.
I have been noting down pandemic silver linings, and this is one did not occur to me. To take your point further, given the workhorse industrialization the mRNA platform has been given during Covid, turning it on the other infectious diseases might mean millions or tens of millions lives saved over the coming decade or two. A (pseudo) black swan of a pandemic leads to a white swan!
A Malaria vaccine would be awesome. I have no idea if that’s possible though. I’ve known people with Malaria and have personally taken the (expensive) pills to protect myself. It all sucks.
The hard part about vaccinating against Malaria isn’t the vaccine platform — it’s finding an antigen to target that has the desired effect. But there is progress on that front:
It doesn't even have to be an exogenous disease. There are trials being scheduled for their use in autoimmune disease, IIRC, by sensitizing tnf-regulator cells to autoantigens (or perhaps consequent interleukins, I forget).
The have already been used to cure the mouse model of MS.
A mRNA vaccine basically sics our immune systems on something. Our immune systems are fairly adaptable and will kill even cancer cells if they can tell them apart from healthy tissue.
The first generation were definitely first world only, but it looks like there are variations being developed that are more appropriate for less developed areas. The m1283 vaccine is currently under trials and is supposed to be stable at refrigerator temperatures.
Given the antibiotic stagnation, could we possibly develop something similar to target bacteria? Aka inject instructions in their genome to self destroy?
In addition to phage therapy option mentioned here, there's also a class of synthetic polymers that selectively disrupts only bacterial DNA. Those molecules can't cross the nucleus and therefore are not toxic to eucaryotes.
This therapeutic direction has two key advantages over other approaches:
1. There's no way bacteria can develop resistance to it in the next 1b years, since those synthetic polymers bind to free DNA without any preference to particular sequences. Therefore, there's no known mechanism (mutations, horizontal gene transfer, etc) that can provide immunity against this class of agents.
2. Being a "small" molecule it has much less risk of eliciting an immune response ( unlike phages, who may invoke some response from immune cells which can decrease the potency of the treatment)
Not toxic directly. Disrupting "good" bacteria that we co-exist with isn't always harm free, as I'm sure the people researching those polymers are well aware of.
That is possible, but we're talking about different time constants here. Antibiotic resistance can arise in a few generations. Evolving a different membrane composition that will block that particular toxin and not the other ingredients the cell requires to function (amino acids, carbohydrates, etc), is much less probable to take place in such a short time
Bacteria could evolve "antibodies" to these molecules, or enzymes to get rid of them. See CRISPR, plasmid transfer and colony signaling ... bacteria got quite sophisticated defenses.
The whole concept of phage therapy is somehow based on this: Bacteriophages inject DNA into specific bacteria that makes them copy the phage inside them until they burst open.
The issue with phage therapy is that it has to be targeted.
With antibiotics, they are very broad spectrum so you can throw augmentin at routine infections and it'll usually work.
With phages, you have to be much more specific. Phage X for bacteria Y. It's not necessarily hard figure out what bacteria it is, but it takes time and expensive lab work.
That's true, but I have a thesis for why this might be good for the biotech ecosystem.
A lot of people will dismiss phage therapy on economic grounds, suggesting that you'd need to essentially design a new phage therapy for each individual infection you wanted to treat. But, with the advances we're seeing in microfluidics, diagnostics, gene sequencing, computational biology, laboratory automation, and the theory of precision medicine, that host specificity can turn from a disadvantage to an advantage. We know there are a lot of human-dwelling bacteria we wouldn't want to knock but can't save from a broad-spectrum treatment. With a personalized phage therapy, this isn't as much of a concern, and with the above advances, custom therapeutic design can scale economically.
But here's the most important implication of phage-host specificity for biotech business models. When a biotech company gets approved to roll out custom therapies for each individual patient, that opens the door to solving two important roadblocks to biotech innovation. First, firms could get around the problem where they're subject to regulatory scrutiny based on a naive interpretation of the difference between their manufacturing costs and their sale prices. Second, such a paradigm of treatment could permit biotechs to offer gradations of service and charge based on how finely-tuned your therapy is. This would enable them to much more closely fit the demand curve of patients. They could bring the latest technology to the masses cheaply and relatively quickly, while charging a premium for the cutting edge.
It's not necessarily hard figure out what bacteria it is, but it takes time and expensive lab work.
There are companies out there developing more rapid test panels that will give an answer within minutes or hours, and they charge in the $200 range to test for dozens of pathogens at once.
Someone I know works for such a company, and a lot of the "doctor ran 20 tests for $x000 when they should have just run one" stories in the news are actually about those types of all-in-one rapid tests, and the insurance/hospital doesn't know how to bill it reasonably.
> It's not necessarily hard figure out what bacteria it is, but it takes time and expensive lab work.
Also you may not have time. If the person has meningitis for example, if you wait to try to figure out what bacteria they have before treating, they will be dead.
Broad spectrum antibiotics are great for this kind of thing in that you can start treatment immediately, and once you figure out the bacteria, narrow the treatment to that type of bacteria.
Not just this, but our immune system recognizes phages and removes them from the blood stream quickly. So you would need a lot of phages to see some value
The other side of this is that people get long term side effects from drugs like augmentin.
Muscle tightness can lead to injuries, depression, anxiety, etc. Not to mention it takes a very very long time to restore gut flora to pre-treatment conditions.
With enough money I'm sure they could make very very quick tests for each bacteria type that are commonly targeted.
Time is a huge deal. There's a conflict right now between sepsis guidelines and antibiotic stewardship guidelines on when you should start treating, and having to wait for both the diagnostic and the phage prep is sort of a problem.
This is also why bacteria can develop resistance to antibiotics. You can’t develop resistance against something that is 99.999% effective through design
It is not that bacteria can't become resistant to phages. It is that it is comparatively easy to make new phages to the resistant bacteria. Being viruses, they will evolve with the bacteria they target.
The problem with antibiotic resistance is not the resistance itself, but that we don't seem to find new antibiotics anymore. As a result, once bacteria are resistant to all what we have, it is the end.
We aren’t finding new antibiotics anymore because there are only so many human-safe systemic vulnerabilities to take apart/stop bacteria metabolism biochemically without moving into the genetic arena for further variation. What we are really exhausting are the biochemical differences between our cells and the bacteria cells by wiping out things that make the bacteria unique. This is really bad because it drives additional compatability with the human body while eliminating ways for our immune system to tell them apart as well. We have been driving the evolution of bacteria toward this since we discovered penicillin. What we need is to introduce new genes blocks into wild bacteria that make them susceptible to artificial compounds we create while also conferring a survival and even reproduction advantage to them over bacteria that lack the implanted gene blocks. This would balance out the evolutionary force of the artificial compound vulnerability. I’m fully expecting the Jurassic Park chaos mettling with nature speech but we have precious few options when completely resistant strains of new lethal bacteria inevitably emerge.
There are presumably a finite number of chemicals that are of the right molecular size to get where they need to go, kill a reasonbly broad range of bacteria, and don't harm humans. We may have found them all already.
Interestingly, in several phage-treated patients, the bacteria then had increased susceptibility to antibiotics. Combination therapy is a remarkable thing.
Obviously not a biologist, but if you could target a specific protein on the bacterial surface it might work. Alternatively you could CRISPR some human cells that generate the bacteria-killing RNA constantly.
Yes, that would be super cool. But also crazy-risky!! :)
But the risk is not due to chance, its due to the unknowns. Once they're no longer unknowns we'll be able to engineer such a therapy.
Alternatively, once we understand our biology so well, we might as well just patch all the "bugs" so that we don't get infected by harmful pathogens. Or maybe forsake our biology and move on to Silicon ?
Not sure what your point is. If you want to inject genetic material inside an organism to destroy one cell - with the mRNA platform you can only do it once. It won't repackage itself and 'infect' another cell.
If you want to make conditions inhospitable for an organism, you can cause a mass-scale change that affects multiple cells via a drug.
I wonder if that won't work as well given that we're not using this to cure COVID while we are currently sick with it. I don't know if Syphilis booster shots would make sense or if the range of things we could need to be regularly inoculated for would be far too broad for this to be useful.
I wonder, if mRNA tech offers the possibility of reintroducing lost of function for cells with mutations like p53 defects. E.g. maybe just do what p53 does, if it's present or not.
Much harder to identify the misbehaving cells, DNA deletions, than making all cells behave, I assume.
I think that is what CureVac is working on. RNA printers. I think even custom therapy can be produced but safety and efficacy is something they can't easily determine.
This is a totally amateur and non professional question. As I understand some techniques are required to ensure that the mrna reaches the cell without being destroyed. What are the chances that these techniques have side effects and we end up with the back story to the movie "I am legend"?
"considerations and challenges include scaling up good manufacturing practice (GMP) production"
Then I think of J&J and its 15M ruined doses, and then wonder whether pharma co's should provide better access to rank & file managers into scientific journals, particularly stuff they are known to be building.
mRNA vaccines are not new, just newer than existing platforms. mRNA vaccine clinical trials which usually last years (or a decade), were completed in 2017, as per the nature article summary. The technology and its effects are well known in both in mice and human models.
Is there residual risk that there were will be some unintended side-effect when billions of doses are administered? Yes, of course. There is no way to prove a vaccine is safe for everyone in all conditions, (see: Popper's falsification and the demarcation problem). Same goes for any other pharma formulation, food stuff or procedure. However, we have to weigh the residual risks against the risk of death from Covid and its variants and risk of long term damage to me or those around me who might be unwittingly in a higher risk category.
Vaccination is a moral obligation and even if I would rather not, decency and civic duty to our fellow humans dictates that I must. And so should you.
Please don't take HN threads into flamewar. It's tedious and evokes worse from others. We're trying for the opposite here.
Especially please don't take HN threads on generic flamewar tangents like "Vaccination is a moral obligation". They're highly repetitive and don't lead any place interesting.
I posted what I thought was a very uncontroversial idea - "vaccination is a moral obligation for me", since Covid is surging again and vaccination rates have flatlined because vaccine hesitancy et.al.
I don't know why this evoked such a negative response. I will just cool off posting comments on HN for a while.
Informed consent, a cornerstone of medical ethics, has very little to do with the fact that we can't prove treatment will not be detrimental in all cases.
Or perhaps you prioritise the group above the individual in all cases and think e.g. the Nuremberg Code is worthless historical artifact?
Just an interesting question here, if you are saying vaccination is a moral obligation does this mean you are a moral realist [0]? My guess is not.
You may mean to say for you vaccination is a moral obligation which if this is the case you are a moral relativist [1] and therefore your moral obligation does not necessarily apply to others.
Of course, my moral obligation only applies to me. But I can advocate for others to follow my line of reasoning through persuasion.
Many moons ago, when I lived in a community where most residents were of the all-organic-no-vax types, I convinced the powers that be that vaccination was a moral obligation for the (mostly young) community due to the effects of infecting young and old and the resulting deaths.
Everyone got a flu vaccine that year. I was not very popular after that ;(
If I get on a Boeing aircraft, I am indeed engaging in an act of faith: that it was built properly, maintained well, and all the rest.
When that faith is violated, say by the control systems having the RANDOMLY_FALL_OUT_OF_THE_SKY flag set to “true”, then society engages in faith-restoring rituals: grounds the aircraft, leads an inquiry, does a recall, that sort of thing.
What you are seeing here is what happens when a large chunk of the population has lost faith in, and thus no longer trusts, its institutions.
Yes it's the human element that makes it a faith act. I have no doubts about the physics. The airplane must fly, it's not a matter of faith. But was it built properly, by qualified workers, has it been maintained properly with no shortcuts taken, are there any design flaws not yet discovered, and is it being operated by qualified, sober, healthy pilots?
Is it.. not? Or rather, what would you prefer to call it?
I've long had that opinion - it is faith, in my mind. It's very logical faith, but faith nonetheless. Not in science exactly, but in the morals, honesty and competency in the results of those performing the science. It's faith that if i was to become an expert in the field, i'd be able to recreate their exact results and deem them correct.
Is this unsound in your mind? I'm fairly anti-religious but i have no problem describing my belief in science based outcomes as faith. It doesn't feel reductive, it feels honest - to me. It takes a leap of.. something, if not faith, to trust the results of results of humans. Some science is bad, some is good, but often you lack the expertise to determine which is which. So you logically go with the common assertions and proceed from there. I do think it's logical, but i don't think that precludes it from also being faith.
However, we have to weigh the residual risks against the risk of death from Covid
But then this made me wonder if there was a paragraph I missed:
Vaccination is a moral obligation
I think it's a mistake to think the weighing process you endorse in the first quote will land everyone with the moral obligation you endorse in the second.
Only if the mechanism of its action contributes to herd immunity. If it provides symptom abatement without lowering infection and transmission, then vaccination of those not at risk can prove counterproductive due to asymptomatic spread.
Death isn't the only negative outcome of covid. We're seeing a relatively high rate of long-term damage caused by low-level symptoms. If we can reduce those symptoms with a (perhaps annual) shot, then covid turns into the "just a cold" that we were all hoping it would be
The replies here seem to be ignoring the point I was making, so I guess I was unclear. I'm going to try once more, hopefully this helps:
The effects of the virus at play are irrelevant... long term, short term, sniffles, death. None of that matters to the topic of moral obligation. Only contagion matters, so let's take two opposing mechanistic scenarios:
1 - Reduced infectiousness (what we expect)
Person A getting the vaccine reduces the chance they will spread it to Person B if exposed and/or infected.
2 - Reduced symptoms (counterintuitive)
Person A getting the vaccine still gets infected and can infect Person B, but no longer has symptoms such as fever. In this situation, Person A actually becomes problematic to the un-vaccinated Person B, since it's not obvious to either individual that Person A is infectious.
In the first scenario, your vaccination potentially helps others. In the second, your vaccination potentially hurts others. The mechanism of action can change altruism into unintended harm. This is why the mechanism of vaccination is so important from social perspective.
> effects of the virus at play are irrelevant... only contagion matters
No, I'm sorry, but hospital ICUs near me are 90+% full again and we're returning to a strict lockdown. Given a hypothetical vaccine which reduces symptoms but transmission, the vaccine still reduces the hospitalization rate, so your un-vaccinated person B will have a better chance at treatment. Your situation #2 presumes that people with mild symptoms will be inclined to stay home -- in my experience, this is not the case.
Huh, that's nonsense. Every vaccination also carries risks, so there can be no moral obligation if the risks outweigh the benefits.
That said, I also disagree with the moral obligation. At the very least, there are also other scenarios to consider. For example if only a small group is at risk and can't be vaccinated (too risky), that small group could be isolated or choose to self isolate. Afaik it already happens with chemotherapy patients who are being isolated. There is no obligation for the rest of the world to disinfect everything and walk around in hazmat suits so that chemotherapy patients can walk freely in the outer world.
Here's the problem: we don't have enough information on long term damage. It could be that there are none, it could be that we'll see them in decades (like shingles).
We do not know. Since we do not know, we need to play it safe. If we are wrong, nothing will happen. If we are right, we have avoided long term damage.
I'm not saying COVID doesn't have long-term impacts in certain portions of the population, but this sentence is pretty important: "However, the findings are observational, and the authors cannot rule out the possibility that rates of diagnoses in general might have decreased indirectly because of the pandemic, particularly in people not admitted to hospital with covid-19."
It's really hard to draw meaningful conclusions when COVID has completely changed all kinds of factors in healthcare ranging from people being stuck at home and eating poorly to opting not to visit the doctor because of overburdened hospitals and fear of infection. I'd like to see some studies a year from now before forming a strong opinion.
> Comparison groups are also important to understand the scale of a problem. To put it bluntly: it’s not very informative to describe people as COVID “long-haulers” if, sixty days after being diagnosed with an illness that is sweeping the world in a devastating pandemic, they report anxiety, fatigue, insomnia, headache etc., without a comparison group!
My anecdotes are my Bayesian truth, and they include neighbors and coworkers with longterm anosmia that I've never had friends experience before COVID. The article you mentioned didn't even address this rather well known symptom... why not? It would seem to be rather measurable and comparable vs earlier baselines.
Herd immunity exists when enough people are incapable of re-transmitting a disease that the R number is below 1, even when we're back to a normal way of living.
It may be that the vaccines will be incapable of giving us herd immunity, but they may allow us to keep the R number below 1 with much less extreme social distancing and lockdown procedures.
Without the vaccines, the only way to get rid of this pandemic is through severe economy-damaging lockdowns and liberty-encroaching contact tracing and quarantining. If we can achieve the same thing with vaccines plus just having to wear a mask when near other people, then I would say that vaccination would still be a moral obligation, even though we haven't achieved herd immunity.
> Immediately end all lockdowns, mask mandates and capacity restrictions. All those aged 70 and above will have the option to stay in quarantine
Aside from the stupidity of the first half, is the last sentence to be taken to mean that everyone under 70 will be dragged forcibly out of their homes and exposed involuntarily? If not, how else are we to understand that only a narrow group will have the “option” of “quarantine”?
> Pass legislation to make Hydroxychloroquine and Ivermectin available over the counter like they are in many foreign countries.
That’s stupid. Why would we make things worse by implicitly endorsing ineffective treatments? We’ve actually come a long way in effective medical interventions for COVID; making those more readily available (though OTC isn’t the right route, even there) makes sense.
> But no, we get ignore all the proof and hide in your homes until everyone can be vaccinated.
Almost nowhere has a policy that could even hyperbolicly be described by any sane person as “hide in your homes”, most places are gradually (some radically, even recklessly) reopening (and many adopting the first part of your first recommendation.) Even the many of the most restrictive places have generally reopened or are on short timetable to, despite retaining mask mandates and distancing/capacity restrictions for many activities.
You mean like India? Check out those COVID numbers and let me know what you find ;)
Indeed it is a virus, and they are used for Malaria. If using the combination of Hydroxychloroquine, Zinc and Azythromicin early in disease progression actually works then... who cares? I mean really. It could work on placebo for all I care. People are dying, you think they will refuse a proven treatment that happens to be a anti-malarial versus an anti-viral?
Regarding people being deficient in Vitamin D, that's uh... literally everyone. I think the only people with normal levels are native tribes that still live outdoors. Check out any study of vitamin D in chronically ill people and see how many have normal levels. These are the same people most susceptible to dying from COVID. Isn't being Vitamin D deficient the most indicative metric of COVID morbidity?
No, not at all. Lockdowns, quarantining and other human rights violations don't help us get rid of the pandemic, they prolong it. To end the pandemic faster, more people need to get exposed to the virus.
Please take this rhetoric elsewhere. No human rights are being violated. We are trying to protect people and buying time until all can be immunized (or, if vaccines didn't exist, allowing health care facilities to handle the load).
We KNOW containment measures work (Ebola, SARS).
If you expose more people to a virus, you risk making the pandemic much worse. Or deadly. Viruses mutate. Every new person exposed is a potential laboratory.
You can contract covid, have it mutate and also spread it to others even if you’ve been vaccinated. There’s supposedly less of a chance to do this if you’re vaccinated but with for profit corporations funding most of the science it should all be taken with a grain of salt.
I think we probably place too much hope in improving technology, in general.
It's a tremendous breakthrough, I'd say. But rather than focus on the tech, I'd rather see a rethinking of our governmental approach to issues concerning public health and how approval processes are set up. I'd rather focus on how we incentivize breakthroughs on issues that are most important, rather than developing another medicine that's 1% better at treating acne, for example. And I'd rather see cultural changes around adopting already existing technologies -- less than half of folks take flu shots!
I'd argue that getting flu shot numbers way up would be more of a breakthrough than any benefits from mRNA, as incredible as it is. Not that we have to choose one or the other. I'm just saying I'd like these other issues to get more prominence.
My fear is that we still don’t fully understand genetic and epigenetic coding and there are probably latent dangers lurking with this class of vaccines that may not even be apparent until a new generation of posterity.
I suppose there's always a (very) small chance that we're making a civilization-ending mistake with this new vaccine :)
On the flip-side, while COVID can cause serious illness (and death), with a survival rate north of 99%, there's virtually no risk of societal collapse if we do nothing (OTOH, our response to it has been far more de-stabilizing).
In the semi-rural area where I live we have 1/3 trumpsters who won't get it due to their political allegiances and 1/3 hippies who won't because woo woo reasons. I am assuming there will be a harsh reckoning in store for this and similar places.
The harsh reckoning will be for the urban areas who subsidize that stupidity, when variants will emerge from among these unvaccinated populations, and we are going to go through this song and dance all over again.
It's also why I'm incensed that vaccine production is ramping up both too slowly, and will top out at too low a number. It can't take six months to vaccinate the first world, and eighteen to vaccinate the developing world against a variant.
Or variants emerging from those vaccinated. It’s nonsense to assume “the unvaccinated are dirty Petri dishes where mutations come from!” Variants can come from vaccines themselves or mutating in the host and then spreading.
If anyone think that’s impossible, such a phenomenon is happening right now in Africa with Polio. Wild Polio is declared to be eradicated. A vaccine derived strain is keeping the outbreak alive.
Sure, it can happen, and viruses spread even through a vaccinated population, but quantity is a quality all of its own. Vaccinate everyone, and the number of opportunities for the virus to mutate and spread drops by orders of magnitude. Vaccinate half the population, and all that you'll do is create a great amount of evolutionary selection pressure for a mutation.
I get that sentiment. There's a question of alignment of incentives.
Covid19 vaccinations are likely to be a thing for many years to come, and there are a number of entities that will be able to produce those future vaccinations. If one of the big vaccine providers produces something that's demonstrably less safe than the others, then the odds of them getting more money for future vaccines goes down.
It's far from a perfect system, and there are a lot of holes, but in this case, things line up pretty well.
In short, you can be confident that these companies are primarily focused on long-term profit, which often aligns with good short and long term outcomes for its customers.
Regardless of your opinion of vaccination being a moral obligation, that does not sway my personal decision whether to take an experimental vaccine for an illness with a 99.5% survival rate.
Collectivist ideals like "vaccinate everyone for the greater good!" does not trump my personal sovereignty and never will. I do not consent.
There are people (not so much on HN, but definitely other places on the net) openly advocating for forced vaccinations and/or completely shunning the unvaccinated from society (to include employment).
Oh, I'm with you on this, but I think it's only a matter of time before things get very uncomfortable.
> Vaccination is a moral obligation and even if I would rather not, decency and civic duty to our fellow humans dictates that I must. And so should you.
By that logic, shouldn't you also through that same sense of decency and civic duty donate to prevent starvation? How is it morally decent to live in an expensive city while that money could prevent others from dying?
In fact, instead of taking that vaccine shouldn't you give it to a school teacher or hospital worker in a country that doesn't yet have the vaccine?
This 'moral obligation' nonsense sounds good at face value but really doesn't hold up in practice.
Like all of you I’m not an expert in the field, but from what I’ve skimmed online it seems like mRNA vaccines have never been used widespread in humans before? This is making me want to take the J&J one instead.
I’m totally open to other opinions though, I haven’t made up my mind on this.