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.

Now, this isn’t dangerous, of course.

Talking about side effects that are of public health concern.

The smallpox vaccine could blind you if you touched the vaccine site and then your eye. It had a 1 or 2 deaths per million vaccines side effect rate.

The live-attenuated polio vaccine can revert to wild type.

"Moderna has a high rate of fever and soreness at the injection site" because it's doing it's job is a very different thing.

This really isn’t true.

A simple search through VAERs shows negligible difference between j&j and moderna/pfizer

But VAERS data also shows significantly more serious adverse incidents compared to other widely-distributed vaccines like polio and hepatitis B.

All that means is that COVID is different.

Also your use of the word "significant" is very suspect.

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

[1]: https://www.usatoday.com/in-depth/graphics/2021/01/14/covid-...

[2]: https://www.cdc.gov/mmwr/preview/mmwrhtml/mm5125a3.htm

[3]: https://apps.who.int/gho/data/view.main.80300?lang=en

[4]: https://www.cdc.gov/nchs/fastats/births.htm

[5]: https://stats.stackexchange.com/a/423964/36229

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.

I got the Moderna as well. The second dose, was quite a ride. Your description of mRNA vaccine, coming from a domain expert is quite soothing.

Then why haven’t we used them before? I’m not arguing with you btw, just asking a question as I have no knowledge in this area whatsoever.

Medical science is slow - and vaccine science moreso, because it is careful. mRNA vaccines were struggling to find a use case.

A major pandemic like this is a huge, urgent shot in the arm, both in terms of money and motivation, that accelerates things.

> A major pandemic like this is a huge, urgent shot in the arm, both in terms of money and motivation, that accelerates things.

And even in terms of ... shots in the arm!

mRNAs against viruses were still in research until the past few years. Researchers were trying to use it against flu until COVID broke out.

https://www.theatlantic.com/ideas/archive/2021/03/how-mrna-t...

Devil's advocate: why were they not successful in developing one against flu, but we're quickly successful when creating one for covid?

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 got the second Moderna shot and I didn't feel a single side-effect. Interesting how that works.

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.

How long does the coating take to be removed? Can the mRNA still be (reverse-)transcribed while in the presence of this coating?

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.

2-3 what?

days

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.

But they also modified the mRNA structure to make it more durable (but still on the order of days/weeks).

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.

https://pubmed.ncbi.nlm.nih.gov/33330870/

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.

hence:

> You're not crazy, but you're probably being unreasonable

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)?

No, not necessarily.

To be fair, young and healthy and Covid 19 vaccine tread the waters of “reasonableness” when combined.

The risk profiles in either direction are so small it’s very hard to discern a meaningful pattern. It probably just doesn’t matter at all what you do.

>> This is making me want to take the J&J one instead.

AFAIK [1], even Viral Vector vaccines haven't been around for a long time either; just the Ebola one apart from CoVID.

The majority of vaccines prevalent since a long time have either been inactivated or attenuated vaccines.

The only CoVID inactivated vaccines are listed here [2], a couple of them being the ones in China, India and Russia.

[1] https://en.wikipedia.org/wiki/Viral_vector_vaccine [2] https://en.wikipedia.org/wiki/COVID-19_vaccine#Inactivated_v...

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

What dispersed all of the fear for me was reading this: https://berthub.eu/articles/posts/reverse-engineering-source...

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 don't have a condition nearly as serious as sarcoidosis, but I also worry that I will be one of the unlucky ones with a more serious side effect.

> 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.

Indirectly! It uses an adenovirus as the vector to do so.

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.

I tell myself this every night when my leg is hurting.

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?

You're right I don't have any of that. And leg is feeling better. I'm probably fine and should stop worrying.

What? That number is huge!

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.

Germany allows AZ again... God this shit in confusing

> Hopefully can avoid a multiple-thousand dollar trip to the ER just to find out its nothing.

Seems that you live in North America. It is utterly bewildering that people are expected to make this determination.

I can go to the ER whenever I suspect a serious problem, to the ultimate cost of... 5 euros. That's the limit. Post-occupation EU backwater country.

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).

>And if that protein turns out to be harmful long term, guess what, the virus has it too.

It's not peer reviewed yet but here is this:https://www.medrxiv.org/content/10.1101/2021.03.05.21252960v... Evidence of the spike protein by itself causing clotting issues.

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.

> If there were problems, even rare ones, we would hear about it by now.

Not if they were long-term effects that took 1-2 years+ to manifest.

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.

They’ve been used for cancer for several years now. They’re not new.