[michaelrpeskin]

Here's my ELI5 attempt. Disclaimer: the immune system is very complex, even experts really don't understand it as much as we think we do. This is a very simplified view of the system, but I think captures a very large fraction of the story.

Let's focus on three types of antibodies - the things your immune system creates in response to a foreign object in your body - for this story:

1) IgM - this is created in your mucosal membranes when you breathe in something foreign. In the context of COVID, we'd expect to find IgM antibodies in people exposed to the virus because the mucosal membranes of the respiratory systems are the first places exposed to a respiratory virus.

2) IgG3 - this is created in your blood and is the main killer of a foreign object. This is what you think of when your immune system is fighting a virus. It also drives the inflammation which is what you generally recognize as the "flu-like symptoms".

3) IgG4 - this is created in response to what we recognize as allergens. For example, if you breathe in a bunch of pollen in the spring, you may have an IgG3 response and feel terrible. Or you body may recognize that that foreign object really isn't a big deal. In this case it will create IgG4 which basically tells your body to ignore the object until it's cleared. It's kind of the opposite of IgG3: rather than ramping up inflammation to fight the object, it's ramps it down and just says "nothing to see here" so you don't waste resources fighting something harmless.

What they found is that vaxxed and boosted people have a ton of IgG4 floating around and little to no IgM and IgG3.

So what does that mean? Here's where people are going to get spun up because we have to create hypotheses and test them. But even stating some hypotheses will cause the political machine to get mad.

1) IgM is really good at stopping viruses early. From this we'd expect that unvaxxed people exposed to COVID to be more resistant to future infections because the first exposure will create IgM and the virus will be stopped/attenuated in the nose. I don't know the state of the research on this, but it's a hypothesis to test.

2) IgG4 is a bad thing in the context of a replicating virus. If you have IgG4, it's telling your body to ignore the virus because it's "just an allergen". That's fine for pollen which will be cleared out of your system, but it's bad for a replicating virus because it can replicate unfettered. The hypothesis to test here is if people who are more vaxxed have more (re)infections of COVID. Another thought is that the infection may never go away and flare up occasionally (long COVID?). Again, I don't know the research, we need to test these hypotheses to understand it.

But it is one piece of the puzzle and a plausible explanation for this (https://www.medrxiv.org/content/10.1101/2022.12.17.22283625v...) where we see a nearly linear increase in vaccine doses and COVID infection. Again, these are just hypotheses and we need to test them without getting political about the vaccine.

This may also be a plausible explanation for COVID related OAS (Original Antigenic Sin) and ADE (Antibody Dependent Enhancement) that some researchers claim they see.

At a minimum we can say that the more vaxxed and boosted a person is, the more "non-standard" (compared to other vaccines) their immune response is, and that's worth further investigation.

[phtrivier]

Thanks for the explanation. Although, as I understand it, I do not see how it can be anything else than a worst case scenario ?

When someone inevitably spins it as "they sold you vaccines that will let you catch the disease _more_ often, we told you so, subscribe to my podcast / buy my book / vote for me / etc...", what is the counterargument ? That we need more data to confirm ? That there can be other factors causing the reinfections ?

At this point, I'm looking forward for someone saying "it's more complicated than that", which is not a great sign :/

[michaelrpeskin]

There may have been nefarious intentions, and a lot of smart people I follow go that way. But I'm still more charitable than just about everyone I know. I call it the "entropy of ignorance". When dealing with a novel rapidly spreading pathogen that we have no experience with, there are more ways to make a wrong decision than a right decision. A wrong decision then opens up more choices where another wrong decision can be made. A purely statistical argument would show that we'd get the outcome wrong.

In non-emergency cases, we have some random people that follow the right path and that message gets amplified and we find a solution. In this case, that didn't happen (or maybe I should say "hasn't yet happened"). We are seeing with the latest twitter files that some people who were more right then wrong were silenced. The bias towards a more right answer was taken away. Why were they silenced? Could be something as simple a trying to make an easy message "anything that promotes vaccine hesitancy is bad" because good people truly believed that the vaccine would get out of it and they didn't want any confusion.

Back to your comment about "worst case scenario." Yes this is bad, if the vaccine (and in particular the boosters) are actually destroying the immune system, we have a problem. Typically we would have tested this for a long time to see this effect (which is not unknown in the immunology community) but for some reason "we didn't have the time" and we rushed it into millions (billions?) of people. That is bad. Can it get worse? Yes! What if the latent IgG4-enabled virus evolves in vaccinated people and we get another outbreak of a worse virus?

You can probably imagine more bad scenarios. I was a co-author on a paper about significant more (1000x) pregnancy and fertility adverse events after the COVID vaccine compared to the flu vaccine. So we're talking generational effects!

Anyway, not to be too doom and gloom here, but I think you're right "it's more complicated than that" and "we need more data" we just need to collect everything we can, make hypotheses, test them, and learn. That requires lots of open communication.

Extra info: earlier this summer I started to put together a figure to illustrate the "entropy of ignorance" It's outdated, I've learned more since then, but this was my best understanding this summer. You can see how it's easy to have a bad decision keep compounding into more bad decisions. And they can easily happen randomly, it doesn't take nefarious reasons.

https://imgur.com/YZKu3Wn

[adamredwoods]

>> Extra info: earlier this summer I started to put together a figure to illustrate the "entropy of ignorance"

Wow, that's heavily biased. "Create a culture of fear and weakness -> Enforce useless mask-mandates"? That's extremely biased (and ignorant in itself).

Also, it does not follow potential ramifications of some major decision, for example, "lockdown -> no" ends there, failing to illustrate outcomes when observing current spread rates, mutation rates, and death rates of a virus.

[phtrivier]

> Typically we would have tested this for a long time to see this effect (which is not unknown in the immunology community) but for some reason "we didn't have the time" and we rushed it into millions (billions?) of people

Well, in all fairness, the "some reason"s were thousands people dying _every day_ in western countries, overloading health systems. Anyone playing the "let's wait two more years, just to be sure" card had a _very_ hard sell.

To follow your analogy, this is probably a situation where there is vastly more wrong decisions to make, and the right ones require the benefits of 20/20 insight, which, well, GPT-42, maybe ?

To roughly quote a former PM from that period: "my job these days is to arbitrage between bad decisions".

This is were the scientific method of searching for the truth clashes with the politics of managing a human society. Not a particularly new debate, I suppose...

For "laughs" : I almost wish we'd go the complete opposite road next time, keeping the vaxxes in the lab as long a possible, just to see the opposition parties everywhere spread conspiracy theories about the "secret vaccine that the government does not want you to take", etc... Just, for a change.

[busymom0]

I think an objective look at the data clearly showed that the people dying or getting hospitalized were either elderly or had comorbidities. So vaccinating the 60 or 65+, obese, and those with comorbidities should have been enough while doing long term testing for the rest. Instead, we got mandates.

[sterlind]

thanks for the explanation. I'm really curious though, how do we know this is unique to the mRNA vaccines, or covid vaccines in general? could infection with SARS-CoV-2 in unvaccinated people also lead to IgG4 production?

Like, the mRNA vaccines are basically doing the first few steps of what the real virus does: attaching to ACE2 receptors with Spike and producing viral proteins from mRNA. It's hard for me to see where the immune system could get led down a different path.

[michaelrpeskin]

Good question. Here's one of the areas where I think we went wrong with this vaccine.

First, let's look at what happens when you're exposed to a respiratory virus. It gets stuck in your mucus membranes and your immune system starts finding matches. Your immune system starts making antibodies that match parts of the virus. There are hundreds of different fragments (epitopes) that your immune system could look for as a "fingerprint". Of those hundreds, your immune system probably picks dozens or so. That means that a later (mutated) infection will likely have overlap with at least one of those and you'll have a quicker response. This also mostly happens in the mucus membranes and IgM gets involved before anything else gets turned on.

A traditional vaccine uses either a dead or live attenuated whole (or at least a large chunk) of the virus. And that's why we typically have success. There are still lots of epitopes and our immune system picks a few to react to. And your immune system will pick different matches than mine, that gives us a broad spectrum herd immunity because we all react to a different part of the virus, and small mutations never get a chance to win.

With this vaccine we did two things wrong.

1 - We picked one protein, the spike protein, as the only match for the immune system. So the immune system only reacts to one match. That means rather than spreading out and trying a broad approach, the immune system gets hyper focused on only one match. From the immune system's perspective, it only has one thing do to so it starts to over focus on one thing. From the population's perspective, we all react to the same thing, that means there's tons of evoluationary pressure for the virus to mutate away from that one protein and it has a free pass in the entire population (Omicron?)

2 - The second factor is the the delivery mechanism. Normally we use something like an adenovirus to deliver the (attenuated/dead) virus to the cells. What we do is simply inject a whole virus, the immune system sees it and starts the response. This isn't as good as a typical infection because IgM never gets involved, but it works good enough. Here with the mRNA vector, we're injecting the instructions to generate the spike protein and then our cells generate the spike protein which are then attacked (and killed) by the immune system. That's a good story and sounds like really cool science fiction. But there are problems with this

2a - Rather than killing an injected adenovirus, your immune system is killing your own cells that have been hijacked to express spike protein. Granted, you have trillions of cells, that's fine. But there are some cells that don't reproduce and you have all of the ones you're ever going to have (e.g. cardiac muscle). The mRNA was supposed to stay at the injection site, but that was shown very early to not be the case. It can go anywhere, and there's a Japanese study that shows that it tends to collect in cardiac muscle, testes, and ovaries. Don't know why.

2b - Your body doesn't really want mRNA floating around in the blood. We have an enzyme creatively named mRNAase that eats up any mRNA that just floats around (like when a normal cell dies and explodes). So to protect the mRNA good enough to get into your cells we did two things, wrap it in a lipid nanoparticle (little fat bubble). Some people are freaked out about that. I don't know enough to comment on the safety of those. The other thing we did is the scary thing: we used changed some of the bases in the mRNA.

DNA has ATCG as it's bases. RNA uses AUCG. The U is uradine. In nature, sometimes (in very small quantities) the uradine is slightly different, and we call that pseudouradine (I'll use P here, but they really use phi as the symbol). It behaves like uradine, but it looks different. It's harder to break down mRNA with P than U, but it's usually in such small quantities that it doesn't matter.

To make mRNA more stable (and resistant to mRNAase), we made the mRNA delivery with much much more P (I forget the numbers, but very high compared to nature). So what's the problem with that? The way this whole thing is supposed to work: Transfect a human cell with mRNA. mRNA makes Spike. Immune system learns about Spike and kills that cell. That cell explodes (apoptosis) and the contents get cleaned up. Any new infections of Spike are primed to be killed by the immune system. But if that mRNA is pseusourdinated, then it doesn't broken down by the mRNAase and it goes on to transfect a new cell and the cycle continues.

So we have constant production of more spike by our own cells, that both keeps the immune system on alert (this can be driving the IgG4 story) and it also means that our immune system keeps attacking our own cells (autoimmunity).

The way it was described to me is that the mRNA was supposed to be like a log falling in the forest, it would naturally rot and get cleaned up. But we manufactured a fiberglass log that looks in all ways like the natural one, but it doesn't rot.

Long post, sorry.

tl;dr - Natural infection means IgM does most of the work. Traditional vaccine trains the immune system on the whole virus. This vaccine trains the immune system on a single protein in a way that causes it to hyperfocus and kill your own cells and keep your immune system on alert.

[bzmrgonz]

Very thorough ELI5, thank you. I wonder how difficult/expensive it is to test for IgG4? I ask because I do routine 7 day water fast every 3 months, and in theory, the body is suppose to repair and expel foreign substances. More importantly, it is also suppose to renew the immune system. I'd like to test the amount of IgG4 in my body.