Wrong antibodies: How the immune system is beginning to tolerate SARS-COV-2

I want to do one more post on the antibody profile we see after vaccination and explain why it signals growing problems down the road. To make the problem understandable, we first need to have a look at what the antibodies do again. Broadly speaking, the antibodies you have are as following:

The important three here are IgM, IgA and IgG, IgD and IgE are not relevant for this discussion. IgA is produced in your mucous membranes. IgM is produced in your bloodstream and shows up mainly in your bloodstream and your mucous membranes, it’s bad at entering organs and can’t reach a fetus in a pregnant woman either. Then there’s IgG. IgG is the one the SARS-COV-2 vaccines manage to induce, they’re very bad at inducing IgM. As I’ve mentioned before, IgM is much better adapted to dealing with rapidly mutating respiratory viruses than IgG, it’s the body’s preferred response.

Have a look at the antibody response curve to this virus and you’ll understand what immunologists seem to want to forget:

Anyone can look at this graph and understand that it’s your homeboy IgM who does the heavy lifting, that is, forcing this virus into retreat. This graph makes it obvious on its own, but if you consider that the RNA and Antigen you detect doesn’t necessarily have to be functional virus particles anymore, it becomes even more obvious that IgM solved the job. IgG is more like a watchman, who looks around after the fight is over, to see whether any cells are still infected and makes sure the body is alerted if the virus tries to return.

Most neutralizing potential in serum is IgM. IgG is better thought of as an antibody that detects this virus, a scout if you will, than an antibody that defeats the viral particles.

The IgG antibodies can be subdivided into four different classes, depending on the type of “tail” (the Fc region) they have, which determines how the rest of the immune system interacts with it. The IgG antibodies are basically scouts, the tails these antibodies have help the rest of the immune system figure out how to deal with the stuff they encounter.

It basically works as following: There is IgG3, which is the most important virus fighter of the IgG’s. It is the greatest complement activator, as it functions to encourage the rest of the immune system to start fighting the thing it encountered.

On the other hand there is IgG4, which is a tolerance inducer. It is unable to activate complement and so when IgG4 binds to a toxin or some other alien particle showing up in your body, your immune system is encouraged not to overreact to it. As an example, if you regularly eat peanuts as a child, you will develop an IgG4 response to peanut allergens, so that your body learns to tolerate these weird proteins showing up in your body, rather than triggering a dangerous allergic reaction. IgG4 basically tags proteins, to tell your immune system: “Yeah, we know this thing, it’s something weird from the external environment, but it’s not really dangerous, don’t worry about it.” IgG4 is the rarest of the four, the virus fighter IgG3 is second rarest.

Then there are IgG1 and IgG2. IgG1 is pretty versatile and used for viruses. IgG2 is more used for bacterial lipopolysaccharides, that is, the carbohydrates of the bacteria in your gut that produce their cell walls among other stuff. If you understand this then it won’t surprise you that IgG1 is pro-inflammatory, whereas IgG2 isn’t. Your gut is full of bacteria, your body needs to tolerate these bacteria instead of going into overdrive against them.

The four IgG’s differ in their ability to bind to the Fc receptor on your white blood cells, which tells them that something needs to be gobbled up (phagocytosis). IgG1 binds very strongly, IgG2 binds very weakly, IgG3 binds very strongly and IgG4 is average in its Fc receptor binding strength.

Think carefully and you’ll understand why it works like this. You don’t want your white blood cells to spend their time eating dead bacteria parts in your gut, the bacteria can eat each other and whatever is not eaten can just become feces, so IgG2 is very bad at binding the Fc receptor.

On the other hand, IgG3 is very good at binding the Fc receptor. IgG4 is average, as although the stuff it binds to needs to be tolerated, it does need to be cleaned up, you don’t want to have bee venom hanging around in your body for a very long time for example.

Now we get to the juice. Have a look with me at how the different antibodies are involved in the neutralizing immune response in plasma (A), compared to their overall level in serum (B):

On the left you see total neutralization activity in plasma, on the right you see its share of total mass in plasma. Our good friend IgM is just 8% of mass, but responsible for 37.5% of neutralization activity. IgG3 is just 3% of mass, but responsible for 42.2% of neutralization activity. Both IgG1 and IgA are responsible for about 22% of neutralization activity. Most important however, we see that despite being 24% of mass, IgG2 and 4 contribute zero neutralizing activity. Neutralizing this virus is mainly the job of IgM and IgG3, as we would expect.

If you were to look in mucous, these numbers would look a little different, you would probably see IgM and especially IgA have a much bigger share of neutralizing activity. But we have to move on, to what we see after vaccination, because this is where it gets worrisome.

The study is called “Class switch towards non-inflammatory IgG isotypes after repeated SARS-CoV-2
mRNA vaccination” and can be found here. We’ll start out with the abstract:

Repeated mRNA vaccinations are an efficient tool to combat the SARS-CoV-2 pandemic. High levels of neutralizing SARS-CoV-2-antibodies are an important component of vaccine-induced immunity. Shortly after the first or second mRNA vaccine dose, the IgG response mainly consists of the pro-inflammatory isotypes IgG1 and IgG3 and is driven by T helper (Th) 1 cells. Here, we report that several months after the second vaccination, SARS-CoV-2-specific antibodies were increasingly composed of non-inflammatory IgG2 and particularly IgG4, which were further boosted by a third mRNA vaccination and/or SARS-CoV-2 variant breakthrough infections. While IgG antibodies were affinity matured and of high neutralization capacity, the switch in constant domains caused changes in fragment crystallizable (Fc)-receptor mediated effector functions, including a decreased capacity to facilitate phagocytosis. IgG4 induction was neither induced by Th2 cells nor observed after homologous or heterologous SARS-CoV-2 vaccination with adenoviral vectors. In addition, IgG2- and IgG4-producing memory B cells were phenotypically indistinguishable from IgG1- or IgG3-producing cells. Since Fc-mediated effector functions are critical for antiviral immunity, the described class switch towards non-inflammatory IgG isotypes, which otherwise rarely occurs after vaccination or viral infection, may have consequences for the choice and timing of vaccination regimens using mRNA vaccines.

I made the important parts bold. What they explain is that the immune system starts responding after sufficient exposure to the Spike protein with different types of antibodies. IgG1, a virus fighter, goes down, along with IgG3, the most important virus fighters of the IgG’s. On the other hands, the two tags that say “don’t overreact to this shit, it’s not dangerous” (IgG2 and IgG4) are becoming more common.

This matters, because when you start to have IgG2 and IgG4 covering the virus particles, the immune system is increasingly just going to ignore this virus. As I showed you in the graph a bit further above, the normal situation is for IgG2 and IgG4 to have ZERO role in neutralizing this virus. These antibodies are just not how you’re supposed to respond to a virus showing up in your body.

But have a look with me at the graph they made where they show how these antibodies change over time in vaccinated people:

FU post 2nd is a followup visit 210 days after the second shot, the rest of this graph speaks for itself.

As you can see, after the second shot there is no IgG4 yet. This only starts showing up once people start suffering breakthrough infections and after the third shot. On the other hand, the IgG3 that is such a big player in fighting this virus goes down. IgG1 and 2 are less relevant, but here we see similar problems: A shift towards IgG2, the one that your body uses to tolerate junk produced by bacteria in your gut.

The important thing to note, illustrated by the followup in this graph, is that the tolerance after two shots of this vaccine gets worse with infections. The infections themselves are training the body to start tolerating the Spike protein.

Why does this happen? My suspicion is as following: The virus became competent at inducing antibody dependent enhancement, as the most neutralizing antibodies no longer work. This means that the virus began replicating in people’s white blood cells. One way to solve this problem, is to stop producing antibodies that activate complement or draw the virus into the Fc receptor: That’s how the virus manages to get into your immune cells and replicate there or damage them.

So, when you start producing the anti-inflammatory tolerance inducing IgG2 and IgG4 antibodies, you get rid of the antibody dependent enhancement problem: The virus becomes less capable of using your own white blood cells to its advantage. The problem of course is that “let’s just tolerate the virus” is not a very smart survival strategy in the long run.

What would normally presumably happen is that the IgM antibodies, which can be relatively variant independent as they are so big that they bind to multiple spots on the Spike protein at once and can tolerate mutations, would start taking over from IgG3, which continues to tag the virus whenever it sees it, but increasingly leaves the job of neutralization to IgM. As I have documented amply by now, we screwed that up with the vaccines: We prevented IgM from joining the fight.

When IgG3 can’t hand over the baton to IgM over time, IgG3 finds itself screwing things up for your white blood cells, by encouraging them to gobble up virus particles coated in increasingly poorly neutralizing antibodies (viral evolution at work), thereby causing more and more of those white blood cells to be damaged or productively infected by the virus, which the body ultimately resolves by moving towards tolerance (IgG2 and especially IgG4).

Or to dumb it all down in a brief summary: IgG3 can’t keep doing the job on its own forever, but with IgM unable to take over the fight, the body finds itself moving towards tolerance of the virus.

And so if you’re wondering: “Where is the antibody dependent enhancement catastrophe everyone was warning about when this vaccination campaign began?” The answer would seem to be: People’s immune systems are trying to avoid an antibody dependent enhancement catastrophe, by switching to the sort of antibodies that don’t enable an antibody dependent enhancement catastrophe. Unfortunately, such antibodies are not meant to fight a virus: They’re the sort of antibodies meant to help you tolerate a bee sting, your homemade sauerkraut or a peanut butter sandwich, without your whole face swelling up from an allergic reaction.

If you’re not convinced of my explanation, I would encourage you to read the study for yourself. The authors make it pretty clear that what we’re seeing is not normal: You’re not supposed to be seeing a growing IgG4 response against a virus like this.

And so if you’ll forgive me, I have to bring this up again:


Why do we see this virus building up in sewage? Why are our late 2022 lows now higher than our pre-Omicron highs? Well, put this in your pipe and smoke it: Droves of people are stuck tolerating this virus in their body, as the immune system can no longer afford to try to exterminate it.

The consequences of this mess are already much bigger than you think they are. Igor Chudov wrote a good post on the excess mortality, covering a statistical reality I had thought of myself a while ago too.

As Igor explains, the excess mortality we’re dealing with right now is actually much worse than it looks, because in young people, most excess mortality is normally non-medical: In the rare occasions where people die young, they get in car crashes, have a workplace accident, commit suicide, kill each other etcetera. That sort of stuff is largely stable.

When we see 12% increased excess mortality in young UK adults, the implications are that among the vaccinated 80% of young adults in the UK (if you think the unvaccinated are unaffected by whatever is going wrong), medical excess mortality is about 52%. It’s even worse of course, when you take into consideration that a lot of medical excess mortality is also predictable and rather stable. If you were born with a genetic disorder for example, a death as a young adult may be expected and it shows up as medical mortality. Stuff like sickle cell disease, Down syndrome and cystic fibrosis continues as young adult mortality at a pretty stable rate, that sort of stuff doesn’t suddenly jump 10% in a year.

You may think to yourself “why do I see so many cases of young people who died suddenly even though mortality only seems to be up by 10-20%”? The reason is because we now genuinely do have large numbers of young people who are dying unexpectedly. Intuitively a number like 10-20% doesn’t feel shocking, but it becomes much more shocking when you realize the implications.

And please understand: This stuff doesn’t look transitory. Rather, it looks cumulative. Whenever people get infected after receiving the first two shots, their IgG’s shift towards IgG4. Whenever they get another booster, their IgG’s shift towards IgG4. By the time your grandma or a Harvard college student gets shot number five, what do her IgG ratios look like? Ha, you think anyone’s studying that question? They gave this shot to eight mice, that was all they needed to see before deciding to shoot people up with it.

In a sane world you would have followed the first poor guinea pigs who signed up for these shots for a few years. You would notice that although the IgG’s look fine after the first two shots, they start looking wrong after subsequent breakthrough infections and this vaccine would never be approved. But now we’re stuck with this mess.

I don’t wish ill will on the vaccinated, my family and best friends were fooled into signing up for the first two shots but generally rejected the boosters. I have already made a bunch of posts where I explain how to deal with the consequences of this catastrophe, I recommend looking at those if you wish to address the problem.

12 Comments

  1. If someone with an immune response dominated by IgG2 and IgG4 is getting infected twice a year, what do we expect that illness to look like?
    Are the respiratory symptoms going to be relatively mild because of a muted inflammatory response…but it hangs round in the blood stream for months causing damage to the vital organs because the immune system isn’t clearing it?
    Maybe I am on the wrong track but does it mean “COVID” won’t seem that bad but people are being prematurely aged and accumulating heart and brain and diverse organ damage that manifests as seemly unrelated issues later and reduces life expectancy?

    • It’s a good question: What does it look like, when your body tolerates a SARS-COV-2 infection?

      To start with, I would expect such people to be superspreaders and to start giving rise to novel variants over time. Infections would become increasingly persistent, which fits what we witness in sewage (the lows getting higher).

      >people are being prematurely aged and accumulating heart and brain and diverse organ damage that manifests as seemly unrelated issues later and reduces life expectancy?

      There is already good evidence of COVID aging organs, so it seems likely to me.

      Personally, I’m inclined to suspect tolerance plays a role in the “died suddenly” phenomenon. It seems perfectly plausible to me that tolerating a virus that damages your endothelium can lead to massive strokes.

      Excess mortality in young European adults is higher in 2022 than it was in 2021. Direct (ie within days) mortality from the vaccines would have led to some of the excess mortality seem in 2021.

      The excess mortality we see now in 2022 seems the result of interaction between the virus and the vaccine.

  2. How does this shift in IgG priority match with the forecast depletion of CD4 and CD8 T lymphocytes? Are they two separate effects of the vaccine or are they somehow linked?

  3. I suppose that healthy unvaccinated individuals have the needed IgG4 and IgM responses to fight and clear the virus. But the healthy unvaccinated are still subject to repeated infections due to Omicron’s immune escape. Correct? Still subject to the erosion of the immune system due to repeated infections?

    Also, it seems to reason that the infected unvaccinated will ‘feel’ sick due to the inflammatory Ig response.

    • >But the healthy unvaccinated are still subject to repeated infections due to Omicron’s immune escape. Correct? Still subject to the erosion of the immune system due to repeated infections?

      It seems to depend on where you live. Places with very low vaccination rates, low obesity rates and a relatively young population seem to have a transient sort of herd immunity. After enough people there have had one or two infections, r0 drops below 1. Demographic changes or viral evolution can then make such communities susceptible again.

      For most unvaccinated people in Western nations this doesn’t apply. You’re still less likely to get infected, less likely to spread it and when you do get infected your infection lasts shorter, but yes, you would still expect to see damage to the immune system, as this is a problem intrinsic to the virus. It’s one of the first things they reported in Wuhan.

      To put it bluntly, we’re being dragged down with the sinking ship. That’s what happens when you interfere with the natural mechanisms that would normally have led to herd immunity.

      It’s what makes me very angry. The reason we have droves of children in hospitals now is because they’re constantly getting exposed to SARS-COV-2. They’re constantly getting exposed to it because we can’t get r0 below 1. We can’t get r0 below 1, because we have people who had three or more shots and turn into superspreaders.

      I might be wrong, if someone can demonstrate that Romania and Bulgaria also now have hospitals full of kids with RSV I’ll happily reconsider, but for all practical purposes it looks like the elderly who choose to believe a government that pretends they can just vaccinate themselves out of this mess are our weakest link.

  4. How do people like Leonardi get this so wrong? He still touts the vaccines as the best approach, and claims immune imprinting is only happening in the (re)infected.

    On another note, I saw an article recently which was looking at how bats manage to survive living in such dense colonies, since they are necessarily exposed to an endless barrage of viruses. The conclusion was basically tolerance – their immune systems have learned not to overreact to the myriad viruses they face. Unfortunately, we aren’t bats.

    • >How do people like Leonardi get this so wrong? He still touts the vaccines as the best approach, and claims immune imprinting is only happening in the (re)infected.

      Yeah it’s bizarre. He doesn’t want to see it. It seems that once you’ve made the commitment with your own body, all ability to critically reflect on this vaccine that now shows very clear evidence of negative efficacy against infection goes out of the window.

  5. Hospitals in Romania are indeed full of kids with rsv, including lots of babies. However, there are relatively few hospital beds anyway, concentrated in big cities, where vax rates are >60%. Definetely worse cases than previous flu and rsv epidemics, the current one manifests as pneumonia, very bad symptoms.

    • Thanks, if you can point me to any dataset it would be useful too.

      But yeah when your city is above 60% it’s over, you’re tipped into constant reinfections.

      Constant twice a year infections from a virus with such wide tissue tropism and intrinsic virulence as SARS-COV-2 is unsustainable.

    • Booster uptake was only 10% in Romania and Bulgaria…not clear how much of a difference that will make, still get OAS from the first shots.
      You would struggle to find any city in the world outside Africa that doesn’t have a 60% vax rate. Tbilisi, Sofia, Bucharest, Quito, Bogota, Guadalajara, Montevideo, Christchurch, Budapest, Bratislava, Zagreb…doesn’t matter where you go.

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