A few shower thoughts on IgG4 and spike tolerance

Either wholly catastrophic, or maybe a bit of optimism in an Omicron era?

Update 12/28/2022: As Brian Mowrey pointed out in the comment section, he posted a follow-up study from Pfizer in which “imprinting” of sorts appeared to have occurred in some vaccinated/infected individuals. As it appears, vaccination not only created Wuhan-specific antibodies, but strangely appear to also have created Ba.1-specific antibodies as well, and this effect doesn’t appear to be achieved through natural infection.

The argument here may be that the Wuhan spike may serve as a universal template (like a universal spike). If true, this may be a concern in that even routine vaccination with Wuhan may influence the response to other variants and may produce an IgG4 class shift even against Omicron without exposing individuals to Omicron itself.

Consider reading Brian’s post, and hopefully more information comes to light that helps to piece everything together, including seeing if distance from last vaccination and routine exposure to Omicron may lead to novel B cell maturation and specificity against Omicron not affected by class shifting.

The Actual "Imprinting" Study

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Apologies, readers! Although I am catching back up on my reading family events are still happening which is making it a bit difficult to spend time to write longer articles.

So in the meantime, I wanted to write a few shower thoughts about Igor Chudov’s (and apparently Coffee & COVID’s) post on continuous IgG4 class switching class switching, leading to spike tolerance.

Booster-Caused IgG4 Immune Tolerance Explains Excess Mortality and "Chronic Covid"

This work builds off of Igor’s, as well as Brian Mowrey’s (and likely many other’s) prior works raising concerns about the possibility of spike tolerance occurring due to continuous vaccination.

Tolerance Cometh: IgG4 After Multiple-mRNA Doses

Brian Mowrey’s post (linked above) provides some information on IgG4 which is worth reading, but for those who would like a quick rundown there are 4 different subclasses of IgG antibodies, aptly labeled IgG1, IgG2, IgG3, and IgG4.

In the first 3 subclasses all antibodies have what is known as an effector region (noted as the Fc Region in the figure below), which is a region at the base of the “Y” shape of an IgG antibody. This portion binds to effector cells such as specific innate immune cells and T-cells, and they produce immunological effects by signaling for the destruction or removal of whatever the antibody’s paratope (the antigen binding site) binds to.

However, during times of increased antigen exposure, the different subclasses may shift over to eventually become IgG4 dominant. In the case of the IgG4 subclass, the Fc Region is modified and loss of effector function occurs, causing the eventual phenomenon of tolerance as the antibodies can no longer signal to effector cells.

Now, tolerance isn’t inherently bad, as with allergies (which are one of the main places where IgG4 antibodies are wanted) tolerance prevents the immune system from overreacting to an exogenous substance, as the immune response and inflammation to an allergen can end up being far more detrimental than just leaving the allergen be.

So IgG4 is argued to be anti-inflammatory, in that the shunted effector response means that the immune system will not overreact and produce widespread inflammation that can be detrimental. In fact, as Brian points out in his post, many inflammatory markers are needed in order to induce this class shift towards IgG4.

That’s all well and good for rather inert molecules and proteins, but when it comes to pathogens this can be rather dangerous as it means that the body no longer will produce the necessary downstream immunological cascade of events in order to target said specific pathogen.

Note that the paratope (the sequence of amino acids that bind to the epitope of the antigen, noted as the antigen binding site in the figure above) remains unchanged, and so IgG4 antibodies can still bind to antigens. However, they just can’t signal anymore to effector cells or for additional help in that manner, which can be rather dangerous for infections if they can no longer be dealt with.

This is one of the reasons why IgG4 antibodies are likely found with cancer, as the immune system attempts to control the growth of cancerous cells by utilizing antibody-mediated processes. However, after a while the immune system likely gets tired of dealing with the cancer, the class switch towards IgG4 occurs, and antibody-mediated removal of cancer is halted and unchecked growth continues on.

And so now the production of IgG4 spike tolerance is extremely concerning, as it hypothetically would suggest that many people would not be able to properly deal with SARS-COV2, allowing the virus to spread and likely cause more severe illness.

So let’s be clear; the class switching is unprecedented and is clearly not something that should be happening, and it is absolutely something that the vaccine manufacturers should have looked into, but given that this is a phenomenon of repeat exposure they likely never even considered this in their clinical trials, only looking for whether neutralizing antibodies are still being produced.

Which makes the situation a bit ironic, as I have stated that IgG4 can still bind to antigens but lack the effector functions to signal to effector cells. Therefore, neutralizing assays wouldn’t inherently be able to tell whether the antibodies being looked at are IgG1, 2, 3, or 4, but rather if any antibodies are just sticking in general.

So the need to find neutralizing antibodies, without looking at what subclasses are doing the neutralization is just another example of the failures in the research into these vaccines.

Altogether, on the surface all of this is alarming and extremely concerning.

However, with that being said I wanted to raise a few points worth considering that may provide some white-pilling perspective.

Spike Tolerance to Wuhan in an Omicron Era

One big criticism of the vaccines have been that they have never been updated for each variant. Well, aside from all of the serious safety and efficacy concerns, to say the least.

So people who have been vaccinated have been continuously vaccinated against the Wuhan spike. This would tell us that spike tolerance would likely be directed at the Wuhan spike-a rather troubling state of affairs if we were still in a Wuhan era.

However, Wuhan is just a distant strain of the virus. Now that we are in an Omicron-infested era the dynamics have changed.

I have argued that Omicron has changed the landscape of COVID, to the extent that Omicron was so distant relative to prior variants that it started an immunological do-over of sorts.

People both vaccinated and unvaccinated (included those naturally infected) were susceptible to Omicron.

In reality, if we were to actually label variants of interest, it may be better to consider Omicron as its own variant and Alpha, Beta, and Delta all under the umbrella of sub-Wuhan (just a random opinion, to be honest).

This also comes with the fact that we don’t know where Omicron came from, and evidence may suggest a lab origin of this variant.

Interestingly, at the time, many people considered Omicron from the perspective of a black hatter/white hatter event.

In short, a black hatter is someone who may cause an event to happen that leads to downstream damage or catastrophic events, such as a hacker who takes advantage of a weakness and uses it to release the personal information of millions of online users.

In contrast, a white hatter may seek out vulnerabilities and alert people to these issues in order to prevent catastrophe.

In any case, the emergence of Omicron led a few people to speculate whether its emergence was a possible white hatter event, in that its more mild symptoms may mean that we can quickly move on, including no longer needing the vaccines.

And interestingly, this may be where Omicron may remove us from the IgG4 conundrum, as the antigens for Omicron are so distant from prior variants that spike tolerance may not be as detrimental as we may consider it to be.

Note that this is where a distinct contrast compared to allergens needs to be made.

It is true that allergens do not self-replicate. It’s also true that allergens are not constantly changing, and so IgG4 responses to an unchanging antigen are likely to persist.

However, if the antigen itself is constantly changing then that may present with a different story.

Note that Omicron meant many of the Wuhan-specific antibodies lost their neutralizing capacity, so even if many of these B cells shuffle over to IgG4 producers, they wouldn’t be able to stick to Omicron’s antigens, and would all be a wash regardless of loss of effector functions due to class shifting.

So in a very loose, hypothetical sense, the era of Omicron may make the concerns over spike tolerance somewhat moot, as novel B cell responses may still be made against Omicron specifically, as noted by Brian Mowrey at the end of his article:

Probably, the Wuhan-spike-directed B Cells of triple-dosed mRNA Covid vaccine recipients will continue to convert to the tolerance-promoting IgG4 subclass the more they are exposed to spike.

However, novel B Cell responses after infection with the Omicron siblings (see “B Cells Anonymous”) may add new IgG1 B Cells to the pool.

Of course, all of this is speculative, and so we may come to find out that this is certainly not the case.

However, note that many studies on IgG4 antibodies don’t explain exactly which epitopes these IgG4 antibodies target, and the evidence of so-called “breakthrough” infections tends to be rather limited.

Strangely, the recent Science article, which seems to be the formally published version of the July pre-print Brian covered, doesn’t make note of the variants that vaccinees were infected with compared to the pre-print version.

The July pre-print notes the following (emphasis mine):

Finally, we asked whether subsequent infections with SARS-CoV-2 can also activate IgG4-switched memory B cells. We identified twelve persons from a study cohort of break-through infections (CoVaKo) who were vaccinated twice with SARS-CoV-2 mRNA vaccines and who experienced a breakthrough infection 25 to 257 days after the second mRNA vaccination (Suppl. Table 4). Infection was confirmed by PCR (2x Alpha, 7x Delta, 3x Omicron variant) and then serum samples were collected on the day of study inclusion (visit (V) 1, typically within the first week), two (V2) and four weeks (V4) after the PCR. In all individuals, we detected an anamnestic antibody response with an initial increase in spike-binding antibodies from V1 to V2 (Fig. 6).

PCR serves as a rather poor proxy for variant recognition compared to genomic sequencing, so it’s hard to argue whether these variants are the proper variants unless timing was used to infer the variant.

It’s also worth noting that infection didn’t appear to lead to IgG4 class shifting to a similar degree as vaccination, although the researchers argue that the class shifting is likely due to months of germinal center (GC) maturation.

And even with that being said, if the IgG4 antibodies lose their effector function, they may still be able to bind and provide some neutralizing capacity, if any.

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A bit of optimism?

In short, the class shifting is something not considered by those who continue to tout out the vaccines, and evidence continues to mount that this is a possible concern that should have been addressed prior to vaccine rollout.

However, as we are in an Omicron era, the actual effects of the spike tolerance may not be as severe, as continuous targeting of Wuhan spike may infer tolerance to Wuhan spike in particular, meaning that novel immune responses to Omicron specifically may form.

Of course, the ever-pesky concept that is original antigenic sin may be used as a rebuttal to this argument by suggesting that people who have been vaccinated will ONLY form antibodies against Wuhan spike, and therefore will continue to produce anti-Wuhan spike even when presented with Omicron spike.

The anti-Wuhan spike will continuously shift over to IgG4, and the cycle continues ad infinitum, locking people into a never-ending sequence of Wuhan spike boosting and tolerance.

I and Brian Mowrey have argued against this idea before, as it’s a rather reductive argument for the complexities that are the immune system. There’s also the fact that some of the initial arguments about OAS may have been rather disingenuous and eventually took on a life of its own, as Brian Mowrey noted in his series on the initial construction of OAS (note: my interpretation; not Brian’s).

With that being said, evidence would need to suggest whether Omicron infection in vaccinees will incur an Omicron-specific response, or if this may spell some doom for what’s been going on. This would require understanding the paratopes of these antibodies and whether they target Omicron specifically, Wuhan specifically, or are cross-reactive to both spikes.

We should also remember that spike antigens are not the only antigens worth considering. Although possibly the most important anti-nucleocapsid antibodies, as well as antibodies against other SARS-COV2 antigens can still be formed and provide some protection.

Evidence suggests that vaccinees can become seropositive for anti-nucleocapsid antibodies after a “breakthrough infection”, suggesting that an immune response can still be made against other antigens even if the response to the spike may become rather shot through vaccination.

But what remains the most critical aspect of this whole debacle is the fact that tolerance would suggest that we cannot chase the variants with continuous mRNA vaccination.

With the introduction of bivalent boosters, we are now entering into a territory in which we are trying to catch up with Omicron, and may in fact result in tolerance to Omicron spike through repeat Omicron-specific vaccination. If Omicron sublineages remain the dominant variant, then the end result may be tolerance to a still-circulating form of the virus that would leave many unable to create a new, novel protection.

All of this remains to be seen, but in any case the fact that tolerance is occurring should tell us that continuous vaccination will be more detrimental rather than beneficial.

It’s fortunate that bivalent booster uptake has been rather low (relative to the time of the article’s writing), and hopefully it will be kept that way in the near future, but this should tell us that we cannot chase the variants with continuous vaccination.

Anyways, the next microbiome post will come in another day or two. Apologies for the delay!

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