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The Actual "Imprinting" Study
Another shoe drops: A revisit to Quandt, et al., which shows lack of novel B Cells after BA.1 infection - and implications for tolerance non-escape.
Perhaps there is a function for the word “imprinting,” in a context other than merely describing how we already understand immunity to work, after all. One that divorces the term from the myth of OAS, and OAS’s obsession over antibody levels to prior virus models - because that is not the issue potentially in need of a new descriptor.
Instead, this new term will be wedded from the start to the discrete question of generation of new memory B Cell lines to a variant virus, or not (re-use of old, shared memory B Cell lines).
This would not imply anything about inability to re-tool the immune response after infection with future variants, à la mythical OAS (quite the opposite; though we will leave the question of infinite variant-“boosting” off of the table), but would instead suggest an inability to escape from Covid-vaccine-induced tolerance to other (any?) versions of the spike protein.
Put succinctly, a paper from BioNTech showed that although the Covid-vaccinated responded to BA.1 infection with abundant BA.1-neutralizing antibodies, they did so without making any “BA.1 spike exclusive” B Cells (as in not-cross-immune with Wuhan, implying no new B Cell lines were formed against spike).
A fully “Omicron”-tailored immune response was thus created out of the original Covid vaccine spike toolset, by remixing the same Covid vaccine spike-binding B Cells… which are already potentially progressing toward IgG4 tolerance.
Obviously, the previous post on this subject is a recommended primer for this one.
And so, on with the show.
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“Imprinting” Proposed definition
A condition where memory B Cells in practice are immunodominant in advance for related (variant) antigens of a virus.
This would not be an intrinsic property, i.e. “blind-spot” of the immune system, but would arise when “imprinting” antigens wind up as self-immunodominant (vs. likely or possible variants). (“Immunodominant” means what it sounds like: An epitope that is more likely to attract the immune system’s attention than others on the same life-form. Here I am simply expanding the term to include future versions of the life-form rather than just other physical structures within it.)
For example, the pre-enrichment of BNT162b2-prompted antibodies against multiple future variants, as observed by Röltgen, K. et al., might be a sign of self-immunodominance. For whatever reason (likely due to lower immunogenic “dosage” of spike), this isn’t found after natural infection, so self-immunodominance may not be a property of the spike protein itself, but of the context of exposure:
While the reader may not have encountered these findings before, they have been remarked upon extensively in other papers since being published in January. Including by the BioNTech paper we will discuss today.
Again, imprinting would be a condition that operates “in practice.” Once current antibodies have enough affinity against contextually possible (functional) alternate epitopes to outcompete natural IgM, no new B Cell lineages will be formed. The host is in practice “imprinted” because the laws of physics are not going to suddenly make it possible for the virus to present an epitope that current super-enriched antibodies do not have affinity for.
To build again off of the Röltgen, et al. results, natural infection may typically lead to a mix of “rough draft” and high affinity results from person-to-person, whereas the persistent, repeated, and monomaniacal presentation of spike caused by the mRNA vaccines guarantees a high-affinity result leading to self-immunodominance. Alternately, natural infection just tends to leave more of a “door” open for variant viruses to elude previous antibodies and B Cells, compared to constant maintenance of high antibody levels in the Covid vaccine schedule - in the same way that B Cell nonplasticity can be shown in lab animals but not in natural conditions.
This working model may not fit for the Omicron siblings, which have such radical mutations to the spike design. In that case, a new working model would be required. For now we will treat it as applying, if only due to artificial super-elevations of vaccine-model antibody via triple and quadruple-dosing.
With that introduction, let’s discuss what was observed with B Cells in the BioNTech Omicron breakthrough study.
A recent paper has transformed “imprinting” into this summer’s favorite buzzword. The paper doesn’t show anything that it has been alleged to show, nor anything that I would deem worth the reader’s attention. Modern Discontent already published an excellent review of the flaws, while I was in hiatus mode.
Becoming a subscriber of Modern Discontent’s substack is a highly lucrative investment of your time and money, and is believed to improve the marriage prospects of your progeny.
I may yet offer a review of the bad “Imprinting” study of my own. Today’s post, in fact, was intended to be just that. But, while I was reviewing previous papers dealing with post-BA.1 immune responses… I caught something odd.
First, I revisited the BA.1 infection outcomes study from Austria. Here’s a header about it.
“Omicron” Immunity Throwback 1: Rössler, et al.As previously reviewed, in this modestly-sized retrospective study, prior exposure with the Covid vaccine, SARS-CoV-2 infection, or both, all lead to a higher anti-BA.1 response post-BA.1 infection vs naive exposure. This is regardless of symptoms (as in, the unvaccinated are not simply less frequently symptomatic).
So, as a sort of “opposite-OAS,” we see here that those with more previous exposure to pre-Omicron spike and/or whole virus, mount a more robust response against BA.1 after infection - even when ample time is given for seroconversion and affinity maturation, etc. However, this poor performance appears to be contradicted by unvaccinated post-infection results in another study (below).
Next, I revisited the BioNTech “Breakthrough” study. Here’s another header for that one.
“Omicron” Immunity Throwback 2: Quandt, et al.Also previously reviewed on Unglossed, this in-house BioNTech study compares both before and after results in neutralizing BA.1 after BA.1 infection, this time just for subjects previously dosed 2 or 3 times with the Pfizer/BioNTech Covid vaccine.
Green are results for Covid-vaccinated who have not yet been infected with BA.1. It may surprise the reader to know that this will be highly relevant for our (possible future) look at Reynolds, et al.: It is not normal for Covid-vaccinated to have high neutralizing antibodies against BA.1 before even being infected with it. That is not the spike protein they were mRNA-dosed with.
Pink and purple are post-infection results. They are exactly what we would expect to see if everything that has ever been said about “OAS” is a fabrication: The triple-injected, BA.1-infected can neutralize BA.1 just as well as Wuhan; the double-injected, BA.1-infected even more-so (due to their naturally waning response against Wuhan).
And so naturally, an OAS-proponent would turn to the B Cell results from the same study, where it would appear that this “new memory” against BA.1 is an illusion - those cross-reactive B Cells which were already present have simply expanded. While a number of B Cells specific for BA.1 spike were found (B Cells that are attached-to by fluorescent-tagged BA.1 spike but not also attached-to by fluorescent-tagged Wuhan spike), these were already present before BA.1 infection. Meanwhile, fluorescent-tagged BA.1 Receptor Binding Domain is not found to stick to any cells that don’t also get stuck-to by Wuhan RBD (“shared”) at any point.
Left, is B Cells that tagged whole spike stick to; right, B Cells that tagged Receptor Binding Domain stick to.
Pink and purple are post-infection results. They are exactly what we would expect to see if everything that has ever been said about “OAS” is totally brilliant and true: Post-infection, BA.1-spike-specific B Cells are comparable in percentage to Wuhan-spike-specific; but on the other hand they already were before (green). It is the “shared” B Cells - those which both spikes stick to - that have expanded. For the Receptor Binding Domain, all B Cells which BA.1 RBD can stick to can also be stuck-to by Wuhan RBD (i.e. shared). Both results suggest no new B Cells to BA.1’s unique epitopes were made at all.
The BioNTech authors propose that this is evidence of “imprinting” - the Covid-vaccinated can now only pull from the bag of epitopes included in the Wuhan spike and Receptor Binding Domains (which for whatever reasonincluded a percentage that already scored as BA.1-specific in the pre-infection set).
Of course, all conclusions about imprinting (or OAS) that fail to use a naive (uninfected, unvaccinated) control group are perilous. But a second BioNTech-associated study appears to strongly support this one.Among unvaccinated University of Texas Medical Branch patients infected with BA.1, serum neutralization of a SARS-CoV-2 mutant with BA.1 spike was robust and not accompanied by neutralization of the classic model.
And so, it is not the case that the key immunogenic epitopes on BA.1 just happen to be those shared with Wuhan (i.e., those which escaped BA.1’s extensive remodeling of the spike protein).
A thought that struck me, here, was J.J. Couey’s old theory (on Twitch videos which have long since expired) that the spike protein of SARS-CoV-2 was, on release, a “perfect roll” for ACE-2 binding, designed (in some grant-application-writing genius’s mind) as a universal coronavirus vaccine. Is it thus possible that the reason the Covid-vaccinated B Cells say “neutralize BA.1” using the words (epitopes) taught to them by the Wuhan spike, is that they still spell “neutralize BA.1” as well or better than words based on BA.1?
It seems a bit science fiction. But we can imagine that perhaps the natural BA.1-infected created a sculpture of BA.1’s spike out of putty, whereas the Covid-vaccinated reassembled their Mr.-Potato-Head parts to create simulacrum of BA.1’s spike that looks even realer than the real thing.
To quote the BioNTech authors:
In aggregate, our results suggest that despite possible imprinting of the immune response by previous vaccination, the preformed B-cell memory pool can be refocused and quantitatively remodeled by exposure to heterologous S proteins to allow neutralization of variants that evade a previously established neutralizing antibody response.
In other words - the B Cell pool formed by exposure to the Wuhan spike model is effectively universal. Was that by design?
However - and here is where I stopped and reformulated this entire post - the revisit to the results of Röltgen, et al. suggest that the spike protein may be a bystander in these developments. The naturally infected, in red, do not appear to be “front-loading” an enriched response against future variants:
That leaves us with the keep-it-simple,-stupid possibility that this is simply more backlash from overdosing the immune system with a target antigen (more comments on this in the footnotes).
Regardless of whether it is a property of the original spike design or of the unnatural delivery, it is an indisputable fact that the Covid-vaccinated in Quandt, et al. appear to have stitched together a “perfect” neutralizing response against BA.1 using only the B Cells already seeded by the epitopes in the Wuhan design. In contrast to the trope that Covid-vaccine-anti-spike response is a “one trick pony,” it may in fact turn out to be a horse of every color possible.
And, of course, all of these endlessly re-arrangeable, immunodominant anti-spike B Cell and antibody models, potentially, are already on the raft toward conversion to IgG4 and tolerance.
So although Covid-vaccinated IgG4 antibodies will (after reshuffling for the new variant) blunt the virus from entering cells in the artificial conditions of a neutralization assay, during actual infection they will sabotage the ability of T Cells to take out infected cells.
Again, hopefully this is all just an outcome of artificially elevated antibodies due to repeat boosting. An end to boosting, I think, could still be the way to promote generation of new B Cell lines against spike that are not prone to tolerance (assuming that anything having to do with regulatory T Cells is not in its own way already “imprinted” against variant epitopes).
Cross-variant IgG4 sabotage of Killer T Cells would lead to more frequent failure of asymptomatic, abortive infection, more frequent “rebound” during Paxlovid treatment, and general prolonging of viral shedding (at least into the respiratory tract; IgG4 antibodies may still blunt viremia leading to invasion of other organs). In other words: Negative efficacy; negative efficacy; and negative efficacy. Eventually, Covid-vaccinated infections may resemble the experiences of the immunosuppressed, where virus can be cultured or sequenced for months on end.
If tolerance is in fact widespread among the Covid vaccinated, the Omicron siblings seemingly offered a ticket off of the raft. Quandt, et al. suggests that even these mutants are not different enough to escape the “imprint” of mRNA-induced super-dose of spike.
Which is not OAS. It’s not “original” if you have to shove the thing down the immune system’s craw for so long that tolerance develops before the “imprint” takes hold. I think that’s a fair line in the sand for me to draw.
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A surprisingly immediate reference to my review of Francis’s 1956 “absorption” experiment, wherein cross-reacting ferret antibodies were all easily shown to be expansions of antibodies against the primary infection virus, and yet human antibodies were authentically new. In a likewise manner, normal avoidance of self-immunodominance (generation of novel B Cell lineages to variant viruses) can rely in part on the natural waning of antibodies to “break in case of emergency” level. This waning ensures that future variants demonstrate to the immune system (i.e. to naive B Cells in germinal centers) that a new antigen has arrived, whereas with artificially super-elevated antibodies the germinal centers are akin to a king whose advisors won’t disclose a famine.
Rössler, A. et al. “Neutralization Profile after Recovery from SARS-CoV-2 Omicron Infection.” nejm.org.
Previously reviewed in “The Austria Omicron Study.”
Quandt, J. et al. “Omicron breakthrough infection drives cross-variant neutralization and memory B cell formation.” biorxiv.org.
Previously reviewed in “Week-End Review: 22.4.8.”
Perhaps the BA.1 EPE insert is sticking to B Cells for previous coronaviruses…
Kurhadea, C. et al. “Neutralization of Omicron sublineages and Deltacron SARS-CoV-2 by three doses of BNT162b2 vaccine or BA.1 infection.” Emerging Microbes & Infections. 2022, VOL. 11, NO. 1, 1828-1832.
See footnote 1.