The impact of antibody class shifts on non-SARS2 respiratory viruses: A response to Alex Berenson

I have just returned from my journey to lovely Britain. I’ll share with you all a post on my wonderful experience there, but today I first wish to address something else, a post by Alex Berenson.

I’ve generally appreciated Berenson’s work during the pandemic, as one of the last critical journalists we have: Pointing out how strange new treatment procedures seemed to lead to excess mortality that should have been avoidable, pointing out the high rate of adverse side effects of the unprecedented vaccination experiment, this is all work that has helped save lives.

There are other places where I find myself annoyed by what seems like a persistent refusal to accept the tremendous impact of the disaster our ruling class has created, like his insistence on pretending that long COVID is not a thing. Humans are not supposed to get infected by neurotropic sarbecoviruses, when we do see billions of people get infected you can expect some people to suffer long term side effects. Berenson is far from being alone in this, there are some out there who even insist on dismissing all the evidence of a lab-leak, because they’re so emotionally attached to the idea of SARS2 being a nothingburger.

Berenson is a rather quarrelsome man, which is the sort of personality type you need to see in journalists. The job of a journalist is not to offer you Truth on a silver platter, it is to cast a beam of light into the darkness. But every once in a while he makes the sort of knee-jerk dismissals of established scientific observations that harm his credibility. And that’s the impression I got, when I saw what I could only interpret as a jab at yours sincerely:

I don’t mind disagreement or criticism, but it has to be based on actual arguments. This is no such thing. This is an out of hand dismissal of my warning. And of course this Rintrah Radagast guy from the Netherlands is such a fringe weirdo that we can’t mention him by name. All of which is fine by me, I’m not in the business of trying to offer you truth on a silver platter, I’m in the business of showing you how I interpret what I see.

When I run into out of hand dismissals of my warnings however, I do feel an urge to address them. And to do so, I need to explain to you some basic principles of biology. There are different 21 amino acids our bodies use to build the proteins we use. Our antibodies bind to epitopes generally 4 to 12 amino acids in length, with six or seven being the most common.

With 21 different possibilities at six locations, you would find yourself looking at 85 million possible epitopes. What are the chances that an antibody we deploy against SARS2, would affect another pathogen? Diminishing unlikely you might think. And yet, you would be wrong.

To start with, we have to note amino acid usage won’t be randomly distributed: Some will be used more than others. The amino acids that are used are impacted by molecular constraints: Some sequences are just structurally impossible, you can’t just swap an amino acid with any other. Just seven amino acids compose more than half the coronavirus proteome.

Then more importantly, your own body is limited in the regions it can deploy useful antibodies against. A virus needs to have strange amino acid sequences in a part of its protein exposed on the surface, for your body to be able to generate useful neutralizing antibodies against it. Whenever your plasma cells secrete an IgG antibody to neutralize an RNA respiratory virus, the risk of such an antibody binding to your own tissues has to be avoided. For the viruses this creates a huge incentive, to evolve in a manner that leads the parts of their protein structures that are exposed to the immune system to resemble the sort of tissues they infect, at the amino acid length that antibodies target.

To state this in a different manner: If a virus infects the nasal tract of ferrets, then after a while, you’ll find that when you look at the sort of proteins ferret immune systems deploy antibodies against to fight off this virus, those proteins will through evolution over time begin to resemble the sort of proteins produced by cells in the ferret’s nasal tract. This is at least true, if you zoom in at the sort of length of amino acid chains that antibodies bind to: Six or seven consecutive amino acids.

And so it should come as expected, that when you zoom in at the six or seven consecutive amino acid level of SARS-COV-2, you’ll find that we see a lot of resemblance here, to the sort of amino acid sequences we see in human beings. You can look at a chart of the overall resemblance here:

The weird thing you’ll notice here, is that there is high resemblance for two animals: Mice and humans. This is very hard to interpret as anything other than evidence of this virus having evolved through passage through humanized mice, as has been discussed here on this blog before.

The important thing to consider, is that all the other RNA respiratory viruses that infect our respiratory tracts, are subject to the same evolutionary pressure: They survive by trying to make all their surface level protein structures visible to the immune system resemble the protein structures of the sort of tissues they replicate themselves in, at least they will tend to seek out such resemblance at the level of six or seven consecutive amino acids.

Generally speaking they won’t be perfect at this, because there is always a trade-off: Your protein still needs to be able to perform its function. In the case of SARS-COV-2, Spike protein needs to resemble your own respiratory epithelium, but it also needs to be capable of binding with high affinity to the ACE2 receptor. And so what you’ll tend to see are small spots in the genome, places where the whole thing just looks slightly different from anything commonly seen in our bodies. Those are the sort of spots an antibody can bind.

Have a look at this map of where the antibodies bind:

You can see there are just small spots that unvaccinated human beings seek out. We like to target SARS2’s fusion protein, we like to target HR2 and then beyond that we seek out different regions from one person to the next. The sort of spots you will target will depend on which small bits of Spike protein your infected cells present on their surface, which will depend on your HLA genes, which vary massively from one person to the next. Those genes vary a lot, because that makes it difficult for these nasty viruses to arrive at some sort of highly effective solution that would work on everyone: It’s nice to have a safe lock, until everyone in your village buys the same lock as you and the burglars start working on figuring out how to open it.

The important thing to understand here, is that not just SARS2, but every other RNA respiratory virus that regularly infects us finds itself subject to the same selection processes. Influenza will have a handful of surface level proteins, with regions commonly targeted by antibodies. It will increase its ability to spread when it evolves to make those regions resemble our own proteins in the respiratory tract, so that we can’t easily deploy effective antibodies against it. Respiratory Syncytial virus will find itself under the same incentives, as does rhinovirus, as does metapneumovirus, as do numerous others.

This is one of the main mechanisms that lead to viral interference: The tendency for some RNA respiratory viruses to struggle to spread themselves when other RNA respiratory viruses are spreading. Antibodies against one such virus, are often sufficiently cross-neutralizing, to stop another such virus from spreading itself. There is for example cross-immunity between the closely related metapneumovirus and respiratory syncytial virus. These viruses generally don’t cause simultaneous waves: A wave from one makes it difficult for the other one to spread. We now know why this is: Two independent antibodies have been isolated that happen to neutralize both.

With influenza and SARS-COV-2, we see a similar effect. It was known that people have pre-existing T-cell immunity against SARS-COV-2. Some of this was thought to be due to the regular human corona viruses, but we now know there are eleven T-cell epitopes shared between Influenza and SARS-COV-2. An infection by Influenza thus generates immunity that can also be useful against SARS-COV-2.

One of the mysteries you run into with SARS-COV-2, is that influenza vaccination protects against severe disease. A study from Qatar that I mentioned earlier found an 89% reduction in risk of severe COVID, in people vaccinated against influenza. Another study provides us with the explanation for such observations: It’s all just largely the same antibodies, tackling different viruses. I quote:


We found that peptide specific antibodies induced by influenza A H1N1 (flu) strains cross react with the most critical receptor binding motif of the SARS-CoV-2 spike protein that interacts with the ACE2 receptor. About 55–73% of COVID-19 negative blood donors in Stockholm had detectable antibodies to this peptide, NGVEGF, in the early pre-vaccination phase of the pandemic, and seasonal flu vaccination trended to enhance SARS-CoV-2 antibody and T cell immunity to this peptide. Twelve identified flu/SARS-CoV-2 cross-reactive T cell peptides could mediate protection against SARS-CoV-2 in 40–71% of individuals, depending on their HLA type. Mathematical modelling taking pre-immunity into account could fully predict pre-omicron SARS-CoV-2 outbreaks.

[…]

The presence of a specific cross-immunity between Influenza A H1N1 strains and SARS-CoV-2 provides mechanistic explanations to the epidemiological observations that influenza vaccination protects people against SARS-CoV-2 infection.


This is why I explained to you, that a class shift in our antibody repertoire induced by mRNA vaccination followed by SARS2 breakthrough infections towards IgG4 carries the risk of affecting other pathogens as well, particularly other RNA respiratory viruses.

On the one hand, there will be viruses that see IgG3 antibodies affecting their reproductive success shift towards IgG4, which is just not meant for neutralizing virus particles. They would be expected to enjoy an immediate fitness benefit from such a population wide shift towards IgG4.

On the other hand, there will be viruses that may not yet enjoy benefits from a population wide homogeneous class shift towards IgG4 right now, but that would be able to benefit after undergoing mutation. Some of these mutations may be relatively easy to acquire, requiring just a single nucleotide mutation, others will take much longer, requiring changes to multiple amino acids, or requiring two nucleotide mutations affecting the same codon.

And again, I’m asking you politely to consider that maybe this strange anonymous Dutch blogger isn’t just inventing this from thin air. In fact, I’d like you to consider for a moment that maybe this suggestion would go a long way towards explaining some other issues we see in late 2022, that we didn’t see in late 2021 back when the IgG class shift had barely begun.

Have a look at some strange patterns we now observe:

If the elderly have antibodies against influenza, but those antibodies shifted towards IgG4, you could expect them to become asymptomatic spreaders: They’re infected, but don’t suffer the inflammatory symptoms that lead us humans to recognize we’re infected. If children then get exposed at higher rates and to a higher initial dose, hospitalizations could be expected to increase dramatically. Britain similarly has its deadliest flu season since the Swine flu.

These findings are weird: COVID tends to kill the same sort of people who would die from influenza. After years of mass mortality from COVID, you generally wouldn’t expect a very nasty influenza season. You would expect it however, if the population has suffered some sort of immune impairment, which other viruses have learned to use to their advantage through natural selection.

SARS2 is capable of causing direct immune damage, this should not be underestimated. Plasmacytoid dendritic cells are harmed by an infection, they are responsible for our early interferon response. However, we now have clear evidence that it is also capable of causing immune damage facilitated by vaccination. After mRNA vaccination, breakthrough infections allows SARS2 to shift our antibody repertoire from IgG3 towards IgG4. At least for now, it appears unable to do so in unvaccinated people who have not suffered infections severe enough to require hospitalization.

As far as I can tell, the shift towards IgG4 appears to be a compensatory response. As SARS2 evolved, it began to mutate in ways that allow it to escape the most potently neutralizing antibodies, leaving poorly neutralizing antibodies and antibodies that allow it to productively infect your monocytes and other white blood cells by binding to the Fc receptor. This generally kills those cells and triggers large amounts of harmful inflammation.

The IgG antibodies differ in their ability to bind to the Fc receptor. In contrast to IgG1 and IgG3 (normal antibodies to deploy against a respiratory virus, IgG2 and IgG4, both of which are increasing their share of the response, are much worse at binding to the Fc receptor. As a result you’re still neutralizing the virus particles, without helping the virus as much to get into your white blood cells through the Fc receptor.

It’s not a great solution however, because we deploy IgG3 for a number of reasons: It’s good at binding to the Fc receptor, so your white blood cells can eat the viral particle. However, it also has a much longer hinge region, which has been found to help it become more potent at neutralization.

Finally, just as all the antibodies have a variable region, which differs from one antibody to the next, the antibodies also have a constant region under the variable region, which is generally similar within an antibody isotype (for example, IgG4). The constant region switches when there is a class switch.

IgG3 in humans is strangely variable, we have all sorts of different IgG3’s that we can produce, natural selection seems to have favored our ability to produce a wide variety of different IgG3’s and some people can produce types of IgG3 the rest of us can’t.

It seems that some of the IgG3’s may have a constant region that is particularly useful to enhance the neutralization potential of these IgG3 antibodies. We know IgG3 is extremely good at neutralizing SARS-COV-2 compared to all the other antibodies, we just don’t yet know exactly why this is.

And so I will emphasize again, that we use these IgG3 antibodies for all the RNA respiratory viruses. Antibodies we use against one such virus, are also used against another. This is the explanation underlying the effectiveness of influenza vaccination against severe SARS-COV-2, you don’t just have to believe me, I gave you the sources of authors agreeing with me in this conclusion.

And if you understand this, then you understand that you don’t want to see IgG4 take over the baton from IgG3. We need these antibodies. The IgG3->4 shift threatens our relationship with other RNA respiratory pathogens too.

The big question we now face is: How far will this process continue? How much of our antibody repertoire is shifted towards IgG4, in response to constant unprecedented mass infection, after the failed mass vaccination experiment? After a breakthrough infection after the third shot, you’re looking at a 42% IgG4 dominant immune response. Will novel variants disable other chunks of our antibody repertoire?

These are questions we now need to hear answers to. I would love to tell you that SARS2 has turned into just another obscure respiratory pathogen for academics to worry about, but that’s just not the world we live in, after a failed vaccination campaign has harmed our collective immune response to this virus and prohibited the development of herd immunity.


Note: In my first version of this post I said that Berenson is “disagreeable”, which is a lot harsher than I meant. It’s not my first language. Quarrelsome seems to be a better fit.

30 Comments

  1. Ironically, Alex Berenson tweeted this last week about mainstream media: ““Almost certainly no” is not no. It’s also not “this is a conspiracy theory and you’re a ghoul for mentioning it.” It is a step in the right direction”

    That is exactly what he did to you there. He didn’t dismiss your theory, just called it “vanishingly unlikely” (which is not “impossible”).
    It’s a step in the right direction.

  2. Rintrah, as you know, I share many of your views and took some effort to spread your previous ideas.

    As for this one, I am genuinely not sure. I have seen a lot of “pandemic immunological theories,” and some of them proved true, and some did not.

    This theory is not as convincing to me as the immune tolerance story.

    For example, “children with flu”: We are not sure how bad is the “children with flu” situation, whether it involves Covid vaccinated children, infants born to covid vaccinated mothers, Covid damage in utero or after birth, etc etc.

    A lot of flu pandemic scarecrow reporting is done as part of a public health messaging campaign to encourage flu vaccination.

    As a Covid writer, I find the lack of information, coverup of dangers of covid reinfections, and misplaced fear porn to be frustrating on the one hand and a challenge that I can seize on, on the other hand.

    The point is that health authorities hide very important data, while stoking fear about things that can lead us astray in our guesswork and reporting.

    The immune tolerance story was highly defensible. This flu and RSV story may prove right and prophetic, but it needs more confirmation to be proven.

    Keep doing great work and seek more evidence — you may prove right in the end!!!

  3. The virus is neurologically active for sure. At peak infection, I had vivid and atypically totally bizarre dreams. I hypothesize that this (delerium) is indicative of active brain infection/damage. Following my really bad delta infection, I had fog. I have little recollection of the 3-6 month period after. I was functional, could work, but it is a blind spot in my memory. Spouse had Omicron, had vivid dreams too, but wasn’t as much impacted as I was. This is my only infection (thankfully) that the memory loss was experienced. I feel a about 90-95% recovered 18 months later, but I have a little more trouble with names now.

    It would be an interesting survey to find those who had “dreams”. This thing is bad, and likely causes various sorts of permanent damage.

    I lurk from time to time, you make some good points

    • I had COVID a year ago, am unvaccinated. I assume it was Omicron. Compared to other infections I’ve had such as flu, it was mild, but still worse than a cold. I had a high fever and body aches, but the respiratory symptoms remained confined to my head/sinuses. I never developed a cough and my oxygen level remained at 98-99%. The two weirdest things that happened with it: I started my period a week early while symptomatic, which never ever happens, and it was extremely heavy for all 4 days, which also never happens. The other thing was basically what you mention. I had mental changes – depression, rage, almost a personality change, to be honest. It was very unsettling and strange. But after a week, I felt like myself again and my cycle returned to normal the next month also.

    • >The virus is neurologically active for sure. At peak infection, I had vivid and atypically totally bizarre dreams. I hypothesize that this (delerium) is indicative of active brain infection/damage.

      Yeah I suspect this is caused by Spike binding to the nicotinic acetylcholine receptors. You could get effects reminiscent of anticholinergic deliriants. It is a hellish experience.

      • It was horrible. I would wake up, after a couple hours sleep, intermittent sleep 20 hrs/day, totally freaked out/scared. Could have been made worse by O2 deprivation blood Ox was mid to high 80s. Though at rest i was 90s.

    • Neither my vaccinated/boosted husband nor I (unvaccinated) have had covid. We think. No fever, no respiratory problems, no coughs, nothing like that. And no brain fog nor memory problems. Intermittent exhaustion; that is all (with negative tests). But since around July of 2022 – a wastewater peak in our area – we’ve both had vivid and exceedingly long yet boring dreams. I figured it was dread Cthulhu, but maybe it is covid eating our brains.

    • infection end of may 2022. Daughter brought it from Scotland to Austria.
      I had vivid dreams too. Interestingly they “commented” on the actual phase I was in.
      One or two days higher fever (around 39°C) – no dreams.
      Then, third day, I dreamt of “breaking sticks into halves”
      next day of “heavy sorting work”
      and 2,3 days later (one week after infection) of a box being tied in chains – the signal “it’s over now” .. all of it was really hard, exhausting work within the dreams.

      and another observation: approx. 2 or 3 weeks after it was over I felt better with more energy than before. This happened to several of my work collegues (unvaxxed) too who are semi-professionel bycycle enthusiasts – it was measurable.

  4. If Alex doesn’t have a bone to pick with someone, he will be miserable. Like his IVM trope, we have to give him some opportunity to pick a fight. Sometimes it’s legit (like his criticism of Steve re brain dead football players), other times, it’s simply an oversized ego. At the least, it forces us all to test our assumptions. Goodness, you do it all the time for those of us believing in a 6 day creation, ‘revelation of John is genuine end times prophecy, climate change is God prepping us for the end of the world’ believers. Disagreement invites deeper understanding of our own positions. Great insight anyway on the IgG process by the way.

  5. If you think it over, it sound like a mild Marek disease scenario: the vaccinated are low symptom spreaders, driven by tolerance, while the rest suffer symptomatic disease due to the high prevalence of virus/-es in the society. This is a pretty damning situation and how it evolves depends on what the longer term consequences for the two groups are:
    1. what happens with the people that tolerate the virus(-es)? Do they suffer systemic disease or find a way to live with the virus long term.
    2. what happens with the unvaxxed, who get constantly exposed to large loads of virus(-es). Do they succumb to this constant onslaught of repeating exposures or eventually develop an ironclad immunity and are able to fend off the infections.
    Given the toxicity of the spike protein, the systemic disease for those tolerating the infections is pretty certain. Will the unvaxxed, or at least the stronger part of them, be able to outlive this doom-loop?
    In any case, you folks, do whatever possible to up your immunity: good food, good sleep, exercise, supplements you name it. Rintrah’s scenario is, albeit possible, I think far from certain. Vaccinated do develop N-antibodies as well, so there is hope that, be it with squealing tyres, we will avoid the crash after all.

  6. There have been a flurry of substack reactions to the study regarding IgG4 antibodies.
    I doubt that Berenson was referring to you.
    Yes, he is a prickly character.

  7. I am doubtful about ability of influenza vaccination to promote covid immunity.
    Half of Americans get influenza vaccination every year And if it provided this much pre-immunity to covid, would there be one million plus covid deaths?
    Plus the influenza vaccines are updated every year showing that older influenza vaccines are not effective against new influenza strains, never mind SARS2?

    • >Half of Americans get influenza vaccination every year And if it provided this much pre-immunity to covid, would there be one million plus covid deaths?

      It depends on your age. In ~36 year old healthcare workers, the sort of people studied in the Qatar study, it will be pretty effective. That’s how we arrive at the 89% figure.

      I would never claim this figure applies to the whole population. It’s merely a good indicator that we’re dealing with a bunch of cross-reactive antibodies, which suggests that bad vaccines that trigger a class switch for COVID antibodies will impact the response against influenza too.

      The problem of course is that influenza and COVID both tend to mainly kill the elderly, in whom all vaccines are less effective.

      In addition these vaccines are all generally thought to be subject to diminishing returns. The influenza vaccine becomes less effective if you’ve already had it in previous years.

  8. The IgG4 abs are isomeric antibodies, not the normal (standard/typical) abs, which have been created by the immune system in response to the cmRNA vaccines coded with Pseudouridine (an isomer of Uridine). The cmRNA vaccines have nothing to do with Sars-Cov-2 (a pathogen which is coded with Uracil, not Pseudouridine). Omicron is Mers-Cov-2, and is currently regaining its prion domain (see the CH.1.1 variant, which features the P681R mutation of Delta). Omicron needed a helper, and that was MPV, in order to regain/activate the prion domain. MPV and Omicron have common genome (sequences from Plasmodium falciparum and Yersinia Pestis). MPV is mousepox, and poxviridae is not a virus but a variant of M. leprae. Sars-Cov-2 and Mers-Cov-2 have multiple bacterial epitopes, which means that the correct treatment was to administer antibiotics (for M. avium and M. influenzae). Sars-Cov-2 and Mers-Cov-2 are mycobacterium and not viruses.

    What is going to happen next? Coronaflu (Omicron with its now activated prion domain) and Coronapox (the reassortment of Omicron and MPV).

    • Sandokhan…in the event you revisit this article and your comment, can you provide information (e.g. references) for your claim that Sars-Cov-2 and Mers-Cov-2 are mycobacterium vice viruses? If true, might this be some clue as to (any) effectiveness with the treatments via HCQ and IVM (fungal antidotes) coupled to antibiotics?

  9. I’m not sure that asymptomatic tolerance is what we’re actually seeing. Plenty of boosted people are experiencing bad covid infections that are not really indicative of tolerance. There are plenty of reports of more recent re-infections being worse than previous bouts.

  10. @G, Kudos for considering a Marek scenario. We pure bloods should not become complacent, patting ourselves on the back while privately rooting for vindication. Covid has a multi-billion population of tolerating spike machines and every incentive NOT to kill them off. Covid may be evolving to be, at best, indifferent to the non-jabbed. I wonder if the most vulnerable population to a future mutation would be never infected before pure bloods.

    • With non-sterilising vaccines, marek is always in the cards. I guess this is also pfizer’s and socialists’s wet dream – control the obedient, make them dependent on yearly shots and punish the outcasts.
      Still I think, a full blown marek scenario is very unlikely. The underlying dynamics resembles local optimisation – the virus seeks immediate and short term infectiousness gains in its main target population, which would be the vaccinated, and I cannot imagine a way for it to plan for not causing long term systemic illness in its hosts. I variant that is nasty for the unvaxxed and mild for the vaxxed is possible but a far stretch … or another lab leak. It all depends now if the healthier part of the vaccinated population will find a way to mount an effective immune reaction despite the disproportionally large IgG4 S-ABs share. For example, by developing potent N-ABs after infection. In the last UK vaccine surveillance report (https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1121345/vaccine-surveillance-report-week-48-2022.pdf , page 40) the prevalence of N-ABs in the blood donors in UK, as of beginning of December 2022, is 80%. This means post infection the vaccinated also develop N-ABs that are independent of the vaccines as they encode only the spike. Not sure if anybody has looked at what’s the subtype of those N-ABs but i would assume they follow the normal healthy pattern, and are not dominated by IgG4’s. That would be fantastic news actually …

      • “or another lab leak.”
        Goodness, you just proposed the exact, most likely way a Marek’s scenario MIGHT occur; on purpose.

        • not so easy, I guess. otherwise they would’ve done it by now. i mean, everything they release will have also second and third order effects. on top comes that virtually everybody (including the ones that do the releasing) will get whatever is released or its mutations and by now, only flat idiots are eager to get the mrna juice.
          funny that nobody speaks about the valneva vaccine – it is apparently a traditional inactivated virus one. does it produce this IgG4 AB shift, could it even help to alleviate the problem by inducing N-ABs in the vaccinated.

          • If you havent one until today, get the actual activated virus vaccine, known as Omikron. It fits better than the wuhan valneva. I got it too in juny last year and had a few days headache. Since that days i am fine and fit until now, like all of the unvaccinated in my circles that get Omikron.

  11. “Not sure if anybody has looked at what’s the subtype of those N-ABs but i would assume they follow the normal healthy pattern, and are not dominated by IgG4’s. That would be fantastic news actually …“

    I really hope and pray to God that that is true. My mental health has been completely shot to shit by this whole horror show.

    • “However, a very strong signal for the linear epitope (S-133: ECDIPIGAGICASYQ; Z-score: 2.7) is located at the furin-protease flanking region site (QTQTN), which is exclusively recognized by convalescent sera and is only exposed when furin has cleaved the S1 domain. This and eight further peptides (Table 1; RBD-75, RBD-76, RBD-106, RBD-107, S-109, S-124, S-125, S-127) are accessible in the cleaved S1 domain. The antibodies binding to this region prevent the spread of the free S1 domain in the body. Another very interesting peptide that is found in both serum types is the S-198: KVEAEVQIDRLITGR. This contains the amino acids K986 and V987, which are both exchanged against proline in the pre-fusion stabilized spike protein of the Comirnaty as well as in the mRNA-1273 vaccine. By looking at the structure of the spike protein, it is noticeable that part KVEAEVQIDR of the peptide is accessible in the opened-state structure and can thus function as a linear epitope in both cases (Figure 3). In the case of the convalescent sera, six peptides (S-199, S-200, S-201, S-202, S-203, S-204) with a Z-score of more than 1.5 were found in the direct vicinity. These six peptides are part of the central helix (CH) in the spike protein that is in direct contact with all of the monomers of the spike and to which there is no access in the pre-fusion state (Figure 3B). It is notable that parts of the first three peptides (S-199–S-201; Table 1) were identical to the epitope TGRLQSLQTYVT that was previously detected in 15% of all of the convalescent sera [8]. The other three peptides (S-202, S-203, S-204) cover parts of the RASANLAATKMSECVLG linear epitope [19]. The regions of this helix are enabled after the dissociation of the S1 domain and the rearrangement of the structure into the post-fusion structure (Figure 3D) [21]. In addition, the N-terminal part of this post-fusion structure has a large linker region, making the entire CH accessible to antibodies. Studies have revealed that up to 70% of the spike proteins on virus particles as well as on infected cells are in the post-fusion conformation [22]. Other studies have shown that the S protein interacts with the structural proteins M and E during the maturation of the spike protein and in the virus particle [23,24]. In vaccine-induced spike protein production, these interactions do not occur. This could have an impact on post-translational N-glycan modifications. The difference in the glycosylation pattern, in addition to the stabilizing mutations K986P and V987P, could play a critical role in S protein flexibility and linear epitope recognition.
      The immune response to the spike might also be affected by the presence of further structural proteins interacting with the spike, as in case of the natural infection. In contrast to this, the spike produced after vaccination with Comirnaty or other vector-based vaccines is exclusively produced in the absence of further viral structural proteins. This could have an impact on the structure of spike as well as on the processing and the accessibility of the spike epitopes.”

  12. The theory of IgG3 to IgG4 shift is vital to investigate. It would explain massive real-world experience I am seeing in US Northeast (persistent multiple infections in non-mRNA group having proximity to mRNA recipients). Could the following early COVID paper shed light on forward looking epitopes? (2021 Nelde et al, Nature Immunology – https://pubmed.ncbi.nlm.nih.gov/32999467/ ) Examined (temporally backward) cell-mediated immune epitope homology in COVID vs. unexposed subjects (through pre-COVID blood samples). My PhD work was in innate immunity so I need some help interpreting acquired cellular immunity results. It strikes me that this reference may provide some insight on forward homology of COVID vs respiratory viruses by examining backward homology of COVID to common cold coronaviruses. 81% of unexposed individuals had pre-existing cross-reactivity of T-cell response to COVID. Abstract below…

    Abstract
    T cell immunity is central for the control of viral infections. To characterize T cell immunity, but also for the development of vaccines, identification of exact viral T cell epitopes is fundamental. Here we identify and characterize multiple dominant and subdominant SARS-CoV-2 HLA class I and HLA-DR peptides as potential T cell epitopes in COVID-19 convalescent and unexposed individuals. SARS-CoV-2-specific peptides enabled detection of post-infectious T cell immunity, even in seronegative convalescent individuals. Cross-reactive SARS-CoV-2 peptides revealed pre-existing T cell responses in 81% of unexposed individuals and validated similarity with common cold coronaviruses, providing a functional basis for heterologous immunity in SARS-CoV-2 infection. Diversity of SARS-CoV-2 T cell responses was associated with mild symptoms of COVID-19, providing evidence that immunity requires recognition of multiple epitopes. Together, the proposed SARS-CoV-2 T cell epitopes enable identification of heterologous and post-infectious T cell immunity and facilitate development of diagnostic, preventive and therapeutic measures for COVID-19.

  13. “The theory of IgG3 to IgG4 shift is vital to investigate. It would explain massive real-world experience I am seeing in US Northeast (persistent multiple infections in non-mRNA group having proximity to mRNA recipients). “

    Do you mean multiple re-infections in the unvaxxed in close proximity to the vaxxed? I’m seeing that too. Unfortunately I’m back in an open plan office and nearly everyone is chronically coughing but still functional. I reckon they’re shedding shitloads of it and will probably inadvertently kill off a lot of unvaxxed first before they themselves die off.

    • There is no harm in using Xlear nasal spray (which is what I’ve used since the start of the pandemic) or the Israeli version (Envovid) or a homemade povidone iodine dilution nasal spray to prevent catching covid. Plus taking a claritin once a day. Those were proven to help prevent infection with earlier strains, and who knows, maybe they still help. It does infect through the nasal passageways (although maybe more through the eyes, now). It is possible that all you need to do is not be the biggest target. And maybe getting hit with a reduced viral load, rather than a massive load, would help.

  14. Hello, some of the testing I perform in my line of work is with immunoassays. I can tell your readers that we absolutely do see antibodies reacting with antigens from things that are something other than what we are testing for. The term used for this is cross-reactivity, and sometimes the chemical/virus/etc. is related to the item we are testing for, and sometimes it’s not. My point is that it happens in a controlled setting, where the manufacturers of this technology are deliberately trying to avoid this cross-reactivity. As you pointed out, in the IgG4 scenario, pathogens have an evolutionary advantage to take on these characteristics. I can’t comment on how likely it is, because it’s honestly beyond my knowledge and expertise. It does seem possible though, and shouldn’t be so flippantly dismissed.

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