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.