So I’ve been looking at the literature a bit and I thought this was interesting. There are different antibodies, that serve to prevent severe SARS2 infection. However, neutralizing antibodies, that can directly prohibit a viral particle’s Spike protein from binding to the ACE2 receptor to allow it entrance into a cell, will tend to bind to the Receptor Binding Domain.
Almost all the monoclonal antibody therapies, consist of IgG antibodies against the Receptor Binding Domain. It’s pretty intuitive thus, to understand that the receptor binding domain is constantly changing. That’s where evolution is putting most pressure.
Eventually however, you run into the point where people have placed such diversified antibody pressure against the Receptor Binding Domain, due to a variety of infections by many different variants over time, that the virus becomes dependent on a different strategy. The Spike protein is a glycoprotein: A combination of a chain of amino acids, with sugar molecules attached to them.
Most of the time, changes to these amino acids will allow the virus to escape highly effective antibodies that show up in most of the population. However, another route towards antibody evasion is by changing the position of sugar molecules attached on important parts of the Spike protein (glycosylation changes).
This is what you see for BA.2.86* (which includes the now dominant JN.1). Part of the reason it’s so successful, is because it figured out how to place a sugar molecule in a position where it blocks a bunch of highly effective antibodies against the Receptor Binding Domain, without interfering with binding to the ACE2 receptor. This glycan on the RBD halved the immunogenicity of the virus.
Of course the vaccinologists don’t feel like giving up, so they try injecting animals with this new BA.2.87 Spike protein. But you start running into diminishing returns here, I’ll explain why. Unlike most other animals, there is one sugar molecule we no longer produce, due to a mutation in our genes: Neu5Gc. We only produce Neu5GA.
Nonetheless this molecule still ends up incorporated into our cells despite our own inability to produce it however, because humans tend to eat dairy and meat, from animals that still produce this molecule. So sometimes we have Neu5Gc, in places where Neu5Ga is supposed to be. When people then get infected by this virus or are vaccinated, the IgG antibodies against the sugar molecules on the virus cross-react with this Neu5Gc incorporated into the surface of your cells. This trigger a hyper-inflammatory reaction.
So if this vaccine works in mice (who produce Neu5Gc and thus don’t end up with autoantibodies), that doesn’t mean it’s still safe in humans. Vaccinating against these highly glycosylated variants of the virus can be expected to induce IgG antibodies against the sugar molecules. Those antibodies lead to the risk of hyperinflammatory reactions against people’s own healthy cells, because of the Neu5Gc people incorporate due to the meat and dairy in their diet. This is not my personal vegan doomsday theory, this is what the link above explains.
Through somatic hypermutation, the ability of your cells to rapidly mutate their own genes to make slightly different antibodies, humans ended up with a wide range of different antibodies against the various SARS2 variants that changed their receptor binding domain. On the other hand, there’s another position that seems to play a major role in preventing severe infections.
That position is found in the N-Terminal Domain. There are antibodies against positions in the N-Terminal Domain, that neutralize the virus in an Fc receptor dependent manner. What this means in simple English, is that these antibodies stop the virus from infecting cells, not by interfering with binding to the receptor, but by getting stuck on the N-Terminal Domain of the Spike protein and then attaching to cells of your own immune system with their tail.
This seems to be mostly IgM antibodies that do this, the very large antibodies that are the first to be elevated in blood upon an infection. Such antibodies are large enough to be able to bind multiple Spike proteins or multiple viral particles together. These antibodies don’t last very long however, they decline after a few weeks.
If people’s protection from reinfection by the virus now depends on IgM (and IgA) antibodies, what you would expect to see is rapid reinfection after a few weeks in relatively healthy people. That would suggest the IgG antibodies are now no longer able to meaningfully stop infection.
These IgM antibodies bind to a particular position in the N-Terminal Domain, that is highly immunogenic, because it’s exposed on the surface of the protein (where antibodies can find it) and looks very much unlikely any of your own proteins (which your immune system tries to avoid reacting to).
Because this position generally doesn’t change much over successive versions of the virus you’re infected by, these antibodies are continually being recalled in ever greater amounts. The idea Geert van den Bossche proposes is that protection from the virus now depends mostly on these antibodies in most of the population. I quote:
The virulence-inhibiting effect of PNNAbs (polyreactive non-neutralizing antibodies): PNNAbs bind to Spike-NTD exposed on free infecting virions as a result of diminished neutralizing capacity of potentially neutralizing vaccine-induced antibodies (pNAbs) and thereby enhance viral infectiousness. These Abs have also a virulence-inhibiting activity in that they attach to virus that is tethered to migrating dendritic cells (DC) and thereby prevent transfer of virus from dendritic cells to cells in the lower respiratory tract (LRT) and other internal organs—i.e., high levels of PNNAbs adsorbed on DC-tethered virions inhibit trans infection in the LRT and other internal organs and, thereby, protect vaccinated individuals from severe COVID-19 disease (fig. 1).
So, you have the dendritic cells, which have an Fc receptor, to which these big IgM antibodies that attach to the N-Terminal Domain of the Spike proteins bind. You have high concentrations of these cells at barriers in the body. You find them in high concentrations in the lower lungs.
If something were to change dramatically in the N-Terminal Domain, these big antibodies would suddenly become unable to do their job and shit would presumably hit the fan, as they are one of the last few mechanisms preventing severe infections. That’s the idea.
I wasn’t very convinced of this idea. When you build plausible assumptions on plausible assumptions on plausible assumptions, you don’t necessarily end up with a model of what’s going on. I have been looking for some actual experimental real-world verification that this is what’s going on.
And so, yesterday something was released, that would seem like a form of experimental verification that this is where evolution is now headed. In South Africa, nine sequences were found of a very strange highly mutated version of the virus, now named BA.2.87. The whole thing is described here. All nine of these cases seen so far were found in hospitalized people, suggesting it’s pretty virulent.
Now what’s so remarkable about this version of the virus, other than the fact that it’s apparently locally dominant in parts of South Africa, without spreading very effectively around the world, is that it looks pretty much like what you would expect to see if it tries to avoid these big IgM antibodies that bind to the dendritic cells.
So, what you see is that two very immunogenic parts of the N-Terminal Domain suffered deletions:
This also removes a bond formed between two amino acids, that keeps the whole thing in its proper shape. That of course makes the Spike itself less likely to have its proper shape, so it suggests that yes, we’re reaching the point now, where there is apparently a huge selective pressure to change these parts of the N-Terminal Domain where these big IgM antibodies bind.
Other versions seen in South Africa also show this pattern:
Note, these versions seen in South Africa are (still) pretty unlikely to start rapidly spreading around the world, the way JN.1 did. They have been around for a few months now, without showing up in other countries, so they’re probably not as fit as BA.2.86 was.
But they’re interesting to me, in the sense that they provide experimental verification of what Geert van den Bossche has been arguing: There is now apparently very strong antibody pressure on the N-Terminal Domain.
If a particular phenomenon can happen once in biology, it can happen again. So, it seems quite plausible to me, that we’re going to see this phenomenon happen more around the world, after we’ve now seen it happen twice independently in South Africa. Versions of BA.2.86* could emerge, that suddenly have a bunch of weird mutations in these particular immunogenic parts of the N-Terminal Domain.
There’s another factor that has to be considered. I’ve explained a few times now, that would you would expect to see happen, in response to all the IgG2 and IgG4 antibodies that bind to the virus but don’t tell the immune system to kill infected cells, is that these antibodies would encourage fusogenicity: The ability to spread from one cell to another by fusing cells together, without having to leave the cell and be exposed to the antibodies. The new versions with the shorter NTD don’t just reduce immunogenicity and avoid the IgM antibodies. They are also said to be much more fusogenic. In other words, multiple mechanisms would seem to be favoring this new pattern to emerge, that would be expected to result in greater virulence.
This sudden loss of the most important remaining antibodies, would then be expected to result in a sudden jump in virulence. These versions would probably struggle to spread themselves around the world, but they would be good at spreading within people’s bodies, because the dendritic cells are no longer holding them back.
So this seems to be where we’re headed. The virus first mutated its RBD, to spread rapidly (Delta, Omicron) and increase ACE2 affinity. Then it grew better at targeting those organs where the antibodies can’t reach, the brain and gut. This is what you saw with BA.5. Now the virus has rearranged the sugar molecules on its RBD, so that a variety of antibodies are all unable to do their job of neutralizing the virus.
Since the first Omicron versions, the virus now also gradually grows more persistent in people’s bodies and better able to spread by fusing cells, without having to expose itself to their antibodies.
Finally, we now seem to be reaching an end-game of sorts, where most people’s protection depends almost entirely on large non-neutralizing IgM antibodies, that bind to a very immunogenic position. This position doesn’t exist in SARS1, where these parts of the NTD are smaller, which may be part of the reason why SARS1 was more virulent, yet less capable of spreading rapidly.
This now seems to be causing very strong pressure, to figure out how to avoid those antibodies, allowing versions of the virus to emerge with a destabilized deformed Spike protein, that are worse at spreading themselves, but make up for it by managing to evade these antibodies.
It could be these versions spread locally between people, as now seems to be happening in South Africa. But it could also be that people now end up with persistent infections, that eventually develop these NTD deletions on their own. This would mean that people are infected for weeks, but then their infection suddenly takes a turn for the worse.
SARS-1 was also bad at spreading itself, but its N-Terminal Domain was shorter, these regions where people’s antibodies now bind were presumably less immunogenic than they are in SARS-2. The price SARS2 pays for its more stable Spike protein that allows high infectivity and rapid spread, would seem to be greater immunogenicity in the N-Terminal Domain.
Presumably, such infections would be very severe, as the body is effectively left with no way for antibodies to neutralize these viral particles: The RBD now has glycans at ideal locations. Antibodies developed against the glycan shield sound nice in theory, but such antibodies would take time to develop and the problem would seem to be that such antibodies also react with our own cells due to the Neu5Gc in people’s diet, thus causing the sort of sudden hyperinflammation that we experience as symptoms of the disease:
In case of a viral infection, such as that sustained by SARS CoV-2 or after anti-SarsCoV2-vaccination, in a heavy xenosialylated host presenting with a high grade of inflammatory state of Xenosialitis, it is highly probable and plausible that the virus-neutralizing antibodies, produced to combat the “antigenic alarm”, indiscriminately cross-react against all MCA-contaminated XeSiA-Neu5Gc epitopes exacerbating the pre-existing condition of xenosialites and related forms of autoimmune pathology.
This is essentially the theory. My point is that based on the evidence I’ve now read and the sequences emerging in South Africa in the past few days, the idea that we could see a sudden jump in virulence because the last few IgM antibodies now doing most of the work cease to work has started to sound more plausible.
I have long noticed and remarked upon the studies that suggest people with plant based diets rarely develop severe COVID, whereas there are cases of young healthy bodybuilders who died of it. The most plausible explanation of this phenomenon, would seem to be the high degree of xenosialylation, from Neu5Gc in their diet.
I know there are a bunch of people out there who think that ivermectin or hydroxycholoroquine would save the day, but if that were the case, it would be impossible to sweep under the rug. If there’s a miracle cure out there, we would know by now. It was not possible to do proper trials for anti-HIV drugs, because they worked so well that people started sharing them. In fact, it now seems hydroxycholorquine contributed to the high death toll of the first wave.
So, essentially, what I think you’re looking at is as following:
- Highly fusogenic variants with glycan shielded RBDs establish persistent infections in people, whose innate immune systems are unable to clear the infection.
- These variants become subjected to pressure on their N-Terminal Domain by IgM antibodies that bind them to the Fc receptor of immune cells (mostly dendritic cells). Mutating the N-Terminal Domain suddenly allows them to escape this neutralization. This presumably makes it harder for them to spread from one person to another, but as South Africa now proves, such spread can happen at least to some degree.
- With the most important still functional antibodies now useless, the body would have to rely on antibodies against the glycan shield.
- Because most people already have anti-Neu5c antibodies from the meat and dairy they eat, antibodies deployed against the glycan shield will react with cells that have incorporated Neu5c.
- This will cause hyperinflammation in blood vessels, as these antibodies react against healthy endothelial cells unlucky enough to have Neu5C from meat or dairy. In addition as people continue to receive Neu5C from their diet, the body starts to produce neutralizing antibodies that contain Neu5C, which the body will also have to remove with antibodies that bind to those antibodies.
If you accept this logic, it would follow that people are best off abstaining from food with Neu5C, especially if they were vaccinated. After a few weeks, bacteria in the gut will no longer incorporate Neu5C in their cells. This then allows the antibodies against this glycan to wane. Those antibodies are then not recalled throughout the body, once the body becomes forced to deploy antibodies against the heavily glycosylated Spike protein.
This isn’t just my theory, or the theory from this study I cited. Other people have looked at this and came to the same conclusion. We seem to have lost Neu5C, because lacking this sugar molecule allowed our species to survive deadly outbreaks of viruses in the past:
The absence of Neu5Gc in humans implies that the gene coding the CMAH enzyme hydroxylizing Neu5Ac into Neu5Gc was accidentally inactivated in hominins after the split from ancestors of chimpanzee, 2–6 mya. The observed production of natural anti-Neu5c antibody in humans suggests that, similar to the protective activity of anti-Gal, anti-Neu5Gc could protect against zoonotic viruses presenting Neu5Gc. It is further suggested that anti-Neu5c antibody protected the few hominin offspring, accidentally lacking Neu5Gc, against deadly viral epidemics that eliminated parental hominins synthesizing Neu5Gc. The absence of Neu5Gc in various mammals (e.g., ferret, sperm whale, seal, and New-World monkeys) further suggests that the accidental loss of Neu5Gc and the ensuing production of the natural anti-Neu5Gc antibody have mediated a selection process that contributed to prevention from extinction of a number of mammalian species.
Reintroducing it through our diet, is presumably a bad idea. We know the vaccines have failed dramatically, as evidenced by the continued circulation of the virus. But it would seem that through our Western diets, we’re interfering with the measures of last resort our immune system has to protect us against many viruses, which seem to be so important that we lost a gene after splitting from chimpanzees to protect us. Hence I once again wish to emphasize that people should eat plant-based diets.