A poor strategy: A look at the mechanisms that caused the SARS-COV-2 vaccines to backfire

I’ve been thinking lately about how the pandemic is going to evolve and how the mass vaccination campaign has exacerbated the crisis we’re in, as we receive news of the unprecedented collapse in life expectancy in the United States and massive excess mortality in Europe. When you genuinely understand something, you can make it understandable to others too, so that’s what I wish to accomplish with this post.

To start with, I wish to establish one argument first, which you can either accept or reject:

-The vaccines against SARS-COV-2 have gradually with every successive new variant become less effective. This is what I expected a year ago and when I look at the data, it looks to me as if my expectation has come to fruition. It seems that with Delta we reached negative effectiveness against infection. The birth of Omicron meant we entered the era in which we also face negative effectiveness against hospitalization and death, with successive newer forms of Omicron having increasingly more negative effectiveness. You can find an estimate for when negative effectiveness began in the UK in this study. The negative effectiveness of the vaccines is obscured in most of the officially published data, mainly by the fact that infections for a brief period after the injection are piled into the previous category and by the healthy vaccinee effect: The unvaccinated elderly have large numbers of very sick people among them. In addition, excess mortality statistics suggest that we’re increasingly attributing COVID deaths to non-COVID causes, thus further muddying the picture. To arrive at this conclusion you thus can’t just believe the official data, rather, you mainly have to rely on geographical analysis: Comparing regions of the world with high and low vaccination rates.

You either accept this argument, or you don’t. If you deny the existence of negative effectiveness, this article is not for you. it’s already very long and would get much longer if I wanted to show you all the evidence. The fact that you’re even reading this post makes it likely that you accept it, but it clashes with the official narrative we’re given. It’s illustrated here, in deaths by vaccination status from Public Health Ontario:

You can see how the burden is shifting over time towards people who received multiple doses of the vaccines.

Now comes the following argument:

-The disturbing wave of excess mortality we’re witnessing in Western nations, is mainly a product of the interaction between vaccination, SARS-COV-2 and the human immune system. As long as SARS-COV-2 hasn’t exhausted its pathways towards developing new variants capable of infecting previously exposed people, the wave of excess mortality will continue to get worse, as the damage being caused to our bodies accumulates.

Again, you either accept this argument, or you don’t. If you don’t accept it, if you believe that SARS-COV-2 is becoming a non-issue, you will need to come up with some reason why excess mortality in the EU so far this year has been equal to that of the past two years, even as we should have negative excess mortality because so many of the deaths were frail people with less than two years of life expectancy left. My position is: SARS-COV-2 is doing this, but we’re diagnosing it mainly as cardiovascular and cerebrovascular deaths. Continual evolution and a very bad vaccination strategy transformed this virus into a formidable opponent for our species.

And to explain how this could have happened, I propose my next argument:

Immunity induced by vaccination and immunity induced by natural infection look very different.

What do I mean with this? The vaccine manufacturers sought to take the route of inducing neutralizing antibodies against its Spike protein. This means the antibodies block the Spike protein from binding to the ACE2 receptor, thus preventing the virus from using a cell to produce more copies of itself.

Why did they take this route? That’s the difficult question to which I have no good answer. I think they underestimated the evolutionary potential of this virus and the important role that the diversity of the human immune response plays in our protection against respiratory viruses.

However, natural immunity works through multiple routes. It works through the route mentioned above, induced by vaccination, but it functions through other routes too:

–Antibody dependent cellular cytotoxicity. The infected cells generally display pieces of the virus in their MHC molecule. The antibodies your body produced will bind to it, which alerts your cytotoxic lymphocytes that this is where the action is going on, so they go down there and destroy the infected cell. Importantly, the antibodies against non-Spike proteins work for this too. If for example, an infected cell displays a piece of the nucleocapsid protein and your nucleocapsid antibodies bind to it, your cytotoxic lymphocytes also know to go kill it.

-Training of innate immunity of endothelial cells. Everything in the body is a trade-off, but as the cells lining our blood vessels get exposed more to coronaviruses, they get better at dealing with them, mainly by recruiting the immune cells that need to deal with the coronaviruses. I suspect they also get better at phagocytosis of coronaviruses and start producing more of the Toll-like receptors they use to recognize whether they’ve been infected with viral RNA.

But most importantly, response to the Spike protein is different too. Immunity against the spike protein induced by natural infection is broader, it targets more epitopes. Whereas natural immunity targets 37 different epitopes, vaccine induced immunity targets just 11.

And that leads to the following image:

Convalescent humans have an immune response all over the place, but vaccinated humans don’t. This may seem like just another triviality intriguing for nerds, but it’s not.

This matters, because antibodies to Spike do different things. We all know the neutralization of Spike: An antibody binds to the receptor binding domain of Spike, so now Spike can’t properly bind to the ACE2 receptor. This neutralizes that particular Spike protein.

However, this is not the only mechanism through which antibodies prevent infection. Another common mechanism is opsonization. This means the spike protein is covered with antibodies, which encourages your monocytes to gobble it up and digest the nasty virus.

The fusion protein: A great place to target with antibodies, but not visible for the immune system in the stabilized synthetic Spike

There’s also another route that’s used by your antibodies. It’s the Fusion protein.

After SARS-COV-2 binds to the ACE2 receptor, it uses the fusion protein, to fuse with the cell. The fusion protein is only exposed after binding to the ACE-2 receptor. It’s not exposed in the pre-fusion stabilized Spike found in the science-juice.

You can see the antibodies in vaccinated and convalescent people for the Fusion protein in that image with the red lines I posted above here. FP stands for Fusion Protein. One vaccinated person made decent amounts of fusion protein antibodies, at least three convalescent people did so. The image above suggests it’s the only region natural immunity really focuses on, besides HR2.

In other words, your body struggles to develop immunity against the fusion protein through the vaccines as it’s not exposed in the stabilized pre-ACE2bound state that they created by inserting two proline substitutions into the mRNA science-juice version, so it mainly develops immunity against other parts of the Spike protein.

The highest binding antibodies against the fusion protein, preventing SARS-COV-2 from infecting your cells even if the Spike protein has bound to the ACE2 receptor, are all found in convalescent donors. They call these antibodies “broadly neutralizing antibodies”, because they seem to work against every variant we’ve seen so far. Why are they working against every variant? Because it’s not changing. Why isn’t it changing? Because it’s not under selection. Why is it not under selection? Because vaccines teach people’s immune systems to focus on other ways of disrupting the replication cycle.

Of course evolution requires that if we all stuck with fusion protein antibodies and that was our only way of dealing with this virus, the fusion protein would probably change, or the virus would figure out how to be less dependent on it. In every conflict, strategies against an opponent work better, when he’s not used to them. It’s why left-handed boxers have an advantage.

However, this serves as an important illustration of my point: Even Spike-directed antibody immunity looks and behaves different, depending on whether it was induced by vaccination, or by natural infection. And thus it is also differently affected by the evolutionary dynamics this virus is under.

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What are the implications?

Evolution dictates that predators will tend to preferentially spare those potential victims who don’t resemble their favored prey. Optimizing your toolkit for any particular prey tends to come at the cost of your ability to make use of other potential preys.

SARS-COV-2 is ultimately just another predator, one that preys on us by entering our cells. As a coronavirus it is a versatile virus, but it will inevitably face trade-offs. As we make our immune response more similar to each other through vaccination, we encourage variants to emerge that make optimal use of our increasingly similar ways of fighting off this virus.

An important point often overlooked is that the ability of antibodies to stop the Spike’s RBD from binding to the ACE2 receptor depends on a number of different factors. As an important example, there is the complement. Complement is a kind of molecule your immune system produces, that will bind to antibodies located close to each other. Here’s an image to illustrate it:

Here you can see complement activity, as a share of antibodies, in vaccinated versus convalescent donors. Vaccines induce greater complement activity. Unfortunately however, antibodies can also enhance infection, especially when complement binds to them. Take a look at this:

This is what happens when the antibodies that bind to SARS-COV-2 are covered with complement. In natural immunity, another process tends to happen: SARS-COV-2 is covered with antibodies (opsonization), which then causes monocytes to absorb the antibody coated virus particle. This causes the monocytes to produce inflammation, but importantly, the replication cycle ends here: The virus can not produce more copies of itself in monocytes. As you see explained above, there are some enhancing antibodies produced during an acute infection, but it doesn’t matter much as the body also produces an abundance of neutralizing antibodies.

Only convalescent serum shows opsonizing antibody mediated entry by monocytes, vaccinated serum doesn’t. The monocytes (macrophages and dendritic cells) are doing the job they’re supposed to do: Eating the antibody covered virus particles to demolish them through phagocytosis. You may have seen people argue the vaccines seem to induce tolerance to the virus. This looks correct, insofar as you won’t suffer inflammation from monocytes absorbing antibody covered viral particles.

Antibodies display neutralizing activity, but as their concentrations decline over time, they will start displaying antibody dependent enhancement of infection, in the presence of the C1q complement. And C1q complement relative to IgG antibodies is much higher after vaccination, than after natural infection. The C1q complement allows entry into cells that the virus can productively infect, like respiratory epithelial cells. So, it would look like people are being set up for antibody dependent enhancement of disease.

To dumb it all down: In the unvaccinated you see antibodies all over the Spike protein. This means you can get opsonization. Without enough of such antibodies covering the whole virus, the negatively-charged cell walls of the virus and monocyte repel each other. On the other hand, in the vaccinated you see hotspots, places where a lot of antibodies bind, whereas other places have none. This means you get places where complement will bind to those antibodies located close to each other. Once it does, it helps the virus enter cells in which it can replicate.

High Avidity antibodies versus High Affinity antibodies: You want the prior against viruses that rapidly change how they look!

This brings me to another important topic: Antibodies structurally differ in many ways from each other. An important distinction needs to be reemphasized: Avidity versus affinity. Affinity is the binding strength at a single location, avidity is the total binding strength of an antibody. And so take a look at some of the different antibodies here:

IgA is the one we produce in mucus. IgG is the one we tend to look at when we try to measure quality of the immune response against COVID-19. And then there’s IgM. It appears early during an infection, then it disappears again, then during a reinfection it shows up again. Whereas IgG mainly seems to function to help the immune system recognize a virus, IgM, with its many different legs that together enable high binding strength, seems to be very important in interfering with a virus through its high binding strength.

In convalescent plasma donors, depletion of IgM causes the highest loss in SARS-COV-2 neutralization, depletion of IgG comes second. And yet, almost all the studies tend to look at IgG, rather than IgM. Because it’s so big, IgM is less susceptible to the effects of mutations that change a single amino acid in the virus, whereas IgG antibodies tend to be rendered useless. Whenever people look at IgM (which they don’t do enough, they prefer to look at IgG), they tend to find that it’s very important in protecting against rapidly mutating viruses, like Influenza.

Rather than just being some antibody that temporarily shows up and then disappears again before you reach the holy grail of IgG, IgM is a vital strategy the body utilizes in dealing with rapidly changing respiratory viruses. Unfortunately, vaccination sends the immune system down the road of sending high affinity low avidity IgG antibodies after this virus, rather than IgM antibodies. Take a look at this comparison between naive and breakthrough infections:

IgG antibodies become much higher in breakthrough infections, whereas IgM antibodies become higher in the unvaccinated group. Unfortunately, exposure to high affinity IgG antibodies can interfere with the development of proper IgM antibodies. I quote:

The memory B cells that developed in antibody recipients differed from controls in that they were not enriched in VH3-53, VH1-46 and VH3-66 genes and predominantly expressed low affinity IgM antibodies that carried small numbers of somatic mutations. These antibodies showed altered RBD target specificity consistent with epitope masking, and only 1 out of 77 anti-RBD memory antibodies tested neutralized the virus. The results indicate that pre existing high-affinity antibodies bias memory B cell selection and have a profound effect on the development of immunological memory in humans that may in part explain the shifting target profile of memory antibodies elicited by the 3 50 rd mRNA vaccine dose.

You might be wondering to yourself: Why does the science juice encourage the body to deploy IgG antibodies, whereas natural immunity tends to encourage IgM antibodies? I wonder that too, but it doesn’t seem anyone has a clear answer yet. Quoting from another study:

Recent data revealed that in response to BNT162b2, volunteers developed only moderate levels of anti-S1 IgA and IgM antibodies after both the first and the second doses of the vaccine, in contrast to the strong IgG response (23). Similarly, the BNT162b2 vaccine compared to natural infection induces low anti-S and anti-RBD IgM and IgA responses but does induce a strong IgG response (43). One possible explanation for the relatively low IgM and IgA responses to the vaccine are the lipid components of the vaccine formulation, which are relatively uncharacterized with respect to their effect on the human immune system. Some early work indicates that the lipid components may increase Th1-polarized CD4⁺ T cell responses, thus creating early IgG class-switching that could produce the observed high IgG and low IgA and IgM responses (43).

I don’t know how you could read this with the knowledge that the convalescent response is IgM dominated and interpret what you read here as a win for the vaccine. But here’s something important to keep in mind: With viruses that rapidly change themselves, like Influenza and SARS-COV-2, you will want antibodies that have high avidity, but low affinity. IgM has high avidity, binding to many different places on a viral protein, without having to be a perfect match at those places to be useful. Because IgM is so big, it’s also good at linking up to multiple viral particles simultaneously it’s really good at interfering with viral proteins too.

IgG has low avidity and high affinity: It binds to just two places, but needs to be a perfect match there to be useful, so it easily becomes useless or worse than useless through single mutations on those spots. IgA, which you find in your mucus, would seem to be somewhere in between, with average avidity and affinity.

I think in the explanation I cited above, they missed one important point: People were injected twice, with an identical version of the Spike protein. If the Spike protein looks identical both times, IgG antibodies will receive a relatively large stimulation, compared to if there were subtle differences in the Spike protein that don’t matter for the IgA antibodies but do prohibit the IgG antibodies from doing their job. Or to dumb it all down: The immune system was given the impression that a virus that actually mutates pretty rapidly just looks identical all the time.

Much of what I’m showing you here won’t be radically new for most of you. It’s essentially what Geert van den Bossche explains when he warns about vaccinating children. Children have a bunch of IgM antibodies, big antibodies with high avidity and relatively low affinity. If they start producing high affinity IgG antibodies, those will prevent maturation of the IgM antibodies to deal with COVID-19 and other problems their immune system will need to address. IgM antibodies don’t just disappear when we become adults, but the body will more selectively deploy them, for example to deal with infections like Influenza or SARS-COV-2. But if the IgG antibodies always show up first, the IgM antibodies don’t get to do their job and thus don’t become a proper part of the immune response. The effect becomes that over time, the body gets stuck on an improper immune response through the science-juice. That doesn’t just mean you get problems with SARS-COV-2, particularly in children it can manifest in the form of autoimmune problems too.

And with all these metrics, we could say “well, maybe the human immune system is just wrong and needs a helping hand”. Maybe the human immune system actually has no real clue how to properly fight a corona virus and needs us to instruct it through a pre-fusion stabilized Spike protein. Maybe opsonization followed by ingestion by monocytes is just the wrong approach. Maybe complement needs to bind to the antibodies, even though this enables productive infection of respiratory epithelial cells. Maybe natural immunity is just an error and the immune response needs to consist of high affinity IgG antibodies to a handful of regions of the Spike protein in the pre-fusion state. Maybe those IgM antibodies that make up the vast majority of neutralizing potential in convalescent blood need to mind their own business.

But look around you and that narrative is just hard to sustain. Natural immunity is cumulative: Two infections in an unvaccinated demographic protects better against reinfection than just one infection. There is no evidence of harmful immune imprinting, natural immunity gets better over time. And of course, you should just compare demographics, which I have done many times: The situation gets better in unvaccinated demographics, the virus is having the time of its life in highly boosted communities like Edinburgh. But if we comprehend how immunity differs qualitatively between groups, it allows us to understand what we should expect in the further course of evolution.

I wish to look at one more comparison of regions between vaccinated and naturally immune demographics.

We see here once again the difference in regions where the antibodies bind. You see a big focus on the Fusion protein in the unvaccinated, especially those who were not hospitalized. You also see some antibodies all over the place among the unvaccinated, but again relative uniformity among the vaccinated demographic.

It seems that when you have these long regions, where multiple antibodies bind near to each other, this is where complement tends to be able to bind the antibodies, thereby causing antibody dependent enhancement. You don’t really have a lot of regions like that in the naturally immune: Their antibodies are all over the place, because their immune systems got to see all the epitopes, rather than just the stabilized pre-fusion Spike.

You also see the NTD region, where vaccines develop a strong response. The NTD region evolves to optimally make use of these antibodies, they enhance infection. And most notable, you can see the purple category here, the people who were vaccinated after infection. Their antibody profile looks effectively indistinguishable from those who were vaccinated without prior infection here. In fact, it even looks as if they stopped focusing on the Fusion Protein region that works so well across variants.

While we’re at it, let’s look at the words of the authors themselves: “Epitope binding appeared to change over time after vaccination, but other covariates such as mRNA vaccine dose, mRNA vaccine type, and age did not affect antibody binding to these epitopes. Vaccination induced a relatively uniform escape profile across individuals for some epitopes, whereas there was much more variation in escape pathways in mildly infected individuals.“

What about those CTD antibodies, found in the vaccinated, but not the non-vaccinated demographic? Well, I’ve looked quite hard to figure out what those do. I found nothing remotely interesting. These antibodies would seem to be among the non-neutralizing antibodies that make up a much higher relative share among the vaccinated than among the unvaccinated. And because these are distinct regions, I would expect complement to bind here, perhaps facilitating entry into cells.

You might be wondering: If it’s a problem when antibodies cluster closely together in a particular region, because that causes complement to bind to that region, which then draws the virus into a cell, doesn’t that mean the natural immunity habit of binding a bunch of antibodies to Fusion Protein causes the same problem? I think the answer would be no, because the antibodies bind there when the Spike protein has already moved from its closed to its open state, which means it has already moved into action.

This is the general pattern you run into when you look at the vaccine induced antibody response: Like in natural immunity, neutralization does tend to require binding to the receptor binding domain, but in addition to these antibodies that bind the receptor binding domain, the vaccinated also produce a whole bunch of binding non-neutralizing antibodies, that seem to cause more trouble than good.

Useful antibodies that directly prevent entry into a cell are focused on the Fusion Protein, the NTD or the Receptor Binding Domain. The others are not per definition completely useless, they can for example help your cytotoxic lymphocytes discover infected cells, but they won’t stop infection.

If you look at this image, you also start realizing why the variants tend to emerge first in non-vaccinated regions of the world: The antibody response of the vaccinated doesn’t really generate many neutralizing antibodies against the Receptor Binding Domain anyway. Rather, the main thing setting the vaccinated immune response apart is that they produce more antibodies, as they produce a large bunch of non-neutralizing antibodies as well, that mostly facilitate viral replication.

If you read all of this and perhaps bothered to visit the links, I think you’ll have a decent clue why the vaccine has been such a failure.

To me personally, virologists and immunologists who anticipated that SARS-COV-2 was getting stuck on a genetic dead end around the time the vaccines were being deployed just look stupid and incompetent, but at least under that assumption I understand their belief in this vaccination strategy that was deployed worldwide.

Far more puzzling to me, are the ones who anticipated that it would continue to dramatically change, but didn’t recognize what the implications of that are for the long-term effectiveness of these vaccines. If you go back to my older posts, you will find that I anticipated negative effectiveness would emerge. If I can anticipate it, so should they.

Survival through diversity: The SARS-COV-2 endgame

The versions of the virus that survive are those that are best at spreading themselves, which requires overcoming the antibodies that bind to its proteins, insofar as those antibodies prohibit productive infection of cells, which as I just amply illustrated not all antibodies necessarily do. There is one route we are well familiar with: A mutation happens to a single nucleotide, the new codon leads to the production of a different amino acid in a particular place on the Spike protein, this means high affinity antibodies that needed a particular sequence of amino acids can now no longer bind to the protein.

There is also an alternative route however, which few discuss: If as this virus, you continually increase the affinity of your receptor binding domain to the ACE2 protein, at some point your attraction will become so strong that it exceeds the binding strength of the antibodies. Once that happens it’s over, the antibodies no longer work. Antibodies differ of course in how strong their affinity to the receptor binding domain is, so there will be a point where some antibodies can no longer compete, while other still can.

And it seems that’s where we already are: Once Omicron showed up to the scene, its ACE2 affinity was so much higher than previous variants, that certain antibodies just stopped working. The antibodies that are susceptible to this problem, are high affinity, low avidity antibodies. What this means is that they bind strongly to a particular spot, but they bind to relatively few spots.

Unfortunately, with the newest variants now circulating, the BA.2.75 lineages, this problem will get worse. After all, here you can see the ACE2 affinity of different variants over time:

Fewer antibodies will still be neutralizing Spike by binding to the RBD in the BA.2.75 descendants, but equally important, those that do will have to compete with the rising ACE2 affinity.

What you can see here, is the absence of the trade-off that you would generally expect: “Sure, the Wuhan spike protein can mutate to avoid our antibodies, but those antibody evading mutations will carry a cost in the form of lower ACE2 affinity or structural instability, so they will reduce fitness.” Under that logic, it seemed sensible to deploy a vaccine against the Spike protein.

However, that doesn’t seem to be what has happened so far. The virus could give rise to new versions of its Spike protein, that both make certain neutralizing antibodies useless and become much better at doing the job of binding to the ACE2 receptor.

And so, rather than already suffering under the trade-off, the trade-off either doesn’t have to happen, or lies somewhere in the future. This means we can expect further antibody escape to happen, either through increased ACE2 affinity, or just by avoiding the most relevant human antibodies that neutralize particles by binding to the receptor binding domain.

The speed at which the virus now piles on more Spike mutations, leading to further antibody evasion and/or enhanced ACE2 affinity, is accelerating. As an example, the Netherlands right now has two different lines of BA.2.75 descendants circulating, that have piled three more Spike mutations, all three in the Receptor Binding Domain onto the BA.2.75 framework.

Compare this to the first variants we saw. Alpha had one mutation in its Receptor Binding Domain compared to Wuhan. Delta had a total of two mutations in its Receptor Binding Domain. And yet, right now you’re dealing with versions that pile on new mutations there within weeks. Evolution to evade neutralizing RBD human antibodies has accelerated dramatically, without any apparent cost to overall fitness.

And so this brings us to the question we want to answer: What’s the endgame?

Well, we’ve already seen experiments in labs, to find a variant of the receptor binding domain with the highest ACE2 affinity possible. The experiments were performed, long before anyone had heard of BA.2.75. They came up with a variant of 6 pM affinity for ACE2. In comparison, the highest affinity antibodies discovered so far have an affinity of 50-100 pM. In other words, it really seems a variant can emerge that makes all the neutralizing antibodies effectively non-neutralizing. Under these circumstances, before antibodies get a chance to bind to the RBD, it would bind to the ACE2 receptor.

And so looking at these experiments, you could see which mutations tended to emerge and would be expected to show up in future variants. A number of these mutations they anticipated showed up in Omicron. The main candidate from the experiment expected to show up in Omicron descendants was generally N460K. Now with BA.2.75, we have seen it emerge.

There’s no clear indication the non-vaccine induced adaptive immune response is being overcome. Although evasion of innate immune is steadily improving with successive variants, innate immunity itself is also improving and antibody dependent cellular cytotoxicity, opsonization through non-neutralizing antibodies and binding to the Fusion Protein remain functional responses so far. I would expect this is true for the IgM antibodies too: Vertebrates successfully deploy this strategy against Influenza, it should continue to work against Corona too.

If you have a majority of people with a narrow immune repertoire and a minority of people with a broader immune repertoire, that includes the narrow immune repertoire of the prior group, what reason would you have to focus on developing methods of escaping the alternative challenges this minority throws at you? The selective pressure just doesn’t really exist and these alternative challenges are intrinsically more versatile, so these pathways remain functional.

The big question I’m left with, that almost nobody seems to bother to address, is as following:

-Why would you as a virus not evolve to encourage antibodies to bind to those regions where it benefits you?

Vast swathes of the human population now have high levels of antibodies circulating through their bodies, many of which don’t actually neutralize this virus. We know there are different routes through which the virus uses antibodies:

• A bunch of antibodies that bind close to each other will attract complement, which then allows the virus to productively infect cells. This mostly happens in the vaccine induced immune response, which looks very similar in different people (thereby causing population level selective pressure) and is focused on specific regions of the Spike protein.
• Antibodies that bind to the NTD domain can help pull open the Spike protein, allowing it to infect cells. With Delta, we saw the virus make a change to its NTD, which allowed the antibodies binding to the NTD domain to more effectively pull it open.
• There are even some enhancing antibodies that open up new routes for productive infection, through binding to the RBD.

And so rather than just asking ourselves: “How is the RBD going to change to escape neutralizing antibodies?”

It would be better to ask this question:

“How is the virus going to use the highly homogeneous antibody response in vaccinated demographics to its advantage?”

And I can imagine different scenarios. Perhaps there could be changes to the RBD that encourage antibodies to bind. Perhaps there could be changes to the NTD that encourage more of our antibodies to pull open the Spike protein.

Remember: These sort of changes can only have a selective advantage, because these retards have homogenized the population’s immune response! If some change to the NTD would attract antibodies that now help pull open the protein, but those particular antibodies only show up in a small minority of naturally immune people, then there is no substantial transmission advantage, even when it does come into existence in an infected person!

Ask yourself: Why does BA.2.75 have such a transmission advantage? Is it those changes between 332 and 523 that stop neutralizing antibodies from blocking RBD binding to ACE2? Maybe.

But take a look at the mutation list again. You see a whole bunch of spike mutations clustered close together in the NTD. Why did those changes take place? Is this similar to Delta’s trick, becoming more receptive to antibodies in a place where it helps you out? Is it a trick to get complement to bind to antibodies there?

I don’t know and I’ve seen nobody propose a good explanation. The point is:

Antibody evading mutations in the RBD are just half the picture at best, because like we saw with Delta, this virus has an incentive to encourage your predictable homogeneous antibody response focused on just a few regions of the synthetic Spike protein only visible in the pre-fusion fixated state to start making its job easier!

And so I get the impression that BA.2.75 has such a massive advantage, because training in the body of an infected person for an extended period of time, it figured out at least two things:

-Avoiding RBD neutralizing antibodies.

-Attracting enhancing antibodies to NTD, which either enhance directly, or enhance by attracting complement.

And then once it left that person’s body, it encountered a world in which the now vaccinated population of India is filled with many other people whose immune response looks highly similar to that of the host in which it came into existence.

I can’t emphasize enough, how big of an intervention in the normal functioning of the human immune system it is, to take droves of elderly people and inject them three times a year with this vaccine. Their entire antibody profile for everything is starting to look different, we even see that people who get these shots respond very differently to other pathogens afterwards. The flu shot is dubious enough, but it pales in comparison to what we’re doing now.

It’s only through diversity of the immune response to respiratory pathogens, that Homo Sapiens Sapiens can maintain the population density that it maintains today. Your species has such an abundance of different versions of the Human leukocyte antigen genes that differ from person to person, because it causes you to develop very different immune responses to respiratory pathogens.

You’re generally only sexually attracted, to the scent of someone whose HLA genes differ from your own. This is how important diversity of the human immune response to respiratory pathogens is: It’s so important that you don’t want to have sex with someone whose response looks too similar to your own. And yet, we happily blew it up, injecting everyone multiple times with DNA or mRNA that triggers a massive immune response that homogenizes the antibody repertoire we deploy against respiratory pathogens.

Have you ever wondered, why mortality from SARS-COV-2 has been so high among Indigenous Americans? It’s largely down to the fact that they are the descendants of a bottleneck, of a small group of people who went through the Bering strait. Because of this bottleneck, they have low HLA diversity. With the lower HLA diversity, it becomes harder to recognize many different parts of SARS-COV-2 and individuals in an Indigenous community will respond in similar ways to each other.

There is no real “magic trick” one fits all approach to a virus like this. You survive viruses of this nature, because everyone has a different way of dealing with them. You see this in everything, for example, you can just look at which proteins the antibodies and T-cells respond to in the naturally immune. Most respond to Spike, some to envelope, some to membrane, some to nucleocapsid, it’s different in everyone.

When you get rid of all of that, when you inject everyone with one identical version of the Spike protein, summoning a high affinity low avidity IgG dominated antibody response focused on a handful of epitopes, evolution dictates that this virus has to start playing Aikido with Homo Sapiens Sapiens: It takes your own moves and uses them against you, by accelerating them.

If you were to forget everything I’ve explained here except one thing, I would want it to be this:

The reason our species can maintain high population densities despite being continually infected with a large variety of different respiratory viruses, is because of the overall diversity of the response that different people make against such viruses.

What I expect is that we’re now going to see an evolutionary radiation: The Spike protein has upgraded itself in the form of BA.2.75, but it can still be further refined, with select mutations in the receptor binding domain. Which of those mutations work best, will differ between individuals and populations. This means that we would expect to see different descendants of BA.2.75 circulate together, with (almost) no differences between them, except in the Receptor Binding Domain.

Negative vaccine effectiveness would also be expected to be further exacerbated. You can not really anticipate what BA.2.75 descendants are going to do outside of India based on what you saw in India, just as you couldn’t anticipate what BA.1 was going to do outside South Africa based on what you saw in South Africa.

Deploying the BA.5 booster is a very bad idea, because you can see that BA.2.75 spreads after a BA.5 wave has taken place: It fits into the immunological niche created by a BA.5 wave. Giving people the BA.5 boosters would just have the effect of artificially creating the immunological niche that BA.2.75 tends to use.

I’m convinced that excess mortality this winter will exceed the previous winter, simply because of what we’re already seeing in highly vaccinated places like Scotland. Take a look at the Scottish infection survey:

If this is the level of infection you’re seeing now in the middle of summer in Edinburgh, vastly exceeding anything seen last winter, what do you honestly expect to see in winter?

And sadly, billions of additional people have now also received these vaccines that just don’t work. Most of them will have been infected before they got the shots, so they’re not necessarily sitting ducks for this virus, but scroll back up to look at the antibody profile of people vaccinated after infection and you will see: This can’t be an improvement. I have no clue what countries like India expect to achieve, by vaccinating people who have already been infected.

Their lymphocytes should still be able to hunt down infected cells (ADCC), but they would now also seem to be producing the abundance of non-neutralizing antibodies that cluster tightly together and attract complement, merely helping this virus infect more cells in which it can complete its replication cycle.

I would also expect the response to shift away from IgM due to these shots. People should avoid these vaccines at all cost, even if you’ve already had multiple infections: These vaccines will interfere with the natural immunity you’ve built up.

I don’t have a solution to offer at this moment, but I hope this post has been useful for you to figure out what went wrong.