Complete antibody evasion is easy to evolve

I have to explain one more thing about SARS2. What you see in other species, is that persistent coronavirus infections can suddenly take a dramatic shift. Most cats infected with the feline coronavirus will survive. However, in a handful of cases, the virus manages to evolve mutations that allow it to efficiently infect white blood cells. These versions of the virus are very bad at transmitting themselves to other cats, but for the individual cat unlucky enough to have its viral parasite develop these mutations, it’s generally a death sentence.

This matters, because in the past few months, we’ve seen most of the human population infected with a radically new version of SARS2, with a Spike protein that is essentially optimized for persistent infection. It will take a few months, before we know what the long term outcome is of that.

Most of the antibodies people developed against the Receptor Binding Domain don’t manage to neutralize the new Spike protein, but they will prohibit the immune system from developing a better antibody response that would neutralize viral particles.

So neutralization of viral particles now depends on antibodies binding to the N-Terminal Domain. There are different ways to escape these antibodies. It’s possible through deletions in the three immunogenic loops, roughly corresponding to these amino acids: 14-26 (N1), 141-156 (N3) and 246-260 (N5).

But there are other ways to achieve it too. Proteins consist of long chains of amino acids. Cysteine is one of those amino acids, it helps determine the shape of the overall protein, because two cysteine amino acids in different places in the protein will be attracted to each other and form a bridge. This means that if either of those cysteine amino acids is changed by mutation to some other amino acid, the shape of a whole protein can change as a result.

With SARS2, we have already seen a version emerge that needed just two mutations, one blocking a cysteine in one place and the other adding a new cysteine in a whole other place, to lead to a version of the virus against which none of the NTD antibodies neutralized the virus anymore.

As far as I am aware, neutralizing antibodies that still work against the BA.2.86* Spike (including JN.1), are almost all antibodies against the NTD. Well, as you can see here, by making one cysteine inaccessible and adding another cysteine, the virus can avoid basically all those neutralizing antibodies:

What this shows is that there are a bunch of different mutations, that make the cysteine at position 15 inaccessible. The virus can change position 12, it can change position 13, or it can just get rid of the cysteine at 15 altogether. Any of these options work.

Then it needs to add a different cysteine elsewhere, for the cysteine at 136 to bind to. In this case, it added cysteine at position 152. This was seen in a variant called B.1.640*, which was circulating together with Delta back in 2021, until everything was wiped out by Omicron. It was very good at fusing cells together and it looks like humanity basically dodged a bullet, thanks to Omicron wiping all these lineages out. You have to wonder if nature was feeling merciful, or whether humans themselves hurried to come up with a way to kick the can down the hall. It’s not unthinkable.

But there is basically nothing stopping changes like this from emerging again. And as the B.1.640 case shows, these versions may be perfectly capable of transmitting from one person to another.

Immunity is complex, there are so many variables involved that the whole thing can start to look like a connect the dots puzzle where you choose what you want to draw. But there are a few things we can say:

  1. Vaccination produces abnormally high concentrations of antibodies, to protect the population.
  2. Immunity in people as a result depends very strongly on these antibodies.
  3. The Receptor Binding Domain changes rapidly to avoid these antibodies. This forces the immune system to resort to neutralizing antibodies against the N-Terminal Domain.
  4. It takes a total of two amino acid changes, to avoid all neutralizing antibodies against the N-Terminal Domain.

So what you would expect is as following: In vaccinated people, T cells rapidly recruit B cells to start producing antibodies against the JN.1 Spike. These antibodies will be bad at neutralizing Spike through the receptor binding domain, because of the Original Antigenic Sin problem. It will be even worse when the B cells recruited produce an IgG4 response.

Concentrations of antibodies against the N-Terminal Domain rise greatly too however. These antibodies provide neutralization that clears the virus. Great! That is at least, until you remember: Two amino acid changes are sufficient to overcome all of them.

Breakthrough infections don’t solve this problem. Instead, what they do is they rearrange the immune system, by constantly recalling a particular adaptive response, that was originally induced by the vaccines. Because this adaptive response can fail suddenly and dramatically, as I have now illustrated to you, breakthrough infections don’t solve the problem, they make it worse. There’s a serious and growing risk the antibodies against SARS2 start interfering in the immune response against other pathogens too, because they are continually being recalled and the B cells undergo somatic hypermutation to slightly change their antibodies for new versions of the virus.

So if we already came strangely close to this doomsday scenario, why hasn’t it happened yet and why doesn’t that mean that it will never happen? Because in the past there were still other more obvious ways forward. The most important way forward, was to improve ACE2 affinity. This makes the virus intrinsically more infectious, so it spreads more easily. In addition, it can escape a bunch of antibodies through affinity escape. When the Spike binds stronger to the ACE2 receptor than an antibody does, antibodies can be evaded in that manner too.

But you can expect that there are just certain molecular limits to ACE2 affinity. With very high affinity, the Spike would probably bind to other stuff like red blood cells, before finding the ACE2 molecule. It doesn’t matter if you can theoretically bind strongly to ACE2, if you never get the chance because you’re already stuck on a red blood cell! They create these synthetic spikes in petri dishes with extremely high affinity, stronger than the most potent antibodies, but it’s doubtful they would be viable. You also have to wonder whether they would inadvertently kill the host cell before a viral particle can ever assemble.

So, although BA.2.86 had the highest ACE2 affinity ever seen so far, resulting in the most infectious version of the virus ever, that pattern just can not continue forever. Simple logic dictates that the struggle for survival will now force the virus to embark on different strategies. The most obvious path available now would be to get rid of all those antibodies binding to the NTD. That can happen through a bunch of deletions. But as I just showed you, it can be accomplished with just two amino acid mutations too.

This has already gotten much longer than I had intended it to be, but my point is: The evidence we have reveals that trying to protect people against this virus through an antibody response is a poor strategy, that can fail very suddenly and dramatically, both at an individual level, as well as at the level of entire populations. It doesn’t have to take more than two amino acids.

17 Comments

  1. I realised there’s something else I have never properly addressed. Severe SARS-COV-2 is generally associated with superimposed bacterial infections.

    The NK cells that normally proliferate after a natural infection should generally be able to kill those bacteria too.

    When CD8 T cells are doing the killing, they’re not going to kill those bacteria.

  2. If they were trying to protect people and save the maximum number of years of life, they would have encouraged outdoor exercise, give tax breaks to low BMI people, and test in mass against defficiencies in vitamins and minerals.

    Instead, they encouraged people to stay indoors, stress out and get addicted

    It is immaterial whether they are incompetent or evil. End result is the same.

    God wants people to grow strong souls. They are given plenty of info, and time to repent for lying to themselves.

    Up to the point that the game is up, that is. Stupidity and evil are not allowed to accumulate in the world forever. The goal is to apply to souls enough stressors for them to grow, but not to outright destroy them from childhood.

    Causal reasons are given for the cull, in order to preserve free will. Without free will, soul testing cannot proceed properly. Quite the personal bind for those to whom the Gods have shown themselves directly, isn’t it.

  3. Rad, fasting would be a good cure to the Covid vaccine. What do you think?

    Brown people advocate fasting for a lot of diseases as well as for spirituality.

    • Also you said in the previous post that you’re starting to run out of ideas for topics to write about. Here’s a suggestion: write about what the world will look like for the survivors in, say, 5 years. You touched on this topic already in your “Two Options” article, and back in January 2020 you wrote:

      “And perhaps the bigger taboo is that a good plague doesn’t just make life easier for non-humans, it makes life easier for human beings too. After the Black Death, salaries went up because aristocrats couldn’t find enough peasants to work for them. Peasants spent their days lingering and doing nothing special, because life was easy. When humans live well below their carrying capacity, life is easier. We don’t need to fire up that coal plant, the river dam provides enough electricity. We don’t need to build new houses, the existing houses suddenly go down in price by 50% or more.”

      “We’re faced with huge problems in the decades ahead, but every billion people we manage to get rid of would make our problems much easier. That’s the important thing to consider. It’s nice if we could stabilize our population rather than continuing to grow our numbers, but that doesn’t make our situation sustainable. Cut our population in half? Now a lot of the problems we face become manageable. Places with fresh water shortages suddenly have plenty. Peak oil? We’ll manage.”

      It seems that many humans have a morbid fascination with stories about survivors in post-apocalyptic future worlds, hence why we have so many books, movies and TV shows which cover this subject:

      “Well the premise is quite simple. Take something designed by nature and re-program it to make it work for the body rather than against it.”

      “You’re talking about a virus.”

      “Indeed, yes, in this case the measles virus which has been engineered at a genetic level to be helpful rather than harmful.”

      https://www.youtube.com/watch?v=B3xY6Ffy_wE

  4. I am also sitting around and waiting for the predicted evolution of Sars-Cov-2 into a “highly pathogenic virus.”

    Frustratingly it remains not so pathogenic.

    That said, a young man in his 20s (not my relative for those following me), had a “bad cold” in January and now he is having bad lower airway bronchitis and is taking strong antibiotics. So there’s that

    • >Frustratingly it remains not so pathogenic.

      Careful what you wish for. There was a huge plunge in virulence from Delta to Omicron, but it has been getting steadily more pathogenic since then.

  5. Perhaps it is easy to evolve the necessary mutations to become a killer virus, but perhaps it won’t ever happen.

    It’s starting to seem like a mass death virus doesn’t have to happen, because it MUST not have to happen.

    If it MUST happen, then it seems likely that it would already have happened.

    Must means must. Then we start to get into maybe.

    So now we are left in a situation where it MIGHT happen, or it might not.

    So MAYBE it will happen.

    Which kinda sucks for all of us who want this shitshow to be over with.

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The patients in the mental ward have had their daily dose of xanax and calmed down it seems, so most of your comments should be automatically posted again. Try not to annoy me with your low IQ low status white male theories about the Nazi gas chambers being fake or CO2 being harmless plant food and we can all get along. Have fun!

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