A lot of people don’t like it when I point out that SARS2 has not just become one among many respiratory viruses that affect us humans. It’s still behaving very differently from all the others.
I want to start out today by just comparing two simple numbers: How many people are hospitalized for influenza in a typical year and how many are hospitalized for SARS2? We have the Dutch 2003-2007 numbers here, the average is 1.7 hospital admissions per 100.000 people per year. So for a population of 18 million, that would be 306 hospital admissions.
Right now, this means influenza causes as many hospital admissions in an average year, as SARS2 does in…
A lot of people really don’t like to hear this, they’ll argue the hospitals must just be routinely testing everyone. So for those people, I’ll drop the other graph we have, the percentage of people admitted directly for COVID:
So if we only count the people whose primary admission reason was SARS2, that means we’re now at roughly eight days to outnumber annual flu hospitalizations.
I’ve sought to explain many times, why it was such a bad idea to vaccinate everyone against SARS2 and how we know it has made the pandemic much worse. Those people being hospitalized right now, are being hospitalized because we did something stupid: We dramatically accelerated the evolution of this virus and prevented the population from developing herd immunity.
But allow me one more time, to show you the evidence. In healthy unvaccinated people in Qatar, every infection reduced reinfection risk:
Two infections provided better protection against reinfection than one infection. Once everyone has been exposed to the virus and suffered one or more infections, you would expect to eventually reach herd immunity.
Now contrast this with what we see after vaccination:
Two weeks after vaccination, the vaccine begins to provide protection against infection. But the protection rapidly wanes and you eventually end up with negative efficacy: Vaccination ends up making people more likely to get infected. As a result of this human intervention, we end up with a large cohort of people who remain susceptible.
A lot of people were outraged by the idea of allowing people to get infected to achieve herd immunity. They wanted to vaccinate everyone instead. So what we got as a result is that people still get infected, but now the infections don’t translate into enduring immunity. Nice job guys!
The enduring presence of this cohort of susceptible people, means we end up with an evolutionary radiation: The virus gets a lot of opportunities to mutate, until eventually it stumbles upon versions of itself even unvaccinated healthy people become susceptible to again with sufficiently high exposure. This results in the forever pandemic.
I have already explained this a few times, but I just want to illustrate that you don’t just have to believe me to understand this. This study found that SARS2 vaccination was followed by accelerated evolution of the Spike protein, despite the reduction in viral load in the population.
An important principle I’ve mentioned is that artificial narrow immunological pressure against just one protein (Spike vaccination) will accelerate evolution in ways that natural immunity doesn’t. This study argues that vaccination dramatically accelerates Spike evolution:
The above example illustrates that, despite the reduction of viral transmission by vaccination, viral evolution in neutralizing antibody epitopes may be accelerated by vaccination several-fold. The transient decrease in the number of infections is outweighed by a stronger immune pressure to change. The cost of the transient reduction in virus circulation is the emergence of more transmissible escape mutants and, hence, a higher number of infected individuals in the population in the future.
But more importantly, it confirms what I mentioned myself as well:
We also assumed that the effects of vaccinal and natural immune response on selection pressure are the same. In fact, such symmetry is unlikely, because the number of immune memory cells against an epitope induced by vaccination and natural infection may differ. Figure 4 shows schematically how the substitution rate in epitopes changes with the relative protection (and hence, the selection pressure on epitopes) rendered by the vaccine as compared to the natural infection (compare the red line with the green and blue lines). In addition, vaccines are composed of a section of the spike protein, and the immune system generates antibodies against other viral proteins as well. Thus, the effect of vaccination on the substitution rate in an epitope can be either stronger or weaker than the effect of the natural immune response. Furthermore, the genomic regions where evolution is accelerated will also differ between vaccinal and natural responses. A detailed study based on a mathematical model and immunological data is required to calculate the acceleration of evolution in various epitopes.
In simple English: If someone is developing naturally immunity to SARS2 upon his first infection and SARS2 mutates its Spike protein, that won’t be enough to allow the virus to survive. After all, that person has antibodies, innate immunity and T cell immunity against a variety of epitopes. On the other hand, if a vaccinated person is infected, there is a huge benefit to be derived from mutating the Spike protein. Not just because that person has narrow immunity, but because everyone else in his environment has effectively the same immune response as he does.
So what I’ve spent the past two years arguing is not really controversial anymore: The scientific literature confirms what I’ve told you. Through vaccination they were borrowing from the future, at a very high interest rate. The price to be paid, was for us to end up suffering far more infections eventually.
So what happens now?
SARS-COV-2 evolves, as the human immune response to the virus evolves with it. Generally speaking, there are two mental models you can apply to this process:
-The hCov model of cyclical antibody evasion. In this model the virus just mutates over time, to adjust to what are currently the dominant antibodies in the human population, just like the other four dominant human corona viruses do. The overall traits of the virus don’t change much as a result. This is what most people believe: That we’re now in a stable situation.
-The immune escape pandemic model. Whereas the hCovs have bumped up against a fitness plateau, SARS-COV-2 is just three years old. In other words, it may still get qualitatively better at spreading itself through its hosts over time, getting fitter over time, as our immune systems become worse at stopping it. This would mean the underlying problem gets worse over time.
It’s not very hard to answer which of these two mental models apply. It’s the latter. You just need to look at the studies to confirm this.
Specifically, you have to look at ACE2 affinity: How strongly does the Spike protein of SARS2 bind to the ACE2 receptor, which then allows the virus to get into your cells?
What you see here is that the affinity of BA.2.86, the newest variant, has increased substantially compared to any of the other variants seen so far. The virus is getting progressively better at binding to its most important receptor.
Importantly however, this is not a fluke. The XBB family itself is also evolving towards greater ACE2 affinity:
What you notice with the XBB descendants, is that they’re now flipping the leucine and phenylamine sitting next to each other. When you flip these two around, you evade some antibodies, but importantly, you also further increase ACE2 affinity. This only happens when you flip them, if you change either independently, you don’t increase the ACE2 affinity.
So why does all of this matter? Well, the most important thing to understand, is that how these people test the antibodies against this virus, is not how it works in your body. What they do is that they put the virus particles in a solution with human serum, which contains the antibodies. Then they wait a few minutes, then they introduce the whole mix to the cells that have the ACE2 receptor. Then they check whether the virus can still bind the ACE2 receptor. If it can’t, then the antibodies must have successfully neutralized the virus.
The problem with this method is that within your body, the virus can find the ACE2 receptor before these antibodies get a chance to bind to the virus! The stronger the ACE2 receptor affinity, the more likely that is to happen.
The virus has now evolved towards extremely high infectiousness. The other human corona viruses don’t really get this chance, because they don’t constantly reinfect people, only to be re-exposed to the same antibodies people produced against a previous version of the virus. They are not being placed under this high selective pressure to increase their infectiousness.
In addition, the other hCov viruses have never been placed under homogeneous immune pressure, where a mutation they incur in one person can help infect most of the human population, because everyone produces the same antibodies. But for SARS-COV-2, we saw convergent evolution over 2022.
The result is that we see two simultaneous processes: We see increasing ACE2 affinity over time, as persistent infections give rise to better versions of the Spike protein. But we also see an increase in antibody levels throughout the population:
We’re now in a situation where 91% of people have antibody levels so high, they would qualify as plasma donors.
So to summarize:
We know the underlying situation is getting worse, as the virus keeps getting better at binding to its receptor (increasing infectiousness to break through immunity). This does not so far result in significantly increased sickness however, as the population keeps producing more antibodies.
This however is an unstable situation. We see multiple signs that the immune system can not cope with these circumstances for an extended period of time: The IgG4 antibody class switch and the elevated levels of T cell exhaustion now seen in the general population.
So where does this end?
In the absence of a proper variant-independent immune response, you would expect to see serotypes emerge. For the past year now, we’ve seen the immune system chase the evolving Omicron variants. The antibody response constantly adjusts, to fit what the new variants look like. This ceases to work, when you have multiple very different variants, like we do now.
BA.2.86* is as different from XBB*, as Omicron was from Delta. But unlike Omicron, which had a massive growth advantage over Delta, BA.2.86 has just a modest 40% growth advantage. JN.1 spreads faster than its parent BA.2.86.1, but it sacrifices a lot of ACE2 affinity for immune evasion, so it looks like it may bump into a dead end.
With serotypes you would expect varieties to emerge that benefit from the antibody response we have against different versions of the virus, as we see for Dengue.
But equally important, you now see a growing rise in co-infections: People who are infected by an XBB variety and a BA.2.86 variety simultaneously. This is a problem, because they specialize in infecting different cell types:
Such co-infections would be expected to increase the overall burden placed upon the respiratory, immune and cardiovascular systems.
I expect we will end up thinking of 2022 and 2023 as a temporary return to normal.
One thing you have to keep in mind is that we gave the Omicron variants that emerged in late 2021 the advantage they had. If you vaccinate people by injecting them with something, bypassing the mucosal membranes, you’ll induce an antibody response primarily in their lower lungs and their organs.
The upper respiratory tract is immunologically separate, so after mass vaccination you start to favor variants that affect the upper respiratory tract resulting in reduced observed severity, until eventually there is a strong immune response there too. But now with BA.2.86, the virus returns to the lower respiratory tract (see: CaLu-3).
This process will continue, until you end up with a population with sufficient dead-end hosts to establish herd immunity. There are things you can do to reduce that threshold. The most important thing that can be done is to reduce obesity in the population, which is accomplished through healthy plant based diets.