As I’ve said before, there’s no requirement for the SARS2 virus to evolve to begin behaving like a mild human corona virus that we barely notice. It’s a widely popular myth that viruses must inevitably evolve to become milder because they have to avoid killing their host. Evolution causes viruses to take on whatever form allows them to survive. Whether they become deadlier or less deadly over time is very hard to predict.
For new viruses capable of reinfection, intrinsic virulence can be masked, as more people get reinfected over time and can recall immunity they had already developed. It will seem as if intrinsic virulence has reduced, as almost everyone will have some tools in the toolkit ready for the job. A noticeable exception that makes intrinsic virulence visible may be infants, who were not around the build up immunity to older versions. What you’ve seen over time is that more infants are now being hospitalized with COVID, which is of course an awful thing.
Virulence has to be thought of as a side-effect of a virus pursuing the conditions that allow for its survival over extended periods of time. It’s intuitive to imagine the death of a host would substantially interfere with that, but this is unlikely to be the case when:
-Most transmission happens before severe symptoms emerge.
-The demographic spreading a virus is very different from the demographic dying of it.
-The infection fatality ratio is low to begin with.
All three of these principles apply to SARS2. Finally, as a sidenote, it’s perfectly possible for some viruses to transmit after death, ebola and smallpox are examples of this.
To ask yourself how virulence of SARS2 will evolve it’s more useful to ask yourself: How will this virus have to change its behavior, to enable its persistence in our population? Then you can ask yourself: How would those changes to its behavior affect virulence?
Finally, it’s useful to ask yourself why virulence ever plunged to begin with. The move from Delta to Omicron revealed a sudden dramatic plunge in virulence, evidenced by a sudden wave of infections without an associated substantial spike in deaths in most places. To some degree the plunge in virulence was an illusion brought in by an expansion of the susceptible demographic to include more young people and more people who already had survived an infection, but the reduction in virulence was also a real phenomenon.
The reduction in virulence can be explained through one simple principle: A version of SARS2 that was circulating in rodents jumped back into our species, became known as Omicron and began to spread because its different version of Spike suddenly had a huge transmission advantage in our population. Whatever flaws the virus had for transmission in humans as a result of its time spent in rodents did not weigh up against the massive immune escape advantage it had.
In rodents, SARS2 appears to have a very high fatality rate. Wild SARS2 was found to kill 100% of infected humanized mice, wild SARS2 with the Omicron spike kills 80%, while Omicron itself kills none. So it seems logical to expect there are genes beyond Spike that had to evolve to reduce the extremely high virulence in rodents, so that it could efficiently spread among them.
We also know what some of those mutations probably look like: The virus is relatively competent at suppressing Interferon, which is the equivalent of an alarm bell rang by your cells upon infection by a virus. Viruses that are good at suppressing Interferon tend to be good at spreading up front before the immune system begins to respond.
We know that the Omicron version became less capable compared to Delta of suppressing Interferon due to mutations it incurred. So now we have a pretty decent picture to explain the mystery of a new version of SARS2 suddenly infecting far more people, while killing or severely injuring far fewer than Delta. It’s mainly a combination of three factors:
-Immunity had accumulated in the population.
-A greater share of infections was now among healthy young people.
-The jump of Omicron into rodents required a reduction in virulence for efficient transmission, which was still present once it jumped back into humans.
And it’s mainly that last factor, that is cause for concern. As it spreads in our population, whatever incentive it had to accumulate those mutations is lost again. In fact, what you see lately are a number of reversions to mutations found in the original Omicron versions, back to pre-Omicron variants.
Once Omicron began to evolve in humans again, you could see that Interferon suppression began to increase again. With BA.5 being much better at suppressing Interferon than BA.1 and BA.2. In fact, it seems to have been even better than Delta at it, but it looked pretty similar in Spike to BA.2 and struck in the middle of summer, so it did not have a cataclysmic impact in most places.
Lately, with the new XBB variants you can see that Interferon suppression is increasing again: Different XBB descendants accumulate the same mutations that suppress Interferon.
You can expect there is now a strong incentive to evolve to become better at suppressing Interferon: Until a few months ago, everyone generally had a pretty similar antibody response to SARS2, meaning that any mutation to Spike that works in one person to escape the antibody response would generally work in others. But now, after widely varying vaccination regiments and different patterns of infection with very diverse variants, the antibody response to this virus looks far more diverse than it looked at an earlier stage.
And so the incentives have now shifted: Rather than escaping the antibodies through mutation, you’re better off not getting caught in the act of infecting cells and having those antibodies deployed against you in the first place! A very effective way to do that is by suppressing the Interferon your infected cells produce upon suspecting they are infected by something nasty.
Unfortunately for us humans, viruses that are better at suppressing Interferon tend to be deadlier. SARS2 for example, was much worse initially at suppressing interferon than the original SARS. Mutations to Influenza that help suppress interferon also increase virulence. Mutating a SARS1 gene to reduce interferon suppression reduced virulence.
Viruses tend to run into a problem however, that prevents endlessly improving Interferon suppression: They tend to need a compact code, so genes will often have multiple functions and getting better at Interferon suppression may interfere with other functions. This might be one reason why the hCov viruses have an apparent ceiling to their virulence.
Unfortunately, SARS2 is based on a bat virus. And what sets bats apart from humans? They tolerate viruses of this nature: It’s pretty useful for a defenseless small animal that congregates together in huge numbers in caves to sleep to carry all sorts of deadly viruses: Predators that want to eat them will learn their lesson the hard way. The bats have adaptations to render these viruses relatively safe for them, adaptations we don’t have.
If you suppress Interferon, you’re preventing both the innate and adaptive arms of the immune system from being alerted. There are however aspects of immunity that don’t depend on Interferon. Pathogens like Influenza and SARS2 too, have glycoproteins that they use to enter cells. The NK cells have receptors that resemble the sort of receptors these glycoproteins would normally bind to. This allows the NK cells to recognize cells which are producing these glycoproteins, as they are displayed on the cell’s surface. The NK cells can then destroy those cells, draw other immune cells to the location and produce Interferon themselves.
The adaptive immune response, which was stimulated strongly by vaccination, does strongly depend on interferon however. This makes perfect sense, when you consider that adaptive immunity is the second layer, that comes after innate immunity: The interferon produced by the innate immune system would normally wake up the adaptive forms of immunity.
This is why you wish to see strong trained innate immunity against SARS2 in people. You can expect to see this in India and especially Africa, as well as among the unvaccinated in developed nations.
The problem, as I explained in my previous post as well, is that we have strong reason to believe that we interfered with the training of the innate immune system: Antibodies will bind to these glycoproteins presented on the cell’s surface, preventing the NK cells from doing their job of killing such a cell through binding to the right cytotoxicity receptor, which then allows them to expand. And as the antibody response now shifts to IgG2 and IgG4 in many people, the infected cells may increasingly not get killed at all.
To get them to kill cells and avoid false-positives, it’s generally important that NK cells experience synergistic stimulation of different receptors: It’s like a drone pilot who has a checklist to make sure it’s really “our guy” before someone is drone-bombed. As an example, they also look for patterns associated with damage to a cell, or patterns associated with infection by a pathogen.
The CD8+ T cells, which also kill infected cells for us, don’t seem to bother with this, because they’re being told to kill by other branches of the immune system. And so it seems reasonable to expect that when cells were exposed to Spike mRNA and stealthily fooled into producing only this one single gene, those cells would have stimulated the CD8+ T cells, but not really the NK cells.
The NK cells are harder to understand, because they’re versatile and elegant. And that’s precisely the problem: As they’re not well understood, humans are easily fooled into embarking on dumb experiments that interfere with these NK cells learning to do their job.
To give a metaphor the Americans will perhaps appreciate, it really seems that in a normal situation the NK cells that have taken up residence in tissues that have previously been infected are the immune system’s equivalent of Paul Revere: They’re supposed to be the first ones to notice something’s wrong and the enemy is here again.
Tragically, humanity bet the whole house on the adaptive branches of immunity that are downstream and relatively easy to avoid through improved interferon suppression.
I don’t know of a good solution. Generally speaking vitamin D supplementation stimulates innate immunity over adaptive immunity, zinc helps as well and we have numerous studies showing people with a plant-based diet fare better.