Two Things Are Infinite: The Universe and Politicians’ Stupidity; and I'm not sure about the universe*.

*A parody on Einstein’s original quote: “Two Things Are Infinite: The Universe and Human Stupidity; and I'm not sure about the universe.”

If there’s one thing the COVID crisis has made crystal clear since its very beginning, it’s that politicians are complete idiots when it comes to assessing and solving public health problems, let alone when it comes to recommending, or let’s rather say, the mandatory imposition of so-called sanitary measures. Idiots keep claiming that the rapid evolution of SARS-CoV-2 (SC-2) is the root cause of all the COVID misery and that the immune system simply can’t keep up in its attempts to control the virus. Even bigger idiots will go so far as to argue that we therefore need to “boost” this supposedly failing immune system with COVID-19 (C-19) vaccines, so it can better withstand the endless stream of SC-2 variants that, like clockwork, keep showing up in our wastewater.
Only those with at least a minimal understanding of the evolutionary dynamics of this pandemic realize that the entire course of events actually unfolded in the exact opposite way! The insane mass C-19 vaccination campaigns artificially ramped up humoral immunity across entire populations in a way that was far too weak to prevent viral spread (which is, in fact, what happens when you vaccinate entire populations in the midst of a pandemic!). As a result, highly C-19 -vaccinated populations began exerting collective humoral immune pressure on the virus, but not at a level sufficient to control viral transmission.

It was this steadily increasing immune pressure that drove the selection of ever more mutants, which became progressively more adept at eroding humoral adaptive immunity and eventually came to dominate the viral landscape.

The ultimate outcome was that a highly infectious variant (Omicron) gained the upper hand and managed, especially in C-19 vaccinated individuals, to break through innate cell-mediated immunity, often resulting in symptomatic disease. Yet, thanks to the immune system’s remarkable capacity to adapt, much of the acute damage was contained. That was mainly due to the “extra effort” made by the cell-mediated adaptive immune system (e.g., T cells). Because this reinforcement of the cell-mediated adaptive immune system is actually the result of a dysregulation of the adaptive immune system itself (namely through immune refocusing), it isn’t efficient enough to stop viral transmission. As a consequence of repeated breakthrough infections, chronic T-cell–mediated inflammation develops in at least part of the population - not exclusively, but predominantly among the C-19-vaccinated. Chronic immune inflammatory reactions eventually result in long COVID and/or a range of immune-mediated diseases (including cancer).
In those individuals in whom weakening cell-mediated adaptive immune responses still provide sufficient resistance to the virus -and thus keep the cellular inflammation from escalating into chronic disease or immune pathology- SC-2 variants that manage to break through the humoral arm of the innate immune system (cytokines and the like) gain a fulminant fitness advantage. This is because the strong local inflammation triggered by highly infectious circulating variants in C-19 vaccinees who didn’t succumb to long COVID or immune pathology increasingly elicited the production of cytokines with antiviral activity as a last-resort line of defense (causing, for example, the notorious “razor-blade throat”).

Suboptimal, large-scale immune pressure—arising from poorly specific host responses—can facilitate the parallel expansion of multiple SC-2 variants, thereby increasing opportunities for recombination and the likely emergence of saltation variants with markedly enhanced intrinsic fitness.

In other words, we now find ourselves once again in a situation where the virus threatens to crash straight through another line of defense. This time, however, it’s about breaching the defensive shield set up by the humoral (cytokine-mediated) arm of innate immunity. For the C-19-vaccinated, though not for the unvaccinated who still have a properly trained cell-mediated innate immune system, this really does represent the very last line of defense against the virus. Once that barrier is broken, the virus runs unchecked, leading to rapid systemic spread throughout the body.

We shouldn’t be surprised that this evolution is unfolding only gradually. The reason lies in the fact that the adaptive cell-mediated immune response has become increasingly directed against more conserved viral epitopes and therefore operates with much less antigen specificity. The result is a weak but broad immune pressure, meaning that for any given conserved epitope under immune attack, the selective force is relatively low. New variants in circulation are therefore driven more by the breadth (scope) than by the depth (strength) of immune selection pressure.
In other words, when immune selection pressure becomes diluted due to poor specificity of the suboptimal immune responses, a wide array of co-emerging variants will be granted fitness advantages. Such large-scale viral immune escape results in the parallel circulation and transmission of many antigenically overlapping mutants, thereby raising the chances of recombination events, which may eventually give rise to saltation variants with markedly enhanced intrinsic fitness, particularly in a hostile immune environment. Unlike influenza -where evolutionary leaps usually result from segmental reassortment- SC-2 achieves saltational change through recombination driven by polymerase-mediated template switching in its non-segmented RNA genome. Recombination and saltation are, in fact, the active engine of the viral evolutionary dynamics at this late stage of the C-19 immune escape pandemic.

Consequently, the likelihood of a newly emerging variant ultimately capable of shattering the last barrier of the host’s immune defense (i.e., innate humoral immunity) in highly C-19-vaccinated populations is far more dependent on recombination events producing cytokine-evasive mutants than on strong immune pressure exerted on any single viral epitope.

On predictability

The multitude of co-circulating variants creates a highly fertile ground for recombination and saltational emergence. Both evolutionary theory and empirical SC-2 history strongly suggest this process will continue until a variant eventually arises that brings these evolutionary dynamics to a halt; however, the exact timing of the emergence of a variant capable of breaching the entire immune defense remains inherently unpredictable as it depends on stochastic recombination (who co-infects whom, at what time, under which immune background).
This is analogous to earthquake prediction: although the resolution of short-term forecasting remains poor, the probability can be high -even in the mid-term- when dealing with a highly geologically active region. Similarly, given the extensive co-circulation of antigenically distinct SC-2 immune escape lineages, the emergence of recombinant saltation variants with enhanced immune-escape capacity appears highly probable, if not inevitable, even in the mid-term. Such variants may, in principle, erode the remaining barriers of innate immune defense and thereby enable high viral virulence.

I somehow predict that such a virulent variant (‘HI-VI-CRON’) will only emerge at the very moment my last follower on social media drops off and no longer believes my warnings. I’m saying this to illustrate how, in my view, society as a whole will be taken completely by surprise — like a bolt from the blue.