The Myth of Endless Fine-Tuning and Why Some Experts Believe the Endemicity Narrative

Why a Metastable Pandemic Is Unlikely to Drift Quietly Into Endemicity

An epidemiologist recently jumped to conclusions when, in response to my recent Substack article (https://voiceforscienceandsolidarity.substack.com/p/the-evolutionary-legacy-of-mass-covid?r=y46t6), he wrote me the following:

“Geert, I want to propose an alternative hypothesis. First, booster uptake has been on decline, so that less than 20% or so of the general population is taking them. This means that vaccine efficacy from whatever the population average has been is declining over time. The same applies to the small numbers of people with repeat infections. Thus, virus evolutionary pressure does not need a radical escape, it can continue endemically because small evolutionary changes continue to escape the weakened population immunity.
The idea that there is an evolutionary force successfully mutating the virus is inaccurate. The virus mutates on its own at whatever rate its genetics and host reproduction system allow. It is only selection into a viable reproduction channel that allows particular mutated strains to improve their evolutionary fitness. Thus, both radical and small changes happen all the time, but what is reproductively beneficial is determined by the population environment into which the virus spreads. If the great majority of spread is from minor improvements against weakening population immunity, the population will be fighting those infections and more radical ones will be at a disadvantage because of their much smaller numbers.
So, like for the flu, I don’t see any significant risks of radical strains becoming successful. The flu has been evolving for many decades against weak vaccines and still no radical escape strains”.


I replied as follows, addressing what he presents as an alternative hypothesis.

“Thank you for proposing an alternative hypothesis. However, I believe your analysis illustrates precisely why many epidemiological interpretations of the current SARS-CoV-2 (SC-2) situation remain incomplete: they largely ignore the dynamic interaction between viral evolution and host immunity over time.

To begin with, I fully agree with your statement that there is no “evolutionary force mutating the virus.” I have never claimed otherwise. Mutations arise spontaneously. Selection determines which variants succeed. In fact, everything I have written over the past several years is built on exactly that principle.
What surprises me is that you present this as though it somehow contradicts my hypothesis when it actually forms one of its foundations.

Where we fundamentally disagree is not on mutation. It is on the nature and evolution of the selective pressure acting on the virus.
You argue that declining booster uptake leads to declining population immunity and therefore allows the virus to continue escaping through small incremental changes. But this interpretation overlooks one of the most important immunological realities of the immune escape pandemic: repeated vaccine-breakthrough infections (VBTIs) themselves act as immune boosters of highly Covid-19(C-19)-vaccinated populations.
Even when formal booster uptake declines, breakthrough infections (BTIs) in these populations continue to recall previously primed adaptive immune responses. The immune system is therefore not simply “forgetting” the virus. On the contrary, it is repeatedly being reminded of it.

The crucial question is: Reminded of what?
This is where dynamics become essential. My hypothesis has never been that immune pressure disappears. Quite the opposite. The nature of that pressure changes over time.

Repeated BTIs in highly C-19-vaccinated populations progressively refocus the immune response toward increasingly conserved and less antigen (Ag)-specific viral targets. As a result, classical Ag-specific immune pressure on Spike evolution gradually weakens, while broader adaptive immune mechanisms continue to exert selective pressure on viral transmissibility and propagation. Consequently, the current slowing of viral evolution should not be interpreted as evidence of declining immune pressure over time. It reflects diminishing immune pressure per unit time on conventional antigenic escape pathways while cumulative population-level immune pressure continues to increase in highly C-19-vaccinated populations.

That distinction is critical.

In other words, the delayed evolutionary dynamics we are currently observing in these populations are entirely compatible with growing immune pressure. The virus is not escaping less because immunity is fading. It is escaping less because many of its conventional escape routes are becoming progressively exhausted.

The real question is therefore not whether selection occurs. The real question is:

What type of phenotype will eventually be favored once conventional immune escape begins yielding diminishing returns?

You seem to assume the answer is:

More of the same.

I do not.
History is full of examples where prolonged optimization within a constrained environment eventually gives way to a qualitatively different solution. Evolution does not proceed through endless fine-tuning. When adaptive pathways become saturated, biological systems frequently reorganize and transition to a functionally distinct phenotype.

This is precisely why I find your comparison with influenza particularly inappropriate. Influenza and SC-2 are fundamentally different evolutionary systems.
Seasonal influenza evolves in populations that have acquired herd immunity through repeated natural exposure over many decades. Antigenic drift continues, but it occurs within a relatively stable host-pathogen equilibrium.

The immune escape pandemic I have described is fundamentally different. It is characterized by:

- mass vaccination during active circulation of an acute viral pathogen;

- repeated VBTIs;

- progressive immune refocusing;

- chronic immune stimulation and

- ongoing selection pressure on transmissibility itself.

To invoke influenza as proof that SC-2 cannot undergo a phase transition is somewhat akin to arguing that because rivers usually flow calmly, volcanoes cannot erupt. The systems are totally different.

In fact, I find it fascinating that many critics dismiss the possibility of a phase transition while simultaneously failing to explain why the current situation has become so unusual.
For example:

- Why are genetically unrelated variant families co-circulating for prolonged periods?

- Why do highly mutated saltation variants continue to emerge?

- Why are transmissibility gains becoming increasingly modest?

- Why is viral success becoming increasingly dependent on demographic, geographic, and immunological context?

- Why has the virus failed to settle into the straightforward endemic equilibrium that has repeatedly been promised over the past several years?

And perhaps most importantly:

What biological mechanism allows an endless sequence of increasingly marginal fitness gains to continue forever?

That is the one question I rarely see answered.

The prevailing narrative effectively asks us to believe that SARS-CoV-2 will continue finding small adaptive improvements indefinitely, despite increasing evolutionary constraint and despite mounting evidence that many of its previous adaptive pathways are yielding diminishing returns.
That is not a mechanism. It is an assumption. And assumptions have a habit of collapsing when reality eventually demands an explanation.

Several observations suggest that the current situation is better understood as a chronic, metastable phase rather than a stable endemic equilibrium:

- prolonged co-circulation of genetically distinct variant families;

- repeated emergence of heavily mutated saltation variants;

- increasingly marginal transmissibility gains and

- convergence toward similar functional phenotypes despite increasing genetic diversity.

The last point is particularly important. If immune pressure were truly declining, one would expect relaxation of evolutionary constraints and increasing diversification of adaptive strategies.
Instead, in highly C-19-vaccinated populations, we observe exactly the opposite.
Co-circulating genetically distinct lineages increasingly converge toward similar functional solutions. This suggests that the virus is being funneled into a progressively narrower adaptive space. That is not what one expects from a system approaching stable endemicity. It is what one expects from a metastable system approaching the limits of its current adaptive regime.

Your argument ultimately assumes that the virus can continue finding incremental improvements indefinitely because population immunity is gradually weakening. My argument is that the quality of immune pressure is evolving, not disappearing. The virus continues to adapt but within an increasingly constrained evolutionary corridor.

The issue, therefore, is not whether mutations continue to occur. They always will. The issue is whether the current adaptive strategy remains capable of generating sufficient fitness gains to sustain itself indefinitely. That is where our analyses diverge.

You assume continued incremental adaptation. I see growing evidence of evolutionary saturation, narrowing evolutionary options, and a metastable host-virus equilibrium that is unlikely to persist indefinitely and therefore cannot provide a stable foundation for endemicity. As I have argued in several recent Substack articles, a pandemic caused by an acute viral infection can transition into endemicity only when herd immunity brings viral transmission under sustainable control.
In natural pandemics, herd immunity emerges when sufficient population-level protection develops to interrupt large-scale viral spread and thereby removes the selective pressures that drive continued adaptation. When population-level immunity remains suboptimal, however, this process cannot be completed. Viral transmission persists, immune escape continues, and the host-virus interaction becomes trapped in a chronic evolutionary arms race. Under such conditions, the pandemic does not transition into endemicity but evolves into what I have termed an immune escape pandemic. It is reasonable to postulate that such a state cannot persist indefinitely. As conventional escape pathways become progressively exhausted and the evolutionary corridor narrows, the probability increases that a fundamentally different viral phenotype will eventually be selected. The endpoint of this process is not stable endemicity but a phase transition that profoundly alters the balance between viral adaptation and host immunity.

My hypothesis is that the immune escape pandemic, still very much ongoing in highly C-19-vaccinated populations, can ultimately end only when the virus acquires the capacity to overcome the protective barriers that currently limit its efficient propagation within these populations. In other words, selection will increasingly favor viral phenotypes capable of bypassing adaptive immune responses in population segments whose vaccine-conditioned immunity remains incapable of contributing to sterilizing herd immunity”.