Some scientists find this difficult to reconcile with the idea that BA.3.2 is an immune escape lineage.

I don’t.

In fact, I think it illustrates a fundamental misunderstanding of how viral evolution operates once an immune escape pandemic has entered its chronic phase.

The implicit assumption seems to be the following:

If BA.3.2 evolved under vaccine-driven immune selection pressure, shouldn’t it lose its competitive advantage once it spreads into populations where that immune pressure is much weaker?

At first glance, that might sound quite reasonable. Unfortunately, viral evolution is rarely that simple ─at least not for those who appreciate the evolutionary dynamics of a virus continuously adapting to persistent, incremental, yet suboptimal population-level immune selection pressure on infectivity and transmissibility.
The fundamental mistake made by those who fail to appreciate these evolutionary dynamics is to assume that immune escape and intrinsic transmissibility remain permanently coupled!

They don’t.

Immune selection pressure determines which variants are selected. Once selected, however, those variants no longer compete primarily on the basis of antigenic escape but on the basis of their overall viral fitness.

During the early stages of the pandemic, before substantial population immunity had developed, pre-Omicron variants were primarily selected because they possessed higher intrinsic transmissibility. They simply spread better.

The emergence of Omicron fundamentally changed that evolutionary landscape.
In highly C-19-vaccinated populations, immune escape suddenly became the dominant driver of selection. Hence, variants capable of infecting individuals with vaccine-primed immunity enjoyed an obvious competitive advantage.

But evolution does not optimize only one characteristic. Once immune escape has secured a substantial competitive advantage in highly C-19-vaccinated populations, natural selection is free to optimize every other component of viral fitness that remains evolutionarily accessible, particularly intrinsic transmissibility. Consequently, an immune escape lineage can continue becoming more transmissible even without acquiring additional immune escape mutations.

In other words, once BA.3.2 and its descendants had successfully escaped the prevailing immune landscape, evolution was free to further optimize their intrinsic transmissibility.

Those improvements do not disappear simply because the virus enters a population with lower vaccination coverage!
Indeed, once a lineage has evolved enhanced intrinsic transmissibility on top of immune escape, there is no reason to expect its success to remain confined to highly C-19-vaccinated populations.

On the contrary! Improved intrinsic transmissibility represents a fitness advantage largely independent of the immune status of the next host population.

That is precisely why an immune escape lineage can eventually outperform competing variants even in populations where vaccine-derived immune pressure is relatively modest.

There is therefore nothing paradoxical about BA.3.2 spreading efficiently in poorly C-19-vaccinated regions.

The real mistake is to imagine that immune escape variants remain ‘immune escape specialists.’ Evolution does not preserve labels, though. It preserves fitness.

Once selected, every lineage continues accumulating whatever mutations further improve its reproductive success. This is exactly what one would expect from a virus that has entered a prolonged period of constrained evolution.

Because the competitive advantage conferred by additional immune escape mutations has become increasingly marginal among currently co-circulating SARS-CoV-2 (SC-2) lineages, natural selection is expected to place greater emphasis on mutations that improve other components of overall viral fitness, particularly intrinsic transmissibility.

This may also explain why recent mutation trackers increasingly report amino acid substitutions not only in Spike but also in several non-Spike proteins. Many of these mutations likely provide only marginal improvements in overall viral fitness. Individually, their phenotypic impact is expected to be minimal; collectively, however, they may gradually optimize viral replication, stability, innate immune antagonism or transmissibility while remaining insufficient to fundamentally alter the virus’s biological behavior of the virus. They merely make an already successful lineage slightly more successful.

Paradoxically, this conservative evolutionary strategy may explain the extraordinary duration of the current evolutionary regime. The observation reported by some mutation spotters fits, therefore, remarkably well with the concept of a prolonged metastable phase that I have described repeatedly. The virus continues buying time through countless incremental improvements.

Each small gain postpones ─but does not eliminate─ the need for a fundamentally different adaptive solution.

This is why I do not interpret the current evolutionary dynamics as evidence that SC-2 is settling into endemic equilibrium.

Quite the opposite!

The prolonged coexistence of multiple unrelated immune escape lineages, together with increasingly modest fitness gains and gradual optimization of intrinsic transmissibility, suggests to me that the virus is extracting the last remaining benefits from conventional amino acid-based adaptation.

Whether this process eventually culminates in the phase transition that I have termed Hi-Vi-Cron remains my unchanged prediction.

In conclusion, I certainly do not find it difficult to understand why an immune escape lineage that has subsequently acquired additional transmissibility-enhancing mutations can ultimately dominate even in populations with relatively low C-19 vaccine coverage. On the contrary, once immune escape has been established and selection shifts toward optimizing overall viral fitness, that is precisely what evolutionary theory would predict!

In my view, this prolonged period of incremental adaptation reflects an increasingly metastable evolutionary state in which the virus continues to evolve because immune selection pressure persists, yet the available adaptive options capable of substantially improving viral fitness are becoming progressively exhausted.
The obvious question is therefore not why SC-2 continues to mutate.

The real question is why evolution continues to favor numerous mutations that individually provide only marginal improvements instead of selecting a fundamentally different adaptive solution capable of restoring efficient viral transmission in a population that has become increasingly hostile to viral spread.

The answer may lie in one of evolution’s oldest principles. Natural selection generally prioritizes the safest adaptive route, not necessarily the best one.
Every amino acid substitution represents a relatively inexpensive evolutionary experiment. A single nucleotide change modifies one amino acid while usually preserving the overall architecture of the protein. Most such mutations have little effect, some are harmful, and a few provide a slight competitive advantage. Because they rarely disrupt essential protein function, evolution can continuously sample enormous numbers of these mutations with relatively little risk.

The situation is fundamentally different for glycosylation. Adding, removing or repositioning glycans is much more impactful than a simple additional amino acid substitution. It modifies the three-dimensional organization of the S protein, influences its folding, affects receptor accessibility, protease cleavage, membrane fusion, and interactions with the host glycosylation machinery. Most such changes are therefore expected to be incompatible with efficient viral replication and are likely to be eliminated immediately by purifying selection.

From an evolutionary perspective, amino acid substitutions are therefore cheap whereas glycan remodeling is expensive. This explains why evolution preferentially exhausts the ‘cheap’ adaptive options first, despite their diminishing returns, before eventually being forced into a much riskier but potentially much more rewarding adaptive solution. Evolution consequently continues to exploit every remaining protein-based adaptive opportunity, even when each additional mutation provides only a minute improvement in fitness.

This may explain why today’s mutation trackers continue to document predominantly incremental amino acid substitutions and recombinations rather than evidence of a fundamentally new evolutionary strategy. S continues to accumulate convergent substitutions at familiar positions, while non-S proteins acquire additional mutations that may subtly influence replication, innate immune antagonism or viral fitness^[1].
None of these changes appears to transform the biological phenotype of the virus. Instead, they represent repeated exploration of an increasingly narrow adaptive landscape.

At first glance, the growing number of mutations in viral proteins other than S appears paradoxical. Many of these proteins play no direct role in receptor binding or membrane fusion. Consequently, their capacity to substantially improve viral entry or transmission is inherently limited. They may modestly optimize replication kinetics, antagonize innate immunity, stabilize viral RNA or improve intracellular efficiency, but none can fundamentally overcome the increasingly broad adaptive immune pressure directed against viral transmission!

Why, then, does evolution continue to select such apparently modest improvements?

Because every small, low-risk gain postpones the need for a far riskier evolutionary innovation. As long as another amino acid substitution can still increase fitness by even a fraction of a percent without compromising protein function, natural selection is expected to favor that safe solution over a high-risk structural innovation that has a substantial probability of destroying viral fitness altogether.

Ironically, this very conservatism may explain the extraordinary duration of the current evolutionary regime.

The virus may remain trapped on what evolutionary biologists call a local fitness peak.

Countless incremental mutations continue to produce diminishing ─but still positive─ returns, thereby delaying exploration of a much steeper adaptive pathway whose initial steps carry considerable fitness costs.

Eventually, however, the evolutionary arithmetic changes.

As the cumulative adaptive immune landscape broadens through repeated VBTIs, the selective value of one additional amino acid substitution is expected to become progressively smaller. Conventional protein-based adaptation may eventually reach a point where it can no longer restore efficient viral transmission. At that stage, evolution may increasingly reward adaptive solutions that are currently too risky to compete.

Within the framework of sustained population-level immune pressure, extensive remodeling of the S glycan shield represents the most plausible candidate. Unlike conventional amino acid substitutions, glycan remodeling could simultaneously shield multiple adaptive immune targets, alter receptor accessibility, promote lectin-mediated attachment, facilitate trans infection and trans fusion (cell-to-cell spread), and thereby bypass rather than merely fine-tune the existing vaccine-conditioned adaptive immune landscape (https://www.voiceforscienceandsolidarity.org/scientific-blog/predictions-gvb-on-evolution-c-19-pandemic).
Such changes would undoubtedly impose substantial structural constraints and would likely require several coordinated mutations before becoming viable. Precisely because they are so difficult to achieve, they are expected to emerge only after conventional adaptive routes have become largely exhausted.

This is why I regard glycan remodeling as the virus’s solution of last resort. This is also why it becomes so difficult to predict when exactly a qualitatively different adaptive strategy is going to occur.

Because of the metastable evolutionary situation, the prolonged coexistence of numerous lineages with increasingly modest phenotypic differences should therefore not be interpreted as evidence that SC-2 is settling into endemic equilibrium.

Instead, it may represent the evolutionary signature of a virus that continues to postpone a high-risk but potentially transformative innovation by exploiting every remaining low-risk adaptive opportunity.

The apparent calm does, therefore, not reflect evolutionary stability. It reflects a virus approaching the limits of conventional adaptation.

If SC-2 continues to experience persistent population-level immune selection while conventional amino acid-mediated adaptation yields progressively smaller returns, evolutionary theory suggests that the relative attractiveness of a fundamentally game-changing phase transition will continue to increase. In my view, that is precisely why the current metastable phase deserves far more attention than the comforting narrative that the virus is simply ‘running out of options.’

^[1] Proteins such as N, NSP1, NSP3, NSP6, ORF6, ORF8, and ORF9b can influence replication efficiency, innate immune antagonism, RNA production, and viral load. Those effects can indirectly affect transmission even though they do not participate directly in receptor binding or membrane fusion.

The current evolutionary dynamics of the SARS-CoV-2 (SC-2) pandemic are characterized by:

• A chronic rather than self-limiting evolutionary process, in which repeated vaccine-breakthrough infections (VBTIs) and recurrent viral exposure promote prolonged viral persistence in susceptible hosts, thereby fostering intra-host evolution, the emergence of highly mutated saltation variants, and persistent post-acute sequelae (Long Covid) rather than predominantly acute severe Covid-19 (C-19).

• Prolonged co-circulation of several genetically distinct immune escape lineages that increasingly converge toward similar functional phenotypes enhancing viral transmission, yet without any lineage consistently acquiring a decisive competitive advantage. Consequently, fluctuations in their relative prevalence increasingly depend on subtle demographic, geographic, seasonal, behavioral or vaccination-related differences rather than on major intrinsic fitness advantages.

• A gradual shift in the adaptive landscape, reflected by increasing accumulation of mutations in conserved Spike (S) epitopes as well as in non-S proteins (e.g., ORF7/ORF8), together with an increasing relative contribution of infections in specific demographic groups, particularly young children, within highly C-19-vaccinated populations.
  

Evidence of a narrowing evolutionary corridor

Despite substantial genotypic divergence among currently circulating SC-2 lineages, their phenotypic characteristics increasingly converge while the incremental fitness gains obtained from conventional amino-acid substitutions become increasingly marginal.

Even large evolutionary jumps in S sequence ─as observed in BA.3.2-derived lineages─ combined with increasing diversification in conserved epitopes and non-S proteins, even when combined with a shift of SC-2 infections to more vulnerable populations (i.e., young children), have thus far failed to restore the type of rapid selective sweeps that are required to sustain viral transmission and characterized earlier phases of the pandemic.
These observations suggest that conventional amino-acid-based immune escape may be approaching diminishing evolutionary returns. Should this trend continue, natural selection may increasingly favor alternative adaptive strategies capable of fundamentally altering early virus-host interactions rather than merely modifying antigenic epitopes.
The most plausible mechanism is extensive remodeling of S glycosylation ─particularly through additional O-linked glycosylation sites─ which could substantially alter viral phenotype by simultaneously enabling several distinct mechanisms (see section VI below; https://www.voiceforscienceandsolidarity.org/scientific-blog/predictions-gvb-on-evolution-c-19-pandemic).

Such phenotypic innovations would likely carry a significant intrinsic fitness cost under ordinary circumstances. However, under sufficiently strong population-level immune selection pressure, they could nevertheless acquire a decisive competitive advantage as they would enable full-fledged viral replication and transmission, regardless of the current viral and immunological landscape in highly C-19-vaccinated populations.


A metastable evolutionary equilibrium

In highly C-19-vaccinated populations, the resulting evolutionary constraints generate an increasingly heterogeneous viral landscape characterized by:

• prolonged coexistence of multiple unrelated variant families;

• regional differences in lineage prevalence;

• heterogeneous age distribution of infections;

• recurrent saltation events;

• convergent functional evolution despite genetic diversification.

Taken together, these observations suggest that SC-2 is evolving within an increasingly constrained adaptive landscape. Rather than indicating stable endemicity, I interpret this situation as a metastable evolutionary equilibrium.

Prolonged co-circulation under narrowing evolutionary constraints may eventually create the prerequisites for a major evolutionary phase transition, which I have termed Hi-Vi-Cron.
Rather than representing the next incremental immune escape variant, such a phenotype would fundamentally alter the interaction between virus and host immunity, thereby triggering unconstrained viral replication and transmission within highly C-19-vaccinated populations (https://voiceforscienceandsolidarity.substack.com/p/the-evolutionary-legacy-of-mass-covid).

Which lessons, in my opinion, will be learned once my predictions materialize?

I. The apparent epidemiological calm ─characterized by diminished transmission, delayed viral spread and lack of viral dominance, as well as a shift from acute epidemic waves toward prolonged infection─ is not to be considered evidence that the virus is approaching endemic equilibrium.
Rather, these features reflect increasing evolutionary constraint.

II. As immune escape variants continue competing within an increasingly restricted adaptive space, conventional transmissibility-enhancing mutations converge and yield progressively smaller returns.

Under such conditions, natural selection eventually favors an entirely different coronavirus phenotype capable of bypassing collective vaccine-primed adaptive immunity instead of continuing to optimize conventional immune escape.
Such CoV phenotype uses an unconditioned fitness advantage to overcome its conditioned immune environment.

III. Population-level adaptive immunity that reduces disease severity without generating transmission-curtailing herd immunity perpetuates viral circulation while continuously reshaping the selective landscape that drives further viral adaptation. It thereby paves the way for the virus to transition to a new phenotype capable of breaking through vaccine-primed adaptive immunity in highly C-19-vaccinated populations instead of driving the pandemic toward endemicity.

IV. The longer an acute, self-limiting virus struggles to maintain transmission under increasing but suboptimal immune pressure, the more heterogeneous both the viral landscape and the demographic distribution of infections become.

Such increasing heterogeneity is not evidence of stability but may instead reflect growing evolutionary constraint.

V. The higher the prevalence of vaccine-primed adaptive immune responses in a highly C-19-vaccinated population, the greater the likelihood that, within a given time frame, the resulting suboptimal population-level immune pressure will drive natural selection of a fundamentally different CoV phenotype capable of effectively circumventing collective immune pressure on viral transmission and thereby restoring viral fitness.

VI. As the adaptive landscape becomes increasingly constrained, additional mutations in conserved S epitopes or in non-S proteins provide progressively smaller and less consistent fitness gains. When the population-level immune selection pressure reaches a bottleneck in its ability to drive the emergence of SC-2 variants with a clear and sustained competitive fitness advantage, viral evolution no longer relies on immune escape through amino-acid substitutions in immunologically relevant S-associated peptide epitopes. Instead, continued immune pressure on viral transmission eventually favors a qualitatively different class of adaptive solutions. This phase transition involves remodeling of the S glycan shield^[i]. Rather than simply altering antigenicity, a such transition fundamentally reshapes the early virus-host interaction by simultaneously:

· bypassing critical adaptive immune targets from pre-existing antibody and vaccine-
primed T-cell recognition;

· enhancing viral attachment and entry into susceptible host cells;

· promoting lectin-mediated trans infection;

· facilitating fusion between infected and non-infected host cells, thereby enabling
syncytium formation and enhancing cell-to-cell spread

· and thereby abolishing dependence on evolutionary pathways currently constrained
by increasingly broad vaccine-primed adaptive immune pressure.

Unlike conventional amino-acid-mediated immune escape, this strategy represents a genuine phenotypic innovation, enabling the virus to circumvent rather than continuously fine-tune its interaction with the prevailing adaptive immune landscape. As mentioned above, I have referred to this predicted phenotype as Hi-Vi-Cron.

During this prolonged period of constrained evolution yielding diminishing fitness gains, the apparent epidemiological ‘calm’ creates the illusion that the pandemic has entered a stable endemic phase.

However, this apparent stability (i.e., metastability) reflects an increasingly unstable equilibrium in which evolutionary constraints continue to accumulate while conventional adaptive pathways become progressively exhausted.

The absence of large epidemic waves should therefore not be interpreted as evidence that the evolutionary process has come to an end, but rather as an indication that the system is approaching a critical transition.
Because all of this stands in diametrical opposition to the interpretation advanced by our public-health authorities and leading ‘experts’, I maintain that societies in highly C-19-vaccinated populations will be caught completely off guard.

VII. Hi-Vi-Cron’s principal competitive advantage no longer arises from incremental antigenic escape but from its ability to functionally sideline pre-existing vaccine-primed adaptive immunity.
By relying increasingly on glycan-mediated immune shielding, enhanced viral entry, trans infection, and efficient cell-to-cell dissemination, Hi-Vi-Cron abolishes the effectiveness of both anti-S neutralizing antibodies and S-directed cell-mediated immune responses.

This enables unconstrained viral replication and transmission in highly C-19-vaccinated populations.

Rather than representing merely another immune escape variant, Hi-Vi-Cron constitutes a fundamentally new evolutionary strategy ─one capable of terminating the current metastable host-virus equilibrium by replacing gradual, incremental adaptation with a qualitative evolutionary phase transition; the latter changes the rules of the evolutionary game by adopting a fundamentally different adaptive strategy. In doing so, it exhibits high virulence while acquiring a decisive competitive advantage over all currently circulating SC-2 lineages that have thus far evolved under the constraints imposed by collective, vaccine-primed immune pressure.

^[i] presumably through the acquisition of additional O-linked glycosylation sites or other glycan-mediated structural innovations (https://voiceforscienceandsolidarity.substack.com/p/the-evolutionary-legacy-of-mass-covid)

For clarity, I have placed an “E:“ at the beginning of passages in which I quote the epidemiologist whereas my own responses are preceded by “G:“.

This exchange is just one of many examples illustrating the one-sided perspective through which many scientists fail to understand the impact of mass vaccination on the evolutionary dynamics of the SC-2 pandemic. Yet it also demonstrates that meaningful scientific dialogue remains possible when there is a willingness to engage with competing hypotheses rather than dismiss them outright.

There is clearly a need for greater education and, perhaps even more importantly, for a genuine willingness to consider analyses that challenge the prevailing mainstream narrative. Scientific progress rarely emerges from consensus alone. More often, it advances through the rigorous examination of alternative explanations, especially when established frameworks struggle to account for an increasing number of observations.
Whether one ultimately agrees with my conclusions or not, I believe the continuing inability of conventional models to explain the current evolutionary trajectory of SC-2 should encourage a broader and more open-minded discussion of the mechanisms that may be driving this unprecedented immune escape pandemic.

E: “It seems to me that there is a question of, under the current metastable circumstances of increasingly narrowing immune escape pathways, will a limit eventually be reached where without some major phase transition mutation, the virus eventually dies out. This would be a contest between available new incremental mutations occurring, and existing immune repertoires combatting them. I don’t see it as a given that the mutation rate and possible mutation combinatorics are automatically strong enough to combat population immune suppression for all time. Maybe only strong enough in the first few years or decades of a pandemic but maybe not eventually.

The second thing is that over time, more unvaccinated children will enter the adult population and their initial frequently asymptomatic immune responses will provide a different immune milieu for the virus mutation escape process.

What you are suggesting about a radical mutation that achieves strong immune escape theoretically can happen, but I don’t see any evolutionary force per se that would push it, and we don’t know what it would take statistically in antigen combinatorics to arrive at some effective radical combination. With perhaps 10⁸ mutations occurring in each infected individual and some 10¹⁰ or more infections occurring worldwide, that would be 10¹⁸ mutation combinations, from which maybe about 1% (10¹⁷) escape. The virus spike protein has about 1300 (10^3.1) mutable loci. So this might account for all possible combinations of 17/3.1 = 5.5 loci. A radical mutation combination would therefore have to include functionally beneficial changes in more than 6 spike loci.

Certainly, viral variants with way more than 6 variant spike loci have occurred. But most likely only a few of their variant loci were needed for immune escape and the rest were passive travelers. For a radial variant, it would need 6 or more truly functional variant loci. Possible theoretically, but has not yet occurred in 6 years of viral evolution, and if the immune “loopholes” keep narrowing, it is also theoretically possible that the virus might fail before it happens”.

G: Thank you for engaging with the argument. However, I believe you are still viewing the problem primarily through the lens of mutation statistics rather than through the lens of host-virus evolutionary dynamics.

The first question I would ask is: how exactly do you envision the virus dying out in a population that has failed to generate transmission-curtailing herd immunity?

As I have repeatedly argued, a pandemic caused by an acute viral infection can only transition into endemicity when herd immunity sufficiently suppresses viral transmission and replication. In highly C-19-vaccinated populations, this has not happened. The virus continues to circulate, replicate, and evolve. Consequently, the evolutionary process remains active.

The key driver of immune escape is not the mutation rate itself. Mutations occur continuously. What determines evolutionary success is the selective pressure exerted by the host population. In the current chronic phase of the immune escape pandemic, increasingly transmissible viral lineages and increasingly broad but suboptimal adaptive immune responses are temporarily keeping one another in balance. This is what I refer to as a metastable state. However, metastability should not be confused with stability.

What we currently observe is that conventional adaptive pathways are yielding diminishing returns. Due to structural and steric constraints within the Spike protein, the virus increasingly requires multiple coordinated amino-acid changes to achieve the same incremental fitness gains that previously required only one or two mutations. This explains why transmissibility gains are becoming progressively smaller and why unrelated variant families are converging on similar functional phenotypes.

But this does not mean the virus is running out of evolutionary options. It merely means that one class of adaptive solutions is becoming exhausted.

For years, I have argued that the focus on amino-acid substitutions within Spike is excessively narrow. Evolution is not restricted to the pathways that epidemiological models happen to include. I have repeatedly outlined how changes in glycosylation patterns, for example, could dramatically alter the interaction between the virus and the immune system by facilitating mechanisms such as trans infection, lectin-mediated attachment, enhanced fusion competence, or cell-to-cell spread.

Such a phenotype would undoubtedly carry a substantial intrinsic fitness cost under ordinary circumstances. However, fitness is context-dependent.

If immune pressure on conventional transmission pathways continues to increase, a lineage capable of bypassing vaccine-primed adaptive immune responses could ultimately gain a competitive advantage despite paying such a cost. This is not because some mysterious “evolutionary force” pushes the virus in that direction. It is simply Darwinian selection acting on whatever phenotype happens to be most successful in the prevailing immune environment. That is exactly how evolution works.

You also suggest that over time unvaccinated children entering the adult population could gradually shift the population immune landscape.

The question is whether demographic turnover can occur rapidly enough to outpace viral evolution. I find that highly unlikely.

In most highly C-19-vaccinated countries, annual birth rates typically replace only about 1–2% of the population per year. Even under highly favorable assumptions, it would take several decades before a substantial fraction of the population consisted of individuals whose immune histories were dominated by natural exposure rather than vaccination. By contrast, SC-2 generates new generations every few hours, infects millions of hosts, and continuously explores new evolutionary possibilities. The timescales are simply not comparable.

Furthermore, several recent observations suggest that younger age groups are becoming proportionally more represented among infections caused by highly transmissible circulating variants. If this reflects increasing exposure of children to these variants, then the contribution of naturally acquired immunity to transmission-curtailing herd immunity may be delayed rather than accelerated.

Most importantly, I think your argument still assumes that viral adaptability is primarily a question of combinatorial amino-acid mutations within Spike.

That assumption is precisely what I question. The history of biology repeatedly shows that complex adaptive systems rarely remain trapped indefinitely within a narrowing corridor of increasingly marginal gains. When conventional adaptive pathways become saturated, systems often reorganize around fundamentally different solutions. That is why I find the current situation more reminiscent of a snow cornice hanging over a steep mountainside than of a virus quietly approaching extinction. One can always hope the snow melts before the avalanche is triggered. But hope is not a mechanism.

Likewise, I have yet to see a convincing biological mechanism explaining how a virus that continues to replicate globally, continues to generate new variants, continues to produce saltation events, and continues to face ongoing immune selection pressure will simply “run out of options” and disappear.

Darwin’s principle remains as relevant today as ever:

It is not the strongest that survives, nor the most intelligent, but the one most adaptable to change.

The crucial question is therefore not whether the virus can continue mutating. It can.

The question is whether the host population can adapt more rapidly than a pathogen that generates new generations every few hours while continuously being selected in billions of hosts. That, in my view, is where the burden of proof lies.

E: I take your point. It would be good to have a sense of whether any other respiratory viruses have ultimately given up their main or original mutation repertoire and shifted to a more mutation costly but remaining functional paradigm.

G: The crucial point is that the issue is not whether SARS-CoV-2 will suddenly discover an entirely new mutational repertoire. The issue is the evolutionary landscape in which those mutations are being selected. The current situation is unprecedented because we have never before exposed large populations to non-sterilizing vaccines during the active circulation of a pandemic virus causing an acute self-limiting infection (ASLVI). Had the same strategy been applied to any other pandemic of a virus causing ASLVI, we would have observed similar evolutionary dynamics.

What matters is not the virus per se, but the selective environment in which it evolves.

A virus does not “choose” its mutations. Mutations arise continuously. What determines their success is the immune landscape they encounter. The unique feature of highly C-19-vaccinated populations is that repeated vaccine-breakthrough infections (VBTIs) have progressively shaped that landscape through repeated recall of vaccine-primed adaptive immune responses. This has generated a type of immune conditioning for which we have no historical precedent at the population level. As I have argued in several Substack articles and in my online courses, the relevant selective pressure is no longer narrowly antigen-specific. It has gradually broadened while simultaneously becoming less effective at preventing transmission. This is precisely why the acute phase of the SC-2 pandemic has transitioned into a chronic immune escape pandemic rather than a transition toward stable endemicity.

Consequently, the relevant question is not:

“Can the virus still find mutations?”

but rather:

“Which mutations are being selected in an immune environment that has itself been profoundly modified by mass vaccination and repeated breakthrough infection?”

That is where my analysis differs from conventional epidemiological reasoning.

E: The current vaccines only dealt with the spike protein so mutations elsewhere would be expected at best to be constrained only by post-infection natural immunity rather than vaccine immunity.

G: I am not sure I agree with your suggestion that mutations outside the Spike (S) protein would primarily be constrained by natural immunity rather than vaccine-induced immunity.
This overlooks the dynamic consequences of immune refocusing. Repeated VBTIs do not simply maintain S-directed immune responses. Over time, they progressively recruit broader adaptive immune responses directed against increasingly conserved epitopes, including epitopes located in non-S proteins. In other words, although the original vaccines exclusively targeted the S protein, the immune landscape that subsequently evolved no longer does. Moreover, unlike the S protein, non-S proteins have not been reported to experience structural and spatial constraints under sustained immune selection pressure.
More importantly, however, I do not consider post-infection immunity in previously unvaccinated individuals to be equivalent to vaccine-primed immunity when it comes to driving viral evolution.
As I have explained in my online courses and Substack articles, natural infection in immunologically naïve individuals typically does not exert the same type of antigen-specific immune pressure on actively replicating virus. This is because innate immune mechanisms and early cellular responses eliminate the bulk of the viral load before substantial levels of S-specific neutralizing Abs are generated. This is fundamentally different from the situation created by vaccine-primed adaptive responses or repeated recall thereof during VBTIs (see powerpoint slides of my course at the bottom of this e-mail).
Consequently, natural infection contributes to the development of protective population immunity without exerting the sustained immune selection pressure that drives viral immune escape. This distinction is key to understanding why previous natural pandemics caused by ASLVIs generated transmission-curtailing herd immunity and eventually transitioned into endemicity. Herd immunity curtailed transmission before immune escape became the dominant evolutionary driver. In contrast, vaccine-modified pandemics may instead evolve into prolonged immune escape pandemics.

The situation we are dealing with today is, therefore, fundamentally different: The chronic phase of the immune escape pandemic is not being sustained because the virus possesses some magical capacity to mutate forever. It is being sustained because the virus continues to encounter an immune landscape that favors variants capable of overcoming increasingly broad but still suboptimal adaptive immune responses. That is why one should not view the current evolutionary dynamics as a simple extension of what we have seen with influenza or other endemic respiratory viruses.

E: The risks you describe are essentially quantitatively unknowable.

G: I don’t think the relevant question is whether the risks I describe are precisely quantifiable today.

Many phase transitions in complex systems are difficult to predict quantitatively before they occur. The important question is whether the underlying conditions for such a transition are accumulating.

When I look at:

- the prolonged co-circulation of unrelated variant families,

- the emergence of repeated divergent saltation variants,

- the increasing convergence of viral phenotypes,

- the diminishing returns of conventional immune escape pathways and

- the absence of transmission-curtailing herd immunity,

I see evidence of a system that remains evolutionarily active but increasingly constrained. That is why I describe the current state as metastable.

The virus is not running out of mutations. It is running out of easy evolutionary solutions. And that is precisely why I believe the most important evolutionary event may still lie ahead rather than behind us.

E: It seems that we can only wait and watch.

G: That is unfortunately what experts and public health authorities have been doing all along. Yet there may still be a window of opportunity to set things right. Viral circulation has arguably never been this low since the pandemic began. In my view, options worth considering could include short-term mass administration of antivirals or strategies aimed at enhancing the host’s innate immune defense, such as BCG vaccination.
The problem is that both approaches remain largely theoretical in practice. The necessary scientific understanding of the ongoing host–virus evolutionary dynamics is lacking and so is the political willingness to implement coordinated measures on a population-wide scale.

E: Yes, I agree that the selection side of the mutation process determines what escapes and gets established. This is my normal understanding in more general epidemiologic terms so of course it applies at the immune responses level.

I suspect that s protein mutations have been evolutionarily more effective in escape mechanisms and thus that factors of replication mass producing s protein mutations have also been selected for. Perhaps that is why mutations in other external structures seem to be much less frequent, because they haven’t yet needed selection for propagation benefit. I think your point is that as the s protein mutation process becomes increasingly narrowed, other mutations may end up getting selected if they have propagation benefit, and these of course have no vaccine-based immunity., and there are not enough people with original natural post-infection immunity.

Do you have any particular antivirals in mind? Some like tamoxifen are virtually useless and have appreciable side effects.

G: I am pleased to say that, this time, I can agree with you completely.

Very few scientists take a genuine interest in the glycobiology of viruses. That has always puzzled me. After all, the remarkable role of glycosylation is described in virtually every virology textbook. Glycosite mutations, for example, can help a virus evade adaptive immunity by adding, removing or repositioning glycans that physically shield Ab and Tc epitopes from immune recognition. Unlike amino acid substitutions, which modify the epitope itself, glycans act as a form of molecular ‘camouflage’, preventing immune effectors from accessing their targets. As a result, the virus may reduce the effectiveness of pre-existing adaptive immune responses without necessarily having to alter large portions of its protein sequence. In addition, glycan remodeling can promote alternative modes of viral spread, such as lectin-mediated attachment, trans infection or cell-to-cell transmission, thereby reducing reliance on pathways that are heavily targeted by adaptive immunity.

What makes this particularly interesting is that SC-2 is already estimated to have approximately 30–40% of its S surface covered by glycans. These glycans therefore constitute an enormous potential reservoir for immune evasion. On the other hand, a substantial remodeling of the viral glycosylation profile would undoubtedly come at a significant intrinsic fitness cost. Consequently, such evolutionary potential is unlikely to be exploited unless the immune pressure collectively exerted on the virus becomes sufficiently intense for one or more glycosite mutations to provide a meaningful competitive advantage within the hostile immune landscape of highly C-19-vaccinated populations.

Hence, what is really important for understanding a potential evolutionary phase transition is not whether SC-2 can continue generating additional amino acid substitutions. Rather, the key question is how much additional glycosylation or glycan remodeling remains structurally feasible before essential S functions become compromised. HIV, for example, demonstrates that a virus can remain highly viable while carrying a glycan shield substantially larger than that of SC-2. This does not mean that SC-2 will necessarily evolve in the same direction. However, it does indicate that there remains considerable biological space between the current SC-2 glycan shield (~30–40%) and the degree of glycan shielding that a virus can theoretically tolerate under sufficiently strong immune selection pressure.

From the perspective of the current metastable equilibrium between the virus and host population immunity, one could therefore argue that the central question is not whether SC-2 can still generate additional amino acid substitutions. Rather, it is whether increasing immune pressure and diminishing returns from conventional immune escape will eventually favor a qualitatively different adaptive strategy ─ one that relies more heavily on glycan-mediated phenotypic innovations capable of fundamentally reshaping the host-virus interaction landscape by shielding critical viral epitopes from adaptive immunity while simultaneously enhancing viral entry, trans infection, and cell-to-cell spread.

Whether the current population-level immune pressure is capable of driving SC-2 in such a direction is, of course, impossible to prove at present. Yet there is at least one person on this planet who is firmly convinced that it will...

As intensely as I have immersed myself in the evolutionary dynamics of a virus being relentlessly driven by a collective vaccine-primed adaptive immune response, I must admit that I am less familiar with the practical question of which antiviral agents would be most suitable for eliminating the virus while its circulation remains historically low. That said, several antiviral candidates could reasonably be considered. However, from a purely theoretical epidemiological perspective, synchronization and mass administration may ultimately matter more than modest differences in antiviral potency when the objective is interruption of transmission rather than treatment of individual patients. In many infectious-disease control programs, timing and coverage can be just as important as the efficacy of the intervention itself.

Even if unvaccinated individuals were willing, out of solidarity (!), to participate in such a campaign, it seems rather utopian to expect public health authorities or officially recognized experts to initiate or support a coordinated population-wide effort of that kind.
Unfortunately, acknowledging that the current viral burden may represent a unique window of opportunity would require first acknowledging that the pandemic is not over and that the evolutionary dynamics unfolding before our eyes are not those of stable endemicity!

“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”.

I am therefore trying to reconstruct the chain of evolutionary events as I see it, so that the individual pieces of the puzzle can be understood as parts of a coherent evolutionary process:

• Mass C-19 vaccination during ongoing viral circulation created strong population-level immune pressure on transmissible SC-2 variants.

• This pressure favored the emergence and selection of increasingly infectious immune escape variants.

• These variants generated repeated vaccine-breakthrough infections (VBTIs).

• Repeated VBTIs progressively reinforced immune refocusing toward increasingly obsolete viral targets.

• Immune refocusing contributed to increasingly dysfunctional and less effective antiviral adaptive immune responses.

• Such immune dysfunction created favorable conditions for prolonged and chronic SC-2 infections in susceptible individuals (‘long Covid’).

• Prolonged infections provided an ideal environment for accelerated intra-host viral evolution and the emergence of highly mutated saltation variants under sustained immune pressure.

• Following their emergence, these saltation variants were subjected to population-level selection in highly C-19-vaccinated populations.

• However, the transmissibility gains conferred by successive immune escape mutations have become increasingly marginal, resulting in the long-term co-circulation of only a limited number variant families that have converged on similar adaptive solutions (i.e., XFG, NB.1.8.1 and BA.3.2).

• This prolonged co-circulation under narrowing evolutionary constraints is now creating the conditions for a major evolutionary phase transition, which I have referred to as Hi-Vi-Cron.

In my view, the current evolutionary landscape is therefore not one of stable endemicity, but of metastability. The virus continues to adapt, yet increasingly within a restricted evolutionary corridor in which additional immune escape yields diminishing returns. Such systems do not typically evolve through endless fine-tuning. When incremental adaptive pathways become exhausted, evolutionary systems tend to reorganize — sometimes abruptly and dramatically.

My conclusion remains that mass vaccination with non-sterilizing C-19 vaccines during the circulation of increasingly transmissible SC-2 variants has laid the groundwork for a prolonged immune escape pandemic and may ultimately favor the emergence of a fundamentally different viral phenotype capable of triggering a major evolutionary phase transition in highly C-19-vaccinated populations.

A paper recently published in PNAS reported the detection of nearly full-length SARS-CoV-2 (SC-2) genomes in the feces of Tundra swans and a partial MERS-CoV genome in a Bar-headed goose (https://www.pnas.org/doi/10.1073/pnas.2400023123).
At first glance, this might fuel concerns about migratory birds acting as silent reservoirs for human coronaviruses, raising alarms about potential spillback to humans. However, a closer look at the genomic data, receptor studies, and immunological context points to a different story.

The sequences are unequivocally human-origin SC-2, closely related to human variants of concern (with Beta- and Gamma-like features in the receptor-binding domain; RBD), not distinct avian coronaviruses. This represents reverse zoonosis: from humans to birds, not the other way around.

Receptor Compatibility and the Limits of Productive Infection

The study demonstrates that swan ACE2 receptors can effectively bind the RBDs of these variant SC-2 strains (and Alpha), with cryo-EM structures revealing specific polar and hydrophobic interactions. Pseudotyped viruses with these variants can enter cells expressing avian ACE2, ruling out blanket receptor incompatibility.[1]

Yet, despite this entry potential and the detection of viral RNA in feces, there is no evidence of productive infection, clinical disease, or seroconversion in the birds. This mirrors experimental challenge studies in poultry (chickens, turkeys, ducks, quail, and geese), where direct exposure to SC-2 or MERS-CoV resulted in no disease, no detectable virus replication, and no antibody response.[2]

The Role of Trained Innate Immunity in Birds

This pattern strongly supports the role of trained innate immunity in birds ─ and, most likely, in other animals exposed to circulating SC-2 variants generated within highly COVID-19 (C-19)-vaccinated human populations. Migratory waterfowl like Tundra swans and Bar-headed geese are frequently exposed to diverse avian pathogens, including gammacoronaviruses. Trained immunity involves epigenetic and metabolic reprogramming of innate immune cells, particularly NK-like cells, leading to enhanced, antigen-nonspecific antiviral responses.

These trained responses can rapidly abrogate infection at an early stage through heightened cytokine production, cytotoxicity, and other innate effectors, clearing or containing the virus before it achieves productive replication or triggers adaptive immunity.
In wild migratory species under constant environmental pressure, this primed innate state may be particularly effective against heterologous viruses like human betacoronaviruses.[3]

Reverse Zoonosis in the Context of Viral Evolution in Highly C-19-Vaccinated human Populations

These detections in bird feces are best interpreted as signals of human-to-animal spillover, likely via contaminated wastewater, polluted water sources or environmental exposure where migratory birds feed. The recovered viruses retain human VOC signature mutations while showing additional distinct changes ─ consistent with intra-host evolution.

Mass C-19 vaccination programs, while still associated with diminished prevalence of acute severe disease and case fatalities, are invariably associated with a high prevalence of prolonged or chronic SC-2 infections in C-19-vaccinated human populations. These persistent infections create extended opportunities for intra-host mutation, generating greater viral diversity and lineages with potentially enhanced functional properties.

The presence of these human-derived variants in bird excreta therefore highlights the breadth of SC-2 mutational diversity currently evolving within highly C-19-vaccinated human populations, rather than indicating birds as dangerous amplifying reservoirs.

Reframing the Narrative: Birds as Sentinels, Not Reservoirs

While the original paper emphasizes migratory birds as “potential carriers” posing a public health threat, the combined evidence ─ human-classified sequences, functional receptor binding without clear productive infection, and the plausibility of early innate control ─ supports a quite different view:

Birds, presumably like a diverse subset of other animals, appear capable of effectively responding to exposure to circulating SC-2 sublineages through trained innate immunity, thereby limiting back-transmission to humans.
The findings serve more as environmental mirrors reflecting sustained viral evolution and immune escape driven by immune selection pressure in highly C-19-vaccinated populations than as warnings of an avian-origin threat to global health.

Bottom Line

The detection of human SC-2 variants in Tundra swan feces and similar excreta from other animals is a striking example of reverse zoonosis. It underscores the resilience of birds, and presumably a diverse subset of other animals, via trained innate immunity (including early NK cell-mediated abrogation) far more than their role as relevant carriers for infectious transmission back to humans.

Public health focus might be better directed at understanding and curtailing prolonged SC-2 infections in highly C-19-vaccinated human populations ─ thereby reducing unnecessary intra-host evolutionary opportunities ─ than at fearing migratory birds as a potential breeding ground for sustaining or escalating the immune-escape pandemic.

References

1. Cao J, Liu S, Su C, et al. Genomic and structural evidence of SARS-CoV-2 and MERS-CoV in migratory birds. Proc Natl Acad Sci U S A. 2026;123(27):e2400023123. doi:10.1073/pnas.2400023123

2. Suarez DL, Pantin-Jackwood MJ, Swayne DE, et al. Lack of susceptibility to SARS-CoV-2 and MERS-CoV in poultry. Emerg Infect Dis. 2020;26(12):2974-2976. doi:10.3201/eid2612.202989

3. Netea MG, Domínguez-Andrés J, Barreiro LB, et al. Defining trained immunity and its role in health and disease. Nat Rev Immunol. 2020;20(6):375-388. doi:10.1038/s41577-020-0285-6

):

1. How should public health respond, if at all, to SARS-CoV-2 variants disproportionately affecting children?

2. To what extent does immunity from COVID-19 protect against emerging coronaviruses, including MERS-CoV?

3. What is the zoonotic and pathogenic potential of animal coronaviruses such as PDCoV and SADS-CoV, and what countermeasures are needed?

4. Can we develop broadly active antiviral drugs against coronaviruses?

5. Can we develop broadly protective coronavirus vaccines? A major scientific challenge - not yet in sight, but an important goal.

6. More general and perhaps the most important question: how can societies fully recover from the impact of the pandemic?

I answered them in an unusually kind and moderated manner, which is probably not what most people have come to expect from me. Perhaps that will encourage Pöhlmann and others to take a closer look at my arguments and give them some serious thought. One can always hope. After all, hope springs eternal...

1. How should public health respond, if at all, to SARS-CoV-2 variants disproportionately affecting children?

Before recommending additional interventions, public health authorities should first establish whether children are genuinely more susceptible to a particular variant or whether they merely represent one of the few demographic groups that have largely escaped the immune conditioning experienced by highly C-19-vaccinated adult populations.

From my perspective, the current tendency to interpret higher infection rates in children as evidence of ‘child-adapted variants’ risks confusing cause and effect. I have already addressed this issue in a previous substack article (https://voiceforscienceandsolidarity.substack.com/p/ba322-and-the-imaginary-child-reservoir). Young children rely heavily on broadly reactive innate immune mechanisms and natural antibodies (Abs). They therefore occupy a different immunological landscape than adults repeatedly exposed to vaccine-induced and breakthrough infection-driven adaptive immune stimulation.

The key question is not whether a variant infects more children, but why.

If children are simply serving as a window into what a less immune-conditioned host response looks like nowadays, then vaccination strategies designed to mimic adult immune profiles may prove counterproductive rather than protective. In other words, public health should refrain from vaccinating children against SARS-CoV-2 (SC-2) infection. Time will show that unvaccinated children rapidly train their innate immune system to cope even with SC-2 variants that challenge their natural Abs (https://voiceforscienceandsolidarity.substack.com/p/ba322-and-the-imaginary-child-reservoir).

2. To what extent does immunity from COVID-19 protect against emerging coronaviruses, including MERS-CoV?

This depends entirely on what one means by ‘immunity’.

Ab-mediated cross-protection between highly divergent coronaviruses is generally limited. However, broader cell-mediated innate immune responses may provide varying degrees of heterologous protection.
My concern is that excessive focus on highly antigen (Ag)-specific immune responses will obscure the critical role played by such broadly reactive innate cell-mediated immune defenses. These are often the first and most important barriers against newly emerging pathogens.

The assumption that repeated exposure to SC-2 or repeated vaccination necessarily broadens protection against future coronaviruses remains largely unproven. Indeed, one of the central observations made during the still ongoing immune escape pandemic is that repeated immune focusing (i.e., ‘immune refocusing’) on a continuously evolving target actually reduces the flexibility of future responses rather than enhancing it.


3. What is the zoonotic and pathogenic potential of animal coronaviruses such as PDCoV[1] and SADS-CoV[2], and what countermeasures are needed?

The current zoonotic and pathogenic potential of animal coronaviruses such as PDCoV¹ and SADS-CoV² in humans appears to be very limited. However, the greatest mistake would be to assess these viruses solely through the lens of their current intrinsic characteristics or pathogenicity at the time of spillover.

History repeatedly demonstrates that the most important question is not how dangerous a virus is today, but how it may adapt and evolve after entering a susceptible host population.

The likelihood that a spillover virus establishes sustained productive infection and transmission in a new host species depends not only on its capacity to replicate and generate sufficient infectious pressure, but also on the nature and intensity of the immune selection pressure exerted by the newly infected population.
It is precisely this interaction between viral replication and host immunity that drives adaptation of the virus to its new host.

Countermeasures should therefore focus primarily on reducing opportunities for zoonotic emergence, particularly by limiting industrial high-density animal farming practices that facilitate viral amplification, recombination, and cross-species transmission. At the same time, efforts should aim at strengthening the overall innate immune resilience of susceptible populations, including the preservation of robust cell-based innate immunity.

By contrast, reactive large-scale vaccination of human populations deployed during widespread circulation of newly emerging variants of animal viruses should be avoided.

As vaccines fail to kill virus-infected host cells, they favor evolutionary opportunities for continued viral adaptation under immune pressure, thereby increasing the likelihood of immune escape and the emergence of variants better adapted to transmission within the vaccinated human population.

The lesson of SC-2 is not merely that viruses evolve.
It is that mass deployment of non-sterilizing vaccines during active exposure of a potentially susceptible human population to a multitude of newly generated variants may fundamentally alter the evolutionary interaction between the circulating virus and host immunity.
Under such circumstances, the virus and the adaptive immune system can enter a process of continuous mutual adaptation, creating sustained selective pressure that may ultimately favor viral phenotypes with enhanced transmissibility and virulence (a phenomenon I refer to as in vivo gain-of-function).

For this reason, preparedness strategies should focus not only on preventing spillover events, but also on refraining from population-level immune interventions that intensify and prolong the evolutionary trajectory of emerging immune escape variants.

4. Can we develop broadly active antiviral drugs against coronaviruses?

Probably yes.

Unlike vaccines that depend on recognition of specific Ags, antiviral drugs can target highly conserved aspects of viral replication.
Broadly active antivirals may therefore prove less vulnerable to immune escape-driven evolutionary dynamics.
However, large-scale antiviral deployment should be approached carefully. Any intervention capable of exerting strong selective pressure on viral populations can potentially drive adaptation if used improperly!
The challenge is to use antivirals in ways that suppress viral replication sufficiently while minimizing the risk of selecting resistant variants.

5. Can we develop broadly protective coronavirus vaccines?

This remains one of the greatest scientific challenges.
The difficulty is that coronaviruses possess extraordinary evolutionary flexibility, particularly under strong immune pressure.

From my perspective, the key question is not whether broadly protective vaccines can be developed but whether they can induce the type of immunity required to interrupt transmission without simultaneously generating selective pressures that promote further adaptation.
Currently, there are no vaccines that can broadly induce cytolytic immune responses, i.e., responses capable of eliminating virus-infected cells.

Any such non-sterilizing vaccine will merely promote large-scale viral immune escape when administered during a viral epidemic or pandemic.

Future vaccine strategies may need to place far greater emphasis on:

• Innate cell-mediated immunity and training thereof

• Immune interventions that are not Ag-specific, but rather ‘pathogenicity-specific’ (e.g., via NK cell-based immunization).

rather than relying predominantly on narrowly focused neutralizing Ab responses or MHC-restricted Tc responses.
At present, such a solution remains largely aspirational.

6. Perhaps the most important question: How can societies fully recover from the impact of the pandemic?

The C-19 pandemic can only end when viral transmission and concomitant evolution stop. From a scientific perspective, this would only be possible if only those survive who effectively contribute to the development of sterilizing herd immunity. That requires a combinatorial effect of innate and infection-primed adaptive immunity.

C-19 vaccine-primed immunity, even if subsequently boosted by natural infection, cannot contribute to protective herd immunity.

But true recovery will also require intellectual honesty. Even if SC-2 is ultimately eliminated from the human population, societies cannot fully recover if fundamental questions remain unexamined. Such ‘mental’ recovery does not require universal agreement; it requires open scientific debate, critical reassessment of assumptions, and a willingness to learn from mistakes.

In my view, one of the most damaging consequences of the pandemic has been the widespread belief that complex biological phenomena can be managed through simplistic narratives and linear thinking.

Whether one agrees with my analysis or not, the pandemic has demonstrated the dangers of scientific groupthink, disciplinary silos and suppression of dissenting perspectives.

In conclusion, ultimate recovery will therefore require both the elimination of SC-2 from the human population and the creation of a new culture that values scientific curiosity over scientific certainty, multidimensional analysis over reductionism, and open debate over consensus-driven dogma.
Only then can societies become truly resilient against the next global crisis─whatever form it may take.

[1],[2] PDCoV and SADS-CoV are porcine coronaviruses that infect pigs and cause severe diarrheal disease, especially in newborn piglets. PDCoV stands for porcine deltacoronavirus, and SADS-CoV stands for swine acute diarrhea syndrome coronavirus; both are recognized as emerging/reemerging swine enteric coronaviruses that can lead to dehydration and high piglet mortality.

This interpretation is deeply misleading.

The first problem is simple: finding more BA.3.2.2 sequences in children (see below) does not automatically mean that this variant is truly better adapted to children. Sequencing data are not the same as real-world infection rates. They depend on who gets tested, whose samples are selected for sequencing, where outbreaks are investigated and whether age information is properly recorded. So, even if BA.3.2.2 appears more often in samples from children, this does not prove that children are a special reservoir for this virus.

But even if BA.3.2.2 were temporarily more common in children, that still would not mean that the virus has become ‘child-adapted.’

A much more plausible explanation is that children simply have a different immune background from highly C-19-vaccinated adults. Most adults in highly C-19-vaccinated countries have been repeatedly exposed to the spike (S) protein through vaccination and vaccine-breakthrough infections. Their immune systems have therefore been strongly shaped by repeated exposure to SC-2 antigens. This has created a highly complex, vaccine-imprinted immune landscape. The virus is now trying to escape from this population-level immune pressure, but it is becoming increasingly constrained.
BA.3.2-derived sublineages illustrate this very well. As previously discussed in several of my more recent substack articles, the virus can still add new mutations in the S protein but each additional mutation seems to provide only a smaller and more conditional advantage.

In other words, the virus can still move, but it has less and less room to move. Its evolutionary options are becoming narrower.

This is why BA.3.2.2 should not be seen as evidence of a new child-specific viral strategy. It is more likely a sign that SC-2 is running into the limits of classical S-based immune escape in highly C-19-vaccinated populations.

The authors argue that children, especially those without strong exposure to the original Wuhan-like virus or original C-19 vaccines, may provide a special immunological niche for BA.3.2.2. But this turns the situation upside down.
Children are not just small adults. Their immune systems work differently. Young children rely more strongly on broad, fast-reacting innate humoral and cellular immune effectors. These effectors are not narrowly directed against one specific S variant. They can be trained rapidly through natural exposure to circulating respiratory viruses, including SC-2.

The authors also note that a similar age pattern was not seen when the virus moved from XBB-lineage variants to BA.2.86/JN.1, even though BA.2.86/JN.1 was also antigenically distinct and escaped many antibodies (Abs). They argue that this means simple immune naivety cannot fully explain why BA.3.2.2 appears more often in children. That point deserves an answer.

In my view, the XBB-to-BA.2.86/JN.1 transition was mainly about escape from strong, broadly neutralizing Abs. BA.3.2.2 seems different. It may represent a more limited and stepwise form of S adaptation. By accumulating enough S mutations, BA.3.2.2 may escape not only Omicron-refocused Abs in weakly imprinted people, but also partly alter conserved RBD regions that are normally recognized by broad, naturally occurring IgM Abs in young children. These IgM Abs are part of the child’s early, innate-like defense against infection.

If that is correct, children could be temporarily more susceptible to BA.3.2.2 than to BA.2.86/JN.1. But this would still not mean that BA.3.2.2 is truly adapted to children or that children will become a lasting reservoir.
It would only mean that the virus has found a short-lived opening in a broad innate-Ab barrier. That opening should close rapidly as children’s innate immune responses are trained by exposure, turning children from a temporarily permissive group into an increasingly resistant barrier to sustained BA.3.2.2 transmission.

This is important. A child who is immunologically naïve and more susceptible today can quickly and efficiently train its innate immune system as it gets exposed to circulating SC-2 variants. As this happens, the pool of truly susceptible children shrinks. Instead of becoming a permanent reservoir for BA.3.2.2, children are likely to become increasingly resistant to this and other co-circulating variants.

We saw a similar mistake during the MIS-C (Multisystem Inflammatory Syndrome in Children). At the time, some interpreted the increased disease burden in children as evidence of a special pediatric problem that required mass C-19 vaccination of children!
But the pattern faded. A more plausible explanation is that children’s immune systems matured and became broadly trained through exposure. But not a single one of the so-called experts or public health authorities admitted that they had completely missed the ball in persuading parents to let their young children get vaccinated!
It is reasonable to assume that a similar logic applies here. A temporary increase of BA.3.2.2 in children does not prove sustained child-driven transmission! It simply reflects a temporary gap in immune experience. That gap will close naturally as children get repeatedly exposed and develop broad natural immune protection.

The authors’ suggestion that children should be vaccinated with updated C-19 vaccines therefore misses the point.

If the current problem is the result of a C-19-vaccine-imprinted immune landscape in adults, then imposing a similar vaccine imprint on children is not a solution. It may simply drag children into the same immunological trap.

Young, unvaccinated children may still be able to develop broad, naturally trained protection against SC-2. This protection is not based on repeatedly chasing the latest S variant with updated C-19 vaccines. It is based on the rapid training of innate immune defenses, which reduce infection, viral replication, and transmission.
This is why children will not serve as a persistent reservoir for BA.3.2.2. This is also why BA.3.2.2 is not going to maintain itself indefinitely by spreading through children.
The more likely outcome is that children will become increasingly resistant, thereby adding further non-selective immune pressure on the virus.

This additional pressure may have an important consequence, though. It may not simply push the virus toward yet another small step in S-based immune escape. Instead, it may push the virus toward a more dramatic evolutionary transition.

In my view, SC-2 is now approaching the limits of ordinary antigenic drift. The virus may therefore be forced to find a different route to increase its fitness. I strongly believe that this route will involve changes that are not primarily directed at escaping specific Ab epitopes but at enhancing systemic infection through other mechanisms, such as altered glycosylation patterns or glycan-dependent interactions. This is the type of transition I have described in relation to Hi-Vi-Cron.

In that scenario, the real danger is not that children will become a permanent reservoir for BA.3.2.2. The real danger is that the virus, under growing immune pressure from C-19 vaccinated adults and increasingly resistant children, may be pushed toward a major phase transition.

That is why the current pediatric BA.3.2.2 narrative is so misleading. It takes a sequencing signal and turns it into a vaccine argument. It suggests that children are the problem, when in reality the problem is the population-level immune landscape created by the mass C-19 vaccination experiment.

BA.3.2.2 is, therefore, not a warning that children need another C-19 vaccine. It is a warning that SC-2 is running out of productive S-based escape options in highly C-19-vaccinated populations. Children are not the reservoir. Children are more likely to become the barrier.
And that is exactly why the proposal to vaccinate them against this supposed pediatric threat is not only unnecessary but immunologically insane.

The authors of this recent paper on BA.3.2.2 propose that the apparent enrichment of this highly mutated sublineage in pediatric populations could provide an immunological niche in which the virus may continue to propagate, potentially catalyzing the emergence of secondary variants capable of breaching the imprinted immunity of highly COVID-19 (C-19)-vaccinated adult populations. They therefore suggest that future pediatric SC-2 vaccination strategies should consider variant-matched antigens that combine ‘variant-matched specificity’ with ‘legacy-like breadth.’

This conclusion is not only the purest nonsense from a scientific standpoint; it rests on a fundamental misinterpretation of what the current BA.3.2.2 signal most likely represents.

The increased representation of BA.3.2.2 sequences in younger age groups may indeed be visible in some age-annotated sequencing datasets (see below). However, this should not be confused with robust evidence that BA.3.2.2 is infecting children more efficiently at the population level, let alone that it has become evolutionarily adapted to children as a distinct biological niche.
Sequencing data are inherently conditioned by who gets tested, whose samples are selected for sequencing, how outbreaks are investigated, and how complete the age metadata are. A pediatric enrichment signal in sequence datasets is therefore not equivalent to proof of sustained pediatric transmission.

Even if BA.3.2.2 were genuinely overrepresented among samples from young children, this would still not imply that children serve as a persistent reservoir for BA.3.2-derived sublineages.
It would at most indicate that this lineage is exploiting a transient, immune-history-dependent vulnerability in a demographic group whose immune landscape differs from that of highly C-19-vaccinated adults.

The real issue is not pediatric susceptibility. The real issue is the remarkable contribution of BA.3.2.2 to the current SC-2 landscape as a direct consequence of the increasingly constrained nature of spike (S)-based immune escape from suboptimal population-level immunity following the mass C-19 vaccination campaign.

BA.3.2-derived sublineages illustrate how the evolutionary bandwidth of SC-2 in highly C-19-vaccinated populations is becoming increasingly constrained. As previously discussed in several of my more recent substack articles, the virus continues to accumulate immune-escape mutations within the S protein, while each additional mutation appears to yield only diminishing returns in terms of transmissibility.

In other words, a lineage can still move antigenically, but the accessible beneficial moves become progressively narrower, more conditional, and more host-history-dependent.

This interpretation is fully compatible with the authors’ observation that BA.3.2.2 shows an unusual relationship with immune imprinting and antibody (Ab)-repertoire composition. They argue that BA.3.2.2 preferentially escapes Omicron-specific Class 1/4 Abs enriched in weakly ancestral-imprinted individuals, while remaining sensitive to Wuhan-cross-reactive IGHV3-53/66-encoded Class 1 Abs enriched in strongly imprinted individuals. But this does not prove that BA.3.2.2 is child-adapted. It merely shows that the lineage may exploit a particular Ab-repertoire configuration.

The authors point out that a comparable age skew was not observed during the major antigenic transition from XBB-lineage viruses to BA.2.86/JN.1, despite the broad humoral immune escape and antigenic distinctiveness of the latter lineage. In their view, this contrast argues against immunological naivety alone as the primary driver of BA.3.2.2 enrichment in children. It is therefore important to consider that the XBB-to-BA.2.86/JN.1 transition was largely driven by escape from broadly neutralizing Ab activity, whereas BA.3.2.2 reflects a more constrained and conditional form of S adaptation. Through incremental, threshold-reaching accumulation of S mutations, BA.3.2.2 may not only escape Omicron-refocused Class 1/4 Abs in weakly ancestral-imprinted hosts, but may also partially remodel conserved infection-inhibiting RBD epitopes normally targeted by broadly reactive, naturally occurring IgM Abs in young children.

If so, this could explain why children may be transiently more susceptible to BA.3.2.2 than to BA.2.86/JN.1. However, such susceptibility would not imply genuine pediatric adaptation or durable child-driven transmission.

Rather, it would reflect a temporary breach of a broadly reactive innate-Ab barrier and a conditional, immune-history-dependent advantage in hosts whose Ab repertoire is dominated by broadly RBD-binding, cross-reactive but weakly neutralizing Omicron-refocused specificities. However, this window would be expected to close rapidly as innate immune training intensifies in the pediatric cohort, thereby turning children from a temporarily permissive segment into an increasingly resistant barrier to sustained BA.3.2.2 transmission.

This is because children are not to be considered miniature adults! Their immune protection against SC-2 is not primarily shaped by the same vaccine-imprinted, repeatedly recalled, antigen-specific adaptive immune pathways that dominate in highly C-19-vaccinated adult populations.

Young children rely far more heavily on broadly reactive innate immune mechanisms and natural Abs. Upon repeated exposure to highly transmissible SC-2 variants, these innate immune mechanisms, including their cell-mediated innate immune responses, can be rapidly and efficiently trained.

This is precisely why the idea of children serving as a persistent reservoir for BA.3.2.2 is immunologically implausible.

A temporarily more susceptible pediatric segment will quickly and efficiently develop sterilizing immunity. In the presence of circulating virus, young children are repeatedly exposed to circulating SC-2 variants and this progressively trains broadly protective innate immune responses. As this process unfolds, the pool of truly susceptible pediatric hosts rapidly contracts rather than expands.

This is not the first time that a temporary pediatric signal has been misread as evidence of a unique pediatric disease or transmission niche. We saw similar reasoning during the MIS-C (Multisystem Inflammatory Syndrome in Children) episode, when increased disease burden in children was widely interpreted as evidence of a distinct child-specific pathogenic phenomenon. Yet those patterns waned without requiring mass pediatric C-19 vaccination. The more plausible explanation was maturation and training of broadly protective immune responses in successive pediatric cohorts. But not a single one of the so-called experts or public health authorities admitted that they had completely missed the ball in persuading parents to let their young children get vaccinated!

It is reasonable to assume that a similar logic applies here.

Temporarily enhanced prevalence of BA.3.2.2 in younger age groups does not establish children as a reservoir. It more likely reflects the fact that young children occupy a different immunological landscape from highly C-19-vaccinated adults.
This reverses the authors’ interpretation: the problem does not lie with the pediatric population. The problem lies with the mass C-19 vaccination experiment, which generated the suboptimal, vaccine-imprinted population-level immune landscape now shaping SC-2 evolution.

The authors’ proposal to vaccinate children with C-19 vaccines that combine variant-matched specificity with legacy-like breadth therefore completely misses the point.

Such a strategy would not solve the problem; it would risk dragging children into the same vaccine-imprinted immune landscape that is already driving constrained S-based immune escape in adults.

Young, unvaccinated children are precisely the population segment in which broadly reactive innate immune training can still occur rapidly and efficiently. This process can provide protection against highly mutated sublineages such as BA.3.2.2 and may even generate sterilizing immunity in the pediatric cohort.

Instead of acting as a durable reservoir for BA.3.2.2, children are therefore more likely to become an increasingly resistant barrier to sustained transmission.

This is why the narrative of sustained BA.3.2.2 transmission in pediatric populations ─ allegedly catalyzing the emergence of secondary variants that combine pediatric-evading features with adult-evading mutations and thereby allow the lineage to breach adult imprinted immunity ─ will likely prove to be yet another myth.
The more plausible scenario is the opposite:

As pediatric populations develop sterilizing immunity through rapid innate immune training, they will exert additional, non-selective immune pressure on viral transmissibility.

This pressure will no longer primarily favor incremental antigenic escape within S. Rather, it may help pave the way toward a major viral phase transition.

In my framework, that transition would, therefore, not be mediated by yet another round of classical epitope-specific immune escape. It would be mediated by non-antigen-specific, infection-enhancing changes, including mutations affecting glycosylation patterns or glycan-dependent interactions. These are the kinds of changes I have postulated for Hi-Vi-Cron: a coronavirus phenotype capable of subverting suboptimal adaptive immunity in highly C-19-vaccinated populations and thereby breaching the massive vaccine-imprinted immune barrier.

In conclusion, BA.3.2.2 does not reveal a truly child-adapted phenotype. It exposes a repertoire-dependent vulnerability in weakly ancestral-imprinted hosts. The pediatric enrichment signal should not be mistaken for evidence of a durable child reservoir, nor should it be abused to justify yet another pediatric C-19 vaccination campaign!

The authors’ conclusion turns cause and effect upside down. Children are not the problem. The immunological landscape created by the insane mass C-19 vaccination experiment is the problem.
BA.3.2.2 is not a warning that children must be vaccinated. It is a warning that SC-2 is running out of productive S-based escape options within a highly C-19-vaccine-imprinted population, and that the next evolutionary step may no longer look like ordinary antigenic drift…

https://www.voiceforscienceandsolidarity.org/

Feel free to check it regularly.

I’ll be traveling to Hungary over the next 10–12 days, so I won’t be publishing any new Substack articles before mid-end June. That said, I’ll still share my views on X when I come across comments or opinions I disagree with. And of course, I will stay tuned until the very end of this immune escape pandemic. With regard to the predicted ‘phase transition’, though, I probably won’t need to write a Substack article as I can hardly imagine that it’ll go unnoticed by anyone.

Wishing you all a great summer.

Warmly,
Geert

The Covid-19 pandemic no longer dominates the headlines.
The war in Ukraine has become ‘routine’ and escalation in the Middle East repeatedly seems to stop just short of catastrophe.
Artificial intelligence continues to expand at breathtaking speed while mankind still behaves as though it remains largely under control.

Yet beneath this apparent stability lies something profoundly unsettling.

All these situations share a remarkably similar structural pattern: two highly adaptive entities are locked into a chronic struggle in which neither side is yet capable of fully controlling the other.

This is the hallmark of a metastable system.

Such systems often appear stable precisely because opposing forces temporarily balance one another. But this balance is deceptive. In reality, the system remains fundamentally unstable because both parties continue adapting in ways that progressively increase internal tension while yielding diminishing functional returns.

This is exactly what I have repeatedly described as currently happening in the ongoing immune escape pandemic.


The Immune Escape Pandemic as a Metastable System

Our public health authorities and so-called ‘health experts’ frequently interpret the current evolutionary landscape of SARS-CoV-2 (SC-2) as reassuring. Their simplistic interpretation is based on the following observations:

• fewer severe acute cases, fewer hospitalizations, fewer acute deaths;

• lower wastewater viral loads;

• absence of explosive global waves;

• co-circulation of multiple SC-2 variants without a clearly dominant strain.

These ignorant folks interpret this as evidence that the virus is gradually settling into stable endemicity and becoming seasonal, pretty much like the flu virus!

But what if the opposite is true? What if the apparent calm reflects not true equilibrium but rather a metastable balance generated by chronic adaptation between two competing systems: co-circulating viral variants on the one hand and suboptimal population-level immunity on the other?

In highly C-19-vaccinated regions, the virus continues to evolve under intense immune pressure while the immune system continuously adapts to the virus’s changing phenotype. Each side attempts to escape the control imposed by the other. The result is an evolutionary arms race. At first, this race generates a substantial gain-of-function for both parties: newly selected immune escape variants acquire a substantial fitness advantage and rapidly begin to dominate in prevalence, whereas immune refocusing enables the host population to profoundly reshape its adaptive immune response.

But over time, both systems begin operating within an increasingly constrained adaptive space. The virus continues accumulating mutations, particularly in Spike, yet additional mutations increasingly yield only marginal improvements in transmissibility or immune escape. Simultaneously, the immune system remains chronically activated and repeatedly re-stimulated by breakthrough infections, thereby becoming subject to immune dysregulation while progressively losing efficiency in coordinated viral clearance.

This creates the illusion of stability in highly C-19-vaccinated populations. But metastable systems are not truly stable. They persist only because the opposing adaptive forces remain temporarily balanced.


The Dangerous Illusion of Control

This is precisely why the current epidemiological calm may be so misleading and dangerous. The virus appears partially constrained while the immune system appears only partially protective. Neither side fully wins. Neither side fully loses.

But precisely because neither side gains decisive control, the system itself continuously accumulates tension while attempting to maintain functional adaptability.

Importantly, our incompetent public health authorities and ditto experts make people mistake metastability of the SC-2 landscape in highly C-19-vaccinated populations for endemicity and seasonality! They pretend that recurrent SC-2 infections in these populations are the ‘new normal’ and that society will simply have to live with this new epidemiological situation.

Of course, insane interpretations lead to insane recommendations, the most baffling of which is that age groups with the highest Covid-related death rates should take updated boosters on an annual basis! However, the truth of the matter is that the virus is not under control and that evolution under constraint does not proceed indefinitely through endless fine-tuning. This is not biologically plausible. Once incremental adaptive pathways begin yielding diminishing returns, systems tend to reorganize, sometimes suddenly and dramatically. At some point, even a relatively small negative impact on viral transmissibility may no longer trigger a proportional counterbalance, but instead could suffice to provoke a dramatic phase transition that completely transforms the viral landscape.

In this chronic immune escape pandemic, the ultimate nonlinear adaptive jump is obvious: a new coronavirus, most likely endowed with targeted functionally relevant glycan-site changes on Spike that trigger enhanced viral virulence in large cohorts of vaccine-primed individuals (aka Hi-Vi-Cron).

Escalation of chronic pathogen immune escape into hyperacute disease is not an exception to evolutionary principles. It is a consequence of them. The messages and interpretations spread by public health authorities and so-called ‘health experts’ are therefore highly misleading and profoundly dangerous, as their misinformation will inevitably cause society in highly C-19-vaccinated populations to be caught off guard.


The Same Pattern Exists in Modern Warfare

The ongoing wars in Ukraine and the Middle East strikingly illustrate similar metastable dynamics.

Russia and Ukraine continuously adapt to one another:

• new drones;

• new countermeasures;

• new missile systems;

• new defensive strategies;

• new allies, etc.

Likewise, Iran on the one hand, and the United States joined by Israel on the other, continuously respond to each escalation with carefully calibrated counter-escalation.

At first glance, these conflicts appear ‘under control’ because:

• front lines stabilize;

• peace talks and cease-fire pauses mitigate the acuteness of the conflict;

• neither side fully collapses;

• escalation remains temporarily contained.

Given their global impact, the world therefore begins to regard these wars as a new type of geopolitical management strategy. However, in reality, the system believed to represent the ‘new normal’ continuously accumulates tension. This is because the opposing adaptive military strategies increasingly generate diminishing strategic gains, growing complexity and escalating systemic fragility.

Such balance cannot persist indefinitely. At some point, even a relatively small impact on the adaptability of either enemy may no longer trigger a proportional counterbalance and may already suffice to provoke a dramatic phase transition that completely transforms the battlefield. In modern warfare, the ultimate nonlinear adaptive jump is obvious: nuclear escalation.


AI Represents Another Metastable Arms Race

The same logic increasingly applies to humanity’s relationship with artificial intelligence.

Humanity continuously develops:

• safeguards;

• regulations;

• ethical frameworks;

• alignment strategies.

Meanwhile, AI systems continuously improve in:

• autonomous reasoning;

• self-learning;

• optimization capacity;

• operational independence.

Again, the system currently appears ‘manageable’ because opposing adaptive mechanisms remain temporarily balanced. Given its global foothold, this pseudo-stable equilibrium will soon be considered by many as part of our new ‘normal’ private and professional lifestyle.

However, in this case, the party with the greatest adaptive capacity is obvious. There can be little doubt that mankind’s control may become increasingly fragile as AI approaches autonomous functionality beyond direct human dependence or control.

We all acknowledge that small incremental progress could suddenly trigger AI’s full autonomy,
Incremental adaptation may therefore suddenly give way to a qualitative transition, causing countless individuals to feel completely worthless.

Nature Repeatedly Warns Us About Metastability

Nature provides countless examples of metastable systems accumulating hidden stress before abrupt collapse.

The snow cornice

A snow cornice can hang motionless above a mountain slope for months while internal instability silently increases. Eventually, one additional snowflake, or even some minor vibration, may trigger a catastrophic avalanche.

Tectonic plates

Tectonic plates may remain quiet for decades while pressure continuously accumulates beneath the surface. Then a seemingly minor perturbation suddenly crosses the threshold of what those plates can absorb or compensate for and triggers a massive earthquake.

Material fatigue

Materials exposed to repeated subcritical stress develop microscopic damage that accumulates over time until the structure abruptly fails despite no obvious external warning.

In all these examples:

• the final trigger is not the true cause; it is the proverbial last straw ─ or worse, the final crack that makes the dam give way under the pressure;

• apparent stability is deceptive;

• chronic stress accumulation precedes sudden nonlinear transition to an entirely new configuration.

Why Sudden Transition Becomes Increasingly Likely

The key principle is simple: systems locked in chronic adaptive struggle cannot indefinitely maintain stability through marginal gains. Eventually, adaptive pathways narrow while compensatory mechanisms lose efficiency. This drastically increases the probability that one side undergoes more radical reorganization.

When the stressed system causes metastability at a global level, the impact of the ultimate phase transition will equally be huge and widespread.

In the case of SC-2, the virus almost certainly possesses greater adaptive capacity than the host population because:

i) viral evolution operates exponentially faster;
ii) enormous replication numbers generate continuous experimentation with mutations or recombinations;
iii) structural remodeling may still permit dramatic functional versatility in terms of phenotypic shifts.

I have repeatedly argued that this could eventually involve profound changes in Spike glycosylation or other mechanisms enabling the virus to escape current evolutionary constraints.
People continue to challenge me on the timeline and sometimes even question my credibility because the long-predicted Hi-Vi-Cron has not yet emerged.
However, given that functionally relevant glycan-site changes on Spike are generally rarer than ordinary amino acid substitutions, that viral evolutionary dynamics are slowing down as a result of the marginal gains yielded by additional mutations, and that viral load is becoming more diluted as a result of the increasing prevalence of chronic or prolonged SC-2 infection resulting in more protracted viral shedding, it is not surprising that Hi-Vi-Cron has not yet emerged.

However, we have no way whatsoever of estimating when Hi-Vi-Cron might appear. So to speak, it could be tomorrow, but it could just as well take several more months. In my humble opinion, however, the chance that its appearance will still take many additional months is very small.

In warfare, nuclear weapons represent the nonlinear adaptive leap. We do not know how long it could possibly take before any of the parties involved uses them. It will all depend on how long the chronicity caused by a diversified spectrum of non-nuclear warfare tools and strategies remains sustainable for one or the other enemy.

In AI, autonomous self-directed functionality may represent the nonlinear leap.

Realistically speaking, it is difficult to ignore that all three systems contribute to their own destabilization while chronically evolving as they try to maintain function. Hence, escalation at some point seems highly likely. However, it is impossible to predict which one will be the first to collapse.

The Most Disturbing Realization

What increasingly obsesses me is that all three systems may ultimately produce catastrophic outcomes, not because they were initially uncontrolled but because they remained metastably balanced for too long while continuously accumulating adaptive tension.

Chronic adaptive competition between highly flexible systems that are no longer capable of fully controlling one another may ultimately be the defining characteristic of the next global crisis threatening mankind.

The apparent calm should therefore not reassure us, especially not because metastable systems often appear most stable shortly before they undergo irreversible transition.

However, unlike the selective losses that would be caused by Hi-Vi-Cron, the human losses resulting from nuclear escalation or AI-driven societal collapse and psychological despair would likely be largely random and non-selective.

This is therefore the perfect moment to revisit a purely scientific report that I wrote more than ten years ago, which clearly demonstrates how the incompetent WHO, supported by the equally incompetent Lancet, committed a blunder of historic proportions by vaccinating people during the incubation period according to the so-called ring-vaccination principle.

The catastrophic consequences of this were barely brought to light at the time ─ even though my report reached all relevant global health and regulatory authorities. Instead, the WHO even boasted that the vaccine was 100% effective!
It was a scandal unlike anything I had ever witnessed in my career ─ until it was repeated about seven years later in the context of COVID-19 vaccination, only on a far larger scale!

Despite my repeated requests as Gavi’s Ebola program manager, the WHO pertinently refused ─ under the pretext that those data were confidential (!) ─ to disclose the total number of Ebola-caused deaths, from day one of vaccination onward, in the vaccinated group versus the control group in that pivotal clinical trial.

Anyone who reads this purely scientific account can only conclude that this organization should be dismantled as quickly as possible.

https://www.voiceforscienceandsolidarity.org/scientific-blog/guinea-the-ebola-vaccine-trial-and-the-reported-interim-results

One of the most common manifestations of this problem is the use of scientific concepts whose definitions have gradually drifted away from their original meaning. Once this happens, those concepts become intellectually hollow. They continue to be used with confidence, but no longer describe the phenomenon they were initially meant to define.

The ongoing COVID-19 (C-19) immune escape pandemic offers several striking examples of this problem. Two of the most mind-blowing are the concepts of herd immunity and gain-of- function.


When Herd Immunity Stops Meaning Herd Immunity

Today, even many experts use the term herd immunity to describe virtually any form of adaptive immunity that exists at the population level, whether generated by natural infection, vaccination, or so-called hybrid immunity.

This interpretation is scientifically convenient. But it is conceptually wrong.

Originally, herd immunity referred to a very specific biological phenomenon: the type of population-level protection that naturally emerges during the course of a pandemic caused by an acute (self-limiting) viral infection. Such protection is not merely the sum of antibody (Ab) titers or adaptive immune memory scattered across individuals. It is the result of a coordinated interaction and synergy between innate and adaptive immunity across the exposed population.

This is why this distinction matters enormously:

During natural infection, innate immunity acts as the first line of immune defense and eliminates the bulk of viral load before adaptive immune responses fully mature.
Adaptive immunity then consolidates this protection and can be rapidly recalled upon re-exposure. The resulting immune profile is broad, functionally integrated, and capable of suppressing both infection and onward transmission at the population level, without promoting immune escape! That is true herd immunity. It is the only type of population-level immunity that truly protects against viral infection and transmission. It is, therefore, the only type of population-level immunity that is capable of ending a pandemic of an acute viral infection.

By contrast, a population repeatedly exposed to narrowly focused antigen-specific immune stimulation by continuous circulation of newly emerging viral variants, develops extensive adaptive immune reactivity without ever achieving sterilizing protection or durable interruption of transmission.

In such a situation, the population may appear immunologically ‘experienced,’ yet remain incapable of suppressing viral circulation and immune escape. This is precisely what we have observed in highly C-19-vaccinated populations. It is THE paradox many ‘experts’ fail to grasp.


The Dangerous Confusion Between Immune Activation and Protection

One of the most persistent misunderstandings throughout this pandemic has been the assumption that the mere presence of an immune response automatically equates to protection. Of course, it does not.
An immune system can be highly active and yet poorly aligned with the evolving viral phenotype. Under continuous immune escape pressure, adaptive responses increasingly chase a moving target. The result is not efficient viral clearance, but rather perpetual immune stimulation combined with incomplete control of infection and transmission.

This distinction is exactly what I have been trying to draw the WHO’s attention to ever since it gave the green light to a mass vaccination program against SARS-CoV-2 (SC-2), as it lies at the heart of what I have repeatedly described as the immune escape pandemic.

Breakthrough infections, especially vaccine-breakthrough infections in highly C-19-vaccinated populations, do not merely represent isolated failures of protection. At the population level, they contribute to the repeated reactivation of increasingly misdirected immune responses while simultaneously compromising efficient viral clearance. Such misdirected host immune responses could eventually drive a very dangerous form of viral gain-of-function, as will be explained below.

I remain stunned that mainstream analyses never connect vaccine-breakthrough infections and the resulting misdirected, suboptimal immune responses with a key trigger of large-scale viral gain-of-function and its potentially detrimental consequences.



The Misunderstood Concept of ‘Gain-of-Function’

What scientists and regulators refer to as gain-of-function research is, indeed, another example of conceptual scientific confusion.
Followers recently sent me an article by Jon Fleetwood[2] discussing research funded by the NIH and published by Yao Ma et al. in Applied and Environmental Microbiology[3]. The article frames the work as ‘gain-of-function’ research and raises concerns regarding its implications.

Whether certain forms of genetic viral manipulation should or should not be allowed is ultimately not my role to decide. That responsibility belongs to regulators and oversight bodies, who should define the boundaries transparently and justify them scientifically.
But the debate itself illustrates a much deeper problem: experts frequently fail to place complex biological concepts within their relevant context.

‘Gain-of-function’ is often treated as though it were an intrinsic property of the virus itself–as if a particular genetic modification always automatically, inevitably and universally translates into increased danger. That is a simplistic and misleading interpretation. Whether viral ‘gain-of-function’ observed in vitro should be considered dangerous or harmful is not necessarily determined merely by the genetic modification itself. It largely depends on how that modification is received by the susceptible host or by the susceptible host population when assessing potential individual or public-health harm, respectively.

A viral phenotype cannot be evaluated independently of the host environment in which it operates.

Whether a viral modification confers a meaningful advantage depends fundamentally on:

• the immune status of the host,

• the immunological landscape of the host population,

• or the selective pressures acting on viral transmission and replication.

What follows is what I explained in response to these followers who asked me to comment on the scope of the research in question:

“On the allegedly ‘positive’ side, the publication of Yao Ma et al. relates to an individual prophylactic approach. Such an approach is, of course, largely irrelevant in the context of epidemics or pandemics.

On the allegedly ‘negative’ side, the experimental data reported by Yao Ma et al. relates to a specific environment in which viral survival is threatened by a particular type of epitope-specific neutralizing Ab. Such an environment is, of course, not representative of viral behavior within a given susceptible host or across a susceptible host population.

Conclusion: ‘Gain-of-function’ reflects a viral phenotype or behavior. Because viral replication and transmission inevitably depend, to a large extent, on the immune status of the individual host and the host population, respectively, the impact of any phenotypic change in the virus will likewise depend on the host-specific or population-level immune context.

In other words, in vitro ‘gain-of-function’ observed in a very specific, artificially generated immune environment does not automatically translate into ‘gain-of-function’ across the virus’ host population.

This is particularly relevant for resistance to neutralizing Abs targeting specific epitopes. It is not because a such Ab-resistant variant may be artificially selected under narrowly defined experimental conditions that it will automatically acquire a competitive advantage when introduced into a living mammalian species or host population that does not impose the same selective immune pressure.
In fact, very much the opposite is true.
This is because the host immune response to coronaviruses not only comprises a far more diversified adaptive immune response, but also relies heavily on innate immunity as the first line of immune defense.”


Why In Vitro ‘Gain-of-Function’ Does Not Automatically Translate Into Population-Level Advantage

One of the most overlooked realities in virology is that viral fitness is context dependent.

A variant that demonstrates:

• increased replication in cell culture,

• escape from a monoclonal neutralizing Ab,

• or resistance to narrowly focused immune pressure,

does not automatically become more successful in a real-world host population.

Why?

Because the virus does not interact with isolated Abs in nature. It interacts with:

• innate immunity,

• mucosal immunity,

• heterogeneous adaptive immune responses, which are Ab- and/ or cell-mediated

A mutation that appears advantageous under highly artificial laboratory conditions may therefore confer little or no advantage within a naturally infected population.

This distinction is critical.

The current C-19 immune escape pandemic has repeatedly demonstrated that viral success is not simply determined by molecular escape from specific neutralizing Abs, but by the virus’ ability to navigate the far more complex immune ecosystem of highly C-19-vaccinated populations.
There is one specific scenario, though, in which a single change in, or near, a viral epitope located within a protein responsible for viral infectiousness may trigger a dangerous form of gain-of-function in vivo. This may occur when a variant carrying such a change encounters an immunologically naïve or immunologically weakened individual, or when it infects an immunologically experienced individual at a very high infectious dose.
Under these conditions, such a mutation may enhance or enable the virus’s intrinsic infectiousness and thereby increase its virulence. This is well illustrated by influenza viruses, where point mutations in the hemagglutinin (HA) protein can alter receptor binding, tissue tropism, host range, or proteolytic activation of the virus. For example, mutations in the HA receptor-binding site, such as Q226L and G228S in certain influenza subtypes, are known to shift receptor preference from avian-type α2,3-linked sialic acid receptors toward human-type α2,6-linked sialic acid receptors, thereby facilitating dangerous adaptation to the human upper respiratory tract.
Similarly, acquisition or modification of a polybasic cleavage site in the HA protein of H5 or H7 avian influenza viruses can broaden HA cleavage by ubiquitous host proteases, allowing more systemic viral spread and contributing to high pathogenicity.
A broadly analogous example is the furin cleavage site at the S1/S2 junction of the SC-2 spike (S) protein. This site enables pre-activation of S by furin-like host proteases and can enhance cell entry, cell–cell fusion, tissue tropism, transmissibility and pathogenicity relative to closely related sarbecoviruses lacking such a site. However, as already mentioned, its impact on viral virulence is context-dependent and largely dependent on the innate and adaptive immune status of the exposed individual.

When ‘Gain-of-Function’ Becomes a Population-Level Phenomenon

A critically important nuance must be added to the discussion on gain-of-function. In the previous paragraph, I emphasized that in vitro gain-of-function experiments, such as the artificial selection of variants capable of escaping neutralization by a specific epitope-targeting Ab, should not automatically be interpreted as evidence that the selected variant will acquire a meaningful competitive advantage in a real-world host population. Such experimental systems impose highly artificial and narrowly defined immune pressures that rarely reflect the enormously complex immune landscape encountered in vivo.

However, this does not imply that dangerous gain-of-function cannot occur in vivo. It could even occur at the level of an entire population!

This is where my theory comes in as it argues that mass vaccination during an ongoing pandemic of an acute (self-limiting) viral infection can generate an unprecedented and powerful form of collective immune pressure capable of driving viral evolution toward genuinely dangerous, i.e., harmful, gain-of-function for the highly C-19-vaccinated population.

The difference lies in the scale and nature of the selective pressure involved.

The in vitro experiment criticized by Jon Fleetwood in his Substack article exposes the virus, under artificial laboratory conditions, to a neutralizing Ab, which is directed against a highly specific, narrowly defined epitope.

By contrast, mass vaccination during widespread viral circulation exposes the virus to:

• synchronized in vivo immune pressure exerted by an entire, highly C-19-vaccinated population,

• refocused S-targeting adaptive immune responses, repeatedly induced by large-scale vaccine-breakthrough infections

This results into continuous selection for variants capable of maintaining transmissibility despite widespread immune recognition. This creates a fundamentally different and very complex evolutionary environment.

Under such conditions, the virus is no longer merely selected for resistance to a single Ab or epitope. It is selected for its ability to preserve inter-host transmission under hostile, but increasingly constrained immunological conditions in highly C-19-vaccinated populations.

In my view, this is exactly what drives the prolongation of this immune escape pandemic.
Importantly, this type of collective immune pressure does not simply select for continuous viral immune escape in the classical sense. It progressively narrows the spectrum of viable evolutionary options available to the virus. Incremental mutations capable of preserving transmissibility while escaping immune recognition become increasingly difficult to achieve without compromising intrinsic viral fitness.

The virus continues to evolve, but increasingly within a constrained evolutionary corridor in which extensive S remodelling yields diminishing returns. Yet precisely because this selective pressure operates continuously and on a massive scale, the evolutionary system remains unstable, even though simplistic parameters–such as wastewater viral load, BA.3.2’s failure to rapidly dominate the viral landscape or relatively low mortality rates–may suggest otherwise. This is why I call the current epidemiological situation of SC-2 metastable.

The longer this process continues, the greater the likelihood that the virus eventually acquires a more radical phenotypic solution capable of overcoming the existing constraints.

In that sense, the truly dangerous manifestation of gain-of-function is not necessarily the one acquired in a laboratory under artificially engineered, narrowly defined conditions. It is the kind of in vivo gain-of-function that may emerge from prolonged, large-scale immune selection acting on viral transmission during an ongoing immune escape pandemic, as is still occurring in highly C-19-vaccinated regions.

This distinction is essential because it illustrates, once again, how the same concept–‘gain-of- function’–can become deeply misleading when detached from its broader immunological and population-level context.

The Reductionist Trap

This entire debate –once again– exposes a broader intellectual weakness that has plagued pandemic analysis from the beginning: the tendency to isolate single variables from the multidimensional system in which they operate (see my previous Substack article: ‘When Experts Disagree, Something Bigger Is Being Missed[4]’).

Scientists examine:

• mutations,

• viral immune escape,

• viral transmission curves,

• viral load in wastewater,

• vaccine efficacy,

• C-19 hospitalization and death rates,

as though these existed independently from the constantly evolving interaction between virus and host immunity.

But biological systems do not function in isolation.

The evolutionary behavior of a virus cannot be understood without simultaneously considering:

• the quality and level of host immunity,

• the type of immune pressure imposed at the population level,

• the distinction between innate and adaptive immune responses,

• and the feedback loops created by repeated (vaccine-)breakthrough infections.

Failure to integrate these dimensions inevitably produces distorted conclusions.


The Real Danger of Misunderstood Definitions

The greatest danger of poorly defined concepts is not merely semantic confusion.
It is that they generate policies and scientific narratives that fundamentally misinterpret the underlying phenomenon.

If herd immunity is incorrectly equated with any form of adaptive immune exposure, one may falsely conclude that the pandemic is naturally resolving.

If gain-of-function is reduced to isolated laboratory phenotypes without considering population-level immune dynamics, one may radically overestimate or underestimate real-world risk.

And if immune activation continues to be confused with genuine functional protection, scientists will remain unable to understand why extensive immune escape continues despite widespread ‘immunity.’


Overall Conclusion: Complex Systems Cannot Be Understood Through Hollow Definitions

The current confusion surrounding herd immunity, gain-of-function, endemicity, and immune protection is not accidental. It reflects the failure of linear reasoning to capture the multidimensional nature of complex biological systems.

Definitions that were once scientifically meaningful gradually become emptied of substance when detached from the broader context in which they operate. They continue to circulate in scientific discourse, but increasingly function as intellectual shortcuts rather than explanatory tools.

The immune escape pandemic and relevant accompanying changes in the pathogen’s ‘behavior’ cannot be understood through isolated variables or simplistic narratives. It can only be understood by recognizing the dynamic interaction between:

• viral evolution,

• innate and adaptive immunity,

• immune conditioning at the population level,

• and the selective pressures generated by mass vaccination during an ongoing pandemic.

As long as these interactions remain fragmented across scientific silos, the same confusion will persist:

• immune activation mistaken for protection,

• transient calm mistaken for stability,

• constrained viral evolution mistaken for benign endemicity,

• suboptimal population-level immunity mistaken for protective herd immunity

• individual point mutations misinterpreted as having lethal consequences

• large-scale in vivo gain-of-function mistaken for benign viral immune escape.

But complex systems do not obey simplistic definitions. Reality will eventually prove wrong those who generate scientific confusion by insisting on interpreting multidimensional phenomena through linear frameworks, erroneous definitions, and hollow concepts.

[1] https://voiceforscienceandsolidarity.substack.com/p/when-experts-disagree-something-bigger

[2]

JonFleetwood.com

NIH/NIAID Fund Gain-of-Function COVID Mutant With 679-Fold Antibody Resistance: Journal 'American Society for Microbiology'

A new peer-reviewed study published today in the journal American Society for Microbiology claims that U.S. government–funded researchers deliberately mutated SARS-CoV-2 in a laboratory setting and produced a variant that gained a new functional capability: immune system evasion through antibody resistance…

Read more

3 months ago · 57 likes · 17 comments · Jon Fleetwood

[3] https://journals.asm.org/doi/epub/10.1128/spectrum.00006-26?utm_source=substack&utm_medium=email

[4] https://voiceforscienceandsolidarity.substack.com/p/when-experts-disagree-something-bigger

The current state of the COVID-19 (C-19) pandemic is often described in reassuring terms: declining severity, widespread immunity, transition toward endemicity.

But these interpretations may be built on comforting yet incomplete assumptions.

The coexistence of contradictory expert opinions, each supported by partial data, should prompt a more fundamental question:
whether the frameworks used to interpret this phenomenon are themselves inadequate.

A more comprehensive understanding of the ongoing immune escape pandemic in highly C-19-vaccinated populations requires moving beyond linear reasoning and embracing the multidimensional nature of virus-host immunity interactions and their evolutionary dynamics in these populations.

Only then can we begin to reconcile the apparent contradictions–and avoid policy decisions based on interpretations that may ultimately prove to be not just incomplete, but misleading.

Beyond the Illusion of Simplicity

One does not need to look far to observe that even highly reputed scientists fundamentally disagree on the future trajectory of the C-19 pandemic. Some argue that the virus is progressively attenuating into a benign, common-cold-like pathogen. Others claim that the apparent decline in severity is simply the result of widespread immunity acquired through infection, vaccination, or both–so-called ‘hybrid immunity.’

A recent STAT article (https://www.statnews.com/2026/04/27/is-covid-still-a-thing-expert-analysis-who-needs-vaccine-booster-shot/) encapsulates this divide, asking whether SARS-CoV-2 (SC-2) has become ‘more nuisance than peril’ and presenting a range of expert opinions that attempt to reconcile declining mortality, lower wastewater signals, and reduced clinical burden with a narrative of increasing population protection.

At first glance, these interpretations may seem reasonable. Upon closer inspection, however, they reveal something far more fundamental: a persistent tendency among scientists to interpret complex, multidimensional phenomena through linear and siloed frameworks of reasoning.


The Illusion of Coherent Interpretation

In a dense cloud of observations–declining deaths, fluctuating transmission, decreasing wastewater viral load, immune escape, changing age distribution–it is always possible to identify subsets of data points that align with a given hypothesis. A scientist who believes in progressive attenuation will highlight reduced intrinsic viral virulence. Another who emphasizes immunity will point to widespread exposure and large-scale vaccination resulting in declining mortality.

But this is precisely the problem. Each of these interpretations selectively connects a limited number of observations into a linear narrative, while failing to account for the many others that do not fit that line. The result is not a comprehensive explanation, but rather a series of partial truths, each internally coherent yet inherently contradictory and polarizing the scientific community.

The coexistence of these conflicting interpretations, each supported by ‘objective’ yet selective analyses, while leaving many observations unexplained, is perhaps the strongest indication that none of the prevailing linear frameworks adequately captures the full complexity of the phenomenon. These are, in essence, apparent theories, constructs that hold only as long as critical questions cannot be asked in an open scientific debate.


A Multidimensional Phenomenon Misread as Linear

An alternative and more plausible explanation is that the cloud of observations reflects a system governed not by a simple linear causal chain, but by multidimensional dynamics.

This is because this pandemic–especially one occurring in the context of mass vaccination–is shaped by:

• Viral behavior (mutation, recombination, immune escape)

• Population-level immunity (heterogeneous, dynamic, and largely suboptimal)

• Age-dependent differences in immune profiles

• Feedback loops between viral adaptation and host immunity

• Evolutionary dynamics of all of the above

These factors do not operate along a single axis. They interact in complex and often nonlinear ways. To impose a linear interpretation on such a system is, by definition, to misinterpret it.

A more appropriate approach requires the ability to connect observations across disciplines and dimensions–to recognize patterns that do not align along a single explanatory axis, but instead emerge from the interaction of multiple dimensions.


The Failure to Distinguish Immune Response from Protection

One of the most striking examples of this linear misinterpretation is the widespread assumption that the presence of an immune response equates to protection.

The STAT article repeatedly emphasizes that ‘virtually everyone has at least some immunity’ and uses this as a primary explanation for the reduced impact of circulating SC-2 variants.

This is a critical oversimplification.

An immune response is not synonymous with effective protection. In a rapidly evolving viral system, especially one characterized by ongoing immune escape in highly C-19-vaccinated populations, the immune system may be highly active yet poorly aligned with the circulating viral variants. In such scenario, the immune system is not preventing infection efficiently and population-level immunity is not ensuring rapid abrogation of viral transmission.

In other words, the system is not protected–it is engaged in a continuous, reactive chase of a moving target.


Mistaking Decline for Resolution. The Metastable Trap

Declining mortality, reduced wastewater viral loads and fewer severe cases are widely interpreted as evidence that the pandemic is resolving.

But this interpretation ignores a critical possibility: that the system may have entered a metastable state.

In such a state:

• The virus continues to circulate

• The immune system remains highly active

• Severe outcomes decrease

• But the underlying dynamics remain fundamentally unstable

This apparent ‘calm’ is not necessarily a sign of equilibrium. It may instead reflect a phase of temporary balance under constraint, where neither the virus nor the host immune system has achieved decisive advantage.

As described in my earlier work, this resembles a system that has exhausted its most efficient adaptive pathways.
The virus continues to accumulate mutations, particularly in the spike protein, yet functional gains in transmissibility and fitness become increasingly marginal.
The immune system, in turn, continues to respond, but often in a suboptimal manner because immune responses in highly C-19-vaccinated populations are misaligned with the evolving viral phenotype. Suboptimal immune responses result in recurrent vaccine-breakthrough infections and, thereby, drive a perpetuating reactivation of the misdirected immune responses while further compromising viral clearance. In other words, immune loss-of-function promotes viral immune escape and, therefore, inevitably leads to viral gain-of-function. In addition, misdirected immune responses may not only compromise the functionality of the immune system while promoting viral infectiousness, but also lead to immune pathology.

This leads to a critical insight:

A system can appear stable precisely because it is temporarily unable to evolve effectively within its current constraints. It is therefore not resolving, but instead circulating within an increasingly narrow evolutionary corridor.

Such conditions do not enable an equilibrium–they define a metastable situation.
Metastable systems can persist for extended periods, while remaining inherently unstable. But because the underlying constraints remain unresolved, they are inherently prone to nonlinear transitions once a critical threshold is crossed.

The assumption that SC-2 is simply drifting toward endemicity as a mild seasonal virus fails to account for this possibility. It reflects a linear projection of current trends into the future, without recognizing the structural instability underlying those trends.


Misinterpreting Age-Dependent Patterns

The observation that severe disease is increasingly concentrated in older individuals, very young children, and those with underlying conditions, is often interpreted as evidence that SC-2 is now behaving like other typical seasonal respiratory viruses.

But this common interpretation is simply totally naive as it overlooks the immunological basis of these patterns.

Differences in disease burden across age groups in highly C-19-vaccinated populations cannot reasonably be explained by viral adaptation to specific age groups but are more plausibly explained by differences in immune system conditioning:

• Adults in highly C-19-vaccinated populations often have repeatedly stimulated, spike-focused adaptive responses

• Young children, by contrast, have less conditioned adaptive immunity and rely more on innate responses. Under high infectious pressure, this can result in increased infection rates, not because the virus has adapted to children, but because the immune landscape it encounters in children is distinct.

These differences shape infection dynamics in ways that do not require invoking age-specific viral adaptation. Yet linear reasoning tends to attribute such patterns directly to viral properties rather than to the interaction between virus and host immunity.


The Problem with Short-Term Thinking

A second major limitation in current scientific interpretations is the reliance on short-term trends and extrapolation.

Many predictive models assume that current trends–declining severity, diminishing viral load in wastewater, stable transmission, reduced mortality–will continue in a relatively smooth and predictable manner. But such models are often built on assumptions that fail to capture the nonlinear dynamics of complex systems.

Complex systems often evolve through prolonged periods of inertia, during which little appears to change, followed by sudden, nonlinear transitions once critical thresholds are crossed.

The apparent stability of the current situation may therefore be misleading. It may represent not a final state, but a pre-transitional phase.


Polarization as a Symptom of Analytical Failure

The ongoing disagreement among experts is often interpreted as a natural feature of scientific debate. But in this case, it rather reflects a deeper issue: the inability of linear frameworks to capture a multidimensional reality.

This leads to polarization:

• The ‘attenuation’ camp vs

• The ‘immunity-driven control’ camp

Each side constructs a simplified narrative supported by selective data, while neither adequately explains the full spectrum of observations.

Such polarization is not a sign of healthy scientific pluralism. It is often a sign that the underlying phenomenon is being mischaracterized and misunderstood.

Those capable of ‘connecting the dots’ across disciplines and dimensions–rather than remaining confined to a single line of linear reasoning–are, by virtue of their analytical approach, more likely to approximate the underlying reality.


A Historical Reminder

Scientific history offers many examples of similar patterns.

When Galileo challenged the prevailing worldview by introducing a multidimensional understanding of the Earth and its place in the solar system, his ideas were rejected not because they lacked evidence, but because they conflicted with entrenched linear interpretations.

The lesson is that even today’s highly trained scientists can misinterpret systems or phenomena governed by complex, multidimensional interactions when they rely on linear, reductionist frameworks or models that fail to capture the multidimensional nature of the system they are studying, regardless of how widely accepted those models may be or how much credibility they may derive from scientific authority.

Overall Conclusion: A Metastable System Mistaken for Resolution

The persistent polarization of interpretations–each supported by ‘objective’ yet selective data analyses, while leaving many observations unexplained–is perhaps the most compelling evidence that none of the prevailing linear frameworks adequately captures the reality of the phenomenon under study. These are, at best, partial theories, sustained only insofar as they are not subjected to sufficiently critical scrutiny or open scientific debate.

An alternative–and far more plausible–interpretation is that the seemingly contradictory cloud of observations reflects a system governed not by linear causality but by multidimensional dynamics shaped by interacting intrinsic and extrinsic factors. The interactions between SC-2 and suboptimal population-level immunity–as occurring in highly C-19-vaccinated populations–do not operate along a single axis. The evolutionary dynamics of these complex interactions occur in intricate, nonlinear ways that cannot be reduced to simplistic narratives of attenuation or protection.

Within this framework, the current state of the ongoing immune escape pandemic is best understood as a metastable equilibrium: a condition in which the system appears stable, yet remains fundamentally unstable due to unresolved underlying constraints. The virus continues to evolve under intense immune pressure, while the host immune system remains highly active but increasingly misaligned with the evolving viral phenotype. The result is a system that is neither progressing toward true equilibrium nor collapsing–but instead hovering in a constrained, pseudo-stable state.

Such systems are well known in complex dynamics. They can persist for prolonged periods, creating the illusion of stability, while in reality accumulating tension beneath the surface. Crucially, once certain thresholds are crossed, they do no longer evolve gradually, but undergo abrupt, nonlinear transition. This is the essence of the phase transition I have repeatedly described.

Contrary to the comforting narratives suggesting that SC-2 is steadily attenuating or being brought under control by the diversified spectrum of immune responses generated in highly C-19-vaccinated populations, the current evolutionary dynamics of this pandemic may instead reflect a system that has exhausted its most effective adaptive pathways. Incremental spike mutations yield diminishing returns, while immune pressure continues to intensify. Under such conditions, the likelihood increases that the virus will eventually escape this constraint not through gradual optimization, but through a dramatic, qualitative shift in its interaction with the host.

The analogy with other complex systems is instructive. Just as climatic systems can remain seemingly stable before rapidly transitioning into a new state once critical thresholds are exceeded, or as materials under repeated stress can maintain structural integrity before sudden failure, the present pandemic may be approaching a point at which small additional changes trigger disproportionate consequences.

The failure to recognize this possibility stems from the same limitation that underlies the current polarization of expert opinions: the inability–or unwillingness–to move beyond linear, short-term reasoning. Many scientists remain confined within disciplinary silos, interpreting data through narrowly defined frameworks and extrapolating short-term trends into the future, while neglecting the multidimensional nature of the system.

This is not a failure of intelligence, but of perspective.

Those who think in binary terms–attenuation versus immune protection, viral immune escape versus endemicity–inevitably miss the deeper complexity at play. And in doing so, they promote interpretations that are not only incomplete but truly misleading and potentially harmful, in this case to individual and public health.

In this light, the current disagreement among experts is not surprising. It is the natural consequence of blindly applying linear reasoning to a system that is inherently nonlinear.
The real question, therefore, is not which of the competing linear narratives is correct.
It is whether the phenomenon itself can be understood within a linear framework at all.
If it cannot–and the available evidence increasingly suggests that it cannot–then the apparent calm we observe today should not be interpreted as resolution but as the prelude to a transition whose nature and timing remain uncertain, but whose threat to highly C-19-vaccinated populations can no longer be ignored.

Consequently, one should be highly skeptical of the seemingly reassuring rhetoric from those relying on simplistic linear interpretations, while remaining attentive to the voices of those who have invested the time and effort to engage in a deep, multidimensional analysis of the evolutionary dynamics of this ongoing immune escape pandemic.

This line of reasoning is not just speculative –it reflects a fundamental misunderstanding of the interaction between viral evolution and host immunity.


Mistaking Constraint for Equilibrium

The authors interpret the absence of large synchronized waves and the co-circulation of multiple lineages as evidence of a system moving toward endemic stability. But this ignores a crucial point: co-circulation without dominance is not a sign of equilibrium – it is a hallmark of constraint.
These folks don’t even seem to be aware that previous pandemics were not brought to an end by the sustained co-circulation of multiple viral (sub)lineages. Instead, the pandemic strain itself generally evolved into the form that later became endemic, as seen with the 1918 influenza pandemic (‘Spanish flu’).

As I have repeatedly argued, when a virus accumulates large numbers of spike (S) mutations yet fails to achieve a clear transmissibility advantage, this does not indicate successful adaptation. It indicates that the virus is running out of effective evolutionary options within its current solution space. Incremental amino-acid substitutions – particularly in S protein – are increasingly unable to deliver meaningful gains in transmissibility under widespread immune pressure (https://voiceforscienceandsolidarity.substack.com/p/when-the-system-doesnt-bounce-back; https://voiceforscienceandsolidarity.substack.com/p/the-virus-has-no-big-hands-left-to).

What Zhang et al. describe as ‘complex population immunity’ acting as a barrier to new dominant variants is, in reality, the very mechanism that forces the virus into a constrained, metastable state. This is not stabilization. It is saturation!

The Fiction of ‘Child-Specific Adaptation’

Even more problematic is the suggestion that BA.3.2 preferentially infects young children because of ‘adaptation to age-dependent host factors’ or ‘enhanced immune evasion in children’.
This interpretation is biologically beyond shallow.

Children are not a distinct evolutionary niche requiring specialized viral adaptation. What they represent is something much simpler and far more important: a population with relatively unconditioned adaptive immunity.

In highly Covid-19 (C-19)-vaccinated adult populations, repeated exposure to S-based antigens –through vaccination and infection – has generated a strong but narrowly focused and suboptimal adaptive immune response. This creates intense selective pressure on S-mediated viral entry and immune recognition. The virus responds by accumulating mutations, but those mutations come at a cost: they increasingly compromise intrinsic fitness.

Children, by contrast, are less shaped by this immune conditioning. Their immune responses rely more heavily on innate and broadly reactive mechanisms, and less on narrowly focused, S-specific adaptive responses. Under conditions of high infectious pressure, this can result in relatively higher infection rates – not because the virus has ‘adapted’ to children, but because the immunological landscape differs.

To interpret this as viral adaptation to children is to invert cause and effect.


Repeating the Influenza Fallacy

The analogy to the 2022–23 influenza season – where increased disease burden in younger individuals was attributed to insufficient vaccine coverage – is equally misplaced.
Respiratory virus epidemiology in younger populations is not primarily governed by vaccine coverage. It is shaped by the balance between innate and adaptive immunity. Younger individuals often experience higher incidence during periods of intense viral circulation precisely because their adaptive immunity is less mature or less repeatedly boosted. This is a well-established feature of acute, self-limiting viral infections.
Crucially, these infections contribute to the natural maturation and broadening of immune responses.

To suggest that this pattern should be corrected by expanding C-19 vaccination into younger age groups ignores this fundamental immunological principle. It risks substituting a narrow, antigen-specific immune imprint for a broader, functionally more versatile immune response, thereby promoting immune escape in populations subjected to mass vaccination during an ongoing acute viral pandemic.


Misreading Immune Escape

The deeper issue in Zhang et al.’s reasoning is their failure to recognize what extensive S remodeling actually signifies.
They correctly note that BA.3.2 exhibits substantial immune evasion. But they interpret this as part of a normal adaptive trajectory within a system approaching endemicity!
This misses the critical point:

the virus is investing heavily in mutation, yet achieving only modest epidemiological success and only a poorly pronounced competitive advantage.

That is not efficient adaptation. It is a sign of diminishing returns.

In my previous analyses, I have described this as a situation in which the virus has ‘no big hands left to play’ – the major gains achievable through S-mediated changes have largely been exhausted (https://voiceforscienceandsolidarity.substack.com/p/the-virus-has-no-big-hands-left-to). What remains are increasingly complex and costly mutational combinations that fail to deliver decisive advantages.

This is precisely what one would expect in a system approaching an evolutionary bottleneck.

Metastability, Not Endemicity!

The authors conclude that prolonged co-circulation and absence of global waves may signal a transition toward endemicity.
But this interpretation confuses lack of dominance with stability.

A system in which:

• multiple variants co-circulate,

• none achieves clear dominance,

• extensive mutation fails to translate into clear-cut increased fitness,

is not necessarily stable. It rather points to a metastable situation – a state in which the system persists under constraint but is unable to progress through conventional adaptive pathways.
Such systems do not gradually settle. They often undergo qualitative shifts once existing mechanisms are exhausted (https://voiceforscienceandsolidarity.substack.com/p/from-breakthrough-to-breakdown-when.

A Misguided and Dangerous Policy Implication

Perhaps the most concerning aspect of the commentary is the suggestion that the observed epidemiology might justify increased vaccination of children .

This recommendation rests on a chain of flawed and immunologically ill-founded assumptions:

1. That higher infection rates in children reflect specific viral adaptation rather than age-related differences in population immunity,

2. that this represents a failure of protection rather than a normal immunological process,

3. and that further vaccination would correct this dynamic.

If anything, widespread C-19 vaccination strategies that focus the immune response narrowly on S epitopes may contribute to the very selective pressures driving immune escape of viruses that typically causing acute, self-limiting infections.

To extend such strategies into populations that are currently less immunologically conditioned risks amplifying the underlying problem rather than solving it. And this does not even account for the significant adverse effects associated with mRNA vaccines, which comprise the bulk of the C-19 vaccine arsenal.


Conclusion: When a Lack of Insight and Weak Immunological Understanding Lead So-Called Experts to Misread Patterns

Zhang et al. correctly identify that the epidemiology of BA.3.2 is unusual. But they misinterpret what those patterns mean.

• They interpret constraint as equilibrium.

• They interpret immune pressure as protection.

• They interpret epidemiological shifts as viral adaptation to age groups.

In doing so, they arrive at conclusions that are not only unconvincing but misleading.

It astonishes me beyond words how scientists at top-tier institutions can produce interpretations so empty in substance and so superficial in reasoning.

The current evolutionary behavior of SARS-CoV-2 is not well described by models of smooth adaptation toward endemic coexistence. It is better understood as a system under intensifying constraint, in which conventional evolutionary pathways are yielding diminishing returns.
Recognizing that distinction is not a matter of semantics. It is essential for understanding where this evolutionary trajectory may lead – and for avoiding policy responses that are based on comforting but incorrect assumptions and, as such, profoundly irresponsible from both an individual and a public health perspective.

Lastly, it doesn’t surprise me in the least that The Lancet would publish such nonsense. It only once again confirms how corrupt this journal is, as I already pointed out about ten years ago, when it published the WHO’s manipulated analysis of a vaccine study that supposedly showed 100% (!) efficacy of an Ebola vaccine, as can be read on my website (https://www.voiceforscienceandsolidarity.org/scientific-blog/guinea-the-ebola-vaccine-trial-and-the-reported-interim-results).

.

The aggression directed at me and others for challenging this despicable narrative has still not stopped. To this day, on an almost daily basis, we receive comments from pea-brained fanatics referring to links dating back to the early phase of the mass vaccination program, when a number of pseudo-scientists and so-called ‘science communicators’ were trying to make the public believe that the C-19 vaccines were safe, effective against SC-2 infection, and the best possible means of ending the C-19 pandemic when deployed in mass vaccination campaigns.

One of these articles is, surprisingly enough, still available online:

‘Research debunks myth that COVID vaccination promotes mutations’; https://www.news-medical.net/news/20210813/Research-debunks-myth-that-COVID-vaccination-promotes-mutations.aspx).

As a form of fully justified defamation against all the despicable clowns who still dare to claim that mass C-19 vaccination was a sound strategy for bringing the virus under control, I took the time, one last time, to utterly demolish this perverse view, published in 2021, but to this day still stubbornly upheld by the stakeholders of the C-19 mass vaccination program.

I sincerely hope this lands as a hard slap in the face of all those who dare call themselves researchers or scientists while clearly having failed to understand even the most basic aspects of the virus’s evolutionary dynamics, which directly resulted from this large-scale gain-of-function experiment.

I do so through my critique of the above-mentioned article and of the publication on which it relies (https://www.medrxiv.org/content/10.1101/2021.08.08.21261768v3). I gave my critique the following title:

‘When ‘debunking’ becomes propaganda: a hilarious misunderstanding of viral immune escape evolution’.

Summary

Far from debunking vaccine-driven viral evolution, this article merely reports a short-term ecological association between vaccine coverage and crude mutation frequency. Even if vaccination transiently reduces the overall number of replication events in some settings, that association does not address the real evolutionary issue caused by the mass vaccination program. This is because widespread but suboptimal, non-sterilizing immunity does not need to increase the total number of mutations to accelerate viral immune escape; it only needs to preferentially select the mutants that can replicate and transmit despite that immunity. The relevant issue is therefore not the average number of mutations per sampled genome, but whether the prevailing immune environment promotes the emergence and amplification of mutations that increase fitness under vaccine-shaped immune pressure. In other words, C-19 mass vaccination during the SARS-CoV-2 (SC-2) pandemic caused host populations to repeatedly apply selective filters to the viral landscape, thereby promoting dominant circulation of immune escape variants (i.e., viral variants able to bypass that immunity).


When stupidity reigns...

Every now and then, one comes across a publication whose headline is so triumphalist, and whose underlying argument is so flimsy, that it ends up achieving the exact opposite of what it set out to do.

That is precisely the case for this piece of phantasy claiming to have ‘debunked the myth’ that C-19 vaccination promotes mutations. Far from debunking anything, it merely showcases how easily a crude ecological correlation can be dressed up as evolutionary insight and then sold to the public as settled science.

The problem begins with the most elementary confusion imaginable: the article conflates mutation frequency with immune-driven viral evolution.

These are not the same thing. Not even close.

A virus does not need to generate more random mutations overall for mass vaccination to promote immune escape. It merely needs to replicate in a host population exerting suboptimal, non-sterilizing immune pressure, so that variants with mutations conferring a selective advantage are preferentially retained and amplified. Evolution is not driven by mutation counts alone. It is driven by selection.
That’s how adaptive evolution works. And that is exactly where the article already starts to unravel.

The fatal category error

The article leans heavily on the claim that countries with higher C-19 vaccination rates showed lower ‘mutation frequency’ of the Delta variant over a narrow observation window. From this, it jumps to the sweeping conclusion that vaccination does not promote mutations. But this is a textbook category error.

Even if one were to accept, for the sake of argument, that more vaccination coincided with fewer mutations per sampled genome in a particular place and time, that still would not answer the relevant evolutionary question: what were these fewer mutations like? Under what immune conditions were they selected, and with what phenotypic consequences? Those are the questions that really matter.

A virus evolving in a heavily C-19-vaccinated population with incomplete protection faces a specific immune selective environment. In the latter, the virus is repeatedly exposed to an immune environment that is neither absent nor sterilizing. That is precisely the kind of setting in which immune escape selection can intensify. So the article does not refute the concern at all. It simply fails to explain the mechanism as the authors are immunologically too illiterate to understand how the virus adapts to a life-threatening immune response of the population.

Counting mutations is not the same as understanding evolution

The piece rests on the childish assumption that fewer observed mutations must mean less problematic evolution. That’s complete nonsense.

A viral lineage does not become more dangerous because it accumulates a large pile of random substitutions. It becomes more dangerous when a small number of strategically placed mutations improves its fitness in the prevailing host(ile) environment. A handful of adaptive changes can matter far more than a mountain of neutral noise.

Indeed, under strong selective pressure, diversity may even contract while adaptation accelerates. That is basic evolutionary biology. Suboptimal population-level immune pressure acts as a selection filter. It’s not like the virus sprays mutations around indiscriminately and then announce its presence by raising a simple counter.

So if a highly C-19-vaccinated population imposes a selective bottleneck that favors immune-evasive variants, the number of mutations per genome could even look superficially ‘controlled’ while the virus is in fact becoming better adapted to that very immune landscape.

That is why this publication is so intellectually hollow: it mistakes a crude descriptive metric for mechanistic understanding.

A cross-country snapshot correlation cannot settle a mechanistic evolutionary question

The analysis compares mutation frequency and vaccination coverage across 20 countries and notes an inverse correlation in 16 of them. It also acknowledges obvious outliers such as Australia, Japan, Switzerland, and the United States. Already that should have prompted caution. Instead, the article barrels ahead.

But country-level comparisons of this sort are a graveyard of confounding variables: differences in testing intensity, sequencing depth, timing of Delta introduction, founder effects, travel restrictions, case ascertainment, prior infection rates, public-health interventions, demographic structure, and epidemic phase.
Once one admits that countries differ in all these respects, the claim that C-19 vaccination itself is the decisive explanatory variable becomes little more than wishful thinking dressed in a regression line.

Australia, for example, is treated as an exception because of stricter control measures. But once the authors concede that non-vaccine interventions can materially alter the observed signal, the headline collapses under its own weight.

If control measures, sampling practices, and epidemic timing can shape the outcome, then the article has not isolated C-19 vaccination as a causal explanation at all! It has simply noticed a pattern and attached a preferred narrative to it.

The article quietly concedes the key point it pretends to deny

Perhaps the most amusing part is that the publication itself acknowledges that mutations arising under positive selection pressure, including vaccine-induced immunity, are among the main drivers of viral evolution. That single admission is enough to sink the headline. Because once one accepts that vaccine-induced immunity can act as a selective pressure, the discussion is no longer about whether immunity shapes evolution. It obviously does. The only scientifically serious question is how it shapes evolution.

And here lies the essence of the immune escape theory.

If vaccine-induced immunity were robustly sterilizing, broadly protective, and capable of reliably shutting down infection and transmission, thereby inducing full-fledged herd immunity, the selective space available for immune escape would be far more constrained. But that is not the landscape that emerged. What emerged instead, especially in highly C-19-vaccinated populations, was widespread exposure to a virus replicating under incomplete immune control and repeatedly causing vaccine-breakthrough infections. That kind of landscape is evolutionarily dangerous. It does not eliminate selection pressure. It channels it.

The missing mechanism: population-level selection pressure under incomplete immune control

The article treats viral evolution as though it were adequately captured by comparing average mutation metrics between countries. It is not.

The most consequential immune escape variants are not necessarily born out of some neat country-level average. They may emerge through prolonged propagation in highly C-19-vaccinated populations where the virus remains under partial (i.e., suboptimal) immune pressure and, thereby, circulates long enough to explore adaptive solutions.

What matters is not merely how much virus circulates, but under what immune conditions, at what scale and for how long. In highly C-19-vaccinated populations, the virus is repeatedly tested against a partially effective immune barrier. It is therefore not surprising that selection may enrich for constellations that can better bypass that barrier.
That is exactly what simplistic ecological analyses fail to capture. They do not distinguish between neutral mutational drift and adaptive immune selection. They do not resolve evolutionary dynamics under sustained population-level immune pressure. They do not explain why particular spike constellations emerge and expand. And they certainly do not establish that highly C-19-vaccinated populations do not serve as a breeding ground for selected immune escape phenotypes. They merely serve as propaganda cover for those who are eager to believe that vaccination is incapable of failure, regardless of how it is implemented.

Selection pressure, not mutation arithmetic, is the elephant in the room

The virus doesn’t ‘care’ how many mutations an analyst counts per sequence. What matters to the virus is whether a mutation improves replication, transmission, or immune evasion in the host population it is encountering.

That is why the central premise of this publication is so embarrassingly simplistic.

It treats viral evolution as if it were a spelling contest in which one simply counts how many letters changed. But evolution is not a spelling contest. It is a filtering process. In a highly C-19-vaccinated population, the immune environment becomes a filter. And when that filter is strong enough to exert pressure but too weak to suppress transmission, it may preferentially enrich exactly those variants best able to evade it.

That is not a fringe concept. That is evolutionary logic.

So no, the question is not whether vaccination causes more of fewer mutations in some crude quantitative sense. The question is whether mass vaccination under real-world, non-sterilizing conditions can shape the direction of viral evolution toward immune escape. This article, as well as the original publication by Yeh and Contreras, does not answer that question. It does not even seem to understand it.

Tajima’s D does not save the story

The authors also invoke Tajima’s D as though this somehow upgrades the argument into something sophisticated. It does not.

A negative Tajima’s D may suggest demographic expansion or positive selection, but it does not identify the biological origin of that selection pressure. It does not tell us whether the pressure stems from vaccine-induced immunity, prior infection, changes in host contact structure, founder effects, or other epidemiological processes. Nor does it validate the grandiose claim that vaccine-driven mutation concerns have been ‘debunked.’
At most, it adds a layer of statistical decoration to an argument that remains conceptually confused from top to bottom.

The real-world lesson

What this publication actually demonstrates is something quite different from what it intended.

It demonstrates how readily public-facing science communication can confuse the public by collapsing a mechanistic evolutionary question into a simplistic talking point.

It demonstrates how a narrow, non-peer-reviewed, observational analysis can be inflated into rhetorical certainty. And it demonstrates how eager some commentators were to defend a mass vaccination campaign not by carefully interrogating its evolutionary consequences, but by declaring them impossible before they had even been properly studied.

That was never science. That was messaging. And messaging is precisely what collapses when the virus keeps doing what evolution has always done: adapt to the selective environment it is given.

Conclusion

The article itself admits a point that actually undermines its own rhetorical conclusion. It states that mutations emerging under positive selection pressure, such as vaccine/therapy-induced immunity, are a main driving force of viral evolution. That is a crucial concession. It means the relevant evolutionary question is not whether immunity can shape viral evolution ─it obviously can─ but what kind of immune pressure is being exerted, in which host populations, and whether it is sterilizing or suboptimal. The problem is that C-19 mass vaccination in highly SC-2-exposed populations does not create broad sterilizing immunity; it creates a landscape in which viruses replicating in partially immune hosts are repeatedly challenged and therefore selected for immune escape. The article never refutes that. It merely shows that crude mutation counts may be lower in some more-vaccinated settings during one short observational period. It counts mutations the way a child counts pebbles on a beach, then imagines it has understood the tides. No wonder it misses the current.

Hence, this publication did not debunk the concern that mass C-19 vaccination can promote viral evolution toward immune escape. It merely exposed the primitive inability of the authors to distinguish between mutation frequency and selection-driven adaptation. That is not a minor oversight. It is such a basic conceptual blunder that one is almost tempted to admire the confidence with which it is paraded as insight.

The headline this poor Indian lady used for her article certainly deserves to be remembered, of course not at all as a scientific correction, but as a small monument to the kind of naive astonishment that appears whenever evolutionary biology refuses to obey public-health dogma. Far from debunking a myth, her piece, summarizing the publication by Yeh and Contreras, confirms a different and far more persistent one: that one can understand viral evolution without understanding immune selection!
It reminds me of those pea-brained WHO scientists who pretended that mass C-19 vaccination was the best possible way to stop the SC-2 pandemic. I can only hope that my critique exposes them as ridiculous and strips away every last shred of credibility they still retain in the eyes of the broader public.

And of course, the central feature of this disastrous experiment is its gain-of-function dimension, now playing out not in the laboratory but in the human population itself, a reality that almost nobody dares to openly talk about. And yet, whenever children contract Covid-19 or develop post-infectious multisystemic inflammatory syndromes such as MIS-C, it is suddenly all hands on deck, as though SC-2 were inherently life-threatening to children! There is currently a great deal of discussion about the expansion of BA.3.2 (nicknamed ‘Cicada’) across multiple countries, fueling naïve speculation about its broad array of spike (S)-associated mutations, additional changes in the ORF7/ORF8 accessory proteins (https://academic.oup.com/ve/advance-article/doi/10.1093/ve/veag016/8527524), and its relatively high prevalence in children, the vast majority of whom are, thank God, unvaccinated (https://economictimes.indiatimes.com/news/international/us/new-covid-variant-cicada-ba-3-2-may-be-affecting-children-the-most-experts-say/articleshow/129983942.cms?from=mdr#google_vignette).

All of this seems difficult to interpret for virologists and epidemiologists who remain largely illiterate when it comes to immunology (https://edition.cnn.com/2026/04/02/health/new-covid-variant-cicada).

Some mutation trackers have even gone so far as to claim that a large deletion in ORF7/8 could render dendritic cells (DCs) tolerogenic or somehow ‘silence’ them:

This is, of course, absurd. Such deletions may indeed dampen inflammation and reduce virulence by attenuating innate immune activation (e.g., by reducing the secretion of IL-10, an anti-inflammatory cytokine with antiviral activity). At most, they may reduce DC hyperactivation and thereby contribute to milder acute disease. But they do not induce tolerance, nor do they silence DCs or drive regulatory T-cell dominance. If that were truly the case, BA.3.2 infection in young children would be expected to cause hyperacute disseminated viremia with high mortality. Clearly, that is not what is being observed.
However, for those who have followed not only the evolutionary dynamics of SC-2 in highly C-19-vaccinated populations, but also the way in which the adaptive immune system has been reacting to the evolving virus, understanding the age effect of BA.3.2 is actually quite straightforward. It has everything to do with the lines of immune defense predominantly used by young unvaccinated children, as compared to those predominantly used by vaccinated adolescents and adults.

In essence, it reflects the contrast between protection that still relies primarily on innate immunity, as in young unvaccinated and not yet frequently exposed children, and protection that has shifted toward adaptive mechanisms in C-19-vaccinated and/or repeatedly exposed adolescents and adults.

The bottom line is that BA.3.2 lineages appear to have evolved in a way that further mitigates inflammatory innate immune responses, thereby weakening antiviral immune responses and improving productive infectiousness. This is not new. We have seen an increase of intrinsic viral infectiousness throughout the pandemic as a typical recurrent consequence of viral immune escape. It makes children, especially younger children, temporarily more susceptible than older individuals, particularly in highly C-19-vaccinated populations.
The more immune protection in such populations is provided by durable T cell-mediated control, directed against relatively conserved Tc epitopes, rather than by innate immunity, including innate or so-called ‘natural’ Abs, the greater the relative prevalence of BA.3.2 infection in the pediatric population, which still depends largely on innate immunity for protection against SC-2.

As I have explained repeatedly, recurrent vaccine breakthrough infections in highly C-19-vaccinated populations progressively refocus immune protection away from humoral responses and toward cell-mediated control.
Hence, C-19-vaccinated individuals benefit more from durable T-cell-mediated suppression of acute disease, whereas unvaccinated adolescents and adults have, over time, built a strong immune defense through repeated training of their cell-mediated innate immunity, a type of immune defense that has been sidelined in C-19 vaccinees, as I have discussed many times before, including in my book (https://www.amazon.com.be/-/nl/Geert-Vanden-Bossche-DVM-PhD/dp/9493280802?language=en_GB#detailBullets_feature_div) and earlier manuscripts.
At this late stage of the pandemic, a variant that strongly evades anti-S antibodies (Abs) while simultaneously dampening innate inflammatory responses, such as BA.3.2, therefore has a greater selective advantage in children than earlier variants did.

But this seemingly remarkable epidemiological observation is not the main point. The real point is what it reveals about the relentless evolutionary drive of the virus to secure sustained transmission.

The ‘sweet’ sky, or perhaps I should say ‘the glycans on the S protein’, is the limit.

Mutation trackers, clinicians, and public health experts appear more interested in surveying the share of BA.3.2 lineages across distinct age groups, thereby highlighting the significantly higher odds ratio for the pediatric share of these lineages compared to other lineages:

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They call this an ‘epidemiological signal.’ But they fail to understand that it is far more than that. Young children are currently functioning as sentinels of a virus quietly exploiting the full range of possible S-associated mutations ─not because these confer major fitness gains in the classical sense, but because the fitness advantage they generate increasingly creates steric complexity whose fitness cost requires the virus to incorporate additional immune-evasive S mutations to enable at least some gain, however small.
The children are the canaries in the coal mine, signalling the suffocating hostile immune environment. However, as even the combination and accumulation of multiple S-associated mutations no longer seems to provide sufficient fitness advantage on its own, the virus is now selecting additional mutations capable of subverting innate immune responses, as reflected by the growing pediatric share of BA.3.2 lineages.
And even if that signal were still not enlightening enough, how on earth can our public health authorities and self-proclaimed experts remain blind to an even more important reality: namely, that the acute manifestations of infection are now being kept largely under control by full commitment of the vaccinee’s cell-mediated immunity. In other words, the adaptive immune system has already played all its trump cards to keep disease symptoms caused by a virus that now almost completely escapes the repertoire of pre-existing neutralizing Abs under control (https://share.google/enTrNL7TcP1KzS5bb). And yet, despite openly acknowledging that BA.3.2 is largely resistant to neutralizing Abs induced by updated C-19 vaccines, these authorities and experts act as if continued protection of C-19 vaccinees against acute disease is nevertheless still granted by the vaccines and, therefore, even dare to recommend revaccination (https://time.com/article/2026/03/31/new-covid-variant-cicada/; https://www.today.com/health/coronavirus/new-covid-variant-ba32-cicada-symptoms-2026-rcna265088; https://www.peoplespharmacy.com/articles/the-cicada-variant-covid-went-underground-but-its-back).
Meanwhile, the T-cell machinery is running at full throttle to limit acute damage, while this ─for a normally acute, self-limiting viral infection─ unnatural response is now inevitably also contributing to the growing burden of immune pathology-based Long Covid cases.
Doesn’t a bell ring yet for the general public when, on the one hand, health authorities panic over one or two amino acid substitutions in the infectious protein of influenza virus (i.e. hemagglutinin), yet remain astonishingly calm when dozens of new mutations rapidly accumulate in the spike protein of BA.3.2, the very protein responsible for the infectivity of SARS-CoV-2?
“It’s worth keeping an eye on it,” or “we’re watching it closely” they say (https://indianexpress.com/article/health-wellness/cicada-covid-variant-ba-3-2-explained-10616891/; https://economictimes.indiatimes.com/news/international/us/new-covid-variant-cicada-ba-3-2-may-be-affecting-children-the-most-experts-say/articleshow/129983942.cms?from=mdr#google_vignette; https://www.today.com/health/coronavirus/new-covid-variant-ba32-cicada-symptoms-2026-rcna265088).
But anyone should understand that if such a profound viral metamorphosis does not immediately amount to a death sentence for the host, then this can only mean one of two things: either the host is still being well protected by trained innate immunity, as is largely the case in the unvaccinated, or the adaptive immune system is making extraordinary efforts to nevertheless prevent acute collapse, as is most likely the case in the vast majority of C-19 vaccinees. The deletions in ORF7/8, together with the astonishingly resourceful combinations of new spike-associated mutations in BA.3.2, make it increasingly clear, however, that even these extraordinary efforts by the adaptive immune system may ultimately not suffice to control viral transmission across multiple highly C-19-vaccinated populations. This is because the circulating lineages can now also subvert some inflammatory cytokine pathways, thereby undermining the antiviral effect of these innate immune components while compromising the protective contribution of adaptive responses.

While the immune system in Covid-19 vaccinees is gradually reaching the limits of its compensatory capacity in this way, the virus still retains substantial room to further enhance its reproductive fitness.

It would indeed be naive to assume the virus has no powerful strategies left to deploy! Even if the repertoire of amino acid substitutions that confer a clear competitive advantage appears increasingly constrained, the S protein retains a broad range of potential glycosylation changes that could drive a dramatic phase transition. As I have described in detail before, the selection of an appropriate glycan constellation on the surface of the S protein could, in highly C-19 vaccinated populations, radically alter the pathogenesis of infection by enabling the virus to bypass antigen-presenting cells altogether, especially DCs, and thereby rapidly spread throughout the host’s body via trans-infection and trans-fusion (https://www.trialsitenews.com/a/from-enhanced-infectiousness-to-enhanced-virulence-why-a-glycosylation-driven-shift-in-sars-cov-2-evolution-has-become-increasingly-likely-2cc974ed; https://www.trialsitenews.com/a/plausibility-of-more-extended-o-glycosylation-as-last-resort-for-sars-cov-2-immune-escape-e1a08faf).

This is not science fiction, but unfortunately a scenario that I consider highly realistic.

The viral evolutionary dynamics currently observed are precisely consistent with the prelude to such a major shift (https://www.trialsitenews.com/a/from-breakthrough-to-breakdown-simplified-version-d1eaad91; https://voiceforscienceandsolidarity.substack.com/p/the-virus-has-no-big-hands-left-to; https://voiceforscienceandsolidarity.substack.com/p/when-the-system-doesnt-bounce-back).

The only force that could prevent such an outcome is sterilizing group immunity, the famous ‘herd immunity.’. But as I have mentioned so often, the absence of the latter is precisely the most characteristic and at the same time the most damaging effect of the insane mass C-19 vaccination program.

Both statements cannot be true at the same time!

If viral evolution were truly reduced to small, incremental antigenic adjustments with limited individual impact, then the epidemiological consequences should likewise be modest. Minor changes yield minor effects. That is the very definition of incrementalism. Yet, the notion of ‘meaningful waves’ implies something entirely different. At the population level, a wave becomes ‘meaningful’ only when there is a substantial increase in viral fitness, whether through enhanced intrinsic transmissibility, immune evasion or pathogenic interaction (virulence) with the host. Such outcomes are not the linear sum of trivial changes; they reflect non-linear dynamics within the evolutionary landscape.

This brings us to a fundamental principle of evolutionary biology:

When a system operates under increasing constraint, adaptive progress through small, independent steps becomes progressively inefficient. The marginal fitness gain of individual mutations diminishes, especially in a highly COVID-19-vaccinated host population shaped by widespread prior exposure and converging immune pressure.

So how, then, can the virus continue to produce ‘meaningful waves’?

There are only two logically consistent answers.

Either these waves are not truly meaningful–mere statistical noise dressed up as significance–or they arise from cooperative interactions between Spike (S)-associated mutations, where combinations of changes produce effects that far exceed the sum of their parts. The latter is not speculation. It is a well-established evolutionary mechanism known as epistasis. As previously explained, the phenotypic effect of currently observed S-associated mutations likely arises from sterically mediated interactions among them (https://www.trialsitenews.com/a/plausibility-of-more-extended-o-glycosylation-as-last-resort-for-sars-cov-2-immune-escape-e1a08faf). I call it ‘steric epistasis.’
And here lies the key of all misinterpretation related to the ongoing evolutionary dynamics of SC-2 in highly COVID-19-vaccinated populations. Such sterically mediated interactions are precisely what enables qualitative shifts in phenotype (https://voiceforscienceandsolidarity.substack.com/p/everyone-knows-a-pus-filled-abscess). Epistasis largely explains how evolution crosses fitness valleys and reaches new adaptive peaks. It is how systems transition, not gradually, but abruptly, into new regimes of behavior.
In other words, what is being described as ‘stacking over time’ is, in reality, the precondition for a functional jump. Calling it incremental does not make it so.

Moreover, the discussion is often artificially narrowed to amino acid substitutions, as if changes in amino acid sequences alone define the virus’s adaptive potential. This overlooks a critical and far more flexible layer of viral evolution: the glycosylation landscape of the S protein.

Glycosylation is not merely decorative. It is functionally decisive. Changes in glycan shielding can alter antigenicity, modulate receptor accessibility, and reshape interactions with the host immune system–all without requiring extensive sequence divergence. These modifications provide the virus with a powerful means of reconfiguring its phenotype under immune pressure (https://voiceforscienceandsolidarity.substack.com/p/scientific-summary-4-pp-on-plausibility?r=y46t6)..

Importantly, such changes are inherently non-linear in their effects. A shift in glycosylation pattern can abruptly transform how the immune system perceives and handles the virus or....how the virus gets a handle on the host immune system! This is not gradual drift; it is reorganization at the interface between virus and host.

So the idea that the virus can indefinitely ‘struggle’ against widespread immunity through marginal gains is not biologically plausible.
Evolution under constraint does not proceed through endless fine-tuning. When incremental pathways lose efficiency, systems tend to reorganize–sometimes suddenly. This is not an exception to evolutionary rules. It is a consequence of them.

Which brings us back to the original claim. To assert that the virus has ‘no big hands left to play,’ while simultaneously acknowledging the emergence of ‘meaningful waves,’ is not a nuanced position. It is an internally inconsistent one. If the waves are real, then so is the mechanism behind them. And that mechanism, by definition, involves the potential for non-linear, qualitative change.

In evolutionary terms, the game is not over. It is, in fact, highly likely of approaching a turning point.

The current evolutionary behavior of SC-2 bears indeed resemblance -at least conceptually- to a system undergoing material fatigue.
Under repeated cycles of immune pressure, the virus continues to accumulate mutations, yet these increasingly fail to translate into meaningful gains in transmissibility.

Much like microstructural damage accumulating in a stressed material, the virus appears to be operating within a narrowing adaptive corridor, maintaining apparent functionality while progressively losing evolutionary flexibility. Such systems can remain deceptively stable for extended periods, even as internal constraints intensify.

However, once critical thresholds are approached, further incremental adjustments cease to be effective, and the system becomes susceptible to abrupt, nonlinear transitions.
In materials, this manifests as fracture; in viral evolution, it may manifest as a qualitative shift in strategy - one that no longer relies on incremental amino-acid substitutions but instead uses changes in its glycosylation profile to alter the fundamental interaction between the virus and the host immune system.

In that sense, the current ‘metastable’ phase should not be mistaken for equilibrium (i.e., no endemicity!), but rather understood as a state of accumulated strain, in which the apparent calm may precede a sudden and disproportionate change in evolutionary behavior (HiViCron).

However, in materials subjected to repeated stress, failure is not the only outcome. Long before fracture occurs, systems may accumulate subcritical damage, i.e., microstructural changes that do not immediately destroy integrity, yet impair performance and persist over time.
The system continues to function but no longer returns fully to its original state after each stress cycle.
In a biological context, one might view conditions such as Long Covid through a loosely analogous lens: not as catastrophic system failure but as a manifestation of repeated perturbation without full recovery, where residual dysfunction accumulates despite the absence of overt acute disease.

While the analogy is not literal, it highlights an important point, namely that systems under chronic stress may exhibit persistent, non-resolving, long-lasting effects before collapse.