Imagine that, seven or eight years ago—before the COVID-19 (C-19) pandemic began, long before mass C-19 vaccination was launched, and before repeated waves of SARS-CoV-2 (SC-2) infection and reinfection became a routine feature of the viral landscape—virologists had somehow been shown the evolutionary picture we see today.
Suppose they had been told that a newly emerged human coronavirus (CoV) would generate an extraordinary succession and, eventually, a plethora of genetically and antigenically diversified descendants; that multiple immune-escape lineages would coexist and compete; that mutations affecting immune recognition of the virus would repeatedly arise and converge at similar sites; and that this diversification would continue for years despite enormous levels of population immunity.
Would scientists have shrugged their shoulders?
Would public-health experts have said: "Nothing particularly concerning here. None of the variants currently appears to cause substantially more severe disease."
I very much doubt it!!
They would probably have considered the phenomenon itself remarkable and potentially threatening—perhaps even ominous.
In 2018, the first question would have been: What is driving this?
The remarkable feature is not that SC-2 mutates. Mutation is intrinsic to RNA-virus evolution.
What would have commanded attention is the repeated emergence and selection of viral descendants capable of maintaining transmission in populations containing exceptionally high levels of pre-existing immunity.
Scientists would have asked what selection pressures were driving this diversification, why evolution repeatedly converged on particular antigenically relevant sites, how much additional adaptive space remained available to the virus, and—perhaps most importantly—what would happen once additional immune-escape mutations began providing progressively smaller increments in viral fitness.
That last question deserves far more attention than it currently receives.
The simultaneous circulation of multiple antigenically diversified SC-2 lineages demonstrates that the virus continues to explore a substantial evolutionary landscape. Yet the interpretation of public health authorities and so-called health experts remains largely reassuring as long as newly emerging variants do not demonstrably cause more severe disease than their immediate predecessors.
But that answers a very different question.
The absence of increased virulence today tells us about the phenotype of the variants circulating today. It does not tell us where the evolutionary process generating them is heading.
Perhaps one reason this extraordinary situation attracts comparatively little attention is simply that we got used to it.
Another SC-2 lineage appears.
It carries another unusual constellation of mutations.
It competes with other (co-)circulating lineages.
Neutralizing antibody (Ab) recognition changes again.
A new version of the vaccine antigen (i.e., spike [S] protein) is recommended.
A parallel with the yearly flu shot is drawn.
And life continues.
After six years, what would have seemed extraordinary in 2018 has now become the virological wallpaper of 2026.
But familiarity should not be confused with biological normality.
The relevant question is no longer simply whether each newly emerging variant causes more severe disease than the variant immediately preceding it. The more consequential question is: What does the continuing proliferation of increasingly diversified immune-escape lineages tell us about the evolutionary landscape through which SC-2 is presently moving?
This is where my interpretation differs fundamentally from the prevailing one.
The present diversification is evidence that SC-2 remains under intense population-level evolutionary selection. But as immune-escape mutations accumulate, their incremental contribution to viral fitness cannot necessarily continue increasing indefinitely. Indeed, the increasingly marginal competitive advantage conferred by successive mutations may indicate that the virus is approaching diminishing returns within its current adaptive regime.
However, evolution does not stop when one adaptive route begins to provide diminishing returns.
It explores another one.
My hypothesis is therefore that sustained population-level immune pressure, particularly in highly C-19-vaccinated populations, will ultimately favor viral descendants that acquire qualitatively new functional capacities, enabling them to effectively sideline the population-level immune mechanisms that presently constrain their biological behavior.
This would represent much more than another incremental step in antigenic drift.
It could constitute a true evolutionary phase transition.
And one molecular route by which such a transition could conceivably occur deserves, in my view, far greater attention: spectacular remodeling of the S glycosylation profile through strategically positioned O-glycosite mutations.
S is not simply a protein surface on which Abs recognize amino acid epitopes.
It is extensively glycosylated. These glycans can sterically influence what portions of the S protein are accessible to Abs, alter conformational dynamics, modify receptor accessibility and profoundly affect the way the immune system perceives the viral surface.
This distinction is crucial.
Conventional immune escape largely involves changing the viral structures that Abs recognize. Strategically altered glycosylation can instead change whether those structures remain physically accessible to Ab recognition in the first place. Failure of Abs to recognize the virus inevitably results in enhanced viral infectiousness, trans-infectiousness and transfusion. This is precisely why I have previously drawn attention to the potential evolutionary importance of O-glycosite mutations.
As I already argued in an earlier contribution, sustained population-level immune pressure could ultimately select mutations that create or enhance strategically positioned O-linked glycosylation, particularly in regions where additional carbohydrate shielding could profoundly alter Ab access to biologically important areas of the S protein (https://www.voiceforscienceandsolidarity.org/scientific-blog/predictions-gvb-on-evolution-c-19-pandemic).
O-linked glycosylation is particularly interesting because it does not depend on the same strict consensus sequon as classical N-linked glycosylation. Changes in the local amino acid environment may therefore alter O-glycan attachment or occupancy in ways that could disproportionately remodel the antigenic landscape.
The evolutionary significance of such mutations could be enormous.
Instead of having to modify individual Ab epitopes one by one, the virus might acquire a small number of strategically positioned O-glycosite changes that substantially alter the physical accessibility of entire antigenic regions.
In other words: The virus would no longer simply be changing the target. It could be hiding the target.
That would represent a very different evolutionary solution.
The potential importance of O-glycosite mutations lies precisely in their ability to produce nonlinear phenotypic effects.
A single amino acid substitution may normally alter one Ab contact site or modestly change receptor affinity.
But a mutation that modifies site-specific glycosylation could, in principle, reorganize the steric environment surrounding multiple epitopes simultaneously.
Such remodeling could alter:
It is therefore entirely conceivable that a very small number of mutations could produce a disproportionately large change in the way the virus interacts with population immunity.
That is fundamentally different from the gradual accumulation of conventional escape mutations.
And it is precisely the type of evolutionary innovation that could generate a phase transition rather than merely another variant wave.
A true evolutionary phase transition, as I use the term here, cannot simply mean that SC-2 acquires another handful of RBD substitutions and becomes another few-fold less sensitive to neutralizing Abs!
That would be quantitative evolution along an already familiar axis.
The transition I am referring to would be qualitative.
It would involve acquisition of a viral phenotype capable of functionally bypassing immune mechanisms that presently constrain the virus at the population level.
In that context, O-glycosite evolution becomes particularly intriguing.
A strategically positioned mutation that creates, enhances or redirects O-glycan occupancy could potentially shield biologically crucial S regions without requiring wholesale alteration of the underlying amino acid sequence.
And if the virus were simultaneously able to preserve, or even improve, the functional properties required for efficient transmission, such a configuration could represent an evolutionary breakthrough.
The decisive event would therefore not simply be "more glycosylation."
It would be the emergence of a new glycosylation architecture with a major selective advantage under the prevailing immune pressure.
That is what could transform a gradual evolutionary process into a sudden phenotypic transition.
This point matters.
The possibility that altered O-linked glycosylation could eventually play a major role in SC-2 evolution is not an explanation introduced retrospectively after observing today's variants. I raised this possibility years ago.
At that time, I argued that prolonged immune pressure in highly C-19-vaccinated populations could eventually force SC-2 to search for a qualitatively different escape mechanism once conventional antigenic variation could no longer provide sufficient additional fitness (https://www.voiceforscienceandsolidarity.org/scientific-blog/predictions-gvb-on-evolution-c-19-pandemic).
I specifically discussed O-glycosite mutations as one possible route toward such an evolutionary breakthrough.
The prediction was—and remains—a hypothesis. But the evolutionary circumstances that motivated it have certainly not disappeared. Quite the contrary!
We now observe prolonged co-circulation of multiple diversified immune-escape lineages, while successive mutations appear to confer increasingly modest additional fitness advantages relative to their immediate predecessors.
That is exactly the situation in which one should begin asking whether the virus is approaching diminishing returns within its current evolutionary strategy.
This is why I believe assessing each new SC-2 lineage primarily by asking whether it currently causes more hospitalizations than its immediate predecessor risks missing the larger evolutionary picture.
The individual lineage may not be the message.
The collective evolutionary search may be.
Multiple diversified lineages are simultaneously exploring different solutions within a profoundly altered population immune landscape.
Each individual lineage provides only a snapshot.
The swarm reveals the process.
The relevant scientific question is therefore not merely: Which variant wins this month?
It is: What phenotype will eventually win when incremental immune escape no longer provides enough additional fitness?
And perhaps even more specifically: Could the decisive breakthrough arise from O-glycosite mutations that profoundly remodel the S glycosylation profile and thereby change the rules of immune recognition altogether?
This is where the concept of diminishing returns becomes important.
If the adaptive benefit of yet another conventional immune-escape mutation becomes progressively smaller, that does not mean viral evolution has reached an endpoint. It merely means that evolution may have reached a bottleneck at which selection increasingly favors alternative solutions capable of conferring a larger fitness gain.
Evolutionary systems do not have foresight but they relentlessly select whatever phenotype works best under the prevailing conditions. If one adaptive pathway becomes saturated, another may suddenly become much more valuable.
A new O-glycosylation pattern that profoundly modifies Ab accessibility could potentially provide such an alternative route. The change required might be genetically modest but its phenotypic consequence might not be!
That is why a phase transition can appear sudden even though the evolutionary pressure generating it has been accumulating for years.
Had evolutionary virologists been shown today's picture before the pandemic, they would surely have demanded intensive investigation into the selection pressures generating it and into its possible endpoints. They would not necessarily have predicted exactly which phenotype would emerge. Nor could they have known whether O-glycosite mutations, receptor-related changes, altered cell tropism or some other mechanism would eventually provide the decisive breakthrough.
But neither, I strongly suspect, would they have accepted the argument that because none of the currently circulating descendants produces dramatically greater clinical severity, the evolutionary process itself is therefore harmless!
That inference simply does not follow.
There is an enormous difference between saying:
"We currently see no evidence that this variant causes more severe disease."
and saying:
"We therefore see no reason for concern about the evolutionary trajectory producing these variants."
The first is an epidemiological observation.
The second is an evolutionary assumption.
Six years into the pandemic, surveillance naturally concentrates on immediate measurable outcomes: hospitalizations, intensive-care admissions, mortality and short-term vaccine effectiveness.
Those observations, however, reflect only the tip of the iceberg in highly C-19-vaccinated regions. They provide little insight into the much larger mass beneath the surface: the latent potential of the virus's evolutionary dynamics.
Major evolutionary transitions need not announce themselves gradually through changes in each of those indicators.
A system can appear phenotypically stable while selection pressure continues to accumulate and the virus explores alternative solutions.
The question I therefore believe deserves urgent attention is not whether today's SC-2 variants are substantially more virulent than yesterday's.
It is whether the extraordinary diversification we are witnessing represents the last stage of one adaptive regime, and whether, in highly C-19-vaccinated regions, the progressively diminishing fitness returns from conventional immune escape are preparing the conditions for selection to shift toward a fundamentally different viral phenotype.
If that hypothesis is correct, the most consequential variant of this pandemic will not necessarily be the one that escapes another class of neutralizing Abs a little better. It may be the one that acquires a qualitatively different way of interacting with population immunity.
And, as I predicted years ago, spectacular remodeling of the S O-glycosylation profile through strategically positioned O-glycosite mutations could provide one route toward precisely such a transition.
That would not simply represent the next step on the evolutionary staircase.
It could represent the point at which the virus finds another staircase altogether.
And that is why I find today's apparent complacency so remarkable.
We have become so accustomed to watching SC-2 evolve that we may have confused familiarity with biological normality.
Had we been shown the same evolutionary picture in 2018, I suspect the alarm bells would have been deafening! Perhaps the most important question today is why we can barely hear them anymore...
Geert Vanden Bossche received his DVM from the University of Ghent, Belgium, and his PhD degree in Virology from the University of Hohenheim, Germany. He held adjunct faculty appointments at universities in Belgium and Germany. After his career in Academia, Geert joined several vaccine companies (GSK Biologicals, Novartis Vaccines, Solvay Biologicals) to serve various roles in vaccine R&D as well as in late vaccine development.
Geert then moved on to join the Bill & Melinda Gates Foundation’s Global Health Discovery team in Seattle (USA) as Senior Program Officer; he then worked with the Global Alliance for Vaccines and Immunization (GAVI) in Geneva as Senior Ebola Program Manager. At GAVI he tracked efforts to develop an Ebola vaccine. He also represented GAVI in fora with other partners, including WHO, to review progress on the fight against Ebola and to build plans for global pandemic preparedness.
Back in 2015, Geert scrutinized and questioned the safety of the Ebola vaccine that was used in ring vaccination trials conducted by WHO in Guinea. His critical scientific analysis and report on the data published by WHO in the Lancet in 2015 was sent to all international health and regulatory authorities involved in the Ebola vaccination program. After working for GAVI, Geert joined the German Center for Infection Research in Cologne as Head of the Vaccine Development Office. He is at present primarily serving as a Biotech / Vaccine consultant while also conducting his own research on Natural Killer cell-based vaccines.
Email: info@voiceforscienceandsolidarity.org
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