Why the current ‘calm’ in SARS-CoV-2 evolution is an illusion of stability (‘endemicity’) and actually signals growing instability

You Can Lock Down Society But Not Viral Evolution in Highly Covid-19-Vaccinated Populations!

A new SARS-CoV-2 (SC-2) variant called BA.3.2 has attracted attention for several months now. At first glance, it might look like just another addition to the long list of Omicron subvariants. But a closer look suggests that something more fundamental may be unfolding.

BA.3.2 is not a typical variant. It carries a very large number of mutations, particularly in the spike (S) protein-the primary target of the immune response following natural infection and the target antigen used in all current COVID-19 (C-19) vaccines. In simple terms, it looks like the virus has made a large evolutionary jump (so-called ‘saltatory evolution’) rather than gradual step-by-step changes.

Scientists such as Kei Sato and colleagues have pointed out that BA.3.2 seems particularly good at evading antibodies (as reported on X by The Sato Lab). That is already notable. But what makes the situation more interesting is what happens next. Despite all these changes, BA.3.2 has not taken over.
As observed and reported on X by mutation spotters such as R. Hisner, the variant does not spread like a clearly ‘better’ virus would. Instead, it competes with other variants, rises somewhat in some places, and then levels off or declines (as reported on X by S. Pöhlmann, based on multiple independent tracking analyses across different countries). In other words, it behaves indecisively.

A Strange Pattern

Normally, when a virus evolves a major advantage, one of two things happens:

- it spreads quickly and replaces other variants or

- it disappears because the changes come at a significant fitness cost

BA.3.2 does neither. It persists, but without clearly winning. This is unusual and scientifically highly informative. It suggests that the virus may no longer be evolving freely. Instead, it may be running into increasing immunological and structural constraints as explained in several of my previous Substack articles.

What Changed?

Earlier in the pandemic, the virus mainly evolved to spread faster. Any mutation that improved transmission had a clear advantage. This became particularly pronounced once large parts of populations became vaccinated and immune escape variants-culminating in Omicron-were selected under population-level immune pressure.

Today, the situation is very different. Highly C-19-vaccinated populations now have some level of collective immunity, although suboptimal and narrowly focused, especially against the S protein. This creates strong immune pressure on the S protein, which is largely responsible for viral entry and infectivity.

At first, the virus readily escaped from this pressure by changing those S-associated targets, a phenomenon often referred to as immune refocusing, where the adaptive immune response is redirected toward alternative, often less immunogenic and more conserved epitopes on S protein. But over time, a problem arises as I already described in a series of previous Substack articles:

i) many of the most relevant immune targets have already been altered

ii) new mutations provide diminishing returns because functional and spatial constraints increasingly limit viability of additional S-based mutations

iii) earlier escape mutations cannot be reversed without restoring immune sensitivity and losing fitness advantage

The result is that the virus becomes trapped in a narrowing evolutionary corridor.

Why This Matters

In such a situation, even large changes-like those seen in BA.3.2-may no longer lead to clear evolutionary success. That is exactly what we are observing. BA.3.2 (sub)lineages are characterized by:

a) a high number of mutations

b) strong immune escape properties

c) lack of clear epidemiological dominance

This combination suggests that additional immune escape mutations no longer translate into decisive competitive advantage.

In other words, immune-driven selection pressure appears to be reaching functional limits in its ability to select variants that clearly outcompete others.

Ongoing Spread Keeps the System Active in Highly C-19-vaccinated Populations

Another key point is that the virus is still spreading widely.
Even though severe disease is less common, the virus still spreads widely: many infections are mild or even unnoticed, allowing the virus to circulate easily. In addition, some people develop chronic infection and carry the virus for longer periods, thereby contributing to extended viral shedding and giving it more time to evolve.

As long as the virus continues to replicate at scale, it keeps exploring new mutations even if a shift in predominance from immune pressure–driven selection to fitness-driven selection slows down viral evolutionary dynamics.

This matters because evolution depends on numbers:

i) more infections and/or prolonged transmission periods entail more replication
ii) more replication causes more mutations
iii) more mutations increase the probability of a newly emerging lineage capable of
breaking through the entire immune system

Hence, as long as the infectious viral burden remains sufficiently elevated in highly C-19-vaccinated populations, the virus continues to generate and test new configurations within a constrained fitness landscape.

No Endemicity But An Unstable Situation

What we are seeing now is not a stable endpoint and therefore not consistent with what our public health authorities and so-called ‘experts’ are trying to make people believe, namely that the virus has simply transitioned into a benign endemic phase!

Instead, it resembles a system under pressure because

i) the virus continues to replicate and change (as reflected by wastewater surveillance
samples)

ii) but gains are limited and inconsistent/ fluctuating

iii) variants compete, yet no single variant clearly dominates

This type of situation can persist for some time, but it reflects dynamic instability rather than equilibrium. Small changes in viral properties, the population’s immune background or socio-environmental determinants can lead to noticeable fluctuations in the prevalence of BA.3.2 or other co-circulating variants in highly C-19-vaccinated populations.

This persistent reshuffling of variant proportions is itself a hallmark of a metastable system. But it usually does not last forever because new mutations have less and less functional impact and old changes cannot be undone.

Together, this suggests that the virus is not settling into stability-it continues to experience additional immune pressure (albeit weaker) and to evolve (albeit less efficiently) while still searching for a way to adapt to the hostile immune environment of highly C-19-vaccinated populations (albeit at a much slower pace).

What appears as ‘calm’ may actually reflect a system under tension.

Although this system can persist for a while, such unstable balances in complex systems often end not gradually, but suddenly, i.e., when changes accumulate sufficiently to push the system past a tipping point, triggering a phase transition.

What About the United States?

The U.S. adds an important piece to the puzzle.
Although BA.3.2 has been detected in some clinical and wastewater surveillance samples from multiple states, it currently plays no significant role in the U.S. SC-2 landscape. Yet the same overall pattern is observed: multiple variants continuously rise and fall in relative proportion, without any single lineage establishing long-term dominance (see figure below).

This is important as it indicates that the underlying phenomenon is not specific to BA.3.2.

Whether BA.3.2 will become more prevalent in the US or not remains uncertain but this does not change the overall observation that the virus as a whole is in a state where it keeps evolving while no variant clearly dominates. Hence, even in the absence of significant BA.3.2. co-circulation, the virus appears to be evolving within constraints, without reaching a stable solution. Hence, the presence of BA.3.2 is not required to demonstrate that the system itself is metastable and unresolved.

What Could Happen Next?

If current conditions persist-ongoing transmission combined with a constrained evolutionary landscape-the probability increases that a new variant with a markedly different antigenic and/or functional profile, enabling a much stronger competitive advantage, could emerge.

However, because the virus is operating under decreased additional immune pressure and within a restricted evolutionary space, it may take time for such a variant to arise. In order for a new viral lineage to acquire a truly significant fitness advantage, it would likely need to overcome existing adaptive immune memory while also effectively exploiting early infection dynamics.

As highly C-19-vaccinated populations are characterized by suboptimal adaptive immune responses and insufficiently trained cell-based innate immunity, they constitute an excellent breeding ground for such a lineage.

Such development would represent a qualitative shift in virus-host interaction, rather than a simple continuation of current trends.

It is difficult to envisage how such a qualitative shift could enable the virus to overcome the overall host immune response and maintain infectivity without becoming highly virulent.

This is where I anticipate the chronic phase of this immune escape pandemic to transition into a hyperacute phase, driven by a late, highly virulent Omicron descendant (HI-VI-CRON).
However, as the transition to a lineage that spreads very efficiently and outcompetes all other circulating variants may require some lag time, the emergence of HI-VI-CRON is unlikely to occur overnight (i.e., within a single day).
But let us be clear: this does not mean that the current situation should be mistaken for stability.

In Summary

BA.3.2 is unlikely to evolve consistently into the next dominant variant. But, together with the persistent fluctuations in co-circulating variants, it significance as a warning signal could be much more relevant than its epidemiological or clinical impact:

A signal that viral evolution is no longer evolving in a simple, predictable way as driven by selective immune pressure on S-associated B and Tc epitopes.

A signal that current immune and transmission dynamics are constraining viral adaptation in highly C-19-vaccinated populations.

A signal that the system is becoming unstable rather than settling down.

What looks like calm is, in reality, a system under pressure, still searching for a viable evolutionary path forward. As the current evolutionary dynamics suggest that continued instability is far more plausible than smooth resolution, the question doesn’t seem to be whether such a path will emerge but rather when it will do so.