Wait... Isn't BA.3.2 Supposed to Need Covid-19-Vaccinated People?

Wait... Isn't BA.3.2 Supposed to Need Covid-19-Vaccinated People?

Who Told BA.3.2 It Wasn't Allowed to Spread There?

One of the more interesting observationsrecently shared by mutation trackers is that BA.3.2-derived lineages appear toperform remarkably well not only in highly Covid-19 (C-19)-vaccinatedpopulations, but also in regions where vaccine coverage has remained relativelylow (https://x.com/longdeserttrain/status/2083538912039805070?s=12).

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

I don't.

In fact, I think it illustrates afundamental misunderstanding of how viral evolution operates once an immuneescape pandemic has entered its chronic phase.

The implicit assumption seems to be the following:

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

At first glance, that might sound quitereasonable. Unfortunately, viral evolution is rarely that simple ─at least notfor those who appreciate the evolutionary dynamics of a virus continuouslyadapting to persistent, incremental, yet suboptimal population-levelimmune selection pressure on infectivity and transmissibility.
The fundamental mistake made by those who fail to appreciate these evolutionarydynamics is to assume that immune escape and intrinsic transmissibilityremain permanently coupled!

They don't.

Immune selection pressure determines whichvariants are selected. Once selected, however, those variants no longer competeprimarily on the basis of antigenic escape but on the basis of their overallviral fitness.

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

The emergence of Omicron fundamentallychanged that evolutionary landscape.
In highly C-19-vaccinated populations, immune escape suddenly became thedominant driver of selection. Hence, variants capable of infecting individualswith vaccine-primed immunity enjoyed an obvious competitive advantage.

But evolution does not optimize only one characteristic. Once immune escape hassecured a substantial competitive advantage in highly C-19-vaccinatedpopulations, natural selection is free to optimize every other component ofviral fitness that remains evolutionarily accessible, particularly intrinsictransmissibility. Consequently, an immune escape lineage can continuebecoming more transmissible even without acquiring additional immune escapemutations.

In other words, once BA.3.2 and itsdescendants had successfully escaped the prevailing immune landscape, evolutionwas free to further optimize their intrinsic transmissibility.

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

On the contrary! Improved intrinsictransmissibility represents a fitness advantage largely independent of theimmune status of the next host population.

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

There is therefore nothingparadoxical about BA.3.2 spreading efficiently in poorly C-19-vaccinatedregions.

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

Once selected, every lineage continuesaccumulating whatever mutations further improve its reproductive success. Thisis exactly what one would expect from a virus that has entered a prolongedperiod of constrained evolution.

Because the competitive advantage conferredby additional immune escape mutations has become increasingly marginal amongcurrently co-circulating SARS-CoV-2 (SC-2) lineages, natural selection isexpected to place greater emphasis on mutations that improve other componentsof overall viral fitness, particularly intrinsic transmissibility.

This may also explain why recent mutationtrackers increasingly report amino acid substitutions not only in Spike butalso in several non-Spike proteins. Many of these mutations likely provideonly marginal improvements in overall viral fitness. Individually, theirphenotypic impact is expected to be minimal; collectively, however, they maygradually optimize viral replication, stability, innate immune antagonism ortransmissibility while remaining insufficient to fundamentally alter thevirus's biological behavior of the virus. They merely make an alreadysuccessful lineage slightly more successful.

Paradoxically, this conservativeevolutionary strategy may explain the extraordinary duration of the currentevolutionary regime. The observation reported by some mutation spotters fits,therefore, remarkably well with the concept of a prolonged metastablephase that I have described repeatedly. The virus continues buyingtime through countless incremental improvements.

Each small gain postpones ─but doesnot eliminate─ the need for a fundamentally different adaptive solution.

This is why I do not interpret thecurrent evolutionary dynamics as evidence that SC-2 is settling into endemicequilibrium.

Quite the opposite!

The prolonged coexistence of multipleunrelated immune escape lineages, together with increasingly modest fitnessgains and gradual optimization of intrinsic transmissibility, suggests to methat the virus is extracting the last remaining benefits from conventionalamino acid-based adaptation.

Whether this process eventuallyculminates in the phase transition that I have termed Hi-Vi-Cron remains myunchanged prediction.

In conclusion, I certainly do not find it difficult to understand why animmune escape lineage that has subsequently acquired additionaltransmissibility-enhancing mutations can ultimately dominate even inpopulations with relatively low C-19 vaccine coverage. On the contrary, onceimmune escape has been established and selection shifts toward optimizingoverall viral fitness, that is precisely what evolutionary theory would predict!

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