Are Newly Emerging Saltation Variants the Desperate Harbingers of an Imminent Surge in COVID-19 Case Fatalities in Highly C-19 Vaccinated Populations?

Mutation trackers[1] are increasingly concluding that the SARS-CoV-2 (SC-2) virus has mutated to a point where it can no longer significantly increase its infectiousness due to the high fitness[2] costs associated with the pleiotropy[3] exhibited by the divergent saltation variants[4] currently co-dominantly circulating.

Pleiotropic effects are tightening the viral transmission bottleneck and increasing population-level transmissibility pressure on viral trans infection in highly Covid-19 (C-19) vaccinated populations.

Pleiotropic effects are now increasingly reported in newly emerging saltation variants as a result of escape mutations (including NTD-glycan-adding mutations) occurring at the N-terminal domain (NTD). As pleiotropic effects may cause unrelated viral properties to have antagonistic effects on viral infectiousness, they are prone to constraining evolutionary changes at the receptor-binding domain (RBD), despite the collective transmissibility pressure on the virus. The counterbalancing effects on viral infectiousness eventually result in a tight viral transmission bottleneck .

As tight transmission bottlenecks make these escape mutations prohibitively costly, mutation analysts predict that new mutations will occur in chronically infected individuals that enable enhanced intra-host viral infection. The Bloom lab, for example, expects that ‘evolution will eventually solve this pleiotropic puzzle through some epistatic combination of mutations’.

Epistasis refers to the interaction between different genetic loci, where the effect of one mutation can mask, modify, or enhance the effect of another. These interactions are particularly relevant in the context of glycosylation mutations, as the glycosylation process involves complex biochemical pathways where multiple genes and enzymes interact. However, what’s the likelihood that multiple amino acid or even glycosylation mutations at different sites will mutate simultaneously in ways that enable a higher fitness level?

While I do agree that evolution will eventually solve this pleiotropic puzzle, I don’t think the solution is going to be one that simply needs more time for a more transmissible epistatic combination of several mutations to occasionally emerge in a single infected individual and become dominant. In my opinion, the chances of this randomly happening in due time (!) are slim.

In any case, to solve the prolonged and hence life-threatening transmission bottleneck issue, the virus is now likely to shift gears and focus on enhancing intra-host rather than inter-host transmissibility. Mutation trackers currently wonder whether this will resolve the virus’s transmission bottleneck and whether this potentially even result in severe disease (“We’ve been lucky so far…Let’s hope our luck holds”). It’s remarkable to find that at this late stage in the pandemic, mutation trackers are for the first time highlighting the potential threat posed by the current evolutionary dynamics of the virus. However, they’re still ignoring any link between the large-scale vaccination program with non-sterilizing C-19 vaccines and the initial convergent evolutionary path of viral mutations or the subsequent large-scale vaccine-breakthrough infections that drove immune refocusing and eventually led to a diversified spectrum of more infectious immune escape variants. Because this has ultimately resulted in a metastable situation that now translates into a viral transmission bottleneck, the only way for the virus to escape is to select mutations that will promote its intra-host transmission.

How did the large-scale emergence of diversified immune escape variants eventually transition into a narrow viral transmission bottleneck?

The occurrence of an inter-host transmission bottleneck of a highly infectious virus, which used to yield a panoply of immune escape variants, can only be explained by enhanced adsorption of highly infectious progeny virus on dendritic cells (DCs) patrolling the upper respiratory tract (URT). This is because enhanced viral infectiousness hampers viral trans infection, which mediates intra-host transmission (https://bit.ly/3NYokkE). This explains why, above a certain threshold, an increase in intrinsic viral infectiousness will significantly reduce viral shedding and likely cause highly C-19 vaccinated populations to promote the selection of escape variants that will no longer adsorb onto patrolling DCs, despite their enhanced intrinsic infectiousness.

In other words, highly infectious variants that suffer from an inter-host transmission bottleneck would automatically generate high selection pressure on viral trans infectiousness, i.e., on viral intra-host transmissibility, which is associated with viral virulence. The emergence of a new coronavirus (CoV) escaping such collective transmissibility pressure on viral virulence represents a deadly threat to highly C-19 vaccinated populations.

Viral transmission bottlenecks[5] entail a reduced potential for viral adaptation... unless they promote a fundamental change in the type of selection pressure exerted on the virus.

Transmission bottlenecks constrain adaptive evolution by limiting the spread of newly arising mutations and reducing the efficiency of selection on these mutations along transmission chains (see figure appended at the bottom). As strong and sustained immune selection in highly C-19 vaccinated populations has now dramatically reduced the large genetic diversity initially generated by the mass vaccination program (https://pubmed.ncbi.nlm.nih.gov/39060204/), the rapid transmission of currently co-circulating, highly infectious viral variants likely results in a viral (inter-host) transmission bottleneck. However, while bottlenecks are associated with reduced genetic variation, they do not necessarily constrain the virus's ability to adapt as they may promote another type of mutations that are advantageous for viral survival. This is because these distinct mutations may counteract the inhibition mechanisms resulting from newly acquired viral traits (e.g., from enhanced intrinsic infectiousness) that underlie these bottlenecks and affect viral fitness in a fundamentally different way. Such mutations may be selected when enhanced viral infectiousness is at risk of imposing a fitness cost due to limited inter-host transmission, for example, when highly infectious immune escape variants hamper or inhibit viral trans infection. In my book (https://bit.ly/3NYokkE), I explain how such highly infectious lineages constrain inter-host transmission pathways, thereby causing a viral transmission bottleneck. Provided there is sufficient transmissibility pressure on the virus, a new type of mutation(s) may be selected that promotes intra-host transmission by abolishing the inhibition of viral trans infection.

Mutation spotters and molecular epidemiologists attribute the successive emergence of saltation variants to chronic SC-2 infections in single immunosuppressed individuals. I disagree.

I do not concur with the notion that SC-2 causes chronic infection. I believe instead that the repeated detection of the virus is due to prolonged adsorption of SC-2 to patrolling DCs in the URT. This distinction is important as many scientists currently give the impression that saltation variants result from occasional or random mutations in single, chronically infected patients. These saltation variants, having a slight reproductive advantage, begin to compete with other circulating variants. However, if the currently observed saltation variants were merely the result of random mutations in chronically SC-2-infected patients, one could not explain the fairly rapid and widespread succession of these newly emerging variants—particularly in highly C-19 vaccinated populations. Viral evolution through the occasional occurrence of favorable mutations in a multitude of chronically infected individuals is indeed much slower than viral evolution driven by selection pressure.

Genetic divergence of saltation variants does not necessarily imply their origin from chronic infections in single individuals.

Whereas unique variants may emerge under individual-specific selective pressure on the virus, they are also entirely compatible with collective selective pressure on distinct RBD-associated sites whose mutation entails similar changes in viral infectiousness through pleiotropic effects. This is because:

Strong selective pressure creates a fast "arms race" dynamic where advantageous mutations spread quickly within the viral population.

Hence, the scientific postulate that transmission bottlenecks limit the spread of novel mutations and reduce the efficiency of selection—thereby constraining the evolution of highly transmissible SC-2 variants (https://www.nature.com/articles/s41467-023-36001-5) —does not generally apply.

It is well known that saltation variants are typically rare but can arise under intense selective pressure. However, it is difficult to understand how more infectious saltation variants could become broadly and rapidly (co-)dominant in the absence of a collective tightening of the inter-host transmission bottleneck. In the absence of large-scale selection pressure, most mutations are neutral or deleterious. Randomly occurring adaptive mutations that overcome intrinsic transmission bottlenecks are rare and take much longer to accumulate.

If the rapid and widespread emergence of divergent saltation variants were due to prolonged infections in immunosuppressed individuals, there would also be no reason for these variants to primarily—or exclusively— emerge in highly C-19 vaccinated countries. Their rapid and widespread propagation in the absence of population-level immune pressure on viral transmissibility would require these variants to emerge independently and in parallel in a multitude of chronically infected individuals, which is highly unlikely.

But even the assumption that SC-2 variants may cause chronic infection is highly questionable, as previously mentioned. While I agree that a large portion of highly infectious virions remains detectable in the URT without causing acute infection, there is no clear evidence that SC-2 causes ‘productive’ chronic infection. This is because highly infectious variants may adsorb to URT-resident DCs in individuals who experienced breakthrough infections following vaccination or natural infection without causing productive infection. This already explains why increased viral infectiousness eventually results in reduced shedding, leading to an overall inter-host transmission bottleneck in highly C-19 vaccinated populations, as mentioned in the previous paragraph. This bottleneck causes these populations to collectively exert selective transmissibility pressure on viral trans infectiousness (i.e., on viral virulence). This phenomenon would not only explain the elevated speed of the currently observed viral evolutionary dynamics in all highly C-19 vaccinated regions but also strongly suggest that collective, population-level influences on the virus—rather than occasional mutations in single individuals—are driving the enhanced evolutionary dynamics during a SC-2 pandemic in these populations.

It is therefore undeniable that the large-scale vaccination program initially caused highly vaccinated populations to exert immune pressure on intrinsic infectiousness of SC-2 and thereby transformed a natural pandemic in an immune escape pandemic. In my opinion, there is also no doubt that this immune escape pandemic is now on the brink of transitioning into a virulent pandemic due to the increasing intra-host transmissibility pressure that highly C-19 vaccinated populations collectively exert on the intrinsic trans infectiousness of the virus. The fact that we have not yet seen a spectacular increase in the incidence of severe disease merely suggests that the collective pressure on the virus to shift from high intrinsic infectiousness to high intrinsic virulence has not yet crossed a critical threshold.

Conclusion: Immune or transmissibility selection pressure accelerates viral evolution, driving the emergence of variants at a pace far beyond what would occur from occasional favorable mutations alone. I therefore do not concur with the viewpoint that the epistatic combination of multiple mutations occurring during spread of highly transmissible variants is highly unlikely, or that prolonged or chronic infections in single individuals would be required to drive the evolutionary selection of highly mutated, so-called saltation variants.

Given the high intrinsic infectiousness of currently circulating immune escape variants and the collective pressure exerted on viral trans infection by the increasingly tight transmission bottleneck in highly C-19 vaccinated populations, it is difficult to believe that the virus is not already preparing a surge in C-19 case fatalities in highly C-19 vaccinated populations.

If I am right and the mutation trackers are wrong, then we will not witness a gradual, protracted emergence of divergent, highly infectious saltation variants over a longer timescale. Instead, we will see the rapid, sudden emergence of divergent, highly virulent saltation variants. The latter will likely mediate their increased virulence through fundamental changes in their glycosylation profile, giving rise to an entirely new type of CoV—“Hivicron.”

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[1] The stated perspectives of mutation spotters and analysts (mostly virologists, evolutionary biologists or molecular epidemiologists) are primarily derived from their recent posts on social media platforms (e.g., https://x.com/JPWeiland; https://x.com/jbloom_lab; https://x.com/LongDesertTrain; https://x.com/DPruss6; https://x.com/yunlong_cao).

[2] Viral fitness refers to the ability of a virus to replicate and propagate within a host and/or across populations. It encompasses survival, reproduction, and transmission efficiency.

[3] A pleiotropic effect occurs when a mutation influences multiple, seemingly unrelated viral characteristics (e.g., virus neutralizability, RBD-ACE2 binding affinity or avidity). This effect is often the result of an allosteric effect. For the purpose of this article, ‘allosteric effect’ is defined as the effect of a mutation at the RBD of spike (S) protein on the protein’s infectiousness through interaction of the mutated site with other functionally important domains, thereby causing altered neutralizability or binding of S-associated domains other than those comprised within the RBD.

[4] For the purpose of this article, saltation variants refer to mutations that confer sudden, significant changes in viral properties.

[5] For the purpose of this article, transmission bottleneck refers to a significant reduction in the genetic diversity of a virus as it passes from one host to another. This phenomenon occurs when only a small subset of the virus population in the original host successfully establishes an infection in the new host, often due to the selection of certain variants. These selected variants enable viral adaptation to the exposed host (population).