Is the spike protein of KP.2 adorned with additional glycan chains?

Recently, it has been described how the SARS-CoV-2 (SC-2) KP.2 variant (JN.1.11.1.2) is capable of rapidly gaining ground on the hitherto predominant 'parent' variant, namely JN.1 (itself descending from BA.2.86; https://www.biorxiv.org/content/10.1101/2024.04.24.590786v1; fig. 1). This evolution sharply contrasts with the trend observed so far, namely that the fitness advantage of new JN.1 descendants is not strong enough to sufficiently displace JN.1, thus causing different, more transmissible JN.1 variants to consecutively emerge (https://www.voiceforscienceandsolidarity.org/scientific-blog/how-things-could-change-het-kan-verkeren).
According to the concept illustrated in fig. 2 below, which depicts the shift from virus internalization into antigen-presenting cells (APCs) to virus adsorption onto APCs, heightened virus adsorption onto migratory dendritic cells (DCs), coupled with KP.2's enhanced resistance to binding by vaccine-primed potentially neutralizing antibodies (pNAbs), diminishes cytotoxic T lymphocyte (CTL) activation and thus reignites virus spread. This would enable SC-2 variants showing an increased degree of glycosylation to promote their transmission. This is because increased glycosylation of viral surface proteins, for example, the spike (S) protein, can enhance binding of glycosylated viruses to lectins[1] expressed on the surface of DCs. The reinforced interaction of the virus with lectins expressed on DCs will only increase the adsorption of progeny virions and thus the immune pressure on the non-neutralizing polyreactive antibodies (PNNAbs) [https://www.voiceforscienceandsolidarity.org/scientific-blog/i-can-now-spot-the-tsunami-at-the-horizon; https://www.voiceforscienceandsolidarity.org/scientific-blog/jn-1-quasispecies].

Despite the fact that additional virus glycosylation likely hampers intrinsic viral infectiousness, it is still possible that increased viral transmission will ultimately result in increased viral fitness of KP.2 relative to JN.1.  This indeed seems plausible, as additional glycosylation is likely to further reduce viral susceptibility to binding by pNAbs. Furthermore, because of their increased adsorption on DCs, the intrinsic infectiousness of JN.1 progeny virions is constrained as well.

The above-described dynamics of virus evolution and spread could explain the appearance and increasing spread of KP.2: “The escalating variant frequency of KP.2 underscores the variant’s ability to outcompete existing lineages and establish itself as a significant contributor to the ongoing pandemic dynamics” (https://www.thailandmedical.news/news/study-identifies-virological-characteristics-of-the-sars-cov-2-kp-2-variant-one-of-the-variants-behind-spring-s-silent-covid-19-surge).

As far as I am aware, the glycosylation profile of KP.2 has not yet been reported. However, it is evident that despite its significantly reduced intrinsic infectiousness (i.e., compared to JN.1), KP.2 exhibits a clear competitive advantage in terms of its spread. Nonetheless, I believe that the fitness advantage of KP.2 will ultimately prove insufficient to ensure the virus's continued dissemination. Therefore, I feel very concerned that the KP.2 variant will soon be replaced by a new coronavirus (CoV) lineage, in which the S protein's glycosylation will fully overcome the virulence-inhibiting effect of PNNAbs. Only then will the virus regain an effective growth advantage. However, this dramatic increase in viral replication will primarily occur within infected hosts rather than through inter-host transmission.

In conclusion, it is crucial to investigate KP.2's glycosylation profile to better understand its unique virological behavior and determine whether KP.2 could herald the emergence of a new CoV lineage with enhanced virulence potential for COVID-19 vaccine recipients. Regardless of the  underlying structural changes in the S protein, it seems likely that KP.2’s ability to establish itself as a significant contributor to the JN.1 quasispecies population suggests the virus's readiness to undergo a dramatic structural and functional transformation (https://www.voiceforscienceandsolidarity.org/scientific-blog/jn-1-quasispecies). This readiness could precipitate the sudden emergence of a new CoV lineage, namely HIVICRON, capable of inducing a significant surge in enhanced severe disease across highly COVID -19 vaccinated populations.

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[1] Lectins are proteins that can bind specifically to certain carbohydrate structures present on the surface of pathogens, such as viruses.

Fig. 1:

Fig. 2:

Early Omicron descendants enter target host cells via PNNAb-dependent enhancement of infection (Œ). PNNAbs bind to progeny virus tethered to these DCs, which subsequently migrate to the lungs and other distal organs (). On the other hand, previously SIR-primed Abs bind with low-affinity to the antigenically more distant immune escape variant, thereby generating  Ab-virus complexes that are taken up into patrolling APCs (Ž). Enhanced uptake of large Ab-virus complexes into APCs facilitates strong activation of CTLs, thereby enabling the elimination of virus-infected host cells.

Highly infectious Omicron descendants do not rely on PNNAb-dependent enhancement of infection to enter target host cells. Replication of highly infectious variants generates an immunological environment that promotes their adsorption onto tissue-resident DCs. Due to their high level of intrinsic infectiousness, newly emerging, more transmissible Omicron descendants (e.g., members of the JN.1 clan) will therefore enhance the adsorption of progeny virions on migratory DCs and thereby reduce viral uptake by APCs. Reduced viral uptake by APCs will promote the priming of CD4+ T cells. Some of these T cells may be self-reactive, while others are foreign-centered but fail to serve as T helper cells to assist in boosting of previously SIR-primed Abs due to a lack of immune recognition of the corresponding S-associated B cell epitopes comprised within large Ab-coated virus complexes. Diminished boosting of previously primed anti-S Abs results in diminished production of PNNAbs.
As these more infectious and inflammatory variants (i.e., the JN.1 clan) steadily increase in prevalence, diminished production of PNNAbs, combined with their enhanced binding to highly infectious DC-tethered progeny virions leads to a steadily increasing immune pressure on viral virulence in highly Covid-19 (C-19) vaccinated populations. This is thought to eventually trigger the selection of a new Coronavirus lineage that has the capacity to cause PNNAb-mediated enhancement of vaccine breakthrough infections in highly C-19-vaccinated populations, thereby causing a massive wave of enhanced severe C-19 disease.