Omicron is not what was initially considered a mysterious blessing...

I am herewith reacting to a recent paper titled: “Omicron breakthrough infection drives cross-variant neutralization and memory B cell formation”:

https://www.biorxiv.org/content/10.1101/2022.04.01.486695v1.full.pdf

To more accurately reflect what Omicron breakthrough infections actually do, I would like to rephrase this title as follows:

“Omicron breakthrough infection drives the evolution of SARS-CoV-2 (SC-2)towards new variants that are characterized by high infectiousness, high virulence and lack of immunogenicity of potentially neutralizing epitopes.”

This, of course, does not endorse the conclusions of the authors.Their publication is a tricky one as it erroneously generates the expectation that, despite imprinting of the immune response by previous vaccination, the antibodies elicited upon a breakthrough infection with Omicron are well-suited to protect vaccinees against a myriad of new variants that may emerge. The authors even suggest that a C-19 vaccine that is adapted to the Omicron spike protein (S) would be a promising avenue to achieve this goal.

Why are these scientists so terribly wrong?

Their assumption would be correct if it were not for the fact that widespread breakthrough infections in a population that is largely endowed with vaccine-induced immunity from which Omicron has escaped are causing that population to exert massive immune pressure on viral virulence by virtue of boosting non-neutralizing Abs in the highly vaccinated population. These very same Abs are responsible for further enhancing viral infectiousness and will thereby enable the ACE2 (angiotensin converting enzyme-2) receptor on epithelial cells to outcompete broadly neutralizing Abs for binding to the receptor-binding motif ^{(note 1)} of S protein (S-RBM). Although very effective in vitro, the protective effect of broadly neutralizing antibodies (Abs) elicited in Omicron-infected vaccinees will be short-lived as they first need to mature and rise at high titers before they will be able to outcompete ACE2 receptor for binding to the S-RBM. This is to say that- despite the induction of Abs that have broad cross-neutralizing capacity in vitro, it will take time for these Abs to control viral infection and hence, viral transmission in vivo. Delayed control of infection and concomitant prolongation of viral shedding maypredispose to long-haul Covid.

Natural selection of new, O-glycosylated variants, which I have predicted to rapidly emerge (https://www.voiceforscienceandsolidarity.org/scientific-blog/predictions-gvb-on-evolution-c-19-pandemic),would allow to overcome binding of both, potentially infection-inhibiting (i.e., neutralizing) Abs directed at theimmuno dominant receptor-binding domain (RBD) and potentially ‘trans infection’-inhibiting ^{(note 2)} (i.e., virulence-mitigating) Abs directed at the conserved antigenic site within the N-terminal domain of S protein (S-NTD). Consequently,O-glycosylation of the S-RBD would overcome population-level immune pressure that results from boosting of vaccine-primed Abs directed at conserved NTD-specific epitopes that cross-protect against severe disease. This is because NTD-associated ‘trans infection’-inhibiting (i.e., virulence mitigating) epitopes will be shielded against their corresponding Abs by the O-glycosites inserted at the predicted O-glycosylation sites of the new variants (New covariants). At the same time, these O-glycosites would also shield RBD-associated infection-inhibiting (i.e., neutralizing) epitopes against their corresponding Abs. Natural selection of the O-glycosylated Newco variants would, therefore, enable SC-2 to effectively counter the growing virus-neutralizing and virulence-mitigating capacity of a highly vaccine-experienced population that is exposed to Omicron, and thereby relieve the pressure on the viral life cycle.

The more Omicron expands in prevalence and the more frequently vaccinees get re-exposed and fall victim to breakthrough infections, the higher the prevalence of both elevated virulence-mitigating anti-S Abs will become.  The higher this prevalence and the higher the anti-S Ab titers, the higher the site occupancy of the predicted O-glycosylation sites will need to be for Newco variants to resist the trans infection-inhibiting immune response of Omicron-infected vaccinees. This is because more densely O-glycosylated variants will more effectively prevent mitigation of viral virulence. Given the population-level immune pressure caused by the exposure of highly vaccinated populations to the highly infectious Omicron, Newco variants will primarily rely on glycosite instead of amino acid mutations in their RBD to gain the required fitness advantage in a landscape of increasing population-level immune pressure on S-NTD.

This already explains why the upcoming Newco variants are likely to evolve to a super variant that is not only highly infectious but also highly virulent and fully resistant to C-19 vaccines, including those that have been adapted to the spike protein of the circulating variant. This is why the authors of this paper are desperately wrong in thinking that tailoring the vaccines to the polypeptide sequence of S on the dominantly circulating variant would have a beneficial effect on the outcome of the mass vaccination program. On the contrary, usage of so-called ‘updated’ vaccines to continue this program will only aggravate the outcome due to further boosting of anti-NTD Ab titers.

Conclusion:In the absence of large scale antiviral prophylaxis, the vicious circle of steadily increasing immune pressure causing steadily rising infection rates will ultimately drive highly vaccinated populations to promote the expansion of a super variant that will likely be featured by full resistance to potentially neutralizing epitopes (due to lack of immunogenicity of these epitopes) combined with a high propensity to cause Ab-dependent enhancement of infection (ADEI; facilitated by the infection-enhancing Abs) and a high propensity for causing ADEI-mediated Ab-dependent enhancement of disease (ADED).This is how the evolutionary dynamics of the virus will unfold and how the end station of this misguided mass vaccination program will look.

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Note 1: Although RBM is normally poorly immunogenic (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833242/), Abs against the RBM are likely elicited when infection-enhancing (i.e., trans infection-inhibiting) Abs bind to S-NTD on the close state-constrained virions tethered to migratory dendritic cells and thereby induce a structural re-arrangement of S-RBD such as to allow for immune recognition of the RBM.

Note 2: Trans infection-inhibiting Abs hamper trans infection of host target cells at the lower respiratory tract by infectious SC-2 virus tethered to migrating DCs (a presentation which stabilizes S in closed position). Inhibition of trans infection impedes trans fusion and, therefore, mitigates virulence (i.e., prevents severe / systemic C-19 disease). The very same Abs have an infection-enhancing effect when they bind to the open conformation of S (i.e., when S is expressed on free virions at the level of the upper respiratory tract).

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