Why are breakthrough infections with Omicron anything but a blessing and why will re-vaccination of C-19 vaccinees with an updated S(Omicron)-based C-19 vaccine make things even worse?

I am herewith reacting to the scientifically simplistic and naïve conclusions drawn in some recent scientific publications:

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

https://www.medrxiv.org/content/10.1101/2022.04.29.22274477v1.full.pdf

One has no choice but to react to these papers as their authors reach some dangerous but false conclusions such as:

“However, vaccination increase neutralization capacity against these emerging variants and would likely offer good protection against severe disease” or:

“In aggregate, our results suggest that despite possible imprinting of the immune response by previous vaccination, the preformed B-cell memory pool can be refocused and quantitatively remodeled by exposure to heterologous S proteins to allow neutralization of variants that evade a previously established neutralizing antibody response” or:

“…..our observations suggest that a vaccine adapted to the Omicron S protein could similarly reshape the B-cell memory repertoire and therefore may be more beneficial than an extended series of boosters with the existing Wuhan-Hu-1 spike based vaccines”

‍

The question in the title of this article can be phrased more clearlyas follows:

Why do breakthrough infections with Omicron have a deleterious impact on both, individual and public health? Why will re-vaccination of C-19 vaccinees with an updated S(Omicron)-based C-19 vaccine during a pandemic make breakthrough infections even more likely and further increase population-level immune pressure on viral virulence?

Breakthrough infections with Omicron will rapidly recall non-neutralizing infection-enhancing antibodies (Abs) in previously C-19 vaccinated individuals and thereby enable disproportionally high binding of these Abs to the conserved infection-enhancing site within the N-terminal domain of spike (S) protein (S-NTD) [1]. This binding is likely to induce conformational changes that prevent Absdirected at the receptor-binding domain of S protein (S-RBD) from binding to their variable neutralizing epitopes. Upon breakthrough infection, these Abs will, indeed, take much more time to mature and to rise to high concentrations. As boosting of infection-enhancing Abs in previously vaccinated individuals will promote Ab-dependent enhancement of infection (ADEI), potentially broadly neutralizing anti-S(Omicron) Abs that - following breakthrough infection with Omicron - are raised against the receptor-binding motif (RBM)(note 1) will be readily out competed by the ACE2 (angiotensin convertin genzyme-2) receptor (which is highly expressed on the surface of epithelial cells in the upper respiratory tract) for binding to the RBM of S protein. This will be the case for as long as these Abs have not achieved high affinity and have not raised to high concentrations.  

Consequently, broadly neutralizing Abs in C-19 vaccinees who have experienced a breakthrough infection are unlikely to prevent viral entry into epithelial host cells until they have achieved a level of affinity and concentration that enables them to outcompete ACE2 for binding to the S-RBM. However, as high neutralizing anti-S-RBM titers are required to prevent viral entry/ infection and override ADEI,broad protection after Omicron breakthrough infection is short-lived. Vaccinees are, therefore, becoming rapidly susceptible tore-infection.

In conclusion, poor neutralizing capacity of anti-S Abs in vaccinees not only enhances their susceptibility to breakthrough infection with Omicron but is also suspicious of delaying viral clearance, thereby promoting prolonged viral shedding and potentially predisposing vaccinees to long-haul Covid while causing them to exert sustained immune pressure on viral virulence [1]. The likelihood of breakthrough infections in C-19 vaccinees will even further increase upon their re-vaccination with an updated S(Omicron)-based C-19 vaccine during the pandemic. This is because re-vaccination will boost the infection-enhancing anti-S Abs and thereby further increase the susceptibility of vaccinees to breakthrough infection. This will result in an even higher capacity of the ACE2 receptor to outcompete broadly neutralizing anti-S(Omicron) Abs for binding to the S-RBM.  

Based on the mechanism explained above, it also follows that high titers of non-neutralizing infection-enhancing Abs in vaccinees who experienced a breakthrough infection with Omicron (whether or not facilitated by re-vaccination with an updated S[Omicron]-based C-19 vaccine) will prevent these individuals from exerting immune pressure on variable or conserved S-RBD neutralizing epitopes. This is to say that breakthrough Omicron infections in vaccinees, especially when re-vaccinated with an updated S(Omicron)-based C-19 vaccine during a pandemic, will cause highly vaccinated populations to exert substantial immune pressure on viral virulence (i.e., on S-NTD) [1] but not on viral infectiousness (i.e., on S-RBD). The higher the prevalence of elevated titers of non-neutralizing infection-enhancing Abs, the higher the population-level immune pressure on viral virulence and viral transmission in the host population. On the other hand, elevated titers of non-neutralizing infection enhancing Abs shorten the duration of individual protection after breakthrough infection and increase the risk for a vaccinated individual to develop long-haul Covid. It follows that i) highly vaccinated populations are now paving the way for breeding variants that will not only be highly infectious but also highly virulent in vaccinees [1] and ii) that protection of vaccinees subsequent to breakthrough infection will only be of short duration while their susceptibility to long-haul Covid will dramatically increase.

None of this applies to non-vaccinated individuals as their recovery from symptomatic SC-2 disease

1. results in improved innate immunity that – thanks to the epigenetic mechanism of innate immune adaptation (training!) - will confer more effective sterilizing immunity upon future exposure and

2. generates anti-S Abs that efficiently neutralize the virus as these Abs are induced by the circulating variant (and not by the heterologous S protein of the Wuhan strain used in the vaccine) and will only have to deal with a low viral load because most (if not all!) of the viral inoculum from a new infection will be taken care of by the host’s improved first line of immune defense, which got trained thanks to its previous disease-fighting experience.

Based on all the above, it is scientifically naïve and wrong to extrapolate a ‘snapshot of superiority’ of individual in vitro data from virus-neutralizing assays to an alleged overall clinical and epidemiological advantage of C-19 vaccination preceding breakthrough infection with Omicron. Lack of understanding of immunology and the impact of non-neutralizing Abs on the infectious and pathogenic behavior of SARS-CoV-2 leads our health authorities to erroneous and very dangerous conclusions in that they consider re-vaccination of C-19 vaccinees with an updated S(Omicron)-based C-19 vaccine, for example, a promising avenue to control the pandemic whereas this is only going to precipitate the emergence of SARS-CoV-2 variants that combine high infectiousness in vaccinees with high virulence and full resistance to foreign-centered C-19 vaccines.

‍

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.

---

References:

1. https://www.voiceforscienceandsolidarity.org/scientific-blog/predictions-gvb-on-evolution-c-19-pandemic