Once again, our scientists, experts and public health officials have no clue how this pandemic is going to end - some even think it will never end and conveniently refer to an ‘endemic’ state. The origin of their endless blind spot lies in the fact that they lack even the slightest insight into the complex interactions between the virus and the collective immunity of highly Covid-19 (C-19)-vaccinated populations. Molecular biologists and epidemiologists, or the now-famous mutation spotters/trackers, are mainly engaged in molecular stamp collecting, where each mutation in the viral genome is mapped out as quickly and precisely as possible and neatly added to their collection. But do these collectors also understand the rationale behind the issuing of those stamps, or do they simply want to pad their CVs by meticulously describing and documenting the stamps they collected?
As for the virus, we now know that the main driver behind the frantic succession of new circulating variants is the immune pressure exerted on the virus by the population. The mostly gentle ripples of SARS-CoV-2 (SC-2) infections that sweep through populations with clockwork regularity by now almost symbolize a high degree of C-19 vaccination coverage. Once you understand how that immune pressure builds up and the threat it poses to the survival of the virus, it becomes much easier to see where highly C-19 vaccinated populations are ultimately heading. Yes, I say ‘ultimately’, because anyone who gains insight into this matter clearly understands that this situation must indeed come to an end soon.
At this moment, the pandemic is in a phase where the virus is sufficiently controlled by a variety of T cells that have been refocused by vaccine-breakthrough infections (VBTIs). This T cell immunity strongly limits inter-host transmission but cannot completely prevent it. Consequently, population-level immunity in highly C-19 vaccinated populations has not stopped the pandemic but merely transformed it from one characterized mainly by acute illness to one dominated by chronic disease (i.e., with a rising number of Long COVID cases). In the fight against the virus, dysregulated T cell immune responses are supported by the humoral arm of the innate immune system, namely antiviral cytokines, which - unlike cellular innate immunity - remain further stimulated by VBTIs. This is the only arm of the immune system that, so far, the virus has left untouched in its struggle to evade immunity in highly C-19 vaccinated populations.
Of course, the question arises whether, given the increasing immune pressure on the virus exerted by the population’s sub-sterilizing T cell immunity, inter-host transmission can still be sustained. After the sidelining of cellular innate immunity and the dysregulation of both the humoral (exemplified by IgG4 Ab-mediated ‘tolerance’) and cellular (exemplified by chronic T cell-mediated inflammation) adaptive immune arms, the virus might now also affect the humoral arm of the innate immune system and shift antiviral cytokine activity toward a pro-inflammatory, virus-promoting immune inflammatory response when, during its replication, mutants or recombinant variants arise that exhibit appropriate changes in their versatile spike-associated sugar patterns.
Such a change in the phenotypic properties of the virus could be just as dramatic as the one that previously gave Omicron a spectacular fitness advantage.
In the further text of this manuscript, I explain why we can reasonably expect such a similarly spectacular 'antigenic shift' at this stage of the pandemic, how and why this mechanism is the only way for the virus to guarantee its continued replication and transmission, and why the emergence of such a strongly altered coronavirus (‘Hivicron’) would mark the definitive end of this pandemic, which has now evolved into a chronic phase. Moreover, I draw a parallel with the immunological pressure that paved the way to the emergence of Omicron back 4 years ago.
Finally, anyone reading this will understand why the dead dogma that ‘the more infectious a virus becomes and the faster it spreads, the more it tends to become less harmful’ is an absolutely stupid statement that suddenly attributes strategic thinking capacity to a virus (as it is based on the ‘reasoning’ that highly virulent viruses that quickly kill their hosts may reduce their chances of spreading!).
To understand all this, and especially also why I keep emphasizing that society in highly C-19 vaccinated regions will be caught off guard, we must, as always, start with the immunology rather than the virus. Given its relevance to the current stage of this pandemic, we will first set out to examine the contribution of the humoral innate immunity and how it can evolve from antiviral to proviral.
Antiviral versus pro-inflammatory infection-enhancing cytokines
Anti-viral cytokines such as type I interferons promote upregulation of lectins (like DC-SIGN) on URT (upper respiratory tract)-patrolling dendritic cells (DCs), which enables these cells to capture and retain the virus locally, thereby limiting viral infectivity and transmission while preventing systemic dissemination, even in the absence of adaptive immunity. This is because DC surface-expressed lectins interact with sugars expressed on the surface of SC-2 virions and thereby enable adsorption of these SC-2 particles onto the surface of these DCs.
Experimental evidence supporting cytokine-driven containment of viruses in the URT highlights the crucial role of early and effective innate immune responses, especially interferons[1] (IFNs) and certain pro-inflammatory cytokines[2] (https://www.nature.com/articles/s41467-022-28508-0. Several studies have shown that inflammatory cytokines such as IFNs enhance DC lectin expression and thereby enable these cells to trap and control virus at mucosal sites:
https://pubmed.ncbi.nlm.nih.gov/14582815/
https://pmc.ncbi.nlm.nih.gov/articles/PMC9295932/
https://www.nature.com/articles/s41467-022-28508-0.
Whereas early and controlled production of inflammatory cytokines with antiviral activity promotes virus tethering to mucosa-resident DCs and thereby leads to efficient virus containment, dysregulated, excessive, or prolonged production of pro-inflammatory cytokines may cause tissue damage, promote migration of infected cells and, therefore, promote systemic viral dissemination (virulence).
In the presence of strong, but non-sterilizing, adaptive T cell immunity, effective virus containment at the upper respiratory tract (URT) mediated by antiviral cytokines promotes natural selection and dominant prevalence of newly emerging (recombinant) variants potentially capable of escaping cytokine-mediated binding to URT-patrolling DCs.
Such escape would enhance viral infectivity and trigger massive production of pro-inflammatory cytokines, resulting in high virulence and systemic dissemination of this new type of coronavirus, thereby causing high-level viremia.
Followers are starting to doubt my analysis as none of what I am predicting is manifesting yet!
At this stage of the chronic immune escape pandemic, ‘Hivicron’ has not yet emerged as there is still no evidence of a recombinant variant capable of escaping adsorption to mucosa-resident DCs, despite the presence of strong T cell-mediated immunity. The latter continues to confer protection to the majority of C-19 vaccinees although a steadily increasing number of them are now progressing to chronic immune pathology, i.e., long COVID. However, as mentioned above, this situation puts viral infectivity, already constrained by the antiviral activity of early inflammatory cytokines, under immune pressure and thereby promotes natural selection and the dominant spread of a newly emerging, high-virulence-enabling CoV lineage. Until that happens, many C-19 vaccinees may indeed be spared from severe C-19 disease and long COVID despite regular exposure to highly infectious circulating variants. I expect things to change dramatically in highly C-19 vaccinated populations once a high-virulence-enabling immune escape variant emerges and rapidly spreads, both inter- and intra-host (i.e., ‘Hivicron’).
Of course, there is no need to believe any of what I am predicting. But keep in mind that this is exactly why I argue that society in highly C-19–vaccinated regions will be caught off guard.
Conclusion:
The large-scale prevalence of rising titers of subneutralizing antiviral antibodies (Abs) promoted the natural selection and dominant spread of Omicron, enabling nonneutralizing Ab–dependent enhancement of respiratory viral infection while still providing protection against severe disease (i.e., high virulence). Likewise, the widespread prevalence of substerilizing antiviral T cell–mediated immunity will likely promote the natural selection and fulminant spread of Hivicron, enabling pro-inflammatory cytokine–dependent enhancement of severe disease (i.e., high virulence) while failing to protect against systemic viral viremia.
Hence, I firmly believe that the end of this ongoing chronic immune escape pandemic will be marked by a single, large-scale wave of hyperacute systemic inflammatory disease associated with high-level viremia.
So, how will the unvaccinated folks deal with the end of this pandemic?
However profound and dramatic such a wave may be, I remain firmly convinced that it will not affect healthy, unvaccinated individuals. This is because the enhanced cytolytic function of trained natural killer (NK) cells is not dependent on antigen-presenting cells (APCs) or dendritic cells (DCs) for their direct activity against virus-infected target cells. Even though a recombinant ‘virulent’ variant is likely to incorporate changes in the viral surface structure (most likely in the spike-associated sugar glycan chains) that impair the virus’s ability to bind to and be taken up by APCs (e.g., mucosa-resident DCs), this will not diminish the capacity of trained NK cells to kill virus-infected epithelial cells at an early stage of infection (i.e., before viral progeny is produced). Why not?
The defining functional feature of NK cells remains their intrinsic ability to conduct ‘natural killing’ of cellular targets without prior sensitization https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2015.00601/full
This is to say that the ‘education’ of NK cells into ‘trained’ or ‘memory-like’ innate immune cells results from functional reprogramming following epigenetic changes (e.g., due to repeated activation during prolonged exposure to circulating SC-2 variants) [https://onlinelibrary.wiley.com/doi/full/10.1111/imr.13384].
The target recognition and cytolytic function of these cells is therefore an intrinsic capability of the NK cell itself after training and does not rely on continuous antigen presentation [https://pmc.ncbi.nlm.nih.gov/articles/PMC11114903/]. In other words, NK cell cytotoxicity is typically governed by the integration of signals from activating and inhibitory receptors directly at the immunological synapse with the target host cell, rather than requiring priming or help from APCs or DCs [https://www.sciencedirect.com/science/article/pii/S0006497120558874].
It is, therefore, fair to conclude that the capacity of NK cells to recognize and directly kill virally infected or transformed cells remains largely independent of APCs or DCs and will not be compromised by Hivicron’s immune escape strategy.
[1] Interferons (IFNs) are a specific subclass of cytokines, largely involved in antiviral defense. They are subdivided mainly into type I (e.g., IFN-α, IFN-β), type II (IFN-γ), and type III interferons. Type I IFNs have potent antiviral and immunomodulatory effects and can have both pro- and anti-inflammatory properties.
[2] Pro-inflammatory cytokines are a group of cytokines that primarily promote inflammation. They include interleukins such as IL-1, IL-6, tumor necrosis factor alpha (TNF-α), and also interferon-gamma (IFN-γ). These cytokines orchestrate immune cell activation, recruitment, and cause inflammation aimed at fighting infections but can also contribute to tissue damage if excessive.
Geert Vanden Bossche received his DVM from the University of Ghent, Belgium, and his PhD degree in Virology from the University of Hohenheim, Germany. He held adjunct faculty appointments at universities in Belgium and Germany. After his career in Academia, Geert joined several vaccine companies (GSK Biologicals, Novartis Vaccines, Solvay Biologicals) to serve various roles in vaccine R&D as well as in late vaccine development.
Geert then moved on to join the Bill & Melinda Gates Foundation’s Global Health Discovery team in Seattle (USA) as Senior Program Officer; he then worked with the Global Alliance for Vaccines and Immunization (GAVI) in Geneva as Senior Ebola Program Manager. At GAVI he tracked efforts to develop an Ebola vaccine. He also represented GAVI in fora with other partners, including WHO, to review progress on the fight against Ebola and to build plans for global pandemic preparedness.
Back in 2015, Geert scrutinized and questioned the safety of the Ebola vaccine that was used in ring vaccination trials conducted by WHO in Guinea. His critical scientific analysis and report on the data published by WHO in the Lancet in 2015 was sent to all international health and regulatory authorities involved in the Ebola vaccination program. After working for GAVI, Geert joined the German Center for Infection Research in Cologne as Head of the Vaccine Development Office. He is at present primarily serving as a Biotech / Vaccine consultant while also conducting his own research on Natural Killer cell-based vaccines.
Email: info@voiceforscienceandsolidarity.org
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