WARNING: if you are an individual with a predisposition to experience anxiety, then you might consider NOT reading this content to avoid feeling the discomfort that reading this material could cause. This content discusses hypothetical scenarios only based on molecular information observed at the research level. If you or your loved one has been vaccinated with mRNA vaccines, you could find this content distressing despite its theoretical nature. Please proceed at your own discretion.

Consequences of underappreciating the complexity of the immune system

The course of the pandemic has certainly turned out to be different than what was originally hoped and promised by the authorities when mass vaccination was pushed as a quick solution to stop infection so as to reach herd immunity and then bring the pandemic to an end. Since then, it has been hard to find any convincing scientific explanations for exactly why the total course of events (lockdowns, masks, mass vaccinations) turned out like this, especially concerning the amount and virulence of the variants. Instead, the most commonly used term to explain the situation is that the virus has become “endemic” - a euphemistic term that merely indicates that the virus is just here to stay now.

Currently, the most thorough and on-going explanation of events still comes to us courtesy of Dr. Geert Vanden Bossche via his website. For a great primer or review, check out Merogenomics’ blog post on Dr. Bossche’s explanation of the pandemic and future expectations.

Maybe because Dr. Bossche’s overview of the interplay between our immune systems and the virus is so complicated to understand, it seems beyond the typical explanations offered by experts to their governing officials that are then handed down to the public. This is a serious and grave problem. Especially, when comparing Dr. Bossche’s views and predictions against the official narrative and it quickly becomes a stumbling block that this complexity means he is not even being remotely appreciated by those governing the healthcare management decisions even though his track record clearly shows he is on to something. As time passes and data races in, it is becoming easily apparent that they are worlds apart.

In an attempt to make Dr. Bossche’s central theme more understandable, Merogenomics wanted to offer a diagrammatical chart of this virus-immune system interplay to help better explain what is happening, and perhaps provide some clarity how he apparently formulates his dire predictions with regard to the future of the pandemic. More and more people are definitely being captivated by Dr. Bossche as he has taken it upon himself to launch and support the education needed in order to explain his reasonings. Central to this, is his assertion that innate immunity is completely underappreciated in the current approach to managing the pandemic. This lack of appreciation has reached such egregious levels amongst the authorities in some corners of the world, that our natural immunity post-infection has been disregarded or ignored as a viable alternative to vaccination. We owe a huge debt of gratitude to Dr. Bossche - whether his predictions turn out to be correct or not - for his teachings on the role of innate immunity.

Below is my best attempt at a diagrammatical explanation of Dr. Bossche’s concepts, but do not be surprised if this continues to grow in complexity as we learn and understand more on this topic. Dr. Bossche often teaches the concepts piecemeal, as if forgetting that practically no one in the world has his background knowledge of viruses, the immune system, and the effect of vaccines on both. We go into a deeper explanation of all the concepts below the diagram.

Cell-based innate immunity is where it’s at!

We are going to go from left to right, and in our explanations, we will try to stick as close as possible to Dr. Bossche’s own language.

We begin this story with the emergence of the more infectious SARS-CoV-2 variants, the infamous immune escape variants which arrived with the emergence of the Omicron variants. Immune escape variants are a dreadful outcome during a pandemic because it means the virus has managed to evolve to escape our immune system’s defenses and therefore can continue to wreak havoc on a population. Worries about the possibility of the immune escape variants due to vaccination during the pandemic never managed to make it mainstream but now here we are and everybody is getting familiar with Omicron.

As it stands, we now have a divided society with vaccinated and unvaccinated populations and their differing immunological consequences on the SARS-CoV-2 virus. It is these immunological consequences that during the pandemic will have a very different effect than if we vaccinated prophylactically and not during the pandemic (where there is a heavy presence of an insulting virus in a population). Since we still find ourselves in a pandemic, here is where we get to Dr. Bossche’s key thoughts as to what these effects will be.

Generally, whether you are vaccinated or not, there are two main immune responses to infection: innate immune response and adaptive immune response. Both of these also have antibody and cellular responses.

We shall start with the highly vaccinated populations.

First, let’s focus on the part of the adaptive immune response that we are all familiar with - the production of antibodies. The type of antibodies that we all want post-vaccination (or post-natural infection) are neutralizing antibodies. Unfortunately, these are not the only type of antibodies that can be produced. There are also antibodies that can promote virus infection of cells. We have referred to these in the past as infection-facilitating antibodies, whereas Dr. Bossche simply refers to them as infection-enhancing antibodies (IEABs).

It is these infection-enhancing antibodies that are the culprit behind all the problems.

As the Omicron immune escape variants emerged, so did their ability to bypass many of the neutralizing antibodies that have been produced by the vaccines. That still leaves the infection-enhancing antibodies available, and the vaccinated populations will exhibit high titers (large quantity) of these long-lived antigen-specific infection-enhancing antibodies.

These infection-enhancing antibodies are very specific against the original spike protein of Wuhan SARS-CoV-2, quite logically, as that is what people were vaccinated with for the immune system to recognize. Due to their high specificity to recognize and bind the spike protein, these infection-enhancing antibodies from the vaccines can outcompete the innate immunity antibodies which are not specific against any regions of the spike protein.

Instead, the innate immunity antibodies recognize sugar patterns that decorate the surface of all our cells as well as SARS-CoV-2. Thus, innate immunity antibodies recognize entirely different types of information on the surface of cells or pathogens than the adaptive immunity antibodies which recognize very specific three-dimensional patterns associated with viral proteins.

By learning to recognize the patterns of sugars that decorate the outside of either our cells or other invading pathogens (which will often mimic the sugar pattern of our cells) the innate immunity can differentiate our own ‘self’ sugar patterns from ‘self-mimicking’ sugar patterns of the pathogens or even our own ‘altered self’ sugar patterns of our own diseased cells. Thus, innate immunity is very nuanced in being able to distinguish closely related patterns of sugars with which adaptive immunity just cannot cope. Mainly, the adaptive immune system distinguishes ‘foreign’ protein patterns from our own ‘self’ protein patterns.

As a consequence of assessing such different worlds, the adaptive immunity antibodies excel as their high specificity for protein shapes outmatch the innate immunity antibodies with their more generic assessment of sugar patterns on top of either such proteins or membranes in which these proteins are embedded in.

This is the crux of the entire mass vaccination during a pandemic problem because we need the innate immune antibodies to recognize these sugar patterns and trigger the Cell-Based Innate Immune System (CBIIS), as Dr. Bossche refers to it, to be activated first or almost immediately on exposure to the virus and start dealing quickly with either the pathogen or disease cells. These innate immune cells are basically natural killer (NK) cells and as a consequence, prior to the adaptive immune system being activated, and thus prior to any antibodies being produced which takes days, the innate immune system can already recognize the virus through sugar patterns and start destroying it and/or the cells that might have been infected with the virus. Importantly, while NK cells are doing this, they also become more adept at recognizing the latest version of the virus.

The failure to recognize and acknowledge the pivotal and initial role of the innate immunity in clearing the virus is what Dr. Bossche seems to lament most often because as a consequence we have misplaced our focus on only adaptive immunity’s antibody production while completely ignoring or failing to understand that the very antibodies produced through repeated vaccine stimulation or through frequent infections will in fact, suppress the innate immune system.

As a severe consequence, in a vaccinated individual or vaccinee, the virus can now easily bypass the initial response of the cell-based innate immune system which also means no training of the NK cells takes place. This in turn enhances the susceptibility of these vaccinated individuals to re-infection and can even promote virus evolution towards even more infectious variants that will subsequently re-target them as well. This happens because (in vaccinees) the variants encounter not only a stunted cell-based innate immune system mechanism that does not start the destruction and removal of the initial viral load but also there are no fully neutralizing antibodies (remember the vaccines all code from only the original spike proteins) available to deal with the new variant’s virus load – double whammy! So, the overall effect of this inability to properly clear the virus due to the suppressed effect of the cell-based innate immune system is what allows the variant to evolve past any antibodies that are attacking it. Thus, if this then happens in enough people in a population at the same time, a natural selection of increasingly infectious immune escape variants will occur.

This is why we are seeing an unprecedented evolution of a virus all across the world like we have never witnessed before. We accidentally bombarded the virus with too many antibodies while there was too much virus around and the virus learned (evolved) to go around these antibodies, and continues to be learning.

This is how Dr. Bossche posits the existence of these multiple immune escape variants - the more infectious SARS-CoV-2 variants – came to be and how the evolution of the virus shall continue.

Also, perhaps we are failing to recognize this very dangerous trajectory of virus evolution because paradoxically, the infection-enhancing antibodies while enhancing viral infection, might at the very same time make these more infectious SARS-CoV-2 variants milder in nature – this was the topic of our last blog post dedicated to Dr. Bossche’s theories.

Basically, the infection-enhancing antibodies binding to SARS-CoV-2 virus prevent its tethering to migrating dendritic cells (DCs) which would have then transported the virus to the lower respiratory tract which is how you end up with severe COVID-19 disease. By the way, the virus achieves this tethering by what else, sugar molecules! The binding of infection-enhancing antibodies to the virus blocks the sugar molecules decorating the virus needed for binding the dendritic cells, which is how you end up with more infectious variants that are milder. This is why we have seen hospitalizations and mortality rates due to SARS-CoV-2 decline.

This in turn produces an illusion that we have gained protection from severe COVID-19 disease due to vaccinations but such protection is only short-lived until more infectious variants emerge and then the call for constant booster vaccines will be a vain bid to increase the total antibody count to increase the ever-dwindling numbers of neutralizing antibodies while disastrously increasing the numbers of infection-enhancing antibodies thus leading to the worse case scenario. Or prior to the emergence of deadly virulence-enhancing mutations - Dr. Bossche’s biggest worry.

Decreasing capacity to defend

The infection-enhancing antibodies have another sinister role besides suppressing the cell-based innate immune system and enhancing infection.

The infection-enhancing antibodies also increase viral uptake by antigen-presenting cells (APCs) which is one of the many ways how our immune system combats infection. Antigen-presenting cells, as their name suggests, are immune cells that present fragments of viruses (antigens) that these cells have engulfed and destroyed to other immune cells called T-cells. The receptors used in the display of these virus fragments/antigens are called Major Histocompatibility Complex (MHC) class I. Normally, the presentation of these antigens results in the activation of cytotoxic CD8+ T-cells (killer T-cells) that recognize that very specific virus fragment presented to them on MHC class I receptors. In other words, the cytotoxic T-cells are restricted to recognizing a specific antigen.

However, some of these MHC class I receptors present universal antigens that are also found in other sugar-coated viruses (also referred to as glycosylated viruses as another word for sugars is glycans). Because these cytotoxic T-cells are activated by universal antigens, they are referred to as polyspecific MHC class I unrestricted cytotoxic T-cells, believed to possibly be the early responders among cytotoxic T-cells. These T-cells will reduce the infection in the upper respiratory tract (but not prevent it) but they will also end up recognizing and killing the antigen-presenting cells that present these universal viral antigens. However, this could prevent these antigen-presenting cells from priming B cells to recognize new viral fragments of Omicron-derived spike protein, whether through natural infection or vaccination with updated variant vaccines. This means that vaccinated individuals do not have a good ability to develop new antibodies that will recognize new variants, even if they are to be vaccinated with updated Omicron vaccines, as the cells that take on the new vaccine could be destroyed prior to priming of the immune system taking place. Thus, vaccinated individuals are stuck in responding primarily with the antibodies produced to the very original variant that started the pandemic, a concept referred to as antigenic original sin, or immunological imprinting.

This means that vaccinated individuals are having reduced training of innate immunity as well as reduced training of adaptive immunity at the same time while appearing completely normal without symptoms of the disease from the infections of either SARS-CoV-2 or other glycosylated viruses.

All of this together has two consequences among the highly vaccinated populations. First, it leads to a formation of an asymptomatic reservoir of ‘more virulent’ SARS-CoV-2 variants (such as BA.4 and BA.5 of the Omicron family) among the vaccinees, as well as some other glycosylated viruses causing acute self-limiting viral infection (infections that can spread asymptomatically such as seasonal influenza, respiratory syncytial virus and viruses responsible for vaccine-preventable infections: measles, mumps, rubella, varicella, rotavirus – although those vaccinated against these in childhood will not serve as a reservoir for these viruses) or acute self-limiting viral disease (infections that spread symptomatically by viruses that have evolved reduced susceptibility to our innate immune system such as zoonotic influenza [e.g., avian influenza virus], or parapox virus [e.g., monkeypox virus]). Because the majority do not show any symptoms or serious symptoms, once again, we are falling prey to an illusion that everything is going back to normal while vaccinated individuals keep getting and spreading infections that continuously drive the evolution of these viruses.

The other possible future consequence will be that this constant infection experienced by the vaccinated community and constant stimulation of the adaptive immune system will eventually lead to exhaustion of the adaptive immune capacity, resulting in a depletion of antibody-producing B cells and cytotoxic CD8+ T cells due to spike-mediated over-activation.

Once these events take place on a larger and larger scale, it will lead to a population immunity collapse that will result in the development of new pandemics. Due to prior lack of training, the normally first responding natural killer cells will become unresponsive or desensitized to these more pathogenic agents. This will of course include the SARS-CoV-2 virus, but also other glycosylated viruses we mentioned above (and we are already witnessing the potential birth of one such pandemic with monkeypox) as well as acute and chronic microbial infections.

With regards to SARS-CoV-2, due to no longer having the same protection from the overactivated immune system as currently observed, the infection-enhancing antibodies will now lead to antibody-dependent enhancement of infection (ADEI) with ‘more virulent’ SARS-CoV-2 that will exhibit the second type of immune escape. This time the evolution of the virus will bypass the infection-enhancing antibodies' ability to prevent the virus from attaching to migrating dendritic cells. In such instance, this second immune escape event will allow infection of the lower respiratory tract once again, but now with a much more infectious form of a virus, leading to severe disease. In other words, antibody-dependent enhancement of severe disease (ADESD).

In addition to the above-stated viral, fungal and bacterial infections, the vaccinated also run an increased risk of experiencing immune-mediated diseases, such as cancer and autoimmune pathologies. Immunopathologies, according to Dr. Bossche, are likely to occur in young, vaccinated children due to their lack of antigen-specific regulatory T-cells which are critical for establishing immunological tolerance, which is the ability of the immune system to not respond to certain antigens, basically those of our own self-origin. Cancer on the other hand is more likely to occur in the remainder of the population due to depletion of antigen-specific MHC class I-restricted T-cells capable of killing neoplastic host cells.

This is the path of the interplay between the immunological responses to the virus that is are now driving the viral evolution. Furthermore, these are the same mechanisms that lead to the more infectious immune escape variants that we now have to now contend with in the first place, and this is also the same mechanism that is going to drive the further evolution of other viruses, such as monkeypox which we are likely witnessing already (now approaching 50 thousand cases worldwide affecting predominantly highly vaccinated countries in mere 4 months since the first reported case).

Natural immunity will win the day

Unvaccinated individuals, on the other hand, will fare the exact opposite of that fate described for the vaccinated. Dr. Bossche has in essence described a night and day difference scenario between these two groups.

Once again, we will start from the left side of the above graph.

First of all, the innate neutralizing antibodies have the capacity to activate the cell-based innate immune system, primarily the natural killer cells by recognizing sugar pattern differences between pathogens and host cells. Furthermore, the natural killer cells are also trained to recognize variant specific patterns upon each virus exposure. Natural killer cells achieve this by having different types of receptors presented on their cellular surface as a consequence of this training. The reason why this is possible in unvaccinated individuals is because they do not suffer from the artificially high levels of adaptive immunity antibodies and therefore their innate immunity antibodies are not sidelined from function and activation of the cell-based innate immune system. This is the primary advantage distinguishing the unvaccinated from the vaccinated individuals.

Something to keep in mind though, when a virus does bypass the formidable cell-based innate immune system of the unvaccinated individuals to induce the adaptive immune system response, the resulting antibodies are typically short-lived and with low-affinity to the spike protein. However, these antibodies can also fail to neutralize SARS-CoV-2 and act as infection-enhancing antibodies that may temporarily increase susceptibility to severe COVID-19 disease in unvaccinated individuals if they happen to be reinfected while the cell-based innate immune system has not yet been trained in them, or if the virus is very infectious or highly concentrated in a population at that very moment when the person is still presenting such low-affinity antibodies or if their cell-based innate immune system weakened at the same time (for example due to aging). Thus, under certain circumstances, the unvaccinated individual can still experience severe disease.

This increased risk of developing severe disease could be especially problematic in a minority of young unvaccinated children due to the fact that their cell-based innate immune system is still untrained as it requires time and exposure to be naturally trained. So, in the current era of more infectious SARS-CoV-2 Omicron variants which increase the likelihood of such virus re-exposures while some child sports these short-lived and low-affinity antibodies from a prior exposure, it can result in another immune “illusion” where it seems that children are losing their prior formidable protection against SARS-CoV-2 offered by their innate immunity. This conundrum may provoke some parents to unwittingly get their children COVID-19 vaccinated leading to the suppression of their innate immune system. Of course, Dr. Bossche strongly argues against this due to the reasons outlined above!

In addition, because the unvaccinated do not suffer from the same level of infection/reinfection rate as the vaccinated individuals (due to the protection from the cell-based innate immune system) and therefore do not exhibit similar levels of activated cytotoxic T-cells, the antigen presenting cells in the unvaccinated still have the ability to exhibit (on MHC class I molecules) new Omicron-derived or novel spike proteins of the latest variants thus allowing priming of B cells to generate antibodies that will then recognize these new antigens. This means that the unvaccinated are also protected by this mechanism against the constantly evolving virus and are not likely to suffer from immunological imprinting (the antigenic original sin). The priming of B cells towards recognition of new emerging variant antigens and the training of natural killer cells to recognize the new emerging variant sugar patterns will continuously lead the unvaccinated to experience greater and greater protection, resulting in an increasingly unlikely likelihood for the unvaccinated to suffer severe COVID-19 disease.

Together, these dynamics are going to lead to an abrupt and spectacular increase in the number of previously healthy vaccinees being hospitalized especially due to SARS-CoV-2 in comparison to hospitalized unvaccinated individuals. When this starts to be very apparent, this will indicate that the second immune escape towards more virulent variants has indeed taken place and therefore this will be a key, predictive parameter to monitor.

What should we expect?

This antibody-dependent enhancement of severe disease or ADESD would probably manifest first in vaccinees with high titers of infection-enhancing antibodies and those who were vaccinated at an early stage of the mass vaccination program (which would negate their opportunity to train their cell-based innate immune system). Accordingly, Dr. Bossche thinks that elderly and vulnerable vaccinees (those with compromised immune systems) will be affected first. Those individuals who had the opportunity to train their innate immune system prior to vaccination may have enough natural immune capacity left to fight off the development of severe disease. Therefore, by this logic, the later a person was vaccinated during the mass vaccination programs, the more likely they are to have more favourable outcomes post-infection with any future more virulent SARS-CoV-2 variants.

But any vaccinated children will be especially negatively affected as their cell-based innate immune system has not had time to be naturally trained while at the same time, due to their young age, their adaptive immune system is also antigen-inexperienced. Hence vaccinated children will be particularly prone to developing severe diseases including from other microbial infections or from immunopathology (for example, autoimmune hepatitis).

In other words, in the vaccinated populations especially, the severity of the outcomes from future waves of variant infections is going to be directly dependent on the individual’s overall level of pathogen-related antigen experience and the level of training of the cell-based innate immune system (if it is still operational), and thus a wide variation among the population could be observed.

Consequently, to protect the vaccinated individuals, Dr. Bossche sees the only remaining option is the use of early treatment of vaccinees with antiviral drugs (such as Ivermectin and Hydroxychloroquine which have been shown historically to be safe and cheap to produce but ironically have been maligned and discredited during the mass vaccination campaign in favour of the “vaccination only” option). This is to take place as soon as post disease symptoms develop but not before, to ensure that the virus does not evolve to limit the effect of these drugs. However, due to the unusual switch from the use of these antiviral drugs and the concerted destruction of the reputation of these drugs, Dr. Bossche worries that these needed efforts will not take place.

Another possible way would perhaps be the development of vaccines that would train the natural killer cells to recognize the variants of interest, thus allowing the innate immune system to respond to infections in the vaccinated individuals despite the corrupting presence of their adaptive immunity antibodies. However, such vaccines have not even been developed yet, so here we are very much in the theoretical realm only.

As you can see, Dr. Bossche paints very stark and contrasting future outcomes for vaccinated versus unvaccinated individuals, especially for the children. Many of the unusual patterns we are now seeing in our populations already can be explained by this theory of the perturbance of innate immunity by the overproduction of antibodies in our populations and overstimulation of T-cells. But most importantly, it provides a hypothesis that is now a subject that can be analyzed in relation to what might be observed in the near future and acted upon. We should all hope that this theory is in fact wrong due to the dire predictions offered by Dr. Bossche while at the same time still bringing much needed attention to the importance of innate immunity in combating infections. If Dr. Bossche does turn out to be correct, we will learn the hard way the immunological consequences of vaccinating during a pandemic, and hopefully, we will never again need to test such a theory again.

This article has been produced by Merogenomics Inc. and edited by Jason Chouinard, B.Sc. Reproduction and reuse of any portion of this content requires Merogenomics Inc. permission and source acknowledgment. It is your responsibility to obtain additional permissions from the third party owners that might be cited by Merogenomics Inc. Merogenomics Inc. disclaims any responsibility for any use you make of content owned by third parties without their permission.

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