Will Omicron induce herd immunity or will it enable SARS-CoV-2 to transition into variants capable of potentiating ADE in vaccinees?
Could Omicron metamorphose into a wolf in sheep’s clothing?
Given the high and steadily increasing vaccine coverage rates in large parts of the world and the ongoing mass vaccination of children and continuation of booster campaigns, I am of the opinion that Omicron has the capacity to evolve into a much less benign variant, regardless of whether or not infection prevention measures are relaxed or lifted.
A coronavirus (CoV) can only replicate and mutate. The widely held belief that during the course of a pandemic viruses tend to become more infectious but less virulent is a myth—one kept alive by those who don’t understand the evolutionary dynamics of a pandemic. The latter are fully dependent upon the outcome of the interplay between the virus and the host immune system at a population level. Abiding by this ‘rule’ is the sole qualifier necessary to be an expert of viral pandemics. For several months I’ve been warning that continued mass vaccination and high vaccine coverage rates would prevent SARS-CoV-2 (SC-2) from generating sufficient herd immunity to control, let alone end, the current pandemic (1, 2, 3). The advent of Omicron hasn’t changed my mind, on the contrary!
Now that mass vaccination campaigns have quickly rendered the virus resistant to the adaptive immune response (cfr. Omicron), I am fearful that this may have a snowball effect. I’ve been postulating that the mechanism of innate immune adaptation to viral exposure (i.e., through a process of epigenetic changes referred to as ‘training’) is compromised in the vaccinated population and I am now predicting that the resulting burden of infectivity will cause massive population-level immune pressure on Omicron. In an attempt to overcome high immune pressure on Omicron’s infectiousness, natural selection of viral mutants that are capable of resisting both the acquired SC-2-specific and the CoV-reactive innate immune response in vaccinees is likely to occur. To understand why I fear that the growing vaccine coverage rates that we’re witnessing in large parts of the world could ultimately promote the propagation a new type of variant that has the capacity to fully resist both types of SC-2-directed immunity in the vaccinated population, one must turn to the ‘rule’ mentioned above:
While the vast majority of healthy unvaccinated individuals continue to resist Omicron’s high infectious pressure by virtue of the ongoing training of their innate immune effector cells (4, 5), a steadily increasing number of vaccinees are now becoming more susceptible to vaccine breakthrough infection and contracting C-19 disease. Although resistance of Omicron’s receptor-binding domain (RBD) to vaccinal anti-S antibodies (Abs) is thought to diminish suppression of innate Abs and therefore enables a predominantly mild course of the disease, a subset of the S-directed Abs may still be able to bind to immunogenic domains situated outside of the RBD of the S protein. Abs directed at the N-terminal domain, for example, have been reported to interact with lipid rafts on target cells via multivalent interactions (6, 7). As multi-specific innate Abs (i.e., IgMs) are known to bind to S using the same type of multivalent interaction, it is reasonable to assume that even non-neutralizing vaccinal Abs still have the capacity to compete with relevant innate Abs for binding to SC-2. It is, therefore, entirely possible that even non-neutralizing vaccinal Abs outcompete innate B1a cell-derived Abs for binding to SC-2, particularly under the following circumstances:
- In the case innate immune effector cells had no opportunity to adapt to viral exposure prior to being short-circuited by vaccinal S-specific Abs (e.g., in case of high-speed mass vaccination programs conducted in populations with relatively low infection rates)
- In the case of C-19 vaccination of children. Although present in high quantities, innate Abs in children are largely naïve (i.e., antigen (Ag)-inexperienced) and therefore prone to being outcompeted by S-specific vaccinal Abs (Note: subjects with naturally acquired Abs are endowed with trained innate immunity as naturally acquired Abs result from the virus breaking through their innate immunity)
- In the case of recent C-19 boosting of vaccinees or subjects who previously recovered from C-19 disease or in the case of re-vaccination with an updated (i.e., anti-Omicron) vaccine. In either case, previously vaccine-induced Abs will be recalled. The recall results in high titers of anti-S Abs which have no neutralizing capacity towards Omicron. It has been reported that—due to antigenic sin—even anti-Omicron vaccines primarily recall Abs directed at the S protein of the Wuhan lineage (8).
Consequently, it becomes obvious that the continuation of mass vaccination campaigns now increasingly targeting children and focusing on booster shots (or Omicron-specific vaccinations) will result in a significant fraction of the vaccinated population compromising their innate B1a-derived Abs (IgMs). There can be no doubt that accelerated mass vaccination campaigns followed by booster shots at intervals as short as 4-5 months and complemented by C-19 vaccination of children will lead to a higher incidence of disease in the vaccinated population. Since innate Abs more readily compete with low-affinity, non-neutralizing anti-S Abs, symptoms of Omicron infection in vaccinees are predominantly mild to moderate. However, the high incidence of disease across a wide variety of vaccinated age groups is likely to drive a massive surge in the population’s anti-Omicron Ab titers. A large peak of anti-(Omicron) S [anti(O)S] seroprevalence could cause high population-level immune pressure on viral infectiousness. However, on a background of high infectious pressure, the heightened S-directed immune pressure exerted by the vaccinated population cannot confer sterilizing immunity. The non-sterilizing immune pressure exerted by the vaccinated population would, therefore, serve as an optimal breeding ground for the selection of variants that are capable of overcoming the S-directed immune pressure placed on Omicron’s infectiousness. Any mutation that changes the physicochemical properties of the virus’ N-terminal domain in ways that strengthen the latter’s interaction with lipid rafts on respiratory epithelial cells would readily facilitate adsorption of viral particles to these cells and mediate fusion of the viral envelope with the target cell membrane such as to allow an alternative route of viral entry into the cell. It is reasonable to assume that the fitness cost of such a change in physicochemical properties is much lower than the one the virus would incur upon selecting and breeding a variant that incorporates a number of immune escape mutations sufficient to avoid neutralization by anti-(O)S Abs while not causing steric hindrance of RBD-ACE-2 receptor interactions. Clearly, viral entry would likely be expedited by a multitude of naturally acquired Abs that bind to Omicron’s RBD without neutralizing the virus, for hydrophobic sites within the N-terminal domain would now serve as a substitute for RBD to trigger viral entry into epithelial host cells. Enhancement of an alternative mechanism of viral entry as enabled by abundant coating of viral particles by anti-(O)S Abs and strong suppression of CoV-reactive innate Abs is likely to cause an accelerated course of the disease. The overall effect would manifest as an increase in pathogenicity/ virulence of the virus. Such antibody-dependent enhancement or exacerbation of C-19 disease (ADE) in vaccinees could have disastrous consequences, not only in vaccinated children but also in older age groups that are highly vaccinated. It is even uncertain whether early multidrug treatment could mitigate such ADE.
Unless the above postulate is scientifically proven wrong or at least improbable, halting mass vaccination and instead implementing large scale antiviral chemoprophylaxis campaigns and raising global awareness about the vital importance of healthy food and a healthy lifestyle in order to dramatically reduce viral infection rates and strengthen people’s innate immunity, respectively, should be declared a health emergency of international concern. On the other hand, no vaccine can contribute to controlling a pandemic of an acute self-limiting viral infection, and for that matter of SC-2, unless it induces sterilizing immunity.
Disruption of the link between infectious cases and severe disease/ death reflects or predicts viral immune escape in the vaccinated population
Based on my understanding of the evolutionary capacity of SC-2 in response to population-level immune pressure, I postulate that dominant expansion of more infectious immune escape variants as a result of ‘symptomatic’ mass vaccination engenders a high incidence of vaccine breakthrough cases in vaccinees and causes the natural link between infectious cases and severe disease or death to be broken in the vaccinated part of the population (a situation that has previously been observed during the ‘delta’ phase of the pandemic and which motivated Boris Johnson to lift the lockdown measures in the UK on July 21st). The disruption of this link enhances the expansion of more infectious immune escape variants that can even resist neutralization by vaccinal anti-S Abs (e.g., in the case of Omicron). Resistance to neutralization by Abs directed at the RBD diminishes, but does not abolish (!), suppression of SC-2 binding by relevant innate Abs, thereby improving protection in vaccinees while failing, however, to prevent viral transmission of the highly infectious Omicron. The resulting dissociation between Omicron’s high infectivity rate (cases) and the incidence of severe C-19 disease/ death is primarily going to lead to a high morbidity rate over the coming weeks, especially in countries with high vaccine coverage rates, and hence cause a high anti-(O)S seropositivity rate in the population. This is to say that the broken link between infections and severe disease/ death in the vaccinated part of the population will now cause this group to exert immune pressure on Omicron’s infectiousness and is, therefore, likely to promote natural selection and adaptation of new immune escape variants that enable an even higher infectiousness. As described above, Omicron could readily transform into a viral variant exhibiting a high degree of virulence in vaccinees without paying a high fitness cost or taking much time to cross the fitness valley.
According to the above, the evolution of the virus as accelerated by the Covid-19 mass vaccination program proceeds in two stages: The first stage consists of erosion of vaccine-induced acquired immune capacity in vaccinees and occurs as a result of expansion in prevalence of more infectious immune escape variants. In a second stage, the innate immune effector capacity in vaccinees becomes more and more eroded as a result of dominant circulation of a highly infectious variant (i.e., Omicron) that serves as a natural booster and – as a result of ‘antigenic sin’ – leads to a rapid recall of previously induced vaccinal Abs in a large fraction (due to high infection rate!) of the vaccinated population. Naturally boosted, non-neutralizing vaccinal Abs have the capacity to compete with relevant innate Abs for binding to Omicron. The ensuing erosion of the first line of immune defense would diminish the capacity of the host’s innate immunity to adapt to viral exposure in a vast portion of the vaccinated population while subsequently promoting the expansion of immune escape variants that – thanks to Ab-dependent coating – are able to strongly suppress CoV-reactive innate IgM and acquire a level of viral infectiousness that is high enough to fully blow through the vaccinee’s first line of immune defense. The bottom line is that training of the host’s innate immune defense resulting from exposure to the highly infectious Omicron is at risk of being ‘too little’ and arriving ‘too late’ in the overwhelming majority of the population (i.e., the vaccinated) to ensure protective herd immunity.
It goes without saying that large scale booster campaigns and vaccination programs using updated (i.e., anti-Omicron) vaccines are only going to inflate surges in infection and morbidity rates in vaccinees and are, therefore, at risk of dramatically expediting selection and adaptation of new SC-2 immune escape variants that could enable a much more pathogenic course of C-19 disease in people whose protective innate immune capacity cannot adequately be trained as a result of vaccine-mediated immune priming.
I cannot imagine how failure to generate herd immunity against Omicron could prevent the type of catastrophe I’ve been warning against since the beginning of 2021.
Why won’t naturally acquired anti-S Abs in unvaccinated healthy people compromise their innate immune defense against Omicron and promote immune escape?
In contrast to the situation in vaccinated people, training of innate immune effector cells in non-vaccinated individuals initially occurs in the absence of S-specific Abs. It is, therefore, reasonable to assume that their SC-2-experienced innate Abs can better resist competition from naturally induced non-neutralizing S-specific Abs for binding to Omicron. In addition, breakthroughs of innate immune defense against SC-2 are unlikely to simultaneously occur in vast portions of the unvaccinated SC-2-experienced population and, therefore, unlikely to cause population-level immune pressure that could drive immune escape.
How will healthy unvaccinated people deal with variants potentiating ADE in vaccinees?
As host cells infected by variants enabling an alternative pathway of receptor-mediated entry into susceptible host cells will be largely eliminated by IgM secreted by SC-2-experienced (i.e., trained!) innate immune effector cells, ADE is not expected to occur in healthy unvaccinated people who previously recovered from mild or moderate C-19 disease, regardless of their S-specific Ab titers. This assumption is based on effective viral clearance by trained innate immunity. By abrogating viral reproduction and transmission at an early stage of infection, effective functional reprogramming (‘training’) of polyreactive innate immune cells not only protects healthy unvaccinated individuals from C-19 disease but also contributes to establishing herd immunity. In case the virus breaks through the first line of immune defense and causes disease, the S-directed Abs acquired upon recovery from disease will also contribute to controlling viral infection upon subsequent exposure. That is why natural immunity (= innate ± naturally acquired immunity) is always superior to C-19 vaccine-induced immunity, regardless of the height of anti-S Abs. (see relevant links on p. 7 in: https://www.voiceforscienceandsolidarity.org).
Lessons (to be) learned
During a CoV pandemic only innate immunity can reliably protect you from clinically relevant disease and generate herd immunity. This is because innate immunity can be trained, is able to recognize all SC-2 variants (and all CoVs) and capable of abrogating viral replication and transmission at an early stage of infection, and because innate Ab secreted by Ag-experienced/ trained B1 effector cells have increased affinity and are, therefore, not suppressed by naturally acquired Abs. However, even a properly trained innate immune system can only function sufficiently so long that it’s not compromised by interfering Ag-specific Abs within a healthy individual. Nutritious food and a healthy lifestyle (no overweight + exercise!) are, therefore, paramount to bring to bear the full capacity of a trained innate immune system such as to ascertain protection from repetitive exposure to SC-2 during a pandemic. Nasal and oral-pharyngeal washes with diluted povidone-iodine or hydrogen peroxide together with supplements such as zinc, vitamin C and D (the latter in winter!) can be game changers when applied at the earliest manifestation of discomfort or even as prophylaxis after high-risk exposure. For as long a no herd immunity is achieved, vulnerable people (i.e., those with underlying diseases or other immune suppressive or immune degenerative conditions) should be protected by adequate infection prevention measures and be granted access to early multidrug therapy.
None of the current C-19 vaccines can block SC-2 transmission and will, therefore, inevitably subvert acquired and undermine innate host immune responses that are directed at SC-2. This will ultimately result in viral immune escape and may even cause the virus to become highly virulent in vaccinees. It is also scientifically plausible to anticipate that prolonged suppression of CoV-relevant innate Abs will lead to an increased incidence in autoimmune disease and other viral respiratory diseases in younger age groups and other infectious or non-infectious immune-mediated diseases (including cancer) in older age groups. To investigate whether there is an increase in the incidence of these diseases in the vaccinated as compared to the unvaccinated part of the population, their occurrence should be closely monitored over the coming weeks and months. A potential increase in the incidence of these diseases would come on top of the frightening increase in adverse events that are directly related to the injection of these vaccines, particularly the genetic C-19 vaccines, as documented in the VAERS (https://vaers.hhs.gov/; US), the Yellow Card system (https://yellowcard.mhra.gov.uk/; UK) or by EudraVigilance (https://www.ema.europa.eu; Europe) [for more information on side effects: see relevant links on p. 21, 25, 31 in: https://www.voiceforscienceandsolidarity.org].
The current C-19 vaccines have been shown to provide partial and short-term protection against hospitalization and death in that they can to some extent prevent C-19 disease from developing into severe disease. This is thought to be due to stimulation of (cross-reactive), non-cytolytic T memory cells (9-13). It is, therefore, reasonable to assume that this effect is due to immune inflammatory cytokines and, therefore, both non-specific and limited in time. As vaccine-induced cytokine-secreting T cells are endowed with memory, their protective effect can be readily recalled upon re-exposure to relevant Tc epitopes comprised within the pathogen (i.e., CoV) or vaccinal immunogen (e.g., S protein). However, stimulation of non-cytolytic Ag-specific T memory cells is suspicious of causing immune inflammatory disease in genetically predisposed individuals. It is well known, indeed, that immune pathology resulting from natural infection or vaccination always involves non-cytolytic T cells. Building an immune intervention strategy on this type of T cells is, therefore, futile and unsafe.
In conclusion, there is no place in this pandemic for any of the current C-19 vaccines. Even the most passionate vaccinologist can only conclude that the current C-19 vaccines are harmful, both from an individual and public health viewpoint, and that their use in mass vaccination campaigns is violating all rules of vaccinology. Instead of cutting the chain of viral transmission, these vaccines are now increasing the rate of infectious cases in the vaccinated as compared to the non-vaccinated population across all age groups (14-19). Furthermore, there is no single scientific rational, let alone scientific data, to believe that their use in mass vaccination campaigns across all age groups (including children and pregnant women!) will not entail detrimental consequences for both individual and public health. Those would come on top of the alarming rate of adverse events that are regularly reported shortly after the injection of the genetic C-19 vaccines. Their administration (without informed consent!) should be halted immediately and replaced by large-scale antiviral chemoprophylaxis at a population level (to control the pandemic in countries with high vaccine coverage rates) and early multidrug treatment at an individual level (to control the disease in vulnerable individuals). The ongoing mass vaccination campaigns are a threat to our human species. Vaccine mandates and immunologic discrimination are, therefore, a crime against humanity and will undoubtedly be referred to as such in the history of mankind.
Once again, I hope I am wrong, but unfortunately, I doubt it. I am afraid to predict that it will take a disaster before these hardened sinners become fully aware of all the harm they’ve been causing to our very own species.
4. “The cellular basis of trained immunity and heterologous protection against secondary infections resides in the functional reprogramming of innate immune cells, which were first observed in invertebrates.” In: Trained Innate Immunity, Epigenetics, and Covid-19: https://www.nejm.org/
9. https://www.voiceforscienceandsolidarity.org : When anti-S(pike) antibodies against Omicron can no longer sustain the narrative, why not resort to T cells?
10. https://www.voiceforscienceandsolidarity.org : Do cross-reactive T cells explain mild course of Omicron infection?
11. https://www.voiceforscienceandsolidarity.org : To all those who continue to attribute abrogation of SARS-CoV-2 infection to pre-existing cross-reactive T cells rather than to innate immunity. The devil is in the detail of peer-reviewed publications.
12. https://www.voiceforscienceandsolidarity.org: Cross-reactive memory T cells are associated with (but not responsible for) protection against SARS-CoV-2 infection in COVID-19 contacts
13. https://www.voiceforscienceandsolidarity.org : ‘Killer’ immune cells still recognize Omicron variant…. oh really?
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