When the Trojan Horse Becomes the Elephant in the Room: Hidden Dynamics of Vaccine-Associated Viral Immune Escape in Highly Covid-19-Vaccinated Populations

‍The mass vaccination program has been the most catastrophic gain-of-function experiment ever conducted in human history-one that will catch highly COVID-19-vaccinated populations by surprise, yet also make Africa great again!

In this manuscript, I explain why immune escape, without overly spectacular clinical consequences, stealthily infiltrates highly COVID-19 (C-19) vaccinated populations that do not generate herd immunity[1] and lays itself in a treacherous ambush-one that many are aware of but prefer to ignore because the problem seems too complex, too embarrassing, or even too controversial. Consequently, the existence of immune escape is by no means denied on the one hand but on the other hand, no one dares to predict its possible consequences, let alone take them into account.

Abstract

Mass vaccination against COVID-19 has profoundly altered the evolutionary trajectory of SARS-CoV-2 (SC-2). By deploying non-sterilizing spike (S)-based vaccines during an active pandemic, highly C-19- vaccinated populations failed to establish herd immunity and instead fostered large-scale viral immune escape. This immune escape extends beyond loss of antibody (Ab)-mediated control of transmission and increasingly involves antiviral cytokine-secreting T cells[2], driving chronic infections and sustained immune pressure on viral transmissibility.
As vaccine breakthrough infections (VBTIs) accumulate, C-19 vaccinees increasingly rely on cytokine-secreting T cells with poor cytotoxic capacity, thereby prolonging viral replication and fueling intra-host selection of ‘cryptic’ escape variants. These variants, once sporadically detected, are now converging through mutations in conserved, cytokine-related Tc epitopes, leading to the expansion of co-circulating variants with enhanced infectiousness. Genomic surveillance often misattributes their rapid spread to minor mutations in more routinely analyzed proteins (e.g., S protein), obscuring the role of cytokine-related immune escape.
This convergent evolution is reshaping the viral landscape and narrowing variant diversity while the rising prevalence of long COVID and viral activity in wastewater highlights the scale of chronic infections sustaining this process. These dynamics parallel the rise of OMICRON, but with a critical shift: Ab-dependent enhancement of infection (ADEI) is now paving the way to glycan-dependent enhancement of infection (GDEI), predicted to culminate in the emergence of a highly virulent variant-termed HIVICRON. By incorporating additional glycosylation sites that impair antigen (Ag) presentation, such a lineage could bypass both humoral and cellular adaptive immunity, enabling multisystemic viral dissemination and hyperacute mortality in highly C-19 vaccinated populations.
In conclusion, vaccine-associated immune escape transforms an acute, self-limiting viral pandemic into a chronic immune escape pandemic of escalating infectiousness and potential hypervirulence. These findings underscore that mass vaccination against an acute self-limiting viral infection (ASLVI) like SC-2 not only undermines vaccine efficacy but also poses a highly worrisome safety risk with implications for both individual and global health in the longer term.

1. Vaccine-associated viral immune escape: not just a matter of vaccine efficacy!

Regulatory authorities are primarily concerned with vaccine safety, whereas manufacturers focus on vaccine efficacy. If a vaccine fails to prevent disease, the producer has little incentive to seek market authorization, as no viable market would exist. Conversely, vaccines that demonstrate some protective effect but raise safety concerns cannot obtain approval since regulators must prevent exposing healthy individuals to unacceptable risks. The C-19 vaccines provide a clear example of the latter type. Although their claimed efficacy was overstated due to bias and was undoubtedly limited in both duration and scope-as clearly demonstrated by the mass vaccination program-the C-19 vaccines did show ‘some’ efficacy: initially against acute Covid-19 disease and later against severe Covid-19 disease. However, despite many unresolved safety concerns-some of which quickly revealed genuine safety issues upon deployment-these vaccines were authorized by regulatory authorities (through unjustified Emergency Use Authorization) and even promoted by public health agencies. This represents an unprecedented example of a large-scale public health scandal driven by bribery and corrupt conflicts of interest, for which both regulatory and public health bodies in the US are now being legitimately and heavily criticized by the new HHS Secretary, RFK Jr., and his staff.

For most people, vaccine safety and efficacy are considered two distinct issues that can be dealt with separately.
The safety issues of the mRNA C-19 vaccines are now extensively documented and beyond obvious to all those who do not automatically dismiss all criticism of C-19 vaccination as conspiracy theory. As for the lack of efficacy, critics of the C-19 mass vaccination program often restrict their arguments to the inability of these vaccines to prevent viral transmission, thereby failing to stop the pandemic. This narrow critique makes it relatively easy for the pharmaceutical industry to continue experimenting with mRNA platforms, extending their scope beyond C-19 vaccines to other vaccines protecting against infectious diseases and even cancer. Indeed, industry efforts are currently focused on developing mRNA vaccines of higher quality (improved purity, characterization, and consistency) and on novel formulations and delivery methods that better control transfection with respect to dose, duration, and localization. Such refinements are expected to reduce officially recognized side effects (e.g., myocarditis). In this way, Big Pharma aims to downplay existing concerns and complaints regarding the side effects of mRNA vaccines and to sufficiently convince regulators of the safety of these genetically engineered vaccines. mRNA vaccine manufacturers hope this strategy will open the door to widespread, unrestrained application of mRNA transfection technologies in humans and animals. That is where the critical importance of vaccine-associated viral immune escape comes in. Immune escape poses a challenge not only to vaccine efficacy but also to vaccine safety! This is because viral immune escape extends far beyond loss of immune control over transmission. In populations mass-vaccinated with vaccines that at best reduce symptoms but fail to block infection and transmission, collective adaptive immunity eventually exerts immense pressure on viral infectiousness. In this manuscript, I explain how this immune pressure currently drives the  selection of escape mutations in otherwise highly conserved cytokine-dependent T cell (Tc) epitopes in chronically infected individuals suffering from chronic inflammatory disease (so-called long Covid). 
How C-19 mass vaccination ultimately drives highly C-19-vaccinated populations to exert immune selection pressure on these cytokine-related viral epitopes and why I am convinced that repeated VBTIs will eventually trigger a massive wave of high viral virulence, and thereby create a major safety concern, is described under section 9.

2. A dangerously naïve myth…

The notion that high viral transmissibility necessarily entails low virulence remains a dangerously naïve myth. The mantra ‘high infectiousness implies low virulence’ is as misguided as suggesting that a virus strategically makes decisions to ensure its replication and survival! This ancestral superstition stems from the fact that a natural pandemic boosts the collective immunity of the population, thereby providing increasing resistance to the virus as it continues to spread, ultimately leading to sterilizing herd immunity. At that stage, the virus can no longer be transmitted, which inevitably brings the pandemic to an end.

3.     Lack of herd immunity in highly C-19 vaccinated populations poses a global safety issue of international concern.

Herd immunity develops because, upon reinfection, the majority of individuals previously exposed to the virus mount sterilizing immunity. This process involves synergy between innate and adaptive responses: Natural Killer (NK) cells rapidly reduce the viral load (independently of activation by Ag-presenting cells [APCs]) to levels low enough for subsequently recalled high concentrations of Abs to neutralize the residual virus without exerting suboptimal immune pressure on the virus (hence, preventing viral immune escape!).
However, non-replicating S-based C-19 vaccines only generate antiviral humoral immunity (inflammatory cytokines and virus-neutralizing Abs) but not antiviral effector cells such as NK cells and S-specific CD8+ T cells. Because these non-sterilizing vaccines were deployed for large-scale immunization during an ongoing pandemic, they failed to induce herd immunity-even with booster doses-and thereby allowed neutralization-resistant variants such as Omicron and its descendants to cause symptomatic VBTIs.

Unlike in a natural pandemic, the continuing spread of the virus in the hostile immunological environment of highly C-19-vaccinated populations has led to successive rounds of VBTIs, thereby refocusing the immune response to Tc immunity and fueling the continuous selection of increasingly infectious viral escape variants while failing to effectively stimulate cellular innate immunity in C-19 vaccinees (https://pubmed.ncbi.nlm.nih.gov/38781962/).

4.   Vaccine-associated adaptive immune refocusing turns a pandemic of acute, self-limiting disease  into an immune escape pandemic of chronic disease and thereby generates a multitude of cryptic viral variants.

C-19 vaccinees who contracted symptomatic VBTI experienced immune refocusing (https://braintrain.mykajabi.com/the-inescapable-immune-escape-pandemic chapter 1), which upon repeated infection has shifted the defensive role from their humoral Abs to the cellular arm of their immune system to provide maximal, albeit insufficient, protection against ever newly emerging variants. In the current ‘chronic’ phase of the pandemic, reinfections in individuals whose innate immune system is naturally compromised, whether left untrained by the non-replicating C-19 vaccines or sidelined by VBTIs, drive sustained stimulation of T cells with suboptimal cytotoxic capacity, thereby fostering prolonged or persistent SC-2 infection. This promotes intra-host selection and shedding of host-specific viral escape variants. Whereas these viral lineages were previously only occasionally detected through wastewater sequencing (hence their designation as ‘cryptic variants’), their appearance in wastewater surveillance has recently become more frequent and widespread (https://doi.org/10.1371/journal.ppat.1012850; https://pmc.ncbi.nlm.nih.gov/articles/PMC12176291/).
Their increase has occurred alongside the detection of ‘classical’ inter-host-selected variants, which are shaped by collective immune pressure transmitted across the chain of infections between different hosts within a given population.

We are currently at a stage of the pandemic where, despite enhanced efforts of the adaptive cellular immune system, viral shedding by an ever-increasing portion of chronically infected individuals cannot be prevented. It is reasonable to assume that rising intra-host immune pressure on the virus enables a growing number of cryptic variants to incorporate escape mutations in dominant cytokine-related Tc epitopes. This convergent evolution of escape mutations in distinct co-circulating variants has led to enhanced infectiousness and to their rapid expansion and dominance (https://www.nature.com/articles/s41579-022-00841-7; https://pubmed.ncbi.nlm.nih.gov/36768588/). Consequently, these dominant variants are now displacing other co-circulating strains and reshaping the viral landscape. As the prevalence of chronic infections (long COVID) continues to rise in highly C-19–vaccinated populations, increasing numbers of cryptic variants are generated. How their growing presence within the viral landscape fueled the successive dominance of co-circulating strains is discussed in more detail under section 6.

5. From enhanced viral infection to increased viral virulence: how non-Ag-specific viral immune escape[3] enables dangerous gain-of-function.

In the current landscape of dysregulated adaptive immune responses, chronic SC-2 infection in C-19 vaccinees drives sustained activation of T cells with suboptimal cytotoxic function and, consequently, prolonged production of antiviral pro-inflammatory cytokines (e.g., interferon-γ[4]; IFN-g). These pro-inflammatory cytokines promote activation and maturation of APCs, thereby facilitating viral particle uptake and enhancing the activation of CD4⁺ T helper cells, which in turn support the proliferation and cytokine secretion of Th-dependent CD8⁺ T cells. (https://pmc.ncbi.nlm.nih.gov/articles/PMC8155612/; https://pmc.ncbi.nlm.nih.gov/articles/PMC6396335/).

Because of the rising prevalence of prolonged C-19 infections, chronic Tc-mediated immune responses have become more widespread, causing highly C-19-vaccinated populations to exert immune pressure on shared cytokine-related Tc epitopes in an ever-growing proportion of C-19 vaccinees. This promotes large-scale viral escape from antiviral cytokine control, thereby fostering transmissibility and paving the way for dangerous glycan-mediated (i.e., non-Ag-specific) immune escape (see under section 9.).
This represents a highly unusual situation: unlike unvaccinated individuals, who benefit from well-trained cellular innate immunity, a large fraction of C-19 vaccinees now increasingly relies on cytokine-secreting T cells to mitigate acute symptoms and prevent severe disease following SC-2 infection (https://www.nature.com/articles/s41467-023-38020-8). Because this scenario did not occur in earlier phases of the pandemic, Tc epitopes-except for a limited set of S-associated epitopes involved in Th-dependent induction of neutralizing anti-S Abs-remained largely conserved during the evolutionary dynamics of SC-2 prior to this ‘chronic’ stage of the pandemic https://www.nature.com/articles/s41423-022-00838-5).

6. When cryptic variants adapt to spread beyond their original host, they can become a reservoir for novel variants with inter-host transmission potential.

Cryptic variants typically arise from intra-host selection[5] during chronic or persistent SC-2 infections within an individual.
Individuals with weakened innate immunity (primarily in naturally immune-suppressed and C-19 vaccinees) exert intra-host immune pressure on productive viral infectiousness, thereby generating a steadily increasing pool of distinct cryptic variants. These variants accumulate many distinct escape mutations due to strong selective pressure in that host. They typically support intra-host replication and immune escape but many of these cryptic variants do not normally become successful inter-host transmitters and hence remain undetected in broader population surveillance. This is partly because their unusual, highly divergent escape mutations may impair their ability to infect or transmit effectively in the wider population where immune and receptor environments differ. This explains why they frequently remain ‘cryptic’ with limited or no spread beyond the original host.

As the pandemic in highly C-19–vaccinated populations has progressively shifted into a stage dominated by chronic infection and disease, viral transmission, and thus viral survival, now increasingly depends on variants shed by chronically infected individuals. Because these variants face the constraint of poor inter-host transmissibility, highly C-19-vaccinated populations are now exerting intensified immune selection pressure on conserved, immunodominant, cytokine-related Tc epitopes (predominantly in the nucleocapsid protein) in order to blunt Tc-mediated control of infection. In other words, newly emerging intra-host variants that reduce or prevent IFN-γ production by inflammatory T cells in chronically infected individuals gain a competitive fitness advantage in these populations (https://www.pnas.org/doi/10.1073/pnas.2203760119; https://pmc.ncbi.nlm.nih.gov/articles/PMC10053418/). Through this adaptation, ‘cryptic’ variants are now likely to evolve greater inter-host transmissibility, leading to the emergence of increasingly transmissible Tc-inhibitory variants.

The more widespread the shedding of these more transmissible variants-and thus, the higher their inter-host transmission and infection rates-the greater the population-level immune pressure on their transmissibility in highly C-19–vaccinated populations. This increasing immune pressure promotes the natural selection of immune escape variants that have acquired mutations capable of reducing or abrogating IFN-γ production by cross-reactive T cells activated through conserved, immunodominant, cytokine-relevant epitopes. In turn, this steadily increases the transmission potential of such variants.
In other words, growing collective immune pressure on cytokine-related Tc epitopes enables intra-host immune selection of new variants to progressively shift toward inter-host immune selection, thereby facilitating the transition of a multitude of previously sporadically detected escape variants (so-called ‘cryptic variants’) into a smaller set of co-circulating viral variants with enhanced infectiousness.

7. Cryptic variants carrying escape mutations in conserved cytokine-related Tc epitopes may remain hidden within existing lineages in genomic surveillance.

Newly emerging, more transmissible intra-host variants that share the same mutation in conserved cytokine-related Tc epitopes will not be detected as distinct co-circulating variants if surveillance analyses focus only on viral proteins or genomic regions that exclude these highly conserved epitopes. This helps explain why the impact of such newly emerging variants may be misinterpreted by surveillance systems as the result of minor mutations in more routinely analyzed proteins (e.g., the S protein), seemingly conferring a higher intrinsic transmission capacity to their parental co-circulating strain and thus apparently accounting for their expansion in prevalence.
In genomic sequencing studies that estimate the relative proportions of co-circulating variants, the contribution of these mutants to the viral landscape will therefore merely present as an apparent ‘booster effect’ on the transmission and propagation of the parental inter-host variant from which they originated. Hence, some pre-existing co-circulating variants may suddenly appear to rapidly expand their relative contribution to the viral landscape until another co-circulating variant--under intensifying immune pressure-acquires a fitness and transmission advantage by incorporating additional Tc-inhibitory mutations in shared, immunodominant cytokine-related Tc epitopes (see figs. 1 and 2).
This dynamic can persist only as long as the growing immune selection pressure on viral transmissibility is partially offset by subdominantly circulating variants that incorporate Tc-inhibitory mutations in other cytokine-related Tc epitopes. However, the greater the contribution of a dominant variant to the overall variant proportion distribution, the lower the likelihood that additional chronic infections will be sustained by subdominant variants, and the less likely it becomes that population-level immune pressure on viral infectiousness and transmissibility will be mitigated.

8. The current viral evolutionary dynamics in highly C-19 vaccinated populations can only be explained by convergent evolution of cytokine-relevant Tc epitopes.

I postulate that as inter-host immune selection pressure on viral transmission progressively increases-driven by the rising prevalence of prolonged or chronic infections in highly C-19–vaccinated populations-escape mutations in shared cytokine-related Tc epitopes of co-circulating SC-2 variants will increasingly undergo convergent evolution at the population level. This convergent adaptation primarily confers a transmission fitness advantage to those variants that cause the majority of infections. As these more transmission-fit variants will rapidly dominate in prevalence, they contribute disproportionately to further immune pressure on inter-host transmissibility (by being responsible for most chronic infections), thereby progressively displacing and outcompeting previously co-circulating inter-host–selected variants.

The convergent evolution reflected in successive increases in dominant prevalence of distinct, co-circulating SC-2 variants-and the accelerated pace at which more transmission-fit lineages achieve dominance across many highly C-19-vaccinated countries-constitutes yet another hallmark of population-level immune pressure on viral transmissibility (see fig. 1).
The pronounced differences, both in the magnitude of infectiousness enhancement between expanding co-circulating variants and in the speed of their prevalence expansion cannot be fully explained by measured differences in their neutralizability, suggesting that convergent evolution of mutations in cytokine-relevant Tc epitopes rather than in virus-neutralizing Bc epitopes are the underlying basis for the differences observed.

It is reasonable to assume that once an immune escape variant derived from the predominantly circulating strain becomes responsible for the vast majority of prolonged or chronic infections, it will rapidly amplify its capacity to evade immune responses directed at cytokine-related Tc epitopes across successive chains of chronic infection. As a result, collective immune pressure on viral transmission will escalate dramatically, ultimately driving the emergence of a decisive mutation that enables full escape from adaptive immunity (see under section 9.).

9. Harbingers of HIVICRON

Beyond the increasing prevalence of chronic C-19 infections (as reflected in rising numbers of long COVID cases) and the heightened viral activity detected in wastewater, a marked rise in both the relative contribution of a co-circulating variant to the overall variant distribution and the speed with which it reaches dominance must be regarded as another critical harbinger of the imminent advent of HIVICRON (see figs. 1 and 2). This is because the enhanced infectiousness of a newly emerging co-circulating variant inevitably further increases population-level immune pressure on its transmissibility by virtue of its higher rate of chronic infection (see section 8. above).
Once its dominance becomes sufficient to account for the majority of newly occurring chronic (re)infections, a steep further increase in Tc-mediated immune pressure on its transmissibility is likely to drive the emergence of a decisive immune escape mutation that enables the virus to bypass Ag presentation altogether and thereby evade all Ag-specific adaptive immune responses. Such a development would allow unrestricted multi-systemic intra-host propagation of the virus.

I anticipate that, as a last resort, intense immune pressure on viral survival will eventually drive the selection of additional glycosylation sites in ways that hinder viral internalization and processing by APCs, thereby silencing Ag presentation and abrogating T helper cell–dependent immune recognition. It is reasonable to assume that escape mutations introducing new glycosylation sites on the SC-2 S protein could block or reduce uptake by APCs and thereby impair immune recognition and effectively silence adaptive immunity by preventing both helper T and effector cell stimulation (https://pmc.ncbi.nlm.nih.gov/articles/PMC7437500/; https://pubmed.ncbi.nlm.nih.gov/34004174/; https://pubmed.ncbi.nlm.nih.gov/38247799/).
It is also reasonable to assume that in individuals lacking trained innate virus-killing immunity, any viral lineage capable of simultaneously breaching both humoral and cellular adaptive immune defenses (i.e., HIVICRON) would trigger a highly virulent infection, resulting in a wave of sudden death.

Although direct experimental evidence for SARS-CoV-2 is lacking, studies in HIV-1 and influenza clearly demonstrate that viral glycosylation shields reduce Ag uptake and processing by APCs and thereby limit T cell priming (https://pubmed.ncbi.nlm.nih.gov/26972002/; https://pubmed.ncbi.nlm.nih.gov/23365085/). Consistent with this, deglycosylated SC-2 S-derived immunogens have been shown to elicit stronger immune responses in animal models, supporting the notion that added glycans on S protein can impair APC-mediated Ag presentation  (https://www.science.org/doi/epdf/10.1126/scitranslmed.abm0899).

10. Will unvaccinated individuals be affected by HIVICRON?

While HIVICRON is expected to trigger widespread, hyperacute systemic viremia in highly C-19-vaccinated populations, its high virulence may come at a fitness cost by reducing its intrinsic infectiousness. This is because the introduction of novel glycan chains adjacent to the S-RBD (receptor-binding domain) may sterically or conformationally interfere with binding of the receptor-binding motif (RBM) to the ACE-2 receptor on target host cells, thereby compromising viral cell entrance, or reduce the  efficiency of furin cleavage and syncytia formation, particularly in the case of the addition of O-glycans around the furin cleavage site (https://pmc.ncbi.nlm.nih.gov/articles/PMC9220273/; https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.1068449/full).

Such reduced intrinsic infectiousness would further improve the protection of unvaccinated individuals against HIVICRON since the level of viral infectivity remains the principal challenge to their trained innate immune system. If HIVICRON’s increased virulence were, indeed, to coincide with diminished intrinsic infectiousness, the probability of even unvaccinated vulnerable individuals developing clinical symptoms would be substantially reduced.
Moreover, the introduction of novel glycosylation sites in combination with previously accumulated escape mutations could justify the recognition of HIVICRON as a distinct coronavirus species.

11.  OMICRON versus HIVICRON

HIVICRON’s trajectory in highly C-19-vaccinated countries is strikingly similar to that of OMICRON.
In the pre-Omicron era of the SC-2 pandemic, large-scale immunization drove widespread stimulation of neutralizing Ab titers. This exerted selective pressure that promoted enhanced resistance of Omicron to B cell-derived neutralizing Abs, ultimately resulting in ADEI in many C-19 vaccinees.
In the late Omicron era, widespread VBTIs induced large-scale stimulation of antiviral cytokine-producing T cells (e.g., IFN-γ-producing T cells). This created selective pressure that promoted enhanced inhibition by Omicron descendants of Tc-derived antiviral cytokines, potentially culminating in GDEI.
GDEI is thought to translate into high virulence, characterized by hyperacute, multisystemic viremia.

Mechanistically, ADEI in individuals with high titers of poorly neutralizing Abs (predominantly C-19 vaccinees) drives large-scale VBTIs that largely sideline innate immunity. However, these infections remain mostly localized to the respiratory tract due to increased virus uptake by tissue-resident dendritic cells or APCs and symptomatic protection conferred by cytotoxic Tc responses.
In contrast, GDEI in individuals exhibiting extensive proliferation of poorly functional antiviral T cells (again, predominantly in C-19 vaccinees) would cause large-scale VBTIs that sideline adaptive immunity, thereby enabling multisystemic viral dissemination and high viral virulence.

In summary: whereas Ab-related mutational escape drives enhanced localized VBTIs and results in high infection rates in highly C-19–vaccinated countries, mutational escape from cytokine-producing T cells is postulated to drive enhanced systemic VBTIs and to result in high virulence in these populations.

12.  Conclusions

An increase in long COVID cases, together with rising viral loads in wastewater and the accelerated dominance of a narrowing spectrum of co-circulating variants, should be regarded as harbingers of a tsunami of multisystemic viremia in highly C-19–vaccinated populations.
The time required for a highly virulent escape lineage to emerge will depend on how quickly the dominantly circulating immune escape variant reaches a prevalence that is sufficiently high for the population to exert immune pressure on its transmissibility at a level that outweighs the variant’s acquired fitness advantage.
Continuous re-exposure to dominantly circulating variants, compounded by the reckless continuation of C-19 vaccination in parts of the population, drives more widespread stimulation of antiviral cytokine-producing T cell responses and thereby further increases immune pressure on cytokine-relevant Tc epitopes of the virus.

The incorporation of convergent, transmission-promoting escape mutations in shared cytokine-related Tc epitopes likely explains the currently observed rise in infectiousness and expansion of one or more co-circulating variants in highly C-19-vaccinated populations (e.g., XFG variant; see figs. 1 and 2).  It is reasonable to assume that, eventually, a single variant will succeed in dominating all other co-circulating variants and thereby rapidly cause the steadily increasing group of chronically infected individuals to exert concentrated immune pressure on these epitopes. Once this pressure can no longer be significantly diluted by subdominantly circulating variants (see fig. 2), I postulate that a decisive escape mutation-enabling the virus to bypass the host’s adaptive immune recognition altogether-will ultimately be selected.

By virtue of a profound change in its glycosylation profile, such a newly emerging coronavirus lineage would likely avoid Ag presentation and thereby breach the remaining Tc-mediated immunity in many C-19 vaccinees, particularly in those vaccinees whose Abs no longer effectively neutralize the virus and whose innate immune system has not been sufficiently trained, since neither C-19 vaccination nor subsequent VBTIs contributed to this training.

In other words, a substantial proportion of C-19 vaccinees in highly vaccinated countries will find themselves without a functional immune defense, thereby enabling this suddenly emerging coronavirus lineage to acquire a high level of viral virulence and unleash a tsunami of hyperacute death. The evolutionary trajectory leading to this anticipated dramatic outcome is depicted in fig. 3.

From the above, it can be unambiguously concluded that mass vaccination-associated efficacy failures-driven by viral immune escape-will, in the long term, inevitably lead to catastrophic safety issue in highly vaccinated populations, compounding the already well-documented adverse events, particularly those associated with the mRNA-based C-19 vaccines.
In other words, large-scale C-19 vaccination should never have been authorized during this pandemic, regardless of the vaccine platform used or any subsequent updates to the vaccinal target Ag.

As emphasized on several occasions, mass vaccination during a pandemic caused by an ASLVI inevitably drives viral immune escape across entire highly vaccinated populations. This process drives immune selection pressure on viral infectiousness and transmissibility rather than enabling the establishment of herd immunity. Hence, even if vaccination were to continue only in smaller cohorts, it would still further increase population-level immune pressure on viral infectiousness by boosting T cell–mediated immunity, thereby accelerating the advent of the HIVICRON tsunami.
The failure to establish herd immunity has already promoted enhanced viral infectiousness through ADEI and will ultimately drive increased viral virulence through GDEI.

13.  References that support or are highly relevant to key mechanistic claims made in this manuscript.

- Cryptic lineages & wastewater evidence (supports ‘cryptic variants’ reservoir and population spread):
Suarez et al., 2025, PLoS Pathogens — Large-scale identification and characterization of cryptic SARS-CoV-2 lineages from publicly available wastewater sequencing; documents persistence and distinct mutational patterns. PLOS+1;
Shafer et al., 2024, Lancet Microbe/Cell Reports Med. — Tracing the origin and persistence of a highly divergent cryptic wastewater lineage (Wisconsin), with longitudinal genomic evolution. PubMed+1

- Convergent evolution & nucleocapsid (supports population-level convergence beyond spike):
Focosi et al., 2024, Vaccines — Review of successive waves of convergent evolution across SARS-CoV-2 genes/proteins, contextualizing repeated adaptive solutions. MDPI (Preprint/early report) PubMed 40503915, 2025 — Convergent evolution in N (203–205) facilitating SARS-CoV-2 replication/fitness; highlights non-spike adaptive hotspots. PubMed

- T-cell epitope conservation & N-specific responses (supports idea that many Tc epitopes stayed conserved while pressure shifts):
Choi et al., 2022, Signal Transduction and Targeted Therapy — Systematic analysis showing high conservation of T-cell epitopes in Omicron (esp. non-spike). Nature
Eser et al., 2023, Nature Communications — Nucleocapsid-specific T cells correlate with protection by limiting upper-airway replication and inflammation. Nature
Yang et al., 2023, Frontiers in Immunology (review) — Overview of immunodominant epitope–specific T-cell responses across SARS-CoV-2 proteome, underscoring N as a key T-cell target. PMC

- Interferon resistance / innate immune evasion (supports immune pressure on cytokine-related control):
Guo et al., 2022, PNAS — Variants of concern exhibit increased interferon resistance, underlining the role of innate immunity in viral evolution. PNAS

Nchioua et al., 2023, EMBO Reports - Omicron BA.1 shows heightened resistance to exogenous IFNs, suggesting evolved escape from cytokine-mediated control. PMC

- Glycosylation of spike & implications for antigen processing/recognition (supports the glycan-centric escape argument):
Parker et al., 2021, Cell Reports / Cell Reports Medicine — HLA-II peptidome mapping from dendritic cells pulsed with spike identifies presented peptides across glycosylated regions, indicating that glycan context shapes presentation. PubMed+1

- Gong et al., 2021, Signal Transduction and Targeted Therapy (review) - Comprehensive review of SARS-CoV-2 and ACE2 glycosylation, covering biological functions and immune implications. Nature

- Hanisch et al., 2024, Cells (review) - Site-specific O-glycosylation of spike: current knowledge on impact on virulence and immune modulation; relevant to glycan-dependent immune escape hypotheses. MDPI

- Renner et al., 2025, Communications Medicine — Modulating spike glycosylation profiles affects immunogen performance, underscoring that glycan patterning has functional immune consequences (vaccine-design angle). Nature

- Variant biology, transmissibility, and immune escape (broad context for selective immune pressures as described in this manuscript):

Carabelli et al., 2023, Nature Reviews Microbiology — Authoritative review of variant biology (transmission, immune escape, fitness), useful as an umbrella reference for your selection-pressure framework. Nature

- Breakthrough infections boosting T-cell responses (supports VBTIs reshaping cellular immunity)
Tarke et al., 2024, The Lancet Microbe - Breakthrough infections enhance variant-specific T-cell responses and remodel the epitope repertoire, consistent with immune refocusing under repeated exposure. ScienceDirect

- Additional notes on fit to specific claims made in this manuscript:

Glycan-mediated APC effects: While direct, human in-vivo proof that added spike glycans reduce dendritic-cell uptake and T-cell priming is still limited, Parker et al. demonstrate what DCs present from spike (including glycosylated regions), and multiple reviews (Gong; Hanisch) plus vaccine-design papers (Renner) support the functional importance of glycosylation to immune visibility/processing. These complement the mechanistic proposal made in this manuscript without over-claiming. Nature+4PubMed+4ScienceDirect+4

Innate/cytokine pressure: Interferon-resistance data (Guo; Nchioua) directly support selection away from cytokine control, aligning with your thesis that pressure is shifting toward non-antigen-specific antiviral pathways. PNAS+1

Convergent evolution & cryptic reservoirs: Recent wastewater studies and convergence reviews strengthen your narrative of population-level convergence emerging from diverse sources (including chronic infections). MDPI+4PLOS+4PMC+4

T-cell epitope conservation & N focus: These help explain why Tc-epitope pressure signals may become visible only later and why N-directed T cells matter for control.

Fig. 1: Distribution of variant proportions over time. The diagram illustrates the accelerated pace at which newly dominant variants expand and the corresponding increase in their overall contribution to the viral landscape (based on projected estimates).

Fig. 2: Dashboard in the US (top section) and prevalence of co-circulating variants over time (bottom section; note: limited sample size); from:         https://public.tableau.com/app/profile/raj.rajnarayanan/viz/USAVariantDB/VariantDashboard)

Fig. 3: How mass C-19 vaccination drives dangerous immune escape in highly C-19 vaccinated populations

One-Page Summary for a General Audience

When the Trojan Horse Becomes the Elephant in the Room: Hidden Dynamics of Vaccine-Associated Viral Immune Escape

COVID-19 (C-19) vaccines were rolled out worldwide with the promise of ending the SARS-CoV-2 pandemic. While they provided temporary protection against severe disease, they were unable to block infection or transmission. This has led to an unintended consequence: instead of stopping the virus, mass vaccination has created strong pressure on the virus to adapt.

Why this matters

- Natural immunity vs. vaccine immunity: Natural infection trains both arms of the immune system-antibodies (Abs) and natural (i.e., innate) killer cells-to quickly eliminate the virus. C-19 vaccines, by contrast, mainly stimulated Abs and some T cell responses, but not the full innate defense.

- No herd immunity: Because the C-19 vaccines did not prevent infection, herd immunity (where the virus can no longer spread in the community) could not develop. This left the virus with space to evolve.

What is happening now

- Vaccine breakthrough infections (VBTIs): In highly C-19 vaccinated populations, repeated reinfections are common. Many individuals, particularly C-19 vaccinees, develop long-lasting or chronic infections (long COVID), which give the virus time to mutate within a host.

- These intra-host mutations create hidden viral versions (cryptic’ variants), often detectable only in wastewater. Over time, these variants converge on the same survival strategy: resisting immune responses in C-19 vaccinees that increasingly rely on pro-inflammatory T cells.

- As these immune escape variants can now spread across highly C-19 vaccinated populations, they displace older ones and thereby change the viral landscape. The result is a narrower set of co-circulating viral strains that use the same immune-evasive tricks to increase their transmissibility, making them harder to control by the adaptive immune system.

Why this is a global concern

High infectiousness no longer means low severity. A popular belief is that viruses naturally evolve to become milder. The opposite may now happen, because chronic infections and immune pressure can drive the virus to blunt the cell-mediated adaptive immune response, enabling it to spread more easily and thereby promoting more widespread viral immune escape and, hence, more chronic infection.
The manuscript warns that ongoing immune escape could eventually produce a highly virulent strain, nicknamed HIVICRON. This variant would be able to bypass both Abs and T cell defenses, spreading throughout the body rather than staying localized to the airways. Such a shift could trigger widespread severe illness and sudden deaths in highly C-19 vaccinated populations.

Unequal impact: In healthy unvaccinated people, the body’s first line of defense-the innate immune system-has been well trained through repeated natural exposure to the virus. By contrast, in many C-19 vaccinated individuals this training was bypassed since the non-replicating C-19 vaccines and later VBTIs did not properly strengthen it. As a result, unvaccinated people with strong innate immunity are better protected against C-19 disease while many C-19 vaccinees can no longer rely fully on either their untrained innate immunity or their weakened adaptive immunity.

Key takeaway

Mass vaccination against COVID-19 has set the stage for a long-term crisis. By failing to generate herd immunity and instead fueling viral immune escape, large-scale use of the C-19 vaccines transformed the pandemic from one of acute, self-limiting disease into an immune escape pandemic of chronic disease, thereby paving the way for SARS-CoV-2 to suddenly escalate its infectiousness and virulence.

[1] Herd immunity arises when a majority of the population acquires natural immunity, where natural immunity refers to sterilizing immunity established at the individual level following infection. Hence, herd immunity can be defined as sterilizing, population-level immunity that develops as a cumulative consequence of individual post-infection immunity naturally acquired after infection.

[2] For the purpose of this manuscript, T cell (Tc) relates to CD4+ T helper or CD8+ T effector cell.

[3] Non-Ag-specific viral immune escape relates to mechanisms that do not rely on escape from Ag-specific neutralizing Abs or production of antiviral cytokines by Ag-nonspecific T cells.

[4] IFN-γ is a multifunctional cytokine with important antiviral effects, including inhibition of viral entry and replication at multiple stages by inducing antiviral gene expression and enzymatic pathways (e.g., nitric oxide synthesis). It enhances Ag presentation by upregulating MHC (major histocompatibility complex) molecules on APCs, thereby boosting adaptive immune responses. IFN-γ also has strong pro-inflammatory effects, activating macrophages and promoting cytokines like IL-1 and TNF-α, which support B cell and cytotoxic T cell (Tc) effector functions. While IFN-γ is mainly secreted by activated CD4+ T helper 1 (Th1) cells, it is also produced by CD8+ cytotoxic T cells and natural killer (NK) cells during the immune response.

[5] Intra-host selection relates to selection that happens within a single host during the course of their infection.

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