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Innate Immune Suppression by SARS-CoV-2

mRNA Vaccinations: The role of G-
quadruplexes, exosomes and microRNAs
+1 Stephanie Seneff , Greg Nigh, Anthony M. Kyriakopoulos, Peter A McCullough

Abstract
The mRNA SARS-CoV-2 vaccines were brought to market in response to the widely perceived
public health crises of Covid-19. The utilization of mRNA vaccines in the context of infectious
disease had no precedent, but desperate times seemed to call for desperate measures. The mRNA
vaccines utilize genetically modified mRNA encoding spike proteins. These alterations hide the
mRNA from cellular defenses, promote a longer biological half-life for the proteins, and provoke
higher overall spike protein production. However, both experimental and observational evidence
reveals a very different immune response to the vaccines compared to the response to infection
with SARS-CoV-2. As we will show, the genetic modifications introduced by the vaccine are likely
the source of these differential responses. In this paper, we present the evidence that vaccination,
unlike natural infection, induces a profound impairment in type I interferon signaling, which has
diverse adverse consequences to human health. We explain the mechanism by which immune
cells release into the circulation large quantities of exosomes containing spike protein along with
critical microRNAs that induce a signaling response in recipient cells at distant sites. We also
identify potential profound disturbances in regulatory control of protein synthesis and cancer
surveillance. These disturbances are shown to have a potentially direct causal link to
neurodegenerative disease, myocarditis, immune thrombocytopenia, Bell’s palsy, liver disease,
impaired adaptive immunity, increased tumorigenesis, and DNA damage. We show evidence from
adverse event reports in the VAERS database supporting our hypothesis. We believe a
comprehensive risk/benefit assessment of the mRNA vaccines excludes them as positive
contributors to public health, even in the context of the Covid-19 pandemic.

Cite as: Stephanie Seneff, Greg Nigh, Anthony M. Kyriakopoulos, et al. Innate Immune
Suppression by SARS-CoV-2 mRNA Vaccinations: The role of G-quadruplexes, exosomes

Non-exclusive
and microRNAs. Authorea. January 21, 2022.
No reuse
DOI: 10.22541/au.164276411.10570847/v1

This is a preprint and has not been peer reviewed. Data may be preliminary.

Keywords: mRNA vaccines; innate immunity; IFN I response; exosomes; G-quadruplexes;

microRNAs; epitranscriptomic interference; cancer; myocarditis; thrombocytopenia.

Introduction

Vaccination is an endeavor to utilize non-pathogenic material to mimic the immunological response

of a natural infection, thereby conferring immunity in the event of pathogen exposure. This goal has
been primarily pursued through the use of both whole organism and attenuated virus vaccines. Use
of fragments of virus or their protein products, referred to as “subunit vaccines,” has been more
technically challenging [1]. In any event, an implicit assumption behind the deployment of any
vaccination campaign is that the vaccine confers the effects of a ‘benign infection,’ activating the
immune system against future exposure, while avoiding the health impacts of actual infection.

Much of the literature on this related to COVID-19 suggests that the immune response to mRNA-
based vaccination is similar to natural infection. A preprint study found “high immunogenicity of
BNT162b2 [Pfizer] vaccine in comparison with natural infection.” The authors found there to be
many qualitative similarities though quantitative differences [2]. Jhaveri (2021) suggests that mRNA
vaccines do what infection with the virus does: “The protein is produced and presented in the same
way as natural infection” [3]. The U.S. Centers for Disease Control and Prevention (CDC) makes the
case based upon antibody titers generated by prior infection vs. vaccination, in addition to
production of memory B cells, to argue that the immune response to vaccination is analogous to the
response to natural infection [4]. It is this similarity in the humoral immune response to vaccination
vs natural infection, paired with both trial and observational data demonstrating reduced risk of
infection following vaccination, that stands as the justification for the mass vaccination campaign.

In this paper we explore the scientific literature suggesting that vaccination with an mRNA vaccine
initiates a set of biological events that are not only different from that induced by vaccination but
are in several ways demonstrably counterproductive to both short- and long-term immune
competence and normal cellular function. These vaccinations have now been shown to
downregulate critical pathways related to cancer surveillance, infection control, and cellular
homeostasis. They introduce into the body highly modified genetic material. A medRxiv preprint has
revealed a remarkable difference between the characteristics of the immune response to an infection
with SARS-CoV-2 as compared with the immune response to an mRNA vaccine against COVID-19 [5].
Differential gene expression analysis of peripheral dendritic cells revealed a dramatic upregulation of
both type I and type II interferons (IFNs) in COVID-19 patients, but not in vaccinees. One remarkable
observation they made was that there was an expansion of circulating hematopoietic stem and
progenitor cells (HSPCs) in COVID-19 patients, but this expansion was notably absent following
vaccination. A striking expansion in circulating plasmablasts observed in COVID-19 patients was also
not seen in the vaccinees. All of these observations are consistent with the idea that the vaccines
actively suppress type I IFN signaling, as we will discuss below. In this paper we will be focusing
extensively, though not exclusively, on vaccination-induced type I IFN suppression and the myriad
downstream effects this has on the related signaling cascade.

Since long-term pre-clinical and Phase I safety trials were combined with Phase II trials, then phase II
and III trials were combined [6]; and since even those were terminated early and placebo arms given
the injections, we look to the pharmacosurveillance system and published reports for safety signals.
In doing so, we find that that evidence is not encouraging. The biological response to mRNA
vaccination as it is currently employed is demonstrably not like natural infection. In this paper we will
illustrate those differences, and we will describe the immunological and pathological processes we
expect are being initiated by mRNA vaccination. We will connect these underlying physiological
effects with both realized and yet-to-be-observed morbidities. We anticipate that implementation of
booster vaccinations on a wide scale will make all of these problems only more acute, and it will
serve to further erode antiviral immune competence and innate cancer surveillance and protection
for the global population subjected to these repeated boosters.

The mRNA vaccines manufactured by Pfizer/BioNTech and Moderna have been viewed as an
essential aspect of our efforts to control the spread of COVID-19. Countries around the globe have
been aggressively promoting massive vaccination programs with the hope that such efforts might
finally curtail the ongoing pandemic and restore normalcy. Governments seem reticent to consider
the possibility that these injections might cause harm in unexpected ways, and especially that such
harm might even surpass the benefits achieved in protection from severe disease. It is now clear that
the antibodies induced by the vaccines fade in as little as 3 to 10 weeks after the second dose [7], such
that people are being advised to seek booster shots at regular intervals [8]. It has also become
apparent that rapidly emerging variants such as the Delta and now the Omicron strain are showing
resistance to the antibodies induced by the vaccines, through mutations in the spike protein [9].
Furthermore, it has become clear that the vaccines do not prevent spread of the disease, but can
only be claimed to reduce symptom severity [10]. A study comparing vaccination rates with COVID-19
infection rates across 68 countries and 294 counties in the United States in early September, 2021,
found no correlation between the two, suggesting that these vaccines do not protect from spread of
the disease [11]. Regarding symptom severity, even this aspect is beginning to be in doubt, as
demonstrated by an outbreak in an Israeli hospital that led to the death of five fully vaccinated
hospital patients [12]. Similarly, Brosh-Nissimov et.al. (2021) reported that 34/152 (22%) of fully
vaccinated patients among 17 Israeli hospitals died of COVID-19 [13].

The increasing evidence that the vaccines do little to control disease spread and that their
effectiveness wanes over time make it even more imperative to assess the degree to which the
vaccines might cause harm. That SARS-CoV-2 modified spike protein mRNA vaccinations have
biological impacts is without question. Here we attempt to distinguish those impacts from natural
infection, and establish a mechanistic framework linking those unique biological impacts to
pathologies now associated with vaccination. We recognize that the causal links between biological
effects initiated by mRNA vaccination and adverse outcomes have not been established in the large
majority of cases.

2. Interferons: An Overview with Attention to Cancer Surveillance

Discovered in 1957, interferon (IFN) earned its name with the recognition that cells challenged by
attenuated influenza A virus created a substance that “interfered with” a subsequent infection by a
live virus [14]. IFN is now understood to represent a very large family of immune-modulating proteins,
divided into three types, designated as type I, II, and III based upon the receptors each IFN interacts
with. Type I IFN includes both IFN-α and IFN-β, and this type is the most diverse, being further divided
into seventeen subtypes. IFN-α alone has thirteen subtypes currently identified, and each of those is
further divided into multiple categories [15]. Type I IFNs play a powerful role in the immune response
to multiple stressors. In fact, they have enjoyed clinical therapeutic value as a treatment option for a
variety of diseases and conditions, including viral infections, solid tumors, myeloproliferative
disorders, hematopoietic neoplasms and autoimmune diseases such as multiple sclerosis [16].

As a group, IFNs play exceedingly complicated and pleiotropic roles that are coordinated and
regulated through the activity of the family of IFN regulatory factors, or IRFs [17]. IRF9 is most
directly involved in anti-viral as well as anti-tumor immunity and genetic regulation [18-20].

Closely related to this are plasmacytoid dendritic cells (pDCs), a rare type of immune cell that
circulate in the blood but migrate to peripheral lymphoid organs during a viral infection. They
respond to a viral infection by sharply upregulating production of type I IFNs. The IFN-α released in
the lymph nodes induces B cells to differentiate into plasmablasts. Subsequently, interleukin-6 (Il-6)
induces plasmablasts to evolve into antibody-secreting plasma cells [21]. Thus, IFNs play a critical
role in both controlling viral proliferation and inducing antibody production. Central to both antiviral
and anticancer immunity, IFN-α is produced by macrophages and lymphocytes when either is
challenged with viral or bacterial infection or encounters tumor cells [22]. Its role as a potent
antiviral therapy has been recognized in the treatment of hepatitis C complications [23],
Cytomegalovirus infection [24], chronic active ebola virus infection [25], inflammatory bowel disease
associated with herpes virus infection [26], and others.

Impaired type I IFN signaling is linked to many disease risks, most notably cancer, as type I IFN
signaling suppresses proliferation of both viruses and cancer cells by arresting the cell cycle, in part
through upregulation of p53, a tumor suppressor gene, and various cyclin-dependent kinase
inhibitors [27,28]. IFN-α also induces major histocompatibility (MHC) class 1 antigen presentation by
tumor cells, causing them to be more readily recognized by the cancer surveillance system [29,30].
The range of anticancer effects initiated by IFN-α production is astounding and occurs through both
direct and indirect mechanisms. Direct effects include cell cycle arrest, induction of cell
differentiation, initiation of apoptosis, activation of natural killer and CD8+ T cells, and others [31].

The indirect anticancer effects are predominantly carried out through gene transcription activation
of the Janus kinase signal transducer and activator of transcription (JAK/STAT) pathway. IFN-α
binding on the cell surface initiates JAK, a tyrosine kinase, to phosphorylate STAT1 and STAT2 [32].
Once phosphorylated, these STATs form a complex with IRF9, one of a family of IRFs that play a wide
range of roles in oncogene regulation and other cell functions [33]. It is this complex, named IFN-
stimulated gene factor 3 (ISGF3), that translocates to the cell nucleus to enhance the expression of at
least 150 genes [31]. IRF9 has been suggested to be the primary member of the IRF family of proteins
responsible for activation of the IFN-α antiproliferative effects, and that appears to be through its
binding to the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor 1 and 2
(TRAIL-R1/2) [34]. IRF7 is another crucial member of the IRF family of proteins involved early in the
response to a viral infection. It is normally expressed in low amounts but is strongly induced by ISGF3.
IRF7 also undergoes serine phosphorylation and nuclear translocation to further activate the
immune response. IRF7 has a very short half-life, so its gene-induction process is transient, perhaps
to avoid overexpression of IFNs [35].

Once TRAIL is bound by IRF9, it is then able to act as a ligand for Death Receptor 4 (DR4) or DR5,
initiating a cascade of events involving production of caspase 8 and caspase 3, and ultimately
triggering apoptosis [36]. Dysregulation of this pathway, through suppression of either IFN-α or IRF9
and the resulting failure to bind TRAIL-R, has been associated with several hematologic malignancies
[37], and has been shown to increase the metastatic potential in animal models of melanoma,
colorectal cancer, and lymphoma [38].

IFN-α both initiates and orchestrates a wide range of cancer suppressing roles. Dunn et al. (2005)
showed that IFN-α plays an active role in cancer immunoediting, its locus of action being
hematopoietic cells that are “programmed” via IFN-α binding for tumor surveillance [39]. It is via the
exceedingly complex interactions between type I IFNs and IRF7 and IRF9 in particular that a great
deal of antiproliferative effects are carried out. This is evidenced by the large number of studies
showing increased tumor growth and/or metastases associated with a wide number of cancer types.

For example, Bidwell et al. (2012) found that, among over 800 breast cancer patients, those with high
expression of IRF7-regulated genes had significantly fewer bone metastases, and they propose
assessment of these IRF7-related gene signatures as a way to predict those at greatest risk [40]. Use
of microRNA to target IRF7 expression has also been shown to enhance breast cancer cell
proliferation and invasion in vitro [41]. Zhao et al. (2017) found a similar role for IRF7 in relation to
bone metastases in a mouse model of prostate cancer [42]. Regarding the anti-cancer mechanism
behind IRF7 expression, Solis et al. (2006) found that IRF7 induces transcription of multiple genes and
translation of their downstream protein products including TRAIL, IL-15, ISG-56 and CD80, with the
noted therapeutic implications [43].

IRF9, too, has a central role to play in cancer surveillance and prevention. Erb et al. (2013)
demonstrated that IRF9 is the mediator through which IL-6 augments the anti-proliferation effects of
IFN-α against prostate cancer cells [44]. Tian et al. (2018) found IRF9 to be a key negative regulator of
acute myeloid leukemia cell proliferation and evasion of apoptosis [45]. It does so, at least in part,
through acetylation of the master regulatory protein p53.

Both IFN-α and IRF9 are also apparently necessary for the cancer-preventative properties of a fully
functional BRCA2 gene. In a study presented as an abstract at the First AACR International
Conference on Frontiers in Basic Cancer Research, Mittal and Chaudhuri (2009) describe a set of
experiments which show for the first time that BRCA2 expression leads to increased IFN-α production
and augments the signal transduction pathway resulting in the complexing of IRF9, STAT1 and
STAT2 described previously [46]. Two years prior, Buckley et al. (2007) had established that BRCA1 in
combination with IFN-γ promotes type I IFNs and subsequent production of IRF7, STAT1, and STAT2
[47]. Thus, the exceedingly important cancer regulatory genes BRCA1 and BRCA2 rely on IRF7 and
IRF9, respectively, to carry out their protective effects.

In a preprint, Mamoor (2020) used gene expression analysis to determine that infection with either
SARS-CoV-1 (in mice) or MERS-CoV (in vitro ) leads to increased production of IRF7 and IRF9, and the
author speculates that “IRF7 and IRF9 may be important for SARS-CoV-2 immune defense in
humans.” [48] This speculation is somewhat confirmed by Rasmussen et al. (2021), who reviewed the
compelling evidence that deficiencies of either IRF7 or IRF9 lead to significantly greater risk of severe
COVID-19 illness [49]. Importantly, they also note that evidence suggests type I IFNs play a singularly
important role in protective immunity against COVID-19 illness, a role that is shared by multiple
cytokines in most other viral illnesses including influenza.

As will be discussed in more detail below, the SARS-CoV-2 spike protein modifies host cell exosome
production. Transfection of cells with the spike gene and subsequent spike protein production results
in those cells generating exosomes containing microRNAs that suppress IRF9 production while
activating a range of pro-inflammatory gene transcripts [50]. Since these vaccines are specifically
designed to induce high and ongoing production of spike proteins, the implications are ominous. As
described above, inhibition of IRF9 will suppress TRAIL and all its regulatory and downstream
apoptosis-inducing effects. IRF9 suppression via exosomal microRNA should also be expected to
impair the cancer-protective effects of BRCA2 gene activity, which depends on that molecule for its
activity as described above. BRCA2-associated cancers include breast, fallopian tube, and ovarian
cancer for women, prostate and breast cancer for men, acute myeloid leukemia in children, and
others [51].

Vaccination has also been demonstrated to suppress both IRF7 and STAT2 [52]. This can be expected
to interfere with the cancer-protective effects of BRCA1 as described above. Cancers associated with
impaired BRCA1 activity include breast, uterine, and ovarian cancer in women; prostate and breast
cancer in men; and a modest increase in pancreatic cancer for both men and women [53].

Reduced BRCA1 expression is linked to both cancer and neurodegeneration. BRCA1 is a well-known
breast cancer susceptibility gene. BRCA1 inhibits breast cancer cell proliferation through activation
of SIRT1 and subsequent suppression of the androgen receptor [54]. In a study conducted by
Suberbielle et al. (2015), reduced levels of BRCA1 were found in the brains of Alzheimer’s patients [55].
Furthermore, experiments with knocking down neuronal BRCA1 in the dentate gyrus of mice showed
that DNA double-strand breaks were increased, along with neuronal shrinkage and impairments in
synaptic plasticity, learning and memory.

Analysis detailed in a recent case study on a patient diagnosed with a rare form of lymphoma called
angioimmunoblastic T cell lymphoma provided strong evidence for unexpected rapid progression of
lymphomatous lesions after administration of the BNT162b2 mRNA booster shot [56]. Comparisons
of detailed metrics for hypermetabolic lesions conducted immediately before and 21 days after the
vaccine booster revealed a five-fold increase after the vaccine, with the post-booster test revealing a
2-fold higher activity level in the right armpit compared to the left one. The vaccine had been injected
on the right side. It is worth pointing out in this regard that lymphoid malignancies have been
associated with suppression of TRAIL R1 [57].

Given the universally recognized importance of optimally functioning BRCA1/2 for cancer prevention
and given the central role of the TRAIL signal transduction pathway for additional cancer
surveillance, the suppression of IRF7 and IRF9 through vaccination and subsequent spike protein
production is extremely concerning for long-term cancer control in injected populations.

3. Considerations in the Design of mRNA Vaccines

The primary goal of the developers of the SARS-CoV-2 mRNA vaccines was to design a vaccine that
could induce a robust antibody response to the spike protein. Preexisting antibodies to spike protein
should cause the invading viruses to be quickly cleared before they could invade host cells, thus
arresting the disease process early on. As stated succinctly by Kaczmarek et. al. (2021) [58]:

“The rationale behind vaccination is to provide every vaccinated person with protection against the
SARS‐CoV‐2 virus. This protection is achieved by stimulating the immune system to produce
antibodies against the virus and to develop lymphocytes that will retain memory and the ability to
fight off the virus for a long time.”

Vaccines generally depend upon adjuvants such as aluminum and squalene to provoke immune cells
to migrate to the injection site immediately after vaccination. In the history of mRNA vaccine
development, it was initially hoped that the mRNA itself could serve as its own adjuvant. This is
because human cells recognize viral RNA as foreign, and this leads to upregulation of type I IFNs,
mediated via toll like receptors such as TLR3, TLR7 and TLR8 [59].

However, with time it became clear that there were problems with this approach, both because the
intense reaction could cause flu-like symptoms and because IFN-α could launch a cascade response
that would lead to the breakdown of the messenger RNA before it could produce adequate amounts
of spike protein to induce an immune response [60]. A breakthrough came when it was discovered
experimentally that the mRNA coding for the spike protein could be modified in specific ways that
would essentially fool the human cells into recognizing it as harmless human RNA. A seminal paper
by Karikó et al. (2005) demonstrated through a series of in vitro experiments that a simple
modification to the mRNA such that all uridines were replaced with pseudouridine could
dramatically reduce innate immune activation against exogenous mRNA [59]. Andries et al. (2015)
later discovered that 1-methylpseudouridine as a replacement for uridine was even more effective
than pseudouridine and could essentially abolish the TLR response to the mRNA, preventing the
activation of blood-derived dendritic cells [61]. This modification is applied in both the mRNA
vaccines on the market [62].

For successful mRNA vaccine design, the mRNA needs to be encapsulated in carefully constructed
particles that can protect the RNA from degradation by RNA depolymerases. The mRNA vaccines are
formulated as lipid nanoparticles containing cholesterol and phospholipids, with the modified mRNA
complexed with a highly modified polyethylene glycol (PEG) lipid backbone to promote its early
release from the endosome and to further protect it from degradation [63]. The host cell’s existing
biological machinery is co-opted to facilitate the natural production of protein from the mRNA
through endosomal uptake of a lipid particle [63]. A synthetic cationic lipid is added as well, since it
has been shown experimentally to work as an adjuvant to draw immune cells to the injection site and
to facilitate endosomal escape. De Beuckelaer et al. (2016) observed that “condensing mRNA into
cationic lipoplexes increases the potency of the mRNA vaccine evoked T cell response by several
orders of magnitude.” [60] Another important modification is that they replaced the code for two
adjacent amino acids in the genome with codes for proline, which causes the spike protein to stay in
a prefusion stabilized form [64].

The spike protein mRNA is further “humanized” with the addition of a guanine-methylated cap, 3’
and 5’ untranslated regions (UTRs) copied from those of human proteins, and finally a long poly(A)
tail to further stabilize the RNA [65]. In particular, researchers have cleverly selected the 3’UTR taken
from globins which are produced in large quantities by erythrocytes, because it is very effective at
protecting the mRNA from degradation and maintaining sustained protein production [66]. This is to
be expected, since erythrocytes have no nucleus, so they are unable to replace the mRNAs once they
are destroyed. Both the Moderna and the Pfizer vaccines adopted a 3’UTR from globins, and the
Pfizer vaccine also uses a slightly modified globin 5’UTR [67]. De Beuckelaer et al. (2016) aptly
summed up the consequences of such modifications as follows: “Over the past years, technical
improvements in the way IVT [in vitro transcribed] mRNAs are prepared (5′ Cap modifications,
optimized GC content, improved polyA tails, stabilizing UTRs) have increased the stability of IVT
mRNAs to such extent protein expression can now be achieved for days after directin vivo
administration of the mRNA.” [60]

However, the optimized analogue cap formation of synthetic mRNAs inevitably forces the recipient
cells to undergo a cap-dependent prolonged translation, ignoring homeostatic demands of cellular
physiology [65]. The cap 2’ O methylation carried out by cap 2’ O methyltransferase (CMTR1) serves
as a motif that marks the mRNA as “self,” to prevent recognition by IFN-induced RNA binding
proteins [68]. Thus, the mRNA in the vaccines, equipped with the cap 2’ O methylation motif, evades
detection as a viral invasion. Furthermore, the overwhelming impetus for cells to perform a single
and artificial approach to translation according to the robust capping and synthetic methylations of
mRNAs in vaccines is fundamentally associated with disease progression due to differential rather
than normal signaling of pattern recognition receptors (PRRs) [69].

The regulatory process controlling mRNA translation is extremely complex, and it is highly disturbed
in the context of mRNA vaccines [65,69]. Briefly, the idea is for mRNA vaccines to achieve the
intended goal (i.e., production of the modified spike protein) through a stealth strategy that
bypasses the natural immunological response to RNA-type viral infection. Injected lipid
nanoparticles containing mRNA are brought to the cell interior via endocytosis. The mRNA escapes
its lipid carrier and migrates to the ribosome, where it is abundantly translated into its final protein
product, following an optimized program for producing large quantities of a specific protein over an
extended period of time. These modified spike proteins then follow one of three primary pathways.
Some are proteolytically degraded and fragments are bound by MHC class I molecules for surface
presentation to cytotoxic T-cells. A second pathway has those same spike fragments bind MHC class
II molecules, move to the cell surface, and activate T-helper cells. A final pathway has soluble spike
proteins extruded from the cell in exosomes, where they can be recognized by B-cell-activated spike-
specific antibodies [70].

In the end, it is through utilization of nanolipids and sophisticated mRNA technology that the normal
immune response to exogenous RNA is evaded in order to produce a strong antibody response
against an exogenous RNA virus.

4. GC enrichment and potential G4 (pG4) structures in vaccine mRNAs

Recently, members of our team investigated possible alterations in secondary structure of mRNAs in
SARS-CoV-2 vaccines due to codon optimization of synthetic mRNA transcripts [71]. This study has
shown that there is a significant enrichment of GC content in mRNAs in vaccines (53% in Pfizer BNT
162b2 and 61% in Moderna mRNA-1273) as compared to the native SARS-CoV-2 mRNA (36%). The
enriched GC content of mRNAs is the result of codon optimization performed during the development
of the mRNAs used in SARS-CoV-2 vaccines, apparently without determining the effect on secondary
structures, particularly the G quadruplex formation [71].

Codon optimization describes the production of synthetic, codon-optimized polypeptides and

proteins used in biotechnology therapeutics (such as the synthetic mRNAs used for SARS-CoV-2
vaccination). The altered codon assignments within the mRNA template dramatically increase the
quantity of polypeptides and/or proteins produced [72]. Synonymous codon replacement also results
in a change in the multifunctional regulatory and structural roles of resulting proteins [73]. For this
reason, codon optimization has been cautioned against due to its consequent changes causing
perturbation in the secondary conformation of protein products with potentially devastating effects
on their resulting immunogenicity, efficacy and function [74,75]. Notably, various human diseases
are the result of synonymous nucleotide polymorphisms [76].

In an experiment where GC-rich and GC-poor versions of mRNA transcripts for heat shock protein 70
were configured in the context of identical promoters and UTR sequences, it was found that GC-rich
genes were expressed several-fold to over a hundred-fold more efficiently than their GC-poor
counterparts [77]. This is partly because all of the preferred mammalian codons have G or C
nucleotides in the third position. It is also well documented that AU-rich elements in the 3’ UTRs can
destabilize mRNA [78]. What may be of particular concern is the fact that GC enrichment content in
vaccine mRNAs results in an enhanced ability for potential G quadruplex (pG4) formations in these
structures, and this could cause onset of neurological disease [79]. Remarkably, the human prion
protein (PrP) genetic sequence contains multiple G4 forming motifs, and their presence may form the
missing link in the initial conversion of PrP to the misfolded form, PrPsc [80]. PrP binding to its own
mRNA may be the seed that causes the protein to misfold. This observation is particularly concerning
in light of the fact that the spike protein has prion-like characteristics [81].

On the one hand, the GC content has a key role in the modulation of translation efficiency and
control of mRNA expression in mammals [82]. Especially during translation initiation, the GC content
operating as a cis-acting mRNA element orchestrates the 43S ribosomal pre-initiation complex
attachment and thereafter the assembly of the eukaryotic translation initiation factor 4EF (eIF4F)
complex. One representative example of this system in action is the regulation of α and β globin
mRNA expression through their 5’ untranslated regions (5’UTRs) [82].

On the other hand, the presence of pG4s in RNAs is implicated in cancer biology as key determinants
of the regulation of G4 RNA binding proteins such as helicase [83]. Generally, the G quadruplexes in
RNAs have essential roles in a) the regulation of gene expression, b) the localization of ribonuclear
proteins, c) the mRNA localization and d) the regulation of proto-oncogene expression [84].

Regarding SARS-CoV-2, relevant studies reveal overwhelming similarities between SARS-CoV-2 pG4s,
including in RNA coding for spike protein, and those sequenced in the human transcriptome [85].
Thus, it can be inferred that synthetic mRNAs in vaccines carrying more pG4 structures in their
coding sequence for spike protein will amplify and compound the potential post-transcriptional
disorganization due to G4-enriched RNA during natural SARS-CoV-2 infection. Moreover, the cellular
nucleic acid binding protein (CNBP), which is the main cellular protein that binds to the SARS-CoV-2
RNA genome in human-infected cells [86], binds to and promotes the unfolding of SARS-CoV-2 G4s
formed by both positive and negative sense template strands of the SARS-CoV-2 RNA genome. A
similar modulation of CNBP on vaccine mRNA G4s and promotion of G4 equilibrium towards
unfolded conformations create favorable conditions for miRNA binding, and this will have a direct
impact on miRNA-dependent regulation of gene expression [87].

The negative-sense RNAs are intermediate molecules produced by the replicase transcriptase
complex (RTC) formed by the nonstructural proteins of coronaviruses (including SARS-COV-2) to
provide efficiency in replication and transcription [88,89]. This, however, introduces another
potentially serious complication associated with vaccination. Co-infection with other negative sense
RNA viruses such as hepatitis C [90] or infection by other coronaviruses contemporaneous with
vaccination periods would provide the necessary machinery of RTC to reproduce negative sense
intermediates from synthetic mRNAs and therefore amplify the presence of pG4s by negative sense
templates. This would result in further epitranscriptomic dysregulation [91].

Summarizing the topic to this point, the enrichment of GC content in vaccine mRNA will inevitably
lead to an increase in the pG4 content of the vaccines. This, in turn, will lead to dysregulation of the
G4-RNA-protein binding system and a wide range of potential disease-associated cellular
pathologies including suppression of innate immunity, neurodegeneration, and malignant
transformation [83].

Concerning the post translational deregulation due to emergence of new G4 structures introduced
by vaccination, one other important issue related to miRNA regulation and pG4s arises. In miRNA
structures, hundreds of pG4 sequences are identified [92]. In their unfolded conformation, as during
binding to their respective targets in 3’ to 5’ sequences of mRNAs, miRNAs switch off the translation
of their respective target mRNA. Alternatively, when in the presence of a G4 ligand, the translation of
their target mRNAs is promoted [93]. Moreover, a vast number of putative miRNA binding sites
overlap with G4s in 3’ UTRs of mRNAs as there are at least 521 specific miRNAs that are predicted to
bind to at least one of these G4s. Overall, 44,294 G4-miRNA potential binding sites have been traced to
possess putative overlapping G4s in humans [87].

As described elsewhere, during the cellular translation of vaccine mRNAs, an increased assembly of a
number of RNA binding protein helicases, such as eIF4A bound to eIF4G, will occur [65]. The presence
of increased pG4s in synthetic mRNAs can potentially amplify binding of RNA binding proteins and
miRNAs. This form of molecular crowding of protein components (helicases) with great affinity for G4
binding [87] will decrease the number of RNA binding proteins binding G4s normally available for
miRNA regulation. This loss of RNA binding proteins as well as miRNA availability for regulation by
binding to G4s can dramatically alter the translational regulation of miRNAs present in cells and
thereby disrupt essential regulation of oncogene expression. An example is the p16-dependent
regulation of the p53 tumour suppressor protein [87,94].

This process is exceedingly complicated yet tantamount to cellular homeostasis. So, again, it merits
summarizing. If pG4s accumulate, as would be expected with an increased amount of GC content in
the vaccine mRNA, this would have an effect of increasing potential G4 structures available during
translation events and this can affect miRNA post-transcriptional regulation. This, in turn, would
either favor greater expression of the oncogenes related to a range of cancers or drive cells to
apoptosis and cell death [95]. The case study described earlier in this paper strongly supports the
hypothesis that these injections induce accelerated lymphoma progression in follicular B cells [56].

miRNA binding recognition patterns are imperfectly complementary to their target regions, and for
this reason they are referred to as “master regulators,” since one miRNA affects a plethora of
different targets [92]. The multitude of pG4s in the mRNA of the vaccine would predictably act as
decoys, distracting miRNAs from their normal function in regulating human protein expression. The
increase in G4 targets due to the vaccine would decrease the availability of miRNAs to target human-
expressed G4s for regulation of gene expression. This can result in downregulation of miRNA
expression which is implicated in cardiovascular pathology [96], onset of neurodegeneration [97],
and/or cancer progression [98].

In most respects within epitranscriptomic machinery, miRNAs are involved in translation repression.
One example, vital for cellular normal housekeeping is that of Mouse double minute 2 homolog
(MDM2), a physical negative regulatory protein of p53. P53 itself is considered the master regulator of
the cellular tumor suppression network of genes. P16 controls the expression of many miRNAs, and,
via miR-141 and mIR-146b-5p binding to MDM2 mRNA, it induces the negative regulation of MDM2,
thus enabling p53 ubiquitination and promotion of cell survival upon DNA damage events [94].
Deregulation of miRNAs that control MDM2 suppression of p53 would predictably lead to an
increased risk to cancer [99].

5. Type I IFNs and COVID-19

Type I IFNs play an essential role in fighting viral infections, and deficiencies in type I IFN signaling
have been associated with poor outcomes from COVID-19 in multiple studies. These cases are often
associated with autoantibodies to type I IFNs. As reviewed below, type I IFNs have been used with
some success in treating severe COVID-19, particularly if administered very early in the disease
process. If, as argued above, the mRNA vaccines interfere with type I signaling, this could lead to
increased susceptibility to COVID-19 in the two weeks following the first vaccine, before an antibody
response has been initiated.

Cells infected with a virus detect the presence of virus replication through a number of pattern
recognition receptors (PPRs), which serve as sentinels sensing aberrant RNA structures that often
form during viral replication. These receptors respond by oligomerizing and subsequently inducing
type I IFNs, ultimately upregulating a large number of proteins involved in suppressing viral
proliferation [100].

A multi-author study by researchers in Paris, France, involving a cohort of 50 COVID-19 patients with
varying degrees of disease severity, revealed that patients with severe disease were characterized by
a highly impaired type I IFN response [101]. These patients had essentially no IFN-β and low IFN-α
production and activity. This was associated with a persistent blood viral load and an exacerbated
inflammatory response, characterized by high levels of tumor necrosis factor α (TNF-α) and Il-6. The
authors proposed type I IFN therapy as a potential treatment option. A paper by several researchers
in the United States also identified a unique and inappropriate inflammatory response in severe
COVID-19 patients, characterized by low levels of both type I and type III IFNs along with elevated
chemokines and elevated expression of Il-6 [102].

Type I IFNs have even been proposed as a treatment option for severe COVID-19. In a hamster model,
researchers exposed hamsters to SARS-CoV-2 and induced an inflammatory response in the lungs
and systemic inflammation in distal tissues. They found that intranasal administration of
recombinant IFN-α resulted in a reduced viral load and alleviation of symptoms [103]. A retrospective
cohort study of 446 COVID-19 patients determined that early administration of IFN-α2b was
associated with reduced in-hospital mortality. However, late IFN therapy increased mortality and
delayed recovery, revealing that early administration of interferon therapy is essential for a
favorable response [104].

A surprising number of people have neutralizing autoantibodies against type I IFNs, although the
underlying etiology of this phenomenon is not understood. A study using longitudinal profiling of
over 600,000 peripheral blood mononuclear cells and transcriptome sequencing from 54 patients
with COVID-19 and 26 controls found a notable lack of type I IFN-stimulated gene responses in
myeloid cells from patients with critical disease [105]. Neutralizing autoantibodies against type I IFNs
were found in 19% of patients with critical disease, 6% of patients with severe disease, and 0% of
patients with moderate disease. Another study based in Madrid, Spain revealed that 10% of patients
with severe COVID-19 disease had autoimmune antibodies to type I IFNs [106]. Finally, Stertz and Hale
(2021) note that, whether due to autoantibodies or perhaps loss-of-function polymorphisms
associated with interferon system genes, deficiencies in interferon production are associated with as
many as 15% of all life-threatening COVID-19 cases [107].

6. Are the methylation strategies for cellular housekeeping generally omitted by vaccine
mRNAs?

Methylation of mRNAs has been evolutionarily devised to control translation of transcripts and
therefore expression of genes by a complex cascade of methylator (writers) and de-methylator
(eraser) and reader proteins. A key methylation of adenosine “N6-methyladenosine (m6A)” in the 5′
UTR of mRNAs regulates normal cell physiology, the inflammatory response and cancer progression.
The role and mechanisms of m6A in human disease is extensive and excellently covered in other
comprehensive reviews [108,109]. Foremost among these, the SARS-CoV-2 molecular vaccination
induces cell stress conditions, as is described by the elevated NF-κB signaling after vaccination
[52,110].

Under conditions of cellular stress which can be induced by a viral infection or disease states such as
cancer, m6A mediates mRNAs to undergo translation preferentially in a cap-independent way [111].
As discussed previously, this is opposite to the impact of mRNA SARS-CoV-2 vaccination, which drives
cells toward a cap-dependenttranslation. Furthermore, under diversified conditions of cellular stress,
there is an overwhelming induction of transcriptome-wide addition of m6A that causes an increased
number of mRNAs to possess 5’UTRs enriched with m6A [111].
Eukaryotic translation initiation factor 4E (eIF4E) is the initial mRNA cap binding protein that directs
ribosomes to the cap structure of mRNAs, in order to initiate translation into protein. The
dependence on cap-dependent translation of vaccine mRNAs will consume a surplus of eIF4E
availability needed to translate an unnaturally high number of synthetic mRNAs. However, the cap-
independent translation takes place without requiring eIF4E to be bound to eIF4F. The competition
for ribosomes will shift towards the cap-independent translation of transcripts, since the mRNAs
undergoing cap-independent translation are equipped, apart from internal ribosome entry sites
(IRES), with special binding motifs that bind to factors that actively recruit mRNAs to the ribosome
cap-independent translational enhancers (CITEs) [112].

Furthermore, this also means that eIF4E, which is a powerful oncogene regulator and cell
proliferation modulator, will sustain its activities by this competition, for an unnaturally prolonged
period of time, trying to counterbalance the competition between robustly-capped mRNAs in
vaccines and IRES-containing mRNAs [113,65]. This type of condition results in dysregulation of co-
transcriptional m6A mRNA modifications and seriously links to molecular progressions of various
cancers [114], as well as creating predisposing conditions for subsequent viral infections [113].

We next consider the impact of mRNA-vaccination-derived spike protein on the cellular IFN system
via massive exosome production.

7. Exosomes and MicroRNAs

An important communication network among cells consists of extracellular vesicles (EVs) that are
constantly released by one cell and later taken up by another cell, which could be in a distant organ.
Small vesicles known as exosomes, formed inside endosomes, are similar in size to viruses, and are
released through exocytosis into the extracellular space to subsequently circulate throughout the
body [115]. Exosomes can deliver a diverse collection of biologically active molecules, including
mRNA, microRNAs, proteins, and lipids [116]. During a viral infection, infected cells secrete large
quantities of exosomes that act as a communication network among the cells to orchestrate the
response to the infection [117].

In a collaborative effort by a team of researchers from Arizona and Connecticut, it was found that
people who were vaccinated with the mRNA vaccines acquired circulating exosomes containing the
spike protein by day 14 following vaccination [118]. They also found that there were no circulating
antibodies to the spike protein fourteen days after the first vaccine. After the second vaccine,
however, the number of circulating spike-containing exosomes increased by up to a factor of 12.
Furthermore, antibodies to spike first appeared on day 14. The exosomes presented spike protein on
their surface, which, the authors argued, facilitated antibody production. When mice were exposed
to exosomes derived from vaccinated people, they developed antibodies to the spike protein.
Interestingly, following peak expression, the number of circulating spike-containing exosomes
decreased over time, in step with the decrease in the level of antibodies to the spike protein.

Exosomes exist as a part of the mRNA decay mechanism in close association under stress conditions
with stress granules (SGs) and P-bodies (PBs) [119,120]. Under conditions of vaccine-mRNA-induced
translation, which could be called “excessive dependence on cap-dependent translation,” there is an
obvious resistance to promotion and assembly of the large decapping complex [65], and therefore
resistance against physiological mRNA decay processes [119]. This would mean that the fate of
particular synthetic mRNAs that otherwise would be determined by the common cellular strategy for
mRNA turnover involving messenger ribonucleinproteins (mRNPs) is being omitted [121].

Furthermore, under conditions of over-reliance on cap-dependent translation by the synthetic

mRNAs in SARS-CoV-2 vaccines [65], many native mRNAs holding considerable IRES and specific
methylations (m6A) in their structure will favorably choose cap-independent translation, which is
strongly linked to mRNA decay quality control mechanisms [114]. In this sense, considerable
deadenylated mRNA products as well as products derived from mRNA metabolism (decay) are
directly linked to exosome cargoes [121].

A fine example of dependence on cap-dependent translation is described in T-cell acute

lymphoblastic leukaemia (T-ALL). Due to mechanistic target of rapamycin C (mTORC)-1 over-
functioning in T-ALL, the cells are driven completely towards cap-dependent translation [122]. An
analogous condition is described by Kyriakopoulos and McCullough (2021) [65]. Even in this highly
aggressive cancerous state, during inhibition of cap-dependent translation in T-ALL cells, there is a
rapid reversion to cap-independent translation [122]. Similarly, a picornavirus infection [123] drives
cells towards cap-independent translation due to inhibition of components of eIF4F complex and
pluralism of IRES in viral RNA.

In humans, there is an abundance of mostly asymptomatic picornavirus infections like the Safford
Virus with an over 90% seroprevalence in young children and adults [124]. In either case, whether an
apoptotic event due to a stress-like condition[125] or an mRNA-cap-driven-like carcinomatous effect
[126], the miRNA levels will be increased due to the increased epitranscriptomic functioning and
enhanced mRNA decay. Because of the high demand for gene expression, high levels of certain
miRNAs will be expected to be contained in exosomes via P bodies [127].

Also, under conditions of overwhelming production of spike protein due to SARS-CoV-2 molecular
vaccination, it would of course be expected that a significant proportion of over-abundant intra-
cellular spike proteins would also be exported via exosome cargoes [128].

A seminal paper by a research team in India investigated the role of exosomes in the cellular response
to internally synthesized SARS-CoV-2 spike protein [50]. They wrote in the abstract:

“We propose that SARS-CoV-2 gene product, Spike, is able to modify the host exosomal cargo, which
gets transported to distant uninfected tissues and organs and can initiate a catastrophic immune
cascade within Central Nervous System (CNS).”

Their experiments involved growing human HEK293T cells in culture and exposing them to SARS-
CoV-2 spike gene plasmids, which induced synthesis of spike protein within the cells. They found
experimentally that these cells released abundant exosomes housing spike protein along with
specific microRNAs. They then harvested the exosomes and transferred them to a cell culture of
human microglia (the immune cells that are resident in the brain). They showed that the microglia
readily took up the exosomes and responded to the microRNAs by initiating an acute inflammatory
response. The role of microglia in causing neuroinflammation in various viral diseases, such as
Human Immunodeficiency Virus (HIV), Japanese Encephalitis Virus (JEV), and Dengue, is well
established. They proposed that long-distance cell-cell communication via exosomes could be the
mechanism by which neurological symptoms become manifest in severe cases of COVID-19.

In further exploration, the authors identified two microRNAs that were present in high
concentrations in the exosomes: miR-148a and miR-590. They proposed a specific mechanism by
which these two microRNAs would specifically disrupt type I interferon signaling, through
suppression of two critical proteins that control the pathway: ubiquitin specific peptidase 33 (USP33)
and IRF9. Phosphorylated STAT1 and STAT2 heterodimers require IRF9 in order to bind IFN-
stimulated response elements, and therefore IRF9 plays an essential role in the signaling response.
The authors showed experimentally that microglia exposed to the exosomes extracted from the
HEK293 culture had a 50% decrease in cellular expression of USP33 and a 60% decrease in IRF9. They
further found that miR-148a specifically blocks USP33 and miR-590 specifically blocks IRF9. USP33
removes ubiquitin from IRF9, and in so doing it protects it from degradation. Thus, the two
microRNAs together conspire to interfere with IRF9, thus blocking receptor response to type I
interferons.

A study by de Gonzalo-Calvo et. al. (2021) looked at the microRNA profile in the blood of COVID-19
patients and their quantitative variance based upon disease severity [129]. Multiple miRNAs were
found to be up- and down-regulated. Among these was miR-148a-3p, the guide strand precursor to
miR-148a. However, miR-148a itself was not among the microRNAs catalogued as excessive or
deficient in their study, nor was miR-590. It appears from these findings that miR148a and miR-590
and their inflammatory effects are unique to vaccination-induced spike protein production.

Tracer studies have shown that, following injection into the arm muscle, the mRNA in mRNA vaccines
is carried into the lymph system by immune cells and ultimately accumulates in the spleen in high
concentrations [130]. Other studies have shown that stressed immune cells in the spleen release
large quantities of exosomes that travel to the brain stem nuclei along the vagus nerve (as reviewed
in Seneff and Nigh (2021) [81]). The vagus nerve is the 10th cranial nerve and it enters the brainstem
near the larynx. The superior and recurrent laryngeal nerves are branches of the vagus that
innervate structures involved in swallowing and speaking. Lesions in these nerves cause vocal cord
paralysis associated with difficulty swallowing (dysphagia) difficulty speaking (dysphonia) and/or
shortness of breath (dyspnea) [131,132]. We will return to these specific pathologies in our review of
VAERS data below.

HEK293 cells were originally derived from cultures taken from the kidney of a human fetus several
decades ago and immortalized through infection with adenovirus DNA. While they were extracted
from the kidney, the cells show through their protein expression profile that they are likely to be of
neuronal origin [133]. This suggests that neurons in the vagus nerve would respond similarly to the
spike protein. Thus, the available evidence strongly suggests that endogenously produced spike
protein creates a different microRNA profile than does natural infection with SARS-CoV-2, and those
differences entail a potentially wide range of deleterious effects.

A central point of our analysis below is the important distinction between the impact of vaccination
versus natural infection on type I IFN. While vaccination actively suppresses its production, natural
infection promotes type I IFN production very early in the disease cycle. Those with preexisting
conditions often exhibit impaired type I IFN signaling, which leads to more severe, critical, and even
fatal COVID-19. If the impairment induced by the vaccine is maintained as antibody levels wane over
time, this could lead to a situation where the vaccine causes a more severe disease expression than
would have been the case in the absence of the vaccine.

Another expected consequence of suppressing type I IFN would be reactivation of preexisting,

chronic viral infections, as described in the next section.

8. Reactivation of Varicella-zoster

Type I IFN receptor signaling in CD8+ T cells is critical for the generation of effector and memory cells
in response to a viral infection [134]. CD8+ T cells can block reactivation of latent herpes infection in
sensory neurons [135]. If type I IFN signaling is impaired, as happens following vaccination but not
following natural infection with SARS-CoV-2, CD8+ T cells’ ability to keep herpes in check would also
be impaired. Might this be the mechanism at work in response to the vaccines?

Shingles is an increasingly common condition caused by reactivation of latent herpes zoster viruses
(HZV), which also causes chicken pox in childhood. In a systematic review, Katsikas et al., (2021)
identified 91 cases of herpes zoster occurring an average of 5.8 days following mRNA vaccination
[136]. While acknowledging that causality is not yet confirmed, “Herpes zoster is possibly a condition
physicians and other healthcare professionals may expect to see in patients receiving COVID-19
vaccines” [136]. In a letter to the editor published in September 20201, Fathy et al. (2021) reported on
672 cases of skin reactions that were presumably vaccine-related, including 40 cases of herpes zoster
and/or herpes simplex reactivation [137]. These cases had been reported to the American Academy
of Dermatology and the International League of Dermatologic Societies’ COVID-19 Dermatology
Registry, established specifically to track dermatological sequalae from the vaccines. There are
multiple additional case reports of herpes zoster reactivation following COVID-19 vaccination in the
literature [138,139]. Lladó et al. (2021) noted that 51 of 52 reports of reactivated herpes zoster
infections happened following mRNA vaccination [140]. Herpes zoster itself also interferes with IFN-α
signaling in infected cells both through interfering with STAT2 phosphorylation and through
facilitating IRF9 degradation [141].

An additional case of viral reactivation is noteworthy as well. It involved an 82-year-old woman who
had acquired a hepatitis C viral (HCV) infection in 2007. A strong increase in HCV load occurred a few
days after vaccination with an mRNA Pfizer/BioNTech vaccine, along with an appearance of
jaundice. She died three weeks after vaccination from liver failure [142].

9. Impaired DNA Repair and Adaptive Immunity

The immune system and the DNA repair system are the two primary systems that higher organisms
rely on for defense against diverse threats, and they share common elements. Loss of function of key
DNA repair proteins leads to defects in repair that inhibit the production of functional B and T cells,
resulting in immunodeficiency. Non-homologous end joining (NHEJ) repair plays a critical role in
lymphocyte-specific V(D)J recombination, which is essential for producing the highly diverse
repertoire of B-cell antibodies in response to antigen exposure [143]. Impaired DNA repair is also a
direct pathway towards cancer.

A seminal study conducted by researchers in Shanghai, China monitored several parameters

associated with immune function in a cohort of patients by conducting single-cell mRNA sequencing
of peripheral blood mononuclear cells (PBMCs) harvested from the patients before and 28 days after
the first inoculation of a COVID-19 vaccine based on a weakened version of the virus [52]. While these
vaccines are different from the mRNA vaccines, they also work by injecting the contents of the
vaccine into the deltoid muscle, bypassing the mucosal and vascular barriers. The authors found
consistent alteration of gene expression following vaccination in many different immune cell types.
Observed increases in NF-κB signaling and reduced type I IFN responses were further confirmed by
biological assays. Consistent with other studies, they found that STAT2 and IRF7 were significantly
downregulated 28 days after vaccination, indicative of impaired type I IFN responses. They wrote:
“Together, these data suggested that after vaccination, at least by day 28, other than generation of
neutralizing antibodies, people’s immune systems, including those of lymphocytes and monocytes,
were perhaps in a more vulnerable state.” [52].

These authors also identified disturbing changes in gene expression that would imply impaired
ability to repair DNA. Up to 60% of the total transcriptional activity in growing cells involves the
transcription of ribosomal DNA (rDNA) to produce ribosomal RNA (rRNA). The enzyme that
transcribes ribosomal DNA into RNA is RNA polymerase I (Pol I). Pol I also monitors rDNA integrity and
influences cell survival [144]. During transcription, RNA polymerases (RNAPs) actively scan DNA to
find bulky lesions (double-strand breaks) and trigger their repair. In growing eukaryotic cells, most
transcription involves synthesis of ribosomal RNA by Pol I. Thus, Pol I promotes survival following
DNA damage [144]. Many of the downregulated genes identified by Liu et al. (2021) were linked to the
cell cycle, telomere maintenance, and both promoter opening and transcription of POL I, indicative
of impaired DNA repair processes [52]

One of the gene sets that were suppressed was due to “deposition of new CENPA [centromere protein
A] containing nucleosomes at the centromere.” Newly synthesized CENPA is deposited in
nucleosomes at the centromere during late telophase/early G1 phase of the cell cycle. This points to
arrest of the cell cycle in G1 phase as a characteristic feature of the response to the inactivated SARS-
CoV-2 vaccine. Arrest of pluripotent embryonic stem cells in the G1 phase (prior to replication
initiation) would result in impaired self-renewal and maintenance of pluripotency [145].

Two checkpoint proteins crucially involved in DNA repair and adaptive immunity are BRCA1 and
53BP1, which facilitate both homologous recombination (HR) and NHEJ, the two primary repair
processes [146,147]. In an in vitro experiment on human cells, the SARS-CoV-2 full-length spike
protein was specifically shown to enter the nucleus and hinder the recruitment of these two repair
proteins to the site of a double-strand break [143]. The authors summarized their findings by saying,
“Mechanistically, we found that the spike protein localizes in the nucleus and inhibits DNA damage
repair by impeding key DNA repair protein BRCA1 and 53BP1 recruitment to the damage site.”

Another mechanism by which the mRNA vaccines could interfere with DNA repair is through miR-148.
This microRNA has been shown to downregulate HR in the G1 phase of the cell cycle [148]. As was
mentioned earlier in this paper, this was one of the two microRNAs found in exosomes released by
human cells following spike protein synthesis in the experiments by Mishra and Banerjea (2021) [50].

10. Immune Thrombocytopenia

Immune thrombocytopenia is an autoimmune disorder, where the immune system attacks

circulating platelets. Immune thrombocytopenic purpura (ITP) has been associated with several
vaccinations, including measles, mumps, rubella (MMR), hepatitis A, varicella, diphtheria, tetanus,
pertussis (DPT), oral polio and influenza [149]. While there is broad awareness that the adenovirus
DNA-based vaccines can cause vaccine-induced immune thrombotic thrombocytopenia (VITT) [150],
the mRNA vaccines are not without risk to VITT, as case studies have been published documenting
such occurrences, including life threatening and fatal cerebral venous sinus thrombosis [151-153].
The mechanism is believed to involve VITT antibodies binding to platelet factor 4 (PF4) and forming
immune complexes that induce platelet activation. Subsequent clotting cascades cause the
formation of diffuse microclots in the brain, lungs, liver, legs and elsewhere, associated with a
dramatic drop in platelet count (Kelton et al., 2021). The reaction to the vaccine has been described
as being very similar to heparin-induced thrombocytopenia (HIT), except that heparin
administration is notably not involved [154].

It has been shown that the mRNA vaccines elicit primarily an immunoglobulin G (IgG) immune
response, with lesser amounts of IgA induced [155], and even less IgM production [156]. The amount
of IgG antibodies produced is comparable to the response seen in severe cases of COVID-19. It is IgG
antibodies in complex with heparin that induce HIT. One can hypothesize that IgG complexed with
the spike protein and PF4 is the complex that induces VITT in response to mRNA vaccines. It has in
fact been shown experimentally that the receptor binding domain (RBD) of the spike protein binds to
PF4 [157].

The underlying mechanism behind HIT has been well studied, including through the use of
humanized mouse models. Interestingly, human platelets, but not mouse platelets, express the
FcγRIIA receptor, which responds to PF4/heparin/IgG complexes through a tyrosine phosphorylation
cascade to induce platelet activation. Upon activation, platelets release granules and generate
procoagulant microparticles. They also take up calcium, activate protein kinase C, clump together
into microthrombi, and launch a cell death cascade via calpain activation. These activated platelets
release PF4 into the extracellular space, supporting a vicious cycle, as this additional PF4 also binds
to heparin and IgG antibody to further promote platelet activation. Thus, FcγRIIA is central to the
disease process [158].

Studies on mice engineered to express the human FcγRIIA receptor have shown that these transgenic
mice are far more susceptible to thrombocytopenia than their wild type counterparts [159]. It has
been proposed that platelets may serve an important role in the clearance of antibody-antigen
complexes by trapping the antigen in thrombi and/or carrying them into the spleen for removal by
immune cells. Platelets are obviously rapidly consumed in the process, which then results in low
platelet counts (thrombocytopenia).

Platelets normally circulate with an average lifespan of only five to nine days, so they are constantly
synthesized in the bone marrow and cleared in the spleen. Antibody-bound platelets, subsequent to
platelet activation via Fcγ receptors, migrate to the spleen where they are trapped and removed
through phagocytosis by macrophages [160]. Fully one third of the body’s total platelets are found in
the spleen. Since the mRNA vaccines are carried into the spleen by immune cells initially attracted to
the injection site in the arm muscle, there is tremendous opportunity for the release of spike-protein-
containing exosomes by vaccine-infected macrophages in the spleen. One can speculate that
platelet activation following the formation of a P4F/IgG/spike protein complex in the spleen is part of
the mechanism that attempts to clear the toxic spike protein.

We mentioned earlier that one of the two microRNAs highly expressed in exosomes released by
human cells exposed to the spike protein was miR-148a. miR-148a has been shown experimentally to
suppress expression of a protein that plays a central role in regulating FcγRIIA expression on
platelets. This protein, called T-cell ubiquitin ligand-2 (TULA-2), specifically inhibits activity of the
platelet Fcγ receptor. miR-148a targets TULA-2 mRNA and downregulates its expression. Thus, miR-
148a, present in exosomes released by macrophages that are compelled by the vaccine to synthesize
spike protein, acts to increase the risk of thrombocytopenia in response to immune complexes
formed by spike antigen and IgG antibodies produced against spike.

11. PPAR-α, Sulfatide and Liver Disease

As we have already stated, an experiment by Mishra and Banerjea (2021) demonstrated that the spike
protein induces the release of exosomes containing microRNAs that specifically interfere with IRF9
synthesis [50]. In this section we will show that one of the consequences of suppression of IRF9 would
be reduced synthesis of sulfatide in the liver, mediated by the nuclear receptor peroxisome
proliferator-activated receptor α (PPAR-α).

Sulfatides are major mammalian serum sphingoglycolipids which are synthesized and secreted
mainly from the liver [161]. They are the only sulfonated lipids in the body. Sulfatides are formed by a
two-step process involving the conversion of ceramide to galactocerebroside and its subsequent
sulfation. Sulfatide is expressed on the surface of platelets, erythrocytes and lymphocytes. Serum
sulfatides exert both anti-coagulative and anti-platelet-activation functions. The enzyme in the liver
that synthesizes sulfatide, cerebroside sulfotransferase, has specifically been found to be induced by
activation of PPAR-α in mice [162]. Therefore, reduced expression of PPAR-α leads to sulfatide
deficiency.

PPAR-α ligands exhibit anti-inflammatory and anti-fibrotic effects, whereas PPAR-α deficiency leads
to hepatic steatosis, steatohepatitis, steatofibrosis, and liver cancer [163]. In 2019, a seminal
experiment was conducted by a team of researchers in Japan on mice with a defective gene for
PPAR-α [161]. These mice, when fed a high cholesterol diet, were susceptible to excess triglyceride
accumulation and exacerbated inflammation and oxidative stress in the liver, along with increased
levels of coagulation factors. The mice also manifested with decreased levels of sulfatides in both the
liver and the serum. The authors hypothesized that cholesterol overload exerts its toxic effects in
part by enhancing thrombosis, following abnormal hepatic lipid metabolism and oxidative stress.
They showed that PPAR-α can attenuate these toxic effects through transcriptional regulation of
coagulation factors and upregulation of sulfatide synthesis, in addition to its effects in ameliorating
liver disease. They proposed that therapies such as fibrates aimed at activating PPAR-α might
prevent high-cholesterol-diet-induced cardiovascular disease.

Tracer studies have shown that the mRNA from mRNA vaccines migrates preferentially to the liver
and spleen, reaching higher concentration there than in any other organs [130]. Thus, there is
potential for suppression of IRF9 in the liver by the vaccine. IRF9 is highly expressed in hepatocytes,
where it interacts with PPAR-α, activating PPAR-α target genes. A study on IRF9 knockout mice
showed that these mice developed steatosis and hepatic insulin resistance when exposed to a high-
fat diet. In contrast, adenoviral-mediated hepatic IRF9 overexpression in obese mice improved
insulin sensitivity and ameliorated steatosis and inflammation [164].
Multiple case reports in the research literature describe liver damage following mRNA vaccines [165-
167]. A plausible factor leading to these outcomes is the suppression of PPAR-α through
downregulation of IRF9, and subsequently decreased sulfatide synthesis in the liver.

12. Guillain Barré Syndrome and Other Neurological Conditions

GBS is an acute inflammatory demyelinating neuropathy associated with long-lasting morbidity and
a significant risk of mortality [168]. The disease involves an autoimmune attack on the nerves
associated with the release of pro-inflammatory cytokines.

GBS is often associated with autoantibodies to sulfatide and other sphingolipids [169]. Activated T
cells produce cytokines in response to antigen presentation by macrophages, and these cytokines
can induce autoantibody production through epitope spreading [170]. The antibodies, in turn, induce
complement activation, which causes demyelination and axonal damage, leading to severe injury to
peripheral neurons [171]. The spike protein has been shown to bind to heparan sulfate, which is a
sulfated amino-sugar complex resembling the sulfated galactose in sulfatide [172]. Thus, it is
conceivable that spike also binds to sulfatide, and this might trigger an immune reaction to the
spike-sulfatide complex.

As described in the previous section, impaired sulfatide synthesis in the liver due to suppression of
IRF9 will lead to systemic sulfatide deficiency over time. Sulfatide deficiency can have major impact
in the brain and nervous system. Twenty percent of the galactolipids found in the myelin sheath are
sulfatides. Sulfatide is a major component of the nervous system, found in especially high
concentrations in the myelin sheath in both the peripheral and the central nervous system.
Deficiencies in sulfatide can lead to muscle weakness, tremors, and ataxia [173], which are common
symptoms of GBS. Chronic neuroinflammation mediated by microglia and astrocytes in the brain
leads to dramatic losses of brain sulfatide, and brain deficiencies in sulfatide are a major feature of
Alzheimer’s disease [174]. Mice with a defect in the ability to synthesize sulfatide from ceramide show
an impaired ability to maintain the health of axons as they age. Over time, they develop redundant,
uncompacted and degenerating myelin sheaths as well as deteriorating structure at the nodes of
Ranvier in the axons, causing the loss of a functionally competent axoglial junction [175].

Angiotensin II (Ang II), in addition to its profound effects on cardiovascular disease, also plays a role
in inflammation in the brain leading to neurodegenerative disease [176]. The SARS-CoV-2 spike
protein contains a unique furin cleavage site not found in SARS-CoV, which allows the extracellular
enzyme furin to detach the S1 segment of the spike protein and release it into circulation [177]. S1
has been shown to cross the blood-brain barrier in mice [178]. S1 contains the receptor binding
domain that binds to ACE2 receptors, disabling them. When ACE2 receptor signaling is reduced, Ang II
synthesis is increased. Neurons in the brain possess ACE2 receptors that would be susceptible to
disruption by S1 released from spike-containing exosomes or spike-producing cells that had taken up
the nanoparticles in the vaccines. Ang II enhances TLR4-mediated signaling in microglia, inducing
microglial activation and increasing the production of reactive oxygen species leading to tissue
damage, within the paraventricular nucleus in the brain [179].

Overexpression of Ang II is a causal factor in neurodegeneration of the optic nerve, causing optic
neuritis, which can result in severe irreversible visual loss [180]. Multiple case reports have described
cases of optic neuropathy appearing shortly after mRNA vaccination for COVID-19 [181,182]. Other
debilitating neurological conditions are also appearing shortly after vaccination, where a causal
relationship is suspected. A case study based in Europe tracking neurological symptoms following
COVID-19 vaccination identified 21 cases developing within a median of 11 days post-vaccination.
The cases had diverse diagnoses including cerebral venous sinus thrombosis, nervous system
demyelinating diseases, inflammatory peripheral neuropathies, myositis, myasthenia, limbic
encephalitis, and giant cell arteritis [183]. Khayat-Khoei et.al. (2021) describe a case series of 7
patients, ages ranging from 24 to 64, presenting with demyelinating disease within 21 days of a first
or second mRNA vaccination [184]. Four had a prior history of (controlled) MS, while three were
previously healthy.

Hearing loss and tinnitus are also known rare side effects of COVID-19. A case study involved a series
of ten COVID-19 patients who suffered from audiovestibular symptoms such as hearing loss,
vestibular dysfunction and tinnitus [185]. The authors demonstrated that human inner ear tissue
expresses ACE2, furin and the transmembrane protease serine 2 (TMPRSS2), which facilitates viral
entry. They also showed that SARS-CoV-2 can infect specific human inner ear cell types.

Another study evaluating the potential for the SARS-CoV-2 virus to infect the ear specifically
examined expression of the receptor ACE2 and the enzymes furin and TM-PRSS2 various types of cells
in the middle and inner ears of mice. They found that ACE2 and furin were “diffusely present in the
eustachian tube, middle ear spaces, and cochlea, suggesting that these tissues are susceptible to
SARS-CoV-2 infection.” [186]. Tinnitus is positively associated with hypertension, which is induced by
elevated levels of Ang II [187].

Headache is a very common adverse reaction to the COVID-19 mRNA vaccines, particularly for
people who are already susceptible to headaches. In a study based on a questionnaire involving 171
participants, the incidence of headaches was found to be 20.5% after the first vaccine, rising to 45.6%
after the second shot [188]. A case study described a 37-year-old woman suffering from a debilitating
migraine attack lasting for 11 days following the second Pfizer/BioNtech mRNA vaccine [189].

Steroids are often used as adjunct therapy to treat migraine [190]. Dexamethasone and other
steroids stimulate PPAR-α receptors in the liver through the steroid receptor, thus offsetting the
effects of IRF9 suppression [191]. A theory for the origins of migraine involves altered processing of
sensory input in the brainstem, primarily trigeminal neurons [192]. The trigeminal nerve is in close
proximity to the vagus nerve in the brainstem, so spike-carrying exosomes could easily reach it along
the vagal route. Magnetic resonance imaging has revealed that structural changes in the trigeminal
nerve reflecting aberrant microstructure and demyelination are a characteristic feature of people
who suffer from frequent migraine headaches [193]. A potential factor linked to either SARS-CoV-2
infection or mRNA vaccination is an excessive level of Ang II in the brainstem due to spike inhibition of
ACE2 receptors. ACE inhibitors and Ang II receptor antagonists have become popular drugs to treat
migraine headaches off-label [194,195]. Migraine headache could thus arise from both the spike
protein’s disruption of ACE2 receptors and the destruction of the myelin sheath covering critical
facial nerves through a microglial inflammatory response and loss of sulfatide. The source of that
spike protein could be either exogenous or endogenous.

13. Bell’s Palsy

Bell’s palsy is a common cranial neuropathy causing unilateral facial paralysis. Even in the Phase III
clinical trials, Bell’s palsy stood out, with seven cases appearing in the treatment arm as compared
to only one in the placebo group [196,197]. A case study reported in the literature involved a 36-year-
old man who developed weakness in the left arm one day after vaccination, progressing to numbness
and tingling in the arm and subsequent symptoms of Bell’s palsy over the next few days. A common
cause of Bell’s palsy is reactivation of herpes simplex virus infection centered around the geniculate
ganglion [198]. This, in turn, can be caused by disruption of type I IFN signaling.

14. Myocarditis

There has been considerable media attention devoted to the fact that COVID-19 vaccines cause
myocarditis and pericarditis, with an increased risk in particular for men below the age of 30
[197,200]. Myocarditis is associated with platelet activation, so this could be one factor at play in the
response to the vaccines [201]. However, another factor could be related to exosomes released by
macrophages infected with the mRNA vaccines, and the specific microRNAs found in those
exosomes.
A study involving patients suffering from severe COVID-19 disease looked specifically at the
expression of circulating microRNAs compared to patients suffering from influenza and to healthy
controls. One microRNA that was consistently upregulated in association with COVID-19 was miR-
155, and the authors suggested that it might be a predictor of chronic myocardial damage and
inflammation. By contrast, influenza infection was not associated with increased miR-155
expression. They concluded: “Our study identified significantly altered levels of cardiac-associated
miRs in COVID-19 patients indicating a strong association of COVID-19 with cardiovascular ailments
and respective biomarkers” [202].

A study comparing 300 patients with cardiovascular disease to healthy controls showed a
statistically significant increase in circulating levels of miR-155 in the patients compared to controls.
Furthermore, those with more highly constricted arteries (according to a Gensini score) had higher
levels than those with lesser disease [203].

Importantly, exosomes play a role in inflammation in association with heart disease. During
myocardial infarction, miR-155 is sharply upregulated in macrophages in the heart muscle and
released into the extracellular milieu within exosomes. These exosomes are delivered to fibroblasts,
and miR-155 downregulates proteins in the fibroblasts that protect from inflammation and promote
fibroblast proliferation. The resulting impairment leads to cardiac rupture [204].

We have already discussed how the S1 segment of the spike protein can be cleaved by furin and
released into circulation. It binds to ACE2 receptors through its receptor binding domain (RBD), and
this inhibits their function. Because ACE2 degrades Ang II, disabling ACE2 leads directly to
overexpression of Ang II, further enhancing risk to cardiovascular disease. AngII-induced
vasoconstriction is an independent mechanism to induce permanent myocardial injury even when
coronary obstruction is not present. Repeated episodes of sudden constriction of a cardiac artery
due to Ang II can eventually lead to heart failure or sudden death [205].

ACE2 suppression had already been seen in studies on the original SARS-CoV virus. An autopsy study
on patients succumbing to SARS-CoV revealed an important role for ACE2 inhibition in promoting
heart damage. SARS-CoV viral RNA was detected in 35% of 20 autopsied human heart samples taken
from patients who died. There was a marked increase in macrophage infiltration associated with
myocardial damage in the patients whose hearts were infected with SARS-CoV. Importantly, the
presence of SARS- CoV in the heart was associated with marked reduction in ACE2 protein expression
[206].

15. Considerations Regarding the Vaccine Adverse Event Reporting System (VAERS)

The Food and Drug Administration’s Vaccine Adverse Event Reporting System (VAERS) is an
imperfect but valuable resource for identifying potential adverse reactions to vaccines. Established
through collaboration between the CDC and FDA, VAERS is “a national early warning system to
detect possible safety problems in U.S.-licensed vaccines.” According to the CDC it is “especially
useful for detecting unusual or unexpected patterns of adverse event reporting that might indicate a
possible safety problem with a vaccine.” (https://vaers.hhs.gov/about.html) Even the CDC
recognizes that adverse events reported to VAERS represent “only a small fraction of actual adverse
events [207]. A widely cited report noted that less than 1% of all vaccine-related adverse events are
reported to VAERS [208]. That assertion, though, has no citation so the basis for the claim is unclear.
Rose (2021) published a much more sophisticated analysis of VAERS data to offer an estimate of
underreporting by a factor of 31 [209]. While it is impossible to determine underreporting with
precision, the available evidence is that underreporting very strongly characterizes the VAERS data.
The information presented below should be understood in that light.

15.1 VAERS Signal for Immune Suppression, Thrombocytopenia and Neurodegeneration

All of the tabulations on the number of reports for a specific condition mentioned in this subsection
are based on a probe of the VAERS database online tool, http://wonder.cdc.gov/vaers.html, on
November 29, 2021 and include all reports for any COVID-19 vaccine but restricted to the US
population.

Over the 31-year history of VAERS, there were a total of 9,153 deaths reported in association with any
vaccine, and 7,114 (78%) of those deaths were linked to COVID-19 vaccines. Importantly, only 14% of
VAERS-reported deaths as of June 2021 could have vaccination ruled out as a cause [210]. This
strongly suggests that these unprecedented vaccines exhibit unusual mechanisms of toxicity that go
well beyond what is seen with more traditional vaccines.

A shocking 96% of all cases linking Bell’s palsy to any vaccine since 1990 were linked to COVID-19
vaccines (3,197 out of 3,331 cases). There were 760 reports of Guillain Barré Syndrome (GBS) for
COVD-19 vaccines. Over 100 cases of optic neuritis or optic neuropathy were listed. A total of 8,298
reports linked migraine headache to COVID-19. There were 52 cases of Herpes zoster oticus linked to
COVID-19 vaccines. This is basically a case of herpes affecting the cranial nerves near the ears.
Hearing loss is a characteristic symptom of Herpes zoster oticus, and it can become permanent
[211,212]. As of November 19, 2021, there were 12,204 cases where ”tinnitus” was mentioned.
Deafness is of course much more serious and therefore less common, and yet it also has a striking
number of hits, coming in at 2,662 cases.

There were 653 VAERS reports linking the COVID-19 vaccines to thrombocytopenia. This is to be
compared with 774 cases reported for all the other vaccines over the 31-year period from 1990 to
2021.

The VAERS database includes many terms related to liver dysfunction, and there were around 2,000
reports in VAERS for various liver-related terms linked to COVID-19 vaccines, such as hepatomegaly
(73 cases), hepatic steatosis (105 cases) hepatic enzyme increased (338 cases), liver disorder (71
cases), liver injury (44 cases), hepatic pain (91 cases) and hepatitis (62 cases).

There were 4,650 cases with dysphagia, 1,697 cases of dysphonia, and 37,132 cases of dyspnea in
reaction to COVID vaccines. As reviewed previously in this paper, a likely cause is vagus nerve
damage due to inflammation induced by exposure to exosomes containing the spike protein and the
associated microRNAs. In addition, there were 13,789 reports of syncope. Vasovagal syncope is the
most common type of syncope among all age groups [213]. 67,682 cases of nausea and 26,630 cases
of vomiting may reflect damage to vagal neurocircuits that play a central role in inducing nausea
and vomiting in response to various insults [214].

Table 1. Number of events in the VAERS database from 1990 to December 12, 2021, where several
terms indicating cancer occurred in association with COVID-19 vaccines or with all other vaccines,
along with the ratio between the two counts. Counts were restricted to data from the United States.
Note that counts for all the other vaccines are totals for 31 years, whereas the COVID-19 counts are
for a single class of vaccines over less than one year.

Counts COVID- Counts All Ratio: COVID-19 vaccines/

Cancer Reports to VAERS
19 vaccines other vaccines All other vaccines
Breast 147 49 3.00
Prostate 32 13 2.46
Lung 82 46 1.78
Colorectal/Colon 30 7 5.00
Ovarian 24 7 3.43
Uterine 11 5 2.20
Uterine leiomyoma 80 12 6.67
Lymphoma (subtype not
52 47 1.11
identified)
B-cell lymphoma 19 3 6.33
Follicular lymphoma 13 1 13.00
Metastasis 13 7 1.86
Glioblastoma 16 3 5.33
Brain neoplasm 22 34 0.65
Neoplasm (unspecified) 71 82 0.87
 Counts COVID- Counts All Ratio: COVID-19 vaccines/
Cancer Reports to VAERS
19 vaccines other vaccines All other vaccines
Hepatic 40 8 5.00
Pancreatic 27 6 4.50
Prostate 23 13 1.77
Squamous cell carcinoma (not
33 25 1.32
otherwise characterized)
Total 735 368 2.00

15.2 VAERS Signal for Cancer

Cancer is a disease generally understood to take months or, more commonly, years to progress from
an initial malignant transformation in a cell to development of a clinically recognized condition.
Since VAERS reports of adverse events are happening primarily within the first month or even the
first few days after vaccination [209], it seems likely that the acceleration of cancer progression
following vaccines would be a difficult signal to recognize. Furthermore, most people do not expect
cancer to be an adverse event that could be caused by a vaccine. However, as we have outlined in our
paper, if the mRNA vaccinations are leading to widespread dysregulation of oncogene controls, cell
cycle regulation, and apoptosis, then VAERS reports should reflect an increase in reports of cancer,
relative to the other vaccines.

This is in fact what VAERS reports reflect, and dramatically so. Table 1 illustrates events involving the
most common cancers reported to VAERS in the US, cancers either newly identified or stable disease
newly progressing. It compares reports related to COVID-19 vaccination to reports related to all other
vaccinations over the 31-year history of VAERS information collection. To obtain this table, we
searched the online resource, http://wonder.cdc.gov/vaers.html, for search terms indicating cancer,
such as “cancer,” “carcinoma,” “mass,” “neoplasm,” etc., and summed over all hits related to a
particular organ, such as “lung.” These data were collected on December 12, 2021.

Notably, there were three times as many reports of breast cancer following a COVID-19 vaccine, and
more than six times the number of reports of B-cell lymphoma. All but one of the cases of follicular
lymphoma were associated with COVID-19 vaccines. Pancreatic carcinoma was more than three
times as high.

This cannot be explained by reference to a disproportionately large number of people receiving an

mRNA vaccination in the past year compared to all other vaccinations. The total number of people
receiving a non-COVID-19 vaccination is unknown, but over the 31 years history of reports VAERS
contains it is unquestionably many orders of magnitude larger than the number receiving an mRNA
vaccination in the past year. Overall, in the above table, twice as many cancer reports to VAERS are
related to a COVID-19 vaccination compared to those related to all other vaccines. That, in our
opinion, constitutes a signal in urgent need of investigation.

16. Discussion

There has been an unwavering message about the safety and efficacy of mRNA vaccinations against
SARS-CoV-2 from the public health apparatus in the US and around the globe. The efficacy is
increasingly in doubt, as shown in a recent letter to the Lancet Regional Health by Günter Kampf
[215]. Kampf provided data showing that the vaccinated are now as likely as the unvaccinated to
spread disease. He concluded: “It appears to be grossly negligent to ignore the vaccinated
population as a possible and relevant source of transmission when deciding about public health
control measures.”

In this paper we call attention to three very important aspects of the safety profile of these
vaccinations. First is the extensively documented subversion of innate immunity, primarily via
suppression of IFN-α and its associated signaling cascade. This suppression will have a wide range of
consequences, not the least of which include the reactivation of latent viral infections and the
reduced ability to effectively combat future infections. Second is the dysregulation of the system for
both preventing and detecting genetically driven malignant transformation within cells and the
consequent potential for vaccination to promote those transformations. Third, mRNA vaccination
potentially disrupts intracellular communication carried out by exosomes, and induces cells taking
up spike mRNA to produce high levels of spike-carrying exosomes, with potentially serious
inflammatory consequences. Should any of these potentials be fully realized, the impact on billions
of people around the world could be enormous and could contribute to both the short-term and long-
term disease burden our health care system faces.

Given the current rapidly expanding awareness of the multiple roles of G4s in regulation of mRNA
translation and clearance through stress granules, the increase in pG4s due to enrichment of GC
content as a consequence of codon optimization has unknown but likely far-reaching consequences.
Specific analytical evaluation of the safety of these constructs in vaccines is urgently needed,
including mass spectrometry for identification of cryptic expression and immunoprecipitation
studies to evaluate the potential for disturbance of or interference with the essential activities of RNA
and DNA binding proteins.

17. Conclusions

It is imperative that worldwide administration of the mRNA vaccinations be stopped immediately

until further studies are conducted to determine the extent of the potential pathological
consequences outlined in this paper. It is not possible for these vaccinations to be considered part of
a public health campaign without a detailed analysis of the human impact of the potential collateral
damage. It is also imperative that VAERS and other monitoring system be optimized to detect signals
related to the health consequences of mRNA vaccination we have outlined. We believe the upgraded
VAERS monitoring system described in the Harvard Pilgrim Health Care, Inc. study, but unfortunately
not supported by the CDC, would be a valuable start in this regard [208].

In the end, we are not exaggerating to say that billions of lives are at stake. We call on the public
health institutions to demonstrate, with evidence, why the issues discussed in this paper are not
relevant to public health, or to acknowledge that they are and to act accordingly. Until our public
health institutions do what is right in this regard, we encourage all individuals to make their own
health care decisions with this information as a contributing factor in those decisions.

Author Contributions: S.S., G.N and A.K. all contributed substantially to the writing of the original
draft. P.M. participated in the process of editorial revisions.

Funding: This research was funded in part by Quanta Computers, Inc., Taipei, Taiwan, under the
auspices of the Qmulus project.

Conflicts of Interest: The authors declare no conflict of interest.

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