Adverse effects of COVID-19 mRNA vaccines: the spike hypothesis

Authors: Ioannis P. Trougakos,1,⁎ Evangelos Terpos,2 Harry Alexopoulos,1 Marianna Politou,3 Dimitrios Paraskevis,4 Andreas Scorilas,5 Efstathios Kastritis,2 Evangelos Andreakos,6 and Meletios A. Dimopoulos2 Trends Mol Med. 2022 Jul; 28(7): 542–554. Publishedonline2022Apr21. doi: 10.1016/j.molmed.2022.04.007PMCID: PMC9021367PMID: 35537987

Abstract

Vaccination is a major tool for mitigating the coronavirus disease 2019 (COVID-19) pandemic, and mRNA vaccines are central to the ongoing vaccination campaign that is undoubtedly saving thousands of lives. However, adverse effects (AEs) following vaccination have been noted which may relate to a proinflammatory action of the lipid nanoparticles used or the delivered mRNA (i.e., the vaccine formulation), as well as to the unique nature, expression pattern, binding profile, and proinflammatory effects of the produced antigens – spike (S) protein and/or its subunits/peptide fragments – in human tissues or organs. Current knowledge on this topic originates mostly from cell-based assays or from model organisms; further research on the cellular/molecular basis of the mRNA vaccine-induced AEs will therefore promise safety, maintain trust, and direct health policies.

Fighting the COVID-19 pandemic with SARS-CoV-2 S protein-encoding mRNA vaccines

COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Box 1 ) and has resulted in millions of deaths worldwide. Nevertheless, for the majority of SARS-CoV-2-infected individuals, COVID-19 will remain asymptomatic or only mildly symptomatic [1,2]. Although SARS-CoV-2 may also circulate in the gastrointestinal tract [3], being a respiratory virus, the virus itself or its related antigens will not, in most cases, impact tissues and organs other than the respiratory system (RS) (Box 1) [4.5.6.]. In patients with severe disease, infection of airway and lung tissues may cause pneumonia and excessive inflammation which can lead to acute respiratory distress syndrome (ARDS) (see Glossary) (Box 1) [7.8.9.10.]. ARDS may then lead to organ damage beyond the RS because of micro-/macro-thromboembolism, hyperinflammation, aberrant complement activation, or extended viremia [7.8.9.10.11.12.13.]. This may be due to the broad expression of its receptor angiotensin-converting enzyme 2 (ACE2) in several cell types and tissues [14.15.16.] which results in an expanding tropism of SARS-CoV-2 for various critical organs (heart, pancreas, kidneys, etc.). If systemic collapse and death are avoided, the postulated direct virus ‘attack’ – or indirect effects due to cytokine storm [10,13] or imbalance of the renin–angiotensin system (RAS) [13] – causing multiorgan damage, possibly foster systemic defects which cause a chronic condition (referred to as long COVID-19) which is independently associated with the severity of the initial illness [17].

Box 1

SARS-CoV-2 infection of human cells

SARS-CoV-2 infection of human cells proceeds via its binding to the cell surface protein ACE2 through the RBD of its protruding S glycoprotein [127] which remains in a metastable prefusion state through the association of subunits 1 (S1) and 2 (S2) via noncovalent interactions [18,19]; the infection process is also facilitated by host proteases [127,128]. In most of SARS-CoV-2-infected carriers the virus is contained in the upper RS, resulting in either no symptoms or mild symptoms [1,2]. A minority will require hospitalization; this is due to severe symptoms which develop due to extensive inflammation, a process often referred to as a ‘cytokine storm’, causing ARDS which may be accompanied by viremia and can lead to systemic multiorgan collapse [7.8.9.10.]. The risk for severe COVID-19 increases significantly with age or pre-existing comorbidities [1,2,129], and younger individuals have a substantially lower risk – even compared to influenza infection [129] – for developing severe COVID-19 [130,131]. It has been postulated that higher pediatric innate interferon responses restrict viral replication and disease progression [132]. In a recent trial, in which young people were intentionally exposed to a low dose of SARS-CoV-2, nearly half of the participants did not become infected, some were asymptomatic, and those who developed COVID-19 reported mild to moderate symptoms, including sore throats, runny noses, sneezing, and loss of sense of smell and taste; fever was less common, and no one developed a persistent cough [133].

SARS-CoV-2 infection in healthy individuals triggers innate as well as adaptive immune system responses, that is, CD4+ and CD8+ T cells and antibodies, including neutralizing antibodies (NAbs) produced by terminally differentiated B cells, which altogether suppress the extent of infection [132,134,135]. As SARS-CoV-2 initially infects the upper RS, defensive immune responses start to develop at respiratory mucosal surfaces, and this is followed by systemic immunity [136,137]. These immune responses are age- and gender-dependent and may either mount poorly in a background of genetic causes and pre-existing morbidities, or become very intense and essentially uncontrolled in severe disease leading to ARDS and systemic failure [11.12.13.].

Following an unprecedented effort of biomedical research and mobilization of resources, two mRNA vaccines – namely BNT162b2 (ComirnatyTM) from Pfizer-BioNTech and the mRNA-1273 of Moderna (encoded antigen: SARS-CoV-2 S protein of the Wuhan-Hu-1 strain) [18.19.20.] – were the first to receive FDA emergency use authorization. In mRNA vaccines, which are characterized by relatively rapid prototyping and manufacturing on a large scale, the S protein-encoding mRNA is delivered via lipid nanoparticles (LNPs) to human cells that produce the mature viral protein or related antigens (Figure 1 , Key figure), which can exhibit a rather wide tissue/organ distribution (discussed later) [20.21.22.]. In addition to the plausible proinflammatory role of LNPs (evidenced also from reported immediate allergic reactions) [23,24] and of packaged mRNA – which has nonetheless been engineered by a replacement of uridine with pseudouridine [20,25,26] so as not to trigger innate immunity through pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) receptors – we surmise that vaccination-mediated adverse effects (AEs) can be attributed to the unique characteristics of the S protein itself (antigen) either due to molecular mimicry with human proteins or as an ACE2 ligand.

Figure 1

Figure 1

Key figure. Antigen expression–localization following cell transfection with spike (S) protein mRNA-containing lipid nanoparticles (LNPs) used in anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccines.

Following LNP internalization and mRNA release, the authentic viral signal peptide (as in the Pfizer–BioNTech and Moderna vaccines) drives antigen production in the lumen of the endoplasmic reticulum (ER) where it adopts its natural transmembrane localization via subunit 2 (S2) anchoring. After sorting in the trans Golgi network (TGN), S protein acquires its final position in the transfected human cell membrane, where S1 is exposed to the extracellular space (i.e., may face circulation). Although the extent of antigen expression per cell remains unknown, it is reasonable to assume that this process results in rather extended decoration of transfected cells with S protein. Furin-mediated proteolytic cleavage (as in SARS-CoV-2-infected cells) in the absence of a mutated S1/S2 furin cleavage site at the TGN may result in shedding of cleaved S1 and conversion of S2 into its postfusion structure (S2*). Antigen sorting and trafficking may also induce the release of S protein-containing exosomes. The events shown will occur in the apical and/or basolateral surfaces of polarized (e.g., epithelial) cells. The Pfizer–BioNTech and Moderna constructs do not contain a mutated S1/S2 furin cleavage site. Further research will clarify the impact of the S1/S2 subunits stabilizing D614G (or other) mutation or of a mutated furin cleavage site in antigen distribution, the immunogenicity of the vaccine, and induced adverse events (AEs). Also shown are dendritic cells (professional antigen-presenting cells, APCs) engulfing circulating antigens, and antibody-mediated binding of B cells to cell-anchored antigens.

As delivered mRNAs can theoretically trigger the production of distinct antigens that can distribute systemically [20], they are radically different from conventional platforms (i.e., inactivated whole-virus vaccines or even protein-subunit nanoparticle vaccines) (Box 2 ) where the produced antigen and its distribution are more predictable. As all COVID-19 vaccines rely on the S protein of the original Wuhan-Hu-1 strain [19,20], the differences across different vaccination platforms thus far reported (Box 2) may relate to the various vectors and formulations and/or the S protein constructs employed.

Box 2

Other types of COVID-19 vaccine

In viral vector vaccines, the S protein coding information is delivered via a replication-deficient adenoviral vector system that contains an encoding dsDNA. In this case, transcripts from adenoviral vectors are generated in the cell nucleus. Here, a major reported AE is immune thromboembolism (including cerebral venous sinus thrombosis) in various organs, probably through excessive innate immune system and endothelial activation [138]. Apart from the S protein itself, AEs can be also attributed to background expression of remaining adenoviral genes or to persisting adenovirus-vector DNA in a transcriptionally active form. Further concerns are the presence of other contaminant proteins, remnants of the vaccine production line, and to pre-existing antivector immunity [20]; this last issue does not apply to the recombinant ChAdOx1-S (Oxford–AstraZeneca) vaccine which employs a nonhuman adenovirus vector. More importantly, the infectious cycle of SARS-CoV-2 takes place exclusively in the cytoplasm, and thus there has been no evolutionary pressure against the presence of splice donor and acceptor sites in its genes. This is a major difference from mRNA vaccines that function in the cytoplasm, since various spliced transcripts from adenoviral vectors can be generated in the cell nucleus [56].

In protein subunit nanoparticle vaccines (e.g., NVX-CoV2373), the S protein is harvested in a cell culture system, purified, and delivered as a trimer via a nanoparticle assembly in an adjuvant. Although preliminary trials indicate that these vaccines can trigger robust immunity [139], reports on AEs are still scarce due to the limited amount of vaccination data.

Finally, in conventional vaccines, the whole virus is inactivated and inoculated using an appropriate adjuvant [26]. A significant benefit is that whereas in the previously discussed technologies the S protein is the sole source of immunogenic epitopes, in this case a wide repertoire of epitopes in other viral proteins is presented. Possible disadvantages include lower immunogenicity, production issues, AEs due to used adjuvant(s) (e.g., aluminum hydroxide), as well as issues that relate to incomplete inactivation of the virus. Given that these vaccines have not reached mass production, reports on possible AEs do not exist.

Anti-SARS-CoV-2 mRNA vaccines and their reported adverse effects

Both the BNT162b2 and mRNA-1273 vaccines are administered intramuscularly and mobilize robust and likely durable innate, humoral, and cellular adaptive immune responses [27.28.29.30.]. Existing data on the available mRNA vaccines are mostly limited to serological analyses. Nonetheless, beyond the assessment of immune responses, the understanding of the safety profile of these vaccines is critical to ensure safety, maintain trust, and inform policy. Reportedly, mRNA vaccines are in general well tolerated, with very low frequencies of associated severe postimmunization AEs. Although rare, AEs include serious clinical manifestations such as acute myocardial infarction, Bell’s palsycerebral venous sinus thrombosisGuillain–Barré syndrome, myocarditis/pericarditis (mostly in younger ages), pulmonary embolism, stroke, thrombosis with thrombocytopenia syndrome, lymphadenopathy, appendicitis, herpes zoster reactivation, neurological complications, and autoimmunity (e.g., autoimmune hepatitis and autoimmune peripheral neuropathies [31.32.33.34.]) (see Clinician’s corner). Apart from AEs documented in clinical trials, most of the syndromes or isolated manifestations have been reported in multicenter or even nationwide retrospective observational studies and case series. Although correlation does not necessarily mean causation, active monitoring and awareness regarding reported postvaccination AEs are essential. Importantly, these associated AEs are significantly less frequent than analogous or additional serious AEs induced after severe COVID-19 [31,32,34]. Some vaccine-induced AEs (e.g., myocardial infarction, Guillain–Barré syndrome) were found to increase with age, while others (e.g., myocarditis, anaphylaxis, appendicitis) were more common in younger people [35,36]. Although myocarditis cases are rather rare, in a study of US military personnel the number was higher than expected among males after a second vaccine dose [37]; similarly, the rate of postvaccination cardiac AEs was higher in young boys following the second dose [38,39]. Finally, a recent study showed an increased risk of neurological complications in COVID-19 vaccine recipients (which was nevertheless lower than the risk in COVID-19 patients) [34]. The molecular basis of these AEs remains largely unknown. We postulate that, since most (if not all) of them are also apparent in severe COVID-19 [31], they may be related to acute inflammation caused by both the virus and the vaccine, as well as in the common denominator between the virus and the vaccine, namely, the SARS-CoV-2 S protein (Box 1). The vaccine-encoded antigen (S protein) is stabilized in its prefusion form in the BNT162b2 and mRNA-1273 vaccines [19,20]; it is therefore plausible that, if entering the circulation and distributing systemically throughout the human body (Figure 2 ), it can contribute to these AEs in susceptible individuals.

Figure 2

Figure 2

Schematic of the vasculature components showing vaccination-produced S protein/subunits/peptide fragments in the circulation, as well as soluble or endothelial cell membrane-attached angiotensin-converting enzyme 2 (ACE2).

(A,B) Parallel to immune system activation, circulating S protein/subunits/peptide fragments (B) binding to ACE2 may occur not only to ACE2-expressing endothelial cells, but also in multiple cell types of the vasculature and surrounding tissues due to antigen diffusion (e.g., in fenestrated or discontinuous capillary beds) (A, red arrows). These series of molecular events are unlikely for any severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related antigen in the absence of severe coronavirus disease 2019 (COVID-19), where SARS-CoV-2 is contained in the respiratory system. In (C) the two counteracting pathways of the renin–angiotensin system (RAS), namely the ‘conventional’ arm, that involves ACE which generates angiotensin II (ANG II) from angiotensin I (ANG I), and the ACE2 arm which hydrolyzes ANG II to generate angiotensin (1–7) [ANG (1–7)] or ANG I to generate angiotensin (1–9) [ANG (1–9)] are depicted. ANG II binding and activation of the ANG II type 1 receptor (AT1R) promotes inflammation, fibrotic remodeling, and vasoconstriction, whereas the ANG (1–7) and ANG (1–9) peptides binding to MAS receptor (MASR) activate antifibrotic, anti-inflammatory pathways and vasodilation. Additional modules of the RAS (i.e., renin and angiotensinogen, AGT) are also shown. Abbreviation: AT1R, angiotensin II type 1 receptor.

Clinician’s corner

Given the plethora of existing data on the available mRNA vaccines, a major ‘known’ is that in the short-term mRNA vaccines are well tolerated by the recipient, and that they can induce a robust immune response and therefore provide prolonged protection against severe COVID-19 (including emerging variants of concern); thus, vaccination remains a major tool for mitigating the COVID-19 pandemic and saving thousands of lives.

It is well established that the risk for severe COVID-19 increases with age or pre-existing comorbidities. Given the ‘unknowns’ discussed herein, boosting doses in healthy children and even adolescents should be delivered only if the benefit–risk profile is clearly established.

Multidisciplinary clinical and basic research aiming at understanding the cellular–molecular basis of the COVID-19 mRNA vaccine-induced AEs – along with active pharmacovigilance and long-term recording in the clinical setting of reported AEs in vaccinated recipients – are critical components for improving vaccines, guaranteeing safety, maintaining trust, and directing health policies.

The technology of the mRNA vaccines will continue to evolve as it opens up a whole new era of novel applications for large-scale development of new vaccines against various infectious and other diseases, including cancer.

There is also evidence that ionizable lipids within LNPs can trigger proinflammatory responses by activating Toll-like receptors (TLRs) [40]. A recent report showed that LNPs used in preclinical nucleoside-modified mRNA vaccine studies are (independently of the delivery route) highly inflammatory in mice, as evidenced by excessive neutrophil infiltration, activation of diverse inflammatory pathways, and production of various inflammatory cytokines and chemokines [41]. This finding could explain the LNPs’ potent adjuvant activity, supporting the induction of robust adaptive immune responses [24]. Interestingly, inflammatory responses can be exacerbated on a background of pre-existing inflammatory conditions, as was recently shown in a mouse model after administration of mRNA–LNPs [42]; this effect was proven to be specific to the LNP, acting independently of the mRNA cargo.

Although chemical modifications in the RNA molecules used in vaccines (detailed earlier) are intended to decrease TLR sensing of external single-stranded RNAs (and thus proinflammatory signals), there is some evidence that modified uracil residues do not completely abrogate TLR detection of the mRNA; also, while efforts are made to reduce double-stranded (ds) RNA production, there may be small amounts of dsRNA that can occasionally get packaged within mRNA vaccines [26].

In this context, frequent booster immunizations may increase the frequency and/or the severity of the reported AEs.

Vaccine-encoded antigen distribution in the human body and possible interactions with human proteins

Following vaccination, a cell may present the produced S protein (or its subunits/peptide fragments) to mobilize immune responses or be abolished by the immune system (e.g., cytotoxic T cells) [25]. Consequently, the debris produced, or even the direct secretion (including shedding) of the antigen by the transfected cells, may release large amounts of the S protein or its subunits/peptide fragments to the circulation (Figure 1) [19,20]. The anti-SARS-CoV-2 vaccine mRNA-containing LNPs are injected into the deltoid muscle and exert an effect in the muscle tissue itself, the lymphatic system, and the spleen, but can also localize in the liver and other tissues [21,22,43,44] from where the S protein or its subunits/peptide fragments may enter the circulation and distribute throughout the body. It is worth mentioning that liver localization of LNPs is not a universal property of carrier nanoparticles, as specific modifications in their chemistry can retain immunogenicity with minimal liver involvement [43,45]. In line with a plausible systemic distribution of the antigen, it was found that the S protein circulates in the plasma of the BNT162b2 or mRNA-1273 vaccine recipients as early as day 1 after the first vaccine injection [46]. Reportedly, antigen clearance is correlated with the production of antigen-specific immunoglobulins or may remain in the circulation (e.g., in exosomes) for longer periods [47,48], providing one reasonable explanation (among others) for the robust and durable systemic immune responses found in vaccinated recipients [49,50]. Therefore, there is likely to be an extensive range of expected interactions between free-floating S protein/subunits/peptide fragments and ACE2 circulating in the blood (or lymph), or ACE2 expressed in cells from various tissues/organs (Figure 2) [14.15.16.]. This notion is further supported by the finding that in adenovirus-vectored vaccines (Box 2), the S protein produced upon vaccination has the native-like mimicry of SARS-CoV-2 S protein’s receptor binding functionality and prefusion structure [51].

Additional interactions with human proteins in the circulation, or even the presentation to the immune system of S protein antigenic epitopes [52] mimicking human proteins (molecular mimicry) may occur [53.54.55.56.]. Reportedly, some of the near-germline SARS-CoV-2-NAbs against S receptor-binding domain (RBD) reacted with mammalian self-antigens [57], and SARS-CoV-2 S antagonizes innate antiviral immunity by targeting multiple pathways controlling interferon (IFN) production [58]. Also, a sustained elevation in T cell responses to SARS-CoV-2 mRNA vaccines has been found (data not yet peer-reviewed) in patients who suffer from chronic neurologic symptoms after acute SARS-CoV-2 infection as compared with healthy COVID-19 convalescents [59]. Given the reported (rare) neurological AEs following vaccination, it was suggested that further studies are needed to assess whether antibodies against the vaccine-produced antigens can cross-react with components of the peripheral nerves [34]. Further concerns include the possible development of anti-idiotype antibodies against vaccination-induced antibodies as a means of downregulation; anti-idiotype antibodies – apart from binding to the protective neutralizing SARS-CoV-2 antibodies – can also mirror the S protein itself and bind ACE2, possibly triggering a wide array of AEs [60]. Worth mentioning is a systems vaccinology approach (31 individuals) of the BNT162b2 vaccine (two doses) effects, where anticytokine antibodies were largely absent or were found at low levels (contrary to findings in acute COVID-19 [61,62]), while two individuals had anti-interleukin-21 (IL-21) autoantibodies, and two other individuals had anti-IL-1 antibodies [63]. In this context, anti-idiotypic antibodies can be particularly enhanced after frequent boosting doses that trigger very high titers of immunoglobulins [64]. Frequent boosting doses may also become a suboptimal approach as they can imprint serological responses toward the ancestral Wuhan-Hu-1 S protein, minimizing protection against novel viral S variants [65,66].

The potential interaction at a whole-organism level of the native-like S protein and/or subunits/peptide fragments with soluble or cell-membrane-attached ACE2 (Figure 2) can promote ACE2 internalization and degradation [67,68]. In support of this, soluble ACE2 induces receptor-mediated endocytosis of SARS-CoV-2 via interaction with proteins related to the RAS [69]. Prolonged loss or reduced ACE2 activity may result in extensive destabilization of the RAS which may then trigger vasoconstriction, enhanced inflammation, and/or thrombosis due to unopposed ACE and angiotensin-2 (ANG II)-mediated effects (Figure 2) [13]. Indeed, decreased ACE2 expression and/or activity contributes, among other things, to the development of ANG II-mediated hypertension in mice, indicating vasculature dysfunction [67]. The baseline expression levels of ACE2 in endothelial cells, or its induced expression levels upon stimulation from other tissue-resident cells, along with the potential of endothelial cells to shed ACE2 to the circulation, or their sensitivity to SARS-CoV-2 infection is debatable [70.71.72.73.]. Nonetheless, even relatively low ACE2 expression levels in endothelial cells (e.g., compared to levels in epithelial cells) [15,16,70,71], along with the high expression levels of ACE2 in other cell types of the vasculature (e.g., heart fibroblasts/pericytes) [15,74], indicate that the vasculature can be sensitive to free-floating S protein or its subunits/peptide fragments (Figure 2). These effect(s), especially in capillary beds, and the prolonged antigen presence in the circulation [46.47.48.], along with the systemic excessive immune response to the antigen, can then trigger sustained inflammation (discussed later) which can injure the endothelium, disrupting its antithrombogenic properties in multiple vascular beds

The SARS-CoV-2 S protein-induced effects in mammalian cells or model organisms

Reportedly, intravenous (i.v.) injection of the S1 subunit in mice results in its localization in endothelia of mice brain microvessels showing colocalization with ACE2, caspase-3, IL-6, tumor necrosis factor α (TNF-α), and C5b-9; it was thus suggested that endothelial damage is a central part of SARS-CoV-2 pathology which may be induced by the S protein alone [75]. Also, the S1 subunit (or recombinant S1 RBD) impaired endothelial function via downregulation of ACE2 [76] and induced degradation of junctional proteins that maintain endothelial barrier integrity in a mouse model of brain microvascular endothelial cells or cerebral arteries; this latter effect was more enhanced in endothelial cells from diabetic versus normal mice [77]. Similarly, the S1 subunit decreased microvascular transendothelial resistance and barrier function in cultured human pulmonary cells [78]. Further, S protein disrupted human cardiac pericytes function and triggered increased production of proapoptotic factors in pericytes, causing endothelial cells death [79]. In support of this, administration of the S protein promoted dysfunction of human endothelial cells as evidenced by, for example, increased expression of the von Willebrand factor [80]. Other reports indicate that S1 can directly induce coagulation by competitive binding to both soluble and cellular heparan sulfate/heparin (an anticoagulant) [81.82.83.84.], while cell-free hemoglobin, as a hypoxia counterbalance, cannot attenuate disruption of endothelial barrier function, oxidative stress, or inflammatory responses in human pulmonary arterial endothelial cells exposed to S1 [85]. Consistently, S protein binds fibrinogen (a blood coagulation factor), and S protein virions have been found to enhance fibrin-mediated microglia activation (data not yet peer-reviewed) and induce fibrinogen-dependent lung pathology in mice [86], while S1 binding to platelets’ ACE2 triggers their aggregation [84]. Interestingly, both the ChAdOx1 (AstraZeneca) and BNT162b2 vaccines can elicit antiplatelet factor 4 (anti-PF4) antibody production even in recipients without clinical manifestation of thrombosis [87].

Intriguingly, the S protein increases human cell syncytium formation [88,89], triggering pyroptosis of syncytia formed by fusion of S and ACE2-expressing cells [90]. Also, in cells or mouse experimental models, it was shown that S removes lipids from model membranes and interferes with the capacity of high-density lipoprotein to exchange lipids [91], inhibits DNA damage repair processes [92], and induces Snail-mediated epithelial–mesenchymal transition marker changes and lung metastasis in a breast cancer mouse model [93].

In support of the possibility that there is a wide range of S protein binders, Aβ1  42 (the 42 amino acid form of amyloid β in cerebrospinal fluid) was found to bind with high affinity to the S1 subunit and ACE2 [94]. Aβ1  42 strengthened the binding of S1 to ACE2 and increased viral entry and production of IL-6 in a SARS-CoV-2 pseudovirus infection mouse model. Data from this surrogate mouse model with IV inoculation of Aβ1  42 showed that the clearance of Aβ1  42 in the blood was dampened in the presence of the extracellular domain of the S protein trimers [94]. Given the wide ACE2 expression in human brain [95], a study of particular interest showed that IV-injected radioiodinated S1 (I-S1) readily crossed by adsorptive transcytosis the blood–brain barrier in male mice, was taken up by brain regions, and entered the parenchymal brain space. I-S1 was also taken up by the lung, spleen, kidney, and liver; intranasally administered I-S1 also entered the brain, although at lower levels than after i.v. administration [96]. Similarly, S1 was found to disrupt the blood–brain barrier integrity at a 3D blood–brain barrier microfluidic model [97]. In support of this, biodistribution studies of the mRNA–LNP platform by Moderna in Sprague Dawley rats revealed the presence of low levels of mRNA in the brain, indicating that the mRNA–LNPs can cross the blood–brain barrier [22].

Finally, it was recently reported that human T cells express ACE2 at levels sufficient to interact with the S protein [98], while it had been shown previously that SARS-CoV-2 uses CD4 to infect T helper lymphocytes, and that S promotes a proinflammatory activation profile on the most potent antigen-presenting cells (APCs) (i.e., human dendritic cells) [99]. If these observations are confirmed, they may explain a SARS-CoV-2 vaccination-mediated AE, namely, reactivation of varicella zoster virus [100,101]

S protein-induced proinflammatory responses and unique gene expression signatures following vaccination

Reportedly, S protein (apart from the LNP–mRNA platform discussed earlier) mediates proinflammatory and/or injury (of different etiology) responses in various human cell types [102.103.104.], and ACE2-mediated infection of human bronchial epithelial cells with S protein pseudovirions induced inflammation and apoptosis [105]. Also, S protein promoted an inflammatory cytokine IL-6/IL-6R-induced trans signaling response and alarmin secretion in human endothelial cells, along with increased oxidative stress, induction of inflammatory paracrine senescence, and higher levels of leucocyte adhesion [106]. Other reports indicate that S protein triggers an inflammatory response signature in human corneal epithelial cells [107], increases oxidative stress and DNA ds breaks in human peripheral-blood mononuclear cells (PBMCs) postvaccination [108], and binds to lipopolysaccharide, boosting its proinflammatory activity [109,110]. Furthermore, S protein induces neuroinflammation and caspase-1 activation in BV-2 microglia cells [111] and blocks neuronal firing in sensory neurons [112]. The S protein-induced systemic inflammation may proceed via TLR2-dependent activation of the nuclear factor κB (NF-κB) pathway [113], while structure-based computational models showed that S protein exhibits a high-affinity motif for binding T cell receptors (TCRs), and may form a ternary complex with histocompatibility complex class II molecules; indeed, analysis of the TCR repertoire in COVID-19 patients showed that those with severe hyperinflammatory disease exhibit TCR skewing consistent with superantigen (S protein) activation [114]. In in vivo mouse models, S protein activated macrophages and contributed to induction of acute lung inflammation [115], while intratracheal instillation of the S1 subunit in transgenic mice overexpressing human ACE2 induced severe COVID-19-like acute lung injury and inflammation. These effects were milder in wild-type mice, indicating the phenotype dependence on human ACE2 expression [78]. Consistently, the S1 subunit has been found to act as a PAMP that, via pattern recognition receptor engagement, induces viral infection-independent neuroinflammation in adult rats [116].

These observations correlate with the finding of a systemic inflammatory signature after the first BNT162b2 vaccination which was accompanied by TNF-α and IL-6 upregulation after the second dose [117]; these effects may also relate to a proinflammatory action of the mRNA–LNP platform (see earlier). In a thorough systems vaccinology study of the BNT162b2 mRNA vaccine effects, younger participants tended to have greater changes in monocyte and inflammatory modules 1 day after the second dose, whereas older individuals had increased expression of B and T cell modules. Moreover, single-cell transcriptomics analysis at the same time point revealed the emergence of a unique myeloid cell cluster out of 18 cell clusters identified in total. This cell cluster does not represent myeloid-derived suppressor cells, it expressed IFN-stimulated genes and was not found in COVID-19 infection; also, it was similar to an epigenetically reprogrammed monocyte population found in the blood of donors being vaccinated with two doses of an influenza vaccine [63]. Whether epigenetic reprogramming underlies the enhanced IFN-induced gene response in C8 cells after secondary BNT162b2 vaccination remains to be clarified. Finally, a comparison between the BNT162b2 vaccine-induced gene expression signatures at day 7 post-prime (d7PP) and post-boost (d7PB) doses and that of other vaccine types (e.g., inactivated or live-attenuated vaccines) exhibited weak correlation both between d7PP and d7PB as well as with other vaccines [63]. These findings suggest the evolution of novel genomic responses after the second dose and, more importantly, the unique biology of mRNA vaccines versus other more conventional platforms. Of particular interest is also the report of a cytokine release syndrome (CRS) – an extremely rare immune-related AE of immune checkpoint inhibitors – post-BTN162b2 vaccination in a patient with colorectal cancer on longstanding anti-programmed death 1 (PD-1) monotherapy; the anti-PD1 blockade-mediated CRS was evidenced by increased inflammatory markers, thrombocytopenia, elevated cytokine levels, and steroid responsiveness [118]. These proinflammatory effects could be particularly pronounced in the elderly, since recent data revealed that senescent cells become hyperinflammatory in response to the S1 subunit, followed by increased expression of viral entry proteins and reduced antiviral gene expression in nonsenescent cells through a paracrine mechanism [119]

The need to investigate the molecular basis of vaccination-induced AEs

Anti-SARS-CoV-2 mRNA vaccines induce durable and robust systemic immunity, and thus their contribution in mitigating the COVID-19 pandemic and saving thousands of lives is beyond doubt. This technology has several advantages over conventional vaccines [120] and opens a whole new era for the development of novel vaccines against various infectious and other diseases, including cancer. Based on currently available molecular insights (mostly in cell-based assays and model organisms), we hypothesize that the rare AEs reported following vaccination with S protein-encoding mRNA vaccines may relate to the nature and binding profile of the systemically circulating antigen(s) (Figure 1Figure 2), although the contribution of the LNPs and/or the delivered mRNA is likely also significant [24,26,41]. Therefore, the possibility of subclinical organ dysfunction in vaccinated recipients which could increase the risk, for example, of future (cardio)vascular or inflammatory diseases should be thoroughly investigated. Given that severe COVID-19 correlates with older age, hypertension, diabetes, and/or cardiovascular disease, which all share a variable degree of ACE2 signaling deregulation, additional ACE2 downregulation induced by vaccination may further amplify an unbalanced RAS. Regarding localization of LNPs in the liver and consequent antigen expression, it is worth mentioning that the liver is continuously exposed to a multitude of self and foreign antigens and can mount efficient immune responses against pathogens as it hosts convectional APCs (e.g., dendritic cells, B cells, and Kupfer cells). Additional liver cell types – such as liver sinusoidal endothelial cells, hepatic stellate cells, and hepatocytes – also have the capacity to act as APCs [121]. It is plausible, though as yet unproven, that as the S protein is produced in liver cells, both conventional and unconventional APCs may prime adaptive but also innate immune responses in the liver’s immunological niche. Despite the liver’s major tolerogenic role [122], the sustained expression of S protein-related antigens (Figure 1) can potentially skew the immune response towards autoimmune-like tissue damage, as in the observed cases of autoimmune hepatitis following vaccination [123,124]. It therefore merits further investigation whether LNPs can transfect any other nonimmunological body tissues bearing cells that can act as unconventional APCs, thus inducing a sustained immune response but also a self-response, as in cases of chronic viral infections [125

Concluding remarks

Although the benefit–risk profile remains strongly in favor of COVID-19 vaccination for the elderly and patients with age-related or other underlying diseases, an understanding of the molecular–cellular basis of the anti-SARS-CoV-2 mRNA vaccine-induced AEs is critical for the ongoing and future vaccination and booster campaigns. In parallel, the prospective pharmacovigilance and long-term monitoring (clinical/biochemical) of vaccinated recipients versus matched controls should evolve in well-designed clinical trials. Moreover, the use of alternative chemistries for LNPs, and of S protein in its closed form (not prone to ACE2 binding) [126], along with the use of SARS-CoV-2 nucleocapsid protein or solely the S RDB, may be valuable alternatives for refined, next-generation mRNA vaccines. Finally, as we essentially do not know for how long and at what concentration the LNPs and the antigen(s) remain in human tissues or the circulation of poor vaccine responders, the elderly, or children (see Outstanding questions), and given the fact that cellular immunity likely persists despite reduced in vitro neutralizing titers [28], boosting doses should be delivered only where the benefit–risk profile is clearly established.

Outstanding questions

What are the localization pattern, transfection efficacy, and clearance rates of the mRNA vaccine LNPs in the human body?

Can we refine LNP chemistry towards retaining transfection efficacy and at the same time assuring on-demand tissue distribution?

Do the adverse inflammatory reactions noted postvaccination also relate – and if yes, to what extent – to LNPs and/or the mRNA used in mRNA vaccines?

What are the mechanistic details of antigen expression, processing, and cellular localization following cell transfection with the LNPs?

What would the impact be of excessive ‘decoration’ of nonprofessional antigen-presenting transfected human (e.g., liver) cells with transmembrane S protein?

Does the antigen or related subunits‐peptide fragments leak into the circulation, and if so, in which form, at what concentration, and for how long? Is there any association with the vaccine-mediated immune responses?

Is the probable binding of the antigen to ACE2 in the vasculature accountable for the cardiovascular, metabolic, or other (e.g., inflammation-related) reported AEs?

Does the antigen cross the blood–brain barrier?

Is there any noteworthy molecular mimicry (especially of the major antigenic sites) between the S protein and the human proteome?

What is the profile of mucosal immunity induced by the mRNA COVID-19 vaccines?

It is the case that vaccination-mediated immunity (two doses) against the used ancestral antigen (Wuhan-Hu-1 S protein) wanes over time, or do we simply partially lose protection due to evolutionary leaps of the S protein (e.g., at the Omicron variant)? In that case, do we really need boosting doses with the same antigen?

Does boosting, apart from raising antibody titers, also promote antibody diversification?

What would be the profile of immune responses and AEs following mRNA-guided expression of the S protein in its closed form (a form not prone to ACE2 binding)?

Alt-text: Outstanding questions

Overall, parallel to the ongoing research on the most challenging topics of SARS-CoV-2 biology, evolving dynamics and adaptation capacity to human species (i.e., transmission–infection rate and disease severity), the basic and clinical research (see Outstanding questions) aiming to understand the molecular–cellular basis of the rare AEs of the existing first-generation mRNA vaccines should be accelerated as an urgent and vital public health priority.

Glossary

Acute respiratory distress syndrome (ARDS)a life-threatening condition in which fluid builds up in the lungs, interfering with the gas exchange function and preventing oxygenation of the blood and organs.
Adverse effect (AE)an undesired effect of a medication or clinical intervention with potentially harmful consequences.
Angiotensin-converting enzyme 2 (ACE2)an enzyme involved in the homeostatic regulation of circulating angiotensin I and angiotensin II levels by converting them to angiotensin (1–9) and angiotensin (1–7) peptides respectively.
Bell’s palsyan idiopathic episode of facial muscle weakness or paralysis on one side of the face. This condition results from dysfunction of the seventh cranial nerve (the facial nerve).
Cerebral venous sinus thrombosisa rare blood-clotting event that occurs in the venous sinuses of the brain and prevents blood from draining out of the brain. As a result, pressure builds up and can lead to swelling and hemorrhage.
Cytokine storma characteristic of COVID-19 (or other disease) where abnormally high levels of circulating cytokines are produced and contribute to disease severity.
Guillain–Barré syndromea rare, autoimmune neurological disorder in which the body’s immune system erroneously attacks the peripheral nerves, causing muscle weakness and, if left untreated, paralysis.
Long COVID-19a term that refers to a range of new, returning, or ongoing symptoms that persist beyond the initial phase of a SARS-CoV-2 infection.
Molecular mimicrythe process in which an immune response against a foreign antigen is inadvertently also directed against a self-antigen that closely resembles the triggering foreign antigen.
Receptor-binding domain (RBD)the part of a binding protein (e.g., in SARS-CoV-2 S protein) used to anchor the protein to its receptor.
Renin–angiotensin system (RAS)a system that is critical in the physiological regulation of (among others) neural, gut, cardiovascular, blood pressure, and kidney functions, as well as fluid and salt balance. It involves the enzyme renin which catalyzes the production of angiotensin I.
Serological analysisany analysis performed with blood serum, usually focusing on measuring antibody levels.
Syncytiuma cell with multiple nuclei resulting from multiple fusions of uninuclear cells.
Viremiathe detection of replication-competent viral particles in the bloodstream.

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1 in 780 German Children Under 5 REQUIRES HOSPITALIZATION Due to Severe Adverse Event Following Pfizer’s mRNA COVID shots

BAuthors: Jim Hoft October 20, 2022 JAMA

According to the findings of German research, one in every 700 children under the age of five who received the Pfizer mRNA Covid vaccine was hospitalized with severe adverse events (SAE), and one in every 200 children had ‘symptoms that were currently ongoing and thus of unknown significance.’

The study, “Comparative Safety of the BNT162b2 Messenger RNA COVID-19 Vaccine vs Other Approved Vaccines in Children Younger Than 5 Years,” was published in JAMA on Tuesday, two days before the CDC’s Advisory Committee on Immunization Practices voted to recommend COVID-19 to be included in the 2023 childhood immunization schedule.

Participants in this retrospective cohort study were German parents or caregivers who had enrolled their children in a Covid-19 vaccination program at 21 outpatient care facilities. The survey used in the study was conducted in a secure online environment. From April 14th, 2022, till May 9th, 2022, a total of 19 000 email addresses were contacted using data from vaccine registration databases.

It concluded that the symptoms reported after Pfizer vaccination were “comparable overall” to those for other vaccines. Let’s see.

  • Any symptoms: 62% higher
  • Musculoskeletal (muscles and bones) symptoms: 155% higher
  • Dermatologic (skin) symptoms: 118% higher
  • Otolaryngologic (ears, nose and throat) symptoms: 537% higher
  • Cardiovascular (heart etc.): 36% higher
  • Gastrointestinal (stomach etc.): 54% higher

It calls these “modestly elevated.” (Note that not all are statistically significant and some confidence intervals are wide, see below.)

In 0.5% of the children (40 of 7,806) symptoms were “currently ongoing and thus of unknown significance”. This is in a study with a 2-4 month follow-up period. That means 0.5% of children had an adverse effect that lasted for weeks or months. In two cases (0.03%), symptoms were confirmed to have lasted longer than 90 days.

Ten children were hospitalised with reported serious adverse events (SAEs), compared to zero with the other vaccines. This reported as 0.1%, as it is out of 7,806. However, the study also states that no hospitalisations were reported for children administered the low dosage of 3 μg. Since it also tells us that 6,033 children received at least one dose of over 3 μg (or unknown dosage), the rate in the relevant cohort is closer to 0.2%, or around one in 500.

Four of the hospitalisations were for cardiovascular injury; one child was hospitalised after both doses for this reason. Four were pulmonary (lung) related. Symptoms of the hospitalised children lasted an average of 12.2 days and a maximum of 60 days. None reported a myocarditis diagnosis. Mercifully, no deaths were reported in this relatively small sample.

The mortality rate in under-20s has been shown to be 0.0003%. The figure for under-fives will be even lower. But even if we unrealistically assume this is the mortality rate for under-fives and the vaccines reduce it to zero, this still means that at least 500 children are hospitalised for every life the vaccines save. In reality the ratio will be much worse than this.

On Wednesday, The Gateway Pundit reported that the CDC’s Advisory Committee on Immunization Practices voted to include the COVID-19 vaccine as part of the Vaccines for Children (VFC) Program.

The Vaccines For Children (VFC) program is a federally funded program that provides vaccines at no cost to children who might not otherwise be vaccinated because of their inability to pay, according to the CDC.

The CDC buys vaccine at a discounted rate for distribution to registered VFC providers. Children who are eligible* for VFC vaccines are entitled to receive those vaccines recommended by the Advisory Committee on Immunization Practices (ACIP).

The advisory committee voted 15-0, without objection.

On Thursday, the CDC’s Advisory Committee on Immunization Practices voted to recommend COVID-19 to be included in the 2023 childhood immunization schedule in 15 unanimous votes.

25% Of People Who Received Covid-19 Vaccination Missed Work Or Reported A “Serious Event” Affecting Their Normal Life Functions, According To CDC Data

Authors: NICOLE DOMINIQUE· Oct 5th 2022

Official data from the CDC has been released due to court orders, as stated by lawyer Aaron Siri. The findings show that 25% of people who got the shot (from a database of 10 million) couldn’t perform normal activities and had to miss work or school afterward.

Lawyer Aaron Siri has successfully obtained reports from the CDC after the Informed Consent Action Network sued the organization twice. The court order required the CDC to release crucial information on the vaccine’s safety. The data is gathered from 10 million individuals who utilized the CDC’s “v-safe” program, a smartphone-based tool where recipients of the Covid-19 vaccine can go for health check-ins. The tool allows people to go on their smartphone and provide information on how they’re feeling post-shot. The newly released data is eye-opening. According to the official CDC data shared by Siri, about 1.2 million people were unable to perform regular activities, 1.3 million had to miss work or school, and another 800,000 people required medical care after getting the vaccine. A total of 3,353,110 recipients were negatively impacted by the jab.

Siri appeared on Fox to talk about the lengthy process of attaining the documents. It took 463 days to receive the data, and Siri believes the CDC could have provided the information in a matter of minutes. “Why did it take numerous legal demands, multiple appeals – two lawsuits in fact – before the CDC finally handed over the v-safe data?” Siri asks.

These findings are very concerning; for years, the vaccine was advertised as “safe” and “effective.” Siri said, “A big reason that they pushed the Covid vaccine is [because] they said, ‘look, not everybody is gonna get – you know – seriously injured by Covid, but for many, it’ll prevent them from having symptoms, being hospitalized, missing work.’ Well, now that we have the data, we could see that getting the vaccine caused 25% of people who got the shot – within this data set of 10 million people – to miss work, to have some serious event affecting their normal life functions.

So far, 68.4% of the U.S. population has been fully vaccinated (as stated by Our World in Data). It’s difficult to determine just how many people have been negatively affected by the vaccine since the information on it seems to be suppressed. The CDC has not yet addressed the released documents, and the information is not available on their website. 

CDC Caught Using False Data To Recommend Kids’ COVID Vaccine

Authors: DYLAN HOUSMAN HEALTHCARE REPORTER June 27, 2022 Daily Caller

The Centers for Disease Control and Prevention (CDC) showcased highly misleading data about the risk of COVID-19 to kids when its expert vaccine advisers voted to recommend vaccines for children under five years old.

The agency featured a pre-print study ranking causes of death in children when it presented data to its Advisory Committee on Immunization Practices (ACIP) earlier this month, after which the committee voted to recommend kids aged six months through four years get vaccinated for COVID-19. The study claimed to show that COVID-19 was a leading cause of death for children in the United States during the coronavirus pandemic, but observers quickly pointed out major flaws in the data which rendered it misleading.

The paper ranks COVID-19 as a top six cause of death for age brackets from 0-19, including under one year old, 1-4 years old, 5-9 years old, 10-14 years old and 15-19 years old. It’s unclear why the authors include 18- and 19-year-olds in pediatric data. A majority of the researchers involved in the paper are from the United Kingdom, where the age of majority is 18 in most jurisdictions.

However, one misleading aspect of the paper, as first pointed out by covid-georgia.com, is that it ranks cumulative COVID-19 deaths alongside annual rates for other causes for death. For instance, in the 1-4 age group, the paper ranks cumulative COVID-19 deaths as the 5th leading cause of death, ahead of heart disease and influenza. But further down the list, it ranks annual COVID-19 deaths in eighth. For every single age group, the cumulative COVID-19 death rate is more than double the annualized death rate.

Another big issue with the CDC data presentation is the conflation of deaths caused directly by COVID-19 versus those for which COVID-19 was just a “contributing” factor. The authors state “we only consider Covid-19 as an underlying (and not contributing) cause of death,” but that is false. 

The paper cites data from the National Center for Health Statistics (NCHS), which tabulates COVID-19 deaths by including any death certificate on which COVID-19 is mentioned, not just cases where it was the primary reason for death. The NCHS data cited by the researchers claims there have been 1,433 pediatric COVID-19 deaths through April 30, 2022. However, the CDC’s own data, which counts only deaths where the virus was the underlying cause, reported 1,088 pediatric deaths during that time period. That’s nearly 25% lower.

When the data is annualized and only includes deaths where the virus was the underlying cause, COVID-19 does not rank as a leading cause of death for young children. For kids under one year old, it ranks 9th, behind influenza and pneumonia, heart disease and homicide. Accidents are about 25 times as likely to kill an infant than COVID-19, according to the CDC data.

Among kids aged 1-4 and 5-9, COVID-19 ranked in a four-way tie for the 8th leading cause of death. For ages 10-14 it ranked in a two-way tie for 8th. For teenagers between 15 and 19 years old, it dropped in the cause of death ranking from 4th to 6th.

The CDC did not respond to multiple requests for comment when asked why it presented this misleading data and how that study made it though the agency’s rigorous review process. The FDA did respond after multiple attempts at contact, stating that “FDA speakers in the June 14-15th meeting of the Vaccines and Related Biological Products Advisory Committee (VRBPAC) did not cite the study in question in their presentations. FDA’s press release announcing the authorizations explains the basis for our determinations.”

One author of the study, Dr. Seth Flaxman, a computer science professor at the Imperial College of London, tweeted after the flaws in the paper were brought to light that the team is working on a revised version to be shared soon. At the time of publication for this article, the revised study did not yet appear to be available. Flaxman did not respond to a request for comment.

The false numbers were parroted by a number of mainstream sources. The data was tweeted out by Trump-era Surgeon General Jerome Adams and former Planned Parenthood president turned CNN medical commentator Leana Wen. However, it was also criticized by a number of healthcare professionals, including Dr. Vinay Prasad.

Still, the CDC continues to recommend getting vaccinated for all American children older than six months.

SARS-CoV-2 and the Vaccination Hype

Authors: Piero Sangaletti Edge-Institute Austria at ER-System Mechatronics, Golling, Austria, Advisory Board of Concerned Scientists, Tampa, Florida USA, Antonietta GattiCofounder and Principal Investigator of Nanodiagnostics, SRL (Società a Responsabilità Limitata), Italy. Clemens Arvay Independent scientist and textbook author in Health Ecology, Vienna and Graz,

Abstract

The engineered spike protein of SARS-COV-2, and the corresponding infectious disease COVID-19 attributed to it, hold in their grip a large portion of humanity. The global race for a counter strategy quickly turned into a search for a vaccine as the preferred means to contain the virus. An unusually rapid development of different and completely new classes of experimental therapies that would widely be referred to as “vaccines” raised questions about safety, especially with regard to emergency use approval (EUA) being granted with unprecedented urgency and hardly any critical scrutiny. At present, independent researchers, even some former proponents and insiders, of the currently ongoing global experiment represented as a “vaccination” campaign point primarily to the lack of public safety studies based on empirical datasets that should be obtainable for the tens of millions, even hundreds of millions, of doses of mRNA and DNA vector therapeutics being distributed as “vaccines”. Studies regarding efficacy and “side effects” (sometimes fatalities or permanent iatrogenic injuries) of these experimental therapies have been by-passed in favor of short-term field data from real patients which inevitably raises scientific and ethical questions particularly in view of the fact that the persons and entities responsible for public safety hold deep financial and other vested interests in speeding along the distribution of the experimental pharmaceutical products. The lack of an open discussion about the experimental therapies for COVID-19 now being applied across all age groups, even children hardly impacted by COVID-19, is worrying. The core principle of open debate without pre-conceptions or vested interests in outcomes has been and continues to be utterly ignored. We hope to engage scientific discussion with the hope of helping decision-makers, the general public, and the media alike to consider the subject-matter of what is at stake in a context of reason rather than panic.

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HHS Secretary Becerra Claims COVID Vaccines ‘Kill People Of Color’ At ‘Twice The Rate Of Whites,’ Vows To ‘Work’ Harder To Get More People Vaccinated

Authors: Alicia Powe Published April 19, 2022

After months of mandates forcing people to get two and three doses of COVID-19 vaccines to keep their jobs attend, school, travel and enter indoor venues, the federal government admits the experimental gene modification shots are killing people.

While vowing to ramp up biomedical tyranny and the effort to get more Americans vaccinated, U.S. Health and Human Services Director Xavier Becerra Experimental claimed the “safe and effective” mRNA shots are killing people with dark skin at a much higher rate than those with light skin.

“By the way, we know that vaccines are killing people of color — blacks, Latinos, indigenous people — at about two times the rate of white Americans,” Becerra explained during a digital “White House Convening on Equity” seminar on April 14.

After months of mandates forcing people to get two and three doses of COVID-19 vaccines to keep their jobs attend, school, travel and enter indoor venues, the federal government admits the experimental gene modification shots are killing people.

While vowing to ramp up biomedical tyranny and the effort to get more Americans vaccinated, U.S. Health and Human Services Director Xavier Becerra Experimental claimed the “safe and effective” mRNA shots are killing people with dark skin at a much higher rate than those with light skin.

“By the way, we know that vaccines are killing people of color — blacks, Latinos, indigenous people — at about two times the rate of white Americans,” Becerra explained during a digital “White House Convening on Equity” seminar on April 14.

After acknowledging the lethality of COVID shots, Becerra explained that approximately 80 percent of the American public is vaccinated.

But the government needs to “work” harder to vaccinate Americans who have refrained from getting inoculated, he argued.

“So, on vaccines, last year, we saw that about two-thirds of white American adults had received at least one shot of vaccine,” Becerra said. “That was just barely over 50 percent for black Americans and Latinos at that particular time. So, again, we’ve got to work.

“Today, a year later, over 80 percent of white American adults have received at least one shot. Over 80% of black American adults have received at least one shot. Over 80 percent of Latino Americans have received at least one vaccine shot.”

While HHS acknowledges the deadly effects COVID vaccines have on minority communities, the Center for Disease Control and Prevention’s Vaccine Adverse Effects System confirms the COVID shots are killing more people than any other vaccine in history.

According to VAERS, only 421 vaccine-related deaths in 2020 prior to the administration of the mRNA shots. In 2021, the number of people who dies after getting vaccinated precipitously spiked with at least 21,914 people died after receiving the COVID shots.

As yet, 5689 people died after receiving a COVID vaccine in 2022.

Meanwhile, the CDC is deploying fleets of federally funded “pandemic” buses to minority communities across the nation to persuade unvaccinated Americans into getting jabbed.

As reported, the CDC’s PANDEMIC (Program to Alleviate National Disparities in Ethnic and Minority Immunizations in the Community) deploys teams of health care workers into minority communities to educate people about why they need to be vaccinated.

According to PANDEMIC grant program materials, PANDEMIC’s goal is to reach groups that may experience “immunization disparities” in racial and ethnic minorities, residents of rural communities, migrant farmworkers, Native Americans, Hispanics, Blacks, and people identifying as part of the LGBTQ community and boost vaccination rates in areas chosen for having “high vaccine-hesitancy rate. ”

“If people aren’t sure [that they want the vaccine], then we have educational materials, and our community health workers and the extension agents will talk to them about their particular questions and try to answer their questions and their concerns. And then…[we] immediately give them the vaccine,” explained Catherine Striley of the University of Florida, who helps oversee the PANDEMIC project.

Worse Than the Disease? Reviewing Some Possible Unintended Consequences of the mRNA Vaccines Against COVID-19

Authors: Stephanie Seneff Computer Science and Artificial Intelligence Laboratory, MIT, Cambridge MA, 02139, USA, Greg Nigh Naturopathic Oncology, Immersion Health, Portland, OR 97214, USA International Journal of Vaccine Theory, Practice, and Research

Abstract

Operation Warp Speed brought to market in the United States two mRNA vaccines, produced by Pfizer and Moderna. Interim data suggested high efficacy for both of these vaccines, which helped legitimize Emergency Use Authorization (EUA) by the FDA. However, the exceptionally rapid movement of these vaccines through controlled trials and into mass deployment raises multiple safety concerns. In this review we first describe the technology underlying these vaccines in detail. We then review both components of and the intended biological response to these vaccines, including production of the spike protein itself, and their potential relationship to a wide range of both acute and long-term induced pathologies, such as blood disorders, neurodegenerative diseases and autoimmune diseases. Among these potential induced pathologies, we discuss the relevance of prion-protein-related amino acid sequences within the spike protein. We also present a brief review of studies supporting the potential for spike protein “shedding”, transmission of the protein from a vaccinated to an unvaccinated person, resulting in symptoms induced in the latter. We finish by addressing a common point of debate, namely, whether or not these vaccines could modify the DNA of those receiving the vaccination. While there are no studies demonstrating definitively that this is happening, we provide a plausible scenario, supported by previously established pathways for transformation and transport of genetic material, whereby injected mRNA could ultimately be incorporated into germ cell DNA for transgenerational transmission. We conclude with our recommendations regarding surveillance that will help to clarify the long-term effects of these experimental drugs and allow us to better assess the true risk/benefit ratio of these novel technologies.

How Vaccine Messaging Confused The Public

Authors: John Gibson the Brownstone Institute 

Pivotal randomized control trials (RCTs) underpinning approval of Covid-19 vaccines did not set out to, and did not, test if the vaccines prevent transmission of the SARS-CoV-2 virus. Nor did the trials test if the vaccines reduce mortality risk. A review of seven phase III trials, including those for Moderna, Pfizer/BioNTech and AstraZeneca vaccines, found the criterion the vaccines were trialled against was just reduced risk of Covid-19 symptoms

There should be no secret about these facts, as they were discussed in August 2020 in the BMJ (formerly the British Medical Journal); one of the oldest and most widely cited medical journals in the world. Moreover, this was not an isolated article, as the editor-in-chief also gave her own summary of the vaccine-testing situation, which has proved very prescient:

“…we are heading for vaccines that reduce severity of illness rather than protect against infection [and] provide only short-lived immunity, … as well as damaging public confidence and wasting global resources by distributing a poorly effective vaccine, this could change what we understand a vaccine to be. Instead of long-term, effective disease prevention it could become a suboptimal chronic treatment.”It was not just the BMJ covering these features of the RCTs. When health bureaucrats Rochelle Walensky, Henry Walke and Anthony Fauci claimed (in the Journal of the American Medical Association) that “clinical trials have shown that the vaccines authorized for use in the US are highly effective against Covid-19 infection, severe illness and death” this was felt sufficiently false that the journal published a comment simply titled “Inaccurate Statement.”

The basis of the comment was that the primary endpoint for the RCTs was symptoms of Covid-19; a less exacting standard than testing to show efficacy against infection, severe illness, and death.

Yet these aspects of the vaccine trials discussed in medical journals are largely unknown by the general public. To measure public understanding of the Covid-19 vaccine trials I added a question about the vaccine testing to an ongoing nationally representative survey of adult New Zealanders.

While not top-of-mind for most readers, New Zealand is a useful place for finding out about public understanding of the vaccine trials. Until recently, when a few doses of AstraZeneca and Novavax vaccines were allowed, it was 100% Pfizer, making it easy to word the survey question very specifically about the Pfizer vaccine trials.

Also, New Zealanders were vaccinated in a very short period, just prior to the survey. In late August 2021 New Zealand was last in the OECD in dosing rates but by December, when the survey was fielded, it had jumped into the top half of the OECD, with vaccinations rising by an average of 110 doses per 100 people in just over three months. 

This rapid rise in vaccination was partly driven by mandates, for health, education, police, and emergency workers and also by a vaccine passport system that blocked the unvaccinated from most places. The mandates were strictly applied, and even people suffering adverse reactions after their first shot, such as Bell’s Palsy and pericarditis, still had to get the second shot. The vaccine passport law had gone through Parliament just prior to the survey, so the vaccines, and what was expected of them, should have been utmost in peoples’ minds. 

The other relevant factor about New Zealand is the government-dominated media, which is either publicly funded, or is heavily subsidized by a “public interest journalism fund” and by generous government advertising of the Covid-19 vaccines. Also, supposedly independent commentators prominent in the media got their talking points about the vaccines from the government in a carefully orchestrated public relations campaign. 

Thus, it was mainly overseas journalists who expressed concern when New Zealand’s Prime Minister made the Orwellian claim that in matters of Covid-19 and vaccines: “Dismiss anything else, we will continue to be your single source of truth.”

Yet a government-controlled media and a vaccine advertising blitz yielded widespread public misunderstanding about the testing the vaccines underwent in pivotal trials. The survey asked if the Pfizer vaccine had been trialled against: (a) preventing infection and transmission of SARS-CoV-2, or (b) reducing risk of getting symptoms of Covid-19, or (c) reducing risk of getting serious sick or dying, or (d) all of the above. The correct answer is (b), the trials only set out to test if the vaccines reduced the risk of getting Covid-19 symptoms.

Only four percent of respondents got the right answer. In other words, 96 percent of adult New Zealanders thought the Covid-19 vaccines were tested against more demanding criteria than is actually the case. 

Currently, most Covid-19 cases in New Zealand are post-vaccination. And despite almost everyone being vaccinated, and most boosted, the rate of new confirmed Covid-19 cases is one of the highest in the world. As people see with their own eyes that one can still get infected they may question what they have been led to (mis)understand about the vaccines.

Elsewhere it is noted that vaccine fanaticism—especially denying natural immunity—fuels vaccine scepticism. As people see that public health authorities lied about natural immunity they will wonder if they also lied about vaccine efficacy. Likewise, as they realise they were given a misleading impression about what the vaccines were trialled against they might doubt other claims about vaccines.

In particular, by believing the vaccines were tested against more demanding criteria than was actually so, public expectations of what vaccination would achieve were likely too high. As the public witnesses a failure of mass vaccination to prevent SARS-CoV-2 infections, and a failure to reduce overall mortality, scepticism about these and other vaccines will grow.

In New Zealand this issue is exacerbated by the Prime Minister creating a false equivalence between Covid-19 vaccines and measles vaccines. Currently the paediatric vaccination rate (which includes the measles vaccine) for indigenous Maori has dropped 12 percentage points in two years and 0.3 million measles vaccines had to be discarded after expiring due to lack of demand. The advertising for Covid-19 vaccines particularly targets Maori, with claims that boosters will protect them against Omicron. The progress of infections is likely to prove this claim to be largely untrue, and so Maori are likely to be even more sceptical about future vaccination, even for vaccines that truly can be described as ‘safe and effective.’

If politicians and health bureaucrats had been honest with the public, setting out the criteria the Covid-19 vaccines were trialed against, and what could and could not be expected of the vaccines, then this widespread misunderstanding need not have occurred. Instead, their lack of honesty is likely to damage future vaccination efforts and harm public health.

Pfizer Hired 600 Employees Due To ‘Large Increase In Adverse Event

Authors: Zachary Stieb The Epoch Times  March 9, 2022

Pfizer hired 600 employees in the months after its COVID-19 vaccine was authorized in the United States due to the “large increase” of reports of side effects linked to the vaccine, according to a document prepared by the company.

Pfizer has “taken multiple actions to help alleviate the large increase in adverse event reports,” according to the document. “This includes significant technology enhancements, and process and workflow solutions, as well as increasing the number of data entry and case processing colleagues.”

At the time when the document—from the first quarter of 2021—was sent to the U.S. Food and Drug Administration (FDA), Pfizer had onboarded about 600 extra full-time workers to deal with the jump.

“More are joining each month with an expected total of more than 1,800 additional resources by the end of June 2021,” Pfizer said.

The document was titled a “cumulative analysis of post-authorization adverse event reports” of Pfizer’s vaccine received through Feb. 28, 2021. It was approved by the FDA on April 30, 2021.

The document was not made public until the Public Health and Medical Professionals for Transparency sued the FDA after the agency claimed it needed decades to produce all the documents relating to the emergency use authorization granted to the company for the vaccine.

Under an agreement reached in February, the FDA must produce a certain number of pages each month.

The analysis of adverse event reports was previously disclosed to the health transparency group, but certain portions were redacted (pdf), including the number of workers Pfizer onboarded to deal with the jump in adverse event reports.

“We asked that the redactions on page 6 of this report be lifted and the FDA agreed without providing an explanation,” Aaron Siri, a lawyer representing the plaintiffs, told The Epoch Times in an email.

After the document was produced, the FDA determined that the three redactions on that page “could be lifted,” an FDA spokesperson told The Epoch Times via email.

The redactions had been made under (b) (4) of the Freedom of Information Act, which lets agencies “withhold trade secrets and commercial or financial information obtained from a person which is privileged or confidential.”

The unredacted version of the document also now shows that approximately 126 million doses of Pfizer were shipped around the world since the company received the first clearance, from U.S. regulators, on Dec. 1, 2020. The shipments took place through Feb. 28, 2021.

It was unclear how many of those doses had been administered as of that date.

Pfizer did not respond to emailed questions, including how many workers it has onboarded to deal with adverse events.

The companies that manufacture the other two COVID-19 vaccines that U.S. regulators have cleared, Moderna and Johnson & Johnson, did not respond when asked if they have seen an increase in adverse events and if they have hired more employees to deal with reports.

The number of post-vaccination adverse event reports to the Vaccine Adverse Event Reporting System, jointly run by the FDA and the Centers for Disease Control and Prevention, has spiked since the vaccines were first cleared.

Problems linked to the vaccines include heart inflammation, blood clotting, and severe allergic shock.

Federal officials say the vaccines’ benefits outweigh the risks, but some experts are increasingly questioning that assertion, particularly for certain populations.