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.

Go to:

References

1. Jin J., et al. Individual and community-level risk for COVID-19 mortality in the United States. Nat. Med. 2021;27:264–269. [PubMed] [Google Scholar]

2. O’Driscoll M., et al. Age-specific mortality and immunity patterns of SARS-CoV-2. Nature. 2021;590:140–145. [PubMed] [Google Scholar]

3. Gaebler C., et al. Evolution of antibody immunity to SARS-CoV-2. Nature. 2021;591:639–644. [PMC free article] [PubMed] [Google Scholar]

4. Andersson M.I., et al. SARS-CoV-2 RNA detected in blood products from patients with COVID-19 is not associated with infectious virus. Wellcome Open Res. 2020;5:181. [PMC free article] [PubMed] [Google Scholar]

5. Wang W., et al. Detection of SARS-CoV-2 in different types of clinical specimens. JAMA. 2020;323:1843–1844. [PMC free article] [PubMed] [Google Scholar]

6. Wölfel R., et al. Virological assessment of hospitalized patients with COVID-2019. Nature. 2020;581:465–469. [PubMed] [Google Scholar]

7. Chen G., et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J. Clin. Invest. 2020;130:2620–2629. [PMC free article] [PubMed] [Google Scholar]

8. Deinhardt-Emmer S., et al. Early postmortem mapping of SARS-CoV-2 RNA in patients with COVID-19 and the correlation with tissue damage. eLife. 2021;10 [PMC free article] [PubMed] [Google Scholar]

9. Fajnzylber J., et al. SARS-CoV-2 viral load is associated with increased disease severity and mortality. Nat. Commun. 2020;11:5493. [PMC free article] [PubMed] [Google Scholar]

10. Gupta A., et al. Extrapulmonary manifestations of COVID-19. Nat. Med. 2020;26:1017–1032. [PubMed] [Google Scholar]

11. Andreakos E., et al. A global effort to dissect the human genetic basis of resistance to SARS-CoV-2 infection. Nat. Immunol. 2022;23:159–164. [PMC free article] [PubMed] [Google Scholar]

12. Galani I.-E., et al. Untuned antiviral immunity in COVID-19 revealed by temporal type I/III interferon patterns and flu comparison. Nat. Immunol. 2021;22:32–40. [PubMed] [Google Scholar]

13. Trougakos I.P., et al. Insights to SARS-CoV-2 life cycle, pathophysiology, and rationalized treatments that target COVID-19 clinical complications. J. Biomed. Sci. 2021;28:9. [PMC free article] [PubMed] [Google Scholar]

14. Gkogkou E., et al. Expression profiling meta-analysis of ACE2 and TMPRSS2, the putative anti-inflammatory receptor and priming protease of SARS-CoV-2 in human cells, and identification of putative modulators. Redox Biol. 2020;36 [PMC free article] [PubMed] [Google Scholar]

15. Muus C., et al. Single-cell meta-analysis of SARS-CoV-2 entry genes across tissues and demographics. Nat. Med. 2021;27:546–559. [PMC free article] [PubMed] [Google Scholar]

16. Ziegler C.G.K., et al. SARS-CoV-2 Receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues. Cell. 2020;181:1016–1035. [PMC free article] [PubMed] [Google Scholar]

17. Blomberg B., et al. Long COVID in a prospective cohort of home-isolated patients. Nat. Med. 2021;27:1607–1613. [PMC free article] [PubMed] [Google Scholar]

18. Martínez-Flores D., et al. SARS-CoV-2 vaccines based on the spike glycoprotein and implications of new viral variants. Front. Immunol. 2021;12 [PMC free article] [PubMed] [Google Scholar]

19. Jackson C.B., et al. Mechanisms of SARS-CoV-2 entry into cells. Nat. Rev. Mol. Cell Biol. 2022;23:3–20. [PMC free article] [PubMed] [Google Scholar]

20. Heinz F.X., Stiasny K. Distinguishing features of current COVID-19 vaccines: knowns and unknowns of antigen presentation and modes of action. NPJ Vaccines. 2021;6:104. [PMC free article] [PubMed] [Google Scholar]

21. European Medicines Agency . European Medicines Agency; 2021. Comirnaty Assessment Report COVID-19 Vaccine Comirnaty. EMA/707383/2020 Corr.1*1. [Google Scholar]

22. European Medicines Agency . European Medicines Agency; 2021. Moderna Assessment Report COVID-19 Vaccine Moderna. EMA/15689/2021 Corr.1*1. [Google Scholar]

23. Moghimi S.M. Allergic reactions and anaphylaxis to LNP-based COVID-19 vaccines. Mol. Ther. 2021;29:898–900. [PMC free article] [PubMed] [Google Scholar]

24. Igyártó B.Z., et al. Future considerations for the mRNA–lipid nanoparticle vaccine platform. Curr. Opin. Virol. 2021;48:65–72. [PMC free article] [PubMed] [Google Scholar]

25. Chaudhary N., et al. mRNA vaccines for infectious diseases: principles, delivery and clinical translation. Nat. Rev. Drug Discov. 2021;20:817–838. [PMC free article] [PubMed] [Google Scholar]

26. Chung Y.H., et al. COVID-19 vaccine frontrunners and their nanotechnology design. ACS Nano. 2020;14:12522–12537. [PMC free article] [PubMed] [Google Scholar]

27. Pegu A., et al. Durability of mRNA-1273 vaccine-induced antibodies against SARS-CoV-2 variants. Science. 2021;373:1372–1377. [PMC free article] [PubMed] [Google Scholar]

28. Sahin U., et al. BNT162b2 vaccine induces neutralizing antibodies and poly-specific T cells in humans. Nature. 2021;595:572–577. [PubMed] [Google Scholar]

29. Trougakos I.P., et al. Comparative kinetics of SARS-CoV-2 anti-spike protein RBD IgGs and neutralizing antibodies in convalescent and naïve recipients of the BNT162b2 mRNA vaccine versus COVID-19 patients. BMC Med. 2021;19:208. [PMC free article] [PubMed] [Google Scholar]

30. Gagne M., et al. Protection from SARS-CoV-2 Delta one year after mRNA-1273 vaccination in rhesus macaques coincides with anamnestic antibody response in the lung. Cell. 2022;185:113–130. [PMC free article] [PubMed] [Google Scholar]

31. Barda N., et al. Safety of the BNT162b2 mRNA Covid-19 vaccine in a nationwide setting. N. Engl. J. Med. 2021;385:1078–1090. [PMC free article] [PubMed] [Google Scholar]

32. García-Grimshaw M., et al. Neurologic adverse events among 704,003 first-dose recipients of the BNT162b2 mRNA COVID-19 vaccine in Mexico: a nationwide descriptive study. Clin. Immunol. 2021;229 [PMC free article] [PubMed] [Google Scholar]

33. Klein N.P., et al. Surveillance for adverse events after COVID-19 mRNA vaccination. JAMA. 2021;326:1390–1399. [PMC free article] [PubMed] [Google Scholar]

34. Patone M., et al. Neurological complications after first dose of COVID-19 vaccines and SARS-CoV-2 infection. Nat. Med. 2021;27:2144–2153. [PMC free article] [PubMed] [Google Scholar]

35. Li X., et al. Characterizing the incidence of adverse events of special interest for COVID-19 vaccines across eight countries: a multinational network cohort study. BMJ. 2021;373 [PMC free article] [PubMed] [Google Scholar]

36. Oster M.E., et al. Myocarditis cases reported after mRNA-based COVID-19 vaccination in the US From December 2020 to August 2021. JAMA. 2022;327:331–340. [PMC free article] [PubMed] [Google Scholar]

37. Montgomery J., et al. Myocarditis following immunization with mRNA COVID-19 vaccines in members of the US military. JAMA Cardiol. 2021;6:1202–1206. [PMC free article] [PubMed] [Google Scholar]

38. Hoeg T., et al. SARS-CoV-2 mRNA vaccination-associated myocarditis in children ages 12–17: a stratified national database analysis. medRxiv. 2021 doi: 10.1101/2021.08.30.21262866. Published online September 8, 2021. [CrossRef] [Google Scholar]

39. Li X., et al. Myocarditis following COVID-19 BNT162b2 vaccination among adolescents in Hong Kong. JAMA Pediatr. 2022 doi: 10.1001/jamapediatrics.2022.0101. Published online February 25, 2022. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

40. Verbeke R., et al. Three decades of messenger RNA vaccine development. Nanotoday. 2019;28 [Google Scholar]

41. Ndeupen S., et al. The mRNA–LNP platform’s lipid nanoparticle component used in preclinical vaccine studies is highly inflammatory. iScience. 2021;24 [PMC free article] [PubMed] [Google Scholar]

42. Parhiz H., et al. Added to pre-existing inflammation, mRNA–lipid nanoparticles induce inflammation exacerbation (IE) J. Control. Release. 2021;344:50–61. [PMC free article] [PubMed] [Google Scholar]

43. Yang R., et al. A core–shell structured COVID-19 mRNA vaccine with favorable biodistribution pattern and promising immunity. Signal Transduct. Target Ther. 2021;6:213. [PMC free article] [PubMed] [Google Scholar]

44. Pardi N., et al. Expression kinetics of nucleoside-modified mRNA delivered in lipid nanoparticles to mice by various routes. J. Control. Release. 2015;217:345–351. [PMC free article] [PubMed] [Google Scholar]

45. Hassett K.J., et al. Optimization of lipid nanoparticles for intramuscular administration of mRNA vaccines. Mol. Ther. Nucleic Acids. 2019;15:1–11. [PMC free article] [PubMed] [Google Scholar]

46. Ogata A.F., et al. Circulating SARS-CoV-2 vaccine antigen detected in the plasma of mRNA-1273 vaccine recipients. Clin. Infect. Dis. 2021;74:715–718. [PMC free article] [PubMed] [Google Scholar]

47. Bansal S., et al. Cutting edge: circulating exosomes with COVID spike protein are induced by BNT162b2 (Pfizer-BioNTech) vaccination prior to development of antibodies: a novel mechanism for immune activation by mRNA vaccines. J. Immunol. 2021;207:2405–2410. [PubMed] [Google Scholar]

48. Cognetti J.S., Miller B.L. Monitoring serum spike protein with disposable photonic biosensors following SARS-CoV-2 vaccination. Sensors (Basel) 2021;21:5827. [PMC free article] [PubMed] [Google Scholar]

49. Goel R.R., et al. mRNA vaccines induce durable immune memory to SARS-CoV-2 and variants of concern. Science. 2021;374 [PMC free article] [PubMed] [Google Scholar]

50. Terpos E., et al. Sustained but declining humoral immunity against SARS-CoV-2 at 9 months postvaccination with BNT162b2: a prospective evaluation in 309 healthy individuals. Hemasphere. 2022;6 [PMC free article] [PubMed] [Google Scholar]

51. Watanabe Y., et al. Native-like SARS-CoV-2 spike glycoprotein expressed by ChAdOx1 nCoV-19/AZD1222 vaccine. ACS Cent. Sci. 2021;7:594–602. [PMC free article] [PubMed] [Google Scholar]

52. Li Y., et al. Linear epitope landscape of the SARS-CoV-2 spike protein constructed from 1,051 COVID-19 patients. Cell Rep. 2021;34 [PMC free article] [PubMed] [Google Scholar]

53. Hwa K.-Y., et al. Peptide mimicrying between SARS coronavirus spike protein and human proteins reacts with SARS patient serum. J. Biomed. Biotechnol. 2008;2008 [PMC free article] [PubMed] [Google Scholar]

54. Kanduc D., Shoenfeld Y. Molecular mimicry between SARS-CoV-2 spike glycoprotein and mammalian proteomes: implications for the vaccine. Immunol. Res. 2020;68:310–313. [PMC free article] [PubMed] [Google Scholar]

55. O’Donoghue S.I., et al. SARS-CoV-2 structural coverage map reveals viral protein assembly, mimicry, and hijacking mechanisms. Mol. Syst. Biol. 2021;17 [PMC free article] [PubMed] [Google Scholar]

56. Kowarz E., et al. Vaccine-induced COVID-19 mimicry syndrome. eLife. 2022;11 [PMC free article] [PubMed] [Google Scholar]

57. Kreye J., et al. A therapeutic non-self-reactive SARS-CoV-2 antibody protects from lung pathology in a COVID-19 hamster model. Cell. 2020;183:1058–1069. [PMC free article] [PubMed] [Google Scholar]

58. Freitas R.S., et al. SARS-CoV-2 spike antagonizes innate antiviral immunity by targeting interferon regulatory factor 3. Front. Cell. Infect. Microbiol. 2021;11 [PMC free article] [PubMed] [Google Scholar]

59. Visvabharathy L., et al. Neuro-COVID long-haulers exhibit broad dysfunction in T cell memory generation and responses to vaccination. medRxiv. 2021 doi: 10.1101/2021.08.08.21261763. Published online October 29, 2021. [CrossRef] [Google Scholar]

60. Murphy W.J., Longo D.L. A possible role for anti-idiotype antibodies in SARS-CoV-2 infection and vaccination. N. Engl. J. Med. 2022;386:394–396. [PubMed] [Google Scholar]

61. Zuo Y., et al. Prothrombotic autoantibodies in serum from patients hospitalized with COVID-19. Sci. Transl. Med. 2020;12 [PMC free article] [PubMed] [Google Scholar]

62. Wang E.Y., et al. Diverse functional autoantibodies in patients with COVID-19. Nature. 2021;595:283–288. [PubMed] [Google Scholar]

63. Arunachalam P.S., et al. Systems vaccinology of the BNT162b2 mRNA vaccine in humans. Nature. 2021;596:410–416. [PMC free article] [PubMed] [Google Scholar]

64. Terpos E., et al. Third dose of the BNT162b2 vaccine results in very high levels of neutralizing antibodies against SARS-CoV-2: results of a prospective study in 150 health professionals in Greece. Am. J. Hematol. 2022;97:E147–E150. [PMC free article] [PubMed] [Google Scholar]

65. Wheatley A.K., et al. Immune imprinting and SARS-CoV-2 vaccine design. Trends Immunol. 2021;42:956–959. [PMC free article] [PubMed] [Google Scholar]

66. Röltgen K. Immune imprinting, breadth of variant recognition and germinal center response in human SARS-CoV-2 infection and vaccination. Cell. 2022;185:1025–1040. [PMC free article] [PubMed] [Google Scholar]

67. Deshotels M.R., et al. Angiotensin II mediates angiotensin converting enzyme type 2 internalization and degradation through an angiotensin II type I receptor-dependent mechanism. Hypertension. 2014;64:1368–1375. [PMC free article] [PubMed] [Google Scholar]

68. Ramos S.G., et al. ACE2 Down-regulation may act as a transient molecular disease causing RAAS dysregulation and tissue damage in the microcirculatory environment among COVID-19 patients. Am. J. Pathol. 2021;191:1154–1164. [PMC free article] [PubMed] [Google Scholar]

69. Yeung M.L., et al. Soluble ACE2-mediated cell entry of SARS-CoV-2 via interaction with proteins related to the renin–angiotensin system. Cell. 2021;184:2212–2228. [PMC free article] [PubMed] [Google Scholar]

70. Ferrario C.M., et al. Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2. Circulation. 2005;111:2605–2610. [PubMed] [Google Scholar]

71. Yang J., et al. Pathological Ace2-to-Ace enzyme switch in the stressed heart is transcriptionally controlled by the endothelial Brg1-FoxM1 complex. Proc. Natl. Acad. Sci. U. S. A. 2016;113:E5628–E5635. [PMC free article] [PubMed] [Google Scholar]

72. McCracken I.R., et al. Lack of evidence of angiotensin-converting enzyme 2 expression and replicative infection by SARS-CoV-2 in human endothelial cells. Circulation. 2021;143:865–868. [PMC free article] [PubMed] [Google Scholar]

73. Nicosia R.F., et al. COVID-19 vasculopathy: mounting evidence for an indirect mechanism of endothelial injury. Am. J. Pathol. 2021;191:1374–1384. [PMC free article] [PubMed] [Google Scholar]

74. Coate K.C., et al. SARS-CoV-2 cell entry factors ACE2 and TMPRSS2 are expressed in the microvasculature and ducts of human pancreas but are not enriched in β cells. Cell Metab. 2020;32:1028–1040. [PMC free article] [PubMed] [Google Scholar]

75. Nuovo G.J., et al. Endothelial cell damage is the central part of COVID-19 and a mouse model induced by injection of the S1 subunit of the spike protein. Ann. Diagn. Pathol. 2021;51 [PMC free article] [PubMed] [Google Scholar]

76. Lei Y., et al. SARS-CoV-2 spike protein impairs endothelial function via downregulation of ACE 2. Circ. Res. 2021;128:1323–1326. [PMC free article] [PubMed] [Google Scholar]

77. Raghavan S., et al. SARS-CoV-2 spike protein induces degradation of junctional proteins that maintain endothelial barrier integrity. Front Cardiovasc. Med. 2021;8 [PMC free article] [PubMed] [Google Scholar]

78. Colunga Biancatelli R.M.L., et al. The SARS-CoV-2 spike protein subunit S1 induces COVID-19-like acute lung injury in Κ18-hACE2 transgenic mice and barrier dysfunction in human endothelial cells. Am. J. Physiol. Lung Cell Mol. Physiol. 2021;321:L477–L484. [PMC free article] [PubMed] [Google Scholar]

79. Avolio E., et al. The SARS-CoV-2 spike protein disrupts human cardiac pericytes function through CD147 receptor-mediated signalling: a potential non-infective mechanism of COVID-19 microvascular disease. Clin. Sci. (Lond.) 2021;135:2667–2689. [PMC free article] [PubMed] [Google Scholar]

80. Panigrahi S., et al. SARS-CoV-2 spike protein destabilizes microvascular homeostasis. Microbiol. Spectr. 2021;9 [PMC free article] [PubMed] [Google Scholar]

81. Clausen T.M., et al. SARS-CoV-2 infection depends on cellular heparan sulfate and ACE2. Cell. 2020;183:1043–1057. [PMC free article] [PubMed] [Google Scholar]

82. Partridge L.J., et al. ACE2-independent interaction of SARS-CoV-2 spike protein with human epithelial cells is inhibited by unfractionated heparin. Cells. 2021;10:1419. [PMC free article] [PubMed] [Google Scholar]

83. Zheng Y., et al. SARS-CoV-2 spike protein causes blood coagulation and thrombosis by competitive binding to heparan sulfate. Int. J. Biol. Macromol. 2021;193:1124–1129. [PMC free article] [PubMed] [Google Scholar]

84. Zhang S., et al. SARS-CoV-2 binds platelet ACE2 to enhance thrombosis in COVID-19. J. Hematol. Oncol. 2020;13:120. [PMC free article] [PubMed] [Google Scholar]

85. Jana S., et al. Cell-free hemoglobin does not attenuate the effects of SARS-CoV-2 spike protein S1 subunit in pulmonary endothelial cells. Int. J. Mol. Sci. 2021;22:9041. [PMC free article] [PubMed] [Google Scholar]

86. Ryu J.K., et al. SARS-CoV-2 spike protein induces abnormal inflammatory blood clots neutralized by fibrin immunotherapy. bioRxiv. 2021 doi: 10.1101/2021.10.12.464152. Published online October 13, 2021. [CrossRef] [Google Scholar]

87. Terpos E., et al. High prevalence of anti-PF4 antibodies following ChAdOx1 nCov-19 (AZD1222) vaccination even in the absence of thrombotic events. Vaccines. 2021;9:712. [PMC free article] [PubMed] [Google Scholar]

88. Cattin-Ortolá J., et al. Sequences in the cytoplasmic tail of SARS-CoV-2 spike facilitate expression at the cell surface and syncytia formation. Nat. Commun. 2021;12:5333. [PMC free article] [PubMed] [Google Scholar]

89. Rajah M.M., et al. SARS-CoV-2 Alpha, Beta, and Delta variants display enhanced spike-mediated syncytia formation. EMBO J. 2021;40 [PMC free article] [PubMed] [Google Scholar]

90. Cheng Y.-W., et al. D614G substitution of SARS-CoV-2 spike protein increases syncytium formation and virus titer via enhanced furin-mediated spike cleavage. mBio. 2021;12 [PMC free article] [PubMed] [Google Scholar]

91. Correa Y., et al. SARS-CoV-2 spike protein removes lipids from model membranes and interferes with the capacity of high-density lipoprotein to exchange lipids. J. Colloid Interface Sci. 2021;602:732–739. [PMC free article] [PubMed] [Google Scholar]

92. Jiang H., Mei Y.-F. SARS-CoV-2 spike impairs DNA damage repair and inhibits V(D)J recombination in vitroViruses. 2021;13:2056. [PMC free article] [PubMed] [Google ScholarRetracted

93. Lai Y.-J., et al. Epithelial–mesenchymal transition induced by SARS-CoV-2 required transcriptional upregulation of Snail. Am. J. Cancer Res. 2021;11:2278–2290. [PMC free article] [PubMed] [Google Scholar]

94. Hsu J.T.-A., et al. The effects of Aβ(1–42) binding to the SARS-CoV-2 spike protein S1 subunit and angiotensin-converting enzyme 2. Int. J. Mol. Sci. 2021;22:8226. [PMC free article] [PubMed] [Google Scholar]

95. Chen R., et al. The spatial and cell-type distribution of SARS-CoV-2 receptor ACE2 in the human and mouse brains. Front. Neurol. 2020;11 [PMC free article] [PubMed] [Google Scholar]

96. Rhea E.M., et al. The S1 protein of SARS-CoV-2 crosses the blood–brain barrier in mice. Nat. Neurosci. 2021;24:368–378. [PMC free article] [PubMed] [Google Scholar]

97. DeOre B.J., et al. SARS-CoV-2 spike protein disrupts blood–brain barrier integrity via RhoA activation. J. NeuroImmune Pharmacol. 2021;16:722–728. [PMC free article] [PubMed] [Google Scholar]

98. Welch J.L., et al. T-cell expression of angiotensin-converting enzyme 2 and binding of severe acute respiratory coronavirus 2. J. Infect. Dis. 2022;225:810–819. [PMC free article] [PubMed] [Google Scholar]

99. Barreda D., et al. SARS-CoV-2 spike protein and its receptor binding domain promote a proinflammatory activation profile on human dendritic cells. Cells. 2021;10:3279. [PMC free article] [PubMed] [Google Scholar]

100. Maldonado M.D., Romero-Aibar J. The Pfizer-BNT162b2 mRNA-based vaccine against SARS-CoV-2 may be responsible for awakening the latency of herpes varicella-zoster virus. Brain Behav. Immun. Health. 2021;18 [PMC free article] [PubMed] [Google Scholar]

101. Psichogiou M., et al. Reactivation of varicella zoster virus after vaccination for SARS-CoV-2. Vaccines. 2021;9:572. [PMC free article] [PubMed] [Google Scholar]

102. Kim E.S., et al. Spike proteins of SARS-CoV-2 induce pathological changes in molecular delivery and metabolic function in the brain endothelial cells. Viruses. 2021;13:2021. [PMC free article] [PubMed] [Google Scholar]

103. Kumar N., et al. SARS-CoV-2 spike protein S1-mediated endothelial injury and pro-inflammatory state is amplified by dihydrotestosterone and prevented by mineralocorticoid antagonism. Viruses. 2021;13:2209. [PMC free article] [PubMed] [Google Scholar]

104. Rahman M., et al. Differential effect of SARS-CoV-2 spike glycoprotein 1 on human bronchial and alveolar lung mucosa models: implications for pathogenicity. Viruses. 2021;13:2537. [PMC free article] [PubMed] [Google Scholar]

105. Li F., et al. SARS-CoV-2 spike promotes inflammation and apoptosis through autophagy by ROS-suppressed PI3K/AKT/mTOR signaling. Biochim. Biophys. Acta Mol. basis Dis. 2021;1867 [PMC free article] [PubMed] [Google Scholar]

106. Meyer K., et al. SARS-CoV-2 spike protein induces paracrine senescence and leukocyte adhesion in endothelial cells. J. Virol. 2021;95 [PMC free article] [PubMed] [Google Scholar]

107. Zhu G., et al. SARS-CoV-2 spike protein-induced host inflammatory response signature in human corneal epithelial cells. Mol. Med. Rep. 2021;24:584. [PubMed] [Google Scholar]

108. Ntouros P.A., et al. Effective DNA damage response after acute but not chronic immune challenge: SARS-CoV-2 vaccine versus systemic lupus erythematosus. Clin. Immunol. 2021;229 [PMC free article] [PubMed] [Google Scholar]

109. Petruk G., et al. SARS-CoV-2 spike protein binds to bacterial lipopolysaccharide and boosts proinflammatory activity. J. Mol. Cell Biol. 2020;12:916–932. [PMC free article] [PubMed] [Google Scholar]

110. Tumpara S., et al. Boosted pro-inflammatory activity in human PBMCs by LIPOPOLYSACCHARIDE and SARS-CoV-2 spike protein is regulated by α-1 antitrypsin. Int. J. Mol. Sci. 2021;22:7941. [PMC free article] [PubMed] [Google Scholar]

111. Olajide O.A., et al. SARS-CoV-2 spike glycoprotein S1 induces neuroinflammation in BV-2 microglia. Mol. Neurobiol. 2022;59:445–458. [PMC free article] [PubMed] [Google Scholar]

112. Moutal A., et al. SARS-CoV-2 spike protein co-opts VEGF-A/neuropilin-1 receptor signaling to induce analgesia. Pain. 2021;162:243–252. [PMC free article] [PubMed] [Google Scholar]

113. Khan S., et al. SARS-CoV-2 spike protein induces inflammation via TLR2-dependent activation of the NF-κB pathway. eLife. 2021;10 [PMC free article] [PubMed] [Google Scholar]

114. Cheng M.H., et al. Superantigenic character of an insert unique to SARS-CoV-2 spike supported by skewed TCR repertoire in patients with hyperinflammation. Proc. Natl. Acad. Sci. U. S. A. 2020;117:25254–25262. [PMC free article] [PubMed] [Google Scholar]

115. Cao X., et al. Spike protein of SARS-CoV-2 activates macrophages and contributes to induction of acute lung inflammation in male mice. FASEB J. 2021;35 [PMC free article] [PubMed] [Google Scholar]

116. Frank M.G., et al. SARS-CoV-2 spike S1 subunit induces neuroinflammatory, microglial and behavioral sickness responses: evidence of PAMP-like properties. Brain Behav. Immun. 2022;100:267–277. [PMC free article] [PubMed] [Google Scholar]

117. Bergamaschi C., et al. Systemic IL-15, IFN-γ, and IP-10/CXCL10 signature associated with effective immune response to SARS-CoV-2 in BNT162b2 mRNA vaccine recipients. Cell Rep. 2021;36 [PMC free article] [PubMed] [Google Scholar]

118. Au L., et al. Cytokine release syndrome in a patient with colorectal cancer after vaccination with BNT162b2. Nat. Med. 2021;27:1362–1366. [PMC free article] [PubMed] [Google Scholar]

119. Camell C.D., et al. Senolytics reduce coronavirus-related mortality in old mice. Science. 2021;373 [PMC free article] [PubMed] [Google Scholar]

120. Kowalzik F., et al. mRNA-based vaccines. Vaccines. 2021;9:390. [PMC free article] [PubMed] [Google Scholar]

121. Racanelli V., Rehermann B. The liver as an immunological organ. Hepatology. 2006;43:S54–S62. [PubMed] [Google Scholar]

122. Horst A.K., et al. Modulation of liver tolerance by conventional and nonconventional antigen-presenting cells and regulatory immune cells. Cell. Mol. Immunol. 2016;13:277–292. [PMC free article] [PubMed] [Google Scholar]

123. Avci E., Abasiyanik F. Autoimmune hepatitis after SARS-CoV-2 vaccine: new-onset or flare-up? J. Autoimmun. 2021;125 [PMC free article] [PubMed] [Google Scholar]

124. Zin Tun G.S., et al. Immune-mediated hepatitis with the Moderna vaccine, no longer a coincidence but confirmed. J. Hepatol. 2021;76:747–749. [PMC free article] [PubMed] [Google Scholar]

125. Harryvan T.J., et al. The ABCs of antigen presentation by stromal non-professional antigen-presenting cells. Int. J. Mol. Sci. 2021;23:137. [PMC free article] [PubMed] [Google Scholar]

126. Carnell G.W., et al. SARS-CoV-2 spike protein stabilized in the closed state induces potent neutralizing responses. J. Virol. 2021;95 [PMC free article] [PubMed] [Google Scholar]

127. Hoffmann M., et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181:271–280. [PMC free article] [PubMed] [Google Scholar]

128. Lan J., et al. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature. 2020;581:215–220. [PubMed] [Google Scholar]

129. Piroth L., et al. Comparison of the characteristics, morbidity, and mortality of COVID-19 and seasonal influenza: a nationwide, population-based retrospective cohort study. Lancet Respir. Med. 2021;9:251–259. [PMC free article] [PubMed] [Google Scholar]

130. Castagnoli R., et al. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children and adolescents: a systematic review. JAMA Pediatr. 2020;174:882–889. [PubMed] [Google Scholar]

131. Goldstein E., et al. On the effect of age on the transmission of SARS-CoV-2 in households, schools, and the community. J. Infect. Dis. 2021;223:362–369. [PMC free article] [PubMed] [Google Scholar]

132. Yoshida M., et al. Local and systemic responses to SARS-CoV-2 infection in children and adults. Nature. 2022;602:321–327. [PMC free article] [PubMed] [Google Scholar]

133. Killingley B., et al. Safety, tolerability and viral kinetics during SARS-CoV-2 human challenge in young adults. Nat Med. 2022 doi: 10.1038/s41591-022-01780-9. Published online March 31, 2022. [PubMed] [CrossRef] [Google Scholar]

134. Zhang J.-Y., et al. Single-cell landscape of immunological responses in patients with COVID-19. Nat. Immunol. 2020;21:1107–1118. [PubMed] [Google Scholar]

135. Low J.S., et al. Clonal analysis of immunodominance and cross-reactivity of the CD4 T cell response to SARS-CoV-2. Science. 2021;372:1336–1341. [PMC free article] [PubMed] [Google Scholar]

136. Cagigi A., et al. Airway antibodies emerge according to COVID-19 severity and wane rapidly but reappear after SARS-CoV-2 vaccination. JCI Insight. 2021;6 [PMC free article] [PubMed] [Google Scholar]

137. Loske J., et al. Pre-activated antiviral innate immunity in the upper airways controls early SARS-CoV-2 infection in children. Nat. Biotechnol. 2021;40:319–324. [PubMed] [Google Scholar]

138. See I., et al. US case reports of cerebral venous sinus thrombosis with thrombocytopenia after Ad26.COV2.S vaccination, March 2 to April 21, 2021. JAMA. 2021;325:2448–2456. [PMC free article] [PubMed] [Google Scholar]

139. Reimer J.M., et al. Matrix-MTM adjuvant induces local recruitment, activation and maturation of central immune cells in absence of antigen. PLoS One. 2012;7 [PMC free article] [

Study Shows Pfizer’s Paxlovid Pill Can Cause Deadly Blood Clots

Authors:  Jim Hoft Published October 13, 2022 

A new study warned that Pfizer’s Paxlovid COVID-19 pill can have harmful interactions with common medications used to treat cardiovascular disease, as what the Gateway Pundit reported in 2021.

Pfizer’s Paxlovid, which contains the drugs nirmatrelvir and ritonavir (NMVr), can interact with several other drugs routinely used to treat cardiovascular disease, according to a study published in the Journal of the American College of Cardiology on Wednesday.

Most of the concerns about drug interactions come from ritonavir, experts said.

“Co-administration of NMVr with medications commonly used to manage cardiovascular conditions can potentially cause significant drug-drug interactions and may lead to severe adverse effects,” according to the reviewed paper.

Paxlovid can cause serious health problems when coupled with common heart disease medication such as statins and blood thinners.

Researchers from Lahey Hospital and Medical Center, Harvard Medical School and other US institutions  found the Covid drug can increase the risk of developing blood clots when taken with blood thinners.

It can also cause an irregular heartbeat when combined with drugs for heart pain and when taken alongside statins it can be toxic to the liver.

Dozens of medications such as aspirin are safe to take with Paxlovid,  the researchers stress. But doctors need to be aware that other drugs can be dangerous and should be discontinued or adjusted while a patient is being treated for Covid.

Dr. Houman Hemmati, Chief Medical Officer of Vyluma, Inc, shared his insights on the study and claimed that people who took Paxlovid are part of the clinical trials.

“The problem is that Paxlovid didn’t have these lengthy phase one, two, and three trials. It was rushed to market under an emergency use authorization, never an approval. And as a result, they’ve skipped a lot of these studies. And so what we’re learning about that drug and its safety is largely based on post-marketing data. What does that mean? It’s people who are actually getting it in the real life, in real-world usage, and then we find out through them,” Hemmati said.\

It’s Not Just the mRNA Vaccines, New Study Shows Pfizer’s Paxlovid Pill Can Cause Deadly Blood Clots

By Jim Hoft
Published October 13, 2022 at 2:00pm
138 Comments

ShareTweetGab ShareTelegramGettr

A new study warned that Pfizer’s Paxlovid COVID-19 pill can have harmful interactions with common medications used to treat cardiovascular disease, as what the Gateway Pundit reported in 2021.

Pfizer’s Paxlovid, which contains the drugs nirmatrelvir and ritonavir (NMVr), can interact with several other drugs routinely used to treat cardiovascular disease, according to a study published in the Journal of the American College of Cardiology on Wednesday.

Most of the concerns about drug interactions come from ritonavir, experts said.

“Co-administration of NMVr with medications commonly used to manage cardiovascular conditions can potentially cause significant drug-drug interactions and may lead to severe adverse effects,” according to the reviewed paper.

TRENDING: DEVELOPING: January 6 Committee Plans to Vote on Whether to Subpoena Trump

Daily Mail reported:

Paxlovid can cause serious health problems when coupled with common heart disease medication such as statins and blood thinners.

Researchers from Lahey Hospital and Medical Center, Harvard Medical School and other US institutions  found the Covid drug can increase the risk of developing blood clots when taken with blood thinners.

It can also cause an irregular heartbeat when combined with drugs for heart pain and when taken alongside statins it can be toxic to the liver.

Dozens of medications such as aspirin are safe to take with Paxlovid,  the researchers stress. But doctors need to be aware that other drugs can be dangerous and should be discontinued or adjusted while a patient is being treated for Covid.

View Fullscreen

https://www.thegatewaypundit.com/wp-content/plugins/pdfjs-viewer-shortcode/pdfjs/web/viewer.php?file=https://www.thegatewaypundit.com/wp-content/uploads/COVID-Drug-Clinical-Bulletin.pdf&attachment_id=797261&dButton=true&pButton=true&oButton=false&sButton=true#zoom=auto&pagemode=none&_wpnonce=ffc03ba1be

Dr. Houman Hemmati, Chief Medical Officer of Vyluma, Inc, shared his insights on the study and claimed that people who took Paxlovid are part of the clinical trials.

“The problem is that Paxlovid didn’t have these lengthy phase one, two, and three trials. It was rushed to market under an emergency use authorization, never an approval. And as a result, they’ve skipped a lot of these studies. And so what we’re learning about that drug and its safety is largely based on post-marketing data. What does that mean? It’s people who are actually getting it in the real life, in real-world usage, and then we find out through them,” Hemmati said.

Watch the video below:

https://platform.twitter.com/embed/Tweet.html?dnt=true&embedId=twitter-widget-0&features=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%3D%3D&frame=false&hideCard=false&hideThread=false&id=1580609407972696065&lang=en&origin=https%3A%2F%2Fwww.thegatewaypundit.com%2F2022%2F10%2Fnot-just-mrna-vaccines-new-study-shows-pfizers-paxlovid-pill-can-cause-deadly-blood-clots%2F&sessionId=a80264af1e32e4655ec7c34a343113a26c063973&theme=light&widgetsVersion=1c23387b1f70c%3A1664388199485&width=550px

It can be recalled that Dr. Jill tested positive for Covid AGAIN  in a ‘rebound’ case after taking Paxlovid earlier in August.

When President Joe Biden, 79, tested positive for Covid and started Paxlovid in July, Joe Biden’s doctor said he had stopped heart medications for Biden’s atrial fibrillation and high cholesterol due to his prescribing Paxlovid to treat Biden’s COVID infection. Atrial fibrillation can cause strokes and is treated by blood thinners to reduce the risk of stroke-causing blood clots being formed.

“His apixaban (ELIQUIS) and rosuvastatin (Crestor) are being held during PAXLOVID treatment and for several days after his last dose. During this time, it is reasonable to add low dose aspirin as an alternative type of blood thinner,” said Biden’s personal physician Dr. Kevin O’Connor.

Quadruple vaxxed Pfizer CEO Albert Bourla announced he tested positive for Covid in August. Bourla also said he started a course of Paxlovid.

The U.S. Food and Drug Administration issued an emergency use authorization for Pfizer’s antiviral pill for the treatment of mild-to-moderate COVID-19 infection on December 2021.

The Gateway Pundit reported that the COVID pill could cause life-threatening reactions when used with many common medications in 2021.

Pfizer’s antiviral oral drug Paxlovid that was developed as an early treatment for Covid-19 can cause severe or life-threatening effects if it is taken in tandem with other common medications including some anticoagulants, anti-depressants, and cholesterol-lowering drugs that are used widely across the US, according to a warning from the Food and Drug Administration (FDA).

There are six pages of warnings about this drug. FDA already know about the adverse event, and yet they still push it on people with COVID-19.

As the Gateway Pundit previously reported, more and more reports of patients taking Pfizer’s antiviral pill experienced a second round of Covid-19 shortly after recovering. Experts are still investigating the causes and they are baffled.

Scientific documentation about post-Paxlovid relapse has been available since last fall. Pfizer’s application to the FDA for emergency use authorization of Paxlovid stated that in the placebo-controlled clinical trial — which included 2,246 participants — “several subjects appeared to have a rebound in SARS-CoV-2 RNA levels around Day 10 or Day 14” after beginning treatment, NBC reported.

Following this report, Pfizer released a statement admitting that it failed to reduce the risk of confirmed and symptomatic COVID-19 infection in adults living with someone who had been exposed to the virus.

Pfizer mRNA Spike Protein Found in Deceased Man’s Brain and Heart: Peer-Reviewed Report

“We know it goes to the brain, it goes to the heart, it produces the spike protein, which damages those cells, causes inflammation… it travels… causing damage to blood vessels and blood clots.”

Authors: Kanekoa Kanekoa News October 6, 2022

Dr. Michael Mörz from the Institute for Pathology in Dresden, Germany, published a case study of an autopsy of a 76-year-old deceased man in the journal Vaccines.

In the report, spike proteins specifically attributed to COVID-19 vaccination targeted blood vessels in the man’s brain and heart.

Incredibly, the report used immunohistochemistry, which uses immune staining methods that light up specific antigens, to determine that “only spike protein but no nucleocapsid protein” could be detected meaning the necrotizing encephalitis (death of brain tissues) as well as the inflammatory changes in the small blood vessels (brain and heart) were caused by COVID-19 vaccination rather than viral infection.

“Surprisingly, only spike protein but no nucleocapsid protein could be detected within the foci of inflammation in both the brain and the heart, particularly in the endothelial cells of small blood vessels. Since no nucleocapsid protein could be detected, the presence of spike protein must be ascribed to vaccination rather than to viral infection. The findings corroborate previous reports of encephalitis and myocarditis caused by gene-based COVID-19 vaccines.”

Study: Nucleocapsid antibody positivity as a marker of past SARS-CoV-2 infection in population serosurveillance studies: impact of variant, vaccination, and choice of assay cut-off. Image Credit: Orpheus FX / Shutterstock
Since the COVID-19 vaccines only encode for the spike protein, but not the nucleocapsid found in natural infection, the autopsy doctor was able to determine that the heart and brain inflammation was caused by COVID-19 vaccination rather than natural infection.

Interestingly, the elderly man who had Parkinson’s Disease (PD) “experienced pronounced cardiovascular side effects, for which he repeatedly had to consult his doctor” after his first Astra Zeneca ChAdOx1 vector vaccine in May 2021.

After his second vaccination with Pfizer’s BNT162b2 mRNA vaccine in July 2021, the family noticed that the elderly man experienced “increased anxiety, lethargy, and social withdrawal.”

Furthermore, “there was a striking worsening of his PD symptoms, which led to severe motor impairment and a recurrent need for wheelchair support”, which the man “never fully recovered from” before receiving his third vaccination (second Pfizer) in December 2021.

Two weeks after the third vaccination, he “suddenly collapsed while eating dinner” without “coughing or any signs of food aspiration”.

He recovered from this more or less, but one week later, he again suddenly collapsed silently while eating his meal, leading to his hospitalization and death shortly thereafter.

The man’s family asked for an autopsy because he had already shown noticeable changes in behavior, cardiovascular symptoms, and worsening of his Parkinson’s Disease symptoms after each COVID-19 vaccination.

“In the brain, SARS-CoV-2 spike protein subunit 1 was detected in the endothelia, microglia, and astrocytes in the necrotic areas. Furthermore, spike protein could be demonstrated in the areas of lymphocytic periarteritis, present in the thoracic and abdominal aorta and iliac branches, as well as a cerebral basal artery. The SARS-CoV-2 subunit 1 was found in macrophages and in the cells of the vessel wall, in particular the endothelium. In contrast, the nucleocapsid protein of SARS-CoV-2 could not be detected in any of the corresponding tissue sections.”

Figure 10. Brain, Nucleus ruber. The abundant presence of SARS-CoV-2 spike protein in swollen endothelium of a capillary vessel shows acute signs of inflammation with sparse mononuclear inflammatory cell infiltrates (same vessel as shown in Figure 12, serial sections of 5 to 20 μm). Immunohistochemical demonstration for SARS-CoV-2 spike protein subunit 1 visible as brown granules in capillary endothelial cells (red arrow) and individual glial cells (blue arrow). Magnification: 200× Source: MDPI-Vaccine
Figure 12. Brain, Nucleus ruber. Negative immunohistochemical reaction for SARS-CoV-2 nucleocapsid protein. Cross section through a capillary vessel. Magnification: 200×. Source: MDPI-Vaccine
Figure 9. Frontal brain. Positive reaction for SARS-CoV-2 spike protein. Cross section through a capillary vessel (same vessel as shown in Figure 11, serial sections of 5 to 20 μm). Immunohistochemical reaction for SARS-CoV-2 spike subunit 1 detectable as brown granules in capillary endothelial cells (red arrow) and individual glial cells (blue arrow). Magnification: 200×. Source: MDPI-Vaccines
Figure 11. Frontal brain. Negative immunohistochemical reaction for SARS-CoV-2 nucleocapsid protein. Cross section through a capillary vessel (same vessel as shown in Figure 9, serial sections of 5 to 20 μm). Magnification: 200×. Source: MDPI-Vaccines

“Immunohistochemistry for SARS-CoV-2 antigens (spike protein and nucleocapsid) revealed that the lesions with necrotizing encephalitis as well as the acute inflammatory changes in the small blood vessels (brain and heart) were associated with abundant deposits of the spike protein SARS-CoV-2 subunit 1. Importantly, spike protein could be only demonstrated in the areas with acute inflammatory reactions (brain, heart, and small blood vessels), in particular in endothelial cells, microglia, and astrocytes. This is strongly suggestive that the spike protein may have played at least a contributing role to the development of the lesions and the course of the disease in this patient.”

Figure 13. Heart left ventricle. Positive reaction for SARS-CoV-2 spike protein. Cross section through a capillary vessel (same vessel as shown in Figure 14, serial sections of 5 to 20 μm). Immunohistochemical demonstration of SARS-CoV-2 spike subunit 1 as brown granules. Note the abundant presence of spike protein in capillary endothelial cells (red arrow) associated with prominent endothelial swelling and the presence of a few mononuclear inflammatory cells. Magnification: 400×. Source: MDPI-Vaccines
Figure 14. Heart left ventricle. Negative immunohistochemical reaction for SARS-CoV-2 nucleocapsid protein. Cross section through a capillary vessel (same vessel as shown in Figure 13, serial sections of 5 to 20 μm). Magnification: 400×. Source: MDPI-Vaccines

Dr. Robert Malone, a critic of the COVID-19 vaccination program, has long warned that the, “synthetic mRNA like genetic material persists in the body for 60 days or longer and produces spike protein at levels higher than is observed with the actual SARS-CoV-2 infection.”

Ominously, the CDC quietly removed the claim that the vaccine generated spike protein “does not last long in the body” from its website between July 16th and July 22nd.

“This is the first time we have had a vaccine go to the brain and go to the heart,” Dr. Peter McCullough, another expert has warned since last year.

“We know it goes to the brain, it goes to the heart, it produces the spike protein, which damages those cells, causes inflammation, and then from there it travels in the body causing damage to blood vessels and causing blood clots.”

Doctor Warns That Majority Of Vaccinated Patients Could Have Permanent Heart Damage, Some May Die Within Three Years

Authors: Adan Salazar – https://www.infowars.com/posts/shock-doctor-warns-that-majority-of-vaccinated-patients-could-have-permanent-heart-damage-some-may-die-within-three-years/

Dr. Charles Hoffe found 62% percent of patients who received COVID mRNA jab test positive for
blood clots…’The concern…is those people will probably all develop right-sided heart failure within
three years and die because they now have increased vascular resistance through their lungs.
A Canadian doctor demands further study into the link between Covid-19 vaccines and blood
clots after his research found clots in a majority of vaccinated patients, some of whom he says
could be dead within three years. During a Zoom meeting with other medical professionals, Dr.
Charles Hoffe explained he’s been running a study on recently vaccinated patients, having them take Ddimer blood tests to determine whether they have blood clots.

Dr. Charles Hoffe found 62% percent of patients who received COVID mRNA jab test positive for
blood clots…’The concern…is those people will probably all develop right-sided heart failure within
three years and die because they now have increased vascular resistance through their lungs.
A Canadian doctor demands further study into the link between Covid-19 vaccines and blood
clots after his research found clots in a majority of vaccinated patients, some of whom he says
could be dead within three years. During a Zoom meeting with other medical professionals, Dr.
Charles Hoffe explained he’s been running a study on recently vaccinated patients, having them take Ddimer blood tests to determine whether they have blood clots.

UK Cardiologist: Pause the COVID Vaccine Program

Authors:  Michelle Edwards September 27, 2022 Nature Reports

One of Britain’s most influential cardiologists, Dr. Aseem Malhotra—citing a duty to his patients, scientific integrity, and the truth—just published what he describes as perhaps the most critical research paper of his prestigious career. His work, fueled by the sudden death of his “very fit and well” father in July 2021, critically appraised the real-world data around the mRNA COVID jab. After nine months of rigorous research and extensive peer review, Malhotra’s paper concludes what many heavily censored brave experts have been saying for months—the massive push to get the mRNA COVID-19 jab into the arms of humanity serves a purely sinister purpose: increased pharmaceutical shareholder profits at any cost. Indeed, with Pfizer in the lead, Malhotra is convinced the current system, which gives big pharma way too much power, is “encouraging good people to do bad things.” On that note, he is calling for all COVID-19 vaccines to be withdrawn. 

In conducting research for his paper titled ‘Curing the pandemic of misinformation on COVID-19 mRNA vaccines through real evidence-based medicine,’ Dr. Malhotra commented on the early headlines around the world making “very bold claims of 95% effectiveness” with the jabs. Likewise, he underscored the slippery way “efficacy” and “effectiveness” were used interchangeably to gloss over the significant difference between controlled trials and real-world conditions. Dr. Molhotra quickly realized the gaping holes in Pfizer’s mRNA clinical trials, noting he was alarmed to learn that there were four cardiac arrests in those who took the vaccine in the trial versus only one in the placebo group. He wrote:

“During early 2021, I was both surprised and concerned by a number of my vaccine-hesitant patients and people in my social network who were asking me to comment on what I regarded at the time as merely ‘anti-vax’ propaganda.

But a very unexpected and extremely harrowing personal tragedy was to happen a few months later that would be the start of my own journey into what would ultimately prove to be a revelatory and eye-opening experience so profound that after six months of critically appraising the data myself, speaking to eminent scientists involved in COVID-19 research, vaccine safety and development, and two investigative medical journalists, I have slowly and reluctantly concluded that contrary to my own initial dogmatic beliefs, Pfizer’s mRNA vaccine is far from being as safe and effective as we first thought.”

In January 2021, Dr. Malhotra, an NHS consultant, Fellow of the Royal College of Physicians, President of the Scientific Advisory Committee of The Public Health Collaboration, and internationally renowned expert in the prevention, diagnosis, and management of heart disease, was one of the first to receive the two-dose Pfizer jab. A firm believer in the “safe and highly effective” vaccines produced during the latter half of the 20th century, Dr. Malhotra states he got the mRNA shots mainly to “prevent transmission of the virus” to his vulnerable patients. In an appearance on Good Morning Britain, he even convinced “vaccine-hesitant” British film director Gurinder Chadha to take the jab.

Nevertheless, following his father’s sudden death, Malhotra was distraught after examining the post-mortem findings. Not long before his death, Malhotra had assessed his 73-year-old father’s heart and determined overall he was in excellent health. His dad, who also received the Pfizer mRNA jabs, walked 10 to 15,000 steps daily and was extremely conscientious of his diet. Yet, with no evidence of an actual heart attack, Malhotra couldn’t explain how his healthy father had two severe blockages in his coronary arteries, which caused his death. He explained:

“There were two severe blockages in his Corona arteries, which didn’t really make any sense with everything. I know [this] both as a cardiologist—someone who has expertise in this particular area—but also by intimately knowing my dad’s lifestyle and his health. 

Not long after that, data started to emerge [that] suggested a possible link between the mRNA vaccine and increased risk of heart attacks from a mechanism of increasing inflammation around the coronary arteries. But on top of that, I was then contacted by a whistleblower at a very prestigious university in the UK. A cardiologist himself, he explained to me that there was similar research findings in his department—and that those researchers have decided to essentially cover it up because they were worried about losing research funding from the pharmaceutical industry.” 

Presently, the sinister, big-pharma profit-driven, tyrannical, Great Reset reality in which we live is unmistakable to many. Still, to have Dr. Malhotra come forward in such a tremendous way indicates the voice of logic and reason is gaining momentum and getting louder. While talk of Sudden Adult Death Syndrome (SADS) and the myriad of sudden deaths we witness daily might yet fool some, many more are becoming increasingly aware of the fraudulent scheme at hand. Pointing to a burgeoning list of adverse events and the long-term uncertainty of vaccine-induced myocarditis, Malhotra’s paper calls out the crooked big pharma business model being employed by the global elite to coerce the world into being injected with the mRNA COVID jab. Published in the Journal of Insulin Resistance, it is well worth reading Dr. Malhotra’s two-part paper in full (here), and watching his Sept. 27 interview with the World Council for Health (here). Meanwhile, with his eyes wide open, in a recent interview, Malhotra conveyed a message he believes every human being needs to hear, declaring:

“[People] need to understand that the current system is encouraging good people to do bad things. At the root of this problem are big, very powerful corporations that have too much influence on government, on healthcare, and on media. And their primary responsibility is to produce profit for their shareholders, not to give you the best treatment. And when you understand that, then we can start doing something to transform the system.

And I don’t say this lightly. It has been well documented that these corporations, unfortunately, in how they go about their business, by misleading people, by their business model being fraudulent, they act like psychopaths—they are a psychopathic entity. Ultimately the conclusion is that we have a psychopathic entity influencing health policy, and that needs to stop—and it needs to stop now.”

Coronavirus and blood clots: Causes, effects and treatment

Authors: Nascimento Pinto MSN

The effects of Covid-19 on people are varied but city doctors have observed that there is a possibility of heart attacks, especially in youngsters. 

Some city experts say heart attacks after Covid-19 are caused due to the presence of blood clots in the body. However, others believe there is neither any scientific evidence to prove blood clot-related heart attacks occur due to Covid-19 nor that the virus causes disproportionally more heart attacks than otherwise. The jury is still out but the fact that heart attacks and blood clots and their presence in people who have suffered from Covid-19 is being discussed cannot be ignored.

Mid-day Online spoke to Dr Manish Hinduja, consultant-cardio thoracic and vascular surgery, Fortis Hospital and Dr Pravin Kahale, consultant, cardiology, Kokilaben Dhirubhai Ambani Hospital to understand more about the causes of blood clots and the effects post-Covid. They also shed light on the symptoms one must be aware of and the preventive measures but while taking expert advice.

What causes blood clots in people after they suffer from Covid-19?

Hinduja: In Covid, clots form in blood vessels because once the virus binds to ACE 2 receptors on blood vessel lining cells, it activates the release of clot-forming proteins. It is also sometimes due to hyperactive inflammation caused by the virus in the body.

Kahale: Any infection which damages the wall of the blood vessels increases the chances of clotting in the body and that is not particularly due to Covid, many infections can also lead to blood clots.

Do blood clots cause heart attacks in people who have suffered from Covid-19? What are the other complications that could occur due to these clots besides heart attacks?

Hinduja: Yes, clots if formed in blood vessels of the heart, can lead to heart attack. Clots can also cause stroke, pulmonary embolism, deep vein thrombosis in legs or arms, and kidney but rarely liver damage.

Kahale: Blood clots can occur due to multiple infections. There is no evidence of blood clot-related heart attacks due to Covid-19. Apart from leg veins called deep vein thrombosis, other complications that can occur are paralysis due to clots in the brain, and lung arteries.

Has there been an increase in the number of heart attacks due to blood clots or people coming with clots after suffering from Covid-19?

Hinduja: Definitely. There is an increase in the number of heart attacks after Covid infection (especially in the younger age group). 

Kahale: There is no evidence that Covid causes disproportionally more heart attacks.

What are the chances of the blood clots occurring? Do they appear more in any particular age group?

Hinduja: About 20-30 per cent of patients with Covid-19 infection needing ICU treatment, show features of blood clot formation within six months of infection. Although it is more common in elderly hospitalised patients, it is also seen in young patients who have no comorbidities.

Kahale: Blood clots in mild to moderate Covid cases are uncommon. In case of severe Covid, the chances of blood clots occurring are still less. There is no particular age which is more susceptible.

Which part of the body do the blood clots occur the most?

While Hinduja says blood clots occur in the lungs, heart and brain vessels, Kahale adds that they mostly occur in leg veins and lung circulation.

Can people avoid getting blood clots after Covid-19?

Hinduja: Yes, preventive treatment with blood thinners and early diagnosis is the key.

Kahale: A patient who has suffered from severe Covid-19 infection can take a blood thinner based on the need, and guidance of a doctor.

Are there any foods people can eat to prevent getting blood clots eventually causing heart attacks? Do they need to make lifestyle changes?

Hinduja: Staying active, avoiding smoking and reducing weight for obese patients can help in reducing the risk. Common foods like ginger, turmeric and garlic have been shown to have some blood thinning effects. However, their role in preventing Covid 19-related blood clots, is not well-documented.

Kahale: In terms of blood clotting due to Covid-19, there are no specific food or lifestyle changes required. The risk of developing blood clots for a patient suffering from severe Covid-19 is only a potential threat until a patient is Covid positive.

What are the signs or symptoms for people to realise they have a blood clot? Why should they be concerned?

Hinduja: There is sudden chest pain, swelling in arms or legs, drowsiness and weakness in limbs.

Kahale: Blood clots depend upon the area where the patient is affected. If it occurs in the lungs, it can cause breathlessness. If it is in the legs, then it can cause swelling of the legs; heart blood clots lead to a heart attack-like chest pain, and clots in the brain can cause paralysis or stroke.

Opinions | How long covid reshapes the brain — and how we might treat it

Authors: Wes Ely August 25, 2022 The Washington Post

The young man pulled something from behind both ears. “I can’t hear anything without my new hearing aids,” said the 32-year-old husband and father. “My body is broken, Doc.” Once a fireman and emergency medical technician, he’d had covid more than 18 months before and was nearly deaf. He was also newly suffering from incapacitating anxiety, cognitive impairment and depression. Likewise, a 51-year-old woman told me through tears: “It’s almost two years. My old self is gone. I can’t even think clearly enough to keep my finances straight.” These are real people immersed in the global public health catastrophe of long covid, which the medical world is struggling to grasp and society is failing to confront.

As such stories clearly indicate, covid is biologically dangerous long after the initial viral infection. One of the leading hypotheses behind long covid is that the coronavirus is somehow able to establish a reservoir in tissues such as the gastrointestinal tract. I believe the explanation for long covid is more sinister.

The science makes it increasingly clear that covid-19 turns on inflammation and alters the nervous system even when the virus itself seems to be long gone. The virus starts by infecting nasal and respiratory lining cells, and the resulting inflammation sends molecules through the blood that trigger the release of cytokines in the brain. This can happen even in mild covid cases. Through these cell-to-cell conversations, cells in the nervous system called microglia and astrocytes are revved up in ways that continue for months — maybe years. It’s like a rock weighing down on the accelerator of a car, spinning its engine out of control. All of this causes injury to many cells, including neurons. It is past time we recognized this fact and began incorporating it into the ways we care for those who have survived covid.

For too long, the mysteries of long covid led many health-care professionals to dismiss it as an untreatable malady or a psychosomatic illness without a scientific basis. Some of this confusion comes down to the stuttering cadence of scientific progress. Early in the pandemic, autopsy findings from patients who died of covid “did not show encephalitis or other specific brain changes referable to the virus” as one report noted. Patients with profound neurological illnesses resulting from covid-19 had no trace of the virus in the cerebrospinal fluid encasing their brains.

These studies left most medical professionals mistakenly convinced that the virus was not damaging the brain. Accordingly, we narrowed our focus to the lungs and heart and then scratched our heads in wonder at the coma and delirium found in more than 80 percent of covid ICU patients. A robust study from the Netherlands showed that at least 12.5 percent of covid patients end up with long covid three months afterward, yet because “brain fog” wasn’t identified until later in the pandemic, these investigators didn’t include cognitive problems or mental health disorders in the data they collected. Thus, this otherwise beautifully executed study almost certainly underestimated the rate of long covid.

Since the early days of the pandemic, we’ve learned a great deal about the neurological effects of SARS-CoV-2. Earlier this year, the UK Biobank neuroimaging study showed that even mild covid can lead to an overall reduction in the size of the brain, with notable effects in the frontal cortex and limbic system. These findings help explain the profound anxiety, depression, memory loss and cognitive impairment experienced by so many long-covid patients.

new study published in the Lancet of more than 2.5 million people matched covid-19 patients with non-covid patients to determine the rate of recovery from mental health complaints and neurological deficits like the depression and brain fog in my own patients. What it revealed is partly encouraging and partly devastating: The anxiety and mood disorders in long covid tend to resolve over months, while serious dementia-like problems, psychosis and seizures persist at two years.

COVID-19 INCREASING STROKE RISKS IN PEOPLE OF ALL AGES

Author: University of Utah Health Communications

The COVID-19 pandemic has been unpredictable as more is learned about the varied side effects of the virus. A typical respiratory infection, such as the flu, usually has a specific set of symptoms and potential complications. With COVID-19, the long-term effects range from neurological complications to loss of taste and smell, trouble focusing (“brain fog”), and chronic fatigue. Another surprising finding from several studies is the heightened risk of stroke and heart attack—and not just for older adults. People under the age of 50 appear to be at much higher risk of these complications too.

One study published in JAMA in April 2021 found that the risk of stroke was more than twice as high for COVID-19 patients when compared to people of the same age, sex, and ethnicity in the general population—82.6 cases per 100,000 people compared to 38.2 cases for those without a COVID-19 diagnosis. 

In another Swedish study published in the August 14, 2021 issue of The Lancet, researchers found that within a week of a COVID-19 diagnosis, a person’s risk of heart attack was three to eight times higher than normal, and their risk of stroke was three to six times higher. The study revealed these risks remained high for at least a month. The average age of people in the study was only 48 years. The data from those diagnosed was compared with 348,000 Swedish people in a similar age range who did not have the virus.

This trend is something Jonathan Kinzinger, DPT, a physical therapist and adjunct assistant professor at University of Utah Health who works with stroke patients at the Craig H. Neilsen Rehabilitation Hospital, has seen up close. 

“We are definitely seeing a huge increase in younger stroke survivors who are post-COVID diagnosis,” Kinzinger says. “We know that vascular complications go along with COVID infections, which can lead to strokes and other cardiovascular issues.”

group of researchers headed by Mark Ellul, PhD, NIHR Clinical Lecturer in Neurology at the Institute of Infection, Veterinary and Ecological Sciences from the University of Liverpool, first observed this in September 2020. They found that the number of patients admitted to the hospital with a large vessel stroke who also had a COVID-19 diagnosis was seven times higher than normal.

Similar findings have also come out of other countries, where the median age for patients who needed thrombectomy surgery to remove a blood clot was down across the board. In one New York Medical Center, the average age of patients with confirmed stroke and COVID-19 diagnosis was 63 years. The average age of stroke patients who tested negative for COVID was much higher (70 years), even when they controlled for age, sex, and other risk factors.

Researchers are still studying the cause of the increased risk. But doctors know that COVID-19 causes an inflammatory response that thickens a person’s blood. Thicker blood is more likely to clot, and clots can lead to stroke. Many of the young people who suffer a stroke after a COVID-19 diagnosis have few (and sometimes no) risk factors normally associated with stroke.

Sometimes these strokes don’t occur for several weeks after a COVID-19 diagnosis, and it’s impossible to predict who might be at risk. For patients recovering from COVID-19 and a stroke, there is the added challenge of an impaired cardio-respiratory system. “Not only are we dealing with strength, motor, and balance deficits that go along with stroke, we also have to work around respiratory issues, tracheostomies, and other complications,” Kinzinger says. Stroke recovery is physically and mentally challenging anyway, and these complications can increase recovery time.

“When someone has a stroke and they are under 50, their whole life is uprooted,” he says. “A lot of people have younger kids or spouses, they may have a career or they’re going to school, so it’s just such a different phase of life than someone who is older.”

What heart and stroke patients need to know about COVID-19 in 2022

Authors: Michael Merschel, American Heart Association News

Two years into the pandemic, researchers have learned a lot about how COVID-19 affects people with heart disease and stroke survivors. But like the coronavirus itself, what everyone needs to know keeps evolving.

“You can’t assume that what was true three months ago is true now,” said Dr. James de Lemos, a cardiologist at UT Southwestern Medical Center in Dallas. Thanks to the omicron variant, “it’s a fundamentally different pandemic than it was at Thanksgiving.”

Early data suggests omicron causes less severe illness but spreads more easily than its predecessors. So heart and stroke patients need to protect themselves, starting with understanding that COVID-19 still is a threat to their health.

“Early on, we recognized that the risk was higher for those with pre-existing cardiovascular disease,” said Dr. Biykem Bozkurt, a cardiologist at Baylor College of Medicine in Houston. According to the Centers for Disease Control and Prevention, people with conditions such as heart failure, coronary artery disease and possibly high blood pressure may be more likely to get severely ill from COVID-19. So can people who have diabetes, are overweight or are recovering from a stroke.

SARS-CoV-2, the virus that causes COVID-19, also has been linked to increased risk of several cardiovascular conditions. According to a September 2021 report from the CDC, people with COVID-19 are nearly 16 times more likely to have heart inflammation, or myocarditis, than uninfected people. The report found about 150 cases per 100,000 people with COVID-19 versus about nine cases per 100,000 people without the virus.

In addition, an August 2021 study in the New England Journal of Medicine showed people with the coronavirus may have a significantly higher, albeit rare, risk of intracranial hemorrhage, or brain bleeding; heart attack; and having an arrhythmia, or abnormal heartbeat.

Researchers don’t have full data on omicron’s effects yet, Bozkurt said, but it’s still affecting people who are vulnerable. “And that’s why the hospitals right now are full.”

The risks of any one person having a severe problem from the new variant are relatively small, de Lemos said. “But the flipside is, given how many people are getting infected right now, the cumulative number of people with COVID-19 complications is still very large.”

De Lemos, who helped create the American Heart Association’s COVID-19 Cardiovascular Disease Registry, said omicron “is obviously wildly more infectious and able to evade the vaccine to some extent, although it does appear that the vaccine seems to prevent severe infections and hospitalizations.”

And overall, “we don’t know a ton about specifically why certain patients with heart disease do less well,” he said, although understanding has evolved over time.

In the beginning, de Lemos said, doctors feared the virus directly infected the heart muscle. “That doesn’t really appear to be the case,” he said.

Instead, it appears that in severe cases, the virus is inflaming the lining of blood vessels of the heart and increasing the likelihood of clotting in the smallest vessels, he said.

COVID-19 also can overwhelm the heart by making it work harder to pump oxygenated blood through the body as the lungs are overwhelmed.

But as they’ve learned more about the coronavirus, doctors have gotten better at fighting it. For example, de Lemos said, they now work proactively to treat blood-clotting disorders in hospitalized patients. And although researchers are working to understand lingering effects known as “long COVID,” it appears long-term implications for the heart look favorable.

“The vast majority of people who have mild COVID infections really appear to have nothing to worry about with their hearts,” he said. “That’s good news, I think, and doesn’t get emphasized enough.”

People with existing heart conditions or a history of stroke still need to protect themselves, and have many ways of doing so.

“Number one: Get vaccinated,” said Bozkurt, who has studied COVID-19 vaccine side effects. “And please, do get a booster.” Reports of rare cases of vaccine-related myocarditis, particularly in younger males, should not dissuade anybody with an existing condition. Most people with pre-existing cardiovascular disease are not young adult males, she noted. And regardless of age, the benefits from vaccines outweigh the risks.

Given how the vaccines don’t seem to be as protective against the spread of omicron, de Lemos said if you’re a heart disease or stroke patient, hunker down for the next several weeks until this wave passes, “and then you’ll be able to re-emerge.”

Patients should avoid indoor crowds, he said, and use a KN95 mask or, when possible, an N95 mask instead of cloth masks when being in a crowd is necessary.

Bozkurt said heart and stroke patients should keep in contact with their health care team and continue taking medications as prescribed. Anybody with symptoms that could be heart-related should seek care immediately. “Do not delay,” she said.

Both doctors said it was important to get information from reliable sources. Some false remedies promoted on social media can actually damage the heart, Bozkurt said.

De Lemos acknowledged that even from reliable sources, advice can shift. “I would say that the information is written in pencil, not in pen, because things are changing so fast.” It can be frustrating for him, even as a scientist, when experts disagree or alter their recommendations, but “that’s the way science goes.”

And even as COVID-19 “remains a bizarrely arbitrary virus in terms of who gets sick and who doesn’t,” he’s optimistic.

“Think about all the progress we’ve made in a year or two, and the remarkable effect of the vaccines, the fact that we have drugs” that should help keep people out of hospitals. Heart and stroke patients need to be extra careful right now, but “as frustrating as it is, we will not be in this situation forever. We really won’t.”

Editor’s note: Because of the rapidly evolving events surrounding the coronavirus, the facts and advice presented in this story may have changed since publication. Visit Heart.org for the latest coverage, and check with the Centers for Disease Control and Prevention and local health officials for the most recent guidance.

If you have questions or comments about this story, please email editor@heart.org.

Latest survey shows the COVID vaccines are a disaster: ~750,000 dead in US

In US, ~5M people who got the vaccine are now unable to work and ~750,000 are dead. The rate of heart issues is 6.6%, far more than they claimed. No wonder our government isn’t doing these surveys!

Authors: Steve Kirsch Jun 25, 2022

“With over 40 years of experience in genomics, bioinformatics and development of monoclonal, protein therapeutic & small molecule drugs and clinical research on them, there is no question that the complexity of the human body insures that some people will be harmed by them. All drugs are poison at high enough concentration and in many instances drugs that are safe for some are deadly to others. It is evident from the data presented by the FDA Vaccine Adverse Event Registry that the mRNA Jabs have caused millions of injuries. This Study, is a pilot extrapolation that needs further investigation, but, if accurate paints a very troubling picture of harms and future harms caused by these jabs that were not required to demonstrate long-term safety or effectiveness! ”

John Murphy, CEO The COV19 Long-haul Foundation

Executive summary

Our latest poll is devastating for the official narrative:

  1. a 6.6% rate of heart injury (>10M Americans)
  2. 2.7% are unable to work after being vaccinated (>5M Americans),
  3. 6.3% had to be hospitalized (>10M Americans)
  4. you were more likely to die from COVID if you’ve taken the vaccine.
  5. Almost as many (77.4%) households lost someone from the vaccines as from COVID. If you believe that 1M people in the US have died from COVID, then this survey indicates that ~750,000 people died from the vaccine (10.18/13.15*1M) with a 95% confidence of at least 600,000 deaths.

The error bar computation on each question is here.

We will be re-running this with a 5,000 sample size soon which will have smaller error bars. But the key point is that even if we choose the most conservative data points, the survey results are inconsistent with the “safe and effective” narrative.

For example, the CDC hasn’t found anyone who has died from the mRNA vaccines and our survey shows at least 600,000 people have died. That’s a big gap. Someone isn’t telling you the truth. Why do we get such a high number every time we run our poll to a different audience?

Anyone can run our poll for $500 if you don’t believe us. I predict nobody in mainstream media will touch this because they don’t want to know the truth.

This is a poll that nobody who is pro-vaccine wants you to see.

The poll will be ignored by the mainstream media, even when we rerun it with 8,000 people and get the same results. You can bank on that.

Introduction

We used a professional to draft most of the survey questions and skip logic for our Jun 25 survey.

Here are the key takeaways from the Jun 25 survey. We use “stratified counts” throughout since these are “normalized” based on the US demographics:

  1. 380 of the 500 people who took the poll were vaccinated after normalization [Q1]
  2. Only 34% of Americans are drinking the Kool-Aid and getting >2 doses [Q1]
  3. 2.63% of the households (13.15/500) had someone who died from the COVID virus [Q19]
  4. 2.03% [1.7%-2.4%] of the households (10.18[8.6-11.8]/500) reported a death from the vaccine in their household [Q15]. This is stunning because it shows that the vaccine has killed almost as many people as the COVID virus has. The authorities say that COVID has killed over 1M people in the US so this suggests that 774,000 people were killed by the vaccine (10.18[8.6-11.8]/13.15[12.3-14.0]=77.4% [64.2%-90.5%]). How can that be a “safe” vaccine? The 95% confidence intervals say over 600,000 Americans have been killed by the vaccine. Even if this is overestimated by a factor of 10X, this is devastating for the vaccine narrative. There is simply no way to spin this. This is why the “fact checkers” and mainstream media will avoid this survey.
  5. 2.7% of the people who took the vaccine (10.43/380) are so injured they are unable to work [Q7A2]. This is a disaster. So this is 2.7% of the 200M vaccinated people ages 18 and older: >5M severely injured people who can’t work. I don’t know how they will spin this as a positive.
  6. 16.7% (63.7/380) of the people who took the vaccine consider themselves vaccine injured [Q2]. So that’s >30M vaccine injured. I don’t know how they will spin this as a positive.
  7. The survey shows a 6.6% rate of heart injury post-vaccine according to the poll (24.97/380 [Q3]). This is stunning because these are of the people taking the survey reporting their own injury. Nobody could know this better than the survey taker. This is 1,000X higher than the CDC told us. Per Gavi, “The CDC researchers estimated there might be a maximum of 70 cases of myocarditis out of a million second doses given to boys ages 12 to 17.” How could the CDC underestimate this severe adverse event by 3 orders of magnitude?!!? There is something seriously wrong here. Our survey is well within 1 order of magnitude with other rates we’ve been told. This represents 13.3M million people who are seriously injured, probably for life.
  8. 9.2% (35/380) of the people who took the vaccine had to seek medical help for their injury. [Q4]. That’s 18M doctor visits.
  9. 6.3% (23.83/380) of the people who took the vaccine had to be hospitalized for their vaccine injury [Q5] That’s over 12M hospitalizations.
  10. 3.7% (18.83/500) of the households had a person with a heart condition due to the vaccine [Q14]. Since there are 123M households, this is 4.5M new heart conditions. This is a lower estimate than the direct injury above suggesting that people answering this question were answering it for people other than themselves (since otherwise the rate would be higher than the 6.6% direct rate above). So this is another estimate on the number of new heart conditions.
  11. If you got a COVID infection, it’s 17% (36.4/30.98) [Q17] more likely that you were vaccinated, suggesting the vaccine could be making things worse.
  12. If you died from COVID, it was 72% more likely you died after getting the vaccine (6.81/3.95) [Q22]. We were told the opposite by the government.
  13. 46% are planning on getting more vaccines [Q23]. A total of 24.6% of all people are sheep, i.e., even if they are told the vaccine has a good chance of disabling them for life, they will do what the government recommends. These percentages are approximately what is predicted by mass formation theory.
  14. Most people (65%) believed that the hospital treatments for COVID may be responsible for killing people that they lost to COVID, not COVID [Q20]

The survey and underlying data

Jun 25 survey

  1. Jun 25 Pollfish survey summary
  2. Jun 24 Pollfish survey response detail

Here is the skip logic for the Jun 25 survey

Skip logic for June 25 poll

Earlier survey

  1. Jun 24 Pollfish survey summary
  2. Jun 24 Pollfish survey response detail

Latest survey where we broke out the myocarditis rates

  1. Jun 27 Pollfish survey summary
  2. Jun 27 Pollfish survey response detail

Error bars on the numbers

See this error bar computation.

I put the numbers in for the number of people who died. It’s a disaster even if you are on the low end of the error bars: at least 600,000 deaths from the vaccines.

Even if we are off by 10X, the vaccines are a disaster.

Methodology

See my earlier article for a description. No change. It was done by a professional polling organization. If you start the first question, you’re counted. You can’t tell anything about the survey from the first question.

The 500 people are chosen at random and designed to represent a cross-section of America.

The poll size is only 500 since these are test runs.

Therefore, the numbers for the final results could be off. I’ve computed the error bars for each question.

But even if all numbers are a factor of 10 lower, this vaccine is still a complete disaster and should be immediately halted.

Fact checkers welcome

We’ll happily do an interactive session where we show you all the data and the poll results so you can verify they weren’t tampered with. You can even reach out to Pollfish to verify the survey results are legit. We have nothing to hide.

We’ll give you the data files so you can run the poll yourself.

But nobody’s going to fact check this because it would just draw attention to it. So they will have to ignore this and pretend it didn’t happen. That’s what fact checkers do when the facts don’t support the narrative they are paid to support.

Next step

We’ll adjust some of the questions again and re-run the survey with another 500.

Then we’ll increase the size to 5,000 people to reduce the error bars from around 4% to 1%.

We’ll have the final results soon, but we already know the results are devastating.

Summary

The bottom line is this: the mainstream media, the medical community, public health officials, members of Congress, CDC, the “fact checkers,” or anyone else who is pro-vaccine will never run a poll like this to find out the truth.

They don’t want to know the truth and, more importantly, they don’t want you to know the truth either.