COVID-19 Causes Genetic Changes that Create Long-Haul COVID-19 Symptoms, Researchers Find

Gene changes caused by SARS-CoV-2 spike proteins provide a potential answer for what causes long-haul COVID-19, Texas researchers find 

As COVID-19 vaccines become widely available and cases of COVID-19 in the United States begin to drop, the medical community is beginning to focus more on the long-term effects of COVID-19. Sometimes called “long-haul COVID-19,” the varied and long-term effects that a SARS-CoV-2 infection can create are just starting to be understood (See Long-Haul COVID-19 Emerges as a Concern, Potentially Increasing Need for More COVID-19 Antibody Testing).

New research out of Texas Tech University provides a possible explanation for why these symptoms occur. Led by Sharilyn Almodovar, PhD, at the Texas Tech University Health Sciences Center, researchers found that exposing airway cells to the spike protein of the SARS-CoV-2 virus caused genetic changes.

Potential Impact of Exposure to SARS-CoV-2 Spike Protein Alone

“We found that exposure to the SARS-CoV-2 spike protein alone was enough to change baseline gene expression in airway cells,” said Nicholas Evans, a master’s student at the Texas Tech University Health Sciences Center and one of the researchers involved in the study. “This suggests that symptoms seen in patients may initially result from the spike protein interacting with the cells directly.”

This finding that changes in gene expression occur with exposure to the spike protein of SARS-CoV-2 provides a possible explanation of what causes the mysterious, unexplainable symptoms of long-haul COVID-19 that vary from patient to patient. Changes in gene expression can have different effects on different patients, depending on their genetic makeup and their exposure to the virus.

“Our work helps to elucidate changes occurring in patients on the genetic level, which could eventually provide insight into which treatments would work best for specific patients,” says Evans.

Research May Eventually Lead to Clues About Unexplained Illnesses

While the scientific community’s understanding of long-haul COVID-19 is still quite nascent, Almodovar’s team’s findings are one of the first findings in studying long-haul COVID-19 that provide a good explanation for what could potentially be the cause of these symptoms. This new research will undoubtedly lead to further research examining more in-depth which genes are affected and to what extent this impacts different individuals. These findings may also have implications for other previously unexplained illnesses, such as the long-term effects of Lyme disease.

One interesting result of the these findings is that they may explain why some people with long-haul COVID-19 symptoms have relief of their symptoms after getting vaccinated against COVID-19. Authorized COVID-19 vaccines are designed to use human cells to manufacture spike proteins and stimulate immunity. The finding that the spike protein of SARS-CoV-2 may cause long-haul COVID-19 symptoms could explain how vaccines that artificially create a form of the spike protein could cause these symptoms to change.

COVID-19 Vaccine Questions, Further Studies

Another question that this finding raises is if COVID-19 vaccines, which artificially create SARS-CoV-2 spike proteins, could also stimulate changes in gene expression, causing symptoms that mimic long-haul COVID-19 symptoms.

While Almodovar’s team’s research is only the beginning of study into the possibility of gene expression changes driving long-haul COVID-19 symptoms, it may become a foundational concept in this area of research.

Understanding the implications and effects of long-haul COVID-19 will be important for clinical laboratories that provide COVID-19 antibody testing. As the medical community’s understanding of long-haul COVID-19 increases, it may not only increase the demand for serology tests but may also create a demand for other related tests, particularly immunologically-related tests.

Clinical laboratories will benefit from keeping abreast of long-haul COVID-19 related research and being aware of developments that affect how testing will support clinical treatments and outcomes.

Long-Haulers: Spike Protein Present on Covid And in Vaccines Dangerously Modifies Genes Even After Exposure – Texas Tech Uni Study

study by the Texas Tech University published in Biochemistry and Molecular Biology section of the FASEB journal, has found that spike proteins which Covid-19 uses to penetrate cells and is also supplied in abundance by vaccines to stimulate the body’s immune response, modify the body’s genes.

The study coordinators, Nicholas Evans et al. found that even after exposure, these proteins stimulate continued gene expression and inflammatory events that may be behind the long haul Covid and post vaccine syndromes.

Quoting from a review of the study as we published earlier:

“Results from a new cell study at Texas Tech University Health Sciences Center, US, suggest that the SARS-CoV-2 Spike (S) protein can bring about long-term gene expression changes. The findings could help explain why some COVID-19 patients experience symptoms such as shortness of breath and dizziness long after clearing the infection, a condition known as long COVID.

“We found that exposure to the SARS-CoV-2 S protein alone was enough to change baseline gene expression in airway cells,” said Nicholas Evans, one of the researchers. “This suggests that symptoms seen in patients may initially result from the S protein interacting with the cells directly.””

The study is titled “Lung Time No See”: SARS-Cov-2 Spike Protein Changes Genetic Expression in Human Primary Bronchial Epithelial Cells After Recovery” and is published in the Biochemistry and Molecular Biology section of the FASEB journal.

Long Haul Covid and Long Haul Post-Vaccine Syndromes

Long haul covid or Long-COVID or COVID long-haulers according to a new review can present with as many as 55 long term symptoms. The most common of which are “fatigue (58%), headache (44%), attention disorder (27%), hair loss (25%), and dyspnea (24%)…Diseases such as stroke and diabetes mellitus were also present.” Psychiatric problems like dementia and insomnia are also included. Smell and taste deficiency may persist as also cough and lung abnormalities. Autoimmune problems where the body fights itself is also part of this plethora of presentations. Weight loss, palpitations, renal failure, mood disorders, throat pain and sputum, myocarditis, arrhythmia, OCD, intermittent fever, digestive problems are some more.

These same symptoms as well as symptoms of acute covid infection are now reported months after being vaccinated according to Dr. Bruce Patterson, a pioneer in figuring out Covid and Long haul syndromes.

The precise cause of Long-COVID and Long-Post-Vaccine is being investigated but it may be due to organ damage or persistent autoimmune or inflammatory damage after the infection. Another recent study found Epstein Bar virus reactivated in 73% of long haulers and blamed this for the chronic fatigue, raynaud’s phenomenon and other related symptoms in long haulers.

“We found over 73 percent of COVID-19 patients who were experiencing long COVID symptoms were also positive for EBV reactivation.”

The long-lasting gene changes that result from spike proteins as discovered by Texas Tech University may well be the culprits in these prolonged syndromes.

Watch Dr. Patterson Discuss Long Haul Post-Vaccine Syndrome on Dr. Bean

Video culled from @ 20mins

Dr. Thomas E. Levy, MD, JD writes in OrthoMolecular that “depending on the cell types to which such spike proteins bind, a wide variety of diseases with autoimmune qualities can result.” He recommends treating both syndromes the same way with Vitamin C, Ivermectin, Quercetin and other agents.

“long-haul COVID syndrome likely represents a low-grade unresolved smoldering COVID infection with the same kind of spike protein persistence and clinical impact as is seen in many individuals after their COVID vaccinations (Mendelson et al., 2020; Aucott and Rebman, 2021; Raveendran, 2021).”

He further postulates an effect of the spike protein on the ACE2 receptor which has roles in essential pathways that protect blood vessels and other vital physiological processes.

“By itself, the disruption of ACE2 receptor function in so many areas of the body has resulted in an array of different side effects (Ashraf et al., 2021).” Dr Levy writes.

Salk researchers earlier in April found that the spike protein was dangerous to blood vessels by itself, their investigations “proving that the spike protein alone was enough to cause disease.”

Texas Tech University described the dangerous gene-modifying effects of the spike protein as being long-lived and leading to genetic inflammatory changes even after exposure.

“The researchers found that cultured human airway cells exposed to both low and high concentrations of purified S protein showed differences in gene expression that remained even after the cells recovered from the exposure. The top genes included ones related to inflammatory response.”

The study researcher, Nicholas Evans, et al. Concluded:

“Our preliminary results suggest that the SARS-CoV-2 spike protein is enough to change the baseline protein expression in primary HBECs. After recovery, genes related to immune response retained changes in gene expression, and these may indicate relevant long-term effects in asymptomatic patients. Additionally, the interplay between immune response and other pathways after SARS-CoV-2 spike protein exposure should be investigated in the future.”

NewsRescue experts opine: “It is plausible that candidates with lower immunities face more adverse reactions and are on greater risk of Long haul post-vaccine syndrome because it takes longer for their immune system to kick off and wash out the spike proteins produced in the body post vaccine. Studies should investigate any relationship between Long haul post-vaccine and immune compromise.

“Of the various vaccines, AstraZeneca distributed in Africa and the rest of the poorer third world is the worst for many reasons including the fact that it delivers the wild-type unmodified spike protein which has the capacity to transform to the ‘post-fusion’ state and enter the cell and as such has the potential to cause more gene modification or other side effects.”

Animal studies have found toxic effects of spike proteins.

“…those animal studies where Spike protein was produced by a pseudovirus, or the S1 subunit was administered directly. Both of these caused pathology in the animals all by itself, without coronavirus itself being present.”

Vaccine Technology and the Spike Protein

All current vaccines introduce the spike protein in the recipient. Oxford/AstraZeneca and Janssen (Johnson and Johnson) use ‘vectors’, J&J uses adenovirus type 26 (Ad26) as its vector, while AstraZeneca uses a chimpanzee adenovirus to introduce the spike protein. Moderna, Pfizer/BioNTech vaccines introduce mRNA which is a sort of pre-protein. This mRNA is then read by your cells and translated into S1 and modified spike proteins.

While Oxford/AZ introduces the same exact spike protein the virus uses, Moderna, Pfizer/BioNTech and J&J make the body produce a modified spike protein which has the addition of two amino acids (these are the building blocks of proteins), which modify the spike protein so it stays stuck in the ‘pre-fusion’ state and does not switch to the ‘post-fusion’ state which can penetrate the cell.

– Read more:

Certainly more studies shall continue to help humanity deal with these complex new long haul syndromes and to completely reverse the effects of the possible gene modification as reported.

Resolving “Long-Haul COVID” and Vaccine Toxicity: Neutralizing the Spike Protein

Authors: Dr. Thomas E. Levy, MD, JD   July 1, 2021

Although the mainstream media outlets might have you believe otherwise, the vaccines that continue to be administered for the COVID pandemic are emerging as substantial sources of morbidity and mortality themselves. While the degree to which these negative outcomes of the COVID vaccines can be debated, there is no question that enough disease and death have already occurred to warrant cessation of the administration of these vaccines until additional scientifically-based research can examine the balance between its now clear-cut side effects versus its potential (and still not yet clearly proven) ability to prevent new COVID infections.

Nevertheless, enough vaccinations have already been administered to warrant concern that a new “pandemic” of illness and death may well be emerging from the side effects that continue to be documented in steadily increasing numbers. The vaccine-induced “culprit” that is now receiving most of the attention and is the focus of much new research is the COVID virus fragment known as the spike protein. Its physiological impact appears to be doing far more harm than good (COVID antibody induction), and its manner of introduction appears to be fueling its ongoing replication with a continuing presence inside the body for an indefinite length of time.

The physical appearance of the COVID virus can been depicted as a central sphere of viral protein surrounded completely by spear-like appendages. Known as spike proteins, they are very analogous to the quills surrounding a porcupine. And just as the porcupine stabs its victim, these spike proteins penetrate into cell membranes throughout the body. After this penetration, protein-dissolving enzymes are activated, the cell membrane breaks down, the viral sphere enters the cytoplasm through this membrane breach, and the metabolism of the cell is subsequently “hijacked” to manufacture more viral particles. These spike proteins are the focus of a great deal of ongoing research examining vaccine side effects (Belouzard et al., 2012; Shang et al., 2020).

The Spike Protein’s Toxic Effects in the Body

The spike protein first attaches to ACE2 (angiotensin converting enzyme 2) receptors in the cell membranes (Pillay, 2020). This initial binding step is vital to triggering the subsequent sequence of events that brings the virus inside the cell. When this binding is blocked by competition or prompt enough displacement with an appropriate therapeutic agent, the virus cannot enter the cell, the infectious process is effectively stopped, and the immune defenses of the body are freed to mop up, metabolize, and eliminate the viral pathogens, or just the spike protein alone if free and no longer attached to a viral particle.

Although ACE2 is found in many different cells throughout the body, it is especially noteworthy to realize that it is the initial target bound by coronavirus on the epithelial cells lining the airways after pathogen inhalation (Hoffmann et al., 2020). ACE2 expression (concentration) is also especially high on lung alveolar epithelial cells (Alifano et al., 2020). This cell membrane-bound virus can then begin the process that eventually results in the severe acute respiratory syndrome (SARS) seen in clinically-advanced COVID infections (Perrotta et al., 2020; Saponaro et al., 2020). The SARS presentation manifests most clearly when the degree of oxidative stress in the lungs is very elevated. This stage of COVID infection-related extreme oxidative stress is often referred to in the literature as a cytokine storm, and left unchecked this invariably leads to death (Hu et al., 2021).

Increasing concern has focused on the continued presence of the spike protein in the blood by itself, unattached to a virion, following COVID vaccination. Supposedly intended to initiate an immune response to the entire virus particle, the spike protein injections are disseminating throughout the body rather than staying put in the upper arm at the vaccine site while the immune response to it evolves. Furthermore, it also appears that these circulating spike proteins can enter cells on their own and replicate themselves without attached virus particles. This not only wreaks havoc inside those cells, it helps to assure the indefinite presence of the spike protein throughout the body.

It has also been suggested that large amounts of spike protein are just binding ACE2 receptors and not proceeding any further into the cell, effectively blocking or disabling normal ACE2 function in a given tissue. Additionally, when the spike protein binds a cell wall and “stops” there, the spike protein serves as a hapten (antigen) which can then initiate an autoimmune (antibody or antibody-like) response to the cell itself, rather than to the virus particle to which it is usually attached. Depending on the cell types to which such spike proteins bind, a wide variety of diseases with autoimmune qualities can result.

Finally, another worrisome property of the spike protein which alone would be of great concern is that the spike protein itself appears to be highly toxic. This intrinsic toxicity, along with the apparent ability of the spike protein to replicate itself indefinitely within the cells it enters, probably represents the way in which the vaccine can inflict its worst long-term damage, as the production of this toxin can continue indefinitely without other external factors at play.

In fact, the long-haul COVID syndrome likely represents a low-grade unresolved smoldering COVID infection with the same kind of spike protein persistence and clinical impact as is seen in many individuals after their COVID vaccinations (Mendelson et al., 2020; Aucott and Rebman, 2021; Raveendran, 2021).

Post-Vaccine Complications

While the totality of the mechanisms involved are far from being completely understood and worked out, the increasing occurrence of post-vaccine clinical complications is nevertheless very clear-cut and must be addressed as rapidly and effectively as possible. By itself, the disruption of ACE2 receptor function in so many areas of the body has resulted in an array of different side effects (Ashraf et al., 2021). Such clinical complications being seen in different organ systems and areas of the body, can all occur in the following three clinical situations. All three are “spike protein syndromes,” although the acute infection always includes the entirety of the virus particles along with the spike protein during the initial phases of the infection.

  1. in an active COVID-19 infection,
  2. during the long-haul COVID syndrome, or
  3. in response to a spike protein-laden vaccine, include the following:
    • Heart failure, heart injury, heart attack, myocarditis (Chen et al., 2020; Sawalha et al., 2021)
    • Pulmonary hypertension, pulmonary thromboembolism and thrombosis, lung tissue damage, possible pulmonary fibrosis (McDonald, 2020; Mishra et al., 2020; Pasqualetto et al., 2020; Potus et al., 2020; Dhawan et al., 2021)
    • Increased venous and arterial thromboembolic events (Ali and Spinler, 2021)
    • Diabetes (Yang et al., 2010; Lima-Martinez et al., 2021)
    • Neurological complications, including encephalopathy, seizures, headaches, and neuromuscular diseases. Also, hypercoagulability and stroke (AboTaleb, 2020; Bobker and Robbins, 2020; Hassett et al., 2020; Hess et al., 2020)
    • Gut dysbiosis, inflammatory bowel disease, and leaky gut (Perisetti et al., 2020; Zeppa et al., 2020; Hunt et al., 2021)
    • Kidney damage (Han and Ye, 2021)
    • Impaired male reproductive capacity (Seymen, 2021)
    • Skin lesions and other cutaneous manifestations (Galli et al., 2020)
    • General autoimmune diseases, autoimmune hemolytic anemia (Jacobs and Eichbaum, 2021; Liu et al., 2021)
    • Liver injury (Roth et al., 2021)

In structuring a clinical protocol to stop the ravages of persistent spike protein presence throughout the body, it is first important to realize that the protocol should be able to effectively treat any aspect of COVID infection, including those periods during active infection, after “active” infection (long-haul COVID), and during ongoing spike protein presence secondary to either “chronic” COVID infection or resulting from COVID vaccine administration.

Treatment Protocols

As is the case with any treatment for any condition, factors of expense, availability, and patient compliance always play a role in determining what treatment a given patient will actually undergo for a given period of time. As such, no one specific protocol will be appropriate for all patients, even if the same pathology is present. Ideally, of course, the best protocol is to use all of the options discussed below.

When the entirety of the protocol is not possible or feasible, which is most often the case, the combination of HP nebulization, high-dose vitamin C, and appropriately-dosed ivermectin is an excellent way to effectively address long-haul COVID and persistent spike protein syndromes.

Much of the rationale of the protocols is based on what is known about the spike protein and how it appears to inflict its harm. The following aspects of spike protein pathophysiology need to all be considered in crafting an optimal treatment protocol:

  • The ongoing production of spike protein by the vaccine-supplied mRNA into the cells for the purpose of stimulating the production of neutralizing antibodies (Khehra et al., 2021)
  • The binding of the spike protein, with or without an attached virion, to an ACE2 binding site on the cell wall, as an initial step to dissolving that portion of the cell wall, permitting the spike protein (and attached virus particle if present) into the cell
  • The binding of the spike protein to an ACE2 binding site, but just remaining bound to that site and not initiating enzymatic degradation of the cell wall, with or without an attached virion
  • The degree to which circulating spike protein is present in the blood and actively disseminating throughout the body
  • The fact that the spike protein by itself is toxic (pro-oxidant in nature) and capable of generating disease-generating oxidative stress throughout the body. This is addressed most directly by persistent and highly-dosed vitamin C.

Therapeutic Agents and Their Mechanisms

A substantial number of agents have already been found to be highly effective in resolving COVID infections, and even more are continuing to be discovered as worldwide research efforts have so intensely focused on curing this infection (Levy, 2020). Some of the most effective agents and their mechanisms of actions include the following:

  1. Hydrogen peroxide (HP) nebulization. Correctly applied, this treatment eliminates acute COVID pathogen presence and any other chronic pathogen colonizations persisting in the aerodigestive tract. Also, a positive healing effect on the lower digestive tract is typically seen, as less pathogens and their associated pro-oxidant toxins are chronically swallowed. Stunning anecdotal evidence has already been seen documenting the ability of HP nebulization to cure even advanced COVID infections (20 of 20 cases) as a monotherapy. (Levy, 2021). All of the supporting research, scientific analysis, and practical suggestions on this therapy is available as a free eBook download [Rapid Virus Recovery] (Levy, 2021).
  2. Vitamin C. Vitamin C works synergistically with HP in eradicating pathogens. It gives strong general immune support, while working to support the optimal healing of damaged cells and tissues. Clinically, it is the most potent antitoxin ever described in the literature, and no reports of it failing to neutralize any acute intoxication when administered appropriately have been published. Continuing persistent and highly-dosed vitamin C in all its forms will prove to be the most useful intervention when there is a large amount of circulating toxic spike protein present. Intravenous, regular oral forms, and liposome-encapsulated oral forms are all very useful in resolving any infection and neutralizing any toxin (Levy, 2002). There is also a polyphenol-based supplement that appears to allow some humans to synthesize their own vitamin C, which could prove to be of enormous protective and healing capacity with COVID patients and vaccine recipients. (
  3. Ivermectin. This agent has powerful antiparasitic and antiviral properties. Evidence indicates that ivermectin binds the ACE2 receptor site that the spike protein needs to bind to proceed with entry into the cell and the replication of viral protein (Lehrer and Rheinstein, 2020; Eweas et al., 2021). Also, under some circumstances, the binding of the spike protein to the ACE2 receptor does not activate the enzymes needed to enter the cell. Possibly, ivermectin might also competitively displace such bound spike protein from the cell walls as well when a sufficient dose is taken. It also appears that circulating spike protein can be bound up directly by ivermectin, rendering it inactive and making it accessible for metabolic processing and excretion (Saha and Raihan, 2021). Where there has been mass administration of ivermectin for parasitic diseases in Africa there has also been noted a significantly lower incidence of COVID-19 infection (Hellwig and Maia, 2021). Ivermectin is also very safe when administered appropriately (Munoz et al., 2018).
  4. Hydroxychloroquine (HCQ) and Chloroquine (CQ). Both HCQ and CQ have been shown to be very effective agents in resolving acute COVID-19 infections. They have also both been shown to be zinc ionophores that can increase intracellular zinc levels which can then inhibit the enzyme activity needed for viral replication. However, both HCQ and CQ have also been found to block the binding of COVID virus spike proteins to the ACE2 receptors needed to initiate viral entry into the cells, giving scientific support for their utility as more directly interfering with spike protein activity before the virus ever breaches the cell (Fantini et al., 2020; Sehailia and Chemat, 2020; Wang et al., 2020).
  5. Quercetin. Similar to HCQ and CQ, quercetin also serves as a zinc ionophore. And like HCQ and CQ, quercetin appears to also work to block the binding of COVID virus spike proteins to the ACE2 receptors, impairing spike protein-virus entry into the cell, or impairing spike protein alonef from entering the cells (Pan et al., 2020; Derosa et al., 2021). Many other phytochemicals and bioflavonoids are demonstrating this ACE2 binding capacity as well (Pandey et al., 2020; Maiti and Banerjee, 2021).
  6. Other Bio-Oxidative Therapies. These include ozone, ultraviolet blood irradiation, and hyperbaric oxygen therapy (in addition to hydrogen peroxide and vitamin C). These three therapies are highly effective in patients with acute COVID infections. It is less clear how effective they would be for long-haul COVID syndrome and patients suffering from ongoing vaccine-generated spike protein syndromes. That is not to say, however, that all three would not prove to be just as excellent for dealing with the spike protein as with the intact virus. It just remains to be determined.
  7. Baseline Vital Immune Support Supplementation. There are definitely hundreds, and perhaps thousands, of quality vitamin, mineral, and nutrient supplements that are all capable of making some contribution to reaching and maintaining optimal health, while minimizing the chances of contracting any kind of infectious disease. A baseline regimen of supplementation that factors in expense, overall health impact, and convenience should include vitamin C, vitamin D3, magnesium chloride (other forms good, but chloride form optimal for antiviral impact), vitamin K2, zinc, and an iodine supplement, such as Lugol’s solution or iodoral. More specific guidance in dosing can be found in Appendix A of Hidden Epidemic, also available as a free eBook download (Levy, 2017). Specifics on mixing up a solution of magnesium chloride for regular supplementation are also available (Levy, 2020).

[More detail on the therapeutic agents above is available in Chapter 10 of Rapid Virus Recovery]

The suggested optimal way to deal with acute COVID that has evolved into long-haul COVID, or with symptoms consistent with the toxic effects of circulating spike protein post-vaccination, is to always eliminate any active or chronic areas of pathogen proliferation with HP nebulization. Vitamin C supplementation should be optimized at the same time. 50-gram infusions of sodium ascorbate should be administered at least several times weekly as long as there is symptomatology attributable to long-haul COVID and circulating spike protein.

Initially, a 25-gram infusion of sodium ascorbate given three times a day should prove to be even more effective as circulating vitamin C is rapidly excreted. Oral vitamin C supplementation should be taken as well, either as several grams of liposome-encapsulated vitamin C daily, or as a teaspoon of sodium ascorbate powder several times daily. One capsule daily of Formula 216 can be added to this as well.

With the “foundation” of HP nebulization and vitamin C supplementation in place, the best prescription medicines to counter long-haul COVID and circulating spike protein would be with ivermectin first, and then HCQ or HQ if the clinical response is not acceptable. Dosages would need to be determined by the prescribing physician.

Along with the baseline immune support supplements noted above, quercetin, 500 to 1,000 mg daily, should be added as well.

Any and all of the above recommendations should be undertaken with the guidance of a trusted physician or other appropriately-trained health care professional.


Even as the COVID pandemic appears to be slowly subsiding, many individuals are now chronically ill with long-haul COVID and/or with the side effects of a COVID vaccination. It would appear that both clinical situations are primarily characterized by persistent presence of the spike protein and its negative impact on different tissues and organs.

Treatment is aimed at neutralizing the direct toxic impact of spike protein, while working to block its ability to bind the receptors needed to hijack the metabolism of the cell into making new viruses and/or more spike protein. At the same time, treatment measures are taken to assure that there is as complete an elimination of active or smoldering COVID infection remaining in the patient.

The views expressed in this article are the author’s and not necessarily those of the Orthomolecular Medicine News Service or all members of its Editorial Board. OMNS invites alternative viewpoints. Submissions may be sent directly to Andrew W. Saul, Editor, at the email contact address further below.

[Editor’s note: The information in this article is not meant to replace the advice of your doctor. Please consult with your personal physician before making any adjustments to your health care routine.]


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ChAdOx1 interacts with CAR and PF4 with implications for thrombosis with thrombocytopenia syndrome

Authors: ALEXANDER T. BAKERHTTPS://ORCID.ORG/0000-0001-8232-0531RYAN J. BOYDHTTPS://ORCID.ORG/0000-0002-6704-8696DAIPAYAN SARKARHTTPS://ORCID.ORG/0000-0002-4167-2108ALICIA TEIJEIRA-CRESPOCHUN KIT CHANEMILY BATESHTTPS://ORCID.ORG/0000-0003-1378-6981KASIM WARAICHHTTPS://ORCID.ORG/0000-0002-2927-7383JOHN VANTHTTPS://ORCID.ORG/0000-0003-0627-4603ERIC WILSONHTTPS://ORCID.ORG/0000-0002-4104-1445[…]MITESH J. BORADHTTPS://ORCID.ORG/0000-0003-2700-2658 +16 authors Authors Info & Affiliations


Vaccines derived from chimpanzee adenovirus Y25 (ChAdOx1), human adenovirus type 26 (HAdV-D26), and human adenovirus type 5 (HAdV-C5) are critical in combatting the severe acute respiratory coronavirus 2 (SARS-CoV-2) pandemic. As part of the largest vaccination campaign in history, ultrarare side effects not seen in phase 3 trials, including thrombosis with thrombocytopenia syndrome (TTS), a rare condition resembling heparin-induced thrombocytopenia (HIT), have been observed. This study demonstrates that all three adenoviruses deployed as vaccination vectors versus SARS-CoV-2 bind to platelet factor 4 (PF4), a protein implicated in the pathogenesis of HIT. We have determined the structure of the ChAdOx1 viral vector and used it in state-of-the-art computational simulations to demonstrate an electrostatic interaction mechanism with PF4, which was confirmed experimentally by surface plasmon resonance. These data confirm that PF4 is capable of forming stable complexes with clinically relevant adenoviruses, an important step in unraveling the mechanisms underlying TTS.

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Antigen Presentation of mRNA-Based and Virus-Vectored SARS-CoV-2 Vaccines

Authors: Ger T. Rijkers,1,2,* Nynke Weterings,1 Andres Obregon-Henao,3 Michaëla Lepolder,1 Taru S. Dutt,3 Frans J. van Overveld,1 and Marcela Henao-Tamayo3


Infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causes Coronavirus Disease 2019 (COVID-19), which has reached pandemic proportions. A number of effective vaccines have been produced, including mRNA vaccines and viral vector vaccines, which are now being implemented on a large scale in order to control the pandemic. The mRNA vaccines are composed of viral Spike S1 protein encoding mRNA incorporated in a lipid nanoparticle and stabilized by polyethylene glycol (PEG). The mRNA vaccines are novel in many respects, including cellular uptake and the intracellular routing, processing, and secretion of the viral protein. Viral vector vaccines have incorporated DNA sequences, encoding the SARS-CoV-2 Spike protein into (attenuated) adenoviruses. The antigen presentation routes in MHC class I and class II, in relation to the induction of virus-neutralizing antibodies and cytotoxic T-lymphocytes, will be reviewed. In rare cases, mRNA vaccines induce unwanted immune mediated side effects. The mRNA-based vaccines may lead to an anaphylactic reaction. This reaction may be triggered by PEG. The intracellular routing of PEG and potential presentation in the context of CD1 will be discussed. Adenovirus vector-based vaccines have been associated with thrombocytopenic thrombosis events. The anti-platelet factor 4 antibodies found in these patients could be generated due to conformational changes of relevant epitopes presented to the immune system.

1. Introduction

The high morbidity and mortality rate of coronavirus disease of 2019 (COVID-19) has triggered the rapid development of vaccines against its causative agent, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Vaccines are the most effective way to eliminate and control the virus [1,2]. Most of the vaccines developed for COVID-19 have shown very high levels of protection. Within one year after the outbreak of the pandemic and identification of the genomic structure of SARS-CoV-2, a number of highly effective vaccines were approved and used globally, as over 2.5 billion vaccine doses have been administered [3] (dated 25 June 2021; World Health Organization). The two major categories of SARS-CoV-2 vaccines are mRNA-based vaccines and viral vector vaccines, both targeting the Spike protein of the virus [4]. Worldwide, the most used mRNA vaccines are those of Pfizer/BioNTech (BNT162b2, brand name Comirnaty) and of Moderna (mRNA-1273, brand name COVID-19 Vaccine Moderna). The most-used adenovirus vector vaccines are the ones of Oxford/AstraZeneca (ChAdOx1 nCoV-19, brand names Vaxzevria and Covishield) and Jansen/Johnson and Johnson (Ad26.COV2.S, brand name Janssen COVID-19 Vaccine), as well as the Sputnik-V and CanSino vaccines.

Both mRNA vaccines for SARS-CoV-2 as well as viral vector based vaccines have turned out to be highly effective for protection against mild and severe COVID-19 cases. After vaccination, high titers of IgG and IgA antibodies against the Spike protein are generated which, in vitro, show a virus neutralizing capacity, and cytotoxic T cells are activated [5,6,7].

The aim of this review is to delineate the molecular pathways, outside and inside of the cell, which ultimately lead to the presentation of Spike peptides to the immune system. Both the classical antigen presentation routes via MHC class I to CD8+ T cells and via MHC class II to CD4+ T cells, as well as the antigen-presenting routes for presentation to non-conventional T cells, will be reviewed and discussed.

While SARS-CoV-2 vaccines are protecting from the severe illness and deaths due to COVID-19, after large-scale implementation, rare immune-mediated side effects became apparent. In particular, anaphylactic reactions and various thrombotic or abnormal bleeding have raised concern [8,9]. These side effects may be due to abnormal handling or presentation of the vaccine or vaccine additives to the immune system, of which the potential scenarios will be discussed.

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SARS-CoV-2 Spike Protein Impairs Endothelial Function via Downregulation of ACE 2

Authors: Yuyang Lei,1,2,*Jiao Zhang,1,2,5,*Cara R. Schiavon,8,9Ming He,5Lili Chen,2Hui Shen,5,10Yichi Zhang,5Qian Yin,2Yoshitake Cho,5Leonardo Andrade,8Gerald S. Shadel,9Mark Hepokoski,6Ting Lei,3Hongliang Wang,4Jin Zhang,7Jason X.-J. Yuan,6Atul Malhotra,6Uri Manor,8,†Shengpeng Wang,2,†Zu-Yi Yuan,1,† and John Y-J. Shyy5,†

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection relies on the binding of S protein (Spike glycoprotein) to ACE (angiotensin-converting enzyme) 2 in the host cells. Vascular endothelium can be infected by SARS-CoV-2,1 which triggers mitochondrial reactive oxygen species production and glycolytic shift.2 Paradoxically, ACE2 is protective in the cardiovascular system, and SARS-CoV-1 S protein promotes lung injury by decreasing the level of ACE2 in the infected lungs.3 In the current study, we show that S protein alone can damage vascular endothelial cells (ECs) by downregulating ACE2 and consequently inhibiting mitochondrial function.

We administered a pseudovirus expressing S protein (Pseu-Spike) to Syrian hamsters intratracheally. Lung damage was apparent in animals receiving Pseu-Spike, revealed by thickening of the alveolar septa and increased infiltration of mononuclear cells (Figure [A]). AMPK (AMP-activated protein kinase) phosphorylates ACE2 Ser-680, MDM2 (murine double minute 2) ubiquitinates ACE2 Lys-788, and crosstalk between AMPK and MDM2 determines the ACE2 level.4 In the damaged lungs, levels of pAMPK (phospho-AMPK), pACE2 (phospho-ACE2), and ACE2 decreased but those of MDM2 increased (Figure [B], i). Furthermore, complementary increased and decreased phosphorylation of eNOS (endothelial NO synthase) Thr-494 and Ser-1176 indicated impaired eNOS activity. These changes of pACE2, ACE2, MDM2 expression, and AMPK activity in endothelium were recapitulated by in vitro experiments using pulmonary arterial ECs infected with Pseu-Spike which was rescued by treatment with N-acetyl-L-cysteine, a reactive oxygen species inhibitor (Figure [B], ii).Open in a separate windowFigure.

SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2) Spike protein exacerbates endothelial cell (EC) function via ACE (angiotensin-converting enzyme) 2 downregulation and mitochondrial impairment. A, Representative H&E histopathology of lung specimens from 8- to 12 wk-old male Syrian hamsters 5-day post administration of pseudovirus overexpressing Spike protein (Pseu-Spike) or mock virus in control group (n=3 mice per group, 1×108 PFU). Thickened alveolar septa (red arrowhead) and mononuclear cell (red arrow). Scale bar=20 μm. B, Pseu-Spike (n=4) or mock virus (n=4)–infected hamster lungs were subjected to Western blot analysis for pAMPK (phospho-AMPK) T172, AMPK, pACE2 (phospho angiotensin-converting enzyme) S680, ACE 2, MDM2, peNOS S1176, peNOS T494, eNOS (endothelial NO synthase), and β-actin (B, i). Human pulmonary arterial EC (PAECs) were infected with Pseu-Spike or mock virus for 24 h with or without N-acetyl-L-cysteine (NAC; 5 mmol/L) pretreatment for 2 h. The protein extracts were analyzed by Western blot using antibodies against proteins as indicated (n=4; B, ii). C, Representative confocal images of mitochondrial morphology of ECs treated with human recombinant S1 protein or IgG (4 μg/mL) for 24 h (C, i) or infected with human adenovirus ACE2 S680D (ACE2-D) or ACE2 S680L (ACE2-L; 10 MOI) for 48 h (C, ii). Mitochondria were visualized using TOM20 antibody (n=4, 50 cells counted for each replicate). Scale bar=2.5 μm. Tubular: the majority of mitochondria in ECs was >10 μm in length; Intermediate: the mitochondria were <≈10 μm; Fragment: the majority of mitochondria were spherical (no clear length or width). D, Measurement of oxygen consumption rate (OCR, D, i and iii) and extracellular acidification rate (ECAR, D, ii and iv) in ECs infected with ACE2-D vs ACE2-L (10 MOI) for 48 h (n=3) or treated with IgG vs S1 protein (4 μg/mL) for 24 h (n=3). E, Real-time quantitative polymerase chain reaction analysis of the indicated mRNA levels in lung ECs from ACE2-D (n=4) and ACE2-L (n=4) knock-in mice. Eight-week-old ACE2-D and ACE2-L male mice with C57BL/6 background were used. F, Dose-response curves of acetylcholine (ACh, left)- and sodium nitroprusside (SNP, right)–mediated relaxation on the tension of phenylephrine (1 μmol/L) precontracted intrapulmonary artery stripes from Pseu-Spike-(ACh n=8, SNP n=5) or mock (ACh n=6, SNP n=5) virus–infected Syrian hamsters (1×108 PFU; F, i) and ACE2-D (n=6) or ACE2-L (n=5) mice (F, ii). The animal experiments were approved by the ethical committee of Xi’an Jiaotong University. 2-DG indicates 2-Deoxy-D-glucose; ACE2-D, a phospho-mimetic ACE2 with increased stability; ACE2-L, a dephospho-mimetic ACE2 with decreased stability; AMPK, AMP-activated protein kinase; AA/R, antimycin A&Rotenone; ENO2, enolase 2; FCCP, carbonyl cyanide-p-(trifluoromethoxy)phenylhydrazone; H&E, Hematoxylin and Eosin; HK2, hexokinase 2; HO1, heme oxygenase-1; MDM2, murine double minute 2; MOI, multiplicity of infection; NRF1, nuclear respiratory factor 1; peNOS, phospho-eNOS; PFKFB3, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3; Resp, respiration; and TFAM, transcription factor A, mitochondrial.

We next studied the impact of S protein on mitochondrial function. Confocal images of ECs treated with S1 protein revealed increased mitochondrial fragmentation, indicating altered mitochondrial dynamics (Figure [C], i). To examine whether these mitochondrial changes were due, in part, to the decreased amount of ACE2, we overexpressed ACE2 S680D (ACE2-D, a phospho-mimetic ACE2 with increased stability) or S680L (ACE2-L, a dephospho-mimetic with decreased stability)4 in ECs. As shown in Figure [C], ii, ECs with ACE2-L had a higher number of fragmented mitochondria when compared to those with ACE2-D. Performing oxygen consumption rate and extracellular acidification rate assays, we found that ECs overexpressing ACE2-L had reduced basal mitochondrial respiration, ATP production, and maximal respiration compared to ECs overexpressing ACE2-D (Figure [D], i). Moreover, ACE2-L overexpression caused increased basal acidification rate, glucose-induced glycolysis, maximal glycolytic capacity, and glycolytic reserve (Figure [D], ii). Also, ECs incubated with S1 protein had attenuated mitochondrial function but increased glycolysis, when compared with control cells treated with IgG (Figure [D], iii and iv). We also compared the expressions of mitochondria- and glycolysis-related genes in lung ECs isolated from ACE2-D or ACE2-L knock-in mice.4 Shown in Figure [E], the mRNA levels of NRF1HO1, and TFAM (mitochondria biogenesis-related genes) were increased, whereas those of HK2PFKFB3, and ENO2 (glycolysis-related genes) were decreased in lung ECs in ACE2-D mice, as compared to those in ACE2-L mice.

SARS-CoV-2 infection induces EC inflammation, leading to endotheliitis.1,5 Because S protein decreased ACE2 level and impaired NO bioavailability, we examined whether S protein entry is indispensable for dysfunctional endothelium. As shown in Figure [F], i, the endothelium-dependent vasodilation induced by acetylcholine was impaired in pulmonary arteries isolated from Pseu-Spike-administered hamsters, whereas the endothelium-independent vasodilation induced by sodium nitroprusside was not affected. We also compared the acetylcholine- and sodium nitroprusside–induced vasodilation of pulmonary vessels from ACE2-D or ACE2-L mice. As anticipated, acetylcholine-induced vasodilation was hindered in pulmonary arteries isolated from ACE2-L mice in comparison to ACE2-D mice (Figure [F], ii). There was, however, little difference in sodium nitroprusside–induced vasodilation between ACE2-D and ACE-L animals.

Although the use of a noninfectious pseudovirus is a limitation to this study, our data reveals that S protein alone can damage endothelium, manifested by impaired mitochondrial function and eNOS activity but increased glycolysis. It appears that S protein in ECs increases redox stress which may lead to AMPK deactivation, MDM2 upregulation, and ultimately ACE2 destabilization.4 Although these findings need to be confirmed with the SARS-CoV-2 virus in the future study, it seems paradoxical that ACE2 reduction by S protein would decrease the virus infectivity, thereby protecting endothelium. However, a dysregulated renin-angiotensin system due to ACE2 reduction may exacerbate endothelial dysfunction, leading to endotheliitis. Collectively, our results suggest that the S protein-exerted EC damage overrides the decreased virus infectivity. This conclusion suggests that vaccination-generated antibody and/or exogenous antibody against S protein not only protects the host from SARS-CoV-2 infectivity but also inhibits S protein-imposed endothelial injury.

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Salk researchers and collaborators show how the protein damages cells, confirming COVID-19 as a primarily vascular disease

LA JOLLA—Scientists have known for a while that SARS-CoV-2’s distinctive “spike” proteins help the virus infect its host by latching on to healthy cells. Now, a major new study shows that the virus spike proteins (which behave very differently than those safely encoded by vaccines) also play a key role in the disease itself.

The paper, published on April 30, 2021, in Circulation Research, also shows conclusively that COVID-19 is a vascular disease, demonstrating exactly how the SARS-CoV-2 virus damages and attacks the vascular system on a cellular level. The findings help explain COVID-19’s wide variety of seemingly unconnected complications, and could open the door for new research into more effective therapies.

Representative images of vascular endothelial control cells (left) and cells treated with the SARS-CoV-2 Spike protein (right) show that the spike protein causes increased mitochondrial fragmentation in vascular cells. Click here for a high-resolution image.
Credit: Salk Institute

“A lot of people think of it as a respiratory disease, but it’s really a vascular disease,” says Assistant Research Professor Uri Manor, who is co-senior author of the study. “That could explain why some people have strokes, and why some people have issues in other parts of the body. The commonality between them is that they all have vascular underpinnings.”

Salk researchers collaborated with scientists at the University of California San Diego on the paper, including co-first author Jiao Zhang and co-senior author John Shyy, among others.

While the findings themselves aren’t entirely a surprise, the paper provides clear confirmation and a detailed explanation of the mechanism through which the protein damages vascular cells for the first time. There’s been a growing consensus that SARS-CoV-2 affects the vascular system, but exactly how it did so was not understood. Similarly, scientists studying other coronaviruses have long suspected that the spike protein contributed to damaging vascular endothelial cells, but this is the first time the process has been documented.

In the new study, the researchers created a “pseudovirus” that was surrounded by SARS-CoV-2 classic crown of spike proteins, but did not contain any actual virus. Exposure to this pseudovirus resulted in damage to the lungs and arteries of an animal model—proving that the spike protein alone was enough to cause disease. Tissue samples showed inflammation in endothelial cells lining the pulmonary artery walls.

The team then replicated this process in the lab, exposing healthy endothelial cells (which line arteries) to the spike protein. They showed that the spike protein damaged the cells by binding ACE2. This binding disrupted ACE2’s molecular signaling to mitochondria (organelles that generate energy for cells), causing the mitochondria to become damaged and fragmented.

Previous studies have shown a similar effect when cells were exposed to the SARS-CoV-2 virus, but this is the first study to show that the damage occurs when cells are exposed to the spike protein on its own.

“If you remove the replicating capabilities of the virus, it still has a major damaging effect on the vascular cells, simply by virtue of its ability to bind to this ACE2 receptor, the S protein receptor, now famous thanks to COVID,” Manor explains. “Further studies with mutant spike proteins will also provide new insight towards the infectivity and severity of mutant SARS CoV-2 viruses.”

The researchers next hope to take a closer look at the mechanism by which the disrupted ACE2 protein damages mitochondria and causes them to change shape.

Other authors on the study are Yuyang Lei and Zu-Yi Yuan of Jiaotong University in Xi’an, China; Cara R. Schiavon, Leonardo Andrade, and Gerald S. Shadel of Salk; Ming He, Hui Shen, Yichi Zhang, Yoshitake Cho, Mark Hepokoski, Jason X.-J. Yuan, Atul Malhotra, Jin Zhang of the University of California San Diego; Lili Chen, Qian Yin, Ting Lei, Hongliang Wang and Shengpeng Wang of Xi’an Jiatong University Health Science Center in Xi’an, China.

The research was supported by the National Institutes of Health, the National Natural Science Foundation of China, the Shaanxi Natural Science Fund, the National Key Research and Development Program, the First Affiliated Hospital of Xi’an Jiaotong University; and Xi’an Jiaotong University.

VAERS Summary for COVID-19 Vaccines through 11/05/2021

Official Reported Vaccine Adverse Events in the FDA Data Base

For a Complete Report of All Vaccine Reported Adverse Events Through November 5th, 2021 Click Link Below:

Impact and effectiveness of mRNA BNT162b2 vaccine against SARS-CoV-2 infections and COVID-19 cases, hospitalizations, and deaths following a nationwide vaccination campaign in Israel: an observational study using national surveillance data

Eric J HaasFrederick J AnguloJohn M McLaughlinEmilia AnisShepherd R SingerFarid KhanNati BrooksMeir SmajaGabriel MircusKaijie PanJo SouthernDavid L SwerdlowLuis JodarYeheskel LevySharon Alroy-PreisAuthors:

During the analysis period (Jan 24 to April 3, 2021), there were 232 268 SARS-CoV-2 infections, 7694 COVID-19 hospitalizations, 4481 severe or critical COVID-19 hospitalizations, and 1113 COVID-19 deaths in people aged 16 years or older. By April 3, 2021, 4 714 932 (72∙1%) of 6 538 911 people aged 16 years and older were fully vaccinated with two doses of BNT162b2. Adjusted estimates of vaccine effectiveness at 7 days or longer after the second dose were 95∙3% (95% CI 94∙9–95∙7; incidence rate 91∙5 per 100 000 person-days in unvaccinated vs 3·1 per 100 000 person-days in fully vaccinated individuals) against SARS-CoV-2 infection, 91∙5% (90∙7–92∙2; 40∙9 vs 1∙8 per 100 000 person-days) against asymptomatic SARS-CoV-2 infection, 97∙0% (96∙7–97∙2; 32∙5 vs 0∙8 per 100 000 person-days) against symptomatic COVID-19, 97∙2% (96∙8–97∙5; 4∙6 vs 0∙3 per 100 000 person-days) against COVID-19-related hospitalization, 97∙5% (97∙1–97∙8; 2∙7 vs 0∙2 per 100 000 person-days) against severe or critical COVID-19-related hospitalization, and 96∙7% (96∙0–97∙3; 0·6 vs 0·1 per 100 000 person-days) against COVID-19-related death. In all age groups, as vaccine coverage increased, the incidence of SARS-CoV-2 outcomes declined. 8006 of 8472 samples tested showed a spike gene target failure, giving an estimated prevalence of the B.1.1.7 variant of 94∙5% among SARS-CoV-2 infections.

Effectiveness of mRNA BNT162b2 COVID-19 vaccine up to 6 months in a large integrated health system in the USA: a retrospective cohort study

Authors: Sara YTartofPhDaeJeff MSlezakMSaHeidiFischerPhDaVennisHongMPHaBradley KAckersonMDbOmesh NRanasingheMPHaTimothy BFranklandMAcOluwaseye AOgunMDaJoann MZamparoMPHdSharonGrayMSdSrinivas RValluriPhDdKaijePanMSdFrederick JAnguloPhDdLuisJodarPhDdJohn MMcLaughlinPhDd

Between Dec 14, 2020, and Aug 8, 2021, of 4 920 549 individuals assessed for eligibility, we included 3 436 957 (median age 45 years [IQR 29–61]; 1 799 395 [52·4%] female and 1 637 394 [47·6%] male). For fully vaccinated individuals, effectiveness against SARS-CoV-2 infections was 73% (95% CI 72–74) and against COVID-19-related hospital admissions was 90% (89–92). Effectiveness against infections declined from 88% (95% CI 86–89) during the first month after full vaccination to 47% (43–51) after 5 months. Among sequenced infections, vaccine effectiveness against infections of the delta variant was high during the first month after full vaccination (93% [95% CI 85–97]) but declined to 53% [39–65] after 4 months. Effectiveness against other (non-delta) variants the first month after full vaccination was also high at 97% (95% CI 95–99), but waned to 67% (45–80) at 4–5 months. Vaccine effectiveness against hospital admissions for infections with the delta variant for all ages was high overall (93% [95% CI 84–96]) up to 6 months.