A Deeper Dive Into Role of Spike Protein in Myocarditis, Blood Clotting After COVID-19 Vaccination

In this series, “Promise or Peril: Alarming COVID-19 mRNA Vaccine Issues,” we look at how the introduction of mRNA technology lacked an adequate regulatory framework, paving the way for serious adverse events and other concerns related to inadequate safety testing of lipid nanoparticles (LNP), spike protein, residual DNA- and lipid-related impurities, and truncated/modified mRNA species.

Previously, in Part 1, we discussed how the United States. The FDA relaxed the rules for mRNA vaccines in comparison to mRNA therapies and discussed the available data on LNP distribution throughout the body based on animal testing, the lack of human testing, and the lack of mRNA or spike protein biodistribution data. Parts 2 and 3 looked at how LNPs are made, how they behave in the body, and how they affect health.

Now we’ll look at another issue: the cargo in the LNP capsules: the mRNA and its encoded spike protein. The inflammatory response to the spike protein and one of its subunit proteins is discussed, as well as how they may contribute to serious adverse events such as myocarditis and blood clotting.

Dr. Rochelle Walensky, the former U.S. In June 2021, the Centers for Disease Control and Prevention (CDC) stated on “Good Morning America” that myocarditis cases are “really quite rare… minor, self-limited, they generally resolve with rest and standard medications.” However, this assertion was made based on a preliminary review of 300 cases and prior to conducting long-term follow-up.

A study published on August 1 followed 40 Hong Kong adolescents for up to a year. In 26 patients with initial abnormal findings, follow-up testing revealed that 58 percent of those with vaccine-associated myocarditis had persistent heart muscle scarring.

“There exists a potential long-term effect on exercise capacity and cardiac functional reserve during stress,” the study’s authors wrote.

This series shows how exposure to the spike protein causes downstream cardiovascular problems. Given that vaccination causes the body to produce more spike protein, it’s clear that more research was required before vaccination could be licensed.

Summary of Key Facts

• The SARS-CoV-2 spike protein and its S1 subunit have been linked to cardiovascular problems, including an increased risk of blood clotting.
• Following vaccination, the vaccine-induced spike protein and its S1 subunit were discovered in the blood.
• The spike protein has been shown in lab studies to activate white blood cells, which may result in an inflammatory response or clotting.
• Free spike protein was found in the blood of adolescents and young adults with post-mRNA vaccine myocarditis, but not in the blood of healthy control subjects who did not have myocarditis.
• The S1 subunit can interact with ACE2, platelets, and fibrin, which may cause an inflammatory response that leads to serious adverse events such as clots, myocarditis, and neurological problems.
• Lipid nanoparticles (LNP), as discussed in Part 3, act as adjuvants, stimulating the immune system. This innate immune response peaks six hours after vaccination and returns to baseline by day nine, roughly coinciding with the onset of myocarditis, which typically occurs within the first seven days after mRNA COVID-19 vaccination.
• There have been no studies to see how vaccination affects people who have already been infected with SARS-CoV-2.
• Because the spike protein was linked to small vessel microclots during COVID-19 illness, postvaccination cardiovascular effects were to be expected.
• The first deadline for FDA-mandated post-authorization safety studies has passed, but the full report has yet to be made public, to the best of our knowledge.

The spike protein protrudes like a crown of sticky handles from the SARS-CoV-2 virus. The spike protein’s function is to bind to the ACE2 receptor, allowing the virus to enter the cell. The ACE2 receptor is found in many human cells, including those in the lungs, kidneys, gut, heart, and blood vessel lining.
Spike protein is made up of two subunits: S1 and S2. The S1 subunit protein attaches to the ACE2 receptor and sits at the tip of the spike protein. When the spike protein binds to the receptor, it changes shape, allowing the virus to enter. After entering the cell, the SARS-CoV-2 virus uses the cell’s own protein manufacturing process to generate new viral proteins.

The S2 subunit may also disrupt tumor suppression, which could explain why COVID-19 is more severe in cancer patients.

Effective vaccines choose recognizable antigens that elicit a strong immune response. Because it is responsible for attaching to cells and gaining entry, the spike protein was chosen for the mRNA COVID-19 vaccine. According to research, the spike protein and its S1 subunit may also be responsible for cardiovascular complications following infection and vaccination.

According to research, the spike protein is found in the blood after COVID-19 infection and vaccination. The spike protein alters blood clotting and can cause an overactive immune response. A better understanding of these findings, as well as the specific roles that the spike protein and its S1 subunit play, will aid in determining who is most vulnerable to severe disease or vaccine-related adverse events.

Cardiovascular Effects of Spike Protein Following Infection

Despite the small size of the studies, the spike protein was discovered in the blood and clots of severely ill COVID-19 patients. The clinical evidence suggests that the spike protein’s cardiovascular effects have a fingerprint.
A study of 41 patients published in Frontiers in Immunology discovered that 30.4 percent of the 23 hospitalized had significant levels of spike protein in their blood. None of the remaining 18 healthy or mildly ill people had circulating spike protein.
A small case-control study found the spike protein in clots from COVID-19 patients suffering from acute ischemic stroke and myocardial infarction.
Another study discovered the S1 subunit in the plasma of 64% of COVID-19-positive patients, and S1 levels were found to be significantly related to disease severity. The nucleocapsid (N) protein was also found, which is a marker for COVID-19 infection. The authors hypothesized that the presence of S1 and N in plasma indicates that virus fragments enter the bloodstream, possibly as a result of tissue damage.
The exact sequence of events is unknown. Nonetheless, laboratory, clinical, and biopsy findings point to a role for the spike protein and its S1 subunit in blood clotting and heart injury.

Blood Clots Associated With Spike S1 Subunit

In laboratory experiments like the one described in Frontiers in Immunology, the spike protein S1 subunit initiates a chain reaction that creates the ideal conditions for clot formation. The S1 protein binds to the ACE2 receptor on the cells lining the blood vessels in this chain reaction. After binding to ACE2, immune cells are activated.
This cascade effect can also stimulate platelet binding, increasing the risk of clotting. Platelets are essential clotting agents that clump together to stop blood loss after injury. The authors went on to say that in vitro, “our group recently documented that exposing sera from severe COVID-19 patients to endothelial cells induced platelet aggregation.”

In other words, the S1 subunit is of interest because it appears to alter clotting mechanisms in vitro (in a test tube). If the S1 subunit has the ability to affect clotting agents such as fibrin, complement 3, and prothrombin, this could be a mechanism by which SARS-CoV-2 causes cardiovascular complications. Clotting alters blood flow, which can lead to thrombosis, stroke, and heart attack.

Atypical Blood Clots

Blood thinners were given to COVID-19 inpatients and outpatients to reduce the risk of clot formation, but this did not appear to reduce the clotting risk. This could be because the clots formed after S1 subunit exposure are not typical blood clots. Three studies have found that the S1 subunit is important in clotting risk.

1. Clots Resist Normal Disintegration
   First, adding the S1 subunit to healthy blood in the lab resulted in dense, fibrous clot deposits. Even when blood from healthy people was exposed to the S1 subunit, fibrous “amyloid” clots formed.
   The S1 subunit appears to be linked to clotting that is resistant to fibrinolysis, which is the normal breakdown of clots required to restore blood flow after injury. The amyloid clots are depicted in Figure 1 below.

Amyloid clots form when a protein becomes damaged and starts folding abnormally on itself. When these abnormal amyloid proteins build up in the body, they can disrupt normal function.
Figure 1. Amyloid Clots Formed in Response to Spike Protein S1

2. Amyloid Substances Can Be Produced by the S1 Subunit
   Second, certain protein segments on the S1 subunit may be responsible for these dense clots. The spike protein is made up of seven protein segments (peptides) that can cause fibrous (amyloid) substances to form. The fully intact spike protein (S1 and S2 subunits joined together to form the full spike) did not form this amyloid, but the S1 subunit did. This discovery is intriguing because it suggests that the spike protein’s subunits may have distinct effects on cells.
3. Spike inhibits the activity of other clot-inhibiting proteins.
   Third, spike protein can outcompete other proteins, preventing clot formation. In another laboratory experiment designed to better understand how this process works, scientists discovered that the spike protein inhibits proteins involved in clot breakdown.
   In conclusion, laboratory-based research indicates that the spike protein subunit S1 can induce clot formation and impair clot dissolution. While we don’t know how this translates to bodily processes, Epoch Times’ Jan Jekielek discussed clotting and the role of the spike protein with pathologist Dr. Ryan Cole on June 3 and Dr. Paul Marik on May 23. Dr. Cole explained in the interview that the spike protein stays in the body longer, inflames tissues wherever it lands, and acts as an irritant or toxin in the body.

Spike Protein Found in COVID-19-Vaccinated Myocarditis Patients

Spike protein was found in the blood and heart muscles of COVID-19-vaccinated patients with myocarditis but not in those without myocarditis.

Found in blood

The full-length spike protein was found in the blood of vaccinated adolescents with myocarditis but not in those without.
It’s unclear why the spike protein was floating around free and unbound by antibodies. Adolescents who developed myocarditis had immune markers that were similar to those who did not develop myocarditis. In other words, the myocarditis group did not appear to have any immune issues.

Rather, these teenagers may have had an overactive natural immune system. Strong natural (“innate”) immunity aids the body’s ability to fight disease without prior exposure. However, the first responders (inflammatory cytokines) can be exuberant at times. Myocarditis can occur if the innate immune response overreacts.

Found in Heart Muscle

The spike protein, which is coded by mRNA, has also been discovered in heart muscle cells. An endomyocardial (heart muscle) biopsy study was performed on 15 patients who developed myocarditis after vaccination. There was no other viral infection that could have caused the myocarditis.
The researchers discovered SARS-CoV-2 spike protein in nine of the fifteen patients. Immune cells (CD4+ T) were found in the biopsy samples as well. These findings point to an inflammatory response to the spike protein.

According to the authors, “Although a causal relationship between vaccination and the occurrence of myocardial inflammation cannot be established based on the findings, the cardiac detection of spike protein, the CD4+ T-cell-dominated inflammation, and the close temporal relationship argue for a vaccine-triggered autoimmune reaction.”

According to a 2022 modeling study, the spike protein can trigger an autoimmune response by mimicking human molecules, causing antibodies to bind to “self” proteins.

Spike S1 Detected in the Blood of Vaccinated Adults

Another study discovered that the S1 subunit was present in the blood of 11 of 13 adults vaccinated with Moderna’s mRNA-1273 as early as one day after vaccination.
Plasma was drawn from 13 participants at various points during the first month following each dose. To estimate the amount of mRNA translation into protein products, the antigens S1 and spike were measured.

S1 antigen was detected in the plasma of 11 participants after the first 100-microgram dose. In contrast, the spike antigen was found in three of the thirteen participants. The S1 antigen peak was detected five days after vaccination on average. Again, the timing of this S1 peak appears to add to the evidence of an autoimmune response in the week following vaccination.

mRNA Detected in Blood, Lymph Nodes After Vaccination

Vaccine mRNA, which codes for the spike protein and its S1 subunit, is also found in the blood and lymph nodes. Spike-encoded mRNA was found in the blood for 15 days after vaccination and in lymph nodes for up to 60 days. Exosomes containing spikes have been found to circulate in the blood for up to four months. This discovery is significant because it contradicts the CDC’s claim that mRNA is so fragile that it dissolves quickly at the injection site (see Figure 2a in Part 1).
After a viral infection, the lymph nodes continue to produce better-fitting antibodies. This is an important way that our bodies naturally prepare for new variants. High levels of vaccine-induced mRNA and spike protein, on the other hand, may be detrimental when the immune system is asked to respond to future variants. In other words, if the immune system is tasked with producing antibodies against a previous variant, it may be less agile when asked to produce a high-quality antibody against a new variant.

Inadequate Clinical Trials Leave Unresolved Questions

Given what we know about the SARS-CoV-2 virus’s virulence, we should not have assumed that the vaccine-encoded spike protein would be safe.
Given what we know about clotting problems after COVID-19 infection, future research should look into whether the S1 subunit produced in response to vaccination can cause clotting problems via the same pathway. Both lab experiments and human observations should be included in these studies.

Furthermore, we don’t know how much free spike protein is in circulation after infection versus vaccination.

The active ingredient in the COVID-19 vaccines was not studied prior to approval. To test the safety and biodistribution of the mRNA vaccines, the manufacturers used mRNA that encodes for a substitute protein (luciferase).

Pfizer submitted animal biodistribution data to regulatory agencies using luciferase surrogate RNA, as discussed in Part 1 of this series.
These studies, however, were insufficient in describing how mRNA, the spike protein, its S1 subunit, and the LNP carrier would interact with the human body.

We described laboratory findings indicating clotting associated with the S1 subunit in this article. These findings highlight the importance of thorough preclinical research. Pharmaceutical companies’ studies were insufficient to answer these questions.

We didn’t know how people would react to vaccination based on their age, gender, immune status, overall health, or history of prior SARS-CoV-2 infection. The original clinical trials did not include enough people who had already recovered from COVID-19, and they were not designed to provide insight into how prior infection might affect a person’s response to vaccination.

Required Pfizer Post-Authorization Safety Study Unavailable to Public

The pre-authorization studies were clearly insufficient. The FDA has only acknowledged that passive surveillance is insufficient to establish safety after authorization. In response to adverse event reports, the FDA ordered Pfizer to conduct additional research, with the first monitoring report due in October 2022.
The FDA acknowledges this fact on page 6 of the approval letter (see Figure 2 below):
“We determined that an analysis of spontaneous postmarketing adverse events reported under section 505(k)(1) of the FDCA will not be sufficient to assess known serious risks of myocarditis and pericarditis, as well as identify an unexpected serious risk of subclinical myocarditis.”
“Furthermore, the pharmacovigilance system required by section 505(k)(3) of the FDCA is insufficient to assess these serious risks.” As a result, we have determined that you must conduct the following studies based on appropriate scientific data. “Has the FDA received Pfizer’s monitoring report, which was due on October 31, 2022?” The next report, the interim report, is due in October.
Figure 2. FDA Postmarketing Safety Study Requirements

Part 1: FDA Oversight Required for New Vaccines and mRNA Therapies
Part 2: The Health Consequences of Poor COVID-19 mRNA Testing: Miscarriage, Vision Loss, and Immunotoxicity
Part 3: Lifting the Veil: mRNA Lipid Nanoparticle Design Created Potential for Clotting and Immune Overdrive
Part 5 will go over mRNA manufacturing issues involving contamination with double-stranded DNA and the possibility of genome integration.

◊ References

Addgene. Molecular Biology Reference. https://www.addgene.org/mol-bio-reference/#introduction

Alana F Ogata, Chi-An Cheng, Michaël Desjardins, Yasmeen Senussi, Amy C Sherman, Megan Powell, Lewis Novack, Salena Von, Xiaofang Li, Lindsey R Baden, David R Walt, Circulating Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Vaccine Antigen Detected in the Plasma of mRNA-1273 Vaccine Recipients, Clinical Infectious Diseases, Volume 74, Issue 4, 15 February 2022, Pages 715–718, https://doi.org/10.1093/cid/ciab465

Aldén M, Olofsson Falla F, Yang D, Barghouth M, Luan C, Rasmussen M, De Marinis Y. Intracellular Reverse Transcription of Pfizer BioNTech COVID-19 mRNA Vaccine BNT162b2 In Vitro in Human Liver Cell Line. Curr Issues Mol Biol. 2022 Feb 25;44(3):1115-1126. doi: 10.3390/cimb44030073. PMID: 35723296; PMCID: PMC8946961. https://pubmed.ncbi.nlm.nih.gov/35723296/

Allergic Reactions Including Anaphylaxis After Receipt of the First Dose of Pfizer-BioNTech COVID-19 Vaccine — United States, December 14–23, 2020. MMWR Morb Mortal Wkly Rep 2021;70:46–51. DOI: http://dx.doi.org/10.15585/mmwr.mm7002e1

Anderson EJ, Rouphael NG, Widge AT, et al. Safety and Immunogenicity of SARS-CoV-2 mRNA-1273 Vaccine in Older Adults N Engl J Med 2020; 383:2427-2438  https://www.nejm.org/doi/full/10.1056/NEJMoa2028436

Anderson S. CBER Plans for Monitoring COVID-19 Vaccine Safety and Effectiveness. https://stacks.cdc.gov/view/cdc/97349 October 20, 2020. Accessed 3/20/23.

Angeli F, Spanevello A, Reboldi G, Visca D, Verdecchia P. SARS-CoV-2 vaccines: Lights and shadows. Eur J Intern Med. 2021 Jun;88:1-8. doi: 10.1016/j.ejim.2021.04.019. Epub 2021 Apr 30. PMID: 33966930; PMCID: PMC8084611. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084611/#bib0043

Baker, A. T., Boyd, R. J., Sarkar, D., Teijeira-Crespo, A., Chan, C. K., Bates, E., Waraich, K., Vant, J., Wilson, E., Truong, C. D., Lipka-Lloyd, M., Fromme, P., Vermaas, J., Williams, D., Machiesky, L., Heurich, M., Nagalo, B. M., Coughlan, L., Umlauf, S., Chiu, P. L., … Borad, M. J. (2021). ChAdOx1 interacts with CAR and PF4 with implications for thrombosis with thrombocytopenia syndrome. Science Advances. 7(49), eabl8213. https://doi.org/10.1126/sciadv.abl8213

Baumeier C, Aleshcheva G, Harms D, Gross U, Hamm C, Assmus B, Westenfeld R, Kelm M, Rammos S, Wenzel P, Münzel T, Elsässer A, Gailani M, Perings C, Bourakkadi A, Flesch M, Kempf T, Bauersachs J, Escher F, Schultheiss H-P. Intramyocardial Inflammation after COVID-19 Vaccination: An Endomyocardial Biopsy-Proven Case Series. International Journal of Molecular Sciences. 2022; 23(13):6940. https://doi.org/10.3390/ijms23136940

Bloom, K., van den Berg, F. & Arbuthnot, P. Self-amplifying RNA vaccines for infectious diseases. Gene Ther 28, 117–129 (2021). https://doi.org/10.1038/s41434-020-00204-y. https://www.nature.com/articles/s41434-020-00204-y

Chauhan, H., Mohapatra, S., Munt, D.J. et al. Physical-Chemical Characterization and Formulation Considerations for Solid Lipid Nanoparticles. AAPS PharmSciTech 17, 640–651 (2016). https://doi.org/10.1208/s12249-015-0394-x

Chui CSL, Fan M, Wan EYF, et al. Thromboembolic events and hemorrhagic stroke after mRNA (BNT162b2) and inactivated (CoronaVac) COVID-19 vaccination: A self-controlled case series study. Lancet. 2022;(50). https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(22)00234-6/fulltext

Dag Berild J, Bergstad Larsen V, Myrup Thiesson E, et al. Analysis of Thromboembolic and Thrombocytopenic Events After the AZD1222, BNT162b2, and MRNA-1273 COVID-19 Vaccines in 3 Nordic Countries. JAMA Netw Open. 2022;5(6):e2217375. doi:10.1001/jamanetworkopen.2022.17375 https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2793348

daSilva RL. Viral-associated thrombotic microangiopathies. Hematology/Oncology and Stem Cell Therapy. 2011:4(2):51-59. https://www.sciencedirect.com/science/article/pii/S165838761150038X

De A, Ko YT. Why mRNA-ionizable LNPs formulations are so short-lived: causes and way-out. Expert Opin Drug Deliv. 2023 Feb;20(2):175-187. doi: 10.1080/17425247.2023.2162876. Epub 2023 Jan 1. PMID: 36588456. https://pubmed.ncbi.nlm.nih.gov/36588456/

Ehaideb, S.N., Abdullah, M.L., Abuyassin, B. et al. Evidence of a wide gap between COVID-19 in humans and animal models: a systematic review. Crit Care 24, 594 (2020). https://doi.org/10.1186/s13054-020-03304-8

European Medicines Agency https://www.ema.europa.eu/en/documents/assessment-report/comirnaty-epar-public-assessment-report_en.pdf

Faizullin D, Valiullina Y, Salnikov V, Zuev Y. Direct interaction of fibrinogen with lipid microparticles modulates clotting kinetics and clot structure. Nanomedicine. 2020 Jan;23:102098. doi: 10.1016/j.nano.2019.102098. Epub 2019 Oct 23. PMID: 31655206. https://pubmed.ncbi.nlm.nih.gov/31655206/

FDA. Considerations for Human Radiolabeled Mass Balance Studies – Guidance for Industry. https://www.fda.gov/media/158178/download May 2022.

FDA. Development and Licensure of Vaccines to Prevent COVID-19. https://www.fda.gov/media/139638/download

FDA-CBER-2021-5683-0013962 approved on: 09-Nov-2020. A Tissue Distribution Study of a [3H]-Labeled Lipid Nanoparticle-mRNA Formulation Containing ALC-0315 and ALC-0159 Following Intramuscular Administration in Wistar Han Rats. FINAL REPORT Test Facility Study No. 185350 Sponsor Reference No. ALC-NC-0552 https://phmpt.org/wp-content/uploads/2022/03/125742_S1_M4_4223_185350.pdf

Fertig TE, Chitoiu L, Marta DS, Ionescu VS, Cismasiu VB, Radu E, Angheluta G, Dobre M, Serbanescu A, Hinescu ME, Gherghiceanu M. Vaccine mRNA Can Be Detected in Blood at 15 Days Post-Vaccination. Biomedicines. 2022 Jun 28;10(7):1538. doi: 10.3390/biomedicines10071538. PMID: 35884842; PMCID: PMC9313234. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9313234/

Grobbelaar LM et al. SARS-CoV-2 spike protein S1 induces fibrin(ogen) resistant to fibrinolysis: implications for microclot formation in COVID-19   Biosci Rep (2021) 41 (8): BSR20210611. https://doi.org/10.1042/BSR20210611

Hou, X., Zaks, T., Langer, R. et al. Lipid nanoparticles for mRNA delivery. Nat Rev Mater 6, 1078–1094 (2021). https://doi.org/10.1038/s41578-021-00358-0

Iaboni A, Jindal N, Betschel SD, Song C. Second-dose mRNA COVID-19 vaccine safety in patients with immediate reactions after the first dose: A case series. Journal of Allergy and Clinical Immunology: Global. 2022;1(3): 172-174. https://www.sciencedirect.com/science/article/pii/S2772829322000200

Let’s talk about lipid nanoparticles. Nat Rev Mater 6, 99 (2021). https://www.nature.com/articles/s41578-021-00281-4

Li, JX., Wang, YH., Bair, H. et al. Risk assessment of retinal vascular occlusion after COVID-19 vaccination. npj Vaccines 8, 64 (2023). https://doi.org/10.1038/s41541-023-00661-7

Michieletto, D., Lusic, M., Marenduzzo, D. et al. Physical principles of retroviral integration in the human genome. Nat Commun 10, 575 (2019). https://doi.org/10.1038/s41467-019-08333-8

Moghimi, S. M., & Simberg, D. (2022). Pro-inflammatory concerns with lipid nanoparticles. Molecular therapy : The Journal of the American Society of Gene Therapy, 30(6), 2109–2110. https://doi.org/10.1016/j.ymthe.2022.04.011

Naturally Inspired Podcast. Jessica Rose PhD – VAERS, Data And Truth  https://www.audible.com/pd/Jessica-Rose-PhD-VAERS-Data-And-Truth-Podcast/B09YMLJGBN?clientContext=132-5166709-6339436&loginAttempt=true&noChallengeShown=true

Nunez-Castilla J, Stebliankin V, Baral P, Balbin CA, Sobhan M, Cickovski T, Mondal AM, Narasimhan G, Chapagain P, Mathee K, et al. Potential Autoimmunity Resulting from Molecular Mimicry between SARS-CoV-2 Spike and Human Proteins. Viruses. 2022; 14(7):1415. https://doi.org/10.3390/v14071415

Nyström S, Hammarström P. Amyloidogenesis of SARS-CoV-2 Spike Protein. J. Am. Chem. Soc. 2022, 144, 20, 8945–8950. https://pubs.acs.org/doi/10.1021/jacs.2c03925

Ogata AF, Maley AM, Wu C, et al. Ultra-Sensitive Serial Profiling of SARS-CoV-2 Antigens and Antibodies in Plasma to Understand Disease Progression in COVID-19 Patients with Severe Disease, Clinical Chemistry, Volume 66, Issue 12, December 2020, Pages 1562–1572, https://doi.org/10.1093/clinchem/hvaa213

Ohlson J. Plasmid manufacture is the bottleneck of the genetic medicine revolution. Drug Discov Today. 2020 Oct 16;25(11):1891–3. doi: 10.1016/j.drudis.2020.09.040. Epub ahead of print. PMID: 33075470; PMCID: PMC7564888. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564888/

Perico L, Marina Morigi M, Galbusera M, et al.  SARS-CoV-2 Spike Protein 1 Activates Microvascular Endothelial Cells and Complement System Leading to Platelet Aggregation. Front. Immunol. 2022 https://www.frontiersin.org/articles/10.3389/fimmu.2022.827146/full

Qin, S., Tang, X., Chen, Y. et al. mRNA-based therapeutics: powerful and versatile tools to combat diseases. Sig Transduct Target Ther 7, 166 (2022). https://doi.org/10.1038/s41392-022-01007-w

Rafati A, Pasebani Y, Jameie M, et al. Association of SARS-CoV-2 Vaccination or Infection With Bell Palsy: A Systematic Review and Meta-analysis. JAMA Otolaryngol Head Neck Surg. Published online April 27, 2023. doi:10.1001/jamaoto.2023.016 https://jamanetwork.com/journals/jamaotolaryngology/fullarticle/2804297

Rhea EM, Logsdon AF, Hansen KM, Williams LM, Reed MJ, Baumann KK, Holden SJ, Raber J, Banks WA, Erickson MA. The S1 protein of SARS-CoV-2 crosses the blood-brain barrier in mice. Nat Neurosci. 2021 Mar;24(3):368-378. doi: 10.1038/s41593-020-00771-8. Epub 2020 Dec 16. PMID: 33328624; PMCID: PMC8793077. https://pubmed.ncbi.nlm.nih.gov/33328624/

Röltgen K, Nielsen SCA, Silva O. Immune imprinting, breadth of variant recognition, and germinal center response in human SARS-CoV-2 infection and vaccination. Cell 2022;185(6):1025-1040. https://www.cell.com/cell/fulltext/S0092-8674(22)00076-9

Rosenblum HG,  Gee J, Liu R, et al. Safety of mRNA vaccines administered during the initial 6 months of the US COVID-19 vaccination program: an observational study of reports to the Vaccine Adverse Event Reporting System and v-safe. Lancet Infectious Diseases. 2022;22(6):802-812. https://doi.org/10.1016/S1473-3099(22)00054-8

Schmeling, M, Manniche, V, Hansen, PR. Batch-dependent safety of the BNT162b2 mRNA COVID-19 vaccine. Eur J Clin Invest. 2023; 00:e13998. doi:10.1111/eci.13998. https://pubmed.ncbi.nlm.nih.gov/36997290/

Singh N, Bharara Singh A. S2 subunit of SARS-nCoV-2 interacts with tumor suppressor protein p53 and BRCA: an in silico study. Transl Oncol. 2020 Oct;13(10):100814. doi: 10.1016/j.tranon.2020.100814. Epub 2020 Jun 30. PMID: 32619819; PMCID: PMC7324311.

Srinivasan M, Thangaraj SR, Arzoun H. Gene Therapy – Can it Cure Type 1 Diabetes? Cureus. 2021 Dec 19;13(12):e20516. doi: 10.7759/cureus.20516. PMID: 35004071; PMCID: PMC8723777. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8723777/

Trougakos IP, Terpos E, Alexopoulos H, et al. Adverse effects of COVID-19 mRNA vaccines: the spike hypothesis. Cell 2022;28(7): P542-554. https://www.cell.com/trends/molecular-medicine/fulltext/S1471-4914(22)00103-4

Vervaeke P, Borgos SE, Sanders NN, Combes F. Regulatory guidelines and preclinical tools to study the biodistribution of RNA therapeutics. Adv Drug Deliv Rev. 2022 May;184:114236. doi: 10.1016/j.addr.2022.114236. Epub 2022 Mar 26. PMID: 35351470; PMCID: PMC8957368. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8957368/

Wong DWL, Klinkhammer BM, Djudjaj S, Villwock S, Timm MC, Buhl EM, Wucherpfennig S, Cacchi C, Braunschweig T, Knüchel-Clarke R, Jonigk D, Werlein C, Bülow RD, Dahl E, von Stillfried S, Boor P. Multisystemic Cellular Tropism of SARS-CoV-2 in Autopsies of COVID-19 Patients. Cells. 2021 Jul 27;10(8):1900. doi: 10.3390/cells10081900. PMID: 34440669; PMCID: PMC8394956. https://pubmed.ncbi.nlm.nih.gov/34440669/

Yonker LM, Swank Z, Bartsch YC, et al. Circulating Spike Protein Detected in Post–COVID–19 mRNA Vaccine Myocarditis. Circulation. 2023:147(11).  https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.122.061025

Yu CK, Tsao S, Ng CW, Chua GT, Chan KL, Shi J, Chan YY, Ip P, Kwan MY, Cheung YF. Cardiovascular Assessment up to One Year After COVID-19 Vaccine-Associated Myocarditis. Circulation. 2023 Aug;148(5):436-439. doi: 10.1161/CIRCULATIONAHA.123.064772. Epub 2023 Jul 31. PMID: 37523760; PMCID: PMC10373639.

Zheng Y, Zhao J, Li J, Guo Z, Sheng J, Ye X, Jin G, Wang C, Chai W, Yan J, Liu D, Liang X. SARS-CoV-2 spike protein causes blood coagulation and thrombosis by competitive binding to heparan sulfate. Int J Biol Macromol. 2021 Dec 15;193(Pt B):1124-1129. doi: 10.1016/j.ijbiomac.2021.10.112. Epub 2021 Oct 29. PMID: 34743814; PMCID: PMC8553634. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8553634/