In this series, "Promise or Peril: Alarming COVID-19 mRNA Vaccine Issues," we explore how the introduction of mRNA technology lacked an adequate regulatory framework, setting the stage for serious adverse events and other concerns related to inadequate safety testing of lipid nanoparticles (LNP), spike protein, and residual DNA- and lipid-related impurities, as well as truncated/modified mRNA species.
Previously: In Part 1, we introduced how the U.S. Food and Drug Administration (FDA) relaxed the rules for mRNA vaccines compared to mRNA therapies and discussed the available data regarding LNP distribution throughout the body based on animal testing, the fact that human testing wasn't done, and the lack of mRNA or spike protein biodistribution data. In Parts 2 and 3, we explored how the LNPs are constructed and how they behave in the body and affect health.Now, we turn to another problem—the cargo contained in the LNP capsules: the mRNA and its encoded spike protein. We introduce the inflammatory response to the spike protein and one of its subunit proteins and how they may contribute to serious adverse events such as myocarditis and blood clotting.
"There exists a potential long-term effect on exercise capacity and cardiac functional reserve during stress," the authors concluded.
Summary of Key Facts
- The SARS-CoV-2 spike protein and its S1 subunit have known effects on the cardiovascular system, such as an increased risk of blood clotting.
- The vaccine-induced spike protein and its S1 subunit have been found in the blood following vaccination.
- In lab studies, the spike protein activates white blood cells and may trigger 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 healthy control subjects without myocarditis.
- The S1 subunit can interact with ACE2, platelets, and fibrin and may be what leads to an inflammatory response driving serious adverse events, including clots, myocarditis, and neurological problems.
- As discussed in Part 3, lipid nanoparticles (LNP) act as adjuvants, stimulating the immune system. This innate immune response peaks within six hours of vaccination and returns to baseline by about day nine, temporally corresponding to the onset of myocarditis, which typically occurs within the first seven days following mRNA COVID-19 vaccination.
- Studies haven't been done to evaluate how vaccination affects those who have already been infected with SARS-CoV-2.
- The spike protein was implicated in small vessel microclots during COVID-19 illness; thus, postvaccination cardiovascular effects should have been anticipated.
- The first deadline for FDA-mandated post-authorization safety studies has passed, yet to the best of our knowledge, the full report hasn't been made available to the public.
Spike protein is comprised of two parts: the S1 and S2 subunits. The S1 subunit protein sits at the tip of the spike protein and is responsible for attaching to the ACE2 receptor. Once bound to the receptor, the spike protein changes shape to allow the virus to enter. Having accessed the inside of the cell, the SARS-CoV-2 virus uses the cell's own protein manufacturing process to make new viral proteins.
Effective vaccines select recognizable antigens that induce a robust immune response. The spike protein was chosen for the mRNA COVID-19 vaccine because it's responsible for attaching to cells and gaining entry. However, research suggests that the spike protein and its S1 subunit may also be responsible for cardiovascular complications following both infection and vaccination.
Cardiovascular Effects of Spike Protein Following InfectionAlthough the studies are small, the spike protein has been found in the blood and clots of severely ill COVID-19 patients. The clinical evidence suggests a fingerprint of the spike protein’s cardiovascular effects.
Blood Clots Associated With Spike S1 SubunitIn laboratory experiments such as those performed in the Frontiers in Immunology study, the spike protein S1 subunit causes a chain reaction that sets up the right conditions for clots to form. In this chain reaction, the S1 protein binds to the ACE2 receptor on the cells lining the blood vessels. Binding to ACE2 then activates immune cells.
This domino effect can also stimulate platelet binding, increasing clotting risk. Platelets are essential clotting agents that stop blood loss following injury by clumping together. The authors further noted that in vitro, “our group recently documented that exposing sera from severe COVID-19 patients to endothelial cells induced platelet aggregation.”
Atypical Blood ClotsProviding blood thinners to decrease the risk of clot formation did not appear to reduce the clotting risk in COVID-19 inpatients or outpatients. This may be because the clots formed after exposure to the S1 subunit may not be typical blood clots. Three findings suggest that the S1 subunit is important to clotting risk.
1. Clots Resist Normal BreakdownFirst, when the S1 subunit was added to healthy blood in the lab, it created dense, fibrous clot deposits. These fibrous “amyloid” clots formed even when blood taken from healthy people was exposed to the S1 subunit.
The S1 subunit appears to be associated with clotting resistant to fibrinolysis—the normal breakdown of clots necessary to restore blood flow after injury. These amyloid clots are shown in Figure 1 below.
Figure 1. Amyloid Clots Formed in Response to Spike Protein S1
2. S1 Subunit Can Induce Amyloid SubstancesSecond, these dense clots may be caused by certain protein segments on the S1 subunit. The spike protein has seven protein segments (peptides) that can induce fibrous (amyloid) substances. While the fully intact spike protein (S1 and S2 subunits attached to form the full spike) didn't form this amyloid, the S1 subunit did. This finding is interesting because it suggests that the subunits of the spike protein may have unique effects on cells.
3. Spike Blocks Other Clot-Inhibiting ProteinsThird, spike protein can outcompete other proteins, which prevent clots from forming. In another laboratory experiment designed to understand how this process plays out, scientists found that the spike protein blocks proteins important to breaking down clots.
Spike Protein Found in COVID-19-Vaccinated Myocarditis PatientsStudies of COVID-19-vaccinated patients diagnosed with myocarditis found spike protein in the patients' blood and heart muscles but not in those without myocarditis.
Found in BloodThe full-length spike protein has been found in the blood of vaccinated adolescents with myocarditis but not in the blood of those without myocarditis.
It's unclear why the spike protein was circulating freely or unbound by antibodies. The adolescents who developed myocarditis had similar immune markers to those who did not develop myocarditis. In other words, the group with myocarditis didn't appear to have any immune problems.
Found in Heart MuscleThe spike protein coded by mRNA has also been found in heart muscle cells. An endomyocardial (heart muscle) biopsy study was conducted among 15 patients with myocarditis following vaccination. No other viral infection could be found that might have caused the myocarditis.
The investigators found SARS-CoV-2 spike protein in nine of the 15 patients. Immune cells (CD4+ T) were also detected in the biopsy samples. These observations suggest an inflammatory reaction to the spike protein.
The authors concluded: "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."
Spike S1 Detected in the Blood of Vaccinated AdultsAnother study found that 11 of 13 adults vaccinated with Moderna’s mRNA-1273 had the S1 subunit in their blood as early as one day after vaccination.
Plasma was collected from 13 participants at various times during the first month after each dose. The antigens S1 and spike were measured to estimate the amount of mRNA translation into protein products.
mRNA Detected in Blood, Lymph Nodes After VaccinationVaccine mRNA, which encodes the spike protein and its S1 subunit, also persists in the blood and lymph nodes. Following vaccination, spike-encoded mRNA has been found in the blood for 15 days and in lymph nodes for up to 60 days. Spike-laden exosomes have been found circulating in the blood for up to four months. This finding is important because it refutes the CDC's claim that the mRNA is so fragile that it dissolves quickly at the injection site (see Figure 2a in Part 1).
Inadequate Clinical Trials Leave Unresolved QuestionsGiven what we know about the harmful effects of the SARS-CoV-2 virus, we should not have assumed that the vaccine-encoded spike protein would be harmless.
And, given what we know about clotting issues following COVID-19 infection, future studies should test whether the S1 subunit produced in response to vaccination can also cause clotting issues via the same pathway. These studies should include both lab experiments and human observations.
In addition, we don't know the relative amounts of free spike protein in circulation following infection versus vaccination.
In the case of the COVID-19 vaccines, the active ingredient wasn't studied prior to authorization. The manufacturers used mRNA that encodes for a substitute protein (luciferase) to test the safety and biodistribution of the mRNA vaccines.
However, these studies were inadequate in describing how mRNA, the spike protein, its S1 subunit, and the LNP carrier would affect the human body.
In this article, we described laboratory findings showing clotting associated with the S1 subunit. Studies like these reinforce why thorough preclinical studies are so crucial. The studies conducted by pharmaceutical companies weren't sufficient to address these questions.
Required Pfizer Post-Authorization Safety Study Unavailable to PublicPre-authorization studies were clearly inadequate. Post-authorization, the FDA has only acknowledged that passive surveillance is insufficient to establish safety. The agency responded to adverse event reports by requiring Pfizer to conduct additional studies, with the first monitoring report due October 2022.
"We have 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 and identify an unexpected serious risk of subclinical myocarditis.