Admitting that vaccines have health risks is uncomfortable, however safe they are in the vast majority. For influenza vaccines, febrile seizures (convulsions), Guillain–Barré syndrome (autoimmune nerve disorder), and anaphylaxis (severe allergic reaction) can happen. For Covid-19, anaphylaxis can occur from many vaccines, severe and fatal blood clots plus low platelets from AstraZeneca/Oxford (AZ/Ox) and J&J DNA vaccines, and myocarditis (heart inflammation) from Pfizer and Moderna mRNA vaccines.
Thankfully, the risks of these vaccine adverse events are very low and don't outweigh the benefits of vaccines in most situations. Still, it's prudent to understand them further to see if there’s anything else we can do about it.
Risk of heart inflammation from mRNA vaccines
First, heart inflammation has three main types: myocarditis (inflamed heart muscles), pericarditis (inflamed outer linings of the heart), and endocarditis (inflamed inner linings of the heart). But only myocarditis and pericarditis have been associated with mRNA vaccine.
Common clinical signs of mRNA vaccine-related myocarditis and pericarditis are elevated troponin (a blood biomarker of heart muscle damage) levels, abnormal cardiac imaging, and chest pain. Other rarer symptoms include headache, breathlessness, fatigue, and body ache.
Previously in “mRNA Vaccine Safety and Risks: A One-Year Update From the U.S., U.K., and Israel,” I covered two new high-quality population-based studies that shed light on the risks of heart inflammation from mRNA vaccines. I’ll just describe their findings in brief here.
In one of them, researchers from Israel found that individuals vaccinated with Pfizer’s mRNA vaccine had a 3.24-times increased risk of myocarditis within 21 days of either the first or second dose compared to unvaccinated individuals. This equated to an excess of 2.7 events per 100,000 persons. About 90% of those myocarditis cases happened to males aged 20–34 years.
For the second study, researchers from the U.S. calculated that 12–39-year-olds had a 9.8-times increased risk of myocarditis/pericarditis at days 1–21 of vaccination compared to those at days 22–42 of vaccination. This gives an excess of 6.3 cases per million doses. More specifically, 85% of cases affected males, 85% occurred within seven days of vaccination (more commonly after the second dose), 82% led to hospitalization, and 6% led to the intensive care unit (ICU). But 0% of cases led to death.
There are many other studies on mRNA vaccine-related heart inflammation with similar findings too, but the two discussed ones are of higher quality with larger sample sizes and proper control groups. From those two studies, we know that mRNA vaccine-related heart inflammation usually affects males under 40 years, regardless of any underlying medical conditions, within a week of getting the first or, more commonly, the second dose.
Probable theoretical causes
First, it’s unlikely that infections had caused the myocarditis or pericarditis in recently vaccinated individuals. Several case series on this matter did not detect the presence of infections that can cause heart inflammation in recently vaccinated individuals. Yes, heart inflammation is usually caused by infections, including viruses (e.g., SARS-CoV-2, influenza virus, adenovirus, and coxsackievirus) and bacteria (e.g., S. aureus and M. tuberculosis).
Moving on, an animal study offers clues to the probable cause of mRNA vaccine-related heart inflammation. This study examined the blood, tissue, and organ profiles of mice injected with Pfizer’s mRNA vaccine via the intramuscular (muscle) vs. intravenous (vein) route. Surprisingly, the intravenous route induced apoptotic cell death — as well as minor spike protein expression — in heart muscle cells, inflaming the heart muscles; that is, myocarditis. But the mice exhibited no symptoms of illness, suggesting that these biomolecular heart problems were not of clinical severity.
Neither myocarditis nor spike protein expression was present in mice in the intramuscular injection group. The authors then speculate that traces of mRNA vaccine entering the veins by accident during intramuscular injection might induce myocarditis and pericarditis in humans.
“The rare injection of a vaccine into a vein during planned intramuscular injection could contribute to the onset of myopericarditis,” an editorial of the study stated. “This is a relevant question since it is generally not recommended that a person administering the COVID-19 mRNA vaccine aspirate before injecting it into the deltoid muscle.”
Aspiration is the act of pulling back the syringe plunger to try to draw some blood before injecting the substance into the muscles. If blood is drawn, it means that the needle has punctured a blood vessel, and the needle is to be re-inserted. Aspiration has attracted controversies because it is a painful procedure with no confirmed benefits based on decades of research. This is because there are hardly any large blood vessels in the deltoid muscles.
Thus, the Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO) current guidelines don’t recommend aspiration before intramuscular injection of vaccines to minimize pain.
But in the context of the Covid-19 pandemic, where billions of vaccine doses have been given worldwide, we might see subtle harm in not practicing aspiration before intramuscular injection. Yet, there’s also no guarantee that the mass practice of aspiration would not be harmful. So, more research is needed to really know what’s the best method to administer vaccines.
That said, if traces of mRNA vaccine really entered the bloodstream after intramuscular injection, they might be able to enter the T tubules of heart muscle cells (cardiomyocytes) that are large enough to, in theory, allow the mRNA vaccine to pass through.
As the study authors explained: “Smaller mRNA-vaccine lipid-nanoparticles (100nm diameter) can be sucked into larger T tubules (diameter >200 nm) of cardiomyocytes during diastole, but not into T tubules of skeletal myocyte (diameter 20–40 nm). Thus, the T tubule system of cardiomyocytes may concentrate mRNA vaccine lipid-nanoparticles like a sponge.”
The same concern is also suspected for the probable cause of vaccine-induced thrombotic thrombocytopenia (severe and potentially fatal blood clots plus low platelets) from the AZ/Ox and J&J DNA-based vaccines.
"Leo Nicolai [a cardiologist] and his colleagues found in a mouse study that platelets clump together with adenovirus and become activated when the [AZ/Ox] vaccine is injected into blood vessels, but not when it is injected into muscle," Nature News reported. "It’s possible, says Nicolai, that on rare occasions, a vaccine is inadvertently injected into a vein... If so, many cases of VITT might be avoided by asking vaccinators to first draw a small amount of fluid from the injection site with the syringe to check for blood before they actually push the plunger to administer the vaccine. This is already standard practice in some countries, and Denmark has added it to its official guidelines for COVID-19 vaccine administration."
Another hypothesis researchers have raised is molecular mimicry, where antibodies generated against the mRNA vaccine-encoded spike proteins also reacted against heart-related proteins due to similarities in their protein structures. This problem might happen in individuals with a genetic or environmental predisposition to autoimmune disorders.
One more hypothetical cause I learned from an email discussion is that the faster metabolism of younger males might overly metabolize the mRNA vaccine, possibly creating more spike proteins that might generate more inflammation.
After all, in the context of Covid-19 vaccines, the mRNA (and DNA) vaccine relies on the body to produce spike proteins to train the immune system. Older vaccine technology, in contrast, injects a set amount of spike proteins or inactivated virions. So, this hypothesis explains why mRNA vaccine-related heart inflammation affects younger adult males nearly all the time. And why such heart inflammation concerns have not been observed in young people receiving non-mRNA vaccines.
Notably, Moderna’s mRNA vaccine is associated with a 2.5-times increased risk of myocarditis than Pfizer’s, according to unpublished data under review in the U.S. This finding makes sense given that Moderna’s mRNA vaccine dose (100 micrograms) is higher than Pfizer’s (30 micrograms), which could yield more spike protein production.
In the 2023 hallmark cohort study, Yonker et al. analyzed blood samples of 61 young individuals (mean age of 15) who received Pfizer's or Moderna's mRNA vaccine, of whom 16 developed myocarditis, typically after the second dose.
Increased pro-inflammatory mediators and plasma full-length spike protein (mean levels of 33.9 ± 22.4 pg/mL) were detected in vaccinees who developed myocarditis compared to those who did not (nil levels). Interestingly, these circulating spikes were unbound by antibodies (free-floating) and persisted for up to 3 weeks after vaccination (Figure 1).
Anti-spike protein antibody levels and neutralization capacity, as well as T-cell responses, were similar between groups. This observation suggests that differences in antibody abilities to neutralize the spike protein don’t explain myocarditis. Rather, mRNA vaccine-induced overexpression and subsequent leaking of spike protein may explain myocarditis.
In a previous cohort study, Ogata et al. found that 85% of 13 healthy recipients (median age of 24) of Moderna's mRNA vaccine had detectable levels of S1 spike protein in the plasma as early as day 1 after the first dose, which lasted for an average of five days (mean levels of 68 ± 21 pg/mL). Full-length spike protein was also detectable in 23% of recipients for an average of 15 days (mean levels of 62 ± 13 pg/mL) after the first dose. Plasma nucleocapsid was nill in all recipients, indicating the plasma spike protein is of vaccine origin, not SARS-CoV-2.
Taken together, Ogata et al.’s and Yonker et al.’s studies provide novel insights into how mRNA vaccines work. We now know individuals who got the mRNA vaccine may have varying levels of spike proteins in their bloodstream — likely due to accidental mRNA vaccine leakage into the blood — which may cause pathological immune reactions such as myocarditis or thrombocytopenia in a small minority of individuals.
More studies are thus needed to understand why some people exhibit elevated spike proteins in their bloodstream after getting the mRNA vaccine. Who is at risk? What activities trigger it? What is the mechanism of action? (Understanding the mechanism is one step forward to designing or finding an effective therapy that counters said mechanism).