New Research Reveals the Mechanism Linking COVID-19 Vaccines and Rare Myocarditis

Key Points:

• A recent Stanford Medicine study identifies two specific immune proteins, CXCL10 and IFN-gamma, as key drivers in the rare instances of myocarditis following mRNA-based COVID-19 vaccines.
• The condition, myocarditis (heart muscle inflammation), is a rare side effect, most often seen in young males, particularly after the second dose of an mRNA vaccine.
• The risk of myocarditis from COVID-19 infection itself is significantly higher than the risk associated with the mRNA Vaccine Safety profile.

The rapid global rollout of mRNA COVID-19 vaccines transformed the fight against the pandemic. While lauded for their efficacy and rapid development, these vaccines have a known, albeit rare, association with myocarditis-an inflammation of the heart muscle. 

Identifying the Inflammatory Cascade

Stanford Medicine recently published a study based upon the biological pathway that may lead to vaccine-associated myocarditis. The new research, led by Dr. Joseph Wu, gives the clearest explanation yet for why this complication so rarely occurs.

The researchers collated blood data from vaccinated people who had myocarditis and those who did not. They detected significantly high blood levels of two proteins in patients with vaccine-associated myocarditis, namely CXCL10 and IFN-gamma.

The Immune System’s “Friendly Fire”

These two proteins, the Stanford team says, work in tandem like a “tag team” to wreak their havoc. A two-step sequence appears to be what is taking place.

First, the mRNA vaccine stimulates the immune cells, macrophages, representing the very major source of CXCL10.

The second involves the activation of other types of immune cells, known as T cells, by activated macrophages through the released CXCL10 and vaccine components themselves; the T cells, in turn, release IFN-gamma.

The resultant tide of inflammatory activity initiates the invasion of the heart tissue by other phalanxes of warrior immune cells, such as neutrophils. This is unfortunate because this immune cell buildup can result in “friendly fire,” killing innocent heart muscle cells through collateral damage, a process reflected by high blood levels of the cardiac injury biomarker, cardiac troponin.

Context and Incidence Rates

It is important to put this risk into perspective. The symptoms of myocarditis-chest pain, shortness of breath, palpitations-usually appear rapidly, within one to three days after immunization.

The reported incidence rates, while low, have a notable pattern: the risk increases to about one in 32,000 after a second dose, compared with about one in 140,000 after the first dose. 

The highest incidence peaks among young male vaccines aged 30 years or below at roughly one in 16,750, according to the report.

Most importantly, the clinical course for vaccine-associated myocarditis is generally mild, with the majority of cases resolving quickly and with full heart function retained or restored, says Dr. Wu. It is not considered a traditional heart attack, as there is no blockage of blood vessels.

Related Research and Mechanisms

Findings from Stanford Medicine are in line with prior hypotheses on causes, yet they extend them. Other mechanisms have also been investigated.

Molecular Mimicry

According to this theory, the immune system, taught by the vaccine to recognize the spike protein of SARS-CoV-2, would mistakenly perceive similar protein sequences on the heart cells as a threat. 

Antibodies or T cells thus cross-react to mount an autoimmune-like, inflammatory attack on the heart. The idea has been pursued in a systematic review and meta-analysis presented in the NIH archives, emphasizing that determining a causal link is challenging and more research is needed.

Persistent Spike Protein

Another hypothesis, reported by the American Heart Association Journals, is that in some adolescents and young adults who developed myocarditis, there was a consistently high level of full-length spike protein circulating free in the blood, not bound by antibodies. This persistence can act as a prolonged trigger of inflammation.

Besides, myocarditis has hardly ever been attributed to other vaccinations, such as smallpox and influenza; thus, it is not unprecedented in vaccinology that inflammatory responses may sometimes occur as rare reactions.

The Overwhelming Benefit

Public health experts, throughout this process, have consistently reminded that the benefits of vaccination far outweigh the risks. The incidence of myocarditis following SARS-CoV-2 infection is substantially higher-than in some estimates, by dozens of times-compared to the rate associated with the mRNA vaccines.