Myocarditis associated with COVID-19 vaccination | npj Vaccines – Nature.com

The optimal response to a pandemic requires immediate and well-integrated action that includes, implementation of containment measurements, identification of the causative infectious agent, generation of specific diagnostics, and rapid development, authorization and roll-out of safe and effective therapeutics and vaccines. As demonstrated during the COVID-19 pandemic, prevention of disease by vaccination is crucial to reduce hospitalisation, mortality, and disruption of the healthcare system. Recently developed vaccine technologies like the messenger RNA (mRNA) vaccines proved to be most impactful since they paired short development and production timelines with high levels of protection. These vaccines have saved millions of lives and have been key in allowing the re-opening of society after a series of lockdowns.

Wide use of these vaccines was based on a clear positive benefit-risk balance, not only for the most vulnerable subjects prone to develop severe COVID-19, like the elderly and people with specific co-morbidities, but also for healthy individuals including those at young age. COVID-19 vaccines are very safe, nevertheless close safety monitoring post authorization resulted in the prompt identification of very rare adverse reaction events that were thoroughly assessed by EMA Pharmacovigilance Risk Assessment Committee (PRAC), and regulators worldwide. Among these, myocarditis and pericarditis cases emerged as very rare adverse events almost exclusively following immunisation with mRNA vaccines. These rare vaccination-associated disease manifestations could only be discovered post-authorisation since due to their low frequency they could not be identified earlier, not even in large trials involving tens of thousands of volunteers.

Pericarditis is a swelling and irritation of the tissue surrounding the heart (pericardium) and is usually mild and resolves without treatment. Myocarditis is an inflammation of the cardiac muscle (myocardium), which can reduce the ability of the heart to pump blood. In addition to immune activation due to e.g., autoimmunity and exposure to drugs (check-point inhibitors)1 these conditions have been linked to several viral infections2 including infection with SARS-CoV-23 and also to vaccines, like live attenuated virus smallpox vaccines4. More recently pharmacovigilance surveillance and observational studies across the globe have pointed at an increased risk of myocarditis in predominantly younger males post administration of the two COVID-19 mRNA vaccines, Comirnaty and Spikevax, and also after vaccination with the adjuvanted protein-based vaccine Nuvaxovid and the adenovirus vector-based vaccine Jcovden5,6,7,8. Most cases of vaccine associated myocarditis are mild, transient, and self-limiting. However, occasionally, as with myocarditis caused by viral infection, chronic myocarditis and dilated cardiomyopathy might develop which can result in congestive heart failure and may even be fatal in very rare occasion9.

The efforts in collecting pharmacoepidemiology data to define incidence across populations are ongoing. The pathophysiology remains undefined and many disease mechanisms have been postulated10,11. The research data on the disease mechanism available are scarce and a definitive mechanism for the pathogenesis of this adverse event post vaccination is far from being established. In this manuscript we summarize the main pharmacoepidemiology data and highlight recent findings on the pathophysiology of COVID-19 vaccine associated myocarditis. We reflect on the information shared during an ad hoc workshop organized by the European Medicines Agency (EMA) and identify research areas important to improve our understanding of the pathophysiology of this very rare adverse event12. A better understanding of the disease mechanism leading to myocarditis upon vaccination is crucial for the design and use of improved next generation vaccines.

After the global COVID-19 vaccine rollout, the initial reports of a higher than expected number of myocarditis and pericarditis cases following mRNA vaccination emerged already in FebruaryMarch 2021 from Israel13, Spain and the US. Within a few months also other countries reported increased rates (above the background incidence rate) of myocarditis and pericarditis after mRNA vaccination. The rapid identification by pharmacovigilance systems globally was followed by a prompt addition of a myocarditis and pericarditis warning to the product information of Comirnaty, Spikevax vaccines and later on, Nuvaxovid5,6,7 and Jcovden vaccines8. Data for Vaxzevria was reviewed by the PRAC and was considered insufficient to conclude on causal association, also noting that evidence from the literature was conflicting, with some studies14,15,16,17 showing a modest association whereas others did not18,19,20. For Spikevax and Comirnaty, the frequency of myocarditis and pericarditis has been listed as very rare (<1 in 10,000), while for Nuvaxovid and Jcovden it cannot be estimated from the data available so far, as more data are needed to further characterize the risk.

Identification of clinical manifestations of myocarditis is essential for accurate diagnosis and case management. In this context, the most used case definitions for myocarditis are taken from the US CDC11 and the Brighton Collaboration, and some epidemiological studies report on myocarditis by using the European Society of Cardiology diagnostic guidelines. These definitions largely overlap and all incorporate several types of evidence, such as clinical signs/symptoms, electrocardiogram, blood tests, imaging and histopathology, with the positive histopathological findings being regarded as gold standard for the diagnosis. Cardiac MRI is mostly used due its high sensitivity and non-invasive nature, however it is not being used very often for mild cases.

Before COVID vaccines were deployed and administered, it was reported that patients with COVID-19 have approximatively 16 times the risk for myocarditis relative to patients without COVID-193. Matched analyses from medical records (Dec 2020 to May 2021) from the largest health care organization in Israel21 showed that COVID-19 vaccination was associated with an elevated risk of myocarditis (risk ratio, 3.24) compared to unvaccinated and SARS-CoV-2 infection was associated with a substantially increased risk of myocarditis (risk ratio, 18.28) compared to uninfected. It was also noted that a significant lower mortality rate was observed among individuals with myocarditis after mRNA vaccination when compared to those with a viral infectionrelated myocarditis21,22. In line with these results, a more recent study showed that the relative risk of heart failure within 90 days was 0.56 and 1.48 for myocarditis associated with vaccination and COVID-19 disease, respectively23. In summary, compared with myocarditis associated with COVID-19 disease, myocarditis after vaccination with SARS-CoV-2 mRNA vaccines occurs less frequent and in addition is associated with a better clinical outcome23. However, the accurate background incidence rate in healthy people and the actual number of vaccine associated cases are overall difficult to determine, and are most likely under-estimated, as many cases resolve without an actual diagnosis or assistance by healthcare providers and estimating the extent of potential under-reporting in the pharmacovigilance systems still remains a challenge as it may be influenced by numerous factors, including public awareness, the disease severity spectrum, demographics, and/or local practices.

At present, more than three years after licensing of the COVID-19 vaccines in the EU/ European Economic Area, it has been established that the highest risk of developing myocarditis is in males aged 1230 years, within 114 days post vaccination after the second dose of the primary series of vaccination with an mRNA vaccine. Following post approval recognition of the increased risk to develop myocarditis upon mRNA COVID-19 vaccination, many large often nationwide or even global population studies revealed this risk distribution14,16,24,25,26,27,28,29,30. Two large European studies provided estimates of the number of excess cases of myocarditis after the second dose of mRNA vaccine in young vaccinees (below 30 years) compared to unexposed: 0.26 (French national health data system) and 0.57 (Nordic registry data) per 10,000 for Comirnaty, 1.3 and 1.9 per 10,000, respectively, for Spikevax24. For children aged 511 years, the US CDC has reported that myocarditis after mRNA COVID-19 vaccination is much rarer, with only slightly elevated rates above the anticipated background rates31. Importantly, myocarditis has not been reported among children aged 6 months5 years32. Also for adults above 30 and the elderly, only slightly elevated myocarditis rates have been observed upon COVID-19 vaccination2. The US CDC has been following patients aged 1229 years affected by myocarditis for at least 90 days after symptom onset and reported that for most of these the overall quality of life returned to pre-pandemic levels or were fully recovered as per health care provider assessment33. Of the 393 patients with biomarkers and/or imaging findings, 7794% returned to normal or baseline values22,31,33.

It has been documented that classical viral infectionrelated myocarditis is more frequently observed in male than female individuals, from childhood through young adulthood, while women are affected mostly at the postmenopausal age34, which suggests that certain predisposing factors related to age and sex may contribute to the development of myocarditis post infection as well as to post-vaccination.

The vaccine dosing interval could also impact the risk of developing myocarditis post vaccination. In this regard, a study from Canada demonstrated that the extended interval of 8 weeks as compared with a 34 weeks interval between mRNA vaccine doses 1 and 2 was associated with a reduced risk of myocarditis and pericarditis particularly among male individuals aged 1824 years25. Furthermore, in Canada the highest reported incidence was observed among male adolescents aged 1617 years after dose 2 (15.7 per 100,000) and the reporting rate was highest in those with a short (ie, 30 days) dose interval (21.3 per 100,000)26. Similarly, a French pre-print study indicated that for both the Comirnaty and the Spikevax vaccine longer intervals between each consecutive dose may decrease the occurrence of vaccine-associated myocarditis35 in line with a study performed in Hong-Kong also demonstrating that extended intervals between the first and second dose of the Cormirnaty vaccine reduces the risk of myocarditis with 29 percent in vaccinees aged 517 years36. In view of these data, some countries, i.e., Australia, Canada, UK, decided to extend the interval, 812 weeks, between primary course doses specifically for the very high risk group, 1217 years old.

The risk to develop myocarditis upon administering mRNA booster doses has also been studied. Several studies have shown that the risk to develop myocarditis after a booster dose remains elevated but this risk is consistently lower than the risk after the second dose of the primary vaccination27,29,37.

It will be relevant to understand if this pattern holds true also with repeated booster vaccinations with updated COVID-19 vaccines.

mRNA vaccines were the first COVID-19 vaccines to be authorized, distributed, and administered at an unprecedented large scale, while adeno-vectored and protein-based vaccines were authorized subsequently and administered at a smaller scale in the EU/European Economic Area. Initial meta-analysis comparing the risk associated to immunization with these respective vaccines suggested a higher incidence of myocarditis after receiving an mRNA vaccine vs a non-mRNA (adeno-vectored) vaccine2, however this analysis should be updated with data including more recently authorized vaccines. Among the mRNA vaccines, individual studies suggested a higher incidence of myocarditis after a second dose of Spikevax compared to Comirnaty16,38.

Studies on myocarditis associated with COVID-19 vaccination are hampered by several limitations such as: the absence of reliable estimates of the clinically suspected myocarditis frequency in the population prior to COVID19 pandemic, as well as lack of a systematic collection of endomyocardial biopsies to support the confirmation of the diagnosis, especially for clinically mild cases in which collecting biopsies is not warranted. Of note, usually biopsies are not taken, and MRI is not performed in clinically mild cases.

In a study specifically including recently (20 days) COVID-19 vaccinated individuals that died unexpectedly9, it was shown that most of these cases displayed an inflammatory infiltration of the epicardium and the subepicardial fat tissue. This infiltrate was characterized by an identical T cell-dominant immunophenotype and interspersed macrophages. An acute arrhythmogenic cardiac failure was postulated due to the limited pathology observed. No causal association with COVID-19 vaccination can be asserted from this study, but the authors suggested that CD4+T cells are the main drivers of heart-specific autoimmunity in myocarditis39. Additional research is required to assess the relevance of the results obtained.

Original post:

Myocarditis associated with COVID-19 vaccination | npj Vaccines - Nature.com