In an article for npj vaccines in June 2024, experts from the European Medicines Agency (EMA) provide a “concise overview” of the epidemiology of myocarditis, prominent mechanistic insights into the pathophysiology of the disease, and highlight “needed next steps” to characterise the pathophysiology of the disease post-COVID-19 vaccination. Linked mainly to mRNA COVID-19 vaccines, myocarditis and pericarditis caused vaccine safety concerns and contributed to vaccine hesitancy. However, the authors state that available data are “scarce” and there is “no clear understanding of the biological mechanism/s responsible”. They conclude with “perspectives and considerations for public health”.
The demands of a pandemic
The authors reflect that the “optimal” response to a pandemic “requires immediate and well-integrated action” including:
- Implementation of containment measure
- Identification of the causative infectious agent
- Generation of specific diagnostics
- Rapid development, authorisation, 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.”
COVID-19 vaccines
Acknowledging the role of newer vaccine technologies such as mRNA, the authors state that these vaccines have saved millions of lives and facilitated the “re-opening of society” thanks to short development and production timelines paired with high levels of protection. They suggest that the wide use of these vaccines was based on a “clear positive benefit-risk balance” for both vulnerable subjects and healthy individuals.
Although COVID-19 vaccines are “very safe”, the authors credit “close safety monitoring” post authorisation with the “prompt identification” of very rare adverse reaction events. Among these, myocarditis and pericarditis cases emerged and were “almost exclusively” associated with immunisation with mRNA vaccines. Importantly, these manifestations could only be identified post-authorisation because their “low frequency” prevented detection, even in large trials.
Pericarditis is described as “swelling and irritation of the tissue surrounding the heart” and is expected to be mild and resolve without treatment. Myocarditis is the “inflammation of the cardiac muscle”, which reduces the ability of the heart to pump blood. These conditions have been linked to viral infections, including infection with SARS-CoV-2, and to vaccines such as live attenuated virus smallpox vaccines.
With pharmacovigilance surveillance and observational studies, an increased risk of myocarditis in “predominantly younger males” has emerged post administration of the COVID-19 mRNA vaccines, Comirnaty and Spikevax, and vaccination with the adjuvanted protein-based vaccine Nuvaxovid and the adenovirus vector-based vaccine Jcovden. While most cases of vaccine associated myocarditis are “mild, transient, and self-limiting”, chronic myocarditis and dilated cardiomyopathy can develop.
What do we know?
Data collection and research are “ongoing” to define incidence across populations, pathophysiology, and disease mechanisms. In their article, the authors summarise the main pharmacoepidemiology data and findings on the pathophysiology of COVID-19 vaccine associated myocarditis. They also consider information shared during an EMA workshop and identify research areas to improve understanding.
“A better understanding of the disease mechanism leading to myocarditis upon vaccination is crucial for the design and use of improved next generation vaccines.”
The identification of myocarditis as a concern is tracked to February-March 2021 with “higher than expected” numbers of cases reported in Israel, Spain, and the US. As other countries reported similar increases, warnings were added to the relevant vaccines: for Spikevax and Comirnaty the frequency of myocarditis and pericarditis has been listed as “very rare” (<1 in 10,000).
Mechanistic insights
Hypotheses regarding the aetiology of myocarditis post COVID-19 vaccination often relate to hyperimmunity or dysregulated immune responses. Presented in the article are:
- Role of IL-1 RA
- Contribution of innate immunity and cytokines
- Implications for free spike protein
- Molecular mimicry and autoimmunity
- Sex and hormonal differences
What should be done?
Once again, the authors highlight that the risk of myocarditis associated with COVID-19 mRNA vaccination is “much lower” than the risk associated with COVID-19 infection. However, as no definite mechanism for vaccine associated myocarditis has been identified, further research is needed. The EMA will “continuously monitor” emerging evidence and share necessary updates. The authors urge research in three areas:
- Research on epidemiology – it will be “relevant” to characterise the risk of myocarditis after multiple mRNA boosters and the link to timing of administration. This should include both vaccine associated myocarditis patients and background myocarditis patients for “optimal context”. Studies on possible long-term adverse effects of vaccine associated myocarditis are necessary. For a “more comprehensive overview”, public health authorities and academic groups should “join their effort” to study the long-term prognosis of subjects and collect evidence from other vaccine platforms.
- Clinical research – establishing high quality patient cohort(s) to enable the standardised collection of relevant time course samples to support a range of studies is “one of the starting points”. It will also be important to assess existing registries, conduct post-mortem examinations, and perform autopsies of rare lethal cases to “further obtain insights” and better characterise the role interplayed between the two “branches” of the immune system. The presence of the spike protein in patients should also be investigated in larger studies.
- Nonclinical research – the focus should be on “establishing and optimising vaccine and viral infection induced myocarditis animal models”.
Public health implications
The authors recognise that there are challenges in addressing these research questions. However, clarification would “allow for measures to minimise any potential risk” with current vaccines and consider adjustments to vaccine design. While the mRNA platform is an “important addition to the armamentarium of technologies”, adjustments that could reduce the risk of myopericarditis and “boost confidence” would be welcome. Furthermore, this would provide insight into the platform with implications for “a myriad of other areas of medical application”.
To read the full article, click here. We look forward to welcoming representatives from EMA, including contributing author Dr Marco Cavaleri, to the Congress in Barcelona this October. Get your tickets to join us there and don’t forget to subscribe for more on vaccine safety.
