One theory that encompasses both myopericarditis following a COVID-19 infection, as well as post-COVID-19 vaccination, is molecular mimicry between the spike protein and the self-antigen, alpha-myosin, causing direct injury to the myocardium. As this hypothesis does not account for the observed skew towards mRNA vaccines, an alternative theory proposes that the immunogenicity of the mRNA strands as the cause for immune dysregulation and subsequent indirect damage to the myocardial tissue, in predisposed individuals [9].

More recently, another theory has flagged the immunogenicity of the lipid nano particle (LNP) sheath required to deliver the mRNA molecule to host cells in mRNA vaccines, as a potential cause for either direct damage to the myocardial cells, or as another trigger for immune dysregulation. Interestingly, the LNP sheath is also used in the NVX-CoV2373 vaccine, which is required for incorporation of the S-protein into the host [10].

As a shared pathomechanism would tend to lead to similar clinical presentations, it is interesting that both our subjects had mirroring events following their BNT162b2 and NVX-CoV2373 vaccinations. As young individuals who had reactions within 7 days of a non-first dose vaccination, both also fit the same demographic usually seen in post-mRNA vaccine myopericarditis. Both fulfill the criteria of myopericarditis, with presentations of pleuritic chest pain and ECG changes, although subject 1 had a mildly raised CRP and normal troponins, while subject 2 had a normal CRP with markedly high troponins.

Prior to COVID-19, post vaccine myopericarditis had been seen following smallpox vaccination. In contrast to the current COVID-19 vaccines, the smallpox vaccine is a live vaccine comprised of the vaccinia virus, itself known to cause myopericarditis. Although evidence is limited, mixed lymphocytic infiltrate with eosinophil degranulation found on one myocardial biopsy raises the possibility of a hypersensitivity or an auto-immune reaction as the potential mechanism for post-smallpox vaccination myopericarditis [11]. These findings have not been widely observed in COVID-19 vaccination myopericarditis biopsies, suggesting that a different pathogenesis may be involved [12].

Importantly, both of our subjects had clinical resolution of symptoms from their reaction following BNT162b2 for at least 3 months, with subject 2 also demonstrating radiological resolution, before again having myopericarditis after receiving NVX-CoV2373. This signifies that both subjects fit current Australian recommendations for receiving a subsequent non-mRNA vaccine following post mRNA vaccine myopericarditis.

To our knowledge, we are the first to describe post vaccination myopericarditis following the NVX-CoV2373 after also developing myopericarditis with BNT162b2. The similarities in presentation between the reactions of both platforms would suggest a similar pathogenesis, although the exact mechanism remains unknown. Further studies are necessary to identify these mechanisms, as well as to identify biomarkers that may identify vulnerable populations. On-going vigilance is necessary to identify those who may be at an increased risk of post-COVID vaccine myopericarditis.