Autopsy-based histopathological characterization of myocarditis after anti-SARS-CoV-2-vaccination

Clinical Research in Cardiology (2022)Cite this article


Cases of myocarditis, diagnosed clinically by laboratory tests and imaging have been described in the context of mRNA-based anti-SARS-CoV-2 vaccination. Autopsy-based description of detailed histological features of vaccine-induced myocarditis is lacking. We describe the autopsy findings and common characteristics of myocarditis in untreated persons who received anti-SARS-CoV-2 vaccination. Standardized autopsies were performed on 25 persons who had died unexpectedly and within 20 days after anti-SARS-CoV-2 vaccination. In four patients who received a mRNA vaccination, we identified acute (epi-)myocarditis without detection of another significant disease or health constellation that may have caused an unexpected death. Histology showed patchy interstitial myocardial T-lymphocytic infiltration, predominantly of the CD4 positive subset, associated with mild myocyte damage. Overall, autopsy findings indicated death due to acute arrhythmogenic cardiac failure. Thus, myocarditis can be a potentially lethal complication following mRNA-based anti-SARS-CoV-2 vaccination. Our findings may aid in adequately diagnosing unclear cases after vaccination and in establishing a timely diagnosis in vivo, thus, providing the framework for adequate monitoring and early treatment of severe clinical cases.

Graphical abstract


Between December 2020 and March 2021, the European Medicines Agency approved several vaccines on the basis of randomized, blinded, controlled trials: two messenger RNA-based vaccines—Comirnaty, BNT162b2 (Pfizer–BioNTech) and Spikevax, mRNA-1273 (Moderna)—both encoding the spike protein of SARS-CoV-2 encapsulated in lipid nanoparticles as the antigen and two vaccines based on recombinant adenoviruses (Vaxzevira, ChAdOx1 nCov-19 (AstraZeneca), a recombinant chimpanzee adenoviral vector encoding the spike glycoprotein of SARS-CoV-2 and Ad26.COV2.S (Johnson & Johnson/Janssen), a recombinant adenovirus type 26 vector encoding SARS-CoV-2 spike glycoprotein. Recently, the first adapted bivalent COVID-19 booster vaccines targeting Omicron subvariants (BA.1 and BA.4-5, respectively) were authorized across the European Union (EMEA/H/C/005735: Comirnaty Original/Omicron BA.1, Comirnaty Original/Omicron BA.4-5; EMEA/H/C/005791: Spikevax bivalent Original/Omicron BA.1).

As vaccines may cause adverse events (AEFI), it is crucial to record them systematically and assess them for causality both at the population and at the individual level, as proposed by the World Health Organization (WHO) [1]. Detailed analyses should aim to establish or rule out a causal link between vaccination and the event in question. Autopsy is an important measure to identify severe adverse effects and to provide important mechanistic data in this setting. It may allow to identify the population at risk and may help to develop algorithms for prevention or monitoring, facilitating early diagnosis and successful treatment.

Cases of (epi-)myocarditis have previously been documented after immunization against smallpox or influenza in the vaccine adverse events reporting system [23]. Recently, unusual cases of (epi-)myocarditis after vaccination with mRNA-based anti-SARS-CoV-2-vaccines have been documented [4]. These were clinically observed and diagnosed by laboratory and cardiac magnetic resonance imaging, predominantly in males under 30 years of age [5,6,7,8]. Available short-term follow-up data suggest resolution of symptoms [5,6,7]. However, few individuals required intensive care support or even died from acute heart failure. Information about potential long-term health outcomes is not yet available. Verma et al. reported two cases of myocarditis after mRNA vaccination, one of them fatal, revealed by endomyocardial biopsy and autopsy respectively [9]. Histology showed an inflammatory infiltrate predominantly composed of T-cells and macrophages, admixed with eosinophils, B-cells and plasma cells. By reporting similar observations based on different diagnostic techniques (e.g. cardiac magnetic resonance imaging, endomyocardial biopsy), the causality of an potential AEFI can be assessed at the population level [1]. However, in most of these studies comprehensive testing for infectious agents, crucial for the assessment of an AEFI at the individual level, was not reported. As a consequence, a systematic description with histopathological phenotyping as well as molecular analysis of (epi-)myocarditis after anti-SARS-CoV-2-vaccination is still lacking.

Here, we describe the cardiac autopsy findings in five persons who have died unexpectedly within seven days following anti-SARS-CoV-2-vaccination, with vaccine-induced myocardial inflammation representing the likely or possible cause of death. Our findings establish the histological phenotype of lethal vaccination-associated myocarditis.


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