SARS-CoV-2 vaccines and myocarditis

How do patients present?

Patients typically present with chest pain, breathlessness, fever and palpitations.⁴ These symptoms tend to occur 2 to 3 days after the second dose of mRNA vaccine, but the onset can range from 1 to 8 days.⁴ This is often accompanied by abnormalities on electrocardiogram (ECG) and troponin elevation.¹⁴ In children, initial symptoms can be non-specific and include headache, irritability and poor oral intake.¹⁵ For public health surveillance purposes, all cases of myocarditis should meet specific case definition criteria, although there is no universally agreed standard as yet. The Brighton criteria are used in the UK, whereas the Center for Disease Control (CDC) definitions apply in the USA.^16,17

How common is it?

In the UK, the Medicines & Healthcare Products Regulatory Agency (MHRA) gathers reports on suspected myocarditis cases through the Yellow Card Scheme (Table 1).¹ Similarly, spontaneous reports are collated by the US Vaccine Adverse Event Reporting System (VAERS) via the CDC Wonder online tool, and in the European Union/European Economic Area (EU/EEA), by EudraVigilance.¹⁸ It is estimated that the individual risk of SARS-CoV-2 vaccine-related myocarditis in the general population is 0.002–0.004%.¹⁹ To put that in context, the risk of myocarditis in the general population before the pandemic was estimated to be about 0.009%,²⁰ although the true incidence is unknown.²¹ A systematic review revealed that reported vaccine-associated myocarditis cases occurred at an estimated rate of less than 1 in 10,000.^22,23

However, data from passive surveillance systems have several limitations. They rely on clinicians to consistently report adverse events and, thus, it is likely that the true incidence is underestimated. Spontaneous reports are not systematic population surveys; therefore, the exposed population remains unknown. Studies were conducted largely in a few Western countries and, thus, are not generalisable to the wider world population. The issue is further complicated by the heterogeneity of case definitions and adjudication methods used. In the USA, all cases reported to VAERS undergo further safety evaluations by Clinical Immunization Safety Assessment Project investigators to determine whether they meet myocarditis criteria.¹⁶ Of 1,991 suspected myocarditis cases reported to VAERS, only 82% met CDC criteria.⁴ Finally, reports from passive surveillance often assume that the same vaccines were used for the first and the second doses. In the UK and, to a lesser extent, the USA, this was not always the case.¹ Although the limited available evidence, largely from Western countries, currently suggests a low incidence of myocarditis, further long-term studies conducted globally are necessary to establish the true incidence and potential future complications of vaccine-related myocarditis.

Who is at risk?

In the UK, the reported rates for suspected myocarditis and pericarditis are highest among men aged 18–29 followed by men aged 30–39, specifically after the second doses of Pfizer/BioNTech and Moderna vaccines.¹ Myocarditis cases after the AstraZeneca vaccine are spread more evenly across age groups. However, it is possible that these reports simply reflect the background incidence of myocarditis rather than a causal link.¹

This trend has been replicated in studies of vaccine adverse event-reporting systems internationally. In an analysis of 192 million vaccine recipients in the USA, most cases of myocarditis occurred after the second dose of an mRNA vaccine.⁴ The median age was 21 years, and 82% occurred in men with a median time to symptom onset of 2 days. The estimated rate among men by age group was: (1) 70.7 cases per million doses for ages 12–16 years; (2) 105.9 cases per million doses for ages 16 to 17 years ((1) and (2) for Pfizer/BioNTech only); and (3) 52.4 and 56.3 cases per million doses for ages 18–24 years (Pfizer/BioNTech and Moderna vaccines, respectively) (Table 1). The number of events observed exceeded the expected baseline rate of myocarditis for both men and women.⁴

Two Israeli retrospective cohort studies and a case–control study from Hong Kong highlighted an increased rate of myocarditis following Pfizer/BioNTech vaccination compared with the expected background rate.^5–7 Further observational data from Scandinavia, France and Canada suggest that the risk is higher with Moderna than with Pfizer/BioNTech.^8–11 This might reflect the relatively higher dose of mRNA used in the Moderna vaccine. Interestingly, in the Canadian cohort, the overall rates for both vaccines were significantly higher when the interval between doses was 30 or fewer days compared with 56 or more days.¹¹ It is likely that a proportion of cases world-wide remain subclinical and undetected, significantly underestimating the true incidence of myocarditis, even among young male groups.²² Although the myocarditis rates were low within the limited studies available, larger longitudinal population studies performed globally are necessary to confirm this.

How severe is it?

Nearly all cases of cardiac inflammation reported in the literature were mild to moderate in severity. Most patients with myocarditis required a short hospital admission but made a complete recovery by discharge and did not require readmission.^4,24 In a retrospective cohort study of more than 2.5 million Israelis over the age of 16 years, 54 cases of myocarditis were followed for a median duration of 83 days after symptom onset. Left ventricular dysfunction occurred in 14 patients with largely mild symptoms and resolved in the nine patients who had a follow-up echocardiogram.⁵ The outcomes were even more favourable in children and adolescents, where systolic function was preserved in most cases.²⁵

Although mortality in SARS-CoV-2 vaccine-related myocarditis is extremely low,⁸ physicians should be aware of the very rare, apparently fatal cases. In the UK, the Yellow Card scheme recorded seven deaths following the Pfizer/BioNTech vaccine and six following the AstraZeneca vaccine (there are no reports on the Moderna vaccine). This might be linked to the more frequent use of the Pfizer vaccine in the UK (and the AstraZeneca vaccine earlier in the campaign). However, establishing causality using a spontaneous reporting scheme such as the Yellow Card scheme is difficult. Unknown underlying illness or other potential confounders should be considered.¹ There are rare case reports of cardiogenic shock and death.^1,26–28 Most of these were complicated by an underlying illness¹ or involved a rare, idiosyncratic, inflammatory response,^26–28 suggesting that vaccination alone was not the cause of death.

Although the initial data are reassuring, the follow-up period is too short to ascertain the long-term prognosis of patients with myocarditis after vaccination.⁵ In a US follow-up surveillance study of 519 patients followed up beyond 90 days from symptom onset, more than 90% had fully recovered (defined as normalisation of cardiac investigations and quality of life measures).²⁹ On follow-up cardiovascular magnetic resonance (CMR) performed on 151 patients, 81 had residual myocardial scarring.²⁹ Although this might cause concern, initial data from smaller CMR studies point toward a favourable prognosis, at least in the short term.³⁰ Given that most data come from Western countries, it is not known whether the natural history of vaccine-related myocarditis is the same in other parts of the world. Without sufficient follow-up, any severe long-term cardiovascular complications, even among silent or benign cases, cannot confidently be excluded. However, with the passage of time, this appears increasingly less probable.

What is the mechanism of SARS-CoV-2 mRNA vaccine-related myocarditis?

The mechanism underlying the SARS-CoV-2 mRNA vaccine-related myocarditis is unclear. Endomyocardial biopsies are rarely done and have been largely inconclusive.^5,31 SARS-CoV-2 mRNA vaccines contain nucleoside-modified mRNA, encoding the viral spike glycoprotein of SARS-CoV-2.³² Once inside the host cells, the mRNA of the vaccine causes the cells to build the spike protein, which then stimulates an adaptive immune response to identify and destroy the virus. Vaccine-induced immunoglobulin G (IgG) antibodies neutralise the virus by preventing the attachment of SARS-COV-2 spike protein to the angiotensin-converting enzyme 2 receptor of the host cell. Several mechanisms have been proposed, including mRNA vaccine-mediated immune dysregulation in susceptible individuals and molecular mimicry between the spike protein of SARS-CoV-2 and self-antigens.¹⁴ A recent study of 69 biopsy-confirmed cases highlighted the potential role of neutralising antibodies against interleukin-1 (IL-1)receptor antagonist, an endogenous anti-inflammatory receptor, and a hyperphosphorylated isoform.³³ Proinflammatory effects of testosterone have been hypothesised as a minor contributory factor, potentially explaining the higher incidence in men.¹⁴

Although SARS-CoV-2 mRNA vaccine-related myocarditis received significant media attention, vaccine-related myocarditis itself is not a new phenomenon. For instance, it was widely reported with the use of smallpox vaccines.³⁴ There are also emerging data to suggest that asymptomatic myocardial injury following mRNA vaccination is more common than currently appreciated. A pilot active surveillance study showed that subclinical myocardial injury (defined as a troponin T elevation and decline on days 3 and 4 post vaccination) occurred in ∼1 in 35 people.³⁵ This suggests that low-level myocardial injury following mRNA vaccination is more common than previously appreciated in passive surveillance studies because most cases might be asymptomatic and, therefore, never come to clinical attention. The significance of this finding is uncertain and, thus, potential future complications of subclinical myocardial injury cannot currently be excluded.

Risk–benefit analysis

Rates of myocardial injury associated with SARS-CoV-2-infection exceed the rate of vaccine-related myocarditis in most populations, with the possible exception of men under 40 years exposed to the Moderna vaccine.¹² However, such evaluations, based on exploratory subgroup analysis of case series relying on physician coding, should only be viewed as indicative. Most cases of vaccine-related myocarditis are mild and self-limiting, whereas even among adolescents, SARS-CoV-2 infection can cause significant morbidity and mortality,³⁶ including cardiac complications.³⁷ Vaccination in children could additionally prevent multisystem inflammatory syndrome.^38,39 These benefits appear to extend to SARS-CoV-2 variants, including Omicron.⁴⁰ The CDC estimates that, for every 39–47 cases of vaccine-related myocarditis in young men aged 12–29 years, 11,000 COVID-19 cases, 560 hospitalisations, 138 intensive care unit (ICU) admissions, and six deaths could be prevented.¹⁶ Again, with the evidence limited to the Western world, it is not known whether the same risk–benefit applies globally.

Investigations and management of suspected cases

Any acutely ill or unstable suspected cases of SARS-CoV-2-related myocarditis should be referred directly to hospital.⁴¹ Early involvement of a regional cardiology service is advised. Initial investigations should include an ECG, blood tests (full blood count (FBC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), troponin and brain natriuretic peptide (BNP))⁴² and a test to exclude SARS-CoV-2 infection.¹⁴ Imaging studies, including echocardiography and CMR, are sufficient to make the diagnosis.⁴³ Endomyocardial biopsy is the gold-standard test for myocarditis, but is seldom necessary given the self-limiting course of the disease.^5,31,43

All confirmed cases in the UK should be reported to the MHRA.⁴⁴ Management of myocarditis focuses on treating arrhythmias and preventing heart failure.⁴⁵ Symptomatic patients should avoid strenuous physical activity until recovery.⁴⁶ A follow-up CMR 3–6 months from diagnosis⁴⁵ might be beneficial in determining the myocardial scar burden and trajectory of any left ventricular remodelling.^47,48

Vaccination after SARS-CoV-2 vaccine myocarditis

Guidance on vaccination after SARS-CoV-2 vaccine myocarditis is a topic of ongoing debate internationally. There are no agreed international guidelines at present and advice is largely based on expert consensus. In the UK, it is advised that, in all cases, further vaccinations should be deferred until assessment by a cardiologist 8 weeks from diagnosis.⁴⁴ Second or subsequent doses should only be offered after full recovery and careful consideration of the risks and benefits. The most recent approach advocates testing for nucleocapsid antibody (N-antibody) in patients with myocarditis presenting within 2 weeks of the first dose of mRNA vaccine.⁴⁹ N-antibody seropositivity indicates prior exposure to SARS-CoV-2 and might suggest adequate immunity, with likely limited incremental benefit from further vaccination.^49,50 Where N-antibody is negative or in clinically vulnerable individuals, the Pfizer mRNA vaccine is preferred with an interval of at least 12 weeks from the previous dose.⁴⁹ The evidence thus far is scant, but patients who received a second vaccination after the onset of myocarditis did not report any complications.^24,51

Vaccination after non-vaccine-related myocarditis, including SARS-CoV-2-related myocarditis

A history of non-vaccine-related myocarditis or pericarditis is not a contraindication to immunisation.⁵² Cardiovascular comorbidities place patients at a higher risk of death from SARS-CoV-2 infection, and have not been correlated with vaccine-related myocarditis.⁵³ However, the issue remains controversial and further studies in this area are needed.¹⁴ In patients who have recovered from suspected SARS-CoV-2-related myocarditis, the CDC recommends deferring further vaccination until full recovery.⁵⁴

International guidelines

Recommendations for management of cases and further vaccination after vaccine-related myocarditis vary by country and there is no internationally agreed standard at present. In the USA, all suspected cases should be reported to VAERS. Diagnostic evaluation is similar to that in the UK and clinicians are encouraged to follow guidance from the American Heart Association and the American College of Cardiology on myocarditis management and follow-up. Most importantly, the CDC stresses that myopericarditis after vaccination is generally a contraindication to a subsequent dose of any COVID-19 vaccine. US authorities advise that patients should not receive further doses until additional safety data are available. If, after a risk assessment, the decision is made to administer a further vaccine, patients should wait until complete recovery.⁵⁴

In Australia, for confirmed vaccine-related myocarditis cases, further vaccination is considered on a case-by-case basis and is usually deferred until complete recovery.⁴¹ All cases need to be discussed with a specialist immunisation service. Those with suspected vaccine-related pericarditis but normal investigations can receive the next dose if symptom free for at least 6 weeks. In patients with pericarditis with abnormal investigations, the need and choice of further doses are informed by age and sex. Specifically, further doses are usually avoided in affected adolescent boys aged 12–14.⁴¹

In Canada, anyone with myocarditis within 6 weeks of vaccination is advised to defer the next dose. If patients choose to receive another dose, the Pfizer mRNA vaccine should be offered over Moderna.⁵⁵ Further international multi-centre studies are required to establish consensus.

UK COVID-19 booster campaign

The UK autumn/winter booster campaign focused on people over the age of 50 years (an age cohort seemingly not at risk of vaccine-associated myocardial inflammation but at highest risk of SARS-CoV-2 morbidity/mortality);⁵⁶ those under 50 (including children) with specific comorbidities; and healthy healthcare workers.¹³ Although data are still emerging, there have been few reports of suspected myocarditis following booster doses in adults, and no reports in the under 18-year age group in the UK.¹ Based on the overall limited evidence, the myocarditis risk after an mRNA booster in children and adolescents is lower than the risk after the the second dose of the primary series.⁵³ It should be noted that children remain at risk of SARS-CoV-2-related complications.⁵⁷ Boosters have been shown to significantly reduce rates of symptomatic SARS-CoV-2 infections,⁵⁸ emergency department visits and hospitalisations.⁵⁹

Summary

Myocarditis is a possible complication of vaccination with a SARS-CoV2 mRNA vaccine that typically presents in men under age 40 years within 7 days of vaccination. Most cases reported were mild and self-limiting, although evidence is still scarce, and the number of undetected cases could be much higher. In the short term, the risks associated with the vaccine are seemingly outweighed by the morbidity and mortality from SARS-CoV-2 infection, although long-term cardiac consequences are not known. A history of myocarditis from another cause does not appear to increase the risk of SARS-CoV2 mRNA vaccine-related myocarditis. Clinicians should report all suspected cases to their relevant pharmacovigilance authority. The mechanism of this condition is yet to be elucidated, but some data suggest that extending the interval between the doses reduces the risk. With variations in vaccine uptake and guidelines internationally, and research largely limited to the Western world, further studies conducted more globally are needed to establish the incidence of vaccine-associated myocarditis more accurately. Long-term outcome data are awaited, but initial evidence is encouraging and suggests uncomplicated recovery in the overwhelming majority of individuals.