Only after the Covid-19 mRNA vaccines were distributed to the public did we learn it can cause myocarditis (inflammation of heart muscles) in rare cases. It was rare enough that it escaped statistical detection in the initial randomized clinical trials (RCTs).
Because we lack gold-standard RCT data on mRNA vaccine-induced myocarditis, we also lack gold-standard safety data on this condition — any long-term health consequences. But recent observational data, albeit second-rate compared to RCT, has shed light on the long-term health outcomes of survivors of mRNA vaccine-related myocarditis.
Vaccine myocarditis is not as safe as we thought
One such observational data is the study of Kracalik et al. from the Center for Disease Control and Prevention (CDC) and other institutions in the U.S., titled “Outcomes at least 90 days since onset of myocarditis after mRNA COVID-19 vaccination in adolescents and young adults in the USA: a follow-up surveillance study,” published in Lancet Child and Adolescent Health, a highly reputable journal of the Lancet family.
Kracalik et al. collected the health outcomes of 519 survivors (12–29 years, 88% males) of mRNA vaccine myocarditis at 90 days of follow-up, by surveying both the survivors and their healthcare providers.
At ≥90 days of follow-up, the outcomes were as follows:
- 66% of participants (n = 393) were considered fully recovered from myocarditis by their healthcare providers; 15% were considered probably recovered, and 17% were considered not fully recovered.
- But of this 17% who were considered unrecovered (n = 65), 94% (n = 61 out of 65) had improved cardiac conditions and 6% (n = 4 out of 65) had no improvement compared to baseline.
- Although 81% of participants were considered recovered (either fully or probably), 50% of them still reported persistent symptoms at follow-up, most commonly chest pain, fatigue, dyspnea, and palpitations.
- Participants considered not fully recovered reported fatigue (43% vs. 21%) and chest pain while resting (39% vs. 23%) more often than those considered recovered, with the difference being statistically significant. Although a trend was seen towards increased general chest pain, dyspnea, and palpitations in those not fully recovered, such differences were not statistically significant (Figure 1).
- Patients considered not fully recovered were prescribed daily medications more often than those considered recovered: 26% vs. 10% for colchicine, 18% vs. 9% for beta-blockers, 14% vs. 7% for anti-inflammatories, 11% vs. 0.6% for angiotensin II receptor blocker, 9% vs. 3% for ACE inhibitor, 8% vs. 3% for aspirin, 5% vs. 1% for diuretics, 5% vs. 0.31% for corticosteroid, and 3% vs. 1% for other medications. Most of these differences were statistically significant (Figure 2).
- Participants considered recovered and not fully recovered were similar in age, sex, ethnicity, history of SARS-CoV-2 infection and vaccination, underlying medical conditions, and initial myocarditis severity — suggesting these factors were unlikely to influence the outcomes of who recovered and who didn’t.
Overall, the observational cohort study of Kracalik et al. showed that one-fifth of survivors of mRNA vaccine-related myocarditis doesn’t fully recover 3 months later. These unrecovered survivors had more fatigue (and possibly more chest pain, palpitations, and dyspnea) symptoms and more medical prescriptions than those who recovered. However, most of these unrecovered survivors still had better cardiac clinical outcomes than baseline, and none had worse cardiac outcomes over time.
*Figure 2. Medical prescriptions in survivors of mRNA vaccine-related myocarditis, separated by recovery status at 90-day follow-up. If the p-value is <0.05, the difference is statistically significant (red box).
Previously, multiple shorter-term studies showed that most patients with mRNA vaccine-related myocarditis exited hospitalization within days. As a result, we assumed that such an adverse event was not a big deal. But this assumption did not consider what the long-term health outcomes are. The longitudinal study of Kracilik et al., therefore, changed how we view mRNA vaccine-related myocarditis.
How this changes the risk-benefit ratio of mRNA vaccines
First, we need to understand the incidence of mRNA vaccine-related myocarditis, which differs by age, sex, and vaccine type.
A meta-analysis estimated that the incidence of myocarditis is 0.000011–i.e., 1.1 cases per 100,000 or 11 cases per 1,000,000 individuals vaccinated with the mRNA vaccine.
But this is the overall incidence, which is higher in young men, especially after the second dose of Moderna’s mRNA vaccine at 97 excess* cases per 1 million vaccinated young men. This incidence was even higher than the same from Covid-19 at 16 excess cases per 1 million infected young men, according to a large cohort study of over 40 million people in the U.K.
“These findings may justify some reconsideration of the selection of vaccine type, the timing of vaccine doses, and the net benefit of booster doses in young people, particularly in young men,” the study authors stated.
So, it’s apparent that for younger men, the risk of myocarditis from the second dose of Moderna’s mRNA vaccine is greater than Covid-19.
*Excess cases refer to an absolute increase in cases compared to a control group, i.e., myocarditis rate in unvaccinated individuals. Usual incidence cases may not consider the background rate from the control group.
- If the rate of mRNA vaccine-related myocarditis in young men is 97 excess cases per 1 million vaccinees,
- If 19% of young men with mRNA vaccine-related myocarditis don’t fully recover at 3 months,
- Then the rate of persistent health problems after mRNA vaccine-related myocarditis in young men is 18.4 cases per 1 million vaccinees.
That said, mRNA vaccine-related myocarditis is still much milder than virus-related myocarditis, despite the higher incidence in young men.
In a meta-analysis of 23 studies of 854 young patients (90% males) with mRNA vaccine-related myocarditis, 0% died and 0% needed mechanical support, but 93% of patients were hospitalized and 23% were admitted to ICU. Another smaller meta-analysis, however, estimated that mRNA vaccine-related myocarditis has a higher fatality rate of 2.3%.
In a comprehensive study comparing myocarditis severity from mRNA vaccine vs. Covid-19, the former had a much lower mortality rate at 1% vs. 10%. The former also had lower rates of heart failure (1.9% vs. 12.2%) and dilated cardiomyopathy (1% vs. 3.7%) compared to the latter (Figure 3).
Moreover, these chronic heart diseases also come with persistent symptoms such as fatigue, exercise intolerance, breathlessness, cough, palpitations, chest pain, swollen ankles and legs, and dizziness.
In this regard, persistent health problems after myocarditis would also be greater following Covid-19 than its mRNA vaccine.
So, mRNA vaccine-induced myocarditis can sometimes be severe but rarely ever fatal, with a fatality rate close to 0–1%. In contrast, virus-induced myocarditis, including Covid-19, is much more severe and fatal (Figure 3).
*Figure 3. Illustration of the study design, comparing the prognosis of myocarditis after mRNA vaccine vs. Covid-19. In the rightmost panel, the cumulative incidence of heart failure and mortality in Covid-19 myocarditis is about 10% higher than in vaccine myocarditis
That said, risks, albeit small, are best minimized, especially if the benefits are small as well. Though controversial, experts agree that the first two and maybe three mRNA vaccine shots provide the most benefits, especially in mitigating Covid severity. Every booster shot after that gives diminishing returns, particularly when SARS-CoV-2 variants also kept evolving.
To conclude, repeated boosting with mRNA vaccines may not be optimal for young men with a low risk of severe Covid-19, more so in regions with low Covid transmission. Other Covid-19 vaccines — e.g., Johnson & Johnson or AstraZeneca/Oxford DNA, Novavax subunit, or Sinovac inactivated vaccines— may be better choices instead.
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