Buergin Natacha (Orcid ID: 0000-0001-6436-0054)

Sex-specific differences in myocardial injury incidence after

COVID-19 mRNA-1273 Booster Vaccination
Brief Title: Myocardial Injury after COVID-19 mRNA-1273 Booster Vaccination

Natacha Buergin1*, Pedro Lopez-Ayala1*, Julia R. Hirsiger2, Philip Mueller1, Daniela

Median1, Noemi Glarner1, Klara Rumora1, Timon Herrmann1, Luca Koechlin1, Philip Haaf1,
Katharina Rentsch3, Manuel Battegay4, Florian Banderet5,6, Christoph T. Berger2,7, Christian
Mueller1

1
Department of Cardiology and Cardiovascular Research Institute Basel (CRIB), University
Hospital Basel, University of Basel, Basel; 2Department of Biomedicine, Translational
Immunology, University of Basel, Basel; 3Department of Laboratory Medicine, University
Hospital Basel, University of Basel, Basel; 4Department of Infectious diseases & Hospital
Epidemiology , University Hospital Basel, University of Basel, Basel; 5Department of Internal
Medicine, Medical Outpatient Unit, University Hospital Basel, Basel; 6Employee health
service, University Hospital Basel, Basel Switzerland, 7University Center for Immunology,
University Hospital Basel, Basel

*Both have contributed equally and should be considered first author

Word count: 3321 (max. allowed 3500)

Address for correspondence:

Prof. Christian Mueller, Cardiovascular Research Institute Basel (CRIB) and Department of
Cardiology, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland. Phone
Number: +41 61 328 65 49. Fax Number: +41 61 265 53 53. E-mail: [email protected]
This article has been accepted for publication and undergone full peer review but has not been
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differences between this version and the Version of Record. Please cite this article as doi:
10.1002/ejhf.2978
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Buergin Natacha (Orcid ID: 0000-0001-6436-0054)

Abstract (246, maximum 250 words)

Aims: To explore the incidence and potential mechanisms of oligosymptomatic myocardial

injury following COVID-19 mRNA booster vaccination.

Methods and Results: Hospital employees scheduled to undergo mRNA-1273 booster

vaccination were assessed for mRNA-1273 vaccination-associated myocardial injury, defined

as acute dynamic increase in high-sensitivity cardiac troponin T (hs-cTnT) concentration above

the sex-specific upper-limit of normal on day 3 (48-96h) after vaccination without evidence of

an alternative cause. To explore possible mechanisms, antibodies against IL-1RA, the SARS-

CoV2-Nucleoprotein(NP) and -Spike(S1) proteins and an array of 14 inflammatory cytokines

were quantified. Among 777 participants, median age 37 years, 69.5% women, 40 participants

(5.1% [95%CI, 3.7-7.0%]) had elevated hs-cTnT concentration on day 3 and mRNA-1273

vaccine-associated myocardial injury was adjudicated in 22 participants (2.8% [95%CI, 1.7-

4.3%]). Twenty cases occurred in women (3.7% [95%CI, 2.3-5.7%]), two in men (0.8%

[95%CI, 0.1-3.0%]). Hs-cTnT-elevations were mild and only temporary. No patient had ECG-

changes, and none developed major adverse cardiac events within 30 days (0% [95%CI, 0-

0.4%]). In the overall booster cohort, hs-cTnT concentrations (day 3; median 5 [IQR, 4-6] ng/L)

were significantly higher compared to matched controls (n=777, median 3 [IQR, 3-5] ng/L,

p<0.001). Cases had comparable systemic reactogenicity, concentrations of anti-IL-1RA, anti-

NP, anti-S1, and markers quantifying systemic inflammation, but lower concentrations of IFN-

λ1(IL-29) and GM-CSF versus persons without vaccine-associated myocardial injury.

Conclusion: mRNA-1273 vaccine-associated myocardial injury was more common than

previously thought, being mild and transient, and more frequent in women versus men. The

possible protective role of IFN-λ1(IL-29) and GM-CSF warrant further studies.

18790844, ja, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ejhf.2978, Wiley Online Library on [26/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
COVID-19 booster vaccination
Myocardial injury

Cardiac Troponin
mRNA vaccine
Key Words

Myocarditis
COVID-19
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Introduction

Myocardial injury, manifesting clinically as myocarditis, has recently emerged as a possible

severe adverse event following the administration of COVID-19 mRNA-vaccines occurring

mainly in young men a few days after vaccination. Using passive surveillance following

vaccination with BNT162b2-mRNA (Pfizer-BioNTech) or mRNA-1273 (Moderna), COVID-

19 mRNA-vaccination associated myocarditis is currently considered rare1. However, passive

surveillance detects mostly severe cases requiring hospitalization.2,3

We hypothesized that COVID-19 mRNA-vaccine-associated myocardial injury

following booster vaccination may be much more common, as symptoms may be unspecific,

mild or even absent, escaping passive surveillance. Due to waning immunity months after

mRNA COVID-19 vaccinations there is an apparent need for (repeated) booster vaccinations

for billions of people worldwide.4,5 Thus knowing the true incidence of mRNA vaccine-

associated myocardial injury is of major importance for informed decision-making by patients,

physicians and public health authorities.

We therefore conducted a prospective active surveillance study to address this major

unmet need. Secondary aims were to provide a “safety net” for persons identified with COVID-

19 mRNA-vaccine-associated myocardial injury to allow early detection and preventive

measures to avoid possible aggravation, and to evaluate potential mechanisms underlying

COVID-19 mRNA-vaccine-associated myocardial injury.

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Methods

Study design and study population

This prospective investigator-initiated industry-independent active surveillance study was

approved by the local ethics committee. Employees of the University Hospital Basel,

Switzerland, scheduled to receive mRNA-1273 first booster vaccination, and who provided

written informed consent, were offered active-surveillance. Exclusion criteria were cardiac

events or cardiac surgery within 30 days prior to vaccination or patients missing the study visit,

therefore missing hs-cTnT measurement on Day 3.

Active surveillance and laboratory methods

Medical history was assessed on the day of the booster vaccination (day 1). On day 3 (48-96

hours) after vaccination, participants were assessed for possible myocarditis-related symptoms

and a venous blood sample for the measurement of high-sensitivity cardiac troponin T (hs-

cTnT, Elecsys, sex-specific 99th-perentile of healthy individuals and upper-limit of normal

(ULN) 8.9 ng/L in women and 15.5 ng/L in men, limit of detection 3 ng/L) was obtained.6,7 If

the hs-cTnT concentration was elevated on day 3, participants were informed, asked to avoid

strenuous exercise in order to minimize additional strain of the myocardium and associated

cardiomyocyte injury, and offered follow-up including clinical evaluation, a second hs-cTnT

measurement, and a 12-lead electrocardiogram (ECG). The follow up visit was scheduled, if

feasible, the next working day. After extensive discussion with the local ethics committee and

the COVID-19 task force of the University Hospital Basel, it was prioritized that this study

should interfere as little as possible with the motivation of the hospital staff to obtain the

mRNA-1273 first booster vaccination and the logistics of booster vaccination itself.

Accordingly, blood draws were performed only after the vaccination.

Potential mechanisms underlying vaccine-associated myocardial injury

 18790844, ja, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ejhf.2978, Wiley Online Library on [26/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
We evaluated three potential mechanisms of COVID-19 mRNA-vaccination-associated

myocardial injury: anti-IL-1RA-autoantibodies,8 pre-existing vaccine/infection-induced

immunity against SARS-CoV2 (i.e. anti-SARS-CoV2-Nucleoprotein(NP) and -Spike(S1) IgG),

and systemic reactogenicity/inflammation. Anti-IL-1RA-, -NP-, and S1-IgG were quantified

using the Luminex platform (Luminex Corporation, Austin, Texas)9 (Supplementary

Methods). Systemic inflammation was assessed by measuring 14 biomarkers using the

LEGENDplex™ Human Anti-Virus Response Panel (IL-1β, IL-6, IL-8, IL-10, IL-12p70, IFN-

α, IFN-β, IFN-λ1(IL-29), IFN-λ2/3(IL-28), IFN-γ, TNF-α, IP-10, GM-CSF), the IL-1RA assay

(both Biolegend, San Diego, CA, USA), and C-reactive protein (CRP; Elecsys; ULN 5.0 mg/L).

Adjudication of COVID-19 mRNA vaccine associated myocardial injury

Given the in general superior sensitivity of hs-cTnT-elevations versus the ECG or cardiac

imaging for acute myocardial injury,10,11 COVID-19 mRNA vaccine-associated myocardial

injury was defined as acute dynamic hs-cTnT-elevation above the sex-specific 99th-perentile

ULN (8.9 ng/L in women and 15.5 ng/L in men) on day 3, without evidence of an alternative

cause, irrespective of symptoms, ECG, or cardiac imaging abnormalities. In the absence of a

baseline hs-cTnT concentration immediately prior to the vaccination, strict criteria were applied

in the adjudication of COVID-19 mRNA vaccine associated myocardial injury. For the

differentiation of acute COVID-19 mRNA vaccine-associated myocardial injury versus

possible chronic preexisting myocardial injury, four criteria were used: first, the extent of the

hs-cTnT elevation (the higher the elevation, the more likely acute), second, the extent in the

change of hs-cTnT from day 3 to day 4 (the larger the change the more likely acute), third,

previous hs-cTnT measurements if available in the medical history of the participants, and

fourth, the likelihood for hs-cTnT elevation according to known causes of chronic myocardial

injury, including age and preexisting cardiovascular diseases. To emphasize how physicians

could miss COVID-19 mRNA vaccine-associated myocardial injury in women, a sensitivity

analysis, using a uniform ULN cutoff (14 ng/L) was used for adjudication. To further verify
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that COVID-19 mRNA booster vaccination may increase hs-cTnT concentration, hs-cTnT

concentration on day 3 in the overall cohort receiving COVID-19 mRNA booster vaccination

was compared to matched controls.

Follow-up

Major adverse cardiac events (MACE) including acute heart failure, cardiac death, life-

threatening arrhythmia and acute myocardial infarction (AMI) were assessed at 30-day follow-

up. A flowchart of the active surveillance program is depicted in Figure 1A and the Graphical

Abstract.

Matching

To assess cardiomyocyte injury also as a continuous variable, hs-cTnT concentrations on day 3

after vaccination were compared to age-, sex-, history of coronary artery disease/AMI-matched

patients (controls) that had presented with acute chest discomfort to the emergency department

in a multicenter study (NCT00470587) and were centrally adjudicated as having a non-cardiac

cause. Seven hundred seventy-seven booster-vaccinated subjects and 3716 eligible controls

(fulfilling inclusion criteria) were identified. Matching was conducted using a nearest neighbor

propensity score matching method, without replacement of controls and with a case-to-control-

ratio of 1:1.12 For details see Supplementary Methods.

Statistical Analysis

Continuous variables were reported as median and interquartile range (IQR), categorical

variables as counts and percentages. Difference in characteristics between subjects with and

without SARS-CoV-2 mRNA vaccine-associated myocardial injury were assessed using the

Mann Whitney U test for continuous variables, and the Pearson chi2 test or Fisher exact test for

categorical variables, when appropriate. All hypothesis testing was 2-tailed with a significance

level of p<0.05. Statistical analyses were performed using R version 4.1.3 (R Foundation for

Statistical Computing). Reporting is in accordance with the Strengthening the Reporting of

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Observational studies in Epidemiology (STROBE) statement (Supplemental Table 1). We did

not adjust for multiple testing for the evaluation of different potential mechanisms underlying

COVID-19 mRNA-vaccine-associated myocardial injury due to the exploratory nature of the

analysis.
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Results

From December 10th, 2021, to February 10th, 2022, 1871 employees of the University Hospital

Basel were screened (1294 females [69.2%] and 577 males [30.8%]), of which 835 provided

written informed consent to participate in the study, and of these, 777 (93%, 540 females

[69.5%] and 237 males [30.5%]) were eligible for analysis (Table 1, Figure 1 and Figure 2A).

The median age was 37 years (IQR 30-50), and 69.5% were women. Age-, sex-, and history of

coronary artery disease/AMI-matched controls had comparable baseline characteristics

(Supplemental Table 2 and Supplemental Figure 1-3).

COVID-19 mRNA-1273 vaccine-associated myocardial injury

Hs-cTnT concentrations (Supplemental Figure 4) above the sex-specific ULN were detected

in 40 participants (5.1% [95%CI, 3.7-7.0%]). In 18 of them (17 women, median age 59 years

[IQR 57-60], median hs-cTnT concentration 10ng/L [IQR 9-11], Supplemental Table 3), an

alternative cause was considered most likely (Supplemental Table 4). mRNA-1273 vaccine-

associated myocardial injury was adjudicated in 22 patients (2.8% [95% confidence interval

[CI], 1.8-4.3 %]), with 20 cases occurring in women (3.7% [95%CI, 2.3-5.7%]) and 2 in men

(0.8% [95%CI, 0.1-3.0%]), with a median age of 46 years (IQR 33-54). This sex difference was

statistically significant (p=0.03). On day 3, median hs-cTnT concentration of the 20 women and

2 men with mRNA-1273 vaccine-associated myocardial injury was 13.5 ng/l (IQR 9.0-18.8;

Figure 2B). It decreased in all but one patient on the follow up visit to a median value of 6.0

ng/l (IQR 4.0-14.0), being again in the normal range in half of the participants.

In the overall cohort receiving the mRNA-1273 booster, hs-cTnT concentrations (day

3) were significantly higher compared to matched controls (median 5 [IQR 4-6] ng/L vs 3 [IQR

3-5] ng/L, p<0.001). Figure 3 illustrates this difference, indicating an overall shift towards

higher hs-cTnT concentrations in the booster cohort versus matched controls, for both female
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(median 4 [3-6] ng/L vs 2.99 [2.99-4] ng/L) and male (median 6 [5-8] ng/L vs 4 [2.99-6] ng/L)

participants.

None of the participants with elevated markers of myocardial injury related to mRNA

vaccination had a history of cardiac disease (Supplemental Table 5). Eleven participants

(50%) had unspecific symptoms including fever and chills, two had chest pain, and none had

ST-segment depression or T-wave inversion (Supplemental Table 5). Predefined and

prospectively recorded symptoms occurred with comparable frequency in participants

developing mRNA-1273 vaccine-associated myocardial injury versus those that did not.

No definitive case of myocarditis was found. However, the two participants (both

women) with vaccine-associated myocardial injury and chest pain met the Brighton

Collaboration case definition Level 2, indicating probable myocarditis in those patients (0.3%

[95% confidence interval [CI], 0.1-0.9 %]).13

Sensitivity analysis

When using a uniform ULN of 14 ng/L, mRNA-1273 vaccine-associated myocardial injury was

adjudicated in 14 patients (1.8% [95% CI, 1.0-3.0 %]), with 9 cases occurring in women (1.7%

[95%CI, 0.8-3.2%]) and 5 in men (2.1% [95%CI, 0.7-4.9%]), with a median age of 53 years

(IQR 38-56). On day 3, median hs-cTnT concentration of the 9 women and 5 men with mRNA-

1273 vaccine-associated myocardial injury was 17.5 ng/l (IQR 15.5-20.5). It decreased in all

but one patient on the follow up visit to a median value of 14.0 ng/l (IQR 10.0-19.0), being

again below the uniform ULN in half of the participants (Supplemental Figure 5).

MACE

Thirty-day follow-up was completed in 775 participants (99.7%) and no participant developed

MACE (0% [95%CI 0-0.4%]).

Possible mechanisms of mRNA-1273 vaccine-associated myocardial injury

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Antibodies against IL-1RA were detected with comparable and low frequency in participants

with mRNA-1273 vaccine-associated myocardial injury versus those without (1 in 22 [4.5%]

vs 23/742 [3.1%]; Fisher exact test P-value=0.51). The plasma levels of IL-1RA were also

comparable between the two groups. There was no difference in the magnitude of the anti-S1-

IgG and the frequency of subjects positive for anti-NP-IgG (i.e. serological evidence for prior

infection with SARS-CoV2) in participants with mRNA-1273 vaccine-associated myocardial

injury versus those without (Table 2). Also, most tested markers of systemic inflammation had

comparable concentrations in participants with mRNA-1273 vaccine-associated myocardial

injury versus those without. In contrast, levels of IFN-λ1 and GM-CSF were lower in cases with

mRNA-1273 vaccine-associated myocardial injury versus those without (Supplemental

Figures 6 and 7).

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Discussion

This prospective investigator-initiated, industry-independent study was performed to test the

hypothesis that mRNA-1273 booster vaccination-associated myocardial injury may be more

common than currently thought as symptoms may be unspecific, mild or even absent, escaping

passive surveillance detecting only hospitalized cases. We report four main findings.

First, our findings confirmed the study hypothesis. mRNA-1273 booster vaccination-

associated elevation of markers of myocardial injury occurred in about one out of 35 persons

(2.8%), a greater incidence than estimated in meta-analyses of hospitalized cases with

myocarditis (estimated incidence 0.0035%) after the second vaccination.14,15 Elevated hs-cTnT

was independent of previous COVID infection or the interval since the last vaccine dose.

Among the overall group of participants, hs-cTnT concentration on day 3 after mRNA-1273

booster vaccination as a continuous variable, was significantly higher compared to a well-

matched control cohort. Second, all cases were mild with only a transient and short period of

myocardial injury (maximum hs-cTnT concentration 35ng/L). No patient showed ECG changes

and, no patient developed MACE within 30 days. Potentially, such outcomes were averted by

the safety net provided by early detection and early implementation of preventive measures for

deterioration including avoidance of strenuous exercise. Notably, systemic reactogenicity

(fever, chills, body aches), and chest pain occurred with comparable frequency in participants

with versus without mRNA-1273 booster vaccine-associated cTnT elevations. Third, when

using sex-specifc ULN cutoffs for myocardial injury adjudication, mRNA-1273 booster

vaccine-associated myocardial injury occurred significantly more often in women versus men

(3.7% versus 0.8%). This is in striking discrepancy to the sex-distribution of vaccine-associated

myocardial injury in the setting of clinical myocarditis following the first and second

vaccinations detected by passive surveillance, which occurred predominately in young

men.2,3,16 Median age of participants developing mRNA-1273 vaccine-associated myocardial

injury was 46 years. Thereby, also the age-distribution is different to that of most reported
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vaccine-associated clinical myocarditis cases.2,3 When using a uniform (and thereby higher in

women and lower in men compared to the sex-specific) ULN cutoff for adjudication, the

incidence rate of vaccine-associated myocardial injury declined in women and increased in

men. Fourth, the predominate mechanisms underlying mRNA-1273 booster vaccination-

associated myocardial injury did not seem to include antibodies neutralizing IL-1RA, which

were suggested to be involved in the pathophysiology of severe COVID-19 mRNA vaccine-

8
associated myocarditis in young male patients, pre-existing vaccine/infection-induced

immunity against SARS-CoV2, nor systemic inflammation. In contrast, levels of IFN-λ1 and

GM-CSF, both modulators of the immune responses to acute viral infection, vaccination, and

tissue inflammation, were lower in cases with mRNA-1273 vaccine-associated myocardial

injury versus those without.17-19 However, we did not adjust for multiple testing nor for potential

confounders for the evaluation of different potential immunological mechanisms underlying

COVID-19 mRNA-vaccine-associated myocardial injury due to the exploratory nature of the

analysis and should thus be considered as a hypothesis-generating analysis. IFN-λ limits

inflammation induced tissue damage in viral infections20 and in models of ischemic myocardial

injury.21 Whether IFN-λ1 deficiency may reduce myocardial protection and thereby promote

vaccine-associated myocardial injury needs to be further investigated. In a phase 3 trial,

pegIFN- λ reduced hospitalisations and emergency visits in patients with COVID-1922 and in a

phase 2 study, pegIFN- λ accelerated viral decline in outpatients with COVID-19,17,18 thereby

further strengthening the rational of the hypothesis that IFN-λ1 deficiency may be involved in

vaccine-associated myocardial injury. GM-CSF exerts pro-inflammatory effects, and both

administration and inhibition of GM-CSF are tested as potential therapeutics in COVID-19.19

Whether low GM-CSF blood levels are a risk factor for immune-mediated cTnT elevations

remains to be further elucidated. The significantly higher rate of mRNA-1273 booster

vaccination-associated myocardial injury in women versus men may at least partly be related

to the higher vaccine dose per body weight or myocardial mass in women and therefore dose-
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dependent toxic effects. Clinically overt severe vaccination-associated myocarditis may then

occur following a second hit, possibly mediated by neutralizing autoantibodies targeting IL-

1RA, microvascular thrombosis, or direct cardiac myocyte injury unrelated to inflammation.8,23

Our findings following mRNA-1273 booster vaccination extend and corroborate

observations in two recent active surveillance studies after BNT162b2 vaccination.24,25 Among

324 health care workers, mean age 51 years, 59.2% women, who received a fourth dose of

BNT162b2 in Israel, two participants (one woman and one man) developed vaccine-related

myocardial injury on day 3 (incidence 0.6%, maximum hs-cTnI concentration 22.1ng/L). One

had mild symptoms including fever and chest pain, one was asymptomatic. Both had a normal

ECG and echocardiography.24 Among 301 adolescents in Thailand, mean age 15 years,

receiving the second dose of BNT162b2, five participants (incidence 1.7%), all boys, developed

vaccine-related myocardial injury on either day 2 or day 3.25 One of them had very high hs-

cTnT concentrations (593ng/L) and late-gadolinium enhancement indicating myocarditis in

cardiac magnetic resonance (CMR) imaging. When comparing these studies, it is important to

highlight major differences in study population and study methodology.

Therefore, the main finding of this study, that subclinical mRNA vaccine-associated

myocardial injury is much more common than estimated based on passive surveillance, has

been confirmed and generalized in these complimentary cohorts of slightly older health care

workers in Israel and adolescents in Thailand. Additional active surveillance studies are needed

to externally validate two specific findings of this study: the even higher rate of mRNA-1273

booster vaccination associated myocardial injury overall, and particularly in women. At least

in part, these findings seem explained by the use of sex-specific ULN for hs-cTnT in this versus

a uniform ULN in the two other studies, as well as using mRNA-1273, which also had resulted

in a higher rate of hospitalizations due to clinical myocarditis versus BNT162b2 in prior passive

surveillance studies.2,3,26,27 Of note, mRNA-1273 had also resulted in higher immunogenicity

and protection from COVID-19 versus BNT162b2 in large observational studies.28,29

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Vaccine-related myocarditis has previously been reported following smallpox

vaccination with an observed incidence of 16.11/100,000, which was nearly 7.5-fold higher

than the expected background incidence.30 In contrast, myocarditis following other vaccines is

rare.31 Similar to our finding with mRNA vaccination, there is evidence that the frequency of

subclinical myocardial injury may also be higher after smallpox vaccination. A study on US

military personnel found subclinical cTnT elevations in 2.87% of 1081 smallpox vaccinated

subjects, or a 60-times higher rate than overt clinical cases.32 The same study found no cTnT

elevation in 189 subjects vaccinated with the inactivated influenza vaccine. This suggest that

vaccine characteristics are relevant for the observed cTnT increase.

The long-term consequences of vaccine-related myocardial injury detected by transient

and mostly mild hs-cTnT/I elevations on day 2 or 3 are unknown. Given the small extent of

acute cardiomyocyte injury in our study, i.e. cTnT levels of about one-fourth of those observed

in patients with spontaneous myopericarditis,10 and its transient nature, good long-term

outcomes can be expected. COVID-19 associates with a substantially higher risk for

myocarditis that mRNA vaccination33, and myocarditis related to COVID-19 infection has

shown a higher mortality than myocarditis related to mRNA-vaccination.34,35 Thus, for the

majority of individuals, the overall very favorable risk-benefit ratio of booster immunizations

persists.14,15,36-39 However, further studies are needed to assess the impact of mRNA vaccine-

associated myocardial injury on the long-term risk of cardiac arrhythmias and heart failure.

Also, evidence generated in the perioperative setting should help avoid the over-simplistic

assumption that the absence of typical chest pain on day 3 after vaccination in most cases would

per se indicate a favorable prognosis: perioperative myocardial injury not associated with chest

discomfort had comparable unfavorable long-term outcome versus perioperative myocardial

injury with chest discomfort.40

By providing novel insights regarding the incidence, extent, duration, patient

characteristics, possible mechanisms, and outcome of mRNA-1273 booster vaccination-

 18790844, ja, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ejhf.2978, Wiley Online Library on [26/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
associated myocardial injury, this study aims to help patients, physicians, and public health

authorities make informed decisions regarding future booster vaccinations.4 Importantly, this

study also may help manufacturers fine-tune the dose and composition of future vaccines.

It is mandatory to put our findings into perspective with the incidence and extent of

myocardial injury associated with COVID-19 infection. Before the COVID-19 vaccine were

available, the incidence and extent of myocardial injury associated with COVID-19 infection

was much higher than observed in this active surveillance study after booster vaccination.37,41,42

Data on the incidence of COVID-19 associated myocardial injury in populations with high

immunity against SARS-CoV2 are not yet available.

Alternative, yet unlikely, contributors to the elevated cTnT in our study include

cardiomyocyte injury associated with strenuous exercise, or in the context of a high

inflammatory response to the vaccination or a non-cardiac source. While exercise was not

restricted between vaccination and first hs-cTnT measurement, none of the detected cases

reported strenuous exercise preceding the blood draw on day 3. Importantly, prior exercise was

also not restricted among the matched control group, and even strong exercise typically only

leads to an increase in hs-cTnT concentration of on average 1 ng/l.43 Moreover, neither the

clinical symptoms (i.e. fever, chills, muscle sore), nor the measured markers of systemic

inflammation indicated an overshooting inflammatory response in subjects with hs-cTnT

elevation. In contrast to some rather rare chronic active skeletal muscle diseases such as muscle

dystrophies, acute skeletal muscle injury, even when as extensive as in patients with

rhabdomyolysis, has been found not to be a non-cardiac source of elevated hs-cTnT

concentrations.44-46 Also, interference has been reported as a possible confounding factor for

cTn elevations. However, this issue seems to predominantly affect the current hs-cTnI and not

the current hs-cTnT assay.47 Therefore, the acute dynamic increase in hs-cTnT-concentration

following mRNA COVID-19 vaccination has to be considered indicating myocardial injury and

not secondary to the intramuscular injection and local skeletal muscle injury. Lastly, unknown
 18790844, ja, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ejhf.2978, Wiley Online Library on [26/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
prior cardiac disease may have been contributing to some of the extent of myocardial injury

observed. Therefore, conservative criteria were used for the adjudication of mRNA-1273

booster vaccination-associated myocardial injury and 18 additional patients with hs-cTnT

elevation on day 3 were classified as more likely having chronic myocardial injury.

The following limitations should be considered when interpreting our findings. First, to

interfere as little as possible with the motivation of the hospital staff to obtain the mRNA-1273

booster vaccination and its logistics, we restricted the study to blood draws after vaccination.

Thus, baseline hs-cTnT values were not available. The lack of a baseline hs-cTnT concentration

was therefore addressed threefold: a) by requiring a relevant change in hs-cTnT concentration

from day 3 to the follow up visit as additional criteria to adjudicate mRNA vaccine-associated

myocardial injury; b) by conservative adjudication in that 18 participants with mild hs-cTnT-

elevations on day 3 (17 women, one man), and either no available hs-cTnT concentration at

follow up visit or one with no relevant change, were considered to reflect pre-existing known

or assumed cardiac disease rather than mRNA-1273 booster vaccine-associated myocardial

injury (although the differential diagnosis in these 18 patients includes persistent vaccine

associated myocardial injury); Thereby, among the 40 participants (5.1%) detected to have

increased hs-cTnT concentration on day 3 after mRNA-1273 booster vaccination, only 22

participants (2.8%) were adjudicated to have mRNA-1273 vaccine-associated myocardial

injury. For comparison, using the sex-specific 99th-percentile as the ULN, among presumably

healthy individuals only 1% of persons are expected to have increased levels. c) by adding an

age-, sex-, and history of coronary artery disease/AMI matched control group. Despite our

efforts to address the lack of baseline hs-cTnT concentration, we may have still misclassified a

small number of participants. Future studies using baseline values for adjudicating acute

dynamic hs-cTn-elevation above the sex-specific ULN are warranted to confirm our findings.

Second, the time-course of mRNA-1273 vaccine-associated myocardial injury is incompletely

understood. Accordingly, by measuring hs-cTnT on day 3 after mRNA-1273 booster

 18790844, ja, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ejhf.2978, Wiley Online Library on [26/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
vaccination, which was in line with other studies,24 we might have missed cases that peaked

earlier and had already returned to normal on day 3. Third, the 4th universal definition of

myocardial infarction states that “elevated cTn levels may be indicative of acute myocardial

injury if the pattern of values is rising and/or falling”. No specific percentage change was

proposed, thus in some patients the distinction between acute and chronic was challenging. In

those cases, we adjudicated those patients as chronic injury, thus choosing the more

conservative approach. Fourth, this study recruited unselected healthcare workers of a

university hospital. Thereby, the study population was relatively young and 70% women.

Further studies are warranted to extend the findings regarding incidence of mRNA-1273

booster vaccination-associated myocardial injury and 30-day MACE to other populations. Both

may differ particularly in older persons with a higher preexisting burden of cardiovascular

disease. Fifth, no CMR imaging was performed, as the amount of vaccine-induced

cardiomyocyte injury in this study was below the expected limit of detection of CMR for late

gadolinium enhancing myocardial lesions indicative of myocarditis (usually a hs-cTnT

concentration of about 50-100ng/L).10,11 These thresholds were predefined in collaboration with

imaging experts, but are based on expert opinion rather than large prospective studies. Sixth, it

is unknown whether and to what extent early detection and management, such as asking cases

to avoid strenuous exercise, contributed to the excellent outcomes at 30-days. Seventh, given

the absence of another in-vivo technique with comparable sensitivity to hs-cTnT/I regarding

acute cardiomyocyte injury, it remains unknown whether mRNA-1273-vaccine-induced

myocardial injury resulted in cardiomyocyte cell death and thereby irreversible loss of

cardiomyocytes, or sublethal injury.

In conclusion, using active surveillance, mRNA-1273 vaccine-associated mild transient

myocardial injury was found to be much more common than previously thought. It occurred in

one out of 35 persons, was mild and transient, and more frequent in women versus men. Neither

anti-IL-1RA, nor pre-existing vaccine/infection-induced immunity or systemic inflammation

18790844, ja, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ejhf.2978, Wiley Online Library on [26/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
seemed to be dominant mechanisms of myocardial injury. No participant developed MACE

within 30-days.
 18790844, ja, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ejhf.2978, Wiley Online Library on [26/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Funding

This work was supported by research grants from the University of Basel and the University

Hospital Basel, Switzerland.

Conflict of interest

Dr. Koechlin received a research grant from the Swiss Heart Foundation, the University of

Basel, the Swiss Academy of Medical Sciences and the Gottfried and Julia Bangerter-Rhyner

Foundation, as well as the “Freiwillige Akademische Gesellschaft Basel” and speaker honoraria

from Roche Diagnostics and Siemens outside the submitted work. Prof. Mueller has received

research support from the Swiss National Science Foundation, the Swiss Heart Foundation, the

University of Basel, the University Hospital Basel, the KTI, Abbott, Beckman Coulter,

BRAHMS, Idorsia, Ortho Diagnostics, Novartis, Roche, Siemens, and Singulex, as well as

speaker/consulting honoraria from Amgen, Astra Zeneca, Bayer, BMS, Boehringer Ingelheim,

Daiichi Sankyo, Idorsia, Novartis, Osler, Roche, and Sanofi, all outside the submitted work.

C.T.B. has received research support from the Swiss National Science Foundation, the

Uniscientia Foundation, the FSRMM, and ROCHE, all outside of this work, and participated in

a study that received independent funding from Moderna. M.B. has received research support

from the Swiss National Science Foundation. P.L.A has received research grants from the Swiss

Heart Foundation (FF20079 and FF21103) and speaker’s honoraria from Quidel, paid to the

institution, outside the submitted work. The remaining authors have nothing to disclose.
 18790844, ja, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ejhf.2978, Wiley Online Library on [26/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
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 18790844, ja, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ejhf.2978, Wiley Online Library on [26/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Figure legends

Graphical Abstract

Figure 1: Patient Flow chart. Hs-cTnT = high-sensitivity cardiac troponin T

Figure 2: Panel A: Flowchart of the active surveillance program and incidence of mRNA-

1273 vaccination-associated myocardial injury. Panel B: High-sensitivity cardiac troponin T

(hs-cTnT) concentrations in patients with mRNA-1273 vaccination-associated myocardial

injury. The triangles represent the median, points represent the individual patients, the dashed

lines labeled ULN represent the sex-specific upper limit of normal. (Both men with

vaccination-associated myocardial injury had identical concentrations on day 3 (17 ng/L),

therefore only one point is shown. One male patient did not have a follow up visit, hence only

one line is shown).

Figure 3: Cumulative distribution curve of cardiomyocyte injury as quantified by high-

sensitivity cardiac troponin T (hs-cTnT) concentrations stratified by sex. The dashed lines

indicate the sex-specific upper reference limits. Hs-cTnT = high sensitivity cardiac troponin T.
Tables

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No vaccine- Vaccine-

associated associated
Variable Overall p
myocardial myocardial

injury injury

n 777 755 22

Age, median [IQR] 37 [30, 50] 37 [29, 50] 46 [33, 54] 0.12

Sex 0.03

Male, n (%) 237 (30.5) 235 (31.1) 2 (9.1)

Female, n (%) 540 (69.5) 520 (68.9) 20 (90.9)

History of COVID-19 infection 82 (10.6) 80 (10.6) 2 (9.5) 1

Number of previous COVID-19

0.20
vaccinations, n(%)

One vaccination 1 (0.1) 1 (0.1) 0 (0.0)

One vaccination after COVID-19 37 (4.8) 37 (4.9) 0 (0.0)

Two vaccinations 714 (92.0) 694 (92.0) 20 (90.9)

Two vaccinations after COVID-19 24 (3.1) 22 (2.9) 2 (9.1)

Days since last vaccination, median 206.0 205.0 222.0

0.14
[IQR] [188.0, 230.0] [188.0, 229.0] [187.2, 253.2]

History of CAD, n (%) 3 (0.4) 3 (0.4) 0 (0.0) 1

History of AMI, n (%) 1 (0.1) 1 (0.1) 0 (0.0) 1

History of heart surgery, n (%) 3 (0.4) 3 (0.4) 0 (0.0) 1

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No vaccine- Vaccine-

associated associated
Variable Overall p
myocardial myocardial

injury injury

History of myocarditis, n (%) 3 (0.4) 3 (0.4) 0 (0.0) 1

History of heart failure 2 (0.3) 2 (0.3) 0 (0.0) 1

Symptoms following vaccination

n (%)

Chest pain 63 (8.1) 61 (8.1) 2 (9.1) 0.70

Palpitations 70 (9.0) 69 (9.1) 1 (4.5) 0.71

Dyspnea 23 (3.0) 23 (3.0) 0 (0.0) 1

Fever and/or chills 270 (34.7) 263 (34.8) 7 (31.8) 0.95

Body aches 356 (45.8) 347 (46.0) 9 (40.9) 0.80

Biomarkers
5 [4-6] 5 [4-6] 13.5 [9-18.8] <0.001
Hs-cTnT (day 3), median [IQR]

Table 1. Baseline characteristics and vaccine-associated symptoms stratified by

adjudicated vaccine-associated myocardial injury.

IQR: interquartile range. The patient with only one previous vaccination had received Johnson &

Johnson’s Janssen COVID-19 Vaccine which is a full primary immunization. According to Swiss

authorities, past COVID-19 infection and one vaccination were regarded equivalent to having had two

vaccinations (without previous COVID-19 infection) for primary immunization in Switzerland.

History of heart surgery: one bypass surgery, one atrial septal aneurysm and one atrial septal defect.

CAD=coronary artery disease; AMI=acute myocardial infarction

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No vaccine-
Vaccine-associated
Variable Overall associated p
myocardial injury
myocardial injury

n 764 742 22

Antibodies

anti NP (MFI) 138.2 [65.0, 322.6] 139.0 [66.0, 325.0] 103.5 [33.6, 192.8] 0.052

anti S1(MFI) 1641.0 [870.8, 3254.0] 1641.0 [877.8, 3281.0] 1686.5 [757.5, 2614.8] 0.76

anti IL-1RA (MFI) 30.8 [23.0, 48.1] 31.0 [23.0, 48.0] 25.5 [19.5, 46.9] 0.31

Systemic

inflammation

IL-1RA (pg/ml) 621.3 [438.0, 832.0] 621.3 [440.5, 829.1] 605.3 [426.5, 895.2] 0.968

IL-1β (pg/ml) 6.8 [3.4, 13.2] 6.8 [3.4, 13.2] 7.0 [3.6, 9.4] 0.57

IL-6 (pg/ml) 1.7 [0.5, 3.4] 1.7 [0.5, 3.4] 1.5 [0.5, 2.7] 0.62

IL-8 (pg/ml) 4.2 [3.1, 5.9] 4.3 [3.1, 6.0] 3.9 [3.3, 5.7] 0.65

IL-10 (pg/ml) 9.8 [3.9, 25.8] 9.8 [3.9, 25.6] 10.4 [3.2, 31.5] 0.91

IL-12p70 (pg/ml) 10.0 [4.8, 18.1] 10.1 [4.9, 18.2] 8.0 [2.7, 14.3] 0.289

CRP (mg/l) 5.5 [2.8, 10.2] 5.4 [2.8, 10.1] 6.9 [4.3, 10.1] 0.28

TNF-α (pg/ml) 5.6 [1.7, 17.6] 5.7 [1.7, 17.7] 4.1 [1.7, 11.9] 0.43

IFN-β (pg/ml) 3.9 [0.8, 8.9] 3.9 [0.8, 9.1] 3.0 [0.8, 6.4] 0.13

IFN-γ (pg/ml) 16.9 [6.4, 37.5] 16.9 [6.6, 38.0] 15.5 [4.0, 30.4] 0.42
 18790844, ja, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ejhf.2978, Wiley Online Library on [26/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
IFN-α2 (pg/ml) 2.5 [0.7, 5.4] 2.5 [0.7, 5.4] 2.0 [1.3, 3.8] 0.70

IFN-λ1 (pg/ml) 11.4 [3.8, 21.8] 11.8 [3.9, 22.3] 5.3 [2.9, 10.8] 0.015

IFN-λ2-3 (pg/ml) 7.8 [4.1, 12.9] 7.9 [4.2, 12.9] 5.5 [3.1, 8.6] 0.052

GM-CSF (pg/ml) 2.0 [0.6, 4.4] 2.0 [0.6, 4.5] 0.6 [0.6, 2.9] 0.039

IP-10 (pg/ml) 49.8 [25.8, 120.2] 49.8 [25.4, 120.8] 49.5 [31.2, 78.9] 0.984

Table 2. Inflammatory biomarkers stratified by adjudicated vaccine-associated

myocardial injury.

In 13 patients (without vaccine-associated myocardial injury) the volume provided to the

immunology laboratory was insufficient to measure the inflammatory biomarkers.

anti-NP = anti-nucleoprotein antibody; anti-S1 = anti-spike antibody; anti IL-1RA = anti-interleukin 1

receptor antagonist antibody; IL = interleukin; CRP = C-reactive protein; GM-CSF = granulocyte-

macrophage colony stimulating factor TNF = tumor-necrosis factor; IFN = interferon, IP= interferon

gamma-induced protein 10; MFI= median fluorescence intensity

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Graphical Abstract
Figures
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Patients recruited from December 2021
to February 2022
(n=835)

Patients excluded (n=58)

Missed study visit, therefore missing
hs-cTnT on Day 3

Patients with hs-cTnT

available on Day 3 (48-96h)
(n=777)

hs-cTnT ≤ sex- hs-cTnT > sex-

specific ULN specifc ULN
(n=737) (n=40)

Alternative cause for Adjudicated vaccine-

elevated hs-cTnT associated myocardial injury
(n=18) (n=22)

Figure 1. Patient flow chart

18790844, ja, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ejhf.2978, Wiley Online Library on [26/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Figure 2.
18790844, ja, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ejhf.2978, Wiley Online Library on [26/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Figure 3.