
==== Front
Nat Commun
Nat Commun
Nature Communications
2041-1723
Nature Publishing Group UK London

39232036
52038
10.1038/s41467-024-52038-6
Article
Influence of mRNA Covid-19 vaccine dosing interval on the risk of myocarditis
http://orcid.org/0000-0002-1303-8281
Le Vu Stéphane stephane.le-vu@ansm.sante.fr

1
Bertrand Marion 1
Semenzato Laura 1
http://orcid.org/0000-0002-7946-7759
Jabagi Marie-Joelle 1
http://orcid.org/0000-0002-4814-6370
Botton Jérémie 12
Drouin Jérôme 1
http://orcid.org/0000-0001-8687-9092
Weill Alain 1
http://orcid.org/0000-0001-7646-3667
Dray-Spira Rosemary 1
Zureik Mahmoud 13
1 grid.512012.5 EPIPHARE Scientific Interest Group in Epidemiology of Health Products (French National Agency for the Safety of Medicines and Health Products - ANSM, French National Health Insurance - CNAM), Saint-Denis, France
2 https://ror.org/03xjwb503 grid.460789.4 0000 0004 4910 6535 Faculté de Pharmacie, Université Paris-Saclay, Orsay, France
3 grid.463845.8 0000 0004 0638 6872 University Paris-Saclay, UVSQ, University Paris-Sud, Inserm, Anti-infective evasion and pharmacoepidemiology, CESP, Montigny le Bretonneux, France
5 9 2024
5 9 2024
2024
15 77456 2 2024
21 8 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
Myocarditis is the most salient serious adverse event following messenger RNA-based Covid-19 vaccines. The highest risk is observed after the second dose compared to the first, whereas the level of risk associated with more distant booster doses seems to lie in between. We aimed to assess the relation between dosing interval and the risk of myocarditis, for both the two-dose primary series and the third dose (first booster). This matched case-control study included 7911 cases of myocarditis aged 12 or more in a period where approximately 130 million vaccine doses were administered. Here we show that longer intervals between each consecutive dose, including booster, may decrease the occurrence of vaccine-associated myocarditis by up to a factor of 4, especially under age 50. These results suggest that a minimum 6-month interval might be required when scheduling additional booster vaccination.

Dosing interval has been suggested as a modifier in the risk of myocarditis associated with Covid-19 mRNA vaccination. Here, the authors show that longer intervals between each consecutive dose, including booster, may decrease the occurrence of myocarditis, especially under age 50.

Subject terms

Cardiomyopathies
Epidemiology
Infectious diseases
issue-copyright-statement© Springer Nature Limited 2024
==== Body
pmcIntroduction

Covid-19 messenger RNA (mRNA) vaccines are associated with a short-term increased risk of myocarditis, with the highest risk observed after the second dose of the primary series relative to the first1. The risk associated with more distant booster doses also seems to be lower than after the second dose2,3.

In addition, it has been suggested that extending the time between the first two doses may reduce the risk of heart inflammation4. While also accounting for an enhanced (or not inferior) vaccine effectiveness5,6, an optimal interval of eight weeks rather than three to four weeks between the two primary doses ended up being recommended in some countries to mitigate the adverse events7,8.

The pandemic period saw an extensive use of mRNA vaccines for initial vaccination and first boosters. We hypothesized that the variation in dose spacing, relative to the recommended schedules, that naturally occurred during the vaccination campaign could be related to a differential risk of myocarditis after each sequential dose. Probing this association could have important public health implications for the use of subsequent doses of Covid-19 or other mRNA vaccines.

To test this hypothesis, we assessed the role of dosing interval in the risk of vaccine-associated myocarditis for both the two-dose primary series and the third dose (first booster) at a nationwide level. We extended our previous case-control study9 to include all individuals aged 12 and above hospitalized for myocarditis during the first two years of the vaccination campaign. First, we characterized the distribution of dosing intervals by vaccine and dose ranking observed in the French population. Second, we evaluated how the association between exposure to a specific vaccine dose and myocarditis is altered by the time since the previous dose, either converted into discrete categories or treated as a continuous variable. Finally, as myocarditis following vaccination is known to affect preferentially young adults and adolescents and to have a male predominance, we evaluated whether the impact of varying dose intervals differed according to age and sex.

Results

Vaccines received

Between December, 27, 2020 to November, 30, 2022, within a population of 58.5 million persons aged 12 years or older, approximately 40 million first and second doses of the BNT162b2 (Pfizer-BioNTech) vaccine and 6 million first and second doses of the mRNA-1273 (Moderna) vaccine were used for priming (Fig. 1a). For the first booster, approximately 26 and 11 million doses of BNT162b2 and mRNA-1273 vaccines were used respectively. After the use of mRNA-1273 became limited (see “Methods”), few individuals below age 30 received it as a booster. Usage of a fourth or subsequent vaccine dose as booster was mostly restricted to persons over 60 years and was not further considered in this study.Fig. 1 Covid-19 mRNA vaccine doses administered, variation of dosing interval, and associated risk of myocarditis.

In all subfigures, each mRNA vaccine is represented by row. a COVID-19 vaccine doses administered in France by age category from December, 27, 2020 to November, 30, 2022. The number of first four doses only are shown, in million, for each mRNA vaccine. b Distribution of interval between two consecutive doses of mRNA vaccine. Intervals are in days between receipts of dose n and dose n-1. Colour bands correspond to the following categories: less than 3 weeks, 3, 4, 5, 6, or more than 6 weeks since dose 1 at receipt of dose 2 (first column), and less than 5 months, 5, 6, 7, 8, or more than 8 months between dose 2 and 3, or 3 and 4 (last 2 columns). c Adjusted odds ratio (OR) of myocarditis after exposure to mRNA vaccines within 7 days per continuous increment of age, by sex. Lines are OR values and shaded areas are 95% confidence intervals for restricted cubic spline model estimates. Grey line indicates an OR value of 1. d Adjusted odds ratio (OR) of myocarditis per day increment of the dosing interval (time since previous dose at receipt of the second dose (first column) or the first booster (second column)), by age category. Lines are OR values and shaded areas are 95% confidence intervals for restricted cubic spline model estimates. Plots are truncated at the 1st and 99th percentiles of each dosing interval distribution.

Study population

Through the same period, 7911 cases of myocarditis were diagnosed in French hospitals. For each case, 10 control subjects of same sex, age and area of residency (Supplementary Table 1) were sampled and assigned the date of case diagnosis as index date. Study subjects had a median age of 34 years and were at 72% males. A higher proportion of cases (63%) had received at least one dose of mRNA vaccine than in the control group (56%). When considering all individuals with at least one mRNA vaccine dose on their index date, 15% had not (yet) received the second and 60% the third dose. The corresponding time intervals were, therefore, treated as missing in subsequent analyses.

Observed dosing intervals

The distribution of dosing intervals showed substantial variations relative to the initial vaccine schedules guidance (see “Methods”)(Fig. 1b). The observed timing between the first two doses reflects vaccine schedules based on whole numbers of weeks, mainly 3 to 6, with medians of 29 days for the BNT162b and 32 days for the mRNA-1273 vaccine, and for both vaccines 10% intervals below 3 weeks and 20% over 6 weeks. Dosing intervals for the first booster dose were centered on 6 months as recommended, with 15% intervals below 5 months and 12% over 7 months for both vaccines.

Risk of myocarditis

Overall, the risk of myocarditis increased within 7 days after receipt of each of the first, second, and third doses of both the BNT162b and mRNA-1273 vaccines, with odds ratios ranging from 2.0 (95% confidence interval [CI], 1.5–2.6) for the first dose of BNT162b to 22 (95%CI, 16 to 30) for the second dose of mRNA-1273 (Table 1). Odds ratios were 4.2 (95%CI, 3.2 to 5.5) after the third dose of BNT162b and 4.6 (95%CI, 2.8 to 7.4) after the third dose of mRNA-1273 vaccine. Of note, 30 out of 31 patients having developed myocarditis within 7 days after the mRNA-1273 booster received it at half dose (50 µg).Table 1 Association between myocarditis and exposure to mRNA vaccines within 7 days, by dosing interval

Exposure	Dose Rank	Interval Days	Cases No.	Controls No.	Adjusted OR	(95% CI)	
Unexposed	-	-	6922	73433	1	Reference	
BNT162b2	1	-	  75	  579	2.0	(1.5–2.6)	
2	<22	 114	  124	15	(11–20)	
	22–28	  76	  167	7.8	(5.7–11)	
	29–35	  19	   56	5.6	(3.2–9.8)	
	>35	  62	  252	3.5	(2.5–4.8)	
	All	 271	  599	7.1	(6.0–8.5)	
3	<153	  23	   56	6.5	(3.8–11)	
	153–183	  49	  161	4.7	(3.3–6.8)	
	184–213	  29	  106	3.4	(2.0–5.7)	
	>213	   8	   44	1.6	(0.61–4.2)	
	All	 109	  367	4.2	(3.2–5.5)	
mRNA-1273	1	-	  13	   84	2.0	(1.0–4.0)	
2	<22	  36	   14	34	(17–67)	
	22–28	  34	   24	29	(16–54)	
	29–35	  14	    9	19	(7.7–50)	
	>35	  39	   36	13	(7.7–23)	
	All	 123	   83	22	(16–30)	
3	<153	   8	   31	6.4	(2.7–15)	
	153–183	  14	   64	3.5	(1.7–7.1)	
	184–213	   4	   28	3.8	(1.2–12)	
	>213	   5	   11	9.0	(2.2–38)	
	All	  31	  134	4.6	(2.8–7.4)	
Intervals are given in days. “All” denotes all subjects receiving a corresponding dose of vaccine, regardless of the dosing interval. Analyses are adjusted for covariates potentially associated with a risk of myocarditis or vaccine exposure: history (within 5 years of index date unless otherwise mentioned) of myocarditis sarcoidosis, opioid use disorder, coronary artery disease and myocardial infarction, heart failure, antihypertensive drug use, arrhythmia, diabetes, autoimmune disease, respiratory disease, or active cancer; history of antibiotic use (within a month of index date), history of SARS-CoV-2 infection (any positive antigenic or RT-PCR test result within a month of index date), and deprivation index associated with the area of residence. Although included in the models as specific exposure categories, individuals having received either a 4th or subsequent dose or any dose within 8 to 21 days prior to the index date are not presented.

In subgroup analyses (Supplementary Table 2), the risk was increased after any vaccine exposure in males below age 50 and females below 30 years. We found some evidence of an increase after the first booster in men over 50 years. The risk of vaccine-associated myocarditis in relation to continuous age is depicted in Fig. 1c. There was evidence of a threshold at approximately 50 years below which the risk increased as individuals were younger at exposure, except for the BNT162b booster (dose 3) where a smaller risk persisted over 50 years in males. Significant interactions were observed between continuous age and the receipt within 7 days of the second (p < 0.0001) and third (p = 0.026) doses of the BNT162b vaccine, or of the second dose of the mRNA-1273 vaccine (p = 0.035). None of the interaction terms for sex were significant.

Influence of dosing interval

For both vaccines, while the risk within a week following each dose was increased regardless of dosing interval, odds ratios tended to decrease as intervals grew longer (Table 1). The highest risk was found after a second dose of mRNA-1273 administered less than 3 weeks apart from the first one, with an odds ratios of 34 (95%CI, 17 to 67). Estimated association was 4-time lower when the second dose of BNT162b was more than 7 weeks away from the previous one compared to less than 3 weeks away. A similar reduction of risk was estimated between the two extreme categories of dosing interval for the BNT162b booster. Although there was a greater uncertainty, a different pattern of timing relation was observed with the mRNA-1273 booster, with the lowest risk estimates in the intermediate (and recommended) range of dose spacing (5 to 7 months).

These patterns were similar in most cases when stratifying by age, although estimates became imprecise and confidence intervals largely overlap (Supplementary Table 3). The analysis restricted to homologous regimens–where only one vaccine was involved per person–as well as the analysis defining exposure within 21 days prior to the index date led to the same conclusions (Supplementary Tables 4 and 5).

The risk of vaccine-associated myocarditis in relation to continuous dosing intervals is illustrated in Fig. 1d. The decreasing trend in risk of myocarditis as doses are spaced had a steep non-linear portion for intervals below 5 weeks for the second dose of BNT162b and was more linear for the second dose of mRNA-1273 (interaction term between the binary exposure to the vaccine and the interval since the previous dose was significant [p < 0.0001] for the second dose of BNT162b but was not for the second dose of mRNA-1273 [p = 0.43]). For the BNT162b vaccine booster, the risk seemed constant up to 6 months and decreased thereafter. Whereas it tended to increase with the longest intervals for the mRNA-1273 booster, but with great uncertainty. We again generally observed an absence of risk over 50 years for all dosing intervals except in those who received the BNT162b booster the closest to dose 2.

Discussion

In this study, the risk of myocarditis was elevated in the week after each new vaccine dose, including the first booster. This result observed in all age categories from age 12, extends prior observations for young adults2. A longer dosing interval was first proposed as an explanation for the comparatively lower rates of vaccine-associated myocarditis observed in Denmark10. This assumption was confirmed for the primary series of both mRNA vaccines in Ontario’s surveillance system4. Our findings bring new evidence suggesting that longer intervals between each consecutive dose, including booster doses, may decrease the occurrence of vaccine-associated myocarditis, especially among adolescents and adults under 50.

The public health implications are important because the net benefit of frequent booster vaccination appears more limited in the younger population11. In the post pandemic era, the risk of heart inflammation in healthy adults may weigh even more importantly when defining the timing for additional doses12. There is some evidence that dosing intervals for the primary vaccination could be extended relative to those recommended without decreasing the vaccine effectiveness5,6. Our results would support a broad recommendation to provide a minimum spacing of 6 months between doses of mRNA booster to limit the risk of adverse events. However, the trade-off in terms of waning immunity and the provision of effective protection needs to be examined. More specifically, considering the varying risks of severe Covid-19 in different groups of population12, the scheduling of future mass mRNA vaccinations may be adapted to delay the doses in younger population further than for older age groups. For the latter group the benefit of frequent vaccination is more evident and likelihood of an adverse response of myocarditis is smaller.

There are limitations to the interpretability of these results. First, we relied on diagnosis codes associated with hospital admissions to detect myocarditis cases and thus did not include potential episodes that did not lead to hospitalization. Depending on a differential association between vaccine exposure and those mild forms of heart inflammation, this could have over- or underestimated our risk estimates. Second, identification of SARS-CoV-2 infection episodes was probably incomplete because some were not diagnosed or only detected by at-home test without laboratory confirmation. This could have confounded the association between vaccine exposure and onset of myocarditis, but this is likely rare within a 7-day exposure window. Another consequence could be that an undetected infection increases both the interval to a subsequent vaccine dose and the risk of myocarditis. The reduction in the risk of vaccine-induced myocarditis that we observed with longer intervals between doses may therefore be even more important. Third, although the strong consensus that both mRNA Covid-19 vaccines are associated with an increased risk of myocarditis has not yet be overturned, our results apply to the use of those vaccines until end of 2022. The influence of dosing interval on the risk myocarditis might not generalise to the updated Covid-19 vaccines targeting the Omicron XBB.1.5 strain and its descendants.

In conclusion, in this population-based study we find that extended intervals between doses may decrease the risk of myocarditis including after mRNA booster vaccination, for which a minimum 6-month interval might be required. The larger risk of adverse event and smaller benefit of frequent boosting in healthy young adults may warrant that future mass vaccination schedule be adapted. Our findings on Covid-19 vaccines may also apply to other oncoming mRNA-based viral vaccines.

Methods

The study was conducted in compliance with the French regulations on access and processing of personal data from the National Health Data System (Système national des données de santé [SNDS]). Our research group (EPIPHARE) has a regulatory permanent access to the data from the SNDS. This access is granted according to the French Decree No. 2016-1871 of December 26, 2016 and French law articles Art. R. 1461-13 and 14. The research was declared to the Agence nationale de securité du medicament et des produits de santé (ANSM) and the Caisse nationale de l’Assurance Maladie (CNAM) Data Protection Officer under institutional registration reference EP-0311. According to the French law, informed consent and ethical approval from an institutional review board are not required when analysing deidentified existing healthcare data for research purposes.

Data sources

We conducted a matched case-control study within the entire French population aged 12 or older, from the beginning of the Covid-19 vaccination campaign in December, 27, 2020 to November, 30, 2022. By covering the first 2 years of Covid-19 vaccination, this extends our previous study9, that considered people aged 12-50 years in the first 6 months of primary vaccination, and allow to assess the exposure to the third dose (first booster) of mRNA vaccines.

The study was based on data of the National Health Data System (SNDS) which covers more than 99% of the French population (67 million inhabitants)13–15. Data on hospital admission were obtained from the French hospital discharge database (PMSI) and linked at the individual level with the nationwide databases for Covid-19 vaccination (VAC-SI) and testing (SI-DEP).

Outcome and exposures

Cases corresponded to all patients admitted to French hospitals with a diagnosis of myocarditis in the study period. Diagnoses at hospital were typically based on presenting symptoms, electrocardiography, echocardiography and cardiac, magnetic resonance imaging16. We used the codes for myocarditis (I40.x, I41.x, and I51.4) of the International Classification of diseases, 10th revision (ICD-10) for detection. Pericarditis was not evaluated in this study.

Each case was matched to 10 control individuals. Controls were selected from the general population by simple random sampling without replacement within each stratum of age, sex and area of residence (matching criteria), with constraint of not being diagnosed with myocarditis in the study period and being alive at the index date. Control subjects were assigned as the index date for the measure of exposure status the date of hospital admission for myocarditis of their matching case.

Exposure for the main analyses was defined as vaccination with a mRNA vaccine (BNT162b2 from Pfizer-BioNTech or mRNA-1273 from Moderna) 0 to 7 days prior to the index date, considering the first, second and third dose separately. Non-vaccinated subjects, and those vaccinated more than 21 days before the index date were considered to be non-exposed. Of note, France suspended the use of the mRNA-1273 vaccine for all population groups on October, 15, 2021, and made it available again for boosters and primary series on November, 8, 2021–but at half-dose and only for those over 30 years17.

Dosing intervals

Furthermore, vaccine exposure was categorized by the time interval between two consecutive doses. The recommended schedules varied throughout the vaccination campaign in France. Priming doses were initially scheduled 3 weeks apart for the BNT162b2 vaccine18 and 4 weeks apart for the mRNA-1273 vaccine19. At the end of January, 2021, in the context of a limited supply of vaccines and to maximize the number of people with an early first-dose protection, authorities recommended that the dosing interval could be extended to 6 weeks20. The first booster vaccination was to be taken at least 6 months after the second dose for both vaccines17,21. It was recommended that subsequent booster doses be spaced at least 3 months apart specifically for individuals aged 80 years and over, residing in nursing homes, or immunocompromised, and at least 6 months apart for the others22. Also, persons with a documented SARS-CoV-2 infection, either before or after the first vaccination, were recommended to be given the next dose, preferably 6 months and at least 3 months after the infection23.

It should be noted that, for this study, we only considered vaccine exposures preceding either the myocarditis event in cases or the attributed index date in matching controls. So vaccinations (and time intervals between them) that could have occurred after the defined index date were not taken into account in the association analyses.

Covariates

Analyses were adjusted for covariates potentially associated with a risk of myocarditis or vaccine exposure: history (within 5 years of index date unless otherwise mentioned) of myocarditis sarcoidosis, opioid use disorder, coronary artery disease and myocardial infarction, heart failure, antihypertensive drug use, arrhythmia, diabetes, autoimmune disease, respiratory disease, or active cancer; history of antibiotic use (within a month of index date), history of SARS-CoV-2 infection (any positive antigenic or RT-PCR test result within a month of index date), and deprivation index associated with the area of residence13.

Statistical analyses

We used conditional logistic regression models to estimate the odds ratios of myocarditis associated with exposure to mRNA vaccination within a week, adjusted for covariates. The analyses were conducted according to the ranking of vaccine dose (first, second or third dose) and the dosing interval, across the entire study group. Subgroup estimates by sex and age (either in categories or as a continuous variable) were obtained by calculating contrasts on models with corresponding interaction terms. Interactions were tested by Wald chi-square statistic.

Intervals between two consecutive doses were first categorised in 4 categories. Those between first and second doses were divided on week scale (7 days): before 3rd week ( < 22 days), in 3rd week (22–28 days), in 4th week (29 to 35 days), after 4th week ( > 35 days). Those between the second dose and first booster and between subsequent boosters were divided relative to whole number of months (30.4 days): before the 5th month ( < 153 days), in 6th month (153 to 183 days), in 7th month (184–213 days), after the 7th month ( > 213 days).

To also assess the nonlinear relationships between risk factors (dosing interval and age) and myocarditis, we implemented models based on restricted cubic splines24. To overcome coding errors resulting in dubious intervals, we discarded the 1st and 99th percentiles of each dosing interval distribution. Similarly, individuals with a missing dose interval, that is those who were unvaccinated or had received only one dose of vaccine before their index date, were excluded from the evaluation of the effect of dose interval on the risk of myocarditis.

To evaluate the sensitivity of the results to mixed vaccine usage, we replicated the main analysis on the subset of cases and controls that had received the same vaccine for the primary series and first booster (homologous regimens) or were unvaccinated. Finally, we assessed if our findings varied by considering vaccine exposure up to 21 days prior to the index date instead of 7 days.

Data collection used SAS Enterprise Guide version 4.3 software (SAS Institute, Cary, North Carolina) and analyses were performed using R version 4.2.1 (R Foundation for Statistical Computing), with packages survival version 3.3-1 and rms version 6.7-0.

Reporting summary

Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article.

Supplementary information

Supplementary Information

Peer Review File

Reporting Summary

Source data

Source Data

Supplementary information

The online version contains supplementary material available at 10.1038/s41467-024-52038-6.

Author contributions

S.L.V., M.B., A.W., R.D.S., and M.Z. conceived the study. A.W., R.D.S., and M.Z. supervised the project. M.B. and L.S. carried out the clinical data collection and data curation. S.L.V., M.B. and L.S. designed and performed the statistical analyses with M.J.J. and J.B. providing input. S.L.V. wrote the first draft of the manuscript. All authors interpreted the results, provided critical revision of the manuscript and approved its final version for submission.

Peer review

Peer review information

Nature Communications thanks the anonymous reviewers for their contribution to the peer review of this work. A peer review file is available.

Data availability

The minimum dataset that is necessary to interpret, verify, and extend the research in this article is available within the manuscript and its supplementary information. Source data are provided with this paper. According to the principles of data protection and French regulations, the authors are not allowed to publicly release the data from the French National Health Data System (SNDS). However, any person or structure, public or private, for-profit or nonprofit, is able to access SNDS data in order to carry out a study, research or an evaluation in the public interest, upon authorization from the French Data Protection Office (CNIL), via the French Health Data Hub (https://www.health-data-hub.fr/page/faq-english under section “About the data available through the Health Data Hub”, or by contacting hdh@health-data-hub.fr). Source data are provided in this paper.

Code availability

Code and simulated data to reproduce the analyses presented in the paper are publicly available on GitHub (https://github.com/slevu/vadim) and Zenodo (10.5281/zenodo.11280748).

Competing interests

The authors declare no competing interests.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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