Multisystem Inflammatory Syndrome in Children by COVID-19 Vaccination Status of Adolescents in France

COVID-19 mRNA vaccine immunogenicity and effectiveness are well established in adolescents.¹ However, the effect of vaccination on multisystem inflammatory syndrome in children (MIS-C),² a severe complication associated with SARS-CoV-2,³ has not yet been described. Summer 2021 in France was marked by both a fourth wave of COVID-19 cases due to the Delta variant, with a peak in August 2021, and by the recommendation of the French Public Health Agency to vaccinate children aged 12 years or older. We estimated the risk of MIS-C among adolescents by COVID-19 vaccination status during September 2021 and October 2021.

All pediatric patients diagnosed with MIS-C according to World Health Organization criteria and admitted to 1 of the 41 French pediatric intensive care units (PICUs) between September 1, 2021, and October 31, 2021, were included in this study. In addition, all patients with MIS-C who were not admitted to a PICU and mandatorily reported to the French Public Health Agency⁴ during this period were included.

Data regarding age, sex, admission to a PICU, and vaccination status of patients aged 12 to 18 years (hereafter referred to as adolescents) were recorded.

To account for the increasing number of adolescents vaccinated over time, including during the period in which MIS-C cases were measured, hazard ratios (HRs) of unvaccinated vs vaccinated adolescents with at least 1 dose of vaccine were estimated using a Cox proportional hazards model. Given the delays between vaccine injection and immune response and between SARS-CoV-2 infection and MIS-C onset, 3 sensitivity analyses were performed in which adolescents were considered vaccinated at least 14, at least 28, and at least 42 days after the first vaccine dose. The delay of more than 42 days covers the 28 days between the first and second injection and 2 additional weeks to achieve full immunity. Data describing vaccination status per day are available from https://solidarites-sante.gouv.fr/grands-dossiers/vaccin-covid-19/article/le-tableau-de-bord-de-la-vaccination.

All statistical analyses were performed with Stata, version 16.1 (StataCorp), and a 2-sided P < .05 was considered statistically significant.

This study was approved as a medical registry assessment without a requirement for patient consent by the French Advisory Committee on Information Processing in Health Research.

On June 15, 2021, the beginning of the adolescent COVID-19 vaccination campaign, 2.2% of the 4 989 013 adolescents in France were vaccinated with at least 1 dose and 0.2% were fully vaccinated. On October 31, 2021, vaccination rates reached 76.7% of adolescents having received at least 1 dose and 72.8% being fully vaccinated. Vaccines used were BNT162b2 (Pfizer-BioNTech; >95%), mRNA-1273 (Moderna; <5%), and other COVID-19 vaccines (<1%).

From September 1, 2021, to October 31, 2021, a total of 107 children with MIS-C were hospitalized in France and, among them, 33 (31%) were adolescents eligible for vaccination. Adolescents with MIS-C were a median age of 13.7 (IQR, 12.5-14.9) years, 27 (81%) were male, and 29 (88%) were admitted to a PICU. Among them, 0 had been fully vaccinated, 7 had received 1 dose with a median time between vaccine injection and MIS-C onset of 25 (IQR, 17-37) days, and 26 had not been vaccinated. The HR for MIS-C was 0.09 (95% CI, 0.04-0.21; P < .001) after the first vaccine dose compared with unvaccinated adolescents. Sensitivity analyses showed similar results (Table).

Most adolescents with MIS-C for whom vaccination was indicated in France had not been vaccinated. These results suggest that COVID-19 mRNA vaccination was associated with a lower incidence of MIS-C in adolescents. The median of 25 days between single vaccine injection and MIS-C onset compared with a mean 28-day delay between SARS-CoV-2 infection and MIS-C onset⁴ suggests that, in most cases, SARS-CoV-2 infection occurred before or shortly after the vaccine injection, when immune response was incomplete. The absence of MIS-C cases in fully vaccinated children prevented calculation of an HR for this group but suggests that 2 doses are warranted for efficient protection. The study had limitations, including the low number of patients, use of national data to calculate HRs without considering regional variations, and inability to control for individual risks of MIS-C, such as sex, race and ethnicity, and comorbidities.⁵

The association between mRNA vaccination with MIS-C in younger children should be evaluated as vaccines are approved for use in children aged 5 to 11 years. Close monitoring is required given the alert on myocarditis occurring in adolescents after COVID-19 mRNA vaccine.⁶

Corresponding Author: Michael Levy, MD, PhD, Pediatric Intensive Care Unit, Hôpital Universitaire Robert-Debré, Assistance Publique–Hôpitaux de Paris, 48 boulevard Sérurier, 75019 Paris, France (michael.levy@aphp.fr).

Accepted for Publication: December 8, 2021.

Published Online: December 20, 2021. doi:10.1001/jama.2021.23262

Author Contributions: Drs Levy and Angoulvant had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Levy, Recher, Javouhey, Angoulvant.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Levy, Angoulvant.

Critical revision of the manuscript for important intellectual content: Levy, Recher, Hubert, Javouhey, Fléchelles, Leteurtre.

Statistical analysis: Levy, Angoulvant.

Obtained funding: Hubert, Leteurtre.

Administrative, technical, or material support: Recher, Hubert, Javouhey, Leteurtre, Angoulvant.

Supervision: Levy, Javouhey, Angoulvant.

Conflict of Interest Disclosures: Dr Angoulvant reported receiving lecture fees from Pfizer and being the principal investigator of the PANDOR study, which received an unrestricted grant from Pfizer. No other disclosures were reported.

Additional Contributions: We are grateful to Groupe Francophone de Réanimation et d’Urgences Pédiatriques, Santé Publique France, Société Française de Pédiatrie, Groupe de Pediatrie Générale, Groupe de Pathologie Infectieuse Pédiatrique, Société Française de Cardiologie, Filiale de Cardiologie Pédiatrique et Congénitale, Société Francophone Dédiée à L’étude des Maladies Inflammatoires Pédiatriques, and Filière de Santé des Maladies Auto-immunes et Auto-inflammatoires Rares for their participation in the French COVID-19 Paediatric Inflammation Consortium. We thank Daniel Levy-Bruhl, MD, Denise Antona, MD, and Isabelle Parent-du-Chatelet, MD (Santé Publique France Agence Nationale de Santé Publique, Saint-Maurice); David Skurnik, PhD (INSERM U1151-Equipe 11, Paris); and Naïm Ouldali (Hôpital Universitaire Robert-Debré, Paris) for their advice, as well as all the caregivers who included patients in the study. No compensation was provided to these individuals.