Is COVID-19 mRNA vaccination in children associated with subsequent multisystemic hyper-inflammatory syndrome?

In a recent preprint study posted to the medRxiv* server, a team of researchers assessed the possibility of coronavirus disease 2019 (COVID-19) messenger ribonucleic acid (mRNA) vaccine causing multisystem inflammatory syndrome in children (MIS-C) aged 12 to 17 years in France.

Study: Multisystemic inflammatory syndrome following COVID-19 mRNA vaccine in children: a 2 national post-authorization pharmacovigilance study. Image Credit: MilanMarkovic78/Shutterstock


MIS-C is a novel clinical entity characterized by shock, frequent acute cardiac dysfunction, and multi-organ failure requiring intensive care unit transfer of the patient and hemodynamic support. There is documented evidence that associates severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection with MIS-C.

In May 2021, the Food and Drug Administration (FDA) and European Medicines Agency (EMA) authorized the use of the BNT162b2 mRNA COVID-19 vaccine in individuals of 12 to 17 years of age. However, the potential of the SARS-CoV-2 antigens in inducing rare conditions like MIS-C needs further investigation.

About the study

In the present study, the researchers conducted a post-authorization prospective national population-based surveillance to investigate the association of coronavirus disease 2019 (COVID-19) mRNA vaccines with MIS-C in children aged 12 to 17 years in France.

Children under 18 years of age exhibiting fever for more than three days, shock, inflammatory syndrome, or unexplained acute organ dysfunction after receiving the COVID-19 mRNA vaccine in France from June 15, 2021, to January 1, 2022, were eligible for the study. These cases were assessed to verify if they fulfilled the World Health Organization (WHO) criteria for MIS-C. The cases fulfilling the criteria were further reviewed to include patients reporting a delay of fewer than two months between COVID-19 vaccination and the onset of MIS-C.

The national reporting rate of MIS-C after COVID-19 mRNA vaccination per 1,000,000 vaccine doses in 12 to 17-year-old children in France was employed as the primary outcome of the study. The researchers compared the national reporting rate with the rate of post-SARS-CoV-2 MIS-C cases per 1,000,000 infections in 12- to 17-year-old children. The reporting rate of MIS-C after the first and second COVID-19 mRNA vaccine doses in the same age group was considered the secondary outcome.


The results show that nine cases of MIS-C were observed among the 2,028 COVID-19 mRNA vaccine-related adverse drug reactions reported. Complete data for history of documented COVID-19 infection, nasopharyngeal SARS-CoV-2 polymerase chain reaction (PCR), and anti-N serology were available for these MIS-C cases. The onset of the disease was noted two to 42 days after the last vaccination dose was received.

In the cases studied, the median age was 12.5 years, and 89% of patients were male, while three of the male patients had comorbidities like type 1 diabetes, osteochondritis with obesity, and leukemia. Clinical characteristics of MIS-C like cardiac involvement, gastrointestinal symptoms, coagulopathy, mucocutaneous involvement, cytolytic hepatitis, and shock were observed in the patients. However, characteristic manifestations of MIS-C, like the expansion of Vb21.3-expressing T cells, were not detected in the patients in the present study.  

The researchers noted a national reporting rate of 1.1 per 1,000,000 mRNA vaccine doses received by the study group of 12 to 17-year-old children. The national MIS-C reporting rate in children after the first mRNA vaccine dose was 1.2, while in children after the second mRNA dose vaccination, it was 1.0. Additionally, the reporting rate was lower in females as compared to males. In comparison, the reporting rate for the occurrence of MIS-C post-SARS-CoV-2 infection is 113.3 per 1,000,000 in 12-to 17-year-old infected children.


The national reporting rate of 1.1 included cases with no recorded history of SARS-CoV-2 infection, suggesting a link between the COVID-19 mRNA vaccine and MIS-C. The rate of occurrence of MIS-C post-SARS-CoV-2 infection is 100 times higher than post-COVID-19 mRNA vaccination.

Moreover, a recent study noted that COVID-19 mRNA vaccines might reduce the prevalence of MIS-C in SARS-CoV-2-recovered individuals. Taken together,  these study results indicate that COVID-19 mRNA vaccination can significantly lower the risk of MIS-C incidence in the age group of 12 to 17 years.

Clinical features of MIS-C like prolonged hyper-inflammatory state, involvement of multiple organs, and disease severity were observed to be common in both post-SARS-CoV-2-MIS-C occurrences and MIS-C post-COVID-19 mRNA vaccination. Clinical and immunological divergences like the lack of expansion of a subset of T cells indicate a difference in clinical pathways of MIS-C manifestations, which need further investigation.  

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Susha Cheriyedath

Written by

Susha Cheriyedath

Susha has a Bachelor of Science (B.Sc.) degree in Chemistry and Master of Science (M.Sc) degree in Biochemistry from the University of Calicut, India. She always had a keen interest in medical and health science. As part of her masters degree, she specialized in Biochemistry, with an emphasis on Microbiology, Physiology, Biotechnology, and Nutrition. In her spare time, she loves to cook up a storm in the kitchen with her super-messy baking experiments.


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