Hyper inflammatory syndrome following COVID-19 mRNA vaccine in children: A national post-authorization pharmacovigilance study

Background Multisystem inflammatory syndrome in children (MIS-C) is the most severe clinical entity associated with pediatric SARS-CoV-2 infection with a putative role of the spike protein into the immune system activation. Whether COVID-19 mRNA vaccine can induce this complication in children is unknown. We aimed to assess the risk of hyper-inflammatory syndrome following COVID-19 mRNA vaccine in children. Methods We conducted a post-authorization national population-based surveillance using the French enhanced pharmacovigilance surveillance system for COVID-19 vaccines. All cases of suspected hyper-inflammatory syndrome following COVID-19 mRNA vaccine in 12–17-year-old children between June 15th, 2021 and January 1st, 2022, were reported. Cases were reviewed according to WHO criteria for MIS-C. The reporting rate of this syndrome was compared to the MIS-C rate per 1,000,000 12–17-year-old children infected by SARS-CoV-2. Findings Up to January 2022, 8,113,058 COVID-19 mRNA vaccine doses were administered to 4,079,234 12–17-year-old children. Among them, 12 presented a hyper-inflammatory syndrome with multisystemic involvement. Main clinical features included male predominance (10/12, 83%), cardiac involvement (10/12, 83%), digestive symptoms (10/12, 83%), coagulopathy (7/12, 58%), cytolytic hepatitis (6/12, 50%), and shock (5/12, 42%). 4/12 (33%) required intensive care unit transfer, and 3/12 (25%) hemodynamic support. All cases recovered. In eight cases, no evidence of previous SARS-CoV-2 infection was found. The reporting rate was 1.5 (95%CI [0.8; 2.6]) per 1,000,000 doses injected, i.e. 2.9 (95%CI [1.5; 5.1]) per 1,000,000 12–17-year-old vaccinated children. As a comparison, 113 MIS-C (95%CI [95; 135]) occurred per 1,000,000 12–17-year-old children infected by SARS-CoV-2. Interpretation Very few cases of hyper-inflammatory syndrome with multi-organ involvement occurred following COVID-19 mRNA vaccine in 12–17-year-old children. The low reporting rate of this syndrome, compared to the rate of post-SARS-CoV-2 MIS-C in the same age-group, largely supports the vaccination in a context of an important circulation of SARS-CoV-2. Funding ESPID Fellowship Award; Grandir–Fonds de Solidarité Pour L'enfance.

Hyper inflammatory syndrome following COVID-19 mRNA vaccine in children: A national postauthorization pharmacovigilance study Introduction Multisystem inflammatory syndrome in children (MIS-C) is a novel clinical entity first described in April 2020. 1−5 Its association with SARS-CoV-2 infection has been documented, with a previous infection occurring 4 to 6 weeks before MIS-C onset. 4−7 The main clinical features of MIS-C are frequent acute cardiac dysfunction, shock, multi organ failure that often require pediatric intensive care unit transfer and hemodynamic support. 8 Thus, numerous studies showed that MIS-C is by far the most severe clinical syndrome associated with SARS-CoV-2 infection in children and a leading source of morbidity related to SARS-CoV-2 in this age group. 8,9 The pathophysiology of this disease remains unknown, but previous investigations showed that MIS-C is characterized by a cytokine storm 10 associated with a superantigen-like activation of T cells with an expansion of Vb21.3-expressing T cells which is not seen in toxic shock syndrome, Kawasaki disease or other COVID-19 features. 11−14 Notably, SARS-CoV2 spike harbors a motif located in the receptor binding domain that is predicted in silico to interact with Vb region in T cells. Whether antigenic exposure limited to the Spike protein can lead to similar dysregulated immune response remains unknown.
Several COVID-19 mRNA vaccines have been shown to be efficacious and well tolerated in adults, and have been introduced since December 2020. 15 The Articles Post-authorization studies confirmed their major impact on SARS-CoV-2 epidemics, 16 with very few serious adverse events reported to date. 17,18 Israel reported a risk of post-mRNA vaccine myocarditis of 1.76 per 100,000 individual, mainly affecting young males. 19 In children, the immunogenicity, efficacy, as well as frequency of adverse events have been assessed in trials involving thousands of 12-17-year-old children. 20 Based on these studies, the Food and Drug Administration (FDA) and European Medicines Agency (EMA) authorized formulations of mRNA COVID-19 vaccine for ages 12-17-year. However, rare serious adverse events following immunization could not be detected by these clinical trials, which were not designed to assess the risk of rare hyper-inflammatory complications. Especially, whether exposure to SARS-CoV-2 antigens due to mRNA vaccine can induce MIS-C is unknown.
Given the lower burden of SARS-CoV-2 related diseases in children compared to adults, elucidating the safety profile of mRNA vaccine, especially regarding MIS-C, is of critical interest to establish its benefit-risk balance in this population. In this context, monitoring post-vaccine MIS-C has been identified as a priority by the FDA, the EMA, and the French National Agency for Medicines and Health Products safety (ANSM). 21−23 Several cases reports of children with MIS-C following mRNA vaccine recently raised important concerns regarding this potential vaccine-related adverse event. 24−27 Using a well-established national pharmacovigilance surveillance system coordinated by ANSM, 28,29 we aimed to evaluate the potential association of COVID-19 mRNA vaccine and subsequent hyper-inflammatory syndrome in children.

Study design and settings
We conducted a post-authorization prospective national population-based surveillance using the well-established ANSM pharmacovigilance system. 28,29 This network is based on 31 regional pharmacovigilance centers, which cover all the French territory, and is coordinated by ANSM since 1973. 28 All ambulatory or hospital-based health practitioners throughout France or patients that observe a suspected adverse drug reaction (ADR) report the event to the regional center via a secure platform. 28 Reporting of all ADRs, independently of the seriousness or expectedness, is compulsory for health practitioners. All reports undergo a pharmacological, clinical and biological assessment process by a trained assessor of the Regional Center. All reports are then registered in the national computerized pharmacovigilance database, centralized at ANSM, to allow anonymized case

Research in context
Evidence before this study We searched PubMed for articles published in English up to February 15, 2022, using the terms "Multisystem inflammatory syndrome" or "Paediatric inflammatory multisystem syndrome" or "MIS-C" or "PIMS" and "COVID-19 mRNA vaccine". Multisystem inflammatory syndrome in children (MIS-C) is the most severe clinical entity associated with SARS-CoV-2 infection in children. The pathophysiology of this syndrome remains unclear, and concerns have been raised regarding the possibility that exposure to Spike protein antigen with mRNA vaccines could induce a multisystemic hyper inflammatory response. Several case reports of MIS-C following mRNA vaccines involving children of adults have been reported, and a recent surveillance investigation from USA reported several cases of MIS-C in children who received a COVID-19 vaccine. Population-based pharmacovigilance studies are required to assess this risk and compare it to the rate of post SARS-CoV-2 MIS-C.

Implications of all the available evidence
This study shows that very few cases of hyper-inflammatory syndrome, with multisystemic involvement, may be observed after COVID-19 mRNA vaccine in children. The incidence of this event, compared to the rate of MIS-C following SARS-CoV-2 infection in the same age-group population, may help policy makers estimating the benefit-risk balance of COVID-19 mRNA vaccine in children. Large pharmacovigilance studies from other countries are required to precisely determine the role of COVID-19 mRNA vaccine in this syndrome, and to delineate the clinical spectrum of this entity compared to post-SARS-CoV-2 MIS-C.
reviewing at a national level by ANSM and experts in the field, drug causality assessment, and to recommend specific measures if required. 29 The detailed methodology of this French pharmacovigilance system has been previously published. 28,29 As part of the national COVID-19 vaccination campaign, ANSM had put in place a specific reinforced passive and active surveillance system to provide real-time monitoring of COVID-19 vaccines ADRs at a national level. 23,30 This is part of the risk management plan coordinated by the European Medicines Agency (EMA). The objectives are to carry out a continuous assessment of the safety of vaccines COVID-19 vaccines in order to confirm their safety or to quickly take the relevant measures, and to allow the Health Ministry to adapt the vaccination strategy, if necessary. For each marketed COVID-19 vaccine, two to five regional pharmacovigilance centers have been designated to gather and assess on a daily basis all adverse drug reactions reported following immunization. An expert of the organ involved is solicited to analyze all reported cases every week, to identify atypical and/or serious patterns leading to potential safety signals. 23 Then a weekly meeting involving ANSM and all regional pharmacovigilance centers is organized to discuss the expert pharmacovigilance reports, potential safety signals, and new data from the literature, in order to confirm or not safety signals. 23,30 A complete report including the synopsis of these meeting are published by ANSM every two weeks. 23,30 If a national safety signal is validated, appropriate measures are issued in relation with European Medicine Agency to prevent or reduce the likelihood of the risk occurring in vaccinated people. The detailed methodology of this specific COVID-19 vaccine monitoring is available elsewhere. 23,30 Cases review to assess WHO criteria for MIS-C All paediatric cases of inflammatory syndrome, fever > 3 days, shock, or acute organ dysfunction without any obvious cause, occurring any time after COVID-19 mRNA vaccine injection in children under 18 years of age in France reported to the surveillance system from June 15 th , 2021, to January 1 st , 2022, were eligible. Each case was reviewed by a multidisciplinary committee, with experts in pediatric immunization, pediatric infectious diseases, pediatric rheumatology, immunology and internal medicine, pediatric intensive care, pediatric cardiology, and expert pharmacologists from pharmacovigilance centers. All these experts were involved in MIS-C surveillance and management in France as part of the French MIS-C consortium, and developed specific expertise in this field. 5,31,32 Medical records were obtained for all cases to accurately assess if cases fulfilled WHO criteria for MIS-C, with COVID-19 mRNA vaccine exposure replacing SARS-CoV-2 exposure criteria, as indicated by recent Brighton Collaboration definition guidelines. 33 Cases were included after reviewing if they fulfilled WHO MIS-C criteria, with a delay between the last vaccine administration and disease onset < 2 months, based on available data from the literature regarding the delay between SARS-CoV-2 infection and MIS-C onset. 4−6 An important part of the vaccine causality assessment relied on identifying other potential causes for the event. 33,34 For hyper-inflammatory syndrome, extensive investigation of previous exposure to SARS-CoV-2 over the past two months was critical, and relied on investigating history of documented infection, and performing nasopharyngeal SARS-CoV-2 Polymerase chain reaction (PCR) and anti-Nucleocapsid (anti-N) serology. 33,35 National immunization program BNT162b2 COVID-19 mRNA vaccine have been introduced for 12−17-year-old children on June 15th, 2021 in France. 36 It has been followed by mRNA-1273 approval for same age children on July, 27th, 2021. 36 A higher risk of myocarditis or pericarditis has been suggested following mRNA-1273 compared to BNT162b2 in adults younger than 30 years old. 37 This has led French authorities to prioritize BNT162b2 for 12−17-year-old children immunization. Thus, by January 1 st , 2022, the large majority of vaccinated 12−17-year-old children received BNT162b2 (>95%). 32

Outcome measure
The main outcome was the national reporting rate of hyper-inflammatory syndrome following COVID-19 mRNA vaccine per 1,000,000 doses in 12-17-year-old children in France. To calculate national reporting rate, we used as a denominator the total number of COVID-19 mRNA vaccine dose administered in 12-17-year-old children over the study period (available at https://solid arites-sante.gouv.fr/grands-dossiers/vaccin-covid-19/arti cle/le-tableau-de-bord-de-la-vaccination).
We also analyzed the reporting rate of hyper-inflammatory syndrome following COVID-19 mRNA vaccine per 1,000,000 12-17-year-old vaccinated children in France.
Then, we estimated in the same age-group, in the same population, the rate of post-SARS-CoV-2 MIS-C cases per 1,000,000 infections in 12-17-year-old children in France for comparison.
Secondary outcomes were the reporting rate of hyper-inflammatory syndrome following first and second injections of COVID-19 mRNA vaccine in 12-17year-old children in France, reporting rate by sex, and comparison of clinical features of hyper-inflammatory syndrome following COVID-19 mRNA vaccine versus post-SARS-CoV-2 MIS-C cases.

MIS-C following SARS-CoV-2 infection surveillance system
To estimate the rate of post-SARS-CoV-2 MIS-C cases per 1,000,000 infections in 12-17-year-old children in France, we used data from the French COVID-19 Pediatric Inflammation Consortium, coordinated by Public health France. 5,31,32 As previously published, since April 2020, all suspected MIS-C cases in France were mandatorily reported to Public health France. Each suspected case was then assessed following WHO criteria for MIS-C. 5,31,32 Furthermore, Public health France also conducted seroprevalence studies that allowed estimating the proportion of 12-17-year-old old children infected by SARS-CoV-2 since the beginning of the pandemic. 38 Thus, to estimate the rate of post-SARS-CoV-2 MIS-C cases per 1,000,000 infections, we used as a numerator the number of confirmed 12-17-year-old MIS-C cases reported to Public health France since the start of the pandemic, and as a denominator the estimated number of 12-17-year-old French children infected by SARS-CoV-2 since the start of the pandemic, based on Public health France estimations. 38 To avoid any bias in MIS-C rate estimation due to vaccine implementation, 32 we restricted this analysis to the pre-vaccine period, i.e. from the start of the pandemic to June 15 th , 2021.
This surveillance system also collected clinico-biological and short term outcome data of MIS-C cases that fulfilled WHO criteria. 5,31,32 Thus, to compare the clinical presentation of hyper-inflammatory syndrome following COVID-19 mRNA vaccine to post-SARS-CoV-2 MIS-C cases in the same population, we included all unvaccinated 12-17-year-old MIS-C cases fulfilling WHO criteria with available clinical files as same-age and same-population comparator group.

Statistical analysis
We describe patient characteristics with numbers (percentages) for categorical variables and median (interquartile range [IQR]) for quantitative variables. We compared clinical and biological characteristics using non-parametric Fisher's exact test for categorical variables and Mann-Whitney U test for quantitative variables. A two-sided p-value <0.05 was considered statistically significant. Reporting rate of hyper-inflammatory syndrome was expressed as cases per 1,000,000 vaccine injections with 95% CIs. All statistical analyses involved using R v3.6.1 (http://www.R-project.org).

Ethics
For the pharmacovigilance surveillance system, this study was performed according to the authorization from the National Commission on Informatics and Liberty (CNIL) n°2014-302 for the national pharmacovigilance database done by ANSM. For the MIS-C following SARS-CoV-2 infection surveillance system, the study was approved by the INSERM ethics committee for evaluation (IRB00003888). A written information form validated by the ethics committee was given to all participants. Oral consent was obtained from study participants; no family members or participants refused to participate.

Results
From June 15th, 2021 to January 1st, 2022, 8,113,058 COVID-19 mRNA vaccine doses were administered to 4,079,234 12-17-year-old children in France (including 4,079,234 first injections, 3,905,636 second injections, and 128,188 third injections). Over this period, 2,028 adverse drug reactions related to COVID-19 mRNA vaccine have been reported to the pharmacovigilance centers in 12-17-year-old children. Among them, 102 cases of myocarditis or pericarditis (including 78 (76%) males), and 12 cases of hyper-inflammatory syndrome were reported. All hyper-inflammatory syndrome cases fulfilled WHO criteria for MIS-C (Table 1). Ten cases involved BNT162b2 vaccine and 2 cases involved mRNA-1273. Six cases occurred following the first injection, and 6 following the second injection. As for myocarditis and pericarditis, a male predominance was also observed in these hyper-inflammatory syndromes (10/ 12 cases, 83%). The delay between last injection and disease onset ranged from 1 day to 42 days.

Investigation of previous SARS-CoV-2 infection
All 12 cases had complete data for history of documented infection, nasopharyngeal SARS-CoV-2 PCR, and anti-N serology. In one case, a previous infection 7 months before disease onset was reported, but was too far apart to be considered as linked to the disease. All children had negative SARS-CoV-2 PCR, and four children had a positive anti-N serology (Table 1). In 8 cases, no evidence of previous SARS-CoV-2 infection was found (details Table 1). The clinical and biological details of cases depending on SARS-CoV-2 anti Nucleocapsid serology is provided Table S1.
National reporting rate of hyper-inflammatory syndrome following mRNA vaccine Considering all 12 cases of hyper-inflammatory syndrome, a national reporting rate of 1.5 (95% CI [0.8; 2.6]) per 1,000,000 mRNA vaccine doses administered in 12-17-year-old children was observed. Excluding cases for which evidence of previous SARS-CoV-2 infection has been found, the reporting rate was reduced to 1.0 (95% CI [0.4; 1.9]) per 1,000,000 mRNA vaccine doses administered. This reporting rate was similar following the first and the second mRNA vaccine injections (
Some biological parameters also differed between post-vaccine hyper-inflammatory syndrome and post-SARS-CoV-2 MIS-C, including inflammatory parameters ( Table 3). Of note, 2/12 (17%) children with post-vaccine hyper-inflammatory syndrome had a transient hypereosinophilia (compared to 9/199 (5%) in post-SARS-CoV-2 MIS-C). These two children were explored for TRBV11-2/Vb21.3 T cell receptor (TCR) expansion by flowcytometry, none of them had an expansion of this repertory, while it was present in 75% of post-SARS-CoV-2 MIS-C patients. 12 The other patients were not tested for TCR repertoire expression.

Specific therapy and short-term outcomes
Short term outcomes seemed also less severe for postvaccine hyper-inflammatory syndrome, with a lower  rate of PICU transfer (4/12, 33%), compared to 143/199 (72%) for post-SARS-CoV-2 MIS-C (p=0.008, Table 3). Eight children were treated by an administration of intravenous immunoglobulins plus methylprednisolone, of whom one received a subsequent 10mg/kg/day methylprednisolone pulse. Three children received methylprednisolone alone, and one did not receive specific immunomodulator agent. All children fully recovered at the time of discharge. Median length of hospital stay was 7 days (IQR [7; 9]).

Discussion
This post-authorization population-based pharmacovigilance study assessed the risk of hyper-inflammatory syndrome following COVID-19 mRNA vaccine in 12-17year-old children, and compared this rate to post-SARS-CoV-2 MIS-C. We found that this entity was observed with a reporting rate of 1.   Articles reported cases of hyper-inflammatory syndrome in children who received COVID-19 vaccine, with a similar reporting rate (1.0 per 1,000,000 individuals receiving at least one dose). 39 In most cases in our study, no evidence of previous SARS-CoV-2 infection was observed, suggesting a potential link between this entity and COVID-19 mRNA vaccine. This rare serious adverse event should be put in balance with the rate of post-SARS-CoV-2 MIS-C in the same age group in the same population, which was much higher. Two recent studies highlighted that COVID-19 mRNA vaccine may significantly reduce the incidence of post-SARS-CoV-2 MIS-C. 32,40 Taken together, these findings suggest that the benefit-risk balance of COVID-19 mRNA vaccine is largely in favor of the vaccination in this age group, in a context of active circulation of SARS-CoV-2. An important issue is to delineate the clinical spectrum of this entity, which may have overlap with several other diseases. First, an increased risk of myocarditis has been reported following COVID-19 mRNA vaccines, especially in young men. 19,41 These myocarditis mainly occurred after the second dose of vaccine, few days after the injection, and were rapidly resolutive in most cases. 19,41 The male predominance was also observed in post vaccine myocarditis occurring in 12-17 years old French population (78/102 cases, 76%). These characteristics echo to the male predominance observed in our study among children with hyper-inflammatory syndrome following COVID-19 mRNA vaccine (10/12 cases, 83%), as well as the important rate of cardiac involvement (10/12 cases, 83%). On the other hand, myocarditis were classically afebrile, with low inflammatory parameters, and were a mono-organ involvement. 41 These major clinical differences may allow distinguishing these two entities, that however could possibly represent a continuum. Second, all cases of hyper-inflammatory syndrome following COVID-19 mRNA vaccine fulfilled WHO definition for MIS-C.  Table 3: Comparison of clinic-biological features of hyper-inflammatory syndrome following COVID-19 mRNA vaccine and MIS-C post SARS-CoV-2 infection in France.
Categorical variables are described with numbers (percentages) and quantitative variables are described with median (IQR). Biological parameters were at admission, except for CRP, which is the maximal value during the hospitalization. Abbreviations: MIS-C: multisystem inflammatory syndrome in children. Indeed, the prolonged hyper-inflammatory state, the multi-organ involvement and the severity of the disease are principal features of these two entities, 8 indicating at least a major overlap. However, if statistical comparison between these two diseases was limited by the low number of cases, and should be interpreted with caution, our findings suggest that post-SARS-CoV-2 MIS-C may have still higher inflammatory parameters, and more cytopenia. This may be in line with the significantly lower rate of PICU transfer (33% vs 72%) for hyper-inflammatory syndrome following COVID-19 mRNA vaccine cases, which might reflect a less severe immune storm and disease course. Notably, a 4-week delay has been observed in the context of MIS-C following SARS-CoV-2 infection. 42−44 Here, the delay from first antigen exposure to hyper-inflammatory syndrome occurred within a week in 3 patients and after 4−12 weeks in the 9 others. In the cases with early reaction, a hypereosinophilia was seen in 2 patients, a feature not seen in classical MIS-C. This observation might reflect immunoallergic reaction distinct from the superantigenic like features of MIS-C. Expansion of Vb21.3 expressing T cells is a hallmark of the MIS-C and can be easily assessed by flowcytometry. 12 By contrast, the two children with post-vaccination hyper-inflammatory syndrome had no expansion of this T cell subset. Taken together, these clinical and immunological divergences may imply distinct underlying pathways and further studies are required to expand this finding. Third, a recent study coordinated by the CDC reported cases of multisystem inflammatory system in adults (MIS-A) in USA, in vaccinated and unvaccinated adults. 35 Twenty cases were identified, of whom seven were vaccinated. However, all of them had a documented previous exposure to SARS-CoV-2, questioning the direct causal role of mRNA vaccines in these manifestations, and diverging with the pediatric syndrome reported here, with only 4/ 12 patients presenting a seropositivity to N antigen. The issue of delineating these different entities underline the need to extensively investigate cases of hyper-inflammatory syndromes following mRNA vaccines, especially by performing anti-S and anti-N serology, along with exploration for TRBV11-2/Vb21.3 expansion. Because this hyper-inflammatory syndrome following COVID-19 mRNA vaccine was severe with acute multi-organ dysfunction, therapeutic aspects are of major interest. In this cohort, most children were treated by an association of immunoglobulins plus methylprednisolone, following MIS-C therapeutic protocols. 31 Only one child treated with this combination required a therapeutic escalation, and received a methylprednisolone pulse (10mg/kg/day). All children fully recovered. If sample size precludes any definitive conclusion, these findings suggest that the association of immunoglobulins plus methylprednisolone may be a suitable approach while awaiting more evidence regarding these treatments.
Several limitations should be discussed. First, a causal association between COVID-19 mRNA vaccines and hyper-inflammatory syndrome could not be asserted. Indeed, despite extensive investigation for previous SARS-CoV-2 infection in all cases, pauci or asymptomatic SARS-CoV-2 infections are frequent in children, and may not have been documented. Furthermore, false negatives can be observed for anti-Nucleocapsid serology. 45 Thus, we cannot exclude that some of the cases reported here could be related to undiagnosed SARS-CoV-2 infections. Furthermore, an important step in assessing vaccine related adverse events is to compare them to the rate of the disease in unvaccinated populations, as it was done for myocarditis. Because this entity has not been previously described in healthy populations, we could not have a control population to estimate the expected incidence of this disease in unvaccinated children. In addition, as this event is very rare, large population-based pharmacovigilance studies from other countries are required to precise the role of COVID-19 mRNA vaccine in this syndrome. 17 Second, we cannot rule out under reporting of adverse drug events in our population, which may have biased the estimated rate of hyper-inflammatory syndrome. However, following the implementation of COVID-19 mRNA vaccine, a major effort has been made by all pharmacovigilance centers to publicize that the reporting of any suspected adverse drug reaction following these vaccines was mandatory. 28 The impressive number of suspected adverse drug reaction reports (>80,000 between January 2021 and January 2022 in France) suggest that underreporting may have been very rare, especially for serious adverse drug reactions. 28 In France, national guidelines recommend any suspected MIS-C case to be hospitalized, making the possibility of underreporting due to ambulatory care of hyper inflammatory syndrome unlikely .Third, given the very low proportion of 12-17-year-old children vaccinated by mRNA-1273 (<5%), we could not provide an accurate estimation of the risk of hyper-inflammatory syndromes according to COVID-19 mRNA vaccine type. Further studies are required to explore if this risk differ between BNT162b2 and mRNA-1273. Fourth, because mRNA vaccines were only recommended to 12−17-year-old children in France until December 2021, we could not explore the risk of hyper-inflammatory syndrome in younger children.

Conclusion
In this study, we identified cases of hyper-inflammatory syndrome following COVID-19 mRNA vaccines in 12-17-year-old children in France, with multisystemic involvement. This syndrome was very rare, and its reporting rate, in comparison with the rate of MIS-C following SARS-CoV-2 infection in the same age-group, largely supports the vaccination in a context of an important circulation of SARS-CoV-2. This syndrome shared many clinical features with post-SARS-CoV-2 MIS-C, but some clinical, immunological and shortterm outcomes divergences call for further studies to explore its specific pathway.

Contributors
NO, HB, FA, and AB made substantial contributions to the conception or design of the work. NO and AB drafted the manuscript. DA, NO, HB, CLeb, CLev, FS, EJ, BBM, CO, SR, VH, IKP, ND, LDP, XI, CGLG, FA and AB were involved in the acquisition, analysis, or interpretation of data. All authors provided critical revision of the manuscript for important intellectual content. NO and HB had full access to all data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Funding/Support: NO was supported by the 2021 ESPID (European Society for Pediatric Infectious Diseases) Fellowship Award. The French Covid-19 Paediatric Inflammation Consortium received an unrestricted grant from the Square Foundation (Grandir−Fonds de Solidarit e Pour L'enfance).
Data availability: Data are available upon reasonable request to NO (naim.ouldali@aphp.fr).
Role of the Funder/Sponsor: The funders had no role in the design or conduct of the study, collection management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication. We are grateful to every microbiological laboratory staff member who performed severe acute respiratory syndrome coronavirus 2 reverse transcriptase −polymerase chain reaction and antibody testing in each center. None of the persons listed here received compensation for their role in the study.