mRNA Vaccines-MIS-C: French researchers from various universities and pediatric specialists from over 25 hospitals in France have in a new study alarmingly found that COVID-19 mRNA vaccines can cause multisystemic hyper-inflammatory syndrome in children aged 12-17.
The study findings were published on a preprint server and are currently being peer reviewed. https://www.medrxiv.org/content/10.1101/2022.01.17.22269263v1
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.4–6
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.7
Thus, numerous studies showed that MIS-C is by far the most severe form associated with SARS-CoV-2 infection in children and the leading source of morbidity related to SARS-CoV-2 in this age group.7,8
The pathophysiology of this disease remains unknown, but previous investigations showed that MIS-C is characterized by a cytokine storm9 associated with a superantigen-like activation of T cells with an expansion of Vβ21.3-expressing T cells which is not seen in toxic shock syndrome, Kawasaki disease or other COVID-19 features10–13.
Notably, SARS-CoV2 spike harbors a motif located in the receptor binding domain the that is predicted in silico to interact with Vβ region in T cells. Whether antigenic exposure limited to the Spike protein can lead to similar dysregulated immune response remains unknown.
Two COVID-19 mRNA vaccines have been shown to be efficacious and well tolerated in adults, and have been introduced since December 2020.14 Post-authorization studies confirmed their major impact on SARS-CoV-2 epidemics,15 with very few serious adverse events reported to date.16,17
In children, the immunogenicity, efficacy, as well as frequent adverse events have been assessed in trials involving thousands of 12-17-year-old children.18 Based on these studies, the Food and Drug Administration (FDA) and European Medicines Agency (EMA) authorized formulations of BNT162b2 COVID-19 vaccine for ages 12-17-year.
However, rare serious adverse events following immunization could not be detected by these clinical trials. 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).19–21 Several cases reports of children with MIS-C following mRNA vaccine recently raised major concerns regarding this potential vaccine-related adverse event.22–25
Using a well-established national pharmacovigilance surveillance system coordinated by ANSM,26,27 we aimed to evaluate the potential association of COVID-19 mRNA vaccine and subsequent hyper-inflammatory syndrome in children.
To our knowledge, this is the first post-authorization population-based pharmacovigilance study assessing the risk of hyper-inflammatory syndrome following COVID-19 mRNA vaccine in 12-17-year-old children. We found that this entity was observed with an reporting rate of 1.1 (95% CI [0.5; 2.1]) per 1,000,000 doses in this population. In most cases, no evidence of previous SARS-CoV-2 infection was observed, suggesting a 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 100-fold higher. A recent study highlighted that COVID-19 mRNA vaccine may significantly reduce the incidence of post-SARS-CoV-2 MIS-C (Hazard Ratio 0.09 (95% CI, 0.04-0.21)).31 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, cases of myocarditis have been reported following COVID-19 mRNA vaccines, especially in young men.36,37 These cases mainly occurred after the second dose of vaccine, few days after the injection, and were rapidly resolutive in most cases.36,37
The higher rate of hyper-inflammatory syndrome following COVID-19 mRNA vaccine in males, and the rate of cardiac involvement (8/9 cases) suggest similitudes with this entity. However, myocarditis were classically afebrile, with low inflammatory parameters, and were a mono-organ involvement.37 These major clinical differences may allow distinguishing these two entities. Second, all cases of hyper-inflammatory syndrome following COVID-19 mRNA vaccine fulfilled WHO definition for MIS-C.
Indeed, the prolonged hyper-inflammatory state, the multi-organ involvement and the severity of the disease are principal features of these two entities,7 indicating at least a major overlap. However, if statistical comparison between these two diseases was limited by the low number of cases, 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 infection38–40. 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 6 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.11 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.32 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 2/9 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.30 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 the causality of COVID-19 mRNA vaccines assessment was mainly based on investigation for previous SARS-CoV-2 infection. However, pauci or asymptomatic infections are frequent in children, and may not have been documented. Furthermore, false negatives can be observed for anti-Nucleocapsid serology.41 Thus, we cannot exclude that some of the cases reported here could be related to undiagnosed SARS-CoV-2 infections.
Second, 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, which would help in elucidating the vaccine causality.16 Third, 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.26 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.26
Fourth, given the very low proportion of 12-17-year-old children vaccinated by mRNA-1273 (<5%), we could not conduct subgroup analysis to compare 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. Fifth, 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.