Background
Coronavirus disease 2019 (COVID-19) mRNA vaccines demonstrated safety, immunogenicity, and efficacy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in adults, adolescents (12–18 years) and children (5–11 years), and were therefore authorized by the Food and Drug Administration (FDA) and at the end of 2021 by the European Medicine Agency (EMA) for use in children aged 5–11 years [
1‐
3]. There has been debate on whether children should be vaccinated, as the pediatric population generally shows a milder and non-fatal course of COVID-19 compared to adults [
4]. However, in some children, COVID-19 can have severe consequences. There has been an increasing number of reported cases of pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS), also called multisystem inflammatory syndrome in children (MIS-C). This severe hyperinflammatory syndrome, which shares some similarities with Kawasaki disease and some unique clinical features with serious complications, occurs approximately three weeks (range 2–6 weeks) after SARS-CoV-2 infection [
5]. It is defined by the Centers for Disease Control and Prevention (CDC) as a severe illness requiring hospitalization in individuals aged < 21 years, with fever for ≥ 24 h, elevated inflammatory markers with multisystem (≥ 2) organ involvement and a suspected or confirmed SARS-CoV-2 infection within the last four weeks [
6]. Even though MIS-C and Kawasaki disease show phenotypic similarities, there are important differences regarding morbidity and mortality. MIS-C is more associated with gastrointestinal symptoms and cardiovascular system involvement [
7]. Cardiac involvement, including diminished ventricular function, coronary artery dilatation and diffuse myocardial oedema, are more prevalent and severe in MIS-C than in Kawasaki disease and cardiogenic shock is observed in MIS-C in 40–80% of the patients compared to 2–7% in Kawasaki [
7,
8]. Additionally, more than 60% of the MIS-C patients are admitted to the pediatric intensive care unit (PICU) [
7‐
9]. Mortality rates for MIS-C are estimated to be around 1% in high-income countries, but significantly higher in developing countries (reported up to 9%)[
10] and overall higher thanin Kawasaki disease, which has a mortality rate of 0.1–0.3% in patients treated with intravenous immunoglobulin (IVIG) [
11,
12]. MIS-C patients are currently treated with IVIG, glucocorticosteroids, aspirin, supportive treatments, and refractory cases with additional biological DMARDs [
13].
As of May 2022, a total of 8,525 MIS-C patients have been reported in the United States, of whom 69 patients have died [
14]. Available estimates of cases worldwide are lacking. Most MIS-C patients were healthy children, not known to have an underlying medical disorder at time of infection and MIS-C. Until now, the pathophysiology of MIS-C remains largely unknown [
15], but it has been hypothesized that MIS-C is a dysregulated immune response characterized by a cytokine storm associated with a superantigen-like activation of T-cells [
16‐
19].
Currently, it is not clear if available COVID-19 vaccines are able to prevent these serious complications of SARS-CoV-2 infection in children. The purpose of this paper is therefore to perform a systematic literature review and meta-analysis on whether current COVID-19 vaccines have a protective effect on the development of MIS-C in children and adolescents aged 5–18 years.
Discussion
In this systemic literature review and meta-analysis, the effect of the mRNA COVID-19 vaccine on the development of MIS-C has been addressed. This systematic review lends supportive evidence that vaccination of children and adolescents is highly associated with reduced MIS-C development and underscores the importance of vaccination of all eligible children. In our meta-analysis, we found that the pooled OR for MIS-C in vaccinated children compared to unvaccinated children was 0.04 (95% confidence interval: 0.03–0.06).
Studies conducted in France and the United States during the Delta wave have shown a reduced incidence of MIS-C after mRNA COVID-19 vaccination in children aged 12–18 years, with a hazard ratio for the risk of MIS-C of 0.09 after one vaccine dose compared with unvaccinated adolescents in France [
28]. Two doses of the Pfizer-BioNTech vaccine led to a protective effect against MIS-C with an effectiveness of 91% in the US cohort [
29]. In addition, in Denmark, the Pfizer–BioNTech vaccine was protective against MIS-C in 94% during the Delta wave [
30].
Altogether, it can be concluded that the protective effect of vaccination outweighs the triggering effect of vaccination on MIS-C, as the risk of developing MIS-C as an adverse effect of vaccination is much lower (2,9 per 1,000,000 children), compared to the risk of MIS-C post-infection (113 per 1,000,000 children) [
36]. Furthermore, based on the literature so far, it remains unknown if COVID-19 vaccination really can cause MIS-C or whether vaccinated children who developed MIS-C had a recent (sometimes unnoticed) SARS-CoV-2 infection.
It is noteworthy that the conclusions from our systemic review are based mostly on children in the age category of 12–18 years old. On October, 2021 the Pfizer-BioNTech vaccine was approved by the FDA for children aged 5–11 years [
2,
3]. Therefore, the preventive effect seen in adolescents has not yet been evaluated in these younger children [
38]. In 2021, the CDC mentioned that MIS-C was most frequent among children 5–11 years, with 2,316 cases of MIS-C reported in the United States at that time [
39]. However, a plausible explanation for this would be that adolescents were already vaccinated during this period and since this has a protective effect, the number of MIS-C patients among the younger children increased. Based on a benefit-risk analysis from the CDC using recent epidemiological data for both 5–11 years old males and females, 130 MIS-C cases could be prevented for every million Pfizer-BioNTech vaccinations. Thus, the number needed to vaccinate (NNV) was 1,1226, indicating that in order to prevent one MIS-C case in children aged 5–11 years, 1,1226 children should be vaccinated [
39]. In addition to avoiding the development of MIS-C, COVID-19 vaccination also decreases the morbidity and mortality associated with the disease with low numbers of adverse events associated with the vaccination [
40,
41]. In the upcoming months, data should be gathered to make a similar evidence-based conclusion about vaccination and MIS-C in children younger than 12 years.
The exact pathophysiology of MIS-C remains unknown, but recent research showed that patients with MIS-C have a different type of host immune response compared to patients with acute COVID-19. This immune response includes superantigen-like activation of T-cells with expansion of polyclonal expansion of TCR Vbeta 21.3
+ CD4
+ and CD8
+ T-cells, something which is not seen in toxic shock syndrome, Kawasaki disease or COVID-19 in general. In addition, host genetics might alter the susceptibility to develop MIS-C [
16‐
19,
42‐
44].
Possible explanations for a protective mechanism of the vaccine on MIS-C include the prevention of COVID-19, since MIS-C is a complication of this disease and the vaccine does not seem to induce the super-antigen driven T-cell clone, whereas the wildtype infection does. A second hypothesis is that the vaccine could have a direct immune protective effect, preventing a hyper inflammatory condition [
30,
44].
The epidemiology of the COVID-19 virus is changing constantly, and the Omicron variant may lead to a milder disease course but might be also more contagious [
38]. It is not known yet if the Omicron variant is more or less associated with MIS-C compared to other variants [
45]. Future COVID-19 variants may affect the clinical course and may influence the incidence of MIS-C cases.
The studies included in this systematic review were conducted during a period when the Delta variant was dominant and Omicron was looming [
38]. The question arises, whether the conclusions that were made about the Delta era can be translated to the Omicron era. The CDC reported that Omicron has a higher transmission rate [
38]. Since Omicron has become dominant, researchers have focused on comparing COVID-19 and MIS-C cases between the Delta and Omicron era. Following an observational retrospective study that was performed in Rio de Janeiro with children aged 0–18 years, it was concluded that fewer hospital admissions occurred during the Omicron wave [
46]. Besides an increased number of children with acquired immunity due to prior (asymptomatic) SARS-CoV-2 infection and the fact that the Omicron variant is less pathogenic, another explanation for this reduction in hospital admissions could be the increased number of vaccinated children. Miller et al. aimed to compare the incidence of MIS-C cases during the Delta and Omicron waves in the United States and found a clear reduction in incidence and less often severe organ damage during the latter wave [
32]. However, they observed an increase in children aged 5–11 years with MIS-C. Similar observations were observed in Israel [
33]. This could again indicate that the COVID-19 vaccine, which was given to children aged 12–18 years during the Delta wave, has a protective effect on developing MIS-C. These findings might also indicate the importance of COVID-19 vaccination in children aged 5–11 years, although the number of studies in the current systematic review that included this age group was limited. Other possible explanations for the reduced number of (severe) MIS-C cases during the Omicron wave include lower pathogenicity of the Omicron variant, prior SARS-CoV-2 infection and improvement in the treatment of MIS-C.
This systematic review has some limitations. These findings reflect the current reality in the complicated situation of a global pandemic, multiple variant outbreaks (Omicron variant had not been studied in most of the articles) and continuing vaccination processes all over the world with gradual addition of further age groups. Furthermore, the main limitation of the included studies is their small group size and heterogeneous study designs. However, MIS-C is a rare complication and the small group size can therefore still be seen as realistic, especially because the studies are based on national data which enhances statistical power. Another limitation concerns the virus variant, as the studies were conducted during the SARS-CoV-2 Delta wave. It has not yet been investigated whether the mRNA vaccine will also show a high vaccine efficacy against MIS-C during the SARS-CoV-2 Omicron wave or other future variants, and this also cannot be concluded with certainty from this systematic review. This generalization might be complicated even further since an increased number of children around the world will have currently already experienced a SARS-CoV-2 infection. Besides the low number of patients in some studies, there were few reports about regional variation and individual risks factors for MIS-C, such as sex, race/ethnicity, and comorbidities. Miller et al. mention a predominance of males in MIS-C and an increasing proportion of non-Hispanic White and non-Hispanic Black patients during successive COVID-19 waves [
32]. The studies by Levy et al., Zambrano et al., and Nygaard et al. also report a male to female predominance in MIS-C (of 81%, 71% and 73%, respectively) [
28‐
30].This analysis was not designed to evaluate waning immunity or duration of protection against MIS-C. Regarding the safety profile studies, there could be some bias related to recall or notification of adverse events. Nevertheless, it seems unlikely that healthcare providers would not have been notified of important inflammatory complications or MIS-C relapses. Regarding the meta-analysis, not all studies reported information about the number of vaccinated and unvaccinated children without MIS-C and these data had to be collected from national dashboards and censuses. This resulted in some slight discrepancies between age groups of children with and without MIS-C and hence we could not present risk ratios and a NNV, but merely ORs. Also, the funnel plot indicated a possibility of publication bias, but because of the low number of included studies this is uncertain. Nevertheless, the forest plot, I
2 statistic and Cochran’s Q test indicated no heterogeneity of study results and we performed both fixed and random effects meta-analyses with similar results. Finally, it is well possible that some reported cases of MIS-C after a COVID-19 vaccination were related to unnoticed or undiagnosed SARS-CoV-2 infections with false negative infectious investigations.
This review could become an important contribution for discussion whether or not to vaccinate children against COVID-19. Eventually, the review can help to increase international COVID-19 vaccination rates in children from the age of 5 years. Currently, in the United States, only 29% of eligible children have been fully vaccinated in the age group of 5–11 years, and 59% in the age group of 12–17 years [
47].
In the coming period, data collection will have to be continued in order to monitor the incidence of MIS-C, the vaccine efficacy in younger children (< 12 years old) and possible side effects. The epidemiology of SARS CoV-2 infection is changing rapidly and a possible new wave may present. With the small number of cases of MIS-C globally, establishing an international research collaboration would be of great value to combine studies and data effectively [
5]. Finally, more research will be needed to compare MIS-C cases triggered by the Delta, Omicron, and possible future unknown variants [
45].
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