The Lancet Child & Adolescent Health: Multi-system inflammatory syndrome in children (MIS-C) is rare among 12- to 20-year-olds who have received COVID-19 vaccination, study suggests

Reported cases of multi-system inflammatory syndrome (MIS-C) in children and adolescents who had received at least one COVID-19 vaccine dose were rare (estimated at one case per million vaccinated individuals in this age group). The reporting rate for cases without evidence of SARS-CoV-2 infection was 0.3 cases per million vaccinated persons in this age group, according to an observational study published in The Lancet Child & Adolescent Health journal.

Although there is no direct comparator available, this investigation found that the MIS-C case rate in vaccinated children and adolescents aged 12-20 in the USA is substantially lower than previously published estimates in unvaccinated individuals aged 12-20 who had been infected with SARS-CoV-2 during April to June, 2020. [1]

Dr Anna R. Yousaf, U.S. Centers for Disease Control and Prevention (CDC), says, “As part the comprehensive effort to monitor COVID-19 vaccine safety in the United States, CDC has been closely monitoring cases of MIS-C in vaccinated children. Our results suggest that MIS-C cases following COVID-19 vaccination are rare and that the likelihood of developing MIS-C is much greater in children who are unvaccinated and get COVID-19. COVID-19 vaccination is recommended for everyone aged 5 years and older in the United States for the prevention of COVID-19.” [2]

MIS-C, also known as paediatric inflammatory multi-system syndrome (PIM-TS), is a rare condition associated with SARS-CoV-2 infection that was first recognised in April 2020. MIS-C is thought to be an immune overreaction that occurs approximately two to six weeks after SARS-CoV-2 infection in children and adolescents. The symptoms include fever, rash, eye redness, and gastrointestinal symptoms (e.g., diarrhoea, stomach-ache, nausea), and can lead to multi-organ failure. In the USA, reporting of possible MIS-C cases after vaccination is required under COVID-19 vaccine emergency use authorisations.

This study investigated MIS-C cases in children and adolescents aged 12 to 20 years reported during the first nine months of COVID-19 vaccination rollout in the USA (December 14, 2020, to August 31, 2021). [3] A team of specialist doctors and epidemiologists examined 47 reports of potential MIS-C illness that occurred in a person aged 12-20 years at any time after a COVID-19 vaccine dose. Of these 47 reports, 21 fit the CDC MIS-C criteria. These were separated into those with and without evidence of a past or recent SARS-CoV-2 infection from laboratory testing. They calculated case reporting rates using CDC national vaccine surveillance data on the number of individuals aged 12–20 years in the USA who received one or more COVID-19 vaccine doses.

Out of the 21 cases of MIS-C, 15 had evidence of past or recent SARS-CoV-2 infection, while six did not. Over 21 million children and adolescents aged 12–20 years had received one or more doses of a COVID-19 vaccine, amounting to one reported case per million vaccinated individuals in this age group. The reporting rate of MIS-C for those without evidence of SARS-CoV-2 infection was 0.3 cases per million vaccinated individuals.

The authors stress that they are unable to determine if vaccination contributed to the MIS-C illness in these rare cases. As MIS-C was first identified during the pandemic, no baseline rate of inflammatory illnesses in children and adolescents with an unidentified cause exists to estimate a baseline number of cases expected to occur in any nine-month period regardless of COVID-19 infection or vaccination. It is possible that some of the identified cases had other unrecognised inflammatory conditions that coincidentally occurred after vaccination.

Of the 15 individuals with past SARS-CoV-2 infection, three were diagnosed with MIS-C outside the typical two to six-week timeframe (14─42 days) when subsequent MIS-C illness is mostly likely to occur. These three had MIS-C onset 105 days, 191 days, and 238 days after their positive SARS-CoV-2 test.

All 21 individuals were hospitalised, with 12 admitted to an intensive care unit and all were discharged home. The median age was 16 years; 13 were male and eight were female.

All individuals with MIS-C in the study received the Pfizer-BioNTech COVID-19 (BNT162b2) vaccine, which was the only COVID-19 vaccine authorised in the USA for use in those younger than 18 years during the study period. 11 individuals received one dose and 10 received two doses of the vaccine before MIS-C illness onset. Median time from dose to hospitalisation was eight days for those who had received one vaccine dose and five days for those who had received two.

Dr Yousaf continues, “As with COVID-19 illness, clinicians and researchers are still learning about MIS-C. Our investigation highlights the challenges in diagnosing MIS-C, the importance of considering alternative diagnoses, and the need to monitor for MIS-C illness.” [2]

The authors note some additional limitations of their study. It is possible that some of the identified MIS-C cases had other inflammatory illness with similar symptoms, as there is no definitive test for diagnosing MIS-C. Given that lab testing for COVID-19 including antibody testing is imperfect, it is possible that some cases might have been misclassified. Children often experience mild or asymptomatic infection, and milder infections may be less likely to generate antibodies, both of which may result in previous infections going undetected. It is also possible that not all cases of MIS-C following vaccination were reported in the surveillance system, potentially leading to the number of cases being underreported.

Writing in a linked Comment, lead author Dr Mary Beth Son, Boston Children’s Hospital, USA, (who was not involved in the study), says, “Their findings overall are quite reassuring. Reports of MIS-C after COVID-19 vaccination occurred in only 1 per million individuals aged 12–20 years who received one or more doses of a COVID-19 vaccine, and 15 (71%) of 21 individuals with MIS-C had laboratory evidence of antecedent SARS-CoV-2 infection, casting doubt about attribution. This timely report is of special interest to health-care providers, scientists, and policy makers given ongoing, widespread transmission of the omicron (B.1.1.529) variant. … As the pandemic continues to challenge our global community and intense scrutiny of COVID-19 vaccines persists, Yousaf and colleagues’ report is a welcome addition to the growing literature supporting the safety and efficacy of vaccination against SARS CoV-2.”

This study was funded by the U.S Centers for Disease Control and Prevention (CDC). It was conducted by researchers from the CDC COVID-19 response team.

[1] Using a denominator of SARS-CoV-2 infections among unvaccinated individuals, a previous study from April to 1 June, 2020, estimated an MIS-C rate of 224 per million SARS-CoV-2 infections in children aged 11–15 years and 164 per million in those aged 16–20 years:

[2] Quote direct from author and cannot be found in the text of the Article.

[3] Researchers identified possible cases from CDC’s MIS-C national surveillance system, the Vaccine Adverse Event Reporting System (co-administered by CDC and the US Food and Drug Administration), and CDC’s Clinical Immunization Safety Assessment Project.


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