Effectiveness of BNT162b2 (Pfizer-BioNTech) mRNA Vaccination Against Multisystem Inflammatory Syndrome in Children Among Persons Aged 12–18 Years

United States, July-December 2021

Laura D. Zambrano, PhD; Margaret M. Newhams, MPH; Samantha M. Olson, MPH; Natasha B. Halasa, MD; Ashley M. Price, MPH; Julie A. Boom, MD; Leila C. Sahni, PhD; Satoshi Kamidani, MD; Keiko M. Tarquinio, MD; Aline B. Maddux, MD; Sabrina M. Heidemann, MD; Samina S. Bhumbra, MD; Katherine E. Bline, MD; Ryan A. Nofziger, MD; Charlotte V. Hobbs, MD; Tamara T. Bradford, MD; Natalie Z. Cvijanovich, MD; Katherine Irby, MD; Elizabeth H. Mack, MD; Melissa L. Cullimore, MD; Pia S. Pannaraj, MD; Michele Kong, MD; Tracie C. Walker, MD; Shira J. Gertz, MD; Kelly N. Michelson, MD; Melissa A. Cameron, MD; Kathleen Chiotos, MD; Mia Maamari, MD; Jennifer E. Schuster, MD; Amber O. Orzel, MPH; Manish M. Patel, MD; Angela P. Campbell, MD; Adrienne G. Randolph, MD

Disclosures

Morbidity and Mortality Weekly Report. 2022;71(2):52-58. 

In This Article

Abstract and Introduction

Introduction

Multisystem inflammatory syndrome in children (MIS-C) is a severe postinfectious hyperinflammatory condition, which generally occurs 2–6 weeks after a typically mild or asymptomatic infection with SARS-CoV-2, the virus that causes COVID-19.[1–3] In the United States, the BNT162b2 (Pfizer-BioNTech) COVID-19 vaccine is currently authorized for use in children and adolescents aged 5–15 years under an Emergency Use Authorization and is fully licensed by the Food and Drug Administration for persons aged ≥16 years.[4] Prelicensure randomized trials in persons aged ≥5 years documented high vaccine efficacy and immunogenicity§,[5] and real-world studies in persons aged 12–18 years demonstrated high vaccine effectiveness (VE) against severe COVID-19.[6] Recent evidence suggests that COVID-19 vaccination is associated with lower MIS-C incidence among adolescents;[7] however, VE of the 2-dose Pfizer-BioNTech regimen against MIS-C has not been evaluated. The effectiveness of 2 doses of Pfizer-BioNTech vaccine received ≥28 days before hospital admission in preventing MIS-C was assessed using a test-negative case-control design among hospitalized patients aged 12–18 years at 24 pediatric hospitals in 20 states** during July 1–December 9, 2021, the period when most MIS-C patients could be temporally linked to SARS-CoV-2 B.1.617.2 (Delta) variant predominance. Patients with MIS-C (case-patients) and two groups of hospitalized controls matched to case-patients were evaluated: test-negative controls had at least one COVID-19–like symptom and negative SARS-CoV-2 reverse transcription–polymerase chain reaction (RT-PCR) or antigen-based assay results, and syndrome-negative controls were hospitalized patients without COVID-19–like illness. Among 102 MIS-C case-patients and 181 hospitalized controls, estimated effectiveness of 2 doses of Pfizer-BioNTech vaccine against MIS-C was 91% (95% CI = 78%–97%). All 38 MIS-C patients requiring life support were unvaccinated. Receipt of 2 doses of the Pfizer-BioNTech vaccine is associated with a high level of protection against MIS-C in persons aged 12–18 years, highlighting the importance of vaccination among all eligible children.

This study used a test-negative case-control design, commonly used for postauthorization VE evaluations.[6,8] Patients were hospitalized at 24 participating sites in the Overcoming COVID-19 Network, a collaboration between CDC and approximately 70 pediatric hospitals nationwide to assess COVID-19 complications in children and young adults.†† Given that children aged 5–11 years were not recommended to receive the Pfizer-BioNTech vaccine until November 2, 2021,§§ this analysis focused on persons aged 12–18 years.¶¶ VE was assessed by comparing the odds of antecedent vaccination between MIS-C patients and hospitalized controls without evidence of SARS-CoV-2 infection during July 1–December 9, 2021. Case-patients met CDC criteria for MIS-C,*** which included a clinically severe illness requiring hospitalization, temperature ≥100.4°F (38°C) for ≥24 hours or subjective fever, evidence of inflammation (demonstrated by elevated levels of inflammatory markers), involvement of two or more organ systems, no alternative plausible diagnosis, and current or recent SARS-CoV-2 infection, indicated by a positive result from an RT-PCR test, serologic test, or antigen test. Two hospitalized control groups included 1) patients with one or more symptoms consistent with COVID-19, but with a negative result from a SARS-CoV-2 RT-PCR or antigen test (test-negative) and 2) patients without symptoms compatible with COVID-19 who might or might not have received SARS-CoV-2 testing (syndrome-negative).††† Eligible controls were matched to case-patients by site, age group (12–15 years and 16–18 years), and case-patient hospitalization date (within plus or minus approximately 3 weeks).

Vaccination status was verified through searches of state immunization information systems, electronic medical records, or other sources, including documentation from pediatricians or patient immunization cards. For this analysis, persons were categorized as unvaccinated or fully vaccinated on or before the case-patient hospitalization date. Patients were considered unvaccinated if they had received no doses of the Pfizer-BioNTech vaccine; full vaccination in terms of expected protection against MIS-C was defined as receipt of 2 doses of Pfizer-BioNTech COVID-19 vaccine, with receipt of the second dose ≥28 days before hospital admission. The 28-day window was selected because a person is considered fully vaccinated against COVID-19 ≥14 days after receipt of the second dose, and MIS-C generally occurs approximately 2–6 weeks after SARS-CoV-2 infection, with most cases occurring by the fourth week.[1–3] Patients were excluded based on the following conditions: 1) receipt of only 1 vaccine dose; 2) receipt of the second dose within 28 days of hospital admission; 3) age 12–15 years and admission before July 1, 2021 (given that vaccination was not expanded to this age group until May 12, 2021); and 4) receipt of any COVID-19 vaccine other than Pfizer-BioNTech.

Demographic characteristics, clinical information related to the current illness, and SARS-CoV-2 testing history were obtained through parent or guardian interview conducted by trained study personnel or review of electronic medical records.§§§ Descriptive statistics were used to compare characteristics of case-patients and hospitalized controls, and Fisher's exact or Wilcoxon rank-sum tests were used for categorical and continuous variables, respectively. VE against MIS-C was calculated by comparing the odds of full COVID-19 vaccination among MIS-C case-patients and controls using the equation VE = 100 X (1 − adjusted odds ratio). Adjusted odds ratios were calculated using multivariable logistic regression models with Firth penalization to reduce bias contributed by sparse data. Models were adjusted for U.S. Census region, age, sex, and race/ethnicity.[8] To account for potential residual confounding by calendar time related to increasing vaccination coverage, the case-patient hospitalization date was used as a reference point for comparing antecedent vaccination in case-patients and controls. Other factors (underlying health conditions and social vulnerability index) were assessed, but not included in the final model if they did not alter the odds ratio estimate by >5%. Sensitivity analyses were conducted to evaluate VE against MIS-C among patients with serologic evidence of previous infection (because non–MIS-C acute COVID-19 patients might have a positive RT-PCR assay in the absence of serology) and to evaluate whether VE differed by control group. Statistical analyses were conducted using SAS (version 9.4; SAS Institute); statistical significance was defined as p<0.05. This activity was reviewed by CDC and other participating institutions and was conducted consistent with applicable federal law and CDC policy.¶¶¶

During July 1–December 9, 2021, among 117 MIS-C case-patients aged 12–18 years, 15 were excluded from the analysis, including six patients who received only 1 dose by the date of hospitalization, four who received their second vaccine dose within 28 days of hospital admission, and five patients aged 12–15 years who were hospitalized before July 1, 2021. The 283 patients in the primary analysis included 102 MIS-C case-patients and 181 controls (90 [50%] test-negative and 91 [50%] syndrome-negative) (Table 1). The median age among all case-patients and controls was 14.5 years, and 58% had at least one underlying condition (including obesity). COVID-19 vaccination coverage was approximately 5% among case-patients and 36% among controls.

Among the 70 children in this analysis who were fully vaccinated (with 2 doses), one syndrome-negative control patient had received a third dose. Among 102 MIS-C case-patients, five (5%) were fully vaccinated with 2 doses ≥28 days before hospitalization, and 97 (95%) were unvaccinated (Table 2). Overall, 91 (89%) case-patients had cardiovascular involvement, 84 (82%) had gastrointestinal involvement, and 68 (67%) had hematologic involvement. Sixty-two (61%) were admitted to an intensive care unit, and 38 (37%) received life support during hospitalization, including invasive mechanical ventilation, vasoactive infusions, or extracorporeal membrane oxygenation (ECMO). All 38 MIS-C patients requiring life support were unvaccinated; among these, nine patients required invasive mechanical ventilation, 35 received vasoactive infusions and one required ECMO. No deaths among these patients were reported. Hospital length of stay was similar among vaccinated and unvaccinated MIS-C patients (median = 5 days).

VE against MIS-C was 91% (95% CI = 78%–97%) (Table 3).**** In a sensitivity analysis excluding patients with positive RT-PCR or antigen-based SARS-CoV-2 test results and no positive serologic test, VE was 90% (95% CI = 75%–96%). VE against MIS-C was similar, irrespective of control group (test-negative controls: 92%, 95% CI = 77%–97%; syndrome-negative controls: 89%, 95% CI = 70%–96%); therefore, the pooled VE estimate using both control populations was deemed acceptable.

*These authors contributed equally to this report.
These senior authors contributed equally to this report.
§ https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-covid-19/comirnaty-and-pfizer-biontech-covid-19-vaccine
In this context, the test-negative case-control design was used to compare the odds of previous Pfizer-BioNTech vaccine receipt among inpatients without evidence of SARS-CoV-2 infection with case-patients hospitalized for MIS-C. These control patients included those with respiratory virus infection who received a negative test result for SARS-CoV-2 infection (test-negative) or patients without symptoms compatible with COVID-19 (syndrome-negative), including fever, cough, shortness of breath, loss of taste, loss of smell, gastrointestinal symptoms, use of respiratory support for the acute illness, or new pulmonary findings on chest imaging consistent with pneumonia.
**This investigation included patients enrolled from 24 pediatric hospitals in 20 states: Alabama, Arkansas, California, Colorado, Georgia, Illinois, Indiana, Louisiana, Massachusetts, Michigan, Mississippi, Missouri, Nebraska, New Jersey, North Carolina, Ohio, Pennsylvania, South Carolina, Tennessee, and Texas.
†† https://overcomecovid.org/
§§CDC recommendation for pediatric COVID-19 vaccine for children aged 5–11 years: https://www.cdc.gov/media/releases/2021/s1102-PediatricCOVID-19Vaccine.html
¶¶The lower age bound for the study population was set at 12 years and 49 days to allow for the first vaccine dose on the patient's 12th birthday, a second dose 21 days thereafter, and a 28-day window between the patient's second dose and hospitalization for MIS-C.
***CDC case definition criteria for MIS-C are available at https://www.cdc.gov/mis/mis-c/hcp/index.html. For the purposes of this analysis, all MIS-C case-patients were required to have laboratory evidence of current or recent infection (RT-PCR, antigen-, or antibody-based testing).
†††Vaccine effectiveness studies in the context of respiratory viruses most commonly include test-negative controls. Because of potential biases related to the selection of controls, including the potential for misclassification of test-negative patients due to false-negative tests, syndrome-negative controls were also included as a separate control group. Among the 91 syndrome-negative controls, 18 (20%) had no record of SARS-CoV-2 testing. The remaining syndrome-negative controls had a record of SARS-CoV-2 testing by RT-PCR or antigen and received negative test results.
§§§Among the 102 MIS-C case-patients and 181 controls enrolled, 50 (49%) and 113 (62%), respectively, had information obtained through a combination of parent interview and medical records abstraction, while 52 (51%) case-patients and 68 (38%) control patients had information obtained solely through medical records abstraction.
¶¶¶45 C.F.R. part 46.102(l)(2), 21 C.F.R. part 56; 42 U.S.C. Sect. 241(d); 5 U.S.C. Sect. 552a; 44 U.S.C. Sect. 3501 et seq.
****VE against MIS-C was also assessed comparing the odds of antecedent vaccination with the second dose of the Pfizer-BioNTech vaccine ≥14 days before hospital admission. Point estimates did not significantly differ from the primary analysis presented in this report. (VE after 14 days: 86%; 95% CI = 70%–93%.)

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