key: cord-0990367-faue5ywu
authors: Zambrano, Laura D.; Newhams, Margaret M.; Olson, Samantha M.; Halasa, Natasha B.; Price, Ashley M.; Boom, Julie A.; Sahni, Leila C.; Kamidani, Satoshi; Tarquinio, Keiko M.; Maddux, Aline B.; Heidemann, Sabrina M.; Bhumbra, Samina S.; Bline, Katherine E.; Nofziger, Ryan A.; Hobbs, Charlotte V.; Bradford, Tamara T.; Cvijanovich, Natalie Z.; Irby, Katherine; Mack, Elizabeth H.; Cullimore, Melissa L.; Pannaraj, Pia S.; Kong, Michele; Walker, Tracie C.; Gertz, Shira J.; Michelson, Kelly N.; Cameron, Melissa A.; Chiotos, Kathleen; Maamari, Mia; Schuster, Jennifer E.; Orzel, Amber O.; Patel, Manish M.; Campbell, Angela P.; Randolph, Adrienne G.; Murdock, Meghan; Gaspers, Mary Glas; Typpo, Katri V.; Kelley, Connor P.; Sanders, Ronald C.; Yates, Masson; Smith, Chelsea; Crane, Katheryn; Lionetti, Geraldina; Murcia-Montoya, Juliana; Zinter, Matt S.; Villarreal-Chico, Denise; Skura, Adam L.; Peralta, Harvey; Lockwood, Justin M.; Port, Emily; Carson, Imogene A.; Chatani, Brandon M.; Hussaini, Laila; Baida, Nadine; Coates, Bria M.; Rowan, Courtney M.; Stumpf, Mary; Johnston, Marla S.; Boutselis, Benjamin J.; Kucukak, Suden; Chen, Sabrina R.; Weller, Edie; Berbert, Laura; He, Jie; Flori, Heidi R.; Hume, Janet R.; Bruno, Ellen R.; Goertzen, Lexie A.; Levy, Emily R.; Behl, Supriya; Drapeau, Noelle M.; Martin, Lora; Malloch, Lacy; Sanders, Cameron; Patterson, Kayla; Dhanrajani, Anita; Hill, Shannon M.; Kietzman, Abigail; Rinehart, Valerie H.; Hoody, Lauren A.; Schwartz, Stephanie P.; Navas, Angelo G.; Bennett, Paris C.; Twinem, Nicole A.; Tomcany, Merry L.; Staat, Mary Allen; Rohlfs, Chelsea C.; Wolfe, Amber; Douglas, Rebecca L.; Phengchomphet, Kathlyn; Bickford, Megan M.; Wakefield, Lauren E.; Smallcomb, Laura; Stewart, Laura S.; Golchha, Meena; Oates, Jennifer N.; Bowens, Cindy
title: Effectiveness of BNT162b2 (Pfizer-BioNTech) mRNA Vaccination Against Multisystem Inflammatory Syndrome in Children Among Persons Aged 12–18 Years — United States, July–December 2021
date: 2022-01-14
journal: MMWR Morb Mortal Wkly Rep
DOI: 10.15585/mmwr.mm7102e1
sha: 496d59b62f754563d7b648eea05770d51de0e41e
doc_id: 990367
cord_uid: faue5ywu

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.

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 † † 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).

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) (2) (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 † † † 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 syndromenegative 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.

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 casepatients 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 casepatients and 36% among controls.

Among the 70 children in this analysis who were fully vaccinated (with 2 doses), one syndrome-negative control patient § § § 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) 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%; syndromenegative controls: 89%, 95% CI = 70%-96%); therefore, the pooled VE estimate using both control populations was deemed acceptable.

During July-December 2021, a period of Delta variant predominance, a real-world evaluation of VE in 24 U.S. pediatric hospitals found that receipt of 2 doses of the Pfizer-BioNTech vaccine was associated with a high level of protection against MIS-C among patients aged 12-18 years who received their second vaccine dose ≥28 days before hospitalization. Most (95%) patients aged 12-18 years hospitalized with MIS-C were unvaccinated. No fully vaccinated patients with MIS-C required respiratory or cardiovascular life support, as opposed to 39% of unvaccinated MIS-C patients who did. A recent Overcoming COVID-19 hospital network investigation reported high VE (93% [95% CI = 83%-97%]) against COVID-19-related hospitalizations in persons aged 12-18 years (6) . The current findings contribute to the growing body of evidence that vaccination is likely effective in preventing severe COVID-19-related complications in children, including MIS-C. **** 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%.)

The findings in this report are subject to at least seven limitations. First, VE was not assessed against MIS-C attributed to specific variants; however, >99% of COVID-19 cases reported during July-December 2021 resulted from infections with the Delta variant (9) . Second, VE against MIS-C attributed to the B.1.1.529 (Omicron) variant could not be assessed, given the timing of hospital admission of included patients relative to emergence of this variant in the United States. Third, timing of initial SARS-CoV-2 infection relative to vaccination could not be inferred, and this investigation cannot differentiate between protection from acquisition of SARS-CoV-2 infection versus protection against development of MIS-C after infection. Fourth, the timing at which protection against MIS-C is conferred after 2 doses of vaccine is unknown; some protection might be possible within 28 days of vaccination, and this investigation had insufficient power to evaluate VE for 1 dose of vaccine. Fifth, this analysis examines VE against MIS-C conferred only by the Pfizer-BioNTech vaccine. Sixth, although the hospital sites participating in this investigation covered a broad geographic area, the results of this analysis are not generalizable to the entire U.S. pediatric population. Finally, given the short time frame of enrollment, this analysis was not designed to evaluate waning immunity or duration of protection against MIS-C.

As of December 13, 2021, 52.3% of eligible U.S. children and adolescents aged 12-17 years had received the primary Pfizer-BioNTech 2-dose series (10) . In a multistate hospital network, this real-world investigation found that receipt of 2 doses of Pfizer-BioNTech vaccine was strongly associated with prevention of MIS-C among adolescents. Children aged 5-11 years, who are now authorized to receive the Pfizer-BioNTech vaccine, represent the age group at highest risk for MIS-C (1, 3) . This analysis lends supportive evidence that vaccination of children and adolescents is highly protective against MIS-C and COVID-19 and underscores the importance of vaccination of all eligible children. . † Testing for statistical significance was conducted using Fisher's exact test to compare categorical variables or Wilcoxon rank-sum test for medians to compare continuous data. Statistical significance was defined as p<0.05. § CDC/ATSDR SVI documentation is available at https://www.atsdr.cdc.gov/placeandhealth/svi/index.html. Median SVI for case-patients and controls are based on U.S. 2018 SVI data. ¶ Underlying conditions with a missing response (yes/no) were assumed not to be present. ** Other chronic conditions included rheumatologic/autoimmune disorder, hematologic disorder, renal or urologic dysfunction, gastrointestinal/hepatic disorder, metabolic or confirmed or suspected genetic disorder (including obesity), or atopic or allergic condition. † † With the exception of the "pre-admission results available only" category, all other test results were obtained after hospital admission. § § COVID-19 vaccination status included the following two categories: 1) unvaccinated, defined as no receipt of any SARS-CoV-2 vaccine before hospitalization for current illness and 2) fully vaccinated, defined as receipt of both doses of a 2-dose Pfizer-BioNTech vaccination ≥28 days before illness onset. ¶ ¶ Dates are based on those with documented vaccination, not plausible self-report. For controls without COVID-19-like illness, a reference date was set to the admission date of their matched case-patient to account for residual confounding by hospital admission date relative to expanding vaccination coverage. 

What is already known about this topic?

The Pfizer-BioNTech vaccine, currently authorized for persons aged ≥5 years, provides a high level of protection against severe COVID-19 in persons aged 12-18 years. Vaccine effectiveness against multisystem inflammatory syndrome in children (MIS-C), which can occur 2-6 weeks after SARS-CoV-2 infection, has remained uncharacterized.

What is added by this report?

Estimated effectiveness of 2 doses of Pfizer-BioNTech vaccine against MIS-C was 91% (95% CI = 78%-97%). Among critically ill MIS-C case-patients requiring life support, all were unvaccinated.

What are the implications for public health practice?

Receipt of 2 doses of Pfizer-BioNTech vaccine is highly effective in preventing MIS-C in persons aged 12-18 years. These findings further reinforce the COVID-19 vaccination recommendation for eligible children.

Children's Hospital

Children's Hospital Los Angeles

Children's Hospital Los Angeles

Children's Hospital Colorado

Children's Healthcare of Atlanta

Children's Hospital of Chicago

Children's Hospital of New Orleans

Boston Children's Hospital

University of Minnesota Masonic Children's Hospital

Children's Mercy Hospital

Children's Hospital & Medical Center

University of North Carolina at Chapel Hill

Akron Children's Hospital

Cincinnati Children's Hospital

Nationwide Children's Hospital

Children's Hospital of Philadelphia

Medical University of South Carolina Children's Health

Medical University of South Carolina Children's Health

Medical University of South Carolina Children's Health

Meena Golchha, Monroe Carell Jr. Children's Hospital at Vanderbilt

Abbreviation: BNP = brain natriuretic peptide

19 vaccination status included the following two categories: 1) unvaccinated, defined as no receipt of any SARS-CoV-2 vaccine before hospitalization for current illness and 2) fully vaccinated, defined as receipt of both doses of a 2-dose Pfizer-BioNTech vaccination ≥28 days before illness onset

Children's Hospital of New Orleans (Louisiana), Medical University of South Carolina Children's Health (South Carolina), Monroe Carell Jr. Children's Hospital at Vanderbilt (Tennessee), Texas Children's Hospital (Texas)

§ Organ system involvement was defined with the following criteria

shock, elevated troponin, BNP, N-terminal-pro hormone BNP, abnormal echocardiogram, or arrhythmia); 2) Respiratory (e.g., pneumonia, acute respiratory distress syndrome, and pulmonary embolism)

Gastrointestinal (e.g., abdominal pain, vomiting, diarrhea, elevated bilirubin, or elevated liver enzymes); 5) Neurologic (e.g., cerebrovascular accident, aseptic meningitis, or encephalopathy); 6) Hematologic (e.g., elevated D-dimers, thrombophilia

Division of Pediatric Critical Care Medicine

Carolina at Chapel Hill Children's Hospital, Chapel Hill, North Carolina; 21 Division of Pediatric Critical Care, Department of Pediatrics

Division of Critical Care Medicine, Department of Anesthesiology and Critical Care, Children's Hospital of Philadelphia

Multisystem inflammatory syndrome in U.S. children and adolescents

Trends in geographic and temporal distribution of US children with multisystem inflammatory syndrome during the COVID-19 pandemic

New York State and Centers for Disease Control and Prevention Multisystem Inflammatory Syndrome in Children Investigation Team. Multisystem inflammatory syndrome in children in New York State

Silver Spring, MD: US Department of Health and Human Services, Food and Drug Administration

C4591001 Clinical Trial Group. Safety, immunogenicity, and efficacy of the BNT162b2 Covid-19 vaccine in adolescents

Overcoming COVID-19 Investigators. Effectiveness of Pfizer-BioNTech mRNA vaccination against COVID-19 hospitalization among persons aged 12-18 Years-United States

Multisystem inflammatory syndrome in children by COVID-19 vaccination status of adolescents in France

Effectiveness of severe acute respiratory syndrome coronavirus 2 messenger RNA vaccines for preventing coronavirus disease 2019 hospitalizations in the United States

COVID data tracker. Variant proportions

Demographic trends of people receiving COVID-19 vaccinations in the United States

All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Jennifer E. Schuster reports institutional support from Merck for an RSV research study, unrelated to the current work. Adrienne G. Randolph reports institutional support from the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), royalties from UpToDate as the Pediatric Critical Care Section Editor, and participation on a data safety monitoring board (DSMB) for a National Institute of Child Health and Human Development-funded study. Pia S. Pannaraj reports institutional support from AstraZeneca and Pfizer, consulting fees from Sanofi-Pasteur and Seqirus, payment from law firms for expert testimony, participation on a Division of Microbiology and Infectious Diseases DSMB, and an unpaid leadership role in the California Immunization Coalition. Ryan A. Nofziger reports institutional support from NIH for participation in a multicenter influenza study. Satoshi Kamidani reports institutional support from NIH and Pfizer. Charlotte V. Hobbs reports consulting fees from Dynamed and honoraria from Biofire/ Biomerieux. Natasha B. Halasa reports grants from Sanofi and Quidel and an educational grant from Genentech. Natalie Z. Cvijanovich reports a speaker's registration discount at the Society of Critical Care Medicine meeting. Samina S. Bhumbra reports receipt of an NIH, NIAID training grant during September 1, 2019-August 31, 2020. No other potential conflicts of interest were disclosed.

Adjusted VE, % (95% CI)

All controls 5/102 (4.9) 65/181 ( 1) unvaccinated, defined as no receipt of any SARS-CoV-2 vaccine before hospitalization for current illness and 2) fully vaccinated, defined as receipt of both doses of a 2-dose Pfizer-BioNTech vaccination ≥28 days before illness onset. ¶ Analysis excluded 14 MIS-C case-patients who were positive by reverse transcription-polymerase chain reaction only with no serologic evidence of previous infection and 20 controls matched to these patients, given potential misclassification of patients with severe acute COVID-19.