Effectiveness of Monovalent and Bivalent mRNA Vaccines in Preventing COVID-19–Associated Emergency Department and Urgent Care Encounters Among Children Aged 6 Months–5 Years — VISION Network, United States, July 2022–June 2023
Weekly / August 18, 2023 / 72(33);886–892
Ruth Link-Gelles, PhD1; Allison Avrich Ciesla, PhD1,2; Elizabeth A.K. Rowley, DrPH3; Nicola P. Klein, MD, PhD4; Allison L. Naleway, PhD5; Amanda B. Payne, PhD1; Anupam Kharbanda, MD6; Karthik Natarajan, PhD7,8; Malini B. DeSilva, MD9; Kristin Dascomb, MD, PhD10; Stephanie A. Irving, MHS5; Ousseny Zerbo, PhD4; Sarah E. Reese, PhD3; Ryan E. Wiegand, PhD1; Morgan Najdowski, MPH1; Toan C. Ong, PhD11; Suchitra Rao, MBBS11; Melissa S. Stockwell, MD8,12,13; Ashley Stephens, MD8,12; Kristin Goddard, MPH4; Yessica C. Martinez, MPH3; Zachary A. Weber, PhD3; Bruce Fireman4; John Hansen, MPH4; Julius Timbol, MS4; Shaun J. Grannis, MD14,15; Michelle A. Barron, MD11; Peter J. Embi, MD16; Sarah W. Ball, ScD3; Manjusha Gaglani, MBBS17,18; Nancy Grisel, MPP10; Julie Arndorfer, MPH10; Mark W. Tenforde, MD, PhD19; Katherine E. Fleming-Dutra, MD1 (View author affiliations)View suggested citation
What is already known about this topic?
The original monovalent COVID-19 mRNA vaccines were first recommended in the United States in June 2022 for young children; bivalent vaccines were recommended in December 2022. Postauthorization vaccine effectiveness data in this age group are limited.
What is added by this report?
Monovalent and bivalent mRNA vaccines helped provide protection against COVID-19–associated emergency department and urgent care visits among children aged 6 months–4 years (Pfizer-BioNTech) and 6 months–5 years (Moderna).
What are the implications for public health practice?
All children should stay up to date with recommended COVID-19 vaccines, including initiating COVID-19 vaccination immediately when they become eligible.
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On June 19, 2022, the original monovalent mRNA COVID-19 vaccines were approved as a primary series for children aged 6 months–4 years (Pfizer-BioNTech) and 6 months–5 years (Moderna) based on safety, immunobridging, and limited efficacy data from clinical trials. On December 9, 2022, CDC expanded recommendations for use of updated bivalent vaccines to children aged ≥6 months. mRNA COVID-19 vaccine effectiveness (VE) against emergency department or urgent care (ED/UC) encounters was evaluated within the VISION Network during July 4, 2022–June 17, 2023, among children with COVID-19–like illness aged 6 months–5 years. Among children aged 6 months–5 years who received molecular SARS-CoV-2 testing during August 1, 2022–June 17, 2023, VE of 2 monovalent Moderna doses against ED/UC encounters was 29% (95% CI = 12%–42%) ≥14 days after dose 2 (median = 100 days after dose 2; IQR = 63–155 days). Among children aged 6 months–4 years with a COVID-19–like illness who received molecular testing during September 19, 2022–June 17, 2023, VE of 3 monovalent Pfizer-BioNTech doses was 43% (95% CI = 17%–61%) ≥14 days after dose 3 (median = 75 days after dose 3; IQR = 40–139 days). Effectiveness of ≥1 bivalent dose, comparing children with at least a complete primary series and ≥1 bivalent dose to unvaccinated children, irrespective of vaccine manufacturer, was 80% (95% CI = 42%–96%) among children aged 6 months–5 years a median of 58 days (IQR = 32–83 days) after the dose. All children should stay up to date with recommended COVID-19 vaccines, including initiation of COVID-19 vaccination immediately when they are eligible.
As of June 2023, SARS-CoV-2 had resulted in more than 2 million COVID-19 cases, more than 20,000 hospitalizations, and more than 400 deaths among U.S. children aged 6 months–4 years (1,2). The original monovalent mRNA vaccines were authorized in June 2022 for children aged 6 months–4 years (Pfizer-BioNTech*) and 6 months–5 years (Moderna†) based on safety, immunobridging, and limited efficacy data from clinical trials, with recommendations expanded to include bivalent vaccines in December 2022 (3–5). Because efficacy data were limited, postauthorization vaccine effectiveness (VE) data are necessary to understand how well the vaccines work and to help guide development of future vaccine policy for this age group.
VISION,§ a multisite, electronic health care record–based network, evaluated VE against COVID-19–associated emergency department or urgent care (ED/UC) encounters, across six sites in eight states. VISION VE methods have been previously described (6). VISION assessed VE among immunocompetent (7) children aged 6 months–4 years (monovalent Pfizer-BioNTech, 3-dose primary series) and 6 months–5 years (monovalent Moderna, 2-dose primary series) who visited a participating ED/UC during July 4, 2022–June 17, 2023, with a COVID-19–like illness¶ and who received SARS-CoV-2 nucleic acid amplification testing during the 14 days preceding, or up to 72 hours after, the ED/UC encounter. Patients were classified on the index date** as unvaccinated (no COVID-19 vaccine doses received), vaccinated with 1 or 2 monovalent Moderna doses or 1, 2, or 3 monovalent Pfizer-BioNTech doses, or vaccinated with ≥1 bivalent dose. ED/UC encounters were excluded if the most recent vaccine dose was received <14 days before the index date, if the child had received a combination of Moderna and Pfizer-BioNTech vaccine doses, or if a vaccination schedule that was not authorized in the study population had been used (e.g., 4 monovalent Pfizer-BioNTech doses or 3 monovalent Moderna doses). Children who had received bivalent doses were only included if they had a complete primary series (either monovalent or bivalent doses).
VE, stratified by vaccine product and number of doses received, was estimated using a test-negative case-control study design, comparing odds of COVID-19 vaccination versus being unvaccinated in case-patients (those who received a positive SARS-CoV-2 test result) and control-patients (those who received a negative test result).†† Analysis periods varied for each product and dose combination based on differences in recommended schedules for Moderna and Pfizer-BioNTech vaccines.§§ Children became eligible for inclusion in each analysis 2 weeks after the initial date a child could have received each product and dose combination. Analyses were conducted using R software (version 4.2.2; R Foundation). This study was reviewed and approved by institutional review boards at participating sites or under a reliance agreement with the Institutional Review Board of Westat and was conducted consistent with applicable federal law and CDC policy.¶¶
The 90,905 ED/UC encounters in children aged 6 months–5 years eligible for inclusion in the Moderna monovalent analysis included 4,934 (5.4%) case-patients and 85,971 (94.6%) control-patients (Table 1). An additional 96 encounters occurred among control-patients who received ≥1 bivalent Moderna dose. The 81,077 ED/UC encounters in children aged 6 months–4 years eligible for inclusion in the Pfizer-BioNTech monovalent analysis included 4,642 (5.7%) case-patients and 76,435 (94.3%) control-patients. An additional 222 encounters occurred among children who received ≥1 bivalent Pfizer-BioNTech dose; 219 of these were control-patients, and three were case-patients.
To better understand coverage in this population, receipt of monovalent and bivalent doses among all children aged 6 months–5 years, regardless of dose or product received, including children aged 5 years who received a Pfizer-BioNTech dose, was assessed. Among all 5,131 case-patients identified during July 4, 2022–June 17, 2023, a total of 340 (6.6%) had received ≥1 monovalent doses, and three (0.06%) had received ≥1 bivalent dose, regardless of manufacturer. Among all 92,777 control-patients identified during July 4, 2022–June 17, 2023, a total of 11,195 (12.1%) had received ≥1 monovalent dose, and 384 (0.4%) had received ≥1 bivalent dose, irrespective of manufacturer.
VE of a single monovalent Moderna vaccine dose (partial primary series) in children aged 6 months–5 years was 23% ≥14 days after the dose (median = 64 days after the dose), although the 95% CI included the null value (Table 2). VE of 2 monovalent Moderna vaccine doses (complete primary series) in children aged 6 months–5 years was 46% in the 14–59 days after vaccination (median = 38 days). VE of 2 monovalent Moderna vaccine doses was 21% ≥60 days after vaccination (median = 120 days), although the 95% CI included the null value.
VE of a single monovalent Pfizer-BioNTech dose (partial primary series) in children aged 6 months–4 years was 7% ≥14 days after the dose (median = 58 days), although the 95% CI included the null value. VE of 2 doses (partial primary series) was 46% during the 14–59 days after the second dose (median = 37 days). VE of 2 doses was 27% ≥60 days after vaccination (median = 106 days), although the 95% CI included the null value. VE of 3 doses (complete primary series) was 70% during the 14–59 days after vaccination (median = 35 days). VE of 3 doses was 24% ≥60 days after vaccination (median = 124 days), although the 95% CI included the null value. VE of ≥1 bivalent dose, irrespective of manufacturer or age group in children aged 6 months–5 years with a complete primary series was 80% ≥14 days after receipt of the last dose (median = 58 days).
In this multisite analysis from the VISION Network, complete primary mRNA COVID-19 vaccination helped protect against ED/UC encounters in young children, although protection waned in patterns similar to those seen in older children and adults (7,8). In this analysis, receipt of ≥1 bivalent vaccine dose, irrespective of the manufacturer, provided 80% protection for children who had received a complete primary series ≥14 days earlier compared with unvaccinated children; however, few children had received a bivalent dose, so the estimate was imprecise. In addition, the median interval since receipt of the bivalent dose was only 58 days, meaning there was little time for waning to be observed.
A single dose (i.e., an incomplete primary series) of either monovalent Moderna or Pfizer-BioNTech did not provide protection. VE of 2 doses of monovalent vaccine ≥14 days after the second dose was 37% among children aged 6 months–4 years (Pfizer-BioNTech) and 29% among those aged 6 months–5 years (Moderna), aligning with previous data showing effectiveness of ≥2 vaccine doses in young children (9). Of note, the predominantly circulating SARS-CoV-2 variants had evolved substantially from the strain included in the original monovalent COVID-19 vaccines by the time young children became eligible, highlighting the importance of receiving an updated vaccine.
To date, limited VE data are available for young children. A previous analysis of national pharmacy testing data showed generally similar patterns of VE by number of doses and time since vaccination in children aged 3–5 years, but higher VE than in the current analysis (9). This finding might be related to several factors that might have affected the control populations, including differences among children who are tested at pharmacies compared with those who are treated in an ED/UC, different analysis periods leading to different abilities to assess waning of VE, differences in circulating SARS-CoV-2 subvariants between the two analyses, and differences in circulation of other viruses, including respiratory syncytial virus and influenza.
The median interval since receipt of the most recent dose among children who had not completed their primary series was longer than expected based on the recommended dosing intervals: a median of 64 days since Moderna dose 1 compared with the 4–8 weeks recommended between Moderna doses and a median of 58 days since receiving Pfizer-BioNTech dose 1 versus 3–8 weeks recommended between doses 1 and 2; this aligns with available national data showing that approximately 10% of children aged 2–4 years had received ≥1 COVID-19 vaccine dose and only 6.1% had completed the primary series as of May 2023,*** nearly a full year after vaccines were recommended for this age group.
The findings in this report are subject to at least five limitations. First, VE estimates for Moderna and Pfizer-BioNTech are not directly comparable because of different dates of eligibility for completion of the primary series, which might affect product-specific VE estimates. Different rates of SARS-CoV-2 infection in the population and different circulating subvariants during August 1–September 19, 2022 (when VE could only be assessed for a complete Moderna primary series) compared with September 19, 2022–June 17, 2023 (when VE of a complete primary series for both products could be assessed), likely also affects comparability. Second, vaccination coverage among young children, including those in this analysis, is low, and vaccinated children might systematically differ from unvaccinated children (or from those who initiated but did not complete the primary series) in COVID-19 risk or likelihood of seeking care, which could bias VE results. Third, the combination of low vaccination coverage, relatively low SARS-CoV-2 circulation during the study period, and low overall rates of hospitalization in this age group precluded the assessment of VE against more severe outcomes, which is the primary goal of the U.S. COVID-19 vaccination program. In addition, low bivalent vaccination coverage precluded the estimation of product-specific VE. Fourth, this analysis was not able to control for previous infection because of underreporting in the medical record, which might have resulted in biased estimates. By July–August 2022, among children aged 6–11 months, 12–23 months, and 2–4 years, 66%, 74%, and 83%, respectively, had evidence of infection-induced SARS-CoV-2 immunity.††† These findings should therefore be interpreted as the incremental benefit provided by COVID-19 vaccination in a population with a high prevalence of infection-induced immunity. Finally, because these data are from eight states, this analysis might not be representative of the entire U.S. population.
Implications for Public Health Practice
Complete Moderna or Pfizer-BioNTech primary series vaccination helped protect against COVID-19–associated ED/UC visits in young children. Although bivalent vaccination coverage was low in this group, ≥1 dose of bivalent vaccine also helped provide protection. All children should stay up to date with recommended COVID-19 vaccines, including initiating COVID-19 vaccination immediately when children become eligible.§§§
Katherine Adams, Monica Dickerson, Shikha Garg, Eric Griggs, Josephine Mak, Palak Patel, Caitlin Ray, CDC; Beyonce Carrington; Salome Kiduko, Westat; Brad Crane, Padma Dandamudi, Kaiser Permanente Center for Health Research; Ned Lewis, Kaiser Permanente Northern California; Inih Essien, Linda Fletcher, Sheryl Kane, Sunita Thapa, HealthPartners Institute; Briana Kille, Corey Montano, University of Colorado.
Corresponding author: Ruth Link-Gelles, email@example.com.
1Coronavirus and Other Respiratory Viruses Division, National Center for Immunization and Respiratory Diseases, CDC; 2Eagle Health Analytics, San Antonio, Texas; 3Westat, Rockville, Maryland; 4Kaiser Permanente Vaccine Study Center, Kaiser Permanente Northern California Division of Research, Oakland, California; 5Kaiser Permanente Center for Health Research, Portland, Oregon; 6Children’s Minnesota, Minneapolis, Minnesota; 7Department of Biomedical Informatics, Columbia University Irving Medical Center, New York, New York; 8New York-Presbyterian Hospital, New York, New York; 9HealthPartners Institute, Minneapolis, Minnesota; 10Division of Infectious Diseases and Clinical Epidemiology, Intermountain Healthcare, Salt Lake City, Utah; 11School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado; 12Division of Child and Adolescent Health, Department of Pediatrics, Columbia University Vagelos College of Physicians and Surgeons, New York, New York; 13Department of Population and Family Health, Columbia University Mailman School of Public Health, New York, New York; 14Center for Biomedical Informatics, Regenstrief Institute, Indianapolis, Indiana; 15School of Medicine, Indiana University, Indianapolis, Indiana; 16Vanderbilt University Medical Center, Nashville, Tennessee; 17Section of Pediatric Infectious Diseases, Department of Pediatrics, Baylor Scott & White Health, Temple, Texas; 18Department of Medical Education, Texas A&M University College of Medicine, Temple, Texas; 19Influenza Division, National Center for Immunization and Respiratory Diseases, CDC.
All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Nicola P. Klein reports institutional support from Pfizer, Merck, GSK, Sanofi Pasteur, and Protein Sciences (now Sanofi Pasteur). Allison L. Naleway reports institutional support from Pfizer for an unrelated study of meningococcal B vaccine safety during pregnancy study and from Vir Biotechnology for an unrelated influenza study. Suchitra Rao reports grant support from GSK. No other potential conflicts of interest were disclosed.
* Pfizer-BioNTech is recommended as 3 3-μg doses, with ≥3–8 weeks between doses 1 and 2 and ≥8 weeks between doses 2 and 3.
† Moderna is recommended as 2 25-μg doses separated by ≥4–8 weeks.
§ Sites from the CDC-funded VISION Network that contributed data for this analysis were Columbia University (New York), HealthPartners and Children’s Minnesota (Minnesota and Wisconsin), Intermountain Healthcare (Utah), Kaiser Permanente Northern California (California), Kaiser Permanente Northwest (Oregon and Washington), and University of Colorado (Colorado).
¶ Medical events with a discharge code consistent with COVID-19–like illness were included using International Classification of Diseases, Tenth Revision (ICD-10) discharge codes: COVID-19 pneumonia: J12.81 and J12.82; influenza pneumonia: J09.X1, J10.0, J10.00, J10.01, J10.08, J11.0, J11.00, and J11.08; other viral pneumonia: J12*; bacterial and other pneumonia: J13, J14, J15*, J16*, J17, and J18*; influenza disease: J09*, J10.1, J10.2, J10.8*, J11.1, J11.2, and J11.8*; acute respiratory distress syndrome: J80; asthma acute exacerbation: J45.21, J45.22, J45.31, J45.32, J45.41, J45.42, J45.51, J45.52, J45.901, and J45.902; respiratory failure: J96.0*, J96.2*, and R09.2; other acute lower respiratory tract infections: J20*, J21*, J22, J40, J41*, J42, J43*, J47*, J85, J85.0, J85.1, J85.2, J85.3, and J86*; acute and chronic sinusitis: J01*; acute upper respiratory tract infections: J00*, J02*, J03*, J04*, J05*, and J06*; acute respiratory illness signs and symptoms: R04.2, R05, R05.1, R05.2, R05.4, R05.8, R05.9, R06.00, R06.02, R06.03, R06.1, R06.2, R06.8, R06.81, R06.82, R06.89, R07.1, R09.0*, R09.1, R09.2, R09.3, and R09.8*; acute febrile illness signs and symptoms: R50* and R68.83; viral infection, not otherwise specified: B34.9; cause-unspecified gastroenteritis and colitis, unspecified: A09 and K52.9; thrombosis: I82.210, I82.290, I82.220, I82.4*, I82.6*, I82.A1*, I82.B1*, and I82.C1*; acute myocarditis: I40.0, I40.1, I40.8, and I40.9. All ICD-10 codes with * include all child codes under the specific parent code.
** The index date for each encounter was defined as either the date of collection of a respiratory specimen associated with the most recent positive or negative SARS-CoV-2 test result before the encounter or the date of the encounter (if testing occurred only after the encounter date).
†† VE was calculated as (1 − adjusted odds ratio) x 100%. Odds ratios and 95% CIs were estimated using multivariable logistic regression controlling for age, race and ethnicity, sex, calendar day (days since January 1, 2021), and geographic region. Calendar day was modeled as natural cubic splines. Odds ratios in strata with sparse data were calculated using unadjusted exact methods.
§§ Children became eligible for inclusion 14 days after receiving the dose at different times: 1 dose of Moderna and Pfizer-BioNTech on July 4, 2022; 2 doses of Pfizer-BioNTech on July 25, 2022; 2 doses of Moderna on August 1, 2022; 3 doses of Pfizer-BioNTech on September 19, 2022; and bivalent doses on December 24, 2022.
¶¶ 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.
*** https://covid.cdc.gov/covid-data-tracker/#vaccination-demographics-trends (Accessed July 14, 2023).
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- National Center for Health Statistics. Provisional COVID-19 death counts by age in years, 2020–2022. Hyattsville, MD: US Department of Health and Human Services, CDC; 2022. Accessed July 26, 2023. https://data.cdc.gov/d/3apk-4u4f
- Anderson EJ, Creech CB, Berthaud V, et al.; KidCOVE Study Group. Evaluation of mRNA-1273 vaccine in children 6 months to 5 years of age. N Engl J Med 2022;387:1673–87. https://doi.org/10.1056/NEJMoa2209367 PMID:36260859
- Food and Drug Administration; Vaccines and Related Biological Products Advisory Committee. FDA briefing document: EUA amendment request for Pfizer-BioNTech COVID-19 vaccine for use in children 6 months through 4 years of age. Presented at the Vaccines and Related Biological Products Advisory Committee meeting, Silver Spring, MD; June 15, 2022. https://www.fda.gov/media/159195/download
- CDC. Vaccines & immunizations: use of COVID-19 vaccines in the United States. Atlanta, GA: US Department of Health and Human Services, CDC, 2023. Accessed January 18, 2023. https://www.cdc.gov/vaccines/covid-19/clinical-considerations/covid-19-vaccines-us.html
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Suggested citation for this article: Link-Gelles R, Ciesla AA, Rowley EA, et al. Effectiveness of Monovalent and Bivalent mRNA Vaccines in Preventing COVID-19–Associated Emergency Department and Urgent Care Encounters Among Children Aged 6 Months–5 Years — VISION Network, United States, July 2022–June 2023. MMWR Morb Mortal Wkly Rep 2023;72:886–892. DOI: http://dx.doi.org/10.15585/mmwr.mm7233a2.
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