SARS-CoV-2 Epidemiology and COVID-19 mRNA Vaccine Effectiveness Among Infants and Children Aged 6 Months–4 Years — New Vaccine Surveillance Network, United States, July 2022–September 2023

SARS-CoV-2 infection in young children is often mild or asymptomatic; however, some children are at risk for severe disease. Data describing the protective effectiveness of COVID-19 mRNA vaccines against COVID-19-associated emergency department (ED) visits and hospitalization in this population are limited. Data from the New Vaccine Surveillance Network, a prospective population-based surveillance system, were used to estimate vaccine effectiveness using a test-negative, case-control design and describe the epidemiology of SARS-CoV-2 in infants and children aged 6 months-4 years during July 1, 2022-September 30, 2023. Among 7,434 children included, 5% received a positive SARS-CoV-2 test result, and 95% received a negative test result; 86% were unvaccinated, 4% had received 1 dose of any vaccine product, and 10% had received ≥2 doses. When compared with receipt of no vaccines among children, receipt of ≥2 COVID-19 mRNA vaccine doses was 40% effective (95% CI = 8%-60%) in preventing ED visits and hospitalization. These findings support existing recommendations for COVID-19 vaccination of young children to reduce COVID-19-associated ED visits and hospitalization.


Introduction
SARS-CoV-2 infection in young children and adolescents commonly manifests as a mild or asymptomatic illness; however, some children are at risk for severe disease, including those with certain chronic conditions (1,2).COVID-19 mRNA vaccines were recommended for children aged ≥5 years in November 2021, and for infants and children aged 6 months-4 years in June 2022, with further authorizations for bivalent mRNA vaccines during December 2022-April 2023 (3).Vaccination coverage in this population remains markedly lower than that in the adult population, and complete primary series COVID-19 mRNA vaccination coverage in young children has been approximately 5% nationwide since January 2023.† As such, vaccine effectiveness (VE) estimates in * These senior authors contributed equally to this report.† https://covid.cdc.gov/covid-data-tracker/#vaccination-demographics-trendsinfants and children aged 6 months-4 years are limited (4,5).Despite low coverage in this age group, COVID-19-associated hospitalization rates among infants and children aged 6 months-4 years has remained low.§ This analysis assessed the effectiveness of COVID-19 mRNA vaccines in protecting against COVID-19-associated emergency department (ED) visits and hospitalization during the first year of authorization of vaccination for infants and children aged 6 months-4 years, a period when several Omicron sublineages were circulating.¶

Data Collection
The New Vaccine Surveillance Network (NVSN) conducts population-based, prospective surveillance for acute respiratory illness (ARI) in children at seven pediatric medical centers.**During July 1, 2022-September 30, 2023, infants and children aged 6 months-4 years hospitalized or seeking care in EDs for ARI were eligible for enrollment.† † Demographic, clinical, and vaccination data were systematically collected through parent or guardian interview and medical chart abstraction.Respiratory specimens were collected and tested for SARS-CoV-2 and seven other respiratory viruses

Data Analysis
COVID-19 VE to prevent COVID-19-associated ED visits and hospitalization among children with ARI was estimated using a test-negative, case-control design.Case-patients were children with ARI and who received a positive SARS-CoV-2 test result.Control-patients were children with ARI and who received a negative SARS-CoV-2 test result.Children were included in the analysis if they had a verified vaccination status including 1) zero doses of any COVID-19 vaccine product (unvaccinated), 2) 1 dose of any COVID-19 vaccine product (1 dose only), or 3) ≥2 doses of any COVID-19 vaccine product (≥2 doses).Children were excluded if they met NVSN exclusion criteria,*** were enrolled <14 days after receipt of a vaccine dose, received an inconclusive SARS-CoV-2 test result, were missing COVID-19 vaccination data, or if receipt of vaccination was unverified.Pearson's chi-square tests were used to compare demographic and clinical characteristics among case-and control-patients and by vaccination status.VE was estimated using logistic regression models, comparing the odds of receipt of 1 or ≥2 vaccine doses with those with no COVID-19 vaccination between case-and control-patients.Regression models controlled for race, age, calendar time (week of enrollment), and enrollment site.VE was calculated as (1 -adjusted odds ratio) x 100%; estimates with nonoverlapping 95% CIs were considered statistically significant.SAS (version 9.4; SAS Institute) was used to conduct all analyses.This activity was reviewed by CDC, deemed not research, and was conducted consistent with applicable federal law and CDC policy.† † †

Differences Between Case-Patients and Control-Patients
During July 1, 2022-September 30, 2023, among 7,434 infants and children aged 6 months-4 years with ARI enrolled in ED or hospital settings, 387 (5.0%) received a positive SARS-CoV-2 test result, and 7,047 (95.0%) received ¶ ¶ Primary care provider record verification was required after the expiration of the public health emergency in sites without mandatory reporting of COVID-19 vaccines to state immunization information systems.*** 1) age ≥18 years, 2) residence outside surveillance area, 3) admitted patient not enrolled or specimen collected ≤48 hours of hospital admission, 4) fever and neutropenia (absolute neutrophil count <500), 5) newborn who never left the hospital, 6) transferred from another hospital admission of >48 hours, 7) known nonrespiratory cause for admission, 8) duration of illness lasting >10 days, or 9) previous encounter <10 days before hospital admission at the same level or higher level of care and not enrolled.a negative test result (Table 1).Case-patients were significantly younger than were control-patients (median age 15 months versus 22 months, respectively).There was no difference in median length of stay (2 days), sex, race and ethnicity, insurance status, history of prematurity, or underlying medical conditions between case-and control-patients.Case-patients were less likely to receive supplemental oxygen and high-flow nasal cannula respiratory support than were control-patients; however, there was no difference between case-and controlpatients in the proportion who received mechanical ventilation or were admitted to an intensive care unit.Two case-patients (0.5%) were intubated, none received extracorporeal membrane oxygenation, and none died, compared with 69 (1.0%), three (0.9%), and three (0.1%) control-patients, respectively.Other respiratory viruses were detected in 140 (36.2%)casepatients; rhinoviruses/enteroviruses (RV/EV) accounted for one half of these detections, and respiratory syncytial virus accounted for 21.4%.Among control-patients, RV/EV and respiratory syncytial virus also accounted for the majority of detections and were detected in 36.7% and 17.1% of controlpatients, respectively.

Discussion
In this analysis of 7,434 infants and children aged 6 months-4 years with ARI in NVSN, 86.0% had not received any COVID-19 vaccine doses, and clear geographic, age, and racial differences in vaccination coverage were observed: 14 (10.0)14 (10.0) 13 (92.9)0 (-) 1 (7.1) 0.948 EV-D68 ¶ ¶ ¶ 9 ( ¶ Gestational age <37 weeks, restricted to infants and children aged <2 years.** Underlying medical conditions include congenital heart malformation or other heart condition, transplant recipient, cancer, sickle cell anemia, cerebral palsy, seizure disorder or other neurologic or neuromuscular disorder, asthma, reactive airway disease, cystic fibrosis, bronchopulmonary dysplasia, chronic lung disease of prematurity or other chronic lung condition, kidney disease, Down syndrome or other genetic or metabolic disorder, blood disorders, liver disease, diabetes, chronic endocrine condition, chronic gastrointestinal disease, and other developmental disabilities.† † Congenital heart malformation or other heart condition.§ § Immune condition, transplant recipient (peripheral blood stem cells, bone marrow, cord blood, or organ), cancer, and sickle cell anemia.¶ ¶ Cerebral palsy, seizure disorder, or other neurologic or neuromuscular disorder.*** Asthma, reactive airway disease, cystic fibrosis, bronchopulmonary dysplasia, chronic lung disease of prematurity, or other chronic lung condition.
† † † Among hospitalized children only.§ § § Among all children.¶ ¶ ¶ Among children who received a positive SARS-CoV-2 test result only.Abbreviations: NA = not applicable; VE = vaccine effectiveness.* Some estimates are imprecise, which might be because of a relatively small number of persons in each level of vaccination or case-patient status.This imprecision indicates the actual VE could be substantially different from the point estimate shown, and estimates should therefore be interpreted with caution.Additional data accrual could increase precision and allow appropriate interpretation.† VE was estimated by comparing odds of being vaccinated with 1 dose or ≥2 doses among case-patients to the odds of being vaccinated with 1 dose or ≥2 doses among control patients.Calculated as VE = 100 x (1 -odds ratio).Regression models adjusted for race, age, calendar time (week of enrollment), and enrollment site.§ p<0.05.VE estimates, particularly as more vaccines are introduced for respiratory viruses that could bias pediatric VE estimates.

≥2-dose coverage in
Receipt of ≥2 COVID-19 mRNA vaccine doses was 40% effective in preventing COVID-19-associated ED visits and hospitalization.Despite low vaccination coverage and the circulation of several Omicron subvariants, COVID-19associated ED visits and hospitalization among children with ARI enrolled in NVSN were rare, suggesting most children in this age group experience mild illness from these subvariants or have immune protection from previous SARS-CoV-2 exposure (7).These findings indicate that COVID-19 mRNA vaccines are protective and are consistent with other VE estimates for this age group, ranging from 29% for 2-dose Moderna coverage to 43% for 3-dose Pfizer-BioNTech coverage (5); however, low vaccination coverage and low incidence of medically attended COVID-19 limit precision in these VE estimates.

Limitations
The findings in this report are subject to at least five limitations.First, seroprevalence of infection-induced SARS-CoV-2 antibodies in children and adolescents has increased over time, which might affect VE estimates and assessment of severe outcomes, as more children have immunity from previous SARS-CoV-2 infection (8).Second, low vaccination coverage might indicate that vaccinated children are systematically different from unvaccinated children.For example, children with underlying medical conditions might be more likely to be vaccinated and, because of their underlying conditions, Abbreviations: BiPAP = bilevel positive airway pressure; CPAP = continuous positive airway pressure; ECMO = extracorporeal membrane oxygenation; ED = emergency department; EV-D68 = enterovirus D68; HCoV = human coronaviruses; HMPV = human metapneumovirus; NA = not applicable; NH = non-Hispanic; PIV = parainfluenza viruses 1-4; RSV = respiratory syncytial virus; RV/EV = rhinovirus/enterovirus.* Restricted to children enrolled in inpatient and ED clinical settings.† p-value refers to results of Pearson's chi-square comparison.§ p-value measuring difference between unvaccinated children and children receiving ≥2 vaccine doses.¶Gestational age <37 weeks, restricted to infants and children aged <2 years.** Underlying medical conditions include congenital heart malformation or other heart condition, transplant recipient, cancer, sickle cell anemia, cerebral palsy, seizure disorder or other neurologic or neuromuscular disorder, asthma, reactive airway disease, cystic fibrosis, bronchopulmonary dysplasia, chronic lung disease of prematurity or other chronic lung condition, kidney disease, Down syndrome or other genetic or metabolic disorder, blood disorders, liver disease, diabetes, chronic endocrine condition, chronic gastrointestinal disease, and other developmental disabilities.† † Congenital heart malformation or other heart condition.§ § Immune condition, transplant recipient (peripheral blood stem cells, bone marrow, cord blood, or organ), cancer, and sickle cell anemia.¶ ¶ Cerebral palsy, seizure disorder, or other neurologic or neuromuscular disorder.*** Asthma, reactive airway disease, cystic fibrosis, bronchopulmonary dysplasia, chronic lung disease of prematurity, or other chronic lung condition.†† † Among hospitalized children only.§ § § Among all children.¶ ¶ ¶ Among children who received a positive SARS-CoV-2 test result only.

FIGURE. SARS-CoV- 2
FIGURE.SARS-CoV-2 test results and COVID-19 vaccination coverage among infants and children aged 6 months-4 years evaluated in the emergency department or hospitalized with acute respiratory illness, by week (N = 7,434) -New Vaccine Surveillance Network, United States, July 2022-September 2023COVID-19 vaccination coverage among enrolled infants and children, %