BackgroundAnnual national estimates of influenza vaccine effectiveness (VE) typically measure protection against outpatient medically attended influenza illness. We assessed influenza VE in preventing laboratory-confirmed influenza hospitalization in children across two influenza A(H3N2)-predominant seasons.MethodsChildren < 18 years hospitalized with acute respiratory illness were enrolled at 7 pediatric hospitals in the New Vaccine Surveillance Network. We included subjects ≥6 months with ≤10 days of symptoms enrolled during the 2016–2017 and 2017–2018 seasons (date of first through last influenza-positive case for each site). Combined mid-turbinate and throat swabs were tested using molecular assays. We estimated age-stratified VE from a test-negative design using logistic regression to compare the odds of vaccination among cases positive for influenza with controls testing negative, adjusting for age, enrollment month, site, underlying comorbidities, and race/ethnicity. Full/partial vaccination was defined using ACIP criteria. We verified vaccine receipt from state immunization registries and/or provider records.ResultsAmong 3441 children with complete preliminary data, in 2016–2017, 156/1,710 (9%) tested positive for influenza: 91 (58%) with influenza A(H3N2), 5 (3%) with A(H1N1), and 60 (38%) with B viruses. In 2017–2018, 193/1,731 (11%) tested positive: 87 (45%) with influenza A(H3N2), 47 (24%) with A(H1N1), and 58 (30%) with B. VE for all vaccinated children (full and partial) against any influenza was 48% (95% confidence interval, 26%–63%) in 2016–2017 and 45% (24%–60%) in 2017–2018. Combining seasons, VE for fully and partially vaccinated children against any influenza type was 46% (32%–58%); by virus, VE was 30% (4%–49%) for influenza A(H3N2), 71% (46%–85%) for A(H1N1), and 57% (36%–70%) for B viruses. There was no statistically significant difference in VE by age or full/partial vaccination status for any virus (table).ConclusionVaccination in the 2016–2017 and 2017–2018 seasons nearly halved the risk of children being hospitalized with influenza. These findings support the use of vaccination to prevent severe illness in children. Our study highlights the need for a better understanding of the lower VE against influenza A(H3N2) viruses. Disclosures All Authors: No reported Disclosures.