Vaccine Effectiveness Among 5- to 17-year-old Individuals with Prior SARS-CoV-2 Infection: An EHR-Based Target Trial Emulation Study from the RECOVER Project

IMPORTANCEPrior studies have demonstrated the effectiveness of COVID-19 vaccines in children and adolescents. However, the benefits of vaccination in these age groups with prior infection remain underexplored. OBJECTIVETo evaluate the effectiveness of COVID-19 vaccination in preventing reinfection with various Omicron subvariants (BA.1/2, BA.4/5, XBB, and later) among 5- to 17-year-olds with prior SARS-CoV-2 infection. DESIGNA target trial emulation through nested designs with distinct study periods. SETTINGThe study utilized data from the Research COVID to Enhance Recovery (RECOVER) initiative, a national electronic health record (EHR) database comprising 37 U.S. childrens hospitals and health institutions. PARTICIPANTSIndividuals aged 5-17 years with a documented history of SARS-CoV-2 infection prior to the study start date during a specific variant-dominant period (Delta, BA.1/2, or BA.4/5) who received a subsequent dose of COVID-19 vaccine during the study periods were compared with those with a documented history of infection who did not receive SARS-CoV-2 vaccine during the study period. Those infected within the Delta-Omicron composite period (December 1, 2021, to December 31, 2021) were excluded. The study period was from January 1, 2022, to August 30, 2023, and focused on adolescents aged 12 to 17 years and children aged 5 to 11 years. EXPOSURESAt least received one COVID-19 vaccination during the study period vs. no receipt of any COVID-19 vaccine during the study period. MAIN OUTCOMES AND MEASURESThe primary outcome is documented SARS-CoV-2 reinfection during the study period (both asymptomatic and symptomatic cases). The effectiveness of the COVID-19 vaccine was estimated as (1-hazard ratio) *100%, with confounders adjusted by a combination of propensity score matching and exact matching. RESULTSThe study analyzed 87,573 participants during the BA.1/2 period, 229,326 during the BA.4/5 period, and 282,981 during the XBB or later period. Among vaccinated individuals, significant protection was observed during the BA.1/2 period, with effectiveness rates of 62% (95% CI: 38%-77%) for children and 65% (95% CI: 32%-81%) for adolescents. During the BA.4/5 period, vaccine effectiveness was 57% (95% CI: 25%-76%) for children, but not statistically significant for adolescents (36%, 95% CI: -16%-65%). For the XBB period, no significant protection was observed in either group, with effectiveness rates of 22% (95% CI: -36%-56%) in children and 34% (95% CI: -10%-61%) in adolescents. CONCLUSIONS AND RELEVANCECOVID-19 vaccination provides significant protection against reinfection for children and adolescents with prior infections during the early and mid-Omicron periods. This study also highlights the importance of addressing low vaccination rates in pediatric populations to enhance protection against emerging variants. Key PointsO_ST_ABSQuestionC_ST_ABSDoes COVID-19 vaccination protect against reinfection with Omicron subvariants (BA.1/2, BA.4/5, XBB, and later) among children and adolescents aged 5-17 years with prior SARS-CoV-2 infection? FindingsCOVID-19 vaccination significantly reduced the risk of reinfection during the BA.1/2 period, with effectiveness rates of 62% in children and 65% in adolescents. During the BA.4/5 period, vaccination provided moderate protection in children, with effectiveness rates of 57%, but the effectiveness in adolescents (36%) was not statistically significant. For the XBB period and later subvariants, vaccination did not show significant protection in either group. MeaningCOVID-19 vaccination offered meaningful protection against reinfection in pediatric populations during earlier Omicron periods but became less effective with later emerging subvariants, highlighting the challenges of sustaining vaccine effectiveness as the virus continues to evolve.