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.

Importance: Prior 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.

Objective: To 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.

Design: A target trial emulation through nested designs with distinct study periods.

Setting: The study utilized data from the Research COVID to Enhance Recovery (RECOVER) initiative, a national electronic health record (EHR) database comprising 37 U.S. children's hospitals and health institutions.

Participants: Individuals 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.

Exposures: At 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 Measures: The 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.

Results: The 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 Relevance: COVID-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.