Overall Health Effects of mRNA COVID-19 Vaccines in Children and Adolescents: A Systematic Review and Meta-Analysis

Importance: Phase 3 randomized controlled trials (RCTs) of mRNA COVID-19 vaccines in children and adolescents showed efficacy in preventing COVID-19 infections. Vaccines may have non-specific effects; this is not assessed within the current regulatory framework. Objective: Conduct a systematic review and meta-analysis of the phase 3 trials to assess overall and non-specific health effects of the mRNA COVID-19 vaccines in children. Data Sources: PubMed, Embase, Clinical Trials, Web of Science, and regulatory websites were searched for RCTs of mRNA vaccines. The latest trial data was included. Study Selection: All RCTs conducted with mRNA vaccines BNT162b2 and mRNA-1237 in children and adolescents below 18 years of age, with placebo, adjuvant, or other vaccines as controls. Two authors independently screened 1199 studies, six were included in the analysis. Data Extraction and Synthesis: Data on serious adverse events (SAEs) and severe adverse events (AEs) as well as organ-specific diseases was extracted following the PRISMA reporting guideline, with a focus on non-specific infectious events. Risk Ratios (RRs) comparing vaccine and placebo cohorts were calculated separately for each vaccine and combined in Mantel-Haenszel estimates. Main Outcomes and Measures: The primary outcome was SAEs, overall and infectious. Secondary outcomes were severe AEs and lower respiratory tract infection (LRTI) including RSV. Results: The analyses included 25,549 individuals (17,538 mRNA vaccine recipients and 8,011 placebo recipients). The risk of SAEs was similar for vaccine and placebo recipients. Both mRNA vaccines were associated with increased risk of severe AEs in older children. In a combined analysis, the RR was 3.77 (1.56-9.13[0.4% vs 0.1% in vaccine vs placebo recipients]) in above 5 year-olds, and 0.82 (0.53-1.29)[0.8% vs 0.9%])in younger children (p=0.003 for same effect in older and younger children). In the younger children, mRNA vaccines were associated with higher risk of LRTI (RR=3.03 (1.29-7.09)[0.6% vs 0.2%]). Conclusions and Relevance: mRNA vaccines did not increase the risk of SAEs but were associated with an increased risk of severe AEs in older children, and an increased risk of LRTI in the young. Further research into the overall and non-specific health effects of mRNA vaccines is warranted.