Background To date, more than 761 million confirmed SARS-CoV-2 infections have been recorded globally, and more than half of all children are estimated to be seropositive. Despite high SARS-CoV-2 infection incidences, the rate of severe COVID-19 in children is low. We aimed to assess the safety and efficacy or effectiveness of COVID-19 vaccines approved in the EU for children aged 5-11 years.Methods In this systematic review and meta-analysis, we included studies of any design identified through searching the COVID-19 L center dot OVE (living overview of evidence) platform up to Jan 23, 2023. We included studies with participants aged 5-11 years, with any COVID-19 vaccine approved by the European Medicines Agency-ie, mRNA vaccines BNT162b2 (Pfizer-BioNTech), BNT162b2 Bivalent (against original strain and omicron [BA.4 or BA.5]), mRNA-1273 (Moderna), or mRNA-1273.214 (against original strain and omicron BA.1). Efficacy and effectiveness outcomes were SARS-CoV-2 infection (PCR-confirmed or antigen-test confirmed), symptomatic COVID-19, hospital admission due to COVID-19, COVID-19-related mortality, multisystem inflammatory syndrome in children (MIS-C), and long-term effects of COVID-19 (long COVID or post-COVID-19 condition as defined by study investigators or per WHO definition). Safety outcomes of interest were serious adverse events, adverse events of special interest (eg, myocarditis), solicited local and systemic events, and unsolicited adverse events. We assessed risk of bias and rated the certainty of evidence (CoE) using the Grading of Recommendations Assessment, Development and Evaluation approach. This study was prospectively registered with PROSPERO, CRD42022306822.Findings Of 5272 screened records, we included 51 (1 center dot 0%) studies (n=17 [33%] in quantitative synthesis). Vaccine effectiveness after two doses against omicron infections was 41 center dot 6% (95% CI 28 center dot 1-52 center dot 6; eight non-randomised studies of interventions [NRSIs]; CoE low), 36 center dot 2% (21 center dot 5-48 center dot 2; six NRSIs; CoE low) against symptomatic COVID-19, 75 center dot 3% (68 center dot 0-81 center dot 0; six NRSIs; CoE moderate) against COVID-19-related hospitalisations, and 78% (48-90, one NRSI; CoE very low) against MIS-C. Vaccine effectiveness against COVID-19-related mortality was not estimable. Crude event rates for deaths in unvaccinated children were less than one case per 100 000 children, and no events were reported for vaccinated children (four NRSIs; CoE low). No study on vaccine effectiveness against long-term effects was identified. Vaccine effectiveness after three doses was 55% (50-60; one NRSI; CoE moderate) against omicron infections, and 61% (55-67; one NRSI; CoE moderate) against symptomatic COVID-19. No study reported vaccine efficacy or effectiveness against hospitalisation following a third dose. Safety data suggested no increased risk of serious adverse events (risk ratio [RR] 0 center dot 83 [95% CI 0 center dot 21-3 center dot 33]; two randomised controlled trials; CoE low), with approximately 0 center dot 23-1 center dot 2 events per 100 000 administered vaccines reported in real-life observations. Evidence on the risk of myocarditis was uncertain (RR 4 center dot 6 [0 center dot 1-156 center dot 1]; one NRSI; CoE low), with 0 center dot 13-1 center dot 04 observed events per 100 000 administered vaccines. The risk of solicited local reactions was 2 center dot 07 (1 center dot 80-2 center dot 39; two RCTs; CoE moderate) after one dose and 2 center dot 06 (1 center dot 70-2 center dot 49; two RCTs; CoE moderate) after two doses. The risk of solicited systemic reactions was 1 center dot 09 (1 center dot 04-1 center dot 16; two RCTs; CoE moderate) after one dose and 1 center dot 49 (1 center dot 34-1 center dot 65; two RCTs; CoE moderate) after two doses. The risk of unsolicited adverse events after two doses (RR 1 center dot 21 [1 center dot 07-1 center dot 38]; CoE moderate) was higher among mRNA-vaccinated compared with unvaccinated children.Interpretation In children aged 5-11 years, mRNA vaccines are moderately effective against infections with the omicron variant, but probably protect well against COVID-19 hospitalisations. Vaccines were reactogenic but probably safe. Findings of this systematic review can serve as a basis for public health policy and individual decision making on COVID-19 vaccination in children aged 5-11 years.Funding German Federal Joint Committee.Copyright (c) 2023 Elsevier Ltd. All rights reserved.
