Background Children and adolescents in England were offered BNT162b2 as part of the national COVID-19 vaccine roll out from September 2021. We assessed the safety and effectiveness of first and second dose BNT162b2 COVID-19 vaccination in children and adolescents in England. Methods With the approval of NHS England, we conducted an observational study in the OpenSAFELY-TPP database, including a) adolescents aged 12-15 years, and b) children aged 5-11 years and comparing individuals receiving i) first vaccination with unvaccinated controls and ii) second vaccination to single-vaccinated controls. We matched vaccinated individuals with controls on age, sex, region, and other important characteristics. Outcomes were positive SARS-CoV-2 test (adolescents only); COVID-19 A&E attendance; COVID-19 hospitalisation; COVID-19 critical care admission; COVID-19 death, with non-COVID-19 death and fractures as negative control outcomes and A&E attendance, unplanned hospitalisation, pericarditis, and myocarditis as safety outcomes. Results Amongst 820,926 previously unvaccinated adolescents, the incidence rate ratio (IRR) for positive SARS-CoV-2 test comparing vaccination with no vaccination was 0.74 (95% CI 0.72-0.75), although the 20-week risks were similar. The IRRs were 0.60 (0.37-0.97) for COVID-19 A&E attendance, 0.58 (0.38-0.89) for COVID-19 hospitalisation, 0.99 (0.93-1.06) for fractures, 0.89 (0.87-0.91) for A&E attendances and 0.88 (0.81-0.95) for unplanned hospitalisation. Amongst 441,858 adolescents who had received first vaccination IRRs comparing second dose with first dose only were 0.67 (0.65-0.69) for positive SARS-CoV-2 test, 1.00 (0.20-4.96) for COVID-19 A&E attendance, 0.60 (0.26-1.37) for COVID-19 hospitalisation, 0.94 (0.84-1.05) for fractures, 0.93 (0.89-0.98) for A&E attendance and 0.99 (0.86-1.13) for unplanned hospitalisation. Amongst 283,422 previously unvaccinated children and 132,462 children who had received a first vaccine dose, COVID-19-related outcomes were too rare to allow IRRs to be estimated precisely. A&E attendance and unplanned hospitalisation were slightly higher after first vaccination (IRRs versus no vaccination 1.05 (1.01-1.10) and 1.10 (0.95-1.26) respectively) but slightly lower after second vaccination (IRRs versus first dose 0.95 (0.86-1.05) and 0.78 (0.56-1.08) respectively). There were no COVID-19-related deaths in any group. Fewer than seven (exact number redacted) COVID-19-related critical care admissions occurred in the adolescent first dose vs unvaccinated cohort. Among both adolescents and children, myocarditis and pericarditis were documented only in the vaccinated groups, with rates of 27 and 10 cases/million after first and second doses respectively. Conclusion BNT162b2 vaccination in adolescents reduced COVID-19 A&E attendance and hospitalisation, although these outcomes were rare. Protection against positive SARS-CoV-2 tests was transient.

BG has received research funding from the Laura and John Arnold Foundation, the NHS National Institute for Health Research (NIHR), the NIHR School of Primary Care Research, NHS England, the NIHR Oxford Biomedical Research Centre, the Mohn-Westlake Foundation, NIHR Applied Research Collaboration Oxford and Thames Valley, the Wellcome Trust, the Good Thinking Foundation, Health Data Research UK, the Health Foundation, the World Health Organisation, UKRI MRC, Asthma UK, the British Lung Foundation, and the Longitudinal Health and Wellbeing strand of the National Core Studies programme; he is a Non-Executive Director at NHS Digital; he also receives personal income from speaking and writing for lay audiences on the misuse of science. BMK is also employed by NHS England working on medicines policy and clinical lead for primary care medicines data. IJD has received unrestricted research grants and holds shares in GlaxoSmithKline (GSK).

The OpenSAFELY Platform is supported by grants from the Wellcome Trust (222097/Z/20/Z); MRC (MR/V015757/1, MC_PC-20059, MR/W016729/1); NIHR (NIHR135559, COV-LT2-0073), and Health Data Research UK (HDRUK2021.000, 2021.0157). In addition, this research used data assets made available as part of the Data and Connectivity National Core Study, led by Health Data Research UK in partnership with the Office for National Statistics and funded by UK Research and Innovation (grant ref MC_PC_20058). BG has also received funding from: the Bennett Foundation, the Wellcome Trust, NIHR Oxford Biomedical Research Centre, NIHR Applied Research Collaboration Oxford and Thames Valley, the Mohn-Westlake Foundation; all Bennett Institute staff are supported by BG's grants on this work. The views expressed are those of the authors and not necessarily those of the NIHR, NHS England, UK Health Security Agency (UKHSA) or the Department of Health and Social Care. Funders had no role in the study design, collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

This study was approved by the Health Research Authority (REC reference 20/LO/0651) and by the London School of Hygeine and Tropical Medicine Ethics Board (reference 21863).

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

All data were linked, stored and analysed securely using the OpenSAFELY platform, https://www.opensafely.org/, as part of the NHS England OpenSAFELY COVID-19 service. Data include pseudonymised data such as coded diagnoses, medications and physiological parameters. No free text data was included. All code is shared openly for review and re-use under MIT open license [https://github.com/opensafely/vaccine-effectiveness-in-kids]. Detailed pseudonymised patient data is potentially re-identifiable and therefore not shared. Primary care records managed by the GP software provider, TPP were linked to ONS death data and the Index of Multiple Deprivation through OpenSAFELY.