Objectives We investigated SARS-CoV-2 infection trends, risk of SARS-CoV-2 infection and COVID-19 vaccination uptake among school staff, students and their household members in Wales, UK. Design Seven-day average of SARS-CoV-2 infections and polymerase chain reaction tests per 1000 people daily, cumulative incidence of COVID-19 vaccination uptake and multi-level Poisson models with time-varying covariates. Setting National electronic cohort between September 2020 and May 2022 when several variants were predominant in the UK (Alpha, Delta and Omicron). Participants School students aged 4 to 10/11 years (primary school and younger middle school, n = 238,163), and 11 to 15/16 years (secondary school and older middle school, n = 182,775), school staff in Wales ( n = 47,963) and the household members of students and staff ( n = 697,659). Main outcome measures SARS-CoV-2 infection and COVID-19 vaccination uptake. Results School students had a sustained period of high infection rates compared with household members after August 2021. Primary schedule vaccination uptake was highest among staff (96.3%) but lower for household members (72.2%), secondary and older middle school students (59.8%), and primary and younger middle school students (3.3%). Multi-level Poisson models showed that vaccination was associated with a lower risk of SARS-CoV-2 infection. The Delta variant posed a greater infection risk for students than the Alpha variant. However, Omicron was a larger risk for staff and household members. Conclusions Public health bodies should be informed of the protection COVID-19 vaccines afford, with more research being required for younger populations. Furthermore, schools require additional support in managing new, highly transmissible variants. Further research should examine the mechanisms between child deprivation and SARS-CoV-2 infection.