To determine the association between rates of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection following home, community and work-related exposures, to assess real-world relative vaccine effectiveness, and to determine whether anti-receptor-binding domain (RBD) IgG levels were associated with the rates of subsequent infection.

Prospective cohort of 34 months’ duration (February 2021 to December 2023).

Teachers and education workers working ≥8 hours per week in the Canadian province of Ontario.

3155 education workers were eligible for the risk factor analysis; 2977 for the serological analysis.

Rate of SARS-CoV-2 infection.

1909 SARS-CoV-2 infections were reported (0.93 per 1000 participant-days); the highest incidence occurred during the period dominated by the Omicron BA.2 variant (2.01 per 1000 participant-days). Rates of infection were significantly higher following the repeal of the mask mandate. Compared with participants without known contact with an infected person, those in close contact with infected adult or child household members (adjusted HR (aHR) 1.43; 95% CI 1.24 to 1.65 and 1.39; 95% CI 1.17 to 1.65, respectively), coworkers (aHR 1.28; 95% CI 1.10 to 1.50), or individuals from more than one setting (aHR 1.44; 95% CI 1.27 to 1.64) had higher rates of infection. Participants with three or more doses of vaccine were 79%–87% less likely to develop SARS-CoV-2 than participants who had two or fewer vaccine doses. Blood samples with anti-RBD antibody levels in the highest quintile (≥5850 binding antibody unit/mL) were associated with a lower rate of subsequent infection (aHR 0.40; 95% CI 0.23 to 0.72) compared with samples with RBD levels below the threshold of detection.

Risk of SARS-CoV-2 infection in education workers occurred at home as well as the workplace, indicating the need to practise multiple intervention strategies whenever the potential for transmission of respiratory diseases is high. COVID-19 vaccines provided protection through December 2023.