In this real-world cohort study based on Danish nationwide registers, the cumulated proportion, relative risk (RR) of SARS-CoV-2 breakthrough infections, and vaccine effectiveness (VE) were investigated in adolescents aged 12–18 years following vaccination with the BNT162b2 vaccine compared to unvaccinated controls. Adolescents with and without vaccination with the first dose of BNT162b2 between 1 May and 30 September 2021 were included. Effect estimates include proportions with a positive SARS-CoV-2 RT-PCR test among vaccinated and unvaccinated, RR, and VE at three different time points. During Delta-dominance, VE was first 97.6% (95% CI 96.3–98.4), then 96.2% (95% CI 95.4–96.9) in the age group 12–15 and 95.1% (95% CI 94.1–96.0) followed by 95.5% (95% CI 94.8–96.1) in the age group 16–18 years, respectively. During Omicron dominance, VE was 5.8% (95% CI 4.6–7.0) in ages 12–15 years and 9.2% (95% CI 7.7–10.6) in ages 16–18 years. Thus, BNT162b2-vaccine protection was limited during the Omicron era.