Abstract Background Waning protection from 2 doses of coronavirus disease 2019 (COVID-19) vaccines led to third dose availability in multiple countries even before the emergence of the Omicron variant. Methods We used the test-negative study design to estimate vaccine effectiveness (VE) against any severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, any symptomatic infection, and severe outcomes (COVID-19-related hospitalizations or death) by time since second dose of any combination of BNT162b2, mRNA-1273, and ChAdOx1 between January 11, and November 21, 2021, for subgroups based on patient and vaccine characteristics. Results We included 261 360 test-positive cases (of any SARS-CoV-2 lineage) and 2 783 699 individuals as test-negative controls. VE of 2 mRNA vaccine doses decreased from 90% (95% CI, 90%–90%) 7–59 days after the second dose to 75% (95% CI, 72%–78%) after ≥240 days against infection, decreased from 94% (95% CI, 84%–95%) to 87% (95% CI, 85%–89%) against symptomatic infection, and remained stable (98% [95% CI, 97%–98%] to 98% [95% CI, 96%–99%]) against severe outcomes. Similar trends were seen with heterologous ChAdOx1 and mRNA vaccine schedules. VE estimates for dosing intervals <35 days were lower than for longer intervals (eg, VE of 2 mRNA vaccines against symptomatic infection at 120–179 days was 86% [95% CI, 85%–88%] for dosing intervals <35 days, 92% [95% CI, 91%–93%] for 35–55 days, and 91% [95% CI, 90%–92%] for ≥56 days), but when stratified by age group and subperiod, there were no differences between dosing intervals. Conclusions Before the emergence of Omicron, VE of any 2-dose primary series, including heterologous schedules and varying dosing intervals, decreased over time against any infection and symptomatic infection but remained high against severe outcomes.