SARS-CoV-2 transmission in Western Australia, Australia, was negligible until a wave of Omicron variant infections emerged in February 2022, when >90% of adults had been vaccinated. This unique pandemic experience enabled assessment of SARS-CoV-2 vaccine effectiveness (VE) without potential interference from background immunity from prior infection. We matched 188,950 persons who had a positive PCR test result during February–May 2022 to negative controls by age, week of test, and other possible confounders. Overall, 3-dose VE was 42.0% against infection and 81.7% against hospitalization or death. A primary series of 2 viral-vectored vaccines followed by an mRNA booster provided significantly longer protection against infection >60 days after vaccination than a 3-dose series of mRNA vaccine. In a population free from non–vaccine-derived background immunity, vaccines against the ancestral spike protein were ≈80% effective for preventing serious outcomes from infection with the SARS-CoV-2 Omicron variant.