AbstractBackgroundWe estimated combined protection conferred by prior SARS‐CoV‐2 infection and COVID‐19 vaccination against COVID‐19‐associated acute respiratory illness (ARI).MethodsDuring SARS‐CoV‐2 Delta (B.1.617.2) and Omicron (B.1.1.529) variant circulation between October 2021 and April 2022, prospectively enrolled adult patients with outpatient ARI had respiratory and filter paper blood specimens collected for SARS‐CoV‐2 molecular testing and serology. Dried blood spots were tested for immunoglobulin‐G antibodies against SARS‐CoV‐2 nucleocapsid (NP) and spike protein receptor binding domain antigen using a validated multiplex bead assay. Evidence of prior SARS‐CoV‐2 infection also included documented or self‐reported laboratory‐confirmed COVID‐19. We used documented COVID‐19 vaccination status to estimate vaccine effectiveness (VE) by multivariable logistic regression by prior infection status.ResultsFour hundred fifty‐five (29%) of 1577 participants tested positive for SARS‐CoV‐2 infection at enrollment; 209 (46%) case‐patients and 637 (57%) test‐negative patients were NP seropositive, had documented previous laboratory‐confirmed COVID‐19, or self‐reported prior infection. Among previously uninfected patients, three‐dose VE was 97% (95% confidence interval [CI], 60%–99%) against Delta, but not statistically significant against Omicron. Among previously infected patients, three‐dose VE was 57% (CI, 20%–76%) against Omicron; VE against Delta could not be estimated.ConclusionsThree mRNA COVID‐19 vaccine doses provided additional protection against SARS‐CoV‐2 Omicron variant‐associated illness among previously infected participants.