The purpose of this study was to evaluate whether the 2023-2024 formulation of the coronavirus disease 2019 (COVID-19) messenger RNA vaccine protects against COVID-19. Cleveland Clinic employees when the 2023-2024 formulation of the COVID-19 messenger RNA vaccine became available to employees were included. Cumulative incidence of COVID-19 over the following 17 weeks was examined prospectively. Protection provided by vaccination (analyzed as a time-dependent covariate) was evaluated using Cox proportional hazards regression, with time-dependent coefficients used to separate effects before and after the JN.1 lineage became dominant. The analysis was adjusted for the propensity to get tested, age, sex, pandemic phase when the last prior COVID-19 episode occurred, and the number of prior vaccine doses. Among 48 210 employees, COVID-19 occurred in 2462 (5.1%) during the 17 weeks of observation. In multivariable analysis, the 2023-2024 formula vaccinated state was associated with a significantly lower risk of COVID-19 before the JN.1 lineage became dominant (hazard ratio = .58; 95% confidence interval [CI] = .49-.68; P < .001), and lower risk but one that did not reach statistical significance after (hazard ratio = .81; 95% CI = .65-1.01; P = .06). Estimated vaccine effectiveness was 42% (95% CI = 32-51) before the JN.1 lineage became dominant, and 19% (95% CI = -1-35) after. Risk of COVID-19 was lower among those previously infected with an XBB or more recent lineage and increased with the number of vaccine doses previously received. The 2023-2024 formula COVID-19 vaccine given to working-aged adults afforded modest protection overall against COVID-19 before the JN.1 lineage became dominant, and less protection after.