A randomized, double-blind, controlled phase 3 trial was conducted during a COVID-19 outbreak after the initial, stringent zero-Covid policy was relaxed in three provinces. Eligible adults aged ≥18 years who had received three doses of inactivated COVID-19 vaccines 6 months earlier were randomly assigned in a 1:1 ratio to receive either one intramuscular injection of RQ3013 or ZF2001 vaccine. The primary end point was protection against PCR-confirmed symptomatic SARS-CoV-2 infection with onset at least 7 days after the booster. A total of 3,167 and 3,169 eligible participants received one dose of RQ3013 or ZF2001 vaccine, respectively. COVID-19 illness was confirmed in 91 participants in the ZF2001 group (11.8 per 100 person years; 95% confidence interval [CI]: 9.6-14.6) and in 45 participants in the RQ3013 group (5.7 per 100 person-years; 95% CI: 4.3-7.7) during a 4-month follow-up, resulting in a relative efficacy of 51.7% (95% CI, 30.9-66.2%) (p < .001) in an intention-to-treat analysis. The RQ3013 vaccine was also found to be significantly more immunogenic against omicron BA.5 compared to the ZF2001 vaccine. Moderate, transient adverse reaction after vaccination occurred more frequently in the RQ3013 group than in the ZF2001 group. Serious adverse events (SAEs) were rare and occurred almost equally in two groups. All SAEs were not related to the vaccination. These findings suggest that a chimeric mRNA vaccine design involving multiple antigenic epitopes provides broader protection across subvariants and variants of SARS-CoV-2 than the subunit vaccine ZF2001.