Periodically updating coronavirus disease 19 (COVID-19) vaccines that offer broad-spectrum protection is needed given the strong immune evasion by the circulating omicron sublineages. The effectiveness of prototype and BA.4/5-containing bivalent mRNA vaccines is reduced when XBB subvariants predominate. We initiated an observer-blinded, three-arms study in 376 patients in Chinese individuals aged from 18 to 55 years old who had previously received three doses COVID-19 vaccine. Immunogenicity in terms of neutralizing antibodies elicited by a 30-μg dose of XBB.1.5-containing bivalent vaccine (RQ3027), a 30-μg dose of BA.2/BA.5-Alpha/Beta bivalent vaccine (RQ3025) and their precedent 30-μg Alpha/Beta (combined mutations) monovalent mRNA vaccine (RQ3013) and safety are primary and secondary endpoints, respectively. We recorded prescribed COVID-19 cases to explore the preliminary efficacy of three vaccines. RQ3027 and RQ3025 boosters elicited superior neutralizing antibodies (NAbs) against XBB.1.5, XBB.1.16, XBB.1.9.1, and JN.1 compared to RQ3013 at day 14 in participants without SARS-CoV-2 infection. All study vaccines were well-tolerated without serious adverse reactions identified. The incidence rates per 1000 person-years of COVID-19 cases during the 2nd-19th week after randomization were lowest in RQ3027. Overall, our data show that XBB.1.5-containing bivalent booster generated superior immunogenicity and better protection against newer severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants compared to BA.2/BA.5-containing bivalent and Alpha/Beta monovalent with no new safety concerns.