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• Booster vaccinations are necessary to protect against emerging SARS-CoV-2 variants. • We tested three vaccine platforms, mRNA, adenovirus-vector and recombinant protein. • Using different vaccine platforms did not affect booster safety or immunogenicity. • All three vaccines increased immunity against Omicron BF.7, BQ.1.1.3, and XBB.1.5.6. • Fold-increases were similar for ancestor and Omicron variants within a platform. The COVID-19 pandemic is over but the highly immunized or naturally exposed global population still requires booster vaccinations against newly emerging SARS-CoV-2 variants. We assessed safety and immunogenicity of booster doses of COVID-19 vaccines based on three different platforms in a setting that mimics the current routine practice in Brazil. In this phase 3 study from 14 February 2023 to 12 June 2023 we enrolled previously immunized adults to receive an additional booster dose of one of three vaccines. Immunogenicity against ancestor SARS-CoV-2 and Omicron BF.7, BQ.1.1.3, and XBB.1.5.6 sub-lineages was measured as ELISA IgG or virus neutralizing (VNT) antibodies and safety/reactogenicity assessed using diary cards. Volunteers with a history of full primary COVID-19 immunization striated to three cohorts according to their previous booster vaccination history—0 (n = 26), 1 (n = 140) or 2 (n = 606) booster vaccinations—were randomized 2:1:1 to receive either recombinant protein (SCB-2019, Clover), adenovirus-vector (ChAdOx1-S, AstraZeneca/Fiocruz), or mRNA (BNT162b2, Pfizer/Wyeth). Baseline antibody titers were higher in individuals who had received one or two boosters and titers against both ancestor and Omicron sub-lineages increased in all groups regardless of the number of previous booster doses or the vaccine used. Day 28 geometric mean titers (GMTs) and geometric mean-fold rises (GMFR) against all variants were higher after BNT162b than SCB-2019 or ChAdOx1-S, but BNT162b groups displayed more rapid antibody waning at Day 84. Within cohorts each vaccine elicited similar GMFR against the different SARS-CoV-2 strains. All vaccines were well tolerated with similar solicited reactogenicity profiles. Protein, adenovirus-vector or mRNA vaccine boosters were equally well tolerated and immunogenic against ancestor SARS-CoV-2 and Omicron sub-lineages in fully primed adults with 0–2 prior boosters. BNT162b induced the highest immune responses but also the most rapid waning of antibodies 3 months after vaccination. Clinical Trial Registration: ClinicalTrials.gov , identifier NCT05812586. [ABSTRACT FROM AUTHOR]