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Randomized clinical trials comparing the breadth and long-term persistence of immunity between different COVID-19 vaccine types and between ancestral and Omicron-targeted vaccines are limited. The PRIBIVAC study (Phase D) is a randomized clinical trial comparing the immunogenicity of monovalent mRNA vs bivalent mRNA vs protein-based NVX-CoV2373 administered as second booster in 176 triple mRNA-vaccinated adults. Primary objective was neutralizing antibody levels against Omicron subvariants at day 28. A 4th vaccine dose significantly boosted 50% neutralization titers against emerging strain XBB.1.16 by 3.2-, 4.1- and 1.6-fold in monovalent mRNA, bivalent mRNA and NVX-CoV2373 group respectively at day 28. The largest absolute increase in inhibition level at day 28 post-booster was observed against the KP.2 subvariant, with bivalent mRNA vaccines exhibiting the highest neutralization level (91.7%) compared with monovalent mRNA (84.4%; p = .027) and NVX-CoV2373 (81.4%; p < .0001). While bivalent mRNA vaccines elicited the highest early immunogenicity, neutralization levels against all Omicron variants tested waned to similar levels between groups by 12 months post-vaccination. Although NVX-CoV2373 induced a lower peak anti-S antibody response, anti-S decay rate was slower in NVX-CoV2373 compared with mRNA vaccines. The geometric mean anti-S fold change (D360/D28) in NVX-CoV2373 group was higher (0.51) relative to both mRNA vaccines (monovalent: 0.31, p = .010 and bivalent: 0.35, p = .017). Improved neutralizing antibody responses against diverse SARS-CoV-2 variants by the ancestral or variant vaccine highlight the immunological benefits of COVID-19 vaccine boosters regardless of the latest variant-based vaccine. Further studies to determine if different vaccine combinations translate to differing protection against infection remain necessary.