Immune responses after two inactivated COVID-19 vaccine doses, a heterologous third dose and subsequent boosting with bivalent mRNA in adults

To evaluate immune response and safety of a bivalent mRNA booster (ancestral/BA.4/5) vaccine in individuals who had received inactivated COVID-19 vaccine with different heterologous boost regimens. A prospective open-label study of bivalent ancestral/Omicron BA.4/5 was conducted. Healthy participants (age > 18) who completed two doses of inactivated COVID-19 vaccine and received any of these booster vaccines (Ad26.COV2.S, ChAdOx1, or mRNA-based) at least 12 months prior were enrolled. Immunogenicity data (anti-Spike (S) IgG, neutralization antibody titer (NT₅₀) against ancestral and XBB.1.5, and S-specific IFN-γ T- cells) was obtained at baseline, Day 28±7, and Day 90±14. Of 190 participants enrolled; 57 received Ad26.COV2.S, 66 received ChAdOx1, and 67 received mRNA vaccine as the third dose, respectively. Following bivalent mRNA vaccination, anti-S IgG rose at Day 28, and declined at Day 90. In contrast, the NT₅₀ titers against ancestral peaked at Day90. The NT₅₀ against XBB.1.5 peaked at Day 28 with the highest fold rise in the mRNA vaccine subgroup (29.16 [19.55-43.49]), followed by the ChAdOx1 (20.94 [14.18-30.92]), and the Ad26.COV2.S subgroups (13.04 [8.61-19.74]). Geometric concentration of T-cells producing IFN-γ rose comparably in all three subgroups. Bivalent mRNA ancestral/BA.4/5 vaccine enhanced humoral immunity against both ancestral and Omicron XBB1.5, and T-cell immunity in inactivated COVID-19 vaccine primed with different heterologous boost participants. The study was registered at WHO platform: Thai Clinical Trial Registry (TCTR20230811004).