Distinct features of SARS-CoV-2 humoral immunity against Omicron breakthrough infection

Background: SARS-CoV-2 Omicron breakthrough infection (Omicron-BTI) after vaccination has been frequently observed. A more detailed understanding of the humoral immunity against Omicron-BTI is required.Methods: We measured strain-specific live-virus based neutralizing activity, anti-spike IgG, and anti-receptorbinding domain (RBD) IgG titers in individuals with Omicron/BA.1-BTI and directly compared them with controls with diverse combinations of wild-type (WT) mRNA vaccination and infection history. Results: Omicron-BTI individuals showed markedly higher neutralizing titers against all the WT, Delta, and Omicron strains in convalescent sera, compared with unvaccinated Omicron-infection individuals with only Omicron neutralizing activity. Similar tendencies were found in strain-specific anti-spike and anti-RBD IgG titers. The Omicron-specificity (BA.1/WT neutralizing ratio), Omicron-neutralizing efficiency per antibody unit, and anti-Omicron RBD-directivity of anti-spike antibodies in Omicron-BTI individuals were all significantly lower than those in unvaccinated Omicron-infection individuals, but they were equivalent to or higher than those in uninfected vaccinees. The induction of Omicron-specific neutralizing activity after Omicron-BTI was not weakened for eight months from the last vaccination.Conclusions: These findings suggest that cross-reactive vaccine-induced immunity was intensively stimulated following Omicron breakthrough infection, which contributed to Omicron neutralization. Measuring SARS-CoV2 variant-specific antibody levels as well as neutralizing activity is useful for evaluating humoral immunity after breakthrough infection in the current situation of antigenic gaps between vaccinated and epidemic (Omicron sub-lineages) strains.