Publication date: Jul 03, 2025

The emergence of the Omicron variant in late 2021 gave rise to multiple descendent lineages, or sublineages, with progressively increased capacity for antibody evasion. Here we used live virus neutralization assays to quantify and compare homologous (“self”) and cross-neutralizing antibody titers in 170 COVID-19 patients infected with either the Delta variant or an Omicron sublineage (BA. 1, BA. 2, BA. 4/BA. 5, BQ. 1.1, and XBB. 1.5) and 25 uninfected controls who had received the BA. 5 bivalent booster vaccine. In control subjects, neutralizing antibody titers against BA. 5 and earlier sublineages were significantly higher than against the later BQ. 1.1 or XBB. 1.5 sublineages, and differences in antibody titers between immunocompetent and immunocompromised individuals were not significant. In patients infected with an Omicron sublineage, induced cross-neutralizing antibody responses were weaker and less durable against later compared to earlier sublineages. Self-neutralizing antibody titers against BQ. 1.1 or XBB. 1.5 in patients infected with these sublineages were also lower than cross-neutralizing titers against earlier sublineages. Our results suggest that immunological imprinting resulting from prior exposure to SARS-CoV-2 (“original antigenic sin”), whether via natural infection or vaccination, may have impaired neutralizing antibody responses to the later Omicron sublineages. The poorer elicited immunogenicity and increased capacity for antibody evasion of these sublineages explain in part their persistence and ongoing global circulation.

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