biostudies-literatureTubiana JNIAID NIH HHSNHLBI NIH HHSNIGMS NIH HHS111512https://www.ebi.ac.uk/biostudies/studies/S-EPMC9515332biostudies-literatureUnknown41(3)The SARS-CoV-2 Omicron variant evades most neutralizing vaccine-induced antibodies and is associated with lower antibody titers upon breakthrough infections than previous variants. However, the mechanism remains unclear. Here, we find using a geometric deep-learning model that Omicron's extensively mutated receptor binding site (RBS) features reduced antigenicity compared with previous variants. Mice immunization experiments with different recombinant receptor binding domain (RBD) variants confirm that the serological response to Omicron is drastically attenuated and less potent. Analyses of serum cross-reactivity and competitive ELISA reveal a reduction in antibody response across both variable and conserved RBD epitopes. Computational modeling confirms that the RBS has a potential for fuCell reportsReduced B cell antigenicity of Omicron lowers host serologic response.PMC9515332R01 AI163011R01 HL137709R35 GM137905Tubiana JChen KFan LXiang YWolfson HJSchneidman-Duhovny DShi YfalseReduced B cell antigenicity of Omicron lowers host serologic response.The SARS-CoV-2 Omicron variant evades most neutralizing vaccine-induced antibodies and is associated with lower antibody titers upon breakthrough infections than previous variants. However, the mechanism remains unclear. Here, we find using a geometric deep-learning model that Omicron's extensively mutated receptor binding site (RBS) features reduced antigenicity compared with previous variants. Mice immunization experiments with different recombinant receptor binding domain (RBD) variants confirm that the serological response to Omicron is drastically attenuated and less potent. Analyses of serum cross-reactivity and competitive ELISA reveal a reduction in antibody response across both variable and conserved RBD epitopes. Computational modeling confirms that the RBS has a potential for fu2022-01-01T00:00:00Z2022 Oct2026-05-10T05:14:33.82Z2024-12-04T01:39:02.152ZS-EPMC95153323622377410.1016/j.celrep.2022.111512