Leveraged Vaccination to Alleviate Original Antigenic Sin for Enhancing Broad-Neutralizing Antibody Response against SARS-CoV-2 Omicron Subvariants.

Publication date: Jul 01, 2025

Original antigenic sin (OAS), or immune imprinting, triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ancestral (WT) strain vaccine, or infection, has led to weakened neutralizing antibody response against Omicron variant like BA. 2 and subvariant like XBB. This calls for the development of an innovative booster vaccine, or vaccination strategy, that will eliminate, or attenuate, OAS, thus, enhancing broad-neutralizing antibody (bnAb) response. Accordingly, we herein proposed a leveraged vaccination strategy to counter the OAS effect by controlling the antigenic distance of booster vaccine and increasing boost vaccination frequency. We found that prime with WT-RBD and boost with XBB-RBD resulted in significantly higher bnAb response against most Omicron subvariants tested than that after prime with WT-RBD and boost with BA. 2-RBD because the antigenic distance between WT-RBD and XBB-RBD is much longer than that between WT-RBD and BA. 2-RBD. An additional boost with XBB-RBD further enhanced bnAb response. These findings indicate that a leveraged vaccination approach based on antigenic distance could be effective in reducing OAS, thereby strengthening bnAb response against SARS-CoV-2 Omicron subvariants. As such, this vaccination strategy could be just as effective in combating other fast-evolving RNA viruses known for their high transmissibility and infectivity.

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