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

ABSTRACT 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.