Vaccination with the Omicron spike RBD boosts broadly neutralizing antibody levels and confers sustained protection even after acquiring immunity to the original antigen.

The immune evasion of SARS-CoV-2 Omicron variants caused by multiple amino acid replacements in the receptor-binding domain (RBD) of spike protein wanes the effectiveness of antibodies elicited by current SARS-CoV-2 booster vaccination. The vaccines that target Omicron strains have been recently developed, however, there has been a concern yet to be addressed regarding the negative aspect of the immune response known as original antigenic sin. Here we demonstrate that the breadth of neutralizing antibodies against SARS-CoV-2 variants is barely elicited by immunizing monovalent viral antigens via vaccination or natural infection in mice and human subjects. However, vaccination of Omicron BA.1 RBD to pre-immunized mice with the original RBD conferred sustained neutralizing activity to BA.1 and BA.2 not only original pseudoviruses. The acquisition of neutralizing antibody breadth was further confirmed in vaccinated-then-Omicron convalescent human sera in which neutralizing activity against BA.1 and BA.2 pseudoviruses was highly induced. Thus, our data suggest that Omicron-specific vaccines or the infection with Omicron viruses can boost potent neutralizing antibodies to the Omicron variants even in the host pre-vaccinated with the original antigen.