XBB.1.5 monovalent vaccine induces lasting cross-reactive responses to SARS-CoV-2 variants such as HV.1 and JN.1, as well as SARS-CoV-1, but elicits limited XBB.1.5 specific antibodies.

The evolution of the antibody response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is impacted by the nature and number of antigenic exposures. First-generation coronavirus disease 2019 (COVID-19) vaccines encoded an ancestral spike protein. Updated bivalent vaccines and breakthrough infections have shaped the intricate diversity of the polyclonal antibody response and specificity of individual antibody clones. We and others previously showed that bivalent vaccines containing the ancestral and Omicron (BA.5) spikes induce high levels of cross-reactive antibodies but undetectable BA.5-specific antibodies in serum. Here, we assessed sera collected before as well as 1 and 3 months following administration of an updated XBB.1.5 monovalent vaccine to individuals with diverse infection and vaccination histories. Vaccination increased neutralization against recent variants of concern, including HV.1, JN.1, and the vaccine-homologous XBB.1.5. Antibody binding and avidity against ancestral and XBB.1.5 antigens significantly increased after vaccination. However, antibody depletion experiments showed that most of the response was cross-reactive to the ancestral spike, and only low levels of XBB.1.5-specific antibodies to the spike or the receptor-binding domain were detected. Importantly, increased antibody levels were still detectable in circulation 3 months post-vaccination and cross-reacted with severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) as measured by pseudovirus neutralization and binding assays. Overall, our data suggest that the XBB.1.5 monovalent vaccine predominantly elicits a cross-reactive response imprinted by viral spike antigens encountered early during the pandemic.IMPORTANCEUpdated COVID-19 vaccine formulations and SARS-CoV-2 exposure history affect the antibody response to SARS-CoV-2. High titers of antibodies are induced in serum by XBB.1.5 monovalent vaccination. Antibody depletion experiments reveal that the majority of the antibody response is cross-reactive to the ancestral spike, despite vaccination increasing neutralization against recently circulating Omicron variants. Vaccine-induced SARS-CoV-2 antibodies cross-react with SARS-CoV-1 and remain in the bloodstream for at least 3 months after immunization.