Antibody Responses Against Coronaviruses in the Wuhan Population

Prolonged circulation of SARS-CoV-2 may broaden population-level neutralizing antibody responses to diverse coronaviruses; however, the extent of this breadth remains unclear. To address this gap, we assessed serum neutralizing activity in 869 individuals from Wuhan, China, including 78 pre-pandemic samples collected in 2017 and 791 post-pandemic samples obtained in 2025. Specifically, using pseudovirus neutralization assays, sera were tested against a panel of coronaviruses, including circulating SARS-CoV-2 Omicron subvariants XFG and NB.1.8.1. Neutralization was measured at a fixed dilution for all samples and by determination of 50% inhibitory dilution (ID50) for selected sera. In parallel, antigenic cartography and genetic distance analyses were applied to relate functional antigenic relationships to spike protein divergence. Our results showed that, compared with pre-pandemic sera, post-pandemic sera exhibited enhanced neutralizing activity against multiple sarbecoviruses and the merbecovirus MjHKU4r-CoV-1, with mean inhibition increases ranging from 1.7% to 76.5% at a 1:20 dilution. Notably, the largest increases from 51.8% to 76.5% were observed against clade 1b sarbecoviruses. In contrast, neutralizing activity against human alphacoronaviruses and MERS-CoV showed no meaningful enhancement. Moreover, neutralizing titers in post-pandemic sera were strongly correlated across sarbecoviruses, particularly among clade 1b viruses. Antigenic mapping further revealed that several zoonotic sarbecoviruses were antigenically closer to ancestral SARS-CoV-2 than contemporary Omicron subvariants, despite substantially greater genetic divergence. Taken together, these findings demonstrate that cumulative SARS-CoV-2 exposure promotes broadly cross-neutralizing antibody responses within the sarbecovirus subgenus and provide a quantitative framework to inform the rational design of pan-sarbecovirus vaccines and antibody-based countermeasures for future coronavirus preparedness.