Potent type-specific de novo antibodies complement broadly reactive imprinted antibodies in immune responses to SARS-CoV-2 variants.

For rapidly mutating viruses such as influenza viruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), immune memory recalled by antigenically drifted variants primarily comprises antibodies that cross-react to the priming strain rather than de novo elicited responses, a phenomenon termed original antigenic sin or immune imprinting. The composition and functionality of de novo responses elicited by variant exposures remain unclear. Here we isolated and characterized hundreds of recall and de novo neutralizing monoclonal antibodies after sequential exposures to SARS-CoV-2 variants in ancestral-imprinted humans. De novo variant type-specific antibodies used different V(D)J genes that were closer to germline sequence, potently neutralized future variants and targeted distinct receptor binding domain epitopes compared to ancestral cross-reactive (recall) antibodies. Nevertheless, neutralizing responses to the updated 2024-2025 booster were predominantly ancestral cross-reactive. These results reveal the distinct contributions of recall and de novo antibodies to a balanced immune response and underscore the benefit of updated booster vaccines, which augment both subsets.