Imprinting-Like Serological Signatures in Human Adenovirus Infections Revealed by Cross-Adsorption Neutralization Profiling of HAdV-3, HAdV-5, and HAdV-7.

Human adenoviruses (HAdVs) are characterized by extensive type diversity and widespread preexisting immunity, yet whether natural HAdV infection induces immune imprinting, the tendency of the immune system to preferentially recall responses to the first encountered antigenic variant, remains unclear. In this cross-sectional study of 1150 adults, neutralizing antibody (NT50) profiles against HAdV-3, -5, and -7 were determined, and multi-positive sera were analyzed by cross-adsorption neutralization and the cross-antibody contribution index (CACI). Seroprevalences were 69.8% (HAdV-3), 63.0% (HAdV-5), and 51.9% (HAdV-7); multi-positive sera accounted for 64% and increased with age. Cross-adsorption revealed asymmetric heterotypic neutralization: HAdV-3 adsorption markedly reduced anti-HAdV-7 activity in HAdV-3-dominant sera, whereas HAdV-7 adsorption produced only a mild effect on anti-HAdV-3 activity; cross-neutralization involving HAdV-5 was minimal. The median CACI for HAdV-3 to HAdV-7 was 0.81, compared with 0.22 for HAdV-7 to HAdV-3 and 0.04 for cross-species B-C comparisons. Imprinting-like signatures were most frequent in HAdV-3-dominant sera (85%) and increased with age. These findings provide functional serological evidence for directional, type-dependent imprinting-like responses in HAdV infection and underscore the need to assess antibody quality and immune history, beyond neutralizing titers alone, in the design of adenoviral vector-based interventions.