Sustained persistence of blockade antibodies against emerging GII.4 and GII.17 noroviruses revealed by a 5-year community-based serological study

Introduction: GII noroviruses (NoVs) are the leading cause of viral gastroenteritis worldwide. A critical unresolved question is whether natural infection elicits long-lasting protective antibodies, which is paramount for guiding vaccine development. The long-term persistence of functional neutralizing antibodies against the predominant GII genogroup remains poorly characterized. Methods: In a 5-year community-based prospective cohort (2014-2018), we longitudinally assessed seroprevalence, seroincidence, and persistence of blockade antibodies against GII.4, GII.6, and GII.17 NoVs in 449 adults. HBGA (human histo-blood group antigen) associations with susceptibility were also analyzed. Results: GII.4 exhibited the highest and most stable seroprevalence (77.3-79.7%), while GII.17 seroprevalence rose sharply from 41.9% to 72.2%, capturing its emergence as an epidemic strain. Seroincidence was substantial, highest for GII.17 (30.4 per 100 person-years). In contrast to GI NoVs, GII.4 and GII.17 antibody exhibited exceptional persistence, with five-year persistence rate of 94.5% for GII.4 and 81.4% for GII.17, respectively, and no significant decay in blockade activity-both significantly exceeding the 61.2% persistence of GII.6. HBGA susceptibility patterns were distinct: GII.4 and GII.6 were associated with secretor status and Lewis antigens, while only blood type A was linked to GII.17 susceptibility. Conclusion: This study provides the first longitudinal evidence that natural infection with major GII NoVs, particularly GII.4 and the emerging GII.17, elicits robust and sustained functional antibody responses that persist for at least five years. This fundamental genogroup-specific disparity in immune durability, contrasting sharply with transient GI immunity, reveals a new dimension of NoVs immunology and provides a critical evidence base for the design of effective, long-lasting vaccines.