Noroviruses (NoVs) are the predominant cause of acute gastroenteritis (AGE) outbreaks worldwide, posing a substantial public health and economic burden. Globally, NoVs account for an estimated 699 million infections and over 200,000 deaths annually, with genogroup II (GII) strains responsible for the majority of these cases and pandemics (Liu et al., 2025; Lucero et al., 2021). Despite their predominance, critical gaps remain in understanding the serological features of herd immunity, particularly the persistence of functionally neutralizing antibodies and its implications for vaccine design against GII NoVs.

NoVs are classified into 10 genogroups (GI-GX), with GI, GII, and GIV primarily infecting humans (Hardy, 2005). Among these, GII NoVs, especially the GII.4 genotype, have dominated global outbreaks for decades, evolving through antigenic drift and shift to evade population immunity (Barclay et al., 2025; Zhang et al., 2024). Recent years have witnessed the emergence and global spread of non-GII.4 strains, including a significant GII.17 surge across Asia during 2014–2016 (De Graaf et al., 2015). The 2023/24 season marked a global resurgence of GII.17, with prevalence rising to 17–64% of GII detections in six European countries and the US. Therefore, our prospective cohort from 2014–2018 uniquely captured the precise serological footprint of this major epidemiological shift, providing an invaluable dataset to study the immune response to an emerging variant in real-time. While GII.4 declined, most strains clustered with Romania-2021 lineage, indicating a shift from the prior eight years of GII.4 Sydney[P16] dominance (Chhabra et al., 2024). Concurrently, GII.6 has been frequently identified as a major cause of AGE outbreaks in various countries, establishing itself as the second most common strain in young children (Parra et al., 2017). This continuous genetic diversification complicates prevention strategies and underscores the critical need for genotype-specific seroepidemiological data to inform surveillance and vaccine development.

Susceptibility to many NoVs is mediated by human histo-blood group antigens (HBGAs), which function as receptors or co-receptors, with infection risk influenced by polymorphisms in ABO, Lewis, and secretor status phenotypes (Nordgren and Svensson, 2019). While prior studies, including our longitudinal serosurveillance of GI NoVs, have elucidated HBGA-associated susceptibility and antibody dynamics for GI strains (Yu et al., 2023), similar insights for GII NoVs remain fragmented. For instance, GII.4 exhibits broad HBGA binding (Ayyar et al., 2025), whereas GII.17 and GII.6 demonstrate more distinct, strain-specific binding patterns (Huo et al., 2022; Zhang et al., 2015). These interactions directly impact population transmission patterns and are crucial for predicting vaccine efficacy, necessitating community-based studies to refine susceptibility profiles for predominant GII genotypes.

Serological surveillance is pivotal for capturing both symptomatic and asymptomatic infections, which are often substantially underestimated in stool-based studies (Thorne et al., 2018). Assays detecting blockade antibodies, which inhibit the binding of NoV viral-like particles (VLPs) or P proteins to HBGAs, serve as functional correlates of protective immunity. These antibodies are conformation- and genotype-dependent, offering superior specificity compared to cross-reactive IgG-based assays (Lindesmith et al., 2015; Yu et al., 2023). However, analogous longitudinal data for GII NoVs are critically scarce. The longevity of these functionally relevant blockade antibodies—a paramount factor for informing vaccination strategies and dosing intervals—remains largely unknown and represents a significant impediment to vaccine development. Our recent study on GI NoVs demonstrated genotype-dependent antibody persistence, with durations ranging from 2.3 to 4.8 years (Yu et al., 2023). This raises a pivotal question: does the dominant GII genogroup, with its distinct epidemiology, follow a similar pattern of waning immunity, or does it elicit a more robust and sustained antibody response? To address these gaps, we conducted a 5-year prospective cohort study in the Jidong community, China, to investigate the seroprevalence, seroincidence, and antibody persistence against the major GII NoVs genotypes GII.4, GII.6, and GII.17. We further analyzed HBGA-associated susceptibility patterns and antibody dynamics to provide a evidence base for vaccination strategies. This study directly complements our prior work on GI NoVs (Yu et al., 2023), providing a comprehensive serological framework for understanding GII NoV immunity and its persistence in a natural population.

The most significant finding of this 5-year community-based longitudinal study is the exceptional persistence of blockade antibodies against GII.4 and GII.17 NoVs, which stands in direct and stark contrast to the significant antibody decay we previously observed for GI NoVs in the same cohort (Yu et al., 2023). This genogroup-specific disparity in immune memory is a pivotal discovery, suggesting fundamental differences in the nature of immunity across genogroups, with profound implications for vaccine development and surveillance strategies.

The high, stable seroprevalence of GII.4 (77.3-79.7%) reflects its persistent community circulation and enduring dominance as the primary driver of global pandemics (Barclay et al., 2025; Van Beek et al., 2018; Wei et al., 2021). In contrast, GII.17 seroprevalence rose sharply from 41.9% to 72.2% between 2014 and 2018, capturing the serological footprint of its emergence as a major epidemic variant across Asia during this period (Chan et al., 2015; Fu et al., 2015; Matsushima et al., 2015). The seroincidence rates further underscore a substantial burden of infection, particularly for GII.17 (30.38 per 100 person-years), greatly exceeding estimates from stool-based surveillance (Chhabra et al., 2024; Gomes et al., 2025). This discrepancy highlights the significant proportion of asymptomatic or unreported infections detectable only through longitudinal serological studies, confirming the true burden of GII NoV infection is markedly underestimated.

Most strikingly, antibody kinetics differed dramatically between genogroups. In our prior study, GI antibodies exhibited significant decay, with estimated durations of 2.3 to 4.8 years and annual decay rates ranging from -3.6% to -5.9% (Yu et al., 2023). In direct contrast, naturally acquired GII antibodies, particularly against GII.4 and GII.17, were maintained without significant decay over the same five-year period in the same cohort.

The vast majority of GII.4-positive individuals (94.5%) maintained seropositivity over five years, with no significant decline in blockade activity. Similarly, 81.5% of GII.17-positive individuals remained seropositive. This sustained antibody response suggests that natural infection with these GII genotypes is associated with a more sustained humoral immune response compared to GI infections. We hypothesize that the sustained antibody levels could be driven by fundamental differences in immunodominant epitopes that confer greater stability to the humoral response, or by more frequent subclinical re-exposure to continually circulating GII.4 and emergent GII.17 variants, providing natural boosting.

The significantly lower persistence rate and the anomalously high seroreversion observed for GII.6 in 2016 present a intriguing contrast to the stability of GII.4 and GII.17 antibodies. This may indicate a fundamentally different, perhaps less robust, immune response elicited by natural GII.6 infection compared to GII.4 and GII.17 (Kakakhel et al., 2022; Parra et al., 2017). This genotype-specific disparity warrants further investigation through concurrent genetic sequencing of circulating strains to directly link antigenic variation with serological outcomes.

HBGA phenotypes again confirmed their role as critical determinants of host susceptibility, but with patterns distinct from those we observed for GI NoVs. For GII.4 and GII.6, secretor status and specific Lewis phenotypes (Le^b+/Le^y+ and Le^a+b+/Le^x+y+) were strongly associated with infection risk, consistent with their broad HBGA binding profiles (Dai et al., 2015; Zhang et al., 2020). Notably, individuals with the O^- phenotype were significantly protected against GII.4, a finding that aligns with earlier reports but differs from the susceptibility of O⁺ individuals we observed for GI.2 and GI.3 (Yu et al., 2023). For GII.17, blood type A was the primary susceptibility factor, which correlates with its known binding preference for A and B antigens (Tarris et al., 2022; Zhang et al., 2015). This is a simpler susceptibility profile compared to the multi-faceted HBGA associations seen with GI and other GII types. These divergent HBGA binding patterns between GI and GII genotypes underscore the necessity for broadly protective, multivalent vaccines that can overcome the complex host genetic restrictions to infection.

The epidemiological patterns also revealed genotype-specific and genogroup-specific differences. The higher seroprevalence and seroincidence of GII.4 in females suggest potential gender-based differences in exposure or immune response, a trend not observed in our GI study. Furthermore, the increased risk associated with non-Han ethnicity and lower income for GII.6 points to potential socioeconomic and cultural disparities in exposure, factors that should be considered in targeted public health interventions. The observed sociodemographic associations likely reflect complex interactions between genotype-specific transmission patterns, host behavior, and immune history. For instance, the higher GII.4 seroprevalence and seroincidence in females may be related to caregiving roles or occupational exposure, a hypothesis that warrants future study. The increased GII.6 risk associated with non-Han ethnicity and lower income may point to socioeconomic disparities in living conditions, access to sanitation, or dietary practices influencing exposure. The lack of a uniform pattern across genotypes underscores the distinct epidemiology of each strain and highlights the need for multifactorial models in understanding NoV transmission dynamics.

Our findings on the sustained persistence of GII.4 and GII.17 blockade antibodies align with and significantly extend a growing body of evidence on the robustness of GII immune responses. A recent multi-year study also reported remarkably stable blockade antibody titers against historical and contemporary GII.4 variants, suggesting a long-lasting immune imprinting effect from repeated exposures (Lindesmith et al., 2022; Su et al., 2023). Furthermore, the strong association between secretor status and susceptibility to GII.4 and GII.6 infection that we observed has been consistently demonstrated in both outbreak investigations and challenge studies, reinforcing the critical role of HBGAs as a genetic determinant of risk (Dai et al., 2017; Zhang et al., 2020). Our longitudinal community-based data provide a crucial nuance: while HBGA phenotype dictates initial susceptibility, infection can elicit a functional antibody response that is sustained for years. This is particularly relevant for GII.17: while our finding that susceptibility is conferred primarily by blood type A aligns with its known restricted binding profile (Chhabra et al., 2024; Jing et al., 2025), the observation that infection elicits sustained functional immunity provides a novel, key insight for predicting population immunity against this re-emerging genotype. Collectively, these recent studies, combined with our longitudinal evidence, paint a picture of GII NoVs as pathogens that, despite their diversity, can induce potent and lasting functional immunity upon infection, a cornerstone consideration for designing vaccines that aim to mimic natural immunity.

While the samples for this study were collected between 2014 and 2018, the fundamental immunological insights we provide are timeless and critically address a core question in the field. The recent global resurgence of GII.17 in the 2023/24 season (Chhabra et al., 2024; Barclay and Vinjé, 2025) underscores the persistent threat posed by this genotype and validates the importance of understanding the immune response it elicits. Our data, captured during its initial emergence, provide the first longitudinal evidence that infection with this re-emerging variant induces durable, long-lasting functional antibodies. This finding is crucial for predicting population susceptibility and immunity against current and future GII.17 waves. Similarly, the sustained circulation and evolution of GII.4 variants necessitates a deep understanding of the long-term immune response they elicit, which our study definitively shows is robust and persistent. Thus, rather than diminishing its relevance, the specific timeframe of our cohort uniquely allowed us to capture the natural history of an emerging variant and establish a foundational principle of GII antibody durability that is directly applicable to the current NoV landscape.

This study has several limitations. The exclusion of children under 18 limits insights into a highly vulnerable population. The focus on a single community in Northern China necessitates caution in generalizing the findings to other regions with different demographic and genetic backgrounds. Furthermore, as a community-based study in an area of endemic NoV circulation, we cannot definitively determine whether the sustained antibody levels observed, particularly for GII.4, are due to a single infection eliciting a intrinsically long-lived response or to repeated re-infection providing natural boosting. Our data demonstrate the functional maintenance of antibodies over five years but do not delineate the underlying mechanism. Future studies incorporating frequent sampling and molecular surveillance to link re-exposure events with antibody kinetics would be valuable.

In conclusion, this study not only documents the high community burden of GII NoVs but fundamentally advances our understanding of NoVs immunity by demonstrating a clear genogroup-specific disparity in antibody persistence. The exceptional durability of GII.4 and GII.17 blockade antibodies provides a mechanistic basis for the long-term immune imprinting observed in populations and strongly supports the feasibility of developing vaccines that elicit sustained protection. Future vaccine efforts must account for these fundamental differences in immune durability between GI and GII genogroups to achieve broad and long-lasting efficacy.