Abstract
Noroviruses are a major cause of acute gastroenteritis worldwide and are a genetically diverse group of viruses. Since 2002, an increasing number of norovirus outbreaks have been reported globally, but it is not clear whether this increase has been caused by a higher awareness or reflects the emergence of new genogroup II genotype 4 (GII.4) variants. The hypothesis that norovirus prevalence has increased post-2002 and is related to the emergence of GII.4 is tested in this study. Sera collected from children aged <5 years of three Dutch cross-sectional population based cohorts in 1963, 1983 and 2006/2007 (n=143, n=130 and n=376, respectively) were tested for specific serum IgG by protein array using antigens to GII.4 and a range of other antigens representing norovirus GI, GII and GIV genotypes. The protein array was validated by paired sera of norovirus infected patients and supernatants of B-cell cultures with single epitope specificity. Evidence for norovirus infection was found to be common among Dutch children in each cohort, but the prevalence towards different genotypes changed over time. At the genogroup level, GI seroprevalence decreased significantly between 1963 and 2006/2007, while a significant increase of GII and, in particular, specific antibodies of the genotype GII.4 was detected in the 2006/2007 cohort. There were no children with only GII.4 antibodies in the 1963 cohort. This study shows that the high GII.4 norovirus incidence in very young children is a recent phenomenon. These findings are of importance for vaccine development and trials that are currently focusing mostly on GII.4 viruses.
Highlights
Noroviruses belong to the family Caliciviridae and are a major cause of acute gastroenteritis in outbreaks and
To be able to measure the immune response to norovirus infection, ELISA assays based on virus-like particles (VLPs) produced through expression of the viral capsid protein (VP1) have been developed, but these assays cannot distinguish exposure to different genotypes due to high levels of cross-reactivity (Rockx et al, 2005)
Among antigens tested, GI.2 was predominant in 1963 and GII.9 was predominant in 1983. In this cross-sectional population study the norovirus seroprevalence was investigated among children
Summary
Noroviruses belong to the family Caliciviridae and are a major cause of acute gastroenteritis in outbreaks andOne supplementary table and two supplementary figures are available with the online Supplementary Material.sporadic cases for all age groups worldwide (Ahmed et al, 2014). As a surrogate for virus neutralization assays, assays have been developed to measure antibodies that block the binding of noroviruses to histo-blood group antigens (Harrington et al, 2002). These assays eliminate cross-reactivity observed in ELISA assays with VLPs, but are not suitable for population studies since they are difficult to standardize, timeconsuming and need large quantities of serum and VLPs. The VP1 consists of a conserved shell (S) domain and the more variable P domain that contains all immunogenic sites. Upon expression of the norovirus P domain P particles will be formed, which are very stable and immunologically relevant, but which contain less cross-reactive epitopes owing to the absence of the conserved S-domain, as evidenced from comparative immunization studies in mice, will be formed (Tamminen et al, 2012; Tan et al, 2004)
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