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. 2009 Jun;83(11):5363-74.
doi: 10.1128/JVI.02518-08. Epub 2009 Mar 18.

Herd immunity to GII.4 noroviruses is supported by outbreak patient sera

Jennifer L Cannon  1 , Lisa C Lindesmith, Eric F Donaldson, Lauryn Saxe, Ralph S Baric, Jan Vinjé
Affiliations

Herd immunity to GII.4 noroviruses is supported by outbreak patient sera

Jennifer L Cannon et al. J Virol. 2009 Jun.

Abstract

Noroviruses (NoVs) of genogroup II, cluster 4 (GII.4), are the most common cause of outbreaks of acute gastroenteritis worldwide. During the past 13 years, GII.4 NoVs caused four seasons of widespread activity globally, each associated with the emergence of a new strain. In this report, we characterized the most recent epidemic strain, GII.4-2006 Minerva, by comparing virus-like particle (VLP) antigenic relationships and histo-blood group antigen (HBGA) binding profiles with strains isolated earlier. We also investigated the seroprevalence and specificity of GII.4 antibody in the years prior to, during, and following the GII.4 pandemic of 1995 and 1996 using a large collection of acute- and convalescent-phase serum pairs (n = 298) collected from 34 outbreaks. In a surrogate neutralization assay, we measured the blockade of HBGA binding using a panel of GII.4 VLPs representing strains isolated in 1987, 1997, 2002, and 2006 and a GII.3 VLP representing a strain isolated in the mid-1990s. Serum titers required for 50% HBGA blockade were compared between populations. In general, blockade of GII.4 VLP-HBGA binding was greater with convalescent-phase outbreak sera collected near the time of origin of the VLP strain. Heterotypic genotypes did not contribute to herd immunity against GII.4 NoVs based on their inability to block GII.4 VLP binding to HBGA. However, previous exposure to GII.4 NoV followed by infection by GII.3 NoV appeared to evoke an immune response to GII.4 NoV. These results support the hypothesis that herd immunity is a driving force for GII.4 evolution in the U.S. population. The data also suggest that complex patterns of cross-protection may exist across NoV genotypes in humans.

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Figures

FIG. 1.
FIG. 1.
Timeline from 1985 to 2006 indicating the classifications for the populations from which outbreak serum specimens were collected and the VLPs used in this study.
FIG. 2.
FIG. 2.
HBGA binding of GII.4-1987, GII.4-1997, GII.4-2002 (30), GII.4-2006, and GII.3-TV VLPs. Boxes indicated averages, and bars indicate maximum OD values at 405 nm.
FIG. 3.
FIG. 3.
Geometric mean IgG titers in acute- and convalescent-phase sera from outbreak patients seroconverting to GII.4-1997 or GII.4-1987 VLPs. Data are stratified by period and by genotype of the outbreak, including only GII.4 outbreaks (A), GII-unspecified (pre-1988 sera) and non-GII.4 outbreaks (non-GII.4 represents sera from outbreaks caused by GII.1, GII.2, GII.10, and GII.14 NoVs) (B), and only GII.3 outbreaks (C). Boxes represent maximum, mean, and minimum values for geometric mean IgG titers in each category. * indicates a significant difference in mean IgG titers between acute- and convalescent (Conv)-phase sera, and ^ indicates a significant difference between the mean convalescent IgG titers compared to those of GII.4 outbreaks of the pandemic period.
FIG. 4.
FIG. 4.
Blockade of GII.4-2006 VLP by homotypic outbreak sera. Acute-phase (n = 6) and convalescent-phase (n = 6) serum pairs collected during the GII.4-2006 outbreak from which the GII.4-2006 VLP was cloned were assayed for the ability to block homotypic VLP interactions with H type 3. Error bars indicate the standard errors. The dashed line indicates the corresponding BT50 values on the x axis.
FIG. 5.
FIG. 5.
Blockade of GII.4 VLP binding to HBGA by convalescent-phase GII.4 outbreak sera collected during 1988 to 2006. Geometric mean BT50 values for each VLP represent the geometric means of individual BT50 values for each serum sample within the indicated time period. Error bars indicate the standard errors. * indicates significant differences between GII.4-1987, GII.4-1997, or GII.4-2002 VLPs within each period.
FIG. 6.
FIG. 6.
Blockade of GII.4 or GII.3 VLP binding to HBGA by convalescent GII-unspecified outbreaks from the prepandemic period (A), non-GII.4 sera from the lull period (B), GII.3 sera from the pandemic period (C), and GII.4 sera from the pandemic period (D). The dashed line indicates the corresponding BT50 values on the x axis. Error bars indicate the standard errors.
FIG. 7.
FIG. 7.
Murine antiserum blockade of GII.4-1997 and GII.3 binding to HBGA. Antisera collected from mice immunized with GII.4-1997 (n = 3) or GII.3-TV (n = 3) were assayed for the ability to block homotypic VLP (solid symbols) or heterotypic VLP (open symbols) interactions with H type 3. The dashed line indicates the corresponding BT50 values on the x axis.
FIG. 8.
FIG. 8.
Structural models of the GII.3 and GII.4 P-domain dimers. (a) Structural similarities between the GII.3 and GII.4 P-domain dimers suggest that similar structural features would appear on the capsid structure of each VLP or virus. The GII.3 P-domain dimer model is shown in various rotations, and sites that are identical between GII.3 and GII.4 P dimers are shown in black. Blue, chain A; purple, chain B; yellow, site 1 of the putative RBD; orange, site 2 of the putative RBD. (b) Direct comparison of the GII.4 P-domain dimer with the GII.3 P-domain dimer model indicates that a unique extended loop occurs on the GII.3 structure distal to the dimer interface, which would likely provide a unique target for antibody neutralization specific to the GII.3 virus/VLP.
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