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. 2022 Jun 14;14(6):1293.
doi: 10.3390/v14061293.

Antigenic Site Immunodominance Redirection Following Repeat Variant Exposure

Lisa C Lindesmith  1 , Paul D Brewer-Jensen  1 , Michael L Mallory  1 , Mark R Zweigart  1 , Samantha R May  1 , Daniel Kelly  2 , Rachel Williams  3   4 , Sylvia Becker-Dreps  1   5 , Filemón Bucardo  6 , David J Allen  2 , Judith Breuer  3   7 , Ralph S Baric  1
Affiliations

Antigenic Site Immunodominance Redirection Following Repeat Variant Exposure

Lisa C Lindesmith et al. Viruses. .

Abstract

Human norovirus is a leading cause of acute gastroenteritis, driven by antigenic variants within the GII.4 genotype. Antibody responses to GII.4 vaccination in adults are shaped by immune memory. How children without extensive immune memory will respond to GII.4 vaccination has not been reported. Here, we characterized the GII.4 neutralizing antibody (nAb) landscape following natural infection using a surrogate assay and antigenic site chimera virus-like particles. We demonstrate that the nAb landscape changes with age and virus exposure. Among sites A, C, and G, nAbs from first infections are focused on sites A and C. As immunity develops with age/exposure, site A is supplemented with antibodies that bridge site A to sites C and G. Cross-site nAbs continue to develop into adulthood, accompanied by an increase in nAb to site G. Continued exposure to GII.4 2012 Sydney correlated with a shift to co-dominance of sites A and G. Furthermore, site G nAbs correlated with the broadening of nAb titer across antigenically divergent variants. These data describe fundamental steps in the development of immunity to GII.4 over a lifetime, and illustrate how the antigenicity of one pandemic variant could influence the pandemic potential of another variant through the redirection of immunodominant epitopes.

Keywords: antigenic seniority; blockade antibody; immune imprinting; immunodominance; neutralizing antibody; norovirus; variant persistence; variants of concern.

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Conflict of interest statement

L.C.L. and R.S.B. hold patents on norovirus vaccine design and ongoing collaborations with Vaxart, Takeda Vaccines, and HilleVax that are unrelated and do not pose conflict of interest with this report. R.S.B. is a member of the advisory committee for Vaxart and Adagio Therapeutics. S.B.-D. received an investigator-initiated research award from Takeda Vaccines unrelated to this report. P.B.J., M.L.M., M.R.Z., S.R.M., J.B., D.A., R.W., D.K. and F.B. have no conflict of interest to report.

Figures

Figure 1
Figure 1
GII.4 2012 Sydney antigenic site chimera VLPs. (A) Residues of confirmed GII.4 hypervariable antigenic sites/epitopes in VLP studied here. Chimera VLPs are composed of GII.4 2012 Sydney antigenic sites in the backbone of GII.4 1987 Camberwell. (B) Antigenic sites in Panel A, color-coded on the structure of the GII.4 2012 Sydney dimer. Note: sites are colored as distinct entities, but antibodies may bind across sites. RBD: receptor binding domain. (C) VLPs characterized for epitope-specific nAb potency and ligand binding (Log EC50 µg/mL).
Figure 2
Figure 2
GII.4 Sydney infection in young children induces nAb responses to multiple overlapping antigenic sites. Sera from children (n = 20) with an RT-qPCR confirmed first symptomatic GII.4 infection, typed as GII.4 2012 Sydney, were evaluated for nAb titer to GII.4 2012 Sydney, GII.4 1987 Camberwell, and antigenic site chimera VLPs comprised of GII.4 2012 Sydney epitopes in the backbone of GII.4 1987. Y-axis: reciprocal of the serum dilution at 50% inhibitory dose. Marker: individual child. Line: geometric mean titer. Error bars: 95% confidence intervals. Dashed line: limit of detection. * p = 0.02, *** p = 0.0001, **** p < 0.0001 compared to GII.4 1987 Camberwell.
Figure 3
Figure 3
Antigenic site-specific nAb responses vary by age/exposure history. Surveillance sera from children ages ≤ 5 years (n = 65) (A) and adults ≥ 15 years (n = 21) (B) were evaluated for nAb antibody titer to GII.4 2012 Sydney, GII.4 1987 Camberwell, and antigenic site-chimera VLP comprised of GII.4 2012 Sydney antigenic sites in the backbone of GII.4 1987 Camberwell. Only samples with titer ≥ 50 to either GII.4 2012 Sydney or 1987 Camberwell were included in analyses to exclude subjects who are genetically resistant to GII.4 infection. Y-axis: reciprocal of the serum dilution at 50% inhibitory dose. Marker: one individual. Line: geometric mean titer. Error bars: 95% confidence intervals. Dashed line: limit of detection. * p = 0.02, ** p = 0.004, **** p < 0.0001 compared to GII.4 1987 Camberwell.
Figure 4
Figure 4
Variant and antigenic site-specific nAb responses in contemporary adult sera. Sera from adults collected in 2019 (n = 20) were evaluated for nAb titer to a panel of GII.4 variants (A) or antigenic site chimera VLPs comprised of GII.4 2012 Sydney antigenic sites in the backbone of GII.4 1987 Camberwell (B). Only samples with titer ≥ 50 to either GII.4 2012 Sydney or 1987 Camberwell were included in the analysis to exclude subjects who are genetically resistant to GII.4 infection. Y-axis: reciprocal of the serum dilution at 50% inhibitory dose. Marker: individual adult. Line: geometric mean titer. Error bars: 95% confidence intervals. Dashed line: limit of detection. * p = 0.02, ** p = 0.001, **** p < 0.0001 compared to GII.4 1987 Camberwell.
Figure 5
Figure 5
Repeat GII.4 Sydney exposure correlates with antigenic site G nAb titer. nAb titers to GII.4 2012 Sydney and antigenic site-specific responses were compared by Spearman correlational analysis, and the r value was determined. Pairs with insignificant correlation were assigned r = 0. A related GII.4 Sydney strain (GII.4 2012 Sydneyb) was included in the analyses for comparison.
Figure 6
Figure 6
Neutralizing antibody to GII.4 2012 Sydney antigenic site G correlates with nAb to antigenically distinct GII.4 variants. nAb titers to GII.4 variants and antigenic site chimera VLPs were compared by Spearman correlational analysis, and the r value was determined. All pairings were significant. Pairs with high correlation (r ≥ 0.7) are shown.
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