Emergence of a Norovirus GII.4 Strain Correlates with Changes in Evolving Blockade Epitopes

Lindesmith, Lisa C.; Costantini, Verónica; Swanstrom, Jesica; Debbink, Kari; Donaldson, Eric F.; Vinjé, Jan; Baric, Ralph S.

doi:10.1128/jvi.03106-12

Cited by 146 publications

(156 citation statements)

References 56 publications

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“…Most interesting from a biological point of view, and perhaps explaining the observed differences in blocking titers found in this study, the alignment also revealed that the GII.4 NoV strains used in this study have major changes in antigenic epitopes A (amino acids [aa] 294, 296 to 298, 368, and 372), D (aa 393 to 395), and E (aa 407, 412, and 413), as shown in Table 3 (6,7,18,(37)(38)(39). Previous studies have reported epitope A to be highly immunodominant and suggested it was the target of blocking antibodies against early strains (7,38).…”

Section: Discussionmentioning

confidence: 88%

“…Previous studies have reported epitope A to be highly immunodominant and suggested it was the target of blocking antibodies against early strains (7,38). Interestingly, MD145 1987, Grimsby 1995, and Houston 2002 share 4 common residues (H297, D298, T368, and N372), whereas the Sydney strain has different amino acids in all these positions (H297R, D298N, T368E, and N372D) ( Table 3).…”

Section: Discussionmentioning

confidence: 99%

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Human Sera Collected between 1979 and 2010 Possess Blocking-Antibody Titers to Pandemic GII.4 Noroviruses Isolated over Three Decades

Sharma

Carlsson

Czakó

et al. 2017

J Virol

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The emergence of pandemic GII.4 norovirus (NoV) strains has been proposed to occur due to changes in receptor usage and thereby to lead to immune evasion. To address this hypothesis, we measured the ability of human sera collected between 1979 and 2010 to block glycan binding of four pandemic GII.4 noroviruses isolated in the last 4 decades. In total, 268 sera were investigated for 50% blocking titer (BT 50 ) values of virus-like particles (VLPs) against pig gastric mucin (PGM) using 4 VLPs that represent different GII.4 norovirus variants identified between 1987 and 2012. Pre-and postpandemic sera (sera collected before and after isolation of the reference NoV strain) efficiently prevented binding of VLP strains MD145 (1987), Grimsby (1995), and Houston (2002), but not the Sydney (2012) strain, to PGM. No statistically significant difference in virus-blocking titers was observed between pre-and postpandemic sera. Moreover, paired sera showed that blocking titers of Ն160 were maintained over a 6-year period against MD145, Grimsby, and Houston VLPs. Significantly higher serum blocking titers (geometric mean titer [GMT], 1,704) were found among IgA-deficient individuals than among healthy blood donors (GMT, 90.9) (P Ͻ 0.0001). The observation that prepandemic sera possess robust blocking capacity for viruses identified decades later suggests a common attachment factor, at least until 2002. Our results indicate that serum IgG possesses antibody-blocking capacity and that blocking titers can be maintained for at least 6 years against 3 decades of pandemic GII.4 NoV.IMPORTANCE Human noroviruses (NoVs) are the major cause of acute gastroenteritis worldwide. Histo-blood group antigens (HBGAs) in saliva and gut recognize NoV and are the proposed ligands that facilitate infection. Polymorphisms in HBGA genes, and in particular a nonsense mutation in FUT2 (G428A), result in resistance to global dominating GII.4 NoV. The emergence of new pandemic GII.4 strains occurs at intervals of several years and is proposed to be attributable to epochal evolution, including amino acid changes and immune evasion. However, it remains unclear whether exposure to a previous pandemic strain stimulates immunity to a pandemic strain identified decades later. We found that prepandemic sera possess robust

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Human Sera Collected between 1979 and 2010 Possess Blocking-Antibody Titers to Pandemic GII.4 Noroviruses Isolated over Three Decades

Sharma

Carlsson

Czakó

et al. 2017

J Virol

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“…4 norovirus have shown that the P2 region is involved in strain-specific antibody recognition (7,11,12) and contains at least three blockade (potential neutralization) epitopes (13)(14)(15). In epidemic strains, genetic variation in P2 is linked to antigenic changes over time, indicating that molecular evolution in the P2 subdomain is likely driven by escape from human herd immunity (12)(13)(14)(15)(16)(17).…”

mentioning

confidence: 99%

Within-Host Evolution Results in Antigenically Distinct GII.4 Noroviruses

Debbink

Lindesmith

Ferris

et al. 2014

J Virol

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Genogroup II, genotype 4 (GII.4) noroviruses are known to rapidly evolve, with the emergence of a new primary strain every 2 to 4 years as herd immunity to the previously circulating strain is overcome. Because viral genetic diversity is higher in chronic than in acute infection, chronically infected immunocompromised people have been hypothesized to be a potential source for new epidemic GII.4 strains. However, while some capsid protein residues are under positive selection and undergo patterned changes in sequence variation over time, the relationships between genetic variation and antigenic variation remains unknown. Based on previously published GII.4 strains from a chronically infected individual, we synthetically reconstructed virus-like particles (VLPs) representing early and late isolates from a small-bowel transplant patient chronically infected with norovirus, as well as the parental GII.4-2006b strain. We demonstrate that intrahost GII.4 evolution results in the emergence of antigenically distinct strains over time, comparable to the variation noted between the chronologically predominant GII.4 strains GII.4-2006b and GII.4-2009. Our data suggest that in some individuals the evolution that occurs during a chronic norovirus infection overlaps with changing antigenic epitopes that are associated with successive outbreak strains and may select for isolates that are potentially able to escape herd immunity from earlier isolates. IMPORTANCENoroviruses are agents of gastrointestinal illness, infecting an estimated 21 million people per year in the United States alone. In healthy individuals, symptomatic infection typically resolves within 24 to 48 h. However, symptoms may persist for years in immunocompromised individuals, and development of successful treatments for these patients is a continuing challenge. This work is relevant to the design of successful norovirus therapeutics for chronically infected patients; provides support for previous assertions that chronically infected individuals may serve as reservoirs for new, antigenically unique emergent strains; and furthers our understanding of genogroup II, genotype 4 (GII.4) norovirus immune-driven molecular evolution.

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“…The surface exposed, highly variable sites of the P2 subdomain (epitopes A to E) undergo changes that were associated with the emergence of new strains causing NoV outbreaks. 28,36,37 These sites are situated around the HBGA pocket. The binding of NoV to specific HBGA as well as antibody binding is affected by these putative epitopes as well as flanking binding sites.…”

Section: Viral Diversitymentioning

confidence: 99%

Norovirus vaccines: Correlates of protection, challenges and limitations

Melhem

2016

Human Vaccines & Immunotherapeutics

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Norovirus (NoV) is responsible for at least 50% of all gastroenteritis outbreaks worldwide. NoVs are classified into 6 different genogroups (GGI-GGVI) based on the viral capsid protein with NoV genogroup II genotype 4 (GII.4) being the predominant strain causing human diseases. Supportive therapy involving reversal of dehydration and electrolyte deficiency is the main treatment of NoV gastroenteritis. However, the worldwide increased recognition of NoV as an important agent of diarrheal gastroenteritis prompted researchers to focus on establishing preventive strategies conferring long-lasting immunity. This review describes the current status of animal and human vaccine models/studies targeting NoV and addresses the factors hampering the development of a broadly effective vaccine.

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Emergence of a Norovirus GII.4 Strain Correlates with Changes in Evolving Blockade Epitopes

Cited by 146 publications

References 56 publications

Human Sera Collected between 1979 and 2010 Possess Blocking-Antibody Titers to Pandemic GII.4 Noroviruses Isolated over Three Decades

Human Sera Collected between 1979 and 2010 Possess Blocking-Antibody Titers to Pandemic GII.4 Noroviruses Isolated over Three Decades

Within-Host Evolution Results in Antigenically Distinct GII.4 Noroviruses

Norovirus vaccines: Correlates of protection, challenges and limitations

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