GII.4 Human Norovirus: Surveying the Antigenic Landscape

Abstract

Human norovirus is the leading cause of viral acute onset gastroenteritis disease burden, with 685 million infections reported annually. Vulnerable populations, such as children under the age of 5 years, the immunocompromised, and the elderly show a need for inducible immunity, as symptomatic dehydration and malnutrition can be lethal. Extensive antigenic diversity between genotypes and within the GII.4 genotype present major challenges for the development of a broadly protective vaccine. Efforts have been devoted to characterizing antibody-binding interactions with dynamic human norovirus viral-like particles, which recognize distinct antigenic sites on the capsid. Neutralizing antibody functions recognizing these sites have been validated in both surrogate (ligand blockade of binding) and in vitro virus propagation systems. In this review, we focus on GII.4 capsid protein epitopes as defined by monoclonal antibody binding. As additional antibody epitopes are defined, antigenic sites emerge on the human norovirus capsid, revealing the antigenic landscape of GII.4 viruses. These data may provide a road map for the design of candidate vaccine immunogens that induce cross-protective immunity and the development of therapeutic antibodies and drugs.

Keywords: antigenic drift; antigenic landscape; blockade antibodies; epitope; evolution; neutralizing antibodies; norovirus.

Figure 1

GII.4 VP1 diversity over time. Sequence identity of VP1 (capsid), and known blockade antibody epitopes compared to GII.4 US95/96 (represented by GII.4 1997, AFJ04707.1), the first known GII.4 pandemic strain. GII.4 2002, 2004, 2006b, 2009, and 2012 are sequential pandemic strains, represented by isolates, AAZ31376.2, AFJ04709.1, AEX91909.1, and AFV08794.1, respectively. GII.4 1987 (AAK50355.1) is an endemic GII.4 strain that circulated before GII.4 US95/96 emergence. Overall identity within VP1 is high. Identity within the known evolving blockade antibody epitopes is less well conserved, resulting in the emergence of new pandemic strains refractive to herd immunity shaped by previous GII.4 exposure. Epitopes conserved between GII (epitope nanobody-85) and GI/GII strains (epitope TV20) remain largely unchanged over time in GII.4 strains.

Figure 2

Mouse and human anti-epitope A monoclonal antibody blockade of time-ordered GII.4 strain virus-like particles (VLP). (A) Monoclonal antibodies to epitope A were generated in response to the immunization of mice with GII.4 VLPs (1987, 2006, 2009, 2012 mAbs) or the infection of humans (NVB mAbs), and their IC₅₀ for the blockade of VLP-ligand binding declined from highly potent (orange) to no inhibition (blue) as reported in References [25,26,38,39,60,61]. GII.4 2004 data not available. (B) Antigenic drift within epitope A limits the breadth of mAb recognition of epitope A.

Figure 3

Ligand-blockade antibody epitopes are surface exposed and usually within hypervariable loops within the VP1 P2 subdomain. GII.4 2012 P dimer homology model (4OP7) with blocking antibody epitopes color coded.