Dynamic immunodominance hierarchy of neutralizing antibody responses to evolving GII.4 noroviruses

A Novel and Secure Pseudovirus Reporter System Based Assay for Neutralizing and Enhancing Antibody Assay Against Marburg Virus

“…During the genetic evolution of viruses, the unstable living environment creates different selection pressures, which allows the adaptive mutations of the virus to be retained and survive, and then develop into different genotypes and strains. In addition, after the virus infects host cells, to better avoid the attack of the humoral immune response, it often develops in the direction of generating escape mutants ( Park et al, 2020 ; Tohma et al, 2022 ). So, when developing a vaccine against any virus, scientists have received significant attention to the overall protective effect and ability to prevent infection by different strains and isolates of the same virus.…”

Antigenic Site Immunodominance Redirection Following Repeat Variant Exposure

“…Thus, neutralizing antibody responses are commonly assessed with a surrogate neutralization assay that measures the ability of an antibody to block the interaction of HuNoV virus-like particles (VLPs) with a binding ligand. These "blockade" antibodies also neutralize the virus in vitro, and are a proposed correlate of protection and a key metric for vaccine studies [23][24][25][26][27][28][29][30].…”

“…Bioinformatic analyses have predicted nine neutralizing antibody (nAb) antigenic sites, denoted A-I, on the GII.4 capsid protein [15,31]. Seven of these sites have been confirmed with monoclonal antibodies in the surrogate neutralization assay, and each is composed of multiple antibody epitopes, as defined by overlapping antibody binding footprints within and across antigenic sites [24,30,32]. Of these, sites A, C, D, E, and G are under positive selection, resulting in hypervariable regions in the virus capsid protein that define nAb antigenic sites (Figure 1) [15,33].…”

“…Of these, sites A, C, D, E, and G are under positive selection, resulting in hypervariable regions in the virus capsid protein that define nAb antigenic sites (Figure 1) [15,33]. Antibodies to antigenic site/epitope A are dominant in sera from infected people, and site A is a primary target of isolated neutralizing monoclonal antibodies from humans and immunized mice [30,31,33,34]. Amino acid changes in site A highly correlate with new variant emergence.…”

“…Recently, antigenic sites C and G were also reported to be highly correlated with new variant emergence, based on bioinformatic analysis [15,30]. Interestingly, sera and monoclonal antibodies from immunized animals indicate that antigenic site G may be co-dominant with antigenic site A after hyperimmunization with GII.4 2012 Sydney, leading to the hypothesis that a shift in immunodominance from site A and toward sites A and G or A+G may explain the unprecedented persistence of GII.4 2012 Sydney for the past 10 years [15,30]. A mechanism of how this shift in immunodominance would prevent the development of protective immunity to GII.4 2012 Sydney, allowing virus persistence, is unknown.…”