Abstract
Norovirus (NoV) genotype GII.4 is responsible for the majority of NoV infections causing pandemics every few years. A NoV virus-like particle (VLP)-based vaccine should optimally cover the high antigenic variation within the GII.4 genotype. We compared the immune responses generated by VLPs of the ancestral GII.4 1999 strain (GII.4 1995/96 US variant) and the most recent GII.4 Sydney 2012 pandemic strains in mice. No significant differences were observed in the type-specific responses but GII.4 1999 VLPs were more potent in inducing high-avidity antibodies with better cross-reactivity. GII.4 1999 immune sera blocked binding of GII.4 2006 and GII.4 2012 VLPs to the putative receptors in a surrogate neutralization assay, whereas GII.4 2012 immune sera only had low blocking activity against GII.4 2006 VLPs. Amino acid substitution in the NERK motif (amino acids 310, 316, 484, and 493, respectively), altering the access to conserved blocking epitope F, moderately improved the cross-blocking responses against mutated GII.4 2012 VLPs (D310N). NoV GII.4 1999 VLPs, uptaken and processed by antigen-presenting cells, induced stronger interferon gamma (IFN-γ) production from mice splenocytes than GII.4 2012 VLPs. These results support the use of GII.4 1999 VLPs as a major component of a NoV vaccine.
Highlights
Norovirus (NoV) genogroup II (GII).4 is the predominating NoV genotype, causing up to 85% of acute gastroenteritis outbreaks of NoV and sporadic infections worldwide [1]
GII.4 variants recognize a wide range of mucosal polysaccharides [7] and histo-blood group antigens (HBGAs), which are thought to facilitate NoV
immunoglobulin G (IgG) antibodies against GII.4 1999, GII.4 2006, and GII.4 2012
Summary
Norovirus (NoV) GII. is the predominating NoV genotype, causing up to 85% of acute gastroenteritis outbreaks of NoV and sporadic infections worldwide [1]. It is associated with more severe clinical manifestations than other NoV genotypes [2,3]. The predominance of GII. for over two decades is associated with several factors including fast replication and effective person-to-person transmission rates [5,6]. GII. variants recognize a wide range of mucosal polysaccharides [7] and histo-blood group antigens (HBGAs), which are thought to facilitate NoV entry and/or infection [8,9]. NoV vaccine development is largely based on NoV virus-like particles (VLPs) [12,13,14], antigenically identical to the virus particle, despite recent progress in cultivating NoV in vitro [15]
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