Norovirus GII.17 Virus-Like Particles Bind to Different Histo-Blood Group Antigens and Cross-React with Genogroup II-Specific Mouse Sera

Abstract

Majority of norovirus (NoV) outbreaks and sporadic infections in the past 20 years have been caused by GII.4 variants. In 2014, norovirus GII.17 genotype replaced GII.4 strains in several Asian countries and major outbreaks were reported in other continents. As GII.17 is a recently evolved NoV strain, there is a gap especially in immunogenicity data. In the present study we investigated GII.17 virus-like particle (VLP) binding to various cellular ligands, histo-blood group antigens (HBGAs), using human saliva, pig gastric mucin, and synthetic oligosaccharides as HBGA sources. The level of GII.17 immunological cross-reactivity was determined in mice immunized with different monovalent and multivalent NoV VLP compositions. Furthermore, healthy adult volunteers with natural NoV exposure history were analyzed for GII.17-specific seroresponses. The results showed that GII.17 Kawasaki VLPs bind to a wide range of HBGAs, even though fewer than GII.4 VLPs. Immunization of mice with a multivalent VLP formulation containing different genogroup II NoV VLPs was required to obtain the highest magnitude of cross-reactive binding antibodies to GII.17. However, co-immunization with different VLP genotypes did not improve potentially neutralizing antibodies to GII.17, which remained very moderate. Low pre-existing cross-reactive antibodies to GII.17 observed in human adults indicates the presence of a large pool of susceptible individuals in this population. These data suggest that GII.17 and alike newly emerging, distinct NoV genotypes should be considered as an antigenic component for vaccine formulations, which currently widely rely on GII.4-specific immunity.

Immunological Cross-Reactivity of an Ancestral and the Most Recent Pandemic Norovirus GII.4 Variant

“…We suggest that VLP structure (e.g., epitope accessibility), avidity of the antibodies and T-cell immunity might all play important role in heterologous NoV immunity and therefore should be considered in vaccine VLP selection. Based on the results of this study, and our earlier findings [ 48 , 49 , 50 ], the ancestor GII.4 1999 VLPs have an intrinsic property of inducing antibodies with broad cross-reactivity and thus are good candidates for an NoV VLP vaccine.…”

“…The NoV VLP vaccine might also need to be reformulated every few years, or else cross-blocking epitopes could be induced to generate broadly blocking antibodies that protect against a variety of NoV variants [ 28 , 30 , 47 ]. In our earlier studies we have shown that ancestral GII.4 1999 VLPs tend to induce immune responses with better cross-reactivity and higher quality than other NoV genotype VLPs [ 48 , 49 , 50 ]. To further investigate GII.4 1999 VLP potential as a vaccine antigen, we compared the immune responses induced by GII.4 1999 VLPs and the most recent pandemic variant GII.4 2012 VLPs in mice.…”

Simultaneous Immunization with Multivalent Norovirus VLPs Induces Better Protective Immune Responses to Norovirus than Sequential Immunization

“…Even though the NoV VLP vaccine candidates tested in phase I/II clinical trials are either monovalent or bivalent VLP formulations [43,44], it is not known if it might be necessary to upgrade the vaccines according to emerging new variants, such as the sudden emergence of a novel non-GII.4 variant GII.17 in 2014 might suggest. Currently developed vaccines might not provide protection to GII.17 strains due to low cross-reactivity observed by ourselves and others [28,29].…”

“…Sato et al have also shown that GII.4 SYD–specific antibodies did not block GII.17 virus replication. Congruently, we have published that the ancestor GII.4-1999 VLPs are superior to more recent GII.4 variants in inducing cross-reactive responses, including the cross-blocking response to GII.17 VLPs [17,20,28,52]. On the other hand, we observed that when mice are immunized with the quadrivalent NoV VLP mixture containing GI.3, GII.4-1999 (an ancestor GII.4 variant), GII.4 SYD (the most recent pandemic variant), and GII.17, cross-blocking of GII.4 variants 2006 and 2009 (NO) was comparable to homologous GII.4-1999 and GII.4 SYD VLP blocking.…”

“…Exceptionally, in the 2014–2015-winter season, concern over a global pandemic was raised when major non-GII.4 genotype, GII.17 Kawasaki outbreaks were reported on several continents, and GII.17 became the predominant genotype in several Asian countries [27]. Spread of the novel GII.17 strain was enhanced by lack of pre-existing GII.17-specific immune responses in the population and low cross-reactivity of GII.17 with other circulating NoVs [28,29].…”