Genotype Considerations for Virus-Like Particle-Based Bivalent Norovirus Vaccine Composition

Abstract

Norovirus (NoV) genogroup I (GI) and GII are responsible for most human infections with NoV. Because of the high genetic variability of NoV, natural infection does not induce sufficient protective immunity to different genotypes or to variants of the same genotype and there is little or no cross-protection against different genogroups. NoV-derived virus-like particles (VLPs) are promising vaccine candidates that induce high levels of NoV-specific humoral and cellular immune responses. It is believed that a bivalent NoV vaccine consisting of a representative VLP from GI and GII is a minimum requirement for an effective vaccine. Here, we compared the abilities of monovalent immunizations with NoV GI.1-2001, GI.3-2002, GII.4-1999, and GII.4-2010 New Orleans VLPs to induce NoV type-specific and cross-reactive immune responses and protective blocking antibody responses in BALB/c mice. All of the VLPs induced comparable levels of type-specific serum IgG antibodies, as well as blocking antibodies to the VLPs used for immunization. However, the abilities of different VLP genotypes to induce cross-reactive IgG and cross-blocking antibodies varied remarkably. Our results confirm previous findings of a lack of cross-protective immune responses between GI and GII NoVs. These data support the rationale for including NoV GI.3 and GII.4-1999 VLPs in the bivalent vaccine formulation, which could be sufficient to induce protective immune responses across NoV genotypes in the two common genogroups in humans.

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

“…The mechanism behind this finding is unknown but it may be due to stronger affinity of antibodies that GII. VLPs induce (12,28,31,33,39). Furthermore, there are reports of conserved neutralization antibody epitopes located outside HBGA binding pocket, e.g.…”

Characterization of a Norovirus‐specific monoclonal antibody that exhibits wide spectrum binding activities

“…In this study, we successfully produced GI.7 and GII.2 VLPs and identified a mAb that exhibited wide‐spectrum binding activities by immunizing mice with NoV VLPs derived from eight different genotypes. The immunization protocol by using multiple VLPs was based on the facts that NoV vaccine consisting of more than one genotype can induce the production of HBGAs blocking antibodies targeting genotypes not included in the vaccines, suggesting broadened immune responses . The binding site for this mAb was mapped to a site located at the N‐terminus that was conserved among all genogroups.…”

“…The immunization protocol by using multiple VLPs was based on the facts that NoV vaccine consisting of more than one genotype can induce the production of HBGAs blocking antibodies targeting genotypes not included in the vaccines, suggesting broadened immune responses. 17,18 The binding site for this mAb was mapped to a site located at the N-terminus that was conserved among all genogroups. The cross-reactive mAbs produced might be useful for the detection and epidemiology study of NoVs.…”

Prospects and Challenges in the Development of a Norovirus Vaccine

“…Mutations as well as recombination within and between norovirus genotypes in co-infected patients lead to the periodic emergence of new norovirus variants as well as broad genetic and antigenic diversity of circulating norovirus strains. This genetic diversity poses a potential challenge to the development of a broadly protective norovirus vaccines, as some studies show that immunization and natural infection with a norovirus may elicit immunity specific to that norovirus’ genogroup [10–11]. The emergence of GII genotype 4 (GII.4) variants that have caused new global pandemics suggests that evolution of the capsid gene can help the virus escape immunity induced by infection or vaccination [12].…”

“…Immunization of mice with norovirus VLPs has demonstrated that GI VLPs fail to produce antibodies with blocking activity against GII noroviruses and vice versa [10]. A genogroup-specific induction of HBGA-blocking antibodies has also been demonstrated after natural infection in children [11]; however, infection with Norwalk virus (GI.1) in adults induces modest heterotypic HBGA-blocking activity against multiple genotypes including GII.4 [14].…”