Dataset Information

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.

SUBMITTER: Malm M

PROVIDER: S-EPMC4446402 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Genotype considerations for virus-like particle-based bivalent norovirus vaccine composition.

Malm Maria M Tamminen Kirsi K Lappalainen Suvi S Uusi-Kerttula Hanni H Vesikari Timo T Blazevic Vesna V

Clinical and vaccine immunology : CVI 20150422 6

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 beli ...[more]

PMID: 25903355

Similar Datasets

Project description:Abstract Background With the introduction of routine childhood rotavirus vaccination, norovirus is now becoming the major cause of medically-attended gastroenteritis in children. Takeda is developing a norovirus vaccine (NoV) that contains genotypes GI.1 and GII.4 consensus (GII.4c) sequence VLPs. We report the immunogenicity data of NoV administered to children from 6 months up to 4 years of age. Methods Two age cohorts (1 to < 4 years, and 6 to < 12 months, n = 120 per cohort) were enrolled in this ongoing double-blind, randomized, phase 2 dose-finding study conducted in Colombia and Panama. Children received one or two intramuscular doses of NoV formulations containing 15/15, 15/50, 50/50 or 50/150 ?g of GI.1/GII.4c VLPs adjuvanted with 0.5 mg Al(OH)3. Vaccinations were on Days 1 and 29, with saline placebo as dose two to maintain blinding in one dose groups. Antibody responses to each VLP were measured on days 1, 29 and 57 as functional histo-blood group binding antigen blocking antibodies (HBGA), expressed as seroresponse rates (SRR), the proportions displaying ? 4-fold increases over baseline, and geometric mean titres (GMT). Results Each formulation induced dosage-dependent HBGA responses after a single dose, with a further increase after a second dose. In 1- to <4 year-olds HBGA SRR against GI.1 and GII.4c after one dose were 55–62% and 67–82%, respectively. SRR increased to 93–100% and 83–100% after a second dose. In 6 to < 12 month-olds responses were lower after the first dose: SRRs were 10–61% and 17–65% for GI.1 and GII.4c, respectively, increasing to 83–100% and 80–92% after a second dose. GMTs reflected this pattern of responses with higher GMTs for GI.1 and GII.4c achieved with the 50/150 ?g formulation than the other dosages after both vaccinations in both age cohorts. Conclusion In 6–12 month-old infants and children up to 4 years of age, robust immune responses to the bivalent norovirus VLP vaccine candidates were observed; the highest HBGA responses in both age cohorts were observed after two doses of the 50/150 ?g formulation. Further clinical evaluation of these formulations is underway in infants < 6 months of age. Clinical Trial Registration (NCT: 02153112, EudraCT: 2014-000778-20) Disclosures T. Masuda, Takeda Pharmaceuticals International AG: Employee, Salary. I. Lefevre, Takeda Pharmaceuticals International AG: Employee, Salary. P. Mendelman, Takeda Pharmaceuticals International AG: Employee, Salary. J. Sherwood, Takeda Pharmaceuticals International AG: Employee, Salary. S. Bizjajeva, Takeda Pharmaceuticals International AG: Employee, Salary. A. Borkowski, Takeda Pharmaceuticals International AG: Employee, Salary.

Project description:UnlabelledDengue virus (DENV), composed of four distinct serotypes, is the most important and rapidly emerging arthropod-borne pathogen and imposes substantial economic and public health burdens. We constructed candidate vaccines containing the DNA of five of the genotypes of dengue virus serotype 2 (DENV-2) and evaluated the immunogenicity, the neutralizing (Nt) activity of the elicited antibodies, and the protective efficacy elicited in mice immunized with the vaccine candidates. We observed a significant correlation between the level of in vitro virus-like particle secretion, the elicited antibody response, and the protective efficacy of the vaccines containing the DNA of the different DENV genotypes in immunized mice. However, higher total IgG antibody levels did not always translate into higher Nt antibodies against homologous and heterologous viruses. We also found that, in contrast to previous reports, more than 50% of total IgG targeted ectodomain III (EDIII) of the E protein, and a substantial fraction of this population was interdomain highly neutralizing flavivirus subgroup-cross-reactive antibodies, such as monoclonal antibody 1B7-5. In addition, the lack of a critical epitope(s) in the Sylvatic genotype virus recognized by interdomain antibodies could be the major cause of the poor protection of mice vaccinated with the Asian 1 genotype vaccine (pVD2-Asian 1) from lethal challenge with virus of the Sylvatic genotype. In conclusion, although the pVD2-Asian 1 vaccine was immunogenic, elicited sufficient titers of Nt antibodies against all DENV-2 genotypes, and provided 100% protection against challenge with virus of the homologous Asian 1 genotype and virus of the heterologous Cosmopolitan genotype, it is critical to monitor the potential emergence of Sylvatic genotype viruses, since vaccine candidates under development may not protect vaccinated humans from these viruses.ImportanceFive genotype-specific dengue virus serotype 2 (DENV-2) DNA vaccine candidates were evaluated for their immunogenicity, homologous and heterologous neutralizing (Nt) antibody titers, and cross-genotype protection in a murine model. The immunity elicited by our prototype vaccine candidate (Asian 1 genotype strain 16681) in mice was protective against viruses of other genotypes but not against virus of the Sylvatic genotype, whose emergence and potential risk after introduction into the human population have previously been demonstrated. The underlying mechanism of a lack of protection elicited by the prototype vaccine may at least be contributed by the absence of a flavivirus subgroup-cross-reactive, highly neutralizing monoclonal antibody 1B7-5-like epitope in DENV-2 of the Sylvatic genotype. The DENV DNA vaccine directs the synthesis and assembly of virus-like particles (VLPs) and induces immune responses similar to those elicited by live-attenuated vaccines, and its flexibility permits the fast deployment of vaccine to combat emerging viruses, such as Sylvatic genotype viruses. The enhanced VLP secretion obtained by replacement of ectodomain I-II (EDI-II) of the Cosmopolitan genotype vaccine construct (VD2-Cosmopolitan) with the Asian 1 EDI-II elicited significantly higher total IgG and Nt antibody titers and suggests a novel approach to enhance the immunogenicity of the DNA vaccine. A DENV vaccine capable of eliciting protective immunity against viruses of existing and emerging genotypes should be the focus of future DENV vaccine development.

Project description:BackgroundBluetongue virus (BTV) is an economically important, arthropod borne, emerging pathogen in Europe, causing disease mainly in sheep and cattle. Routine vaccination for bluetongue would require the ability to distinguish between vaccinated and infected individuals (DIVA). Current vaccines are effective but are not DIVA. Virus-like particles (VLPs) are highly immunogenic structural mimics of virus particles, that only contain a subset of the proteins present in a natural infection. VLPs therefore offer the potential for the development of DIVA compatible bluetongue vaccines.Methodology/principal findingsMerino sheep were vaccinated with either monovalent BTV-1 VLPs or a bivalent mixture of BTV-1 VLPs and BTV-4 VLPs, and challenged with virulent BTV-1 or BTV-4. Animals were monitored for clinical signs, antibody responses, and viral RNA. 19/20 animals vaccinated with BTV-1 VLPs either alone or in combination with BTV-4 VLPs developed neutralizing antibodies to BTV-1, and group specific antibodies to BTV VP7. The one animal that showed no detectable neutralizing antibodies, or group specific antibodies, had detectable viral RNA following challenge but did not display any clinical signs on challenge with virulent BTV-1. In contrast, all control animals' demonstrated classical clinical signs for bluetongue on challenge with the same virus. Six animals were vaccinated with bivalent vaccine and challenged with virulent BTV-4, two of these animals had detectable viral levels of viral RNA, and one of these showed clinical signs consistent with BTV infection and died.ConclusionsThere is good evidence that BTV-1 VLPs delivered as monovalent or bivalent immunogen protect from bluetongue disease on challenge with virulent BTV-1. However, it is possible that there is some interference in protective response for BTV-4 in the bivalent BTV-1 and BTV-4 VLP vaccine. This raises the question of whether all combinations of bivalent BTV vaccines are possible, or if immunodominance of particular serotypes could interfere with vaccine efficacy.

Dataset Information

Genotype considerations for virus-like particle-based bivalent norovirus vaccine composition.

Publications

Genotype considerations for virus-like particle-based bivalent norovirus vaccine composition.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets