Dataset Information

2276. Immunogenicity of Takeda’s Bivalent Virus-Like Particle (VLP) Norovirus Vaccine (NoV) Candidate in Children From 6 Months up to 4 Years of Age

ABSTRACT: 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.

SUBMITTER: Masuda T

PROVIDER: S-EPMC6255068 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Project description:BackgroundHuman noroviruses (NoVs) are the primary cause of acute gastroenteritis and are characterized by antigenic variation between genogroups and genotypes and antigenic drift of strains within the predominant GII.4 genotype. In the context of this diversity, an effective NoV vaccine must elicit broadly protective immunity. We used an antibody (Ab) binding blockade assay to measure the potential cross-strain protection provided by a multivalent NoV virus-like particle (VLP) candidate vaccine in human volunteers.Methods and findingsSera from ten human volunteers immunized with a multivalent NoV VLP vaccine (genotypes GI.1/GII.4) were analyzed for IgG and Ab blockade of VLP interaction with carbohydrate ligand, a potential correlate of protective immunity to NoV infection and illness. Immunization resulted in rapid rises in IgG and blockade Ab titers against both vaccine components and additional VLPs representing diverse strains and genotypes not represented in the vaccine. Importantly, vaccination induced blockade Ab to two novel GII.4 strains not in circulation at the time of vaccination or sample collection. GII.4 cross-reactive blockade Ab titers were more potent than responses against non-GII.4 VLPs, suggesting that previous exposure history to this dominant circulating genotype may impact the vaccine Ab response. Further, antigenic cartography indicated that vaccination preferentially activated preexisting Ab responses to epitopes associated with GII.4.1997. Study interpretations may be limited by the relevance of the surrogate neutralization assay and the number of immunized participants evaluated.ConclusionsVaccination with a multivalent NoV VLP vaccine induces a broadly blocking Ab response to multiple epitopes within vaccine and non-vaccine NoV strains and to novel antigenic variants not yet circulating at the time of vaccination. These data reveal new information about complex NoV immune responses to both natural exposure and to vaccination, and support the potential feasibility of an efficacious multivalent NoV VLP vaccine for future use in human populations.Trial registrationClinicalTrials.gov NCT01168401.