Norovirus Virus-like Particle Vaccine Research Articles

A phase 2 study of the bivalent VLP norovirus vaccine candidate in older adults; impact of MPL adjuvant or a second dose

IntroductionAcute norovirus gastroenteritis causes significant morbidity and in uncommon cases fatality in older adults. We investigated the safety and immunogenicity of bivalent virus-like particle (VLP) vaccine candidate formulations with and without monophosphoryl lipid A (adjuvant MPL) in this population. MethodsIn this phase II, double-blind, controlled trial 294 healthy adults, ≥ 60 years of age, were randomized (1:1:1:1) to four groups to receive one or two intramuscular immunizations 28 days apart, with 26 18–49 year-old controls who received one MPL-free dose. One-dose groups received placebo on Day 1. Vaccine formulations contained 15 μg GI.1 and 50 μg GII.4c VLP antigens and 500 μg Al(OH)3, with or without 15 μg MPL. We measured histo-blood group antigen blocking (HBGA) antibodies and ELISA Ig at Days 1, 8, 29, 57, 211 and 393, and avidity indices and cell-mediated immunity (CMI). Solicited local and systemic adverse events (AE) were assessed for 7 days and unsolicited AEs for 28 days after each injection. ResultsAfter one dose HBGA antibodies to both VLP antigens increased with similar kinetics and magnitude in all groups; geometric mean titres (GMTs) persisted above baseline through Day 393. GMTs were similar across age strata (18–49, 60–74, 75–84 and ≥ 85 years of age) and unaffected by a second vaccination or MPL. Total Ig showed similar responses. No clinically relevant differences or changes in avidity or CMI were observed between formulations. Both formulations were well tolerated with no vaccine-related SAEs, the most frequent AEs being mild injection site pain and fatigue. ConclusionsAdults over 60 years of age displayed no safety concerns and had similar immune responses to the norovirus VLP vaccine candidate as younger adults, unaffected by increasing age, a second dose or inclusion of MPL. This data supports the further development of the MPL-free vaccine candidate for older adults.

Bivalent Norovirus VLP Vaccine Candidate in Older Adults: Impact of MPL and a Second Dose in a Randomized, Controlled, Double-Blind Clinical Trial

BackgroundAcute norovirus (NoV) gastroenteritis may cause significant morbidity in healthy adults and can prove fatal in older subjects. We investigated the safety and immunogenicity in older adults of one or two doses of an intramuscular bivalent virus-like particle (VLP) vaccine candidate (genotypes GI.1 and multivalent consensus GII.4c) formulated with alum and with and without MPL (3-O-deacyl-4′-monophosphoryl lipid A) adjuvant.MethodsIn a phase II, double-blind, controlled trial, 294 healthy adults ≥ 60 years of age randomized to 4 equal groups received one or two immunizations 28 days apart. One dose groups received placebo (saline) on Day 1. Vaccine formulations contained 500μg Al(OH)3adjuvant with 15μg GI.1 and 50μg GII.4c VLP antigens, with or without 15μg MPL adjuvant. A fifth group of 26 healthy 18–49 year-olds received one dose of MPL-free vaccine. Humoral immunity was assessed as ELISA pan-Ig and histo-blood group antigen blocking (HBGA) antibody titers at Days 1, 8, 29 and 57. Cell-mediated immunity (CMI) and avidity indices (AI) were also measured. Safety was assessed as solicited local and systemic adverse events (AE) for 7 days, and unsolicited AEs until Day 28 after each vaccination.ResultsMarked increases in pan-Ig and HBGA to both genotypes occurred by Day 8 after first vaccination. Geometric mean titers were similar in magnitude in all groups and persisted at similar levels through Day 56. No increases were observed with a second vaccine dose on Day 29 or with the formulations containing MPL. Responses were similar in magnitude when assessed by age groups (60–74, 75–84 and ≥ 85 years of age) and when compared with those to a single vaccine dose in 18–49 year-olds. No clinically relevant differences in CMI responses or changes in antibody avidity were observed between formulations. Both formulations were generally well tolerated, the most frequent reaction being mild pain at the injection site. No vaccine-related SAEs were reported.ConclusionOlder adults aged over 60 years displayed immune responses to NoV VLP vaccines that were similar to those in younger adults with no apparent signs of immunosenescence. These data support the further development of the MPL-free vaccine candidate in older adults.Disclosures J. Sherwood, Takeda Pharmaceuticals International AG: Employee, Salary; J. Cramer, Takeda Pharmaceuticals International AG: Employee, Salary; N. Bouveret Le Cam, Takeda Vaccines Inc.: Employee, Salary; S. Lin, Takeda Vaccines Inc.: Employee, Salary; F. Baehner, Takeda Pharmaceuticals International AG: Employee, Salary; P. Mendelman, Takeda Vaccines Inc.: Employee, Salary; A. Borkowski, Takeda Pharmaceuticals International AG: Employee, Salary

Intranasal delivery of a bivalent norovirus vaccine formulated in an in situ gelling dry powder.

The global health community is beginning to understand the burden of norovirus-associated disease, which has a significant impact in both developed and developing countries. Norovirus virus like particle (VLP)-based vaccines are currently under development and have been shown to elicit systemic and mucosal immune responses when delivered intranasally. In the present study, we describe the use of a dry powder formulation (GelVac™) with an in situ gelling polysaccharide (GelSite™) extracted from Aloe vera for nasal delivery of a bivalent vaccine formulation containing both GI and GII.4 norovirus VLPs. Dose-ranging studies were performed to identify the optimal antigen dosages based on systemic and mucosal immune responses in guinea pigs and determine any antigenic interference. A dose-dependent increase in systemic and mucosal immunogenicity against each of the VLPs were observed as well as a boosting effect for each VLP after the second dosing. A total antigen dose of ≥50 μg of each GI and GII.4 VLPs was determined to be the maximally immunogenic dose in guinea pigs. The immunogenicity results of this bivalent formulation, taken together with previous work on monovalent GelVac™ norovirus vaccine formulation, provides a basis for future development of this norovirus VLP vaccine.

Norovirus Vaccine against Experimental Human Norwalk Virus Illness

Noroviruses cause epidemic and sporadic acute gastroenteritis. No vaccine is available to prevent norovirus illness or infection. We conducted a randomized, double-blind, placebo-controlled, multicenter trial to assess the safety, immunogenicity, and efficacy of an investigational, intranasally delivered norovirus viruslike particle (VLP) vaccine (with chitosan and monophosphoryl lipid A as adjuvants) to prevent acute viral gastroenteritis after challenge with a homologous viral strain, Norwalk virus (genotype GI.1). Healthy adults 18 to 50 years of age received two doses of either vaccine or placebo and were subsequently inoculated with Norwalk virus and monitored for infection and gastroenteritis symptoms. Ninety-eight persons were enrolled and randomly assigned to receive vaccine (50 participants) or placebo (48 participants), and 90 received both doses (47 participants in the vaccine group and 43 in the placebo group). The most commonly reported symptoms after vaccination were nasal stuffiness, nasal discharge, and sneezing. Adverse events occurred with similar frequency among vaccine and placebo recipients. A Norwalk virus-specific IgA seroresponse (defined as an increase by a factor of 4 in serum antibody levels) was detected in 70% of vaccine recipients. Seventy-seven of 84 participants inoculated with Norwalk virus were included in the per-protocol analysis. Vaccination significantly reduced the frequencies of Norwalk virus gastroenteritis (occurring in 69% of placebo recipients vs. 37% of vaccine recipients, P=0.006) and Norwalk virus infection (82% of placebo recipients vs. 61% of vaccine recipients, P=0.05). This norovirus VLP vaccine provides protection against illness and infection after challenge with a homologous virus. (Funded by LigoCyte Pharmaceuticals and the National Institutes of Health; ClinicalTrials.gov number, NCT00973284.).