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

BACKGROUND: Acute 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. METHODS: In 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)(3)adjuvant 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. RESULTS: Marked 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. CONCLUSION: Older 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