Safety and Immunogenicity of Different Formulations of the Takeda Norovirus Vaccine Candidate in Healthy Adults: A Randomized, Controlled, Double-Blind Clinical Trial

Background: Norovirus (NoV) is responsible for a high morbidity burden and is the world’s leading cause of acute gastroenteritis. We investigated immunogenicity and safety in healthy adults of one or two doses of 11 formulations of Takeda’s intramuscular bivalent virus-like particle (VLP) vaccine candidate against NoV genotypes GI.1 and a consensus GII.4.

Methods: This phase II, double-blind, controlled trial, enrolled 420 healthy adults in Belgium, aged 18–64 years. Volunteers, randomized to 14 equal groups, received one or two doses of NoV vaccine candidates, 28 days apart, or hepatitis A vaccine to maintain the blind. All NoV formulations contained Al(OH)₃ adjuvant with 15μg or 50μg of GI.1 VLP antigen and 15μg, 50μg, or 150μg GII.4 VLP antigen, and 0, 15μg, or 50μg MPL adjuvant. Humoral immunity was assessed as ELISA Pan-Ig and histo-blood group binding antigen blocking titers (HBGA) at Days 1, 56, 208 and 393. Exploratory assessments of T and B cell responses were performed at Days 1 and 393. Safety was assessed as solicited local and systemic adverse events for 7 days post-vaccination, and SAEs and significant new medical events throughout the trial.

Results: All groups displayed marked increases in Pan-Ig and HBGA to both genotypes at Day 56 that persisted above base-line levels through Day 393. Anti-GI.1 responses were generally unaffected by antigen content and MPL, whereas anti-GII.4 responses were better with reduced GI.1 VLP content. All vaccine formulations elicited memory T and B cell responses still detectable at Day 393. Formulations with 15μg GI.1/50μg GII.4 without MPL elicited the best balance of responses. All formulations were generally well tolerated, the most frequent reaction being mild pain at the injection site. No vaccine related SAEs were reported. A second dose produced only minor increases in antibodies and no increase in reactogenicity profile.

Conclusion: All NoV vaccine formulations were well tolerated and immunogenic, increased immunity to vaccine antigens persisting up to a year. There were no major benefits of MPL or a second dose in adults presumably exposed at earlier ages. The study identified the most promising Takeda NoV vaccine candidate formulation to be taken further for development in healthy adults.