Clinical Development of the Takeda Norovirus VLP Vaccine Candidate.

Background: Noroviruses (NoVs), are the leading cause of acute infectious gastroenteritis worldwide, with an estimated 200,000 fatalities annually in at risk populations such as the very young and older adults, especially those with underlying conditions, at a global cost of billions of US dollars. NoVs are highly infectious, challenging to neutralize in the environment, and easily spread through multiple routes of transmission including fecal-oral, person-to-person, aerosol, food-borne and contaminated surfaces. Unpredictable outbreaks in closed settings such as hospitals, long-term care facilities, cruise liners, and the military have significant impact. A safe and effective vaccine would be an important tool in the control of this disease.

Methods: Of the 7 currently known NoV genogroups, the most frequent cause of human disease in order of prevalence are genogroups II (GII) and I (GI), the latter including the first identified, Norwalk virus. Takeda Vaccines is developing a bivalent, adjuvanted, norovirus vaccine candidate based on virus-like particles (VLPs) from a GI.1 strain, and a consensus GII.4 sequence derived from three natural GII.4 variants intended to induce a broad immune response in all age groups. Candidate vaccine formulations are adjuvanted with Al(OH)₃and administered intramuscularly.

Results: Investigational formulations were evaluated in Phase I and II trials and a human challenge study, including balanced and unbalanced dosages with 5–150 µg of each VLP, with and without monophosphoryl lipid A (MPL). Approximately 1200 adults and older adults, and 240 children have been enrolled in these trials to date. All NoV candidate vaccine formulations were generally well tolerated with acceptable safety profiles. No vaccine-related SAEs or AESIs were reported. High and rapid immune responses have been observed, assessed as anti-VLP total Ig and IgA, and blocking of histoblood group antigen (HBGA) VLP binding, indicated as a potential serologic correlate of protection in human challenge studies. Responses persist above baseline for up to a year post-vaccination, with no appearance of unexpected medical conditions during this period.

Conclusion: Phase IIb and III studies are planned to finalize the vaccine formulation and schedule, and measure protection in the field.