Takeda Pharmaceutical Company Limited (Takeda) announced results of a phase I/II study of its intramuscular bivalent (GI/GII) norovirus vaccine candidate in healthy adult volunteers who were challenged with the most commonly occurring norovirus (genotype GII.4) that causes gastroenteritis.

The study demonstrated that two doses of the experimental bivalent norovirus were well tolerated, and that the candidate vaccine had a clinically relevant impact on the incidence of norovirus illness after challenge, as well as the severity in breakthrough cases. In addition to the impact on clinical illness, a positive trend toward reduction in viral shedding in stool was observed. The study also provided important information toward optimization of confirmatory lab testing for norovirus disease and infection in a future field trial.

Norovirus gastroenteritis is most commonly associated with vomiting and diarrhea, and occurs in all age groups. In the study, a statistically significant reduction in mild, moderate or severe vomiting and/or diarrhoea was observed in vaccinated subjects, meeting the secondary endpoint of the study. The total number of subjects with gastroenteritis symptoms was also reduced in the vaccine group, but this reduction was not statistically significant and the primary endpoint was not met.

“Norovirus causes nearly 90 per cent of epidemic non-bacterial outbreaks of gastroenteritis around the world, leading to as many as 71,000 hospitalizations each year in the US alone,” said the study’s lead investigator David I. Bernstein, MD, M.A. and director of Infectious Diseases at Cincinnati Children’s Hospital. “There is a critical unmet medical need for a vaccine to combat this significant global health issue, and this vaccine candidate has the potential to address that need.”

“This is the first time that vaccination with a norovirus candidate vaccine has resulted in a reduction of symptoms caused by experimental exposure to the most common strain of norovirus, genotype GII.. We are very encouraged by these findings, from one of the largest human challenge studies performed to date, which pave the way for further development of this first-in-class vaccine,” said Rajeev Venkayya, MD, executive vice president and head of Takeda’s Vaccine Business Division. “The research and development of innovative vaccines like our norovirus candidate reflect Takeda’s commitment to addressing the most important challenges in global public health.”

Results from the phase I/II randomized, double blind, placebo-controlled multi-center study of 98 healthy adults, age 18-50 were:

• There were no cases of severe vomiting and/or diarrhea in the vaccine group versus four in the placebo group following challenge with live norovirus (0.0% vs. 8.3%; p=0.054).
• Although there were numerical reductions (68%) in moderate or severe vomiting or diarrhea, these did not reach statistical significance (6.0% vs. 18.8%; p=0.068).
• A secondary endpoint was met, with a 52 percent reduction against vomiting and/or diarrhea of any severity (20% of people who received the vaccine vs. 41.7% of those who received placebo; p=0.028).
• In those who experienced illness symptoms, severity of illness as measured by the Vesikari scoring system (modified for use in adults) was significantly reduced in vaccinees vs. placebo recipients (mean severity score of 3.1 vs. 5.0, p=0.023).
• Side effects were mostly mild and of limited duration, with pain at the injection site being the most common local reaction, similar to other vaccines. The most common systemic reaction was headache.
• A 4-fold increase in antibody titer was an inadequate measure of disease, as titers in vaccinees showed only a minor increase after challenge. PCR positivity did not differentiate between infection and disease.
• The primary composite endpoint of this study, the reduction of incidence of acute gastroenteritis of any severity and laboratory ascertainment for norovirus, was not met as per above. A manuscript detailing the study will be submitted for publication.

Takeda’s intramuscular bivalent norovirus vaccine contains virus-like particle (VLP) antigens resembling the virus while lacking the ability to reproduce or cause illness. VLPs mimic the natural virus by preserving the authentic structure of the viral capsid, the shell of protein that protects the nucleic acid of a virus.  The human immune system has been shown to respond to a VLP vaccine similar to encountering the live virus, allowing the body to build immune defenses capable of fighting infections. Without genetic material, VLP vaccines are incapable of causing infections themselves.

In a previous challenge study with a vaccine formulated for nasal administration, results showed a significant reduction in gastrointestinal illness in volunteers who were challenged with genotype I.1 norovirus. These results were published in The New England Journal of Medicine on December 8, 2011 . Collectively, the two challenge studies indicate that vaccination may be a useful tool to prevent disease caused by both genogroup I and genogroup II noroviruses, the two genogroups that are most commonly associated with norovirus infection in humans.

Norovirus gastroenteritis is a widespread and potentially severe illness characterized by the acute onset of nausea, vomiting, abdominal cramps, diarrhea and occasionally fever. Noroviruses are highly infective and easily transmitted from person to person or via contaminated environments. Epidemic outbreaks occur in community environments, particularly hospitals, hotels, schools, day care facilities and nursing homes, with mounting socioeconomic cost to families, the health care system and businesses. Military units are significantly affected when the virus strikes, as outbreaks impact combat readiness.  Severe clinical outcomes are reported in older adults, children and immunocompromised individuals in whom infection can lead to substantial complications and can even lead to death.

Takeda has a proven track record of manufacturing and supplying vaccines in Japan for more than sixty years. Takeda’s global vaccine business division was launched in January 2012 to build upon this success, and is headquartered in Deerfield, Illinois. The company acquired LigoCyte Pharmaceuticals and its norovirus vaccine candidate, as well as its proprietary virus like particle vaccine platform and several preclinical vaccine candidates in October 2012. In May 2013, Takeda acquired Inviragen, Inc., and its viral vaccines candidates for emerging infectious diseases, including dengue and hand, foot and mouth disease (HFMD).

Located in Osaka, Japan, Takeda is a research-based global company with its main focus on pharmaceuticals.