First clinical trial results for norovirus vaccine outlined

Oct 28, 2010 (CIDRAP News) – In the first clinical trial of a norovirus vaccine—in which volunteers were deliberately exposed to the common gastrointestinal virus—the inoculation reduced participants' risk of illness by 47%, according to results released recently by LigoCyte Pharmaceuticals, Inc.

In an Oct 25 news release, LigoCyte CEO Donald P. Beeman said the results are "very encouraging, indicating statistically significant reductions in clinical norovirus illness, infection, and severity of illness in subjects who received vaccine compared to those who received placebo."

Preliminary results of the trial, which involved about 80 volunteers, were presented at the Infectious Diseases Society of America's annual conference in Vancouver, B.C., last week, said the company, which is based in Bozeman, Mont.

The Centers for Disease Control and Prevention (CDC) estimates that noroviruses cause about 21 million cases of gastric illness per year in the United States, and there is no vaccine or specific treatment. The virus often spreads via food, and prevention depends primarily on hand washing and safe food and water.

In an interview, Beeman said LigoCyte's vaccine is the first norovirus vaccine to reach the clinical trial stage. The vaccine is a dry powder formulation containing virus-like particles (VLPs) that preserve the structure of the norovius capsid, the protein shell that protects the virus's nucleic acid, the company said. The product is administered topically inside the nose, not inhaled, Beeman explained.

The company is also developing a norovirus vaccine that is given by intramuscular injection and is now in a phase 1 trial, he said.

Trial design
The clinical trial, a phase 1/2 study, was conducted at several sites and led by Robert Atmar, MD, of Baylor College of Medicine, as principal investigator, the company reported. The researchers recruited about 90 healthy adults between the ages of 18 and 50 and randomly assigned them in double-blind fashion to receive two doses of the vaccine or a placebo, 3 weeks apart.

Three weeks after the second dose, the volunteers were admitted to a nursing unit and given a drink containing live norovirus. They were kept in the unit at least 4 days and afterward were monitored with clinical assessments and stool sampling, the company said.

The vaccine was found to have 47% efficacy (P=.006) against any norovirus illness, including mild illness, and 26% efficacy (P=.046) against infection, the firm reported. In the 77 volunteers who fully completed the trial, vaccination decreased the incidence of illness from 69% to 37% and the incidence of infection from 82% to 61%. The severity of illness was also reduced significantly in the vaccinees (P=.011), officials said.

Craig Hedberg, PhD, a foodborne disease expert at the University of Minnesota School of Public Health, who was not involved in the study, said that while the preliminary findings are positive, "a phase 3 trial would need to demonstrate a much stronger effect for this to be a useful vaccine."

Though the vaccine reduced the infection rate, 61% of the vaccinees were still infected, he noted. "The key question here would be to determine if and for how long these persons were capable of transmitting infection," he added. "This is very important for considerations of how the vaccine would be used. If most people still shed virus, the vaccination would not be a great prevention measure for food handlers."

A parallel with rotavirus vaccine?
Beeman, commenting on the efficacy findings, said that in further trials, "We're sure going to try to optimize things that way. We look at the results and recall the early results of rotavirus vaccine trials, and we believe we're in the same ballpark as the early studies of rotavirus vaccine. We need to show good efficacy in preventing severe disease, which is very similar to what you see in rotavirus vaccine for kids."

He said the study includes an assessment of viral shedding, but "we weren't [statistically] powered to get a whole lot of information there. But we'll play close attention in future trials." He noted that data on the degree of viral shedding by individuals are not yet available.

Hedberg said another question concerning any norovirus vaccine is how long the immunity would last. It's not clear that even natural infection confers long-term immunity, he explained. Since the vaccine uses VLPs rather than an intact norovirus, it would probably have to be given annually, like flu vaccines, he said.

"This would be required both because of limited immunity and the variability in norovirus antigenicity that occurs naturally," Hedberg said. "I don't think an annual norovirus shot would be as acceptable as an annual flu shot," since norovirus infection is not as serious an illness as flu.

Concerning duration of immunity, Beeman commented, "Our plan is try and design a vaccine that would give multiple years of protection." He said that noroviruses do evolve and change, but they don't seem to show the same level of "shift and drift" as flu viruses do.

"It looks to us that there's a promise of vaccine lasting more than" a year, he said. "We'll have to wait and see how the trials go and see if we're able to protect against new strains as time goes on."

LigoCyte plans to start a larger phase 2 trial next, Beeman said. The company will examine the results of the phase 1 trial of the intramuscular vaccine before deciding whether to use the intramuscular formulation or the intranasal formulation in the phase 2 study, he explained.

The company has developed VLPs for group I and II (GI and GII) norovirus strains, Beeman said. The intranasal vaccine used in the phase 1/2 trial targeted just one strain, but the intramuscular vaccine targets both, he reported. The two strains together account for about 80% to 90% of norovirus cases, he said.

To reach the market, any norovirus vaccine probably will have to target both GI and GII strains, Beeman said. "We don't believe there's a way to have just one strain of virus in the vaccine. It probably has to be bivalent."

See also:

Oct 25 LigoCyte press release

CDC technical fact sheet on norovirus
http://www.cdc.gov/ncidod/dvrd/revb/gastro/norovirus-factsheet.htm

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