New Bivalent Norovirus Vaccine is Safe and Effective

David Bernstein, MD, MA is a very confident man. He asked vaccine and placebo subjects to drink down a sample of live, active norovirus after randomization in a double-blind, placebo controlled, multi-center trial of an experimental vaccine against the virus. Both groups were then observed for 4 days as inpatients. He was therefore pleased to announce on October 4, at IDWeek 2013, that the vaccine affords good protection and was not associated with serious side effects (and placebo subjects weren’t at severe risk-all trial subjects had been pre-screened for high risk of complications since the study protocol excluded the elderly, the young, and the immunocompromised). 

Now that most kids are vaccinated against rotovirus infection, norovirus has emerged as the most important cause of gastroenteritis in adults and children. It is especially important in schools, in military housing, and on cruise ships-anywhere people are living in close quarters. Dr Bernstein, a professor at University of Cincinatti College of Medicine in the Department of Pediatrics and Director of Cincinnati Children’s Gamble Program and vaccination testing and evaluation unit, notes that “we have all had this.” High-risk groups are at risk for complications and mortality from norovirus, but all of us are at risk for a highly debilitating illness with complete incapacitation and prostration. Typical symptoms are vomiting and diarrhea, with vomiting the predominant complaint.
  
The vaccine contains no active or live virus; it includes 2 immunogenic proteins expressed on a virus-like particle (VLP): the Norwalk variant (GI.1, responsible for 10% to 20% of norovirus infections), and GII.4, responsible for 60% of norovirus infections. These comprise the 2 most  common strains of norovirus. Of the eligible subjects (healthy adults between age 18 and 50 years) 50 were randomized to receive the vaccine, and 48 were randomized to placebo injection. At least 28 days after 2 intramuscular injections (28 days apart), all subjects had oral challenge with active norovius and were monitored in the hospital for acute gastroenteritis. Stool samples were collected at days 1, 2, 3, 4, 10, and 30 to test for anti-NoV antibodies. Subjective scoring scales were used to monitor symptoms.

Though the vaccine is only moderately effective at preventing any infection at all, it does appear to be very effective in preventing severe disease-the kind that causes doctor visits and late-night emergency room visits for dehydration. Among vaccinated subjects, 52% showed evidence of infection by NoV RT-PCR positive stool, compared with 60.4% in the placebo group-that’s only a modest effect. But the key to interpreting this study is to look at the vaccine’s effect on severity. No cases of severe vomiting or diarrhea were observed in the vaccinated group, versus 4 cases in the placebo group (0% vs 8.3%, p=.054). Fewer vaccinated subjects reported moderate or severe diarrhea or vomiting (6.0% vs 18.8%, p=0.068), and fewer vaccinated subjects shed norovirus at day 10 after challenge (22.4% vs 36.2%, p=.179). Vomiting and/or diarrhea of any severity was reduced by the vaccine (10.0% vs 41.7%, p=.028), the only effect that reached statistical significance.

Failing to reach statistical significance is a classic limitation of small studies of moderate effects, so larger field efficacy studies are the next step. Although the vaccine doesn’t prevent all disease, it makes a major dent in severe disease. Dr Bernstein confirms that the next step will be a large trial (with FDA cooperation), but the earliest commercial product is 5 years away. One limitation of the current study was that infection challenge only tested for protection against GII.4; hopefully future studies will confirm similar protection against GI.1.

Take note, this research was sponsored by Takeda Vaccines, and several of the investigators are consultants for or employees of Takeda. As such, be ready to do battle with the anti-vaccine faction, who will claim that the vaccine’s imperfect protection (not unusual); reliance on herd immunity (central to all vaccination strategies); and pharmaceutical industry sponsorship all invalidate scientific evidence of safety and efficacy. Hogwash.

Based on this study and larger ones to come, primary care physicians should be ready to advance public health once a commercial vaccine is available.

Source:
Bernstein DI, Atmar RL, Lyon M, et al. An intramuscluar (IM) bivalent Norovirus GI.1/GII.4 virus-like  particle (VLP) vaccine protects against vomiting and diarrhea in an experimental human GII.4 oral challente study. Paper presented at: IDWeek 2013; October 4, 2013; San Francisco, Calif. Abstract #LB-2. View on IDWeek 2013 Web site.