Among healthy adult volunteers who were inoculated with Norwalk virus, a novel vaccine significantly reduced the rate of infection (61% versus 82%, P=0.05) and gastroenteritis (37% versus 69%, P=0.006) in a per-protocol analysis, according to Robert Atmar, MD, of Baylor College of Medicine in Houston, and colleagues.
The results, which show the feasibility of developing a norovirus vaccine, were similar in the intention-to-treat analysis, the researchers reported in the Dec. 8 issue of the New England Journal of Medicine.
"The future success of vaccine development will be influenced by a number of challenges related to biologic characteristics of norovirus," they wrote. "The frequency and magnitude of serum antibody responses after vaccination were lower than those induced by infection."
In addition, the duration of protection from vaccination is unclear, and the vaccine evaluated in the study protected against the Norwalk strain (genotype GI.1) of norovirus only. Any vaccine brought to market will likely need to protect against both GI and GII strains, and may need to undergo periodic changes in composition to account for genetic drift similar to what occurs with influenza viruses, according to the researchers.
"Noroviruses are antigenically and genetically diverse, with at least eight and 19 genotypes in the GI and GII genogroups, respectively," they noted.
These viruses cause an estimated 21 million cases of gastroenteritis each year in the U.S., with up to 1.1 million hospitalizations as well as 218,000 deaths among children in developing countries. There is no vaccine.
Based on promising preliminary studies, Atmar and colleagues conducted a randomized, double-blind, placebo-controlled trial at four sites to evaluate an investigational norovirus virus-like particle (VLP) vaccine, which contained chitosan and monophosphoryl lipid A as adjuvants.
The researchers enrolled 98 healthy adults ages 18 to 50 (mean age 32.1). All had a functional FUT2 gene and blood group O or A, characteristics that make it likely illness will develop after exposure to the virus.
The participants received two doses of vaccine or placebo three weeks apart and were then inoculated with Norwalk virus. They spent at least four days in the hospital for observation.
Only 84 of the participants received two doses of vaccine or placebo and were challenged with the virus; they comprised the modified intention-to-treat population. After excluding five individuals who experienced a malfunction in their dose-delivery device, one who became infected with another norovirus during the challenge period, and one because of excessive eating followed by vomiting, 77 were included in the per-protocol analysis.
The most frequent symptoms after vaccination were nasal stuffiness, nasal discharge, and sneezing.
Adverse events occurred at similar rates in the two groups after the first dose of vaccine or placebo, but after the second dose nasal symptoms were more frequent in the vaccine group. There were no severe nasal symptoms during the study.
The researchers did not observe any vaccine-related severe adverse events or any new medically significant conditions.
The vaccine was immunogenic, inducing a Norwalk virus-specific IgA seroresponse in 70% of vaccine recipients.
In addition to reduced rates of infection and gastroenteritis, the vaccine was associated with a significant reduction in the severity of disease (P=0.009).
The onset of illness was delayed among vaccine recipients by a nonsignificant 2.1 hours in the per-protocol analysis (P=0.12) and by a significant 4.3 hours in the intention-to-treat analysis (P=0.02).
The vaccine did not impact illness duration.
The authors noted some limitations of the study, including the fact that the placebo did not include the adjuvants from the vaccine; several malfunctions of the dose-delivery device; and the need to evaluate the vaccine's immunogenicity and efficacy in other populations and in a natural setting.
The study was supported by LigoCyte Pharmaceuticals and by a grant from the NIH to the Baylor College of Medicine General Clinical Research Center.
Atmar reported that his institution received money related to the study from LigoCyte Pharmaceuticals. He has been a consultant for GlaxoSmithKline and Novartis and has received money from Haymarket Media for the development of educational presentations. His co-authors reported relationships with the SNBL Clinical Pharmacology Center, LigoCyte, the NIH, Novartis, Denka Pharmaceuticals, Global Vaccines, Immucell, and EMMES. One of the authors is employed by EMMES and two others are employed by LigoCyte.
- Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner
New England Journal of MedicineSource Reference: Atmar R, et al "Norovirus vaccine against experimental human Norwalk virus illness" N Engl J Med 2011; 365: 2178-2187.