Effects of Norovirus VLP Vaccine

Although noroviruses are a leading cause of epidemic acute gastroenteritis and sporadic cases of acute gastroenteritis, a reliable vaccine for these types of viruses has not yet been developed, nor has any specific therapy been developed to treat these viruses. Norwalk virus, the prototypical human norovirus, is the most extensively studied human norovirus. Susceptibility to Norwalk virus infection is dependent on expression of a functional fucosyltransferase 2 (FUT2) gene; persons who have a nonfunctional FUT2 gene are genetically resistant to Norwalk virus infection. In this investigation, the authors sought to test the safety, immunogenicity, and efficacy of an investigational, intranasally delivered norovirus viruslike particle (VLP) vaccine (with chitosan and monophosphoryl lipid A as adjuvants) to prevent acute viral gastroenteritis after challenge with the homologous Norwalk virus strain (genotype GI.1). The investigation [N Engl J Med. 2011;365(23):2178-2187] was a randomized, double-blind, placebo-controlled, multicenter (4 sites) trial. Enrollment began September 2009 and was completed by January 2010. A total of 98 people (of 454 screened patients) were enrolled (mean age, 32.1 years; 41% were women, and 65% had blood type O). Eligible patients were healthy men and women between 18 and 50 years of age who were positive for the presence of fucosyltransferase 2—they had a functional FUT2 gene—as determined phenotypically by means of identification of histo-blood group antigens in saliva. The study was conducted in 2 stages: the vaccination stage and the Norwalk virus challenge stage. Eligible participants were randomly assigned to receive the study vaccine or placebo in a 1:1 ratio, stratified according to clinical site. Vaccine and placebo were administered in 2 intranasal doses given 3 weeks apart. The primary objective was to evaluate the efficacy of the vaccine in preventing the primary end point: viral gastroenteritis caused by the Norwalk virus. Of the 98 participants, 50 received vaccine and 48 received placebo. Of the 90 persons who received 2 doses of vaccine or placebo, 84 participated in the Norwalk virus challenge (of the remaining 6 participants, 4 were lost to follow-up, 1 withdrew, and 1 became pregnant) and constituted the intention-to-treat population for the efficacy evaluation. A total of 82 participants began the challenge phase 3 weeks after completing the vaccination phase. Local and systemic adverse events after vaccination occurred with similar frequency in the vaccine and placebo groups after the first study dose was administered. Systemic symptoms were reported more frequently after the first dose than after the second in both the vaccine group (52% vs 26%) and the placebo group (51% vs 37%). Adverse events (nasal stuffiness, nasal discharge, and sneezing) were reported most frequently on the day of vaccination and declined in frequency going forward. Five Norwalk virus–specific serologic assays were used to measure vaccine immunogenicity. Immune responses were observed most frequently with the use of the total serum antibody ELISA (assays of IgG, IgA, and IgM antibodies combined) and the serum IgA antibody ELISA. These 2 tests showed a seroresponse (defined as an increase by a factor of 4 in serum antibody levels) in 70% of participants in the per-protocol population after 2 doses of study vaccine. Seroresponses were observed less frequently with the IgG, IgM, and histo-blood group antigen–blocking antibody assays. Norwalk virus–associated gastroenteritis occurred in 69% of the placebo recipients and 37% of vaccines, for an absolute reduction with the vaccine of 32 percentage points (P=.006) and a relative reduction of 47%. Vaccination also reduced the relative frequency of Norwalk virus infection after challenge with the virus, with infection occurring in 82% of placebo recipients and 61% of vaccine recipients, for an absolute reduction of 2 percentage points (P=.05) and a relative reduction of 26%.