Norovirus Vaccine against Experimental Human Norwalk Virus Illness

Abstract

Background Noroviruses cause epidemic and sporadic acute gastroenteritis. No vaccine is available to prevent norovirus illness or infection. Methods We conducted a randomized, double-blind, placebo-controlled, multicenter trial to assess 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 a homologous viral strain, Norwalk virus (genotype GI.1). Healthy adults 18 to 50 years of age received two doses of either vaccine or placebo and were subsequently inoculated with Norwalk virus and monitored for infection and gastroenteritis symptoms. Results Ninety-eight persons were enrolled and randomly assigned to receive vaccine (50 participants) or placebo (48 participants), and 90 received both doses (47 participants in the vaccine group and 43 in the placebo group). The most commonly reported symptoms after vaccination were nasal stuffiness, nasal discharge, and sneezing. Adverse events occurred with similar frequency among vaccine and placebo recipients. A Nor-walk virus–specific IgA seroresponse (defined as an increase by a factor of 4 in serum antibody levels) was detected in 70% of vaccine recipients. Seventy-seven of 84 participants inoculated with Norwalk virus were included in the per-protocol analysis. Vaccination significantly reduced the frequencies of Norwalk virus gastroenteritis (occurring in 69% of placebo recipients vs. 37% of vaccine recipients, P = 0.006) and Norwalk virus infection (82% of placebo recipients vs. 61% of vaccine recipients, P = 0.05). Conclusions This norovirus VLP vaccine provides protection against illness and infection after challenge with a homologous virus. (Funded by LigoCyte Pharmaceuticals and the National Institutes of Health; ClinicalTrials.gov number, NCT00973284.)

Identification of a novel cellular target and a co-factor for norovirus infection – B cells & commensal bacteria

“…7 The VP1 protein can self-assemble into viruslike particles (VLPs) that are structurally similar to native virions. Clinical trials testing the efficacy of HuNoV VLPs as vaccine candidates administered intranasally or intramuscularly have demonstrated modest short-term (up to 1 month) protection from developing severe disease, 8,9 results that are encouraging but do not address the critical questions of immunity duration or cross-reactive protective immunity. Development of potentially more effective live attenuated viral vaccines has long been hindered by an inability to culture HuNoVs.…”

Norovirus vaccines: Correlates of protection, challenges and limitations

“…125 Two doses of vaccine or placebo were administered intranasally to healthy 18-50 y adults followed by homologous inoculation with HuNoV. The participants enrolled in this study were likely to develop NoV -associated gastroenteritis due to the expression of O or A blood groups and a functional FUT2 gene.…”

“…This study confirmed HuNoV infection however at a lower rate than those previously reported in other human challenge studies. 125,127 The most recent published data are the results of the phase I clinical trial using VLPs containing GI.1 and GII.4 administered intramuscularly to 18-49 y healthy adults. 130 The results show the ability of this bivalent vaccine to induce serum antibody responses to GI.1 and GII.4 antigens albeit higher in the former.…”

“…Both oral and intranasal modes of immunization elicited ab responses post vaccination (Table 2). 80,104,[123][124][125] Moreover, the intramuscular administration of candidate vaccines containing GI and GII strains stimulated strong immune responses against the vaccine genotype. 129,130 Human challenge studies 77,96 as well as vaccine studies (Table 2) tested the ability of different vaccine formulas to generate cross-reactive immune responses to account for the diversity of the circulating HuNoV strains.…”

More robust gut immune responses induced by combining intranasal and sublingual routes for prime-boost immunization

“…A monovalent GI.1VLP vaccine administered via the intranasal (IN) route was shown to provide good protection in a clinical trial. 7 To overcome the epidemiological differences of GI.1 and GII.4 genotypes, a bivalent VLP vaccine carrying GI.1 and GII.4 genotypes was proposed for IN administration and shown to be immunogenic without the use of adjuvant in a guinea pig model. 8 However, intramuscular administration of monovalent GI.1VLPs has been shown to achieve better antigen delivery and antibody responses in adults at a lower dosage than IN immunization.…”