lipid-a and Caliciviridae-Infections

Vaccines against norovirus, the leading cause of acute gastroenteritis, should protect against medically significant illness and reduce transmission.. In this randomized, double-blind, placebo-controlled trial, 18- to 50-year-olds received 2 injections of placebo or norovirus GI.1/GII.4 bivalent vaccine-like particle (VLP) vaccine with 3-O-desacyl-4'-monophosphoryl lipid A (MPL) and alum. Participants were challenged as inpatients with GII.4 virus (4400 reverse transcription polymerase chain reaction [RT-PCR] units), and monitored for illness and infection.. Per protocol, 27 of 50 (54.0%) vaccinees and 30 of 48 (62.5%) controls were infected. Using predefined illness and infection definitions, vaccination did not meet the primary endpoint, but self-reported cases of severe (0% vaccinees vs. 8.3% controls; P = .054), moderate or greater (6.0% vs. 18.8%; P = .068), and mild or greater severity of vomiting and/or diarrhea (20.0% vs. 37.5%; P = .074) were less frequent. Vaccination also reduced the modified Vesikari score from 7.3 to 4.5 (P = .002). Difficulties encountered were low norovirus disease rate, and inability to define illness by quantitative RT-PCR or further antibody rise in vaccinees due to high vaccine-induced titers. By day 10, 11 of 49 (22.4%) vaccinees were shedding virus compared with 17 of 47 (36.2%) placebo recipients (P = .179).. Bivalent norovirus VLP vaccine reduced norovirus-related vomiting and/or diarrhea; field efficacy studies are planned. Clinical Trials Registration. NCT01609257.

Topics: Adjuvants, Immunologic; Adolescent; Adult; Caliciviridae Infections; Double-Blind Method; Female; Gastroenteritis; Humans; Lipid A; Male; Middle Aged; Norovirus; Vaccination; Viral Load; Viral Vaccines; Young Adult

Noroviruses cause significant morbidity and mortality from acute gastroenteritis in all age groups worldwide.. We conducted 2 phase 1 double-blind, controlled studies of a virus-like particle (VLP) vaccine derived from norovirus GI.1 genotype adjuvanted with monophosphoryl lipid A (MPL) and the mucoadherent chitosan. Healthy subjects 18-49 years of age were randomized to 2 doses of intranasal Norwalk VLP vaccine or controls 21 days apart. Study 1 evaluated 5-, 15-, and 50-μg dosages of Norwalk antigen, and study 2 evaluated 50- and 100-μg dosages. Volunteers recorded symptoms for 7 days after dosing, and safety was followed up for 180 days. Blood samples were collected for serological profile, antibody secreting cells (ASCs), and analysis of ASC homing receptors.. The most common symptoms were nasal stuffiness, discharge, and sneezing. No vaccine-related serious adverse events occurred. Norwalk VLP-specific immunoglobulin G and immunoglobulin A antibodies increased 4.8- and 9.1-fold, respectively, for the 100-μg dosage level. All subjects tested who received the 50- or 100-μg vaccine dose developed immunoglobulin A ASCs. These cells expressed molecules associated with homing to mucosal and peripheral lymphoid tissues.. The intranasal monovalent adjuvanted Norwalk VLP vaccine was well tolerated and highly immunogenic and is a candidate for additional study.

Topics: Adjuvants, Immunologic; Administration, Intranasal; Adolescent; Adult; Antibodies, Viral; Antibody-Producing Cells; Caliciviridae Infections; Chitosan; Double-Blind Method; Gastroenteritis; Hemagglutination Inhibition Tests; Humans; Lipid A; Lymphoid Tissue; Middle Aged; Mucous Membrane; Norwalk virus; Receptors, Lymphocyte Homing; Viral Vaccines; Young Adult

Norovirus (NoV) is a main cause of acute gastroenteritis across all ages worldwide. NoV vaccine candidates currently in clinical trials are based on noninfectious highly immunogenic virus-like particles (VLPs) delivered intramuscularly (IM). Since NoV is an enteric pathogen, it is likely that mucosal immunity has a significant role in protection from infection in the intestine. Due to the fact that IM delivery of NoV VLPs does not generate mucosal immunity, we investigated whether NoV genotype GII.4 VLPs coadministered with aluminum hydroxide (Al(OH)

Topics: Adjuvants, Immunologic; Aluminum Hydroxide; Animals; Antibodies, Viral; Caliciviridae Infections; Female; Humans; Immunity, Humoral; Immunity, Mucosal; Immunoglobulin A; Immunoglobulin G; Lipid A; Mice; Mice, Inbred BALB C; Norovirus; Vaccination; Vaccines, Virus-Like Particle; Viral Vaccines

The newly emerged Norovirus (NoV) Sydney 2012 strain has been sweeping all over the world, causing acute non-bacterial gastroenteritis in adults and children. Due to a lack of cell culture system, virus like particles (VLPs) has been assembled and used as vaccine candidates in preclinical and clinical studies. Expression of the major capsid protein of NoVs using recombinant baculovirus expression system in Sf9 cells leads to formation of VLPs that are morphologically and antigenically similar to true virions. In this study, VLPs were successfully produced using the VP1 of Sydney-2012-like strain and its immunogenicity was evaluated by different routes and its capability in inducing mucosal immune responses in the presence and absence of adjuvants in BALB/c mice. Administration of NoV VLPs in the presence of Al(OH)3 or monophosphoryl lipid A (MPL-A) led to high titers of VLP-specific IgG antibodies. Administration of VLPs orally in the presence of cholera toxin subunit B (CTB) didn't enhance mucosal immune response as less fecal IgA positive mice were observed when compared with those given VLPs only. Our study represents the first immunogenicity study of VLPs derived from current pandemic Sydney 2012 strain and which might have implications in the development of NoVs vaccine in china.

Topics: Adjuvants, Immunologic; Alum Compounds; Animals; Antibodies, Viral; Baculoviridae; Caliciviridae Infections; Cholera Toxin; Female; Gene Expression; Humans; Immunity, Mucosal; Immunization; Lipid A; Mice; Mice, Inbred BALB C; Norovirus; Recombinant Proteins; Sf9 Cells; Spodoptera; Vaccines, Virus-Like Particle; Viral Vaccines; Virion