Norovirus Vaccine Against Experimental Human GII.4 Virus Illness: A Challenge Study in Healthy Adults

Abstract

Background Vaccines against norovirus, the leading cause of acute gastroenteritis, should protect against medically significant illness and reduce transmission. Methods 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. Results 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). Conclusions Bivalent norovirus VLP vaccine reduced norovirus-related vomiting and/or diarrhea; field efficacy studies are planned. Clinical Trials Registration NCT01609257.

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

“…This trial was performed to evaluate the safety and tolerability of 2 doses of NoV VLPs produced in a baculovirus expression system containing GI.1 and GII.4. 129 The vaccine and placebo were administered intramuscularly. Eligible participants were of 18-50 y of age with functional FUT2 gene.…”

“…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. While the majority of these studies recruited healthy adults, HuNoV mainly affects children with acute gastroenteritis requiring hospitalizations.…”

“…125 The intramuscular administration of bivalent vaccine has also been associated with a reduction in acute gastroenteritis. 129 Recent developments have established evidence demonstrating the ability of MuNoVs to persistently infect mouse B cell lines in vitro. 71 The authors also tested the ability of GII.4 isolate to infect human B cell line; the former replicated efficiently in B cells and produced new infectious virus particles.…”

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

“…9 , 10 Intramuscular administration of the bivalent GI.1 and GII.4 VLP vaccine effectively induced genotype-specific antibody titers without adverse events, and the vaccinees were less likely to suffer from gastroenteritis in a challenge study with a natural GII.4 strain. 11 Collectively, past studies claim that IN vaccination needs significant improvements in terms of efficacy.…”