Immunogenicity and specificity of norovirus Consensus GII.4 virus-like particles in monovalent and bivalent vaccine formulations. Parra Gabriel I,Bok Karin,Taylor Ross,Haynes Joel R,Sosnovtsev Stanislav V,Richardson Charles,Green Kim Y Vaccine Noroviruses, a major cause of acute gastroenteritis worldwide, present antigenic diversity that must be considered for the development of an effective vaccine. In this study, we explored approaches to increase the broad reactivity of virus-like particle (VLP) norovirus vaccine candidates. The immunogenicity of a GII.4 "Consensus" VLP that was engineered from sequences of three genetically distinct naturally occurring GII.4 strains was examined for its ability to induce cross-reactive immune responses against different clusters of GII.4 noroviruses. Rabbits immunized with GII.4 Consensus VLPs developed high serum antibody titers against VLPs derived from a number of distinct wild-type GII.4 viruses, including some that had been circulating over 30 years ago. Because the sera exhibited low cross-reactivity with antigenically distinct GI norovirus strains, we investigated the serum antibody response to a bivalent vaccine formulation containing GI.1 (Norwalk virus) and GII.4 Consensus VLPs that was administered to animals under varying conditions. In these studies, the highest homologous and heterologous antibody titers to the bivalent vaccine were elicited following immunization of animals by the intramuscular route using Alhydrogel (Al(OH)(3)) as adjuvant. Our data indicate that the use of both genetically engineered norovirus VLPs that incorporate relevant epitopes from multiple strains and multivalent vaccine formulations increase the breadth of the immune response to diverse variants within a genotype and, thus, prove helpful in the rational design of VLP-based vaccines against human noroviruses. 10.1016/j.vaccine.2012.03.050

6-Valent Virus-Like Particle-Based Vaccine Induced Potent and Sustained Immunity Against Noroviruses in Mice. Frontiers in immunology Norovirus is a major cause of acute gastroenteritis worldwide, and no vaccine is currently available. The genetic and antigenic diversity of Norovirus presents challenges for providing broad immune protection, which calls for a multivalent vaccine application. In this study, we investigated the possibility of developing a virus-like particle (VLP)-based 6-valent Norovirus vaccine candidate (Hexa-VLPs) that covers GI.1, GII.2, GII.3, GII.4, GII.6, and GII.17 genotypes. Hexa-VLPs (30 µg) adjuvanted with 500 µg of aluminum hydroxide (alum) were selected as the optimal immunization dose after a dose-escalation study. Potent and long-lasting blockade antibody responses were induced by 2-or 3-shot Hexa-VLPs, especially for the emerging GII.P16-GII.2 and GII.17 (Kawasaki 2014) genotypes. Hexa-VLPs plus alum elicited Th1/Th2 mixed yet Th2-skewed immune responses, characterized by an IgG1-biased subclass profile and significant IL-4 T-cell activation. Notably, simultaneous immunization with a mixture of six VLPs revealed no immunological interference among the component antigens. These results demonstrate that Hexa-VLPs are promising broad-spectrum vaccines to provide immunoprotection against major GI/GII epidemic strains in the future. 10.3389/fimmu.2022.906275

An oral NoV-rAd5 vaccine with built-in dsRNA adjuvant elicits systemic immune responses in mice. International immunopharmacology Norovirus (NoV) is an enteric pathogen notorious for causing epidemics of acute gastroenteritis. An effective vaccine against NoV is therefore urgently needed. A short double-stranded RNA (dsRNA) has been described that acts as a retinoic-acid-inducible gene-I agonist to induce the production of type I interferon; it also exhibits adjuvant activity. Using built-in dsRNA of different lengths (DS1 and DS2), we developed a recombinant adenovirus 5 (rAd5) expressing NoV VP1, and evaluated its immunogenicity following oral administration in a mouse model. An in vitro study demonstrated that the dsRNA adjuvants significantly enhanced VP1 protein expression in infected cells. The oral administration of both rAd5-VP1-DS vaccines elicited high serum levels of VP1-specific IgG and blocking antibodies, as well as strong and long-lasting mucosal immunity. There was no apparent difference in immunostimulatory effects in immunised mice between the two dsRNA adjuvants. This study indicates that an oral NoV-rAd5 vaccine with a built-in dsRNA adjuvant may be developed to prevent NoV infection in humans. 10.1016/j.intimp.2023.109801

Bivalent norovirus mRNA vaccine elicits cellular and humoral responses protecting human enteroids from GII.4 infection. NPJ vaccines Nucleoside-modified mRNA-LNP vaccines have revolutionized vaccine development against infectious pathogens due to their ability to elicit potent humoral and cellular immune responses. In this article, we present the results of the first norovirus vaccine candidate employing mRNA-LNP platform technology. The mRNA-LNP bivalent vaccine encoding the major capsid protein VP1 from GI.1 and GII.4 of human norovirus, generated high levels of neutralizing antibodies, robust cellular responses, and effectively protected human enteroids from infection by the most prevalent genotype (GII.4). These results serve as a proof of concept, demonstrating that a modified-nucleoside mRNA-LNP vaccine based on norovirus VP1 sequences can stimulate an immunogenic response in vivo and generates neutralizing antibodies capable of preventing viral infection in models of human gastrointestinal tract infection. 10.1038/s41541-024-00976-z