Norovirus Vaccines: Current Clinical Development and Challenges

Abstract

Noroviruses are the major viral pathogens causing epidemic and endemic acute gastroenteritis with significant morbidity and mortality. While vaccines against norovirus diseases have been shown to be of high significance, the development of a broadly effective norovirus vaccine remains difficult, owing to the wide genetic and antigenic diversity of noroviruses with multiple co-circulated variants of various genotypes. In addition, the absence of a robust cell culture system, an efficient animal model, and reliable immune markers of norovirus protection for vaccine evaluation further hinders the developmental process. Among the vaccine candidates that are currently under clinical studies, recombinant VP1-based virus-like particles (VLPs) that mimic major antigenic features of noroviruses are the common ones, with proven safety, immunogenicity, and protective efficacy, supporting a high success likelihood of a useful norovirus vaccine. This short article reviews the recent progress in norovirus vaccine development, focusing on those from recent clinical studies, as well as summarizes the barriers that are being encountered in this developmental process and discusses issues of future perspective.

Mucosal and systemic neutralizing antibodies to norovirus and rotavirus by oral immunization with recombinant rotavirus in infant mice

“…To develop a HuNoV vaccine, several HuNoV VLPs have been assessed in clinical trials (39)(40)(41). In addition, some viral vectors expressing HuNoV VLPs have been used to induce a mucosal response against HuNoV VLPs in mice or humans (i.e., Venezuelan equine encephalitis virus replicon, vesicular stomatitis virus, and adenovirus) (5-8).…”

“…In addition, some viral vectors expressing HuNoV VLPs have been used to induce a mucosal response against HuNoV VLPs in mice or humans (i.e., Venezuelan equine encephalitis virus replicon, vesicular stomatitis virus, and adenovirus) (5-8). Among these viruses, the adenovirus type 5-based HuNoV vaccine is the only one to have been studied in phase I human clinical trials (8, 40). In that model, development of immunity to the adenovirus type 5 expression vector itself would not add significant protection against a second important pediatric enteric infection and so RV immunity would need to be addressed by a separate vaccine.…”

“…The HuNoV virion consists of major capsid protein VP1 and minor capsid protein VP2 surrounding a positivesense RNA genome (33)(34)(35). Exogenously expressed VP1 can form virus-like particles (VLPs) that are structurally and antigenically similar to HuNoV virions (36)(37)(38) and the parenteral administration of such VLPs provides some level of protective immunity to HuNoV in adults (39)(40)(41). Moreover, expression of the protruding or P domain of VP1 that bears the major antigenic sites of HuNoV can yield subunit "P particles" that can also induce immune responses (42,43).…”

Evaluation of a bivalent recombinant vaccine candidate targeting norovirus and rotavirus: Antibodies to rotavirus NSP4 exert antidiarrheal effects without virus neutralization

“…Due to the success of rotavirus vaccines, norovirus has become the most important viral pathogen causing epidemic acute gastroenteritis. Unlike rotavirus, there is currently no commercial vaccine against norovirus, although several vaccines are currently under clinical development (reviewed by Tan 12 ). This lack of vaccines is mainly attributed to the absence of a conventional culture approach for growing human norovirus 13–15 and the lack of a robust animal model for evaluating vaccine candidates.…”

Bovine natural antibody IgM inhibits the binding of human norovirus protruding domain to its HBGA receptors

“…For example, an enzyme‐linked immunosorbent assay (ELISA)‐based binding and blocking assay using recombinant capsid proteins as HuNoV model and saliva samples as HBGA sources has been developed [ 12 ] and used to surrogate neutralization assay [ 13 ] to evaluate vaccine and antivirals. Currently, there are no licensed antiviral drugs or vaccines against HuNoVs [ 14 ].…”