The state of norovirus vaccines

Abstract

Noroviruses represent the most important cause of acute gastroenteritis worldwide; however, currently no licensed vaccine exists. Widespread vaccination that minimizes overall norovirus disease burden would benefit the entire population, but targeted vaccination of specific populations such as healthcare workers may further mitigate the risk of severe disease and death in vulnerable populations. While a few obstacles hinder the rapid development of efficacious vaccines, human trials for virus-like particle (VLP)-based vaccines show promise in both immune response and protection studies, with availability of vaccines being targeted over the next 5-10 years. Ongoing work including identification of important norovirus capsid antigenic sites, development of improved model systems, and continued studies in humans will allow improvement of future vaccines. In the meantime, a better understanding of norovirus disease course and transmission patterns can aid healthcare workers as they take steps to protect high-risk populations such as the elderly and immunocompromised individuals from chronic and severe disease.

Keywords: norovirus; vaccine.

Figure 1.

Factors that complicate norovirus vaccine design. Vaccine development for noroviruses is hampered by several factors including the limited number of challenge and vaccine efficacy studies done in humans, the absence of a cell culture system and limited animal models for testing vaccines, the limited and conflicting data on how long protective immunity lasts after infection or vaccination in humans, differing evolutionary patterns and antigenic profiles between genogroups and among genotypes within genogroups, antigenic variation within GII.4 noroviruses and possibly within other genotypes, and the unknown effects of exposures to multiple norovirus genotypes and strains during a lifetime on the immune response to newly encountered strains.

Figure 2.

GII.4 potential neutralization sites. A, A cryo electron microscopy image shows the virion structure for a GII norovirus. Approximate positions are shown for the capsid protein shell domain (red), the P1 subdomain (yellow/green), and the P2 subdomain (gray). The black circle indicates a single P2 dimer. B, A single GII.4 norovirus capsid P2 dimer (top view) is shown. Evolving surface-exposed blockade epitopes A (dark blue), D (light blue), and E (purple) are shown. Histoblood group antigen interaction sites are shown in black. These blockade epitopes represent potential vaccine and drug targets for GII.4 noroviruses.

Figure 3.

Design of a multivalent norovirus virus-like particle vaccine. A, Large circles represent the 2 major norovirus genogroups that infect humans, GI and GII. Smaller circles within the larger circles represent the 9 (G1) and 22 (GII) individual genotypes within each genogroup. B, Heterogeneity of GI and GII viruses necessitates a multivalent vaccine to maximize protective coverage of multiple genotypes. Multivalent vaccines that contain virus-like particles (VLPs) representing GI.1 and GII.4 components (red circles) cover norovirus genotypes responsible for approximately 80% of outbreaks. However, a multivalent approach likely broadens the immune response to potentially protect against some heterologous norovirus genotypes (green circles) as well. Heterologous genotypes (green) are shown as examples and are not representative of published data. C, Continued work on norovirus VLP vaccines should consider that there will likely be epidemiological changes over time where relative changes in disease burden by different genotypes occur and strain replacement occurs every 2–4 years for GII.4 noroviruses. Thus, norovirus vaccines will need to be reformulated over time C.1: in response to changes in epidemiologically important viruses; and C.2: in response to changing antigenicity of GII.4 noroviruses. Changes in epidemiologically important norovirus genotypes in C.1 are shown as examples and are not representative of published data.