Virus-like particles as future norovirus vaccines

Abstract

Future VirologyVol. 10, No. 8 EditorialFree AccessVirus-like particles as future norovirus vaccinesKari DebbinkKari Debbink*Author for correspondence: E-mail Address: kdebbink@umich.edu Department of Internal Medicine, University of Michigan, MI 48109, USA Department of Microbiology, University of Michigan, MI 48109, USASearch for more papers by this authorPublished Online:13 Aug 2015https://doi.org/10.2217/fvl.15.63AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit Keywords: norovirusvaccinesvirus-like particlesVLPsNoroviruses cause significant gastrointestinal disease worldwide, resulting in the death of an estimated 200,000 children under the age of five each year [1]. In the USA, these viruses annually infect an estimated 21 million people [2], and norovirus disease burden is costly in terms of health care expenditures and resource utilization, lost productivity, loss of contaminated products, decontamination of infected areas and disruption of vacations, events and activities. In the USA alone, norovirus-associated health costs are estimated at US$2 billion annually [3]. Noroviruses are spread via the fecal–oral route through contaminated food, water and surfaces often in settings like retirement communities, educational facilities, military barracks and cruise ships where people are in close proximity. Together, these factors demonstrate that norovirus is an epidemiologically and economically important virus. Unfortunately, there is currently no licensed norovirus vaccine, and several major factors including lack of model systems, viral diversity and a nascent understanding of human immune responses to this pathogen impede the development of efficacious norovirus vaccines. Despite these complications, several vaccine platforms are currently under development, and virus-like particle (VLP) vaccines show promise in human clinical trials.One of the most significant hurdles to studying norovirus is lack of an efficient cell culture and small animal model for human norovirus. Because of this, human norovirus cannot be efficiently cultivated and thus neither the biological relevance of specific mutations nor viral pathogenesis can be directly evaluated using authentic virus. As a consequence, norovirus VLPs have emerged as a surrogate system to indirectly study many aspects of norovirus biology. VLPs are made up of multiple copies of the norovirus capsid protein that self-assemble into empty capsids, retaining the morphological features of the virus that target host cells and are recognized by the human immune system. Importantly, the use of VLPs for norovirus research has allowed for the identification of important antigenic sites for major circulating strains [4,5] and for development of VLP-based vaccine platforms [6,7].Successful licensed VLP vaccines are available for human HPV [8], hepatitis B [9] and hepatitis E [10], demonstrating the excellent potential of the VLP platform. A candidate norovirus VLP vaccine developed by Takeda Pharmaceuticals has already been tested in Phase I and II human clinical trials. To date, this is the only norovirus vaccine candidate to have been tested in humans, and these clinical trials suggest that the VLP platform can be successful for norovirus as well. The Takeda norovirus vaccine is a bivalent vaccine containing VLPs representing two of the over 30 different norovirus genotypes that infect humans [11]: GI.1 Norwalk virus and a recombinant GII.4 consensus sequence. This bivalent vaccine design is meant to address another complication in norovirus vaccine development – namely the vast antigenic diversity among strains. While there appears to be some cross protection between certain groups [12], most genotypes are antigenically distinct [13]. It would be impossible to include all of these antigenically distinct groups in a single vaccine, so vaccine strains will need to be prioritized based on the most epidemiologically important genotypes. Further complicating this, some genotypes exhibit intragenotype antigenic diversity over time as their surface proteins evolve and evade the human immune response. The primary example of this is GII.4 noroviruses, for which a new, antigenically distinct strain emerges every 2–4 years, eventually replacing the previous strain [14]. This genotype also causes approximately 70% of all norovirus outbreaks [15], making it the most epidemiologically significant genotype. In response, the Takeda vaccine features a recombinant GII.4 component that is a consensus sequence of three separate GII.4 strains. By including a VLP that incorporates sequence from different strains, the goal is to induce an immune response that is protective against a variety of GII.4 strains. Recent work examining immune responses from individuals suggests that this approach is promising, as the GII.4 consensus VLP was able to induce blockade responses against VLPs representing strains not included in the vaccine [16]. Despite this, GII.4 evolution over time will still likely necessitate periodic vaccine reformulations. Fortunately, VLP vaccines have the potential to be updated relatively easily.In Phase II clinical trials, vaccination resulted in a 47% relative reduction in vomiting and diarrhea in norovirus infected vaccinees compared with control subjects, but only a 13% relative reduction in complete protection from infection [7]. This result is both promising and disappointing. On one hand, this VLP vaccine clearly has potential to reduce norovirus symptoms, but on the other, there is obvious room for major improvements both in terms of reducing symptoms and providing complete protection. Importantly, though, it is very likely that our fragmented understanding of the human immune response to norovirus, and not the VLP vaccine platform itself, is responsible for the low vaccine efficacy. While human challenge studies and initial vaccine efficacy trials have certainly furthered understanding of norovirus immunity, this work has exposed the complexities of norovirus immunity as it appears to vary by norovirus genotype [12,13], host genetic background [17] and pre-exposure history [16]. We have certainly only begun to explore the tip of the iceberg in respect to understanding the best way to induce broad, sustained protection against important norovirus strains, and future vaccine iterations will likely improve significantly as we learn more.In addition to VLPs, there are other vaccine platforms currently being developed for noroviruses including nanoparticles [18] and virus replicons [19]. A drawback to many newer vaccine strategies is that they have never been safety tested in humans or are at the initial stages of testing. This is problematic in terms of bringing a vaccine to market because unlike tested methods like live-attenuated viruses or inactivated viral vaccines that have known safety bars to pass, these newer, more unknown methods may present novel safety risks that require more rigorous testing. This extends the time it will take for these newer vaccines to win government licensing. In fact, the only vaccine platforms that have been licensed for other viruses are live-attenuated viruses, inactivated viruses (or their derivative subunits) and VLP vaccines. In terms of developing a norovirus vaccine, this is problematic. Of these approved platforms, VLP vaccines are the only currently possible option for human norovirus. Because of the inability to grow human norovirus to high titers outside of humans, there is no way to cultivate the large quantities of virus that would be needed to develop and manufacture a live-attenuated or inactivated vaccine, or to test attenuating mutations needed to ensure safety for a live-attenuated vaccine.Currently, VLP-based vaccines are our best bet for norovirus. They are a vaccine strategy that has been used successfully for other viruses, they have already shown efficacy in human clinical trials, and they can be updated and reformulated based on the most epidemiologically important strains. However, new approaches to developing norovirus vaccines should be encouraged and tested. The immune system response to norovirus is still largely unknown, and it is possible that new vaccine platforms will be able to address and solve immunogenic problems that VLPs cannot. Likewise, VLP technologies will also evolve as we learn more about the interplay between norovirus biology and the host immune response. Future research will hopefully uncover methods to culture noroviruses efficiently in cell culture, allowing for development of live-attenuated or inactivated virus vaccines. VLP vaccines are the immediate future for norovirus vaccines. For the long term, we will have to see.Financial & competing interests disclosureK Debbink has a patent pending (US Application No. 61/887, 101. “Methods and Compositions For Norovirus Blockade Epitopes”). The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.References1 Patel MM, Widdowson MA, Glass RI et al. 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Systemic, mucosal, and heterotypic immune induction in mice inoculated with venezuelan equine encephalitis replicons expressing Norwalk virus-like particles. J. Virol. 76(2), 730–742 (2002).Crossref, Medline, CAS, Google ScholarFiguresReferencesRelatedDetails Vol. 10, No. 8 Follow us on social media for the latest updates Metrics History Published online 13 August 2015 Published in print August 2015 Information© Future Medicine LtdKeywordsnorovirusvaccinesvirus-like particlesVLPsFinancial & competing interests disclosureK Debbink has a patent pending (US Application No. 61/887, 101. “Methods and Compositions For Norovirus Blockade Epitopes”). The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download