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Norovirus Capsid Protein-Derived Nanoparticles and Polymers as Versatile Platforms for Antigen Presentation and Vaccine Development.

ABSTRACT: Major viral structural proteins interact homotypically and/or heterotypically, self-assembling into polyvalent viral capsids that usually elicit strong host immune responses. By taking advantage of such intrinsic features of norovirus capsids, two subviral nanoparticles, 60-valent S60 and 24-valent P24 nanoparticles, as well as various polymers, have been generated through bioengineering norovirus capsid shell (S) and protruding (P) domains, respectively. These nanoparticles and polymers are easily produced, highly stable, and extremely immunogenic, making them ideal vaccine candidates against noroviruses. In addition, they serve as multifunctional platforms to display foreign antigens, self-assembling into chimeric nanoparticles or polymers as vaccines against different pathogens and illnesses. Several chimeric S60 and P24 nanoparticles, as well as P domain-derived polymers, carrying different foreign antigens, have been created and demonstrated to be promising vaccine candidates against corresponding pathogens in preclinical animal studies, warranting their further development into useful vaccines.

SUBMITTER: Tan M

PROVIDER: S-EPMC6781506 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Norovirus Capsid Protein-Derived Nanoparticles and Polymers as Versatile Platforms for Antigen Presentation and Vaccine Development.

Tan Ming M Jiang Xi X

Pharmaceutics 20190912 9

Major viral structural proteins interact homotypically and/or heterotypically, self-assembling into polyvalent viral capsids that usually elicit strong host immune responses. By taking advantage of such intrinsic features of norovirus capsids, two subviral nanoparticles, 60-valent S<sub>60</sub> and 24-valent P<sub>24</sub> nanoparticles, as well as various polymers, have been generated through bioengineering norovirus capsid shell (S) and protruding (P) domains, respectively. These nanoparticle ...[more]

PMID: 31547456

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Project description:Adeno-associated virus (AAV) vectors have been successfully applied in clinical trials for hemophilic patients. Although promising, the clinical results suggest that the capsid-specific CD8+T cell response has a negative effect on therapeutic success. In an in vitro analysis using an engineered AAV virus carrying immune-dominant SIINFEKL peptide in the capsid backbone, we have previously demonstrated that capsid antigen presentation from full (genome containing) AAV capsids requires endosome escape and is proteasome dependent and that no capsid antigen presentation is induced from empty virions. In the present study, we examined capsid antigen presentation from administration of empty virions in animal models. In wild-type mice, similar to AAV full particles, capsid antigen presentation from AAV empty virion infection was dose dependent, and the kinetics studies showed that antigen presentation was detected from 2 to 40 days after AAV empty virion administration. In the transporter associated with antigen processing 1 deficient (TAP-/-) mice, capsid antigen presentation was inhibited from both AAV full and empty virions, but higher inhibition was achieved from AAV full particle administration than that from empty virions. This indicates that the pathway of capsid antigen presentation from AAV transduction is dependent on proteasome-mediated degradation of AAV capsids (mainly for full particles) and that the endosomal pathway may also play a role in antigen presentation from empty particles but not full virions. The capsid antigen presentation efficiency from AAV preparations was positively correlated with the amount of empty virions contaminated with full particles. Collectively, the results indicate that contamination of AAV empty virions induces efficient antigen presentation in vivo and the mechanism of capsid antigen presentation from empty virions involves both endosomal and proteasomal pathways. The elucidation of capsid antigen presentation from AAV empty virions may allow us to rationally design effective strategies to prevent elimination of AAV transduced target cells by capsid specific CD8+ T cells.

Project description:Diarrhea is the most common infection in children under the age of 5 years worldwide. In spite of this, only a few vaccines to treat infectious diarrhea exist, and many of the available vaccines are sparingly and sporadically administered. Major obstacles to the development and widespread implementation of vaccination include the ease and cost of production, distribution, and delivery. Here we present a novel, customizable, and self-assembling vaccine platform that exploits the Vibrio cholerae bacterial biofilm matrix for antigen presentation. We use this technology to create a proof-of-concept, live-attenuated whole-cell vaccine that is boosted by spontaneous association of a secreted protein antigen with the cell surface. Sublingual administration of this live-attenuated vaccine to mice confers protection against V. cholerae challenge and elicits the production of antigen-specific IgA in stool. The platform presented here enables the development of antigen-boosted vaccines that are simple to produce and deliver, addressing many of the obstacles to vaccination against diarrheal diseases. This may also serve as a paradigm for the development of broadly protective biofilm-based vaccines against other mucosal infections.IMPORTANCE Diarrheal disease is the most common infection afflicting children worldwide. In resource-poor settings, these infections are correlated with cognitive delay, stunted growth, and premature death. With the development of efficacious, affordable, and easily administered vaccines, such infections could be prevented. While a major focus of research on biofilms has been their elimination, here we harness the bacterial biofilm to create a customizable platform for cost-effective, whole-cell mucosal vaccines that self-incorporate secreted protein antigens. We use this platform to develop a sublingually administered live-attenuated prototype vaccine based on Vibrio cholerae This serves not only as a proof of concept for a multivalent vaccine against common bacterial enteric pathogens but also as a paradigm for vaccines utilizing other bacterial biofilms to target mucosal infections.

Dataset Information

Norovirus Capsid Protein-Derived Nanoparticles and Polymers as Versatile Platforms for Antigen Presentation and Vaccine Development.

Publications

Norovirus Capsid Protein-Derived Nanoparticles and Polymers as Versatile Platforms for Antigen Presentation and Vaccine Development.

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