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      Novel bovine viral diarrhea virus (BVDV) virus-like particle vaccine candidates presenting the E2 protein using the SpyTag/SpyCatcher system induce a robust neutralizing antibody response in mice

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          Abstract

          Bovine viral diarrhea virus (BVDV) is a pathogen of commercial consequence in cattle. Although many modified live and killed vaccines are commercially available, their drawbacks precipitate the need for new effective vaccines. Virus-like particles (VLPs) are a safe and powerful technology used in several human and veterinary vaccines; however, it is difficult to produce large amounts of BVDV VLPs. In this study, we generated red-spotted grouper nervous necrosis virus (RGNNV) VLPs presenting the BVDV E2 protein (domain I to IIIb) of the Nose (BVDV-1) or KZ-91-CP (BVDV-2) strain by exploiting SpyTag/SpyCatcher technology. Mice immunized twice with 30 μg of RGNNV VLPs conjugated with 10 μg of E2 proteins of the Nose or KZ-91-CP strain with a 14-day interval elicited high (1:512,000 to 1:1,024,000) and moderate (1:25,600 to 1:102,400) IgG titers against E2 proteins of homologous and heterologous strains, respectively. In addition, this prime-boost regimen induced strong (1:800 to 1:3,200) and weak (~1:10) neutralization titers against homologous and heterologous BVDV strains, respectively. Our results indicate that conjugation of the E2 protein to RGNNV VLPs strongly enhances the antigenicity of the E2 protein and that RGNNV VLPs presenting the E2 protein are promising BVDV vaccine candidates.

          Supplementary Information

          The online version contains supplementary material available at 10.1007/s00705-022-05653-x.

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          Most cited references48

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          Vaccine delivery: a matter of size, geometry, kinetics and molecular patterns.

          Researchers working on the development of vaccines face an inherent dilemma: to maximize immunogenicity without compromising safety and tolerability. Early vaccines often induced long-lived protective immune responses, but tolerability was a major problem. Newer vaccines have very few side effects but can be of limited immunogenicity. One way to tackle this problem is to design vaccines that have all the properties of pathogens with the exception of causing disease. Key features of pathogens that can be mimicked by vaccine delivery systems are their size, shape and surface molecule organization. In addition, pathogen-associated molecular patterns can be used to induce innate immune responses that promote adaptive immunity. In this Review, we discuss the approaches currently being used to optimize the delivery of antigens and enhance vaccine efficacy.
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            Peptide tag forming a rapid covalent bond to a protein, through engineering a bacterial adhesin.

            Protein interactions with peptides generally have low thermodynamic and mechanical stability. Streptococcus pyogenes fibronectin-binding protein FbaB contains a domain with a spontaneous isopeptide bond between Lys and Asp. By splitting this domain and rational engineering of the fragments, we obtained a peptide (SpyTag) which formed an amide bond to its protein partner (SpyCatcher) in minutes. Reaction occurred in high yield simply upon mixing and amidst diverse conditions of pH, temperature, and buffer. SpyTag could be fused at either terminus or internally and reacted specifically at the mammalian cell surface. Peptide binding was not reversed by boiling or competing peptide. Single-molecule dynamic force spectroscopy showed that SpyTag did not separate from SpyCatcher until the force exceeded 1 nN, where covalent bonds snap. The robust reaction conditions and irreversible linkage of SpyTag shed light on spontaneous isopeptide bond formation and should provide a targetable lock in cells and a stable module for new protein architectures.
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              Virus-like particles: preparation, immunogenicity and their roles as nanovaccines and drug nanocarriers

              Virus-like particles (VLPs) are virus-derived structures made up of one or more different molecules with the ability to self-assemble, mimicking the form and size of a virus particle but lacking the genetic material so they are not capable of infecting the host cell. Expression and self-assembly of the viral structural proteins can take place in various living or cell-free expression systems after which the viral structures can be assembled and reconstructed. VLPs are gaining in popularity in the field of preventive medicine and to date, a wide range of VLP-based candidate vaccines have been developed for immunization against various infectious agents, the latest of which is the vaccine against SARS-CoV-2, the efficacy of which is being evaluated. VLPs are highly immunogenic and are able to elicit both the antibody- and cell-mediated immune responses by pathways different from those elicited by conventional inactivated viral vaccines. However, there are still many challenges to this surface display system that need to be addressed in the future. VLPs that are classified as subunit vaccines are subdivided into enveloped and non- enveloped subtypes both of which are discussed in this review article. VLPs have also recently received attention for their successful applications in targeted drug delivery and for use in gene therapy. The development of more effective and targeted forms of VLP by modification of the surface of the particles in such a way that they can be introduced into specific cells or tissues or increase their half-life in the host is likely to expand their use in the future. Recent advances in the production and fabrication of VLPs including the exploration of different types of expression systems for their development, as well as their applications as vaccines in the prevention of infectious diseases and cancers resulting from their interaction with, and mechanism of activation of, the humoral and cellular immune systems are discussed in this review.
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                Author and article information

                Contributors
                ktakeuch@md.tsukuba.ac.jp
                Journal
                Arch Virol
                Arch Virol
                Archives of Virology
                Springer Vienna (Vienna )
                0304-8608
                1432-8798
                7 January 2023
                2023
                : 168
                : 2
                : 49
                Affiliations
                [1 ]GRID grid.20515.33, ISNI 0000 0001 2369 4728, Laboratory of Environmental Microbiology, Faculty of Medicine, , University of Tsukuba, ; 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575 Japan
                [2 ]GRID grid.416882.1, ISNI 0000 0004 0530 9488, Exotic Disease Research Group, , National Institute of Animal Health, National Agriculture and Food Research Organization (NARO), ; 6-20-1 Josuihoncho, Kodaira, Tokyo 187-0022 Japan
                [3 ]GRID grid.410773.6, ISNI 0000 0000 9949 0476, College of Agriculture, , Ibaraki University, ; 3-21 Chuo, Ami, Ibaraki 300-0332 Japan
                Author notes

                Handling Editor: Morgana Barboza.

                Author information
                http://orcid.org/0000-0002-2253-4009
                Article
                5653
                10.1007/s00705-022-05653-x
                9825097
                36609880
                ba5ae8cf-ba97-4e8c-ab3a-e130ef8c7020
                © The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature 2023, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                History
                : 7 July 2022
                : 7 November 2022
                Funding
                Funded by: JSPS KAKENHI
                Award ID: 20K07524
                Award Recipient :
                Categories
                Original Article
                Custom metadata
                © Springer-Verlag GmbH Austria, part of Springer Nature 2023

                Microbiology & Virology
                Microbiology & Virology

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