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Orthogonal modular biosynthesis of nanoscale conjugate vaccines for vaccination against infection.

ABSTRACT: Conjugate vaccines represent one of the most effective means for controlling the occurrence of bacterial diseases. Although nanotechnology has been greatly applied in the field of vaccines, it is seldom used for conjugate vaccine research because it is very difficult to connect polysaccharides and nanocarriers. In this work, an orthogonal and modular biosynthesis method was used to produce nanoconjugate vaccines using the SpyTag/SpyCatcher system. When SpyTag/SpyCatcher system is combined with protein glycosylation technology, bacterial O-polysaccharide obtained from Shigela flexneri 2a can be conjugated onto the surfaces of different virus-like particles (VLPs) in a biocompatible and controlled manner. After confirming the excellent lymph node targeting and humoral immune activation abilities, these nanoconjugate vaccines further induced efficient prophylactic effects against infection in a mouse model. These results demonstrated that natural polysaccharide antigens can be easily connected to VLPs to prepare highly efficient nanoconjugate vaccines. To the best of the researchers' knowledge, this is the first time VLP-based nanoconjugate vaccines are produced efficiently, and this strategy could be applied to develop various pathogenic nanoconjugate vaccines.

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Supplementary material (Figs. S1-S9) is available in the online version of this article at 10.1007/s12274-021-3713-4.

SUBMITTER: Li X

PROVIDER: S-EPMC8359766 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Orthogonal modular biosynthesis of nanoscale conjugate vaccines for vaccination against infection.

Li Xin X Pan Chao C Sun Peng P Peng Zhehui Z Feng Erling E Wu Jun J Wang Hengliang H Zhu Li L

Nano research 20210812 2

Conjugate vaccines represent one of the most effective means for controlling the occurrence of bacterial diseases. Although nanotechnology has been greatly applied in the field of vaccines, it is seldom used for conjugate vaccine research because it is very difficult to connect polysaccharides and nanocarriers. In this work, an orthogonal and modular biosynthesis method was used to produce nanoconjugate vaccines using the SpyTag/SpyCatcher system. When SpyTag/SpyCatcher system is combined with p ...[more]

PMID: 34405037

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Project description:UnlabelledConjugate vaccines are known to be one of the most effective and safest types of vaccines against bacterial pathogens. Previously, vaccine biosynthesis has been performed by using N-linked glycosylation systems. However, the structural specificity of these systems for sugar substrates has hindered their application. Here, we report a novel protein glycosylation system (O-linked glycosylation via Neisseria meningitidis) that can transfer virtually any glycan to produce a conjugate vaccine. We successfully established this system in Shigella spp., avoiding the construction of an expression vector for polysaccharide synthesis. We further found that different protein substrates can be glycosylated using this system and that the O-linked glycosylation system can also effectively function in other Gram-negative bacteria, including some strains whose polysaccharide structure was not suitable for conjugation using the N-linked glycosylation system. The results from a series of animal experiments show that the conjugate vaccine produced by this O-linked glycosylation system offered a potentially protective antibody response. Furthermore, we elucidated and optimized the recognition motif, named MOOR, for the O-glycosyltransferase PglL. Finally, we demonstrated that the fusion of other peptides recognized by major histocompatibility complex class II around MOOR had no adverse effects on substrate glycosylation, suggesting that this optimized system will be useful for future vaccine development. Our results expand the glycoengineering toolbox and provide a simpler and more robust strategy for producing bioconjugate vaccines against a variety of pathogens.ImportanceRecently, the rapid development of synthetic biology has allowed bioconjugate vaccines with N-linked protein glycosylation to become a reality. However, the difficulty of reestablishing the exogenous polysaccharide synthetic pathway in Escherichia coli hinders their application. Here, we show that an O-linked protein glycosylation system from Neisseria meningitidis, which has a lower structure specificity for sugar substrates, could be engineered directly in attenuated pathogens to produce effective conjugate vaccines. To facilitate the further design of next-generation bioconjugate vaccines, we optimized a novel short motif consisting of 8 amino acids that is sufficient for glycosylation. Our results expand the application potential of O-linked protein glycosylation and demonstrate a simpler and more robust strategy for producing bioconjugate vaccines against different pathogens. In the future, bacterial antigenic polysaccharides could be attached to major histocompatibility complex binding peptides to improve immunological memory or attached to protein subunit vaccine candidates to provide double immune stimulation.

Project description:The World Health Organization (WHO) prioritizes pneumococcal disease as a vaccine-preventable disease and recommends the inclusion of pneumococcal conjugate vaccines (PCV) in national immunization programs worldwide. However, PCV is not included in the National Immunization Program in China and has low vaccination coverage due to its high cost. To address this, Weifang City implemented an innovative strategy for a 13-valent PCV (PCV13) on June 1, 2021. This strategy aimed to provide one dose of PCV13 free of charge for children aged 6 months to 2 years in registered households and to adopt a commercial insurance model with one dose of PCV13 free of charge in 2023 for children over 2 years old. The Health Commission of Weifang and other departments conducted a comprehensive investigation and considered various factors, such as vaccine effectiveness, safety, accessibility, vaccine price, and immunization schedules, for eligible children (under 5 years old). Stakeholder opinions were also solicited before implementing the policy. The Commission negotiated with various vaccine manufacturers to maximize its negotiating power and reduce vaccine prices. The implementation plan was introduced under the Healthy Weifang Strategy. Following the implementation of this strategy, the full course of vaccination coverage increased significantly from 0.67 to 6.59%. However, vaccination coverage is still lower than that in developed countries. Weifang's PCV13 vaccination innovative strategy is the first of its kind in Chinese mainland and is an active pilot of non-immunization program vaccination strategies. To further promote PCV13 vaccination, Weifang City should continue to implement this strategy and explore appropriate financing channels. Regions with higher levels of economic development can innovate the implementation of vaccine programs, broaden financing channels, improve accessibility to vaccination services, and advocate for more localities to incorporate PCV13 into locally expanded immunization programs or people-benefiting projects. A monitoring and evaluation system should also be established to evaluate implementation effects.

Project description:Several vaccines have been developed against highly pathogenic avian influenza (HPAI), mostly inactivated whole-virus vaccines for chickens. In the EU, one vaccine is authorised in chickens but is not fully efficacious to stop transmission, highlighting the need for vaccines tailored to diverse poultry species and production types. Off-label use of vaccines is possible, but effectiveness varies. Vaccines are usually injectable, a time-consuming process. Mass-application vaccines outside hatcheries remain rare. First vaccination varies from in-ovo to 6 weeks of age. Data about immunity onset and duration in the target species are often unavailable, despite being key for effective planning. Minimising antigenic distance between vaccines and field strains is essential, requiring rapid updates of vaccines to match circulating strains. Generating harmonised vaccine efficacy data showing vaccine ability to reduce transmission is crucial and this ability should be also assessed in field trials. Planning vaccination requires selecting the most adequate vaccine type and vaccination scheme. Emergency protective vaccination is limited to vaccines that are not restricted by species, age or pre-existing vector-immunity, while preventive vaccination should prioritise achieving the highest protection, especially for the most susceptible species in high-risk transmission areas. Model simulations in France, Italy and The Netherlands revealed that (i) duck and turkey farms are more infectious than chickens, (ii) depopulating infected farms only showed limitations in controlling disease spread, while 1-km ring-culling performed better than or similar to emergency preventive ring-vaccination scenarios, although with the highest number of depopulated farms, (iii) preventive vaccination of the most susceptible species in high-risk transmission areas was the best option to minimise the outbreaks' number and duration, (iv) during outbreaks in such areas, emergency protective vaccination in a 3-km radius was more effective than 1- and 10-km radius. Vaccine efficacy should be monitored and complement other surveillance and preventive efforts.

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Orthogonal modular biosynthesis of nanoscale conjugate vaccines for vaccination against infection.

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Orthogonal modular biosynthesis of nanoscale conjugate vaccines for vaccination against infection.

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