Plant-based production of a vaccine against gonorrhoea

该项目的主要优先领域是“可再生资源和清洁增长的生物科学——在新的低碳生物经济中通过基于生物的过程和产品改造工业”。该项目侧重于植物生物技术，因此完全符合BBSRC的范围。该建议将介绍改进疫苗生产绩效的方法；特别是，向植物性表达的过渡提供了大大降低生产能源成本的潜力，特别是在低收入国家。此外，靶向抗原提呈细胞是一种破坏性技术，从某种意义上说，它有可能取代非靶向疫苗方法，从而解决诱导保护性免疫是疫苗开发主要障碍的疾病。淋病奈瑟菌（Neisseria gonorrhoeae, Ng）抗菌素耐药性（AMR）的出现使防治这种细菌成为一项国际优先事项。黄疸是性传播感染（STI）的主要原因，每年造成100亿例病例。无法治疗Ng对女性生殖和胎母健康（通过盆腔炎、异位妊娠、不孕症）产生不利影响，而淋球菌感染是HIV传播的重要辅助因素。此外，对淋球菌（Gc）传播的控制受到抗生素耐药性上升的威胁。虽然疫苗是对抗耐药细菌威胁的重要途径，但由于感染、抗原变异和以前的失败尝试后缺乏保护性免疫，Gc疫苗的研究一直受到阻碍。然而，最近的进展为疫苗开发提供了新的动力——一种用于抵抗脑膜炎奈瑟菌的外膜囊泡疫苗（OMV）与对Ng的适度但显著的保护有关，这提示了一种鉴定保护性抗原的方法。基于单一重组Ng抗原的疫苗接种策略在小鼠感染模型和临床试验中都取得了有限的成功。一种新的方法是使用病毒样颗粒（vlp）——或者最近引入的大型合成大分子组装——作为抗原递送的平台。这些发展为疫苗设计提供了迄今尚未开发的潜力。此外，德里克实验室最近开发了一种技术，可以将任意数量的抗原融合到特定的VLP或组装中。关键的是，该方法还允许单克隆抗体的容易融合：结合针对表面受体的抗体，从而允许靶向树突状细胞或其他抗原呈递细胞的特定亚群。通过将靶标驱动的抗体治疗技术与传统疫苗设计相结合，这一发展有望改变疫苗设计的游戏规则。它可以提供必要的突破，以绕过对Ng再感染的弱保护性免疫的挑战。此外，人们对在生物制药和疫苗中使用基于植物的表达系统越来越感兴趣，特别是在发展中国家的应用。因此，该项目旨在利用Anil Day开发的基于质体的表达方法，使重组蛋白的产量非常高，并将其应用于修饰的VLPs、组装和Ng抗原。

The principal BBSRC priority area addressed by this project is 'Bioscience for renewable resources and clean growth - transforming industries through bio-based processes and products in a new low-carbon bioeconomy'. The project has a focus on plant biotechnology and therefore fits firmly within the BBSRC ambit. The proposal will introduce ways to improve the performance of vaccine production; in particular, transition to plant-based expression offers the potential for much reduced production energy costs, particularly in low income countries. Further, the targeting of antigen presenting cells is a disruptive technology, in the sense that it has the potential to overtake non-target vaccine approaches and thus address disease where induction of protective immunity is a major roadblock to vaccine development. The emergence of antimicrobial resistance (AMR) in Neisseria gonorrhoeae (Ng) has made combatting this bacterium an international priority. Ng is a leading cause of sexually transmitted infection (STI), responsible for >100 million cases annually. The inability to treat Ng adversely impacts female reproductive and foeto-maternal health (through pelvic inflammatory disease, ectopic pregnancy, infertility), while gonococcal infection is an important co-factor for HIV transmission. Furthermore, control of the gonococcal (Gc) transmission is threatened by the rise in antibiotic resistance. While vaccines are an important approach against the threat of resistant bacteria, Gc vaccine research has been hampered by the lack of protective immunity following infection, antigenic variation and previous failed attempts. However, recent advances have provided fresh impetus for vaccine development- an outer membrane vesicle vaccine (OMV) used against Neisseria meningitidis was associated with a modest yet significant protection against Ng, suggesting an approach to identify protective antigens. Vaccination strategies based on single recombinant Ng antigens have met with limited success, both in mouse infection models and clinical trials. A novel approach would be to use virus-like particles (VLPs)- or the more recently introduced large, synthetic macromolecular assemblies- as platforms for antigen delivery. These developments offer a hitherto untapped potential in vaccine design. In addition, the Derrick lab has recently developed a technology which allows the fusion of any number of antigens to a specific VLP or assembly. Critically, the method also allows for facile fusion of monoclonal antibodies: incorporation of antibodies directed against surface receptors thus allows targeting against specific subsets of dendritic or other antigen presenting cells. This development promises a game-changing approach to vaccine design, by combining target-driven antibody therapeutic technologies with traditional vaccine design. It could provide the breakthrough needed to circumvent the challenge of weak protective immunity against Ng reinfection. In addition, there is increasing interest in the use of plant-based expression systems for biopharmaceuticals and vaccines, particularly for application in developing countries. This project therefore aims to exploit methods developed by Anil Day for plastid-based expression, which enables very high yields of recombinant proteins, and apply them to modified VLPs, assemblies and Ng antigens.