Developing novel vaccine formulations for single-dose immunisation

几乎所有目前的疫苗都需要在特定的时间间隔内分两次或三次接种，才能达到完全的效果。单剂免疫是一个由来已久的概念，可以显著提高全球疫苗接种覆盖率。到目前为止，开发单剂疫苗的尝试一直没有成功，关键障碍之一是设计能够在体内实现脉冲式(时间决定)疫苗释放的配方，同时保持抗原稳定性和免疫原性。该项目旨在开发疫苗递送配方，通过将加强疫苗封装成微粒并以可溶性形式与启动疫苗一起接种，将主要-增强疫苗组合成单剂。加强疫苗释放的时间和动力学将由化学成分和制备方法决定。一个特别的重点将放在利用新的生产技术来开发递送制剂(颗粒或凝胶)，以在体内稳定疫苗抗原。具有一系列降解曲线的各种生物相容聚合物将被用来产生具有不同动力学(连续/脉动)和抗原释放时间的颗粒。在模拟“体内”条件下对药物的颗粒大小、单分散性、包封率和释放动力学进行体外分析后，将在体内测试新制剂的药代动力学、安全性和免疫原性。新配方和颗粒生产的开发将包括工艺验证，并探索扩大规模和适用于GMP生产。最初，将使用模型抗原优化配方，然后使用目前最有希望的两种疫苗平台--病毒样颗粒(VLP)和病毒载体--测试这一过程。成功的配方将被推广到小鼠疾病挑战模型中，并与标准的Prime-Boost方案进行比较。该项目的重点是化学成分和配方，理想的候选人将有化学或药理学背景。

Almost all current vaccines require administration in two or three doses and at specific time intervals to achieve full efficacy. Single dose immunisation is a long-standing concept that could significantly improve vaccination coverage globally. Attempts to develop a single dose vaccine have so far been unsuccessful with one of the key obstacles being the design of formulations capable of achieving pulsatile (time-determined) vaccine release in vivo, while preserving antigen stability and immunogenicity. This project aims to develop vaccine delivery formulations that would allow prime-boost vaccination to be combined into a single dose by encapsulating the booster vaccine into microparticles and administering it together with the priming vaccine in soluble form. The timing and kinetics of the booster vaccine release will be determined by the chemical composition and method of preparation. A particular focus will be placed on utilising novel production techniques to develop delivery formulations (particles or gels) to stabilise the vaccine antigen in vivo. Various biocompatible polymers with a range of degradation profiles will be used to produce particles with different kinetics (continuous/pulsatile) and time to antigen release. Following in vitro analysis of particle size, monodispersity, encapsulation efficiency and release kinetics under simulated "in vivo" conditions, new formulations will be tested in vivo for pharmacokinetics, safety and immunogenicity. Development of novel formulation and particle production will encompass process validation and explore scale-up and suitability for GMP production. Initially the formulations will be optimised using a model antigen and will then move to testing the process using two of the currently most promising vaccine platforms, virus like particles (VLPs) and viral vectors. Successful formulations will be taken forward into mouse disease challenge models and compared with standard prime-boost regimens. This project has emphasis on chemical composition and formulation and the ideal candidate will have background in chemistry or pharmacology.