One-step and scalable manufacture of lymphatic - targeting liposomal vaccines

背景资料。疫苗是预防传染病最有效、最具成本效益的方法。然而，全球获得疫苗的机会仍然面临着明显的障碍：据估计，全世界仍有1940万婴儿错过了基本疫苗。为了解决这一问题，需要从制造商到接受者不间断地提供高质量的疫苗。目前，这一供应链受到一系列因素的阻碍，包括疫苗供应不足以及当地储存、处理和管理疫苗的能力有限，因为许多疫苗需要冷藏。因此，供应链的敏捷性与有效和耐热的疫苗系统的开发相结合是必要的。广泛的研究表明，脂质体可作为疫苗抗原的合适佐剂。事实上，项目合作团队的工作已经证明，我们可以控制脂质体的物理化学属性(包括大小、电荷和双层刚性和组成)，以增强佐剂疗效[1]。因此，通过利用脂质体，我们能够减少生产有效疫苗所需的抗原量，从而提高疫苗产量。因此，我们可以使用这些纳米颗粒在疫苗制造中提供经济效率，并降低它们的成本和制造时间。除了它们的佐剂特性外，申请人还证明了通过在这些双层纳米颗粒中加入抗原，蛋白质抗原可以稳定下来。因此，脂质体有可能绕过疫苗冷链供应的需要，并改善当地的能力和供应。然而，脂质体疫苗是复杂的配方，需要新的制造解决方案来允许负担得起的和地理上的获取。为了解决这一问题，我们将在我们之前成功合作的基础上[2]，使用新的微流控工艺来制造复杂的配方，以提高疫苗的效力。因此，我们将在床边和通过可扩展的连续制造来满足他们的制造需求。为了促进疫苗配方中节省剂量的机会，该项目将开发淋巴靶向疫苗。通常，注射后，大约50%的注射剂量的脂质体通过淋巴管引流从注射部位清除，其余剂量保留在注射部位，这取决于脂质体的设计[1]。然而，淋巴内给药已被证明能促进更强的免疫反应[3]。虽然这不是疫苗接种的现实途径，但它表明有必要加强脂质体佐剂对淋巴管的靶向性。因此，该项目将开发耐热的靶向脂质体佐剂，这种佐剂可以通过灵活和自适应的工艺制造，并可以在快速反应模式下放大和缩小。该项目的可测量成果包括：1)开发一种新型的淋巴靶向脂质体佐剂，促进强大的免疫反应；2)设计和设计一种用于床边和连续生产脂质体佐剂的微流控平台。

Background. Vaccines are the most powerful and cost-effective way to prevent infectious diseases. Yet, global access to vaccines continues to face notable barriers: it is estimated that 19.4 million infants worldwide are still missing out on basic vaccines. To address this, an uninterrupted supply of high-quality vaccines, from manufacturer to recipient, is needed. Currently this supply chain is hindered by a range of factors including insufficient vaccine supply and limited local capacity to store, handle and administer vaccines as many require refrigeration. Therefore, agility in the supply chain combined with the development of effective and thermostable vaccine systems is required. A wide range of studies has shown that liposomes act as suitable adjuvants for vaccine antigens. Indeed, work from the project collaborative team has demonstrated that we can control liposomal physicochemical attributes (including size, charge and bilayer rigidity and composition) to enhance adjuvant efficacy [1]. Therefore, by exploiting liposomes we are able to reduce the amount of antigen required to produce effective vaccines and hence enhance vaccine yield. We can thus use these nanoparticles to deliver economical efficiencies in vaccine manufacture and drive down their cost and time of manufacture. In addition to their adjuvant properties, the applicants have also demonstrated that by incorporating antigen within these bilayer nanoparticles, protein antigens can be stabilised. Thus, liposomes could offer the potential to circumvent the need for cold-chain supply of vaccines and improve local capacity and supply. However, liposomal vaccines are complex formulations that require new manufacturing solutions to allow affordable and geographical access. To address this, we will build on our previous successful collaboration [2] and use novel microfluidic processes to manufacture complex formulations which will enhance vaccine efficacy. Thus we will address their manufacturing requirements both at the bedside and through scalable continuous manufacturing. To promote dose-sparing opportunities in vaccine formulation, this project will develop lymphatic-targeting vaccines. Normally, after injection, approximately 50 % of the injected dose of liposomes clears from the injection site by drainage through the lymphatics, with the rest of the dose remaining at the injection site depending on the design of the liposomes [1]. Yet, intralymphatic administration, has been shown to promote stronger immune responses [3]. Whilst this is not a realistic route for vaccination, it demonstrates the need to enhance the targeting of liposomal adjuvant to the lymphatics. Therefore, this project will develop thermostable targeted liposomal adjuvants which can be manufactured using flexible and adaptive processes and can be scaled up and down in a rapidly responsive mode.Measurable outcomes for this project are 1) Develop a novel lymphatic-targeting liposomal adjuvant that promotes robust immune responses and 2) Design and engineering of a microfluidics platform for bedside and continuous manufacturing of liposomal adjuvants.