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

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.

The benefits of the proposed EPSRC Centre for Doctoral Training (CDT) aligned to the EPSRC Centre for Innovative Manufacture of Emergent Macromolecular Therapies will be significant. The CDT will address an acute skills storage of trained manpower, needed to take this industry forward for the benefit of the UK, and ultimately to improve the levels of healthcare provision nationally. This is a radical new opportunity for the industry which suffers from a lack of joined up thinking and hence tends to operate in discrete silos of expertise. The integrated approach offered by the CDT would pay high dividends. UK companies will benefit from access to highly skilled doctorates who will each have benefited from a wide and interdisciplinary research approach created by the CDT. Macromolecular medicines are complex and labile so that bioprocess development times and costs tend to be high due to unforeseen issues that occur during scale-up of the manufacturing process. Currently there is little scope to alter a manufacturing process because the effect of changes cannot be readily predicted. This is compounded by lack of individuals skilled in the methods needed. Our transformative CDT research training agenda will allow for the first time engineers and scientists to create the methods and approaches needed for UK companies to genuinely understand and control directly, for the first time, the quality of output during manufacture, in spite of biological variability. By creating and then testing manufacturing models and methods for whole bioprocesses using the resources of a national EPSRC Centre we shall gain fundamental engineering insights crucial for the more effective direction of acquisitions of experimental data and also the improved design and operation of whole bioprocesses. Manufacturing efficiencies will be raised and waste reduced. Such a vision is consistent with recent efforts by the regulatory authorities, and in particular the Quality by Design (QbD) initiative of the International Committee on Harmonisation (ICH), to develop science-based regulatory submissions for approval to manufacture new biological products. The CDT will create a network to provide a conduit for effective knowledge exchange from the very best academic groups in the UK. A key metric of success will be retention of CDT graduates within the industry where they will be effective in the application of Centre concepts with industrial practice and the adoption of the methods created. Potential patients will benefit as the innovations created by the CDT research will significantly aid reduction in development times of macromolecular medicines, which is particularly crucial for those addressing previously unmet clinical needs and the treatment of severe conditions such as arthritis, cardiovascular disease, viral infections and cancers. By providing industry the capabilities and tools to achieve changes to manufacturing processes we shall open up possibilities for major improvements to processes during production and hence reduce costs to the NHS. The capacity to treat conditions such as rheumatoid arthritis much more effectively in ageing populations is vital but it still poses a problem with respect to stretched NHS budgets. A significantly greater number of drugs will be capable of meeting NICE's thresholds and thus benefit extended patient populations. The UK economy will benefit because the academic research and training offered by the CDT will complement the country's strength in bioscience discovery. Collaboration between bioprocess engineers, process modellers manufacturing experts, regulators and physical scientists will ensure effective knowledge and skills transfer between the science and engineering base and UK industry and the regulating agencies. This will strengthen the UK position in the global healthcare market and attract further R&D investment from global business which recognises the UK as a good place to conduct these activities.