Future Vaccine Manufacturing Hub: Advancing the manufacture and deployment of cost effective vaccines

疫苗生产系统在过去60年中经历了进化优化，偶尔会因新技术而中断（例如，哺乳动物细胞培养物取代基于鸡蛋的系统用于季节性流感疫苗生产）。全球疫苗接种规划取得了巨大成功，但疫苗的生产和分销系统仍然存在与生产和纯化疫苗相关的成本以及需要将疫苗储存在2至8摄氏度之间的问题。这在低收入和中等收入国家的农村地区可能是一项挑战，那里每年有2400万儿童无法获得适当的疫苗接种。另一项挑战是需要迅速应对不断出现的埃博拉病毒和寨卡病毒等新威胁。针对后者制定“第一响应者”战略意味着未来的疫苗制造系统必须克服两种不同类型的挑战：如何设计一个灵活的模块化生产系统，一旦发现新的威胁并对其进行排序，就可以切换到制造模式，并在几周内生产10000剂左右的疫苗，作为局部遏制战略的一部分？2. 如何改进和优化现有的生产工艺，改变疫苗的生产、稳定和储存方式，从而降低成本，提高效率，有效预防现有疾病和新疾病？我们提议的项目是与LMIC合作伙伴共同开发的，作为一种综合方法，将在生命科学、免疫学和工艺系统的新发展基础上，为挑战2带来快速的胜利，使解决挑战1的概念成为现实。挑战1战略的例子是RNA疫苗。合成RNA疫苗的显著优势是能够在几周内迅速生产数千剂疫苗。这提供了一种可行的商业模式，不适用于生产滞后阶段较长的其他技术（病毒载体、哺乳动物细胞培养），从而可以根据需要采购疫苗，避免为快速部署而储存疫苗、监测其持续稳定性和实施过期库存更换周期的相关费用。此外，较低的基础设施和设备成本使得在低收入环境中建立制造业是可行的，在那里，在电力短缺的情况下，所有所需的设备都有可能由发电机驱动的电力供应来运行。这符合分布式灵活平台技术的概念，因为一旦确定威胁，就可以向生产过程提供特定的遗传密码，并且可以毫不拖延地生产特定疫苗的剂量。我们将在这一类别中探讨的其他概念包括酵母和细菌表达颗粒的快速生产，这些颗粒模仿病原病毒和细菌的膜表达成分。挑战2的策略示例建立在我们在蛋白质稳定方面的工作基础上，该工作已被证明可以在100摄氏度以上的温度下保持微妙的蛋白酶的功能。我们将利用这一知识开发新的疫苗稳定和配方平台。这些可用于两种方式：(a)通过重新配制支持从集中冷链运送到患者的最后几英里路程；(b)用于直接生产热稳定形式，即即使不冷藏也能保持数月活性的疫苗。我们认为，在能力和绩效方面实现这些步骤变化的最佳方式是通过基于团队的方法，在两个方面进行深度整合：在英国和LMIC合作伙伴之间，确保从一开始就“融入”所有LMIC考虑因素；在不同学科之间，考虑到应对挑战所需的不同专业知识。

Vaccine manufacturing systems have undergone evolutionary optimisation over the last 60 years, with occasional disruptions due to new technology (e.g. mammalian cell cultures replacing egg-based systems for seasonal influenza vaccine manufacture). Global vaccination programmes have been a great success but the production and distribution systems from vaccines still suffer from costs associated with producing and purifying vaccines and the need to store them between 2 and 8 degrees C. This can be a challenge in the rural parts of low and middle income countries where 24 million children do not have access to appropriate vaccinations every year. An additional challenge is the need to rapidly respond to new threats, such as the Ebola and Zika viruses, that continue to emerge. The development of a "first responder" strategy for the latter means that there are two different types of challenges that future vaccine manufacturing systems will have to overcome: 1. How to design a flexible modular production system, that once a new threat is identified and sequenced, can switch into manufacturing mode and produce of the order of 10,000 doses in a matter of weeks as part of localised containment strategy? 2. How to improve and optimise existing manufacturing processes and change the way vaccines are manufactured, stabilised and stored so that costs are reduced, efficiencies increased and existing and new diseases prevented effectively? Our proposed programme has been developed with LMIC partners as an integrated approach that will bring quick wins to challenge 2 while building on new developments in life sciences, immunology and process systems to bring concepts addressing challenge 1 to fruition.Examples of strategies for challenge 1 are RNA vaccines. The significant advantage of synthetic RNA vaccines is the ability to rapidly manufacture many thousands of doses within a matter of weeks. This provides a viable business model not applicable to other technologies with much longer lag phases for production (viral vectors, mammalian cell culture), whereby procurement of the vaccine can be made on a needs basis avoiding the associated costs of stockpiling vaccines for rapid deployment, monitoring their on going stability and implementing a cycle of replacement of expired stock. In addition, low infrastructure and equipment costs make it feasible to establish manufacture in low-income settings, where all required equipment has potential to be run from a generator driven electrical supply in the event of power shortage. This fits the concept of a distributed, flexible platform technology, in that once a threat is identified, the specific genetic code can be provided to the manufacturing process and the doses of the specific vaccine can be produced without delay. Additional concepts that we will explore in this category include the rapid production of yeast and bacterially expressed particles that mimic membrane expressed components of pathogenic viruses and bacteria.Examples of strategies for challenge 2 build on our work on protein stabilisation which has been shown to preserve the function of delicate protein enzymes at temperatures over 100 degrees C. We shall exploit this knowledge to develop new vaccine stabilisation and formulation platforms. These can be used in two ways: (a) to support the last few miles of delivery from centralised cold chains to patients through reformulation and (b) for direct production of thermally stable forms, i.e. vaccines that retain their activity for months despite being not being refrigerated. We believe that the best way to deliver these step changes in capability and performance is through a team-based approach that applies deep integration in two dimensions: between UK and LMIC partners to ensure that all the LMIC considerations are "baked in" from the start and between different disciplines accounting for the different expertise that will be required to meet the challenges.