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

未来疫苗制造中心：推进具有成本效益的疫苗的制造和部署

• 批准号: EP/R013764/1
• 负责人: Robin Shattock
• 金额: $ 1599.37万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FR013764%2F1
• 关键词: Future; Vaccine; Manufacturing; Hub; Advancing

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.

过去 60 年来，疫苗生产系统经历了进化优化，偶尔会因新技术而受到干扰（例如，哺乳动物细胞培养物取代基于鸡蛋的系统来生产季节性流感疫苗）。全球疫苗接种计划取得了巨大成功，但疫苗的生产和分配系统仍然受到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 摄氏度之间的影响。这对于中低收入国家的农村地区可能是一个挑战，那里每年有 2400 万儿童无法获得适当的疫苗接种。另一个挑战是需要快速应对不断出现的新威胁，例如埃博拉病毒和寨卡病毒。后者的“第一响应者”战略的制定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：1.如何设计灵活的模块化生产系统，一旦识别出新的威胁并对其进行排序，可以切换到制造模式并在几周内生产出10,000剂的数量级，作为局部遏制策略的一部分？ 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、提高效率并有效预防现有和新的疾病？我们提出的计划是与中低收入国家的合作伙伴一起开发的，作为一种综合方法，它将为挑战 2 带来快速胜利，同时以生命科学、免疫学和过程系统的新发展为基础，使解决挑战 1 的概念取得成果。挑战 1 的策略的例子是 RNA 疫苗。合成 RNA 疫苗的显着优势是能够在几周内快速生产数千剂疫苗。这提供了一种可行的商业模式，不适用于生产滞后期较长的其他技术（病毒载体、哺乳动物细胞培养），从而可以根据需要采购疫苗，从而避免了为快速部署而储存疫苗、监测其持续稳定性以及实施过期库存更换周期的相关成本。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成为可能，在电力短缺的情况下，所有必需的设备都有可能通过发电机驱动的电源运行。这符合分布式、灵活平台技术的概念，因为一旦识别出威胁，就可以向制造过程提供特定的遗传密码，并且可以立即生产特定疫苗的剂量。我们将在这一类别中探索的其他概念包括快速生产模仿病原病毒和细菌膜表达成分的酵母和细菌表达颗粒。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超过 100 摄氏度的温度下保留脆弱的蛋白质酶的功能。我们将利用这些知识来开发新的疫苗稳定和配方平台。它们可以通过两种方式使用：（a）通过重新配制支持从集中冷链到患者的最后几英里的交付；（b）直接生产热稳定形式，即尽管不冷藏但仍能保持数月活性的疫苗。 我们相信，实现这些能力和绩效阶跃变化的最佳方式是通过基于团队的方法，在两个维度上进行深度整合：英国和中低收入国家合作伙伴之间，以确保所有中低收入国家的考虑因素从一开始就“融入”；不同学科之间，考虑到应对挑战所需的不同专业知识。

项目成果

Polymer Microarrays Rapidly Identify Competitive Adsorbents of Virus-like Particles (VLPs)

聚合物微阵列快速识别病毒样颗粒 (VLP) 的竞争性吸附剂

• DOI: 10.26434/chemrxiv.12966725
• 发表时间: 2020
• 作者: Alexander M

Precisely targeted gene delivery in human skin using supramolecular cationic glycopolymers

• DOI: 10.1039/d0py00449a
• 发表时间: 2020-06-14
• 期刊: POLYMER CHEMISTRY
• 影响因子: 4.6
• 作者: Blakney, Anna K.;Liu, Renjie;Becer, C. Remzi
• 通讯作者: Becer, C. Remzi

The SARS-CoV-2 spike protein: balancing stability and infectivity.

• DOI: 10.1038/s41422-020-00430-4
• 发表时间: 2020-12
• 期刊: Cell research
• 影响因子: 44.1
• 作者: Berger I;Schaffitzel C
• 通讯作者: Schaffitzel C

Oxygen-Tolerant RAFT Polymerization Initiated by Living Bacteria.

• DOI: 10.1021/acsmacrolett.2c00372
• 发表时间: 2022-08-16
• 期刊: ACS MACRO LETTERS
• 影响因子: 7.015
• 作者: Bennett, Mechelle R.;Moloney, Cara;Catrambone, Francesco;Turco, Federico;Myers, Benjamin;Kovacs, Katalin;Hill, Philip J.;Alexander, Cameron;Rawson, Frankie J.;Gurnani, Pratik
• 通讯作者: Gurnani, Pratik

Methods for Expression of Recombinant Proteins Using a Pichia pastoris Cell-Free System.

• DOI: 10.1002/cpps.115
• 发表时间: 2020-12-01
• 期刊: Current protocols in protein science
• 作者: Aw, Rochelle;Spice, Alex J;Polizzi, Karen M
• 通讯作者: Polizzi, Karen M