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.

在过去的60年里，疫苗生产系统经历了进化优化，偶尔会因新技术而中断（例如，哺乳动物细胞培养取代了季节性流感疫苗生产的蛋基系统）。全球疫苗接种方案取得了巨大成功，但疫苗的生产和分配系统仍然受到与生产和纯化疫苗有关的成本以及需要在2至8摄氏度之间储存疫苗的影响。这在低收入和中等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。另一个挑战是需要迅速应对新的威胁，如不断出现的埃博拉病毒和寨卡病毒。针对后者的“第一反应者”策略的发展意味着未来的疫苗制造系统将必须克服两种不同类型的挑战：1.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进行排序，就可以切换到制造模式，并在几周内生产10，000剂，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，有效预防现有和新的疾病？我们提出的计划是与LMIC合作伙伴一起制定的，作为一种综合方法，将为挑战2带来快速胜利，同时建立在生命科学，免疫学和工艺系统的新发展基础上，将应对挑战1的概念付诸实践。挑战1的策略的例子是RNA疫苗。合成RNA疫苗的显著优势是能够在几周内快速生产数千剂疫苗。这提供了一种不适用于生产滞后期长得多的其他技术（病毒载体、哺乳动物细胞培养）的可行的商业模式，从而可以根据需要采购疫苗，避免了储存疫苗以供快速部署、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，基础设施和设备成本较低，使在低收入环境中建立制造业成为可能，在那里，所有所需设备都有可能在电力短缺的情况下由发电机驱动的电力供应运行。这符合分布式、灵活平台技术的概念，因为一旦识别出威胁，就可以将特定的遗传密码提供给制造过程，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酵母和细菌表达的颗粒，这些颗粒模拟致病病毒和细菌的膜表达组分。挑战2的策略示例建立在我们对蛋白质稳定化的工作基础上，该工作已被证明可以在超过100摄氏度的温度下保持脆弱蛋白酶的功能。我们将利用这些知识开发新的疫苗稳定和制剂平台。这些可以以两种方式使用：（a）通过重新配制来支持从集中冷链到患者的最后几英里的递送，以及（B）用于直接生产热稳定形式，即尽管不被冷藏但仍保持其活性数月的疫苗。 我们认为，实现这些能力和绩效的阶梯式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，以及在不同学科之间，考虑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