Design of formulation processes for improved thermostability of viral vaccines

提高病毒疫苗热稳定性的配方工艺设计

• 批准号: RGPIN-2021-02691
• 负责人: Kamen, Amine
• 金额: $ 3.35万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=742158
• 关键词: Design; formulation; processes; improved; thermostability

Viral vectored vaccines are among the most advanced vaccine candidates currently evaluated in COVID-19 phase-3 clinical trials. Following their manufacturing, thermostability is a critical quality attribute to ensure the efficacy and safe delivery of these life-saving products where needed. Building on an extensive scientific knowledge and know-how of cell-culture produced viruses, we propose for this research program to direct our efforts to study and integrate in the process development cycle, liquid and solid formulations of viral vaccines, an area of process development that remained largely empirical. As a result, a novel hybrid model will enable the freeze-dryer optimal operations in real-time. The long-term objective of this research program is to identify the critical parameters and uncover their mechanisms of action towards integration of expert knowledge for digitally assisted design of liquid and solid formulations of effective viral vaccines with improved thermostability and cost-effectiveness. We aim to 1) Design enhanced liquid formulations and uncover mechanisms involved in the formulation of enveloped viruses such as Vesicular Stomatitis Virus (VSV) and lentivirus in presence of excipients to preserve their biological activity; 2) Design solid formulations and develop mechanistic model for freeze-drying of enveloped and non-enveloped viruses such as VSV and adenovirus vectored vaccines generating a large pool of quality data for Machin Learning; 3) Develop a Hybrid model for freeze-drying process using a digital twin approach by combining mechanistic and data-driven models. The digital twin is connected to the physical freeze-dryer by sensors and feed-back control to accelerate the design and optimal operation of freeze-drying processes of viral vaccines. In collaboration with experts in the field (co-supervisors from McGill), we propose to combine recent advancements in Machine Learning (ML) algorithms to assist the design of experiments and accelerate the design of robust vaccine formulations and processes. Experimentation, validation of results and digital twin-based optimization of freeze-drying process will be executed in our already functional biosafety level-2+ laboratory and supported by our validated process analytical technologies. This research will advance knowledge on formulation of enveloped and non-enveloped viruses leading to discovery of novel excipients and enhanced processes. By focusing the design approach on improving the thermostability of the VSV-vectored Ebola vaccine, we will facilitate the delivery and stockpiling of this life-saving product as well as other products using the same VSV delivery platform of antigens (HIV-1, SARS-CoV-2). Critically, this research program will contribute to training 16 HQPs to respond to the high demand of qualified personnel expressed by the vaccine biomanufacturing industry in Canada.

病毒载体疫苗是目前在 COVID-19 三期临床试验中评估的最先进的候选疫苗之一。在制造完成后，热稳定性是一个关键的质量属性，以确保这些救生产品在需要时的功效和安全交付。 基于细胞培养产生的病毒的广泛科学知识和专业知识，我们建议该研究计划指导我们努力研究病毒疫苗的液体和固体制剂并将其整合到工艺开发周期中，这是工艺开发的一个领域这在很大程度上仍然是经验性的。因此，一种新颖的混合模型将使冻干机实时优化运行。 该研究计划的长期目标是确定关键参数并揭示其作用机制，以整合专家知识，以数字方式辅助设计有效病毒疫苗的液体和固体制剂，并提高热稳定性和成本效益。我们的目标是 1) 设计增强的液体制剂并揭示包膜病毒（例如水泡性口炎病毒 (VSV) 和慢病毒）在赋形剂存在下的制剂所涉及的机制，以保留其生物活性； 2）设计固体制剂并开发用于冷冻干燥包膜和非包膜病毒（例如VSV和腺病毒载体疫苗）的机械模型，为机器学习生成大量高质量数据； 3) 通过结合机械模型和数据驱动模型，使用数字孪生方法开发冷冻干燥过程的混合模型。数字孪生通过传感器和反馈控制连接到物理冻干机，以加速病毒疫苗冻干过程的设计和优化操作。 我们与该领域的专家（来自麦吉尔大学的联合导师）合作，建议结合机器学习（ML）算法的最新进展来协助实验设计并加速稳健疫苗配方和工艺的设计。实验、结果验证和基于数字孪生的冷冻干燥工艺优化将在我们已经正常运作的生物安全 2+ 级实验室中进行，并得到我们经过验证的工艺分析技术的支持。这项研究将增进有关包膜和非包膜病毒配方的知识，从而发现新的赋形剂和增强的工艺。 通过将设计方法的重点放在提高 VSV 载体埃博拉疫苗的热稳定性上，我们将促进这种救生产品以及使用相同 VSV 抗原交付平台（HIV-1、SARS-冠状病毒-2）。 至关重要的是，该研究计划将有助于培训 16 个总部，以满足加拿大疫苗生物制造行业对合格人员的高需求。