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: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=744454
• 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 3期临床试验中评估的最先进的候选疫苗之一。在生产之后，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有效性和安全性。 基于广泛的科学知识和细胞培养产生病毒的专有技术，我们建议本研究计划指导我们努力研究并整合病毒疫苗的液体和固体制剂的工艺开发周期，这是一个主要以经验为基础的工艺开发领域。因此，一种新的混合模型将使冻干机实时优化操作。 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，用于数字辅助设计有效病毒疫苗的液体和固体制剂，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在赋形剂存在下包膜病毒如水泡性口炎病毒（VSV）和慢病毒的配制中涉及的机制，以保持它们的生物活性; 2）设计固体制剂并开发用于包封和非包封的冷冻干燥的机械模型。包膜病毒，如VSV和腺病毒载体疫苗，为Machin Learning产生大量的高质量数据; 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。数字孪生模型通过传感器和反馈控制与物理冻干机相连，以加速病毒疫苗冻干过程的设计和优化操作。 通过与该领域的专家（来自麦吉尔的共同主管）合作，我们建议将机器学习（ML）算法的最新进展联合收割机结合起来，以帮助设计实验并加速设计强大的疫苗配方和工艺。实验、结果验证和基于数字孪生的冻干工艺优化将在我们已经运行的生物安全2+级实验室中进行，并得到我们经验证的工艺分析技术的支持。这项研究将促进包膜和非包膜病毒的配方知识，从而发现新型辅料和增强工艺。 通过将设计方法集中在提高VSV载体埃博拉疫苗的热稳定性上，我们将促进这种拯救生命的产品以及使用相同VSV抗原递送平台的其他产品（HIV-1，SARS-CoV-2）的交付和储存。 至关重要的是，这项研究计划将有助于培训16名HQP，以满足加拿大疫苗生物制造业对合格人员的高需求。