Integrated and Continuous Manufacturing of an Influenza Vaccine

流感疫苗的集成连续生产

• 批准号: 10407154
• 负责人: MICHAEL J BETENBAUGH
• 金额: $ 50万
• 依托单位: MICHIGAN TECHNOLOGICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10407154
• 关键词: Integrated; Continuous; Manufacturing; Influenza; Vaccine

Project Summary Influenza A affects 5-30% of the world’s population annually, resulting in 3 to 5 million cases of serious illness and 250,000 to 500,000 deaths each year. Vaccination is the best way to prevent disease. >80% of the influenza vaccines are made in eggs, and this makes the process slow and not able to quickly change as the influenza virus mutates. The vaccine is optimized to grow in eggs, which makes it a less like the circulating virus, and thus reduces the effectiveness of the vaccine. One way to improve the vaccine is to use cell-based vaccines. However, cells-based vaccines are expensive to produce and the manufacturing facilities are expensive. After 10 years on the market, cell-based vaccines are not the dominate vaccine used in the US. We propose to develop a novel manufacturing process of a cell-based influenza virus like particle (VLP). The process will continuously produce the VLP, which will allow for smaller equipment and thus reduce the cost of building a new manufacturing plant. Continuous processing also reduces operating costs, allowing for the vaccine to be sold at a lower cost and likely competing in price with egg-produced vaccines. The VLP will elicit a stronger immune response than egg-based vaccines and the modular design will allow for quick adaption of the vaccine to the circulating influenza strains. Our team has designed a novel, end to end, continuous process to manufacture an influenza VLP. First, we will continuous produce the VLP in a unique, three-reactor bioreactor cascade that will allow for continuous processing using a baculovirus production system in Sf9 insect cells. There is not currently a continuous baculovirus production system in use. The continuous downstream will use aqueous two-phase extraction and other polishing steps to purify the VLP. Chromatography and other periodic operations will be avoided. The VLP will produce HA protein antigenically identical to the chosen circulating strain with no potential for selection of HA mutations and the HA protein can easily be changed to another circulating influenza strain, as needed. Process analytics will be conducted to confirm the purity and antigenicity of the produced influenza VLP. At the completion of this project, the team will run the first end to end continuous process for one month to produce an influenza VLP and the process economics will be evaluated to determine the economic feasibility of the process. The VLP will have superior immunogenicity to egg-derived vaccines and subunit vaccines. This will be the first ever demonstration of a truly end-to-end continuous VLP production process that will revolutionize biologics manufacturing for multiple products, including other vaccines and gene therapy vectors.

项目摘要 甲型流感每年影响世界5-30%的人口，导致300万至500万严重疾病病例 每年有25万到50万人死亡接种疫苗是预防疾病的最好方法。>80%的 流感疫苗是在鸡蛋中制造的，这使得这个过程很慢，不能像疫苗那样迅速改变。 流感病毒变异。这种疫苗经过优化，可以在鸡蛋中生长，这使得它不像循环的疫苗。 病毒，从而降低了疫苗的有效性。改进疫苗的一种方法是使用基于细胞的 疫苗。然而，基于细胞的疫苗生产昂贵，并且生产设施昂贵。 贵了经过10年的上市，细胞疫苗并不是美国使用的主要疫苗。我们 提出开发基于细胞的流感病毒样颗粒（VLP）的新的制造方法。的 该工艺将连续生产VLP，这将允许更小的设备，从而降低生产成本。 建设新的制造工厂。连续处理还降低了运营成本， 疫苗将以较低的成本出售，并可能与鸡蛋生产的疫苗在价格上竞争。贵宾会引出 比基于鸡蛋的疫苗更强的免疫反应，模块化设计将允许快速适应 流感病毒的疫苗。我们的团队设计了一个新颖的、端到端的、连续的流程 来制造流感病毒VLP首先，我们将在独特的三反应器中连续生产VLP 生物反应器级联，其将允许使用Sf 9中的杆状病毒生产系统进行连续处理 昆虫细胞目前还没有一个连续的杆状病毒生产系统在使用。连续 下游将使用含水两相萃取和其它精制步骤来纯化VLP。 避免色谱分析和其他周期性操作。VLP将抗原性地产生HA蛋白 与所选的循环菌株相同，没有选择HA突变的潜力，并且HA蛋白可以 根据需要，很容易改变为另一种流行的流感病毒株。将进行流程分析， 确认生产的流感病毒VLP的纯度和抗原性。在这个项目完成后，团队 将运行第一个端到端连续过程一个月以生产流感VLP，并且该过程 将评估经济性以确定该方法的经济可行性。贵宾会有上级 免疫原性对蛋源疫苗和亚单位疫苗的影响。这将是首次展示 真正的端到端连续VLP生产工艺，将彻底改变生物制剂制造， 产品，包括其他疫苗和基因治疗载体。