Non-Viral Pandemic Influenza Vaccine Development

描述(由申请人提供)：针对题为“流感产品开发的合作研究伙伴关系”的RFA-AI-06-022，本申请建议实现旨在开发新型流感疫苗的具体里程碑。虽然通常对个别病毒亚型有效，但基于整个流感病毒的疫苗很难快速生产，而且由于病毒表面抗原的迁移和漂移，对不同亚型的活性有限。此外，故意修改IAV可能导致在开发有效疫苗之前产生一种能够引发人类大流行的病毒，造成前所未有的后果。通过新的自然突变或有目的的操作而产生的抑制IAV感染的预防性方法将得到极大的改进，因为疫苗技术的发展提供了对病毒感染的广泛保护，并结合了一种快速有效地将这些表位纳入新疫苗的方法。 针对这一需要，一种新的免疫方法已经被开发出来，它将单层脂质体载体与重组蛋白系统相结合，该重组蛋白系统能够被设计成能够表达选定的抗原表位。在这个项目中，重组蛋白包含了一个保守的IAV M2蛋白序列，该序列是预期构建的，用于代表IAV的各种亚型。以前已经证明，这种疫苗能刺激啮齿动物的主动保护性反应，本提案的目的是开始与将L-IAVM2e-HD候选疫苗推向临床试验相关的过程开发活动。为了在实现这一目标方面取得进展，我们计划完成几个里程碑，包括：开发生产L-IAVM2e-HD疫苗所需的中试规模的工艺和控制；证明使用新工艺生产L-IAVM2e-HD疫苗时，其理化和生物/免疫学特性不会改变。

DESCRIPTION (provided by applicant): In response to RFA-AI-06-022 entitled "Cooperative Research Partnerships for Influenza Product Development" this application proposes to achieve specific Milestones aimed at developing a novel influenza vaccine. While generally effective against individual viral subtypes, whole influenza virus-based vaccines are difficult to manufacture rapidly and demonstrate limited activity against different subtypes due to antigenic shift and drift in the surface antigens of the virus. In addition, deliberate modifications of IAV could result in the production of a virus capable of precipitating a human pandemic with unprecedented consequences before effective vaccines could be developed. Preventative methods for inhibiting infection with IAV created through new, natural mutations or purposeful manipulations, would be greatly improved by the development of vaccine technologies that provide for broad protection against viral infection combined with a method to rapidly and effectively incorporate these epitopes into new vaccines. In response to this need, a new approach to immunization for IAV has been developed that combines a unilamellar liposome carrier with a recombinant protein system that is capable of being engineered to express selected antigenic epitopes. For this project, the recombinant protein incorporates a conserved sequence of the IAV M2 protein prospectively constructed to represent a variety of IAV subtypes. It has been previously shown that this vaccine stimulates active protective responses in rodents and the objective of the present proposal is to begin the process development activities associated with advancing a L-IAVM2e-HD vaccine candidate towards clinical testing. In order to make progress towards this goal, we plan to complete several Milestones including: developing the processes and controls necessary to manufacture a L-IAVM2e-HD vaccine in pilot scale quantities and; demonstrating that the physicochemical and biological/immunological properties do not change when a L-IAVM2e-HD are produced using the new processes.