Development of a Mucosal Nanoemulsion-Adjuvanted RSV Vaccine using Recombinant Pre-Fusion F Protein

摘要 呼吸道合胞病毒（RSV）极其普遍，几乎所有人在两岁时都会感染。 它表现为几种继发性急性呼吸道疾病，包括细支气管炎、支气管炎、肺炎和普通感冒。 RSV在人体中不引起保护性免疫应答，这导致儿童和成人的复发性感染。 感染RSV的婴儿在整个青春期内发生反应性气道疾病（如哮喘）的风险很高。 RSV在成人中的发病机制可导致严重的并发症，包括肺炎、慢性阻塞性肺病、充血性心力衰竭和哮喘。 老年人的风险尤其高。由RSV感染引起的这些疾病联合收割机组合起来代表了巨大的全球健康风险和对全球医疗保健系统的巨大财政负担。 目前没有批准的疫苗可用于预防RSV感染或疾病。 在该SBIR I期提案中，BlueWillow Biologics将生产cGMP种子，用于生产具有保留融合前构象（PrFFP）的重组F蛋白RSV亚基，这将使未来能够生产鼻内PrFFP/NE 01疫苗的临床材料。创新的特点是应用BlueWillow的NanoVaxTM纳米乳剂粘膜佐剂和递送技术来配制PrFFP作为鼻内疫苗。 这种新策略将激活全身和粘膜免疫，这是防止病毒进入和局部感染呼吸道粘膜（包括肺部）所必需的关键保护性免疫反应。目前正在开发的使用F蛋白抗原的先前RSV疫苗已被配制用于肌内递送，其不促进粘膜免疫并且可能损害其针对RSV的有效性。 成功完成SBIR 1期提案将为市场上第一种粘膜NE-RSV疫苗的临床开发和商业发布提供基础。我们将与NIH-VRC签署许可协议，以获得用于PrFFP生产的CHO-DG 44种子的cGMP种子。 之后，我们将从NIH-VRC向BlueWillow进行技术转移，并将在CDMO建立用于未来生产的主细胞库。融合前构象的高抗原性F蛋白与我们创新的NanoVaxTM纳米乳液粘膜佐剂技术的新型组合将产生一种安全有效的鼻内疫苗，以预防老年人的RSV感染和疾病。这种商业产品将满足巨大的未满足的医疗需求。

ABSTRACT Respiratory syncytial virus (RSV) is extremely ubiquitous, with almost all humans acquiring the infection by the age of two. It is manifested by several secondary acute respiratory illnesses including bronchiolitis croup, bronchitis, pneumonia and the common cold. RSV does not elicit a protective immune response in humans, which results in recurrent infections in children and adults. Infants infected with RSV have a high risk of developing reactive airway disease, such as asthma, through adolescence. RSV pathogenesis in adults can lead to serious complications, including pneumonia, chronic obstructive pulmonary disease, congestive heart failure and asthma. The elderly population is at particularly high risk. These illnesses caused by RSV infection combine to represent a massive worldwide health risk and substantial financial burden to the global healthcare system. There is currently no approved vaccine available to prevent RSV infection or disease. In this SBIR Phase I proposal, BlueWillow Biologics will manufacture the cGMP seeds for producing the recombinant F-protein RSV subunit with a preserved pre-fusion conformation (PrFFP), which would enable future manufacturing of clinical material for intranasal PrFFP/NE01 vaccine. The innovative feature is the application of BlueWillow’s NanoVaxTM nanoemulsion mucosal adjuvant and delivery technology to formulate PrFFP as an intranasal vaccine. This new strategy will activate both systemic and mucosal immunity, a key protective immune response necessary to prevent viral entry and infection locally at the respiratory mucosa including the lungs. Previous RSV vaccines currently under development using F-protein antigens have been formulated for intramuscular delivery, which does not promote mucosal immunity and may compromise their effectiveness against RSV. Successful completion of this SBIR phase 1 proposal will provide the foundation for the clinical development and commercial release of the first mucosal NE-RSV vaccine on the market. We will execute the license agreement with NIH-VRC to obtain cGMP seeds of CHO-DG44 seeds for PrFFP production. Following which we will perform technology transfer from NIH-VRC to BlueWillow and master cell bank for future manufacturing will be established at CDMO. The novel combination of highly antigenic F protein in its pre-fusion conformation with our innovative NanoVaxTM nanoemulsion mucosal adjuvant technology will result in a safe and effective intranasal vaccine to prevent RSV infection and disease in the elderly. This commercial product will fulfill an enormous unmet medical need.