Rapid response to pandemic influenza via multi-antigen RNA-based vaccine

通过基于多抗原 RNA 的疫苗快速应对大流行性流感

• 批准号: 10761327
• 负责人: Jasdave Chahal
• 金额: $ 96.66万
• 依托单位: TIBA BIOTECH, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-10 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10761327
• 关键词: Acute; Adjuvant; Antigens; Avian Influenza; BALB/cJ Mouse; Biodistribution; Biotechnology; COVID-19 impact; COVID-19 pandemic; Cells; Clinical; Clinical Trials; Development; Disease Outbreaks; Dose; Economics; Ferrets; Formulation; Future; Generations; Goals; Health; Hemagglutinin; High Pressure Liquid Chromatography; Human; Immune response; Immunity; Immunization; Immunize; Inflammatory; Inflammatory Response; Influenza; Influenza A Virus, H7N9 Subtype; Influenza A virus; Intramuscular; Lead; Libraries; Marketing; Measures; Methods; Modeling; Monitor; Mus; Neuraminidase; Nucleic Acids; Nucleoproteins; Organ; Phase; Process; Proteins; Quality Control; RNA; RNA Degradation; RNA purification; RNA vaccine; Rattus; Readiness; Refrigeration; Regimen; Replicon; Reporting; Research; Rodent Model; Safety; Seasons; Signal Transduction; Technology; Toxic effect; Vaccines; Virion; Virus; Zoonoses; cold temperature; commercialization; design; experimental study; flexibility; high risk; immunogenic; immunogenicity; in vivo; influenza virus vaccine; innovation; lipid nanoparticle; manufacture; meetings; method development; mortality; mouse model; multimodality; nanoparticle delivery; new technology; novel; pandemic disease; pandemic influenza; pandemic potential; phase 1 study; point of care; pre-Investigational New Drug meeting; prevent pandemics; protective efficacy; prototype; respiratory; response; safety assessment; scale up; uptake; vaccine candidate; vaccine development; vaccine efficacy; vaccine evaluation; vaccine safety

Project Abstract Avian influenza A H7N9 causes severe respiratory illness with a high mortality rate, and its zoonotic capacity has raised serious concerns over the possibility of a pandemic. The value of vaccines for pandemic-potential viruses has been demonstrated by the devastating effects of COVID-19 on human health and the economy. Development of H7 Influenza vaccines has lagged, as pandemic influenza vaccines have generally been developed with traditional technologies, and low immunogenicity for H7 products in humans has been reported. The high threat presented by this strain represents a substantial market gap for newer technologies to fill. The COVID-19 pandemic illustrated the potential of RNA vaccines as a rapid-response platform, but also demonstrated their limitations. Current generation vaccines relying on lipid nanoparticle (LNP) delivery are known to elicit unwanted acute inflammatory responses and require ultra-low temperatures for long-term storage and stable refrigeration at the point-of-care, highlighting the need for new delivery approaches. In Phase I studies, Tiba Biotech established Proof-of-Principle that an intramuscular immunization of BALB/cJ mice with a novel, less inflammatory formulation containing a proprietary delivery molecule and highly immunogenic RNA replicons encoding the H7N9 hemagglutinin (HA), Neuraminidase (NA) and Nucleoprotein (NP) at a 1:1:1 mass ratio induced immune responses against all antigens. This approach is expected to increase the immunogenicity and heterotypic protective potential of the vaccine, and the RNABL platform that is utilized maximizes the safely delivered RNA mass content, protects RNA from degradation, and enables efficient uptake by cells in vivo. In Phase II, Tiba Biotech plans to further develop the prototype H7N9 vaccine by evaluating different ratios of RNAs and delivery materials from Tiba’s enhanced RNABL library, developing manufacturing, scale up and quality control processes for the RNA components of the vaccine, determining optimal dosing in a mouse model, establishing protective efficacy in a highly relevant ferret challenge model, and performing preliminary safety assessments and biodistribution studies in rats. These studies will enable a request for a pre-IND meeting, and this meeting will be used to inform further experiments prior to IND filing and clinical trials. Ultimately, this vaccine product will have the potential for commercialization and use in vaccine stockpiling, enabling preparedness in the case of a H7N9 influenza pandemic. In addition, the prototype composition developed here will serve as a platform into which any outbreak antigen sequences could be rapidly implemented.

项目摘要 甲型H7N9禽流感可导致严重呼吸道疾病，死亡率高，其人畜共患能力 引起了人们对大流行的严重关注。疫苗对预防潜在大流行的价值 COVID-19对人类健康和经济的破坏性影响已经证明了病毒的重要性。 H7流感疫苗的开发已经滞后，因为大流行性流感疫苗通常 H7产品是用传统技术开发的，据报道，H7产品在人体内的免疫原性低。 这种菌株带来的高度威胁代表了新技术填补的巨大市场空白。的 COVID-19大流行说明了RNA疫苗作为快速反应平台的潜力，但也 展示了他们的局限性。依赖于脂质纳米颗粒（LNP）递送的当前一代疫苗是 已知其引起不想要的急性炎症反应，并且需要超低温长期 在护理点的储存和稳定的制冷，强调需要新的交付方法。在 I期研究中，Tiba Biotech确立了BALB/cJ肌内免疫 一种新的，较少炎症的配方，含有专有的传递分子和高度 编码H7N9血凝素（HA）、神经氨酸酶（NA）和核蛋白的免疫原性RNA复制子 (NP)以1：1：1的质量比，诱导针对所有抗原的免疫应答。预计这一做法将 增加疫苗的免疫原性和异型保护潜力，以及 最大化安全递送的RNA质量含量，保护RNA免于降解， 在体内被细胞有效摄取。在第二阶段，Tiba Biotech计划进一步开发原型H7N9疫苗 通过评估来自Tiba增强的RNABL文库的RNA和递送材料的不同比例， 疫苗RNA组分的生产、规模放大和质量控制过程， 在小鼠模型中的最佳剂量，在高度相关的雪貂攻击模型中建立保护功效， 并在大鼠中进行初步安全性评估和生物分布研究。这些研究将使 要求召开IND前会议，该会议将用于在IND提交前通知进一步的实验 和临床试验。最终，这种疫苗产品将具有商业化的潜力， 疫苗储备，以便在H7N9流感大流行时做好准备。此外该 这里开发的原型组合物将作为一个平台， 可以迅速实施。