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

项目摘要 甲型H7N9禽流感导致严重呼吸道疾病，死亡率高，其人畜共患病能力 引发了人们对大流行可能性的严重担忧。疫苗对大流行的潜在价值 新冠肺炎对人类健康和经济的破坏性影响证明了病毒的存在。 H7流感疫苗的开发一直滞后，因为大流行性流感疫苗通常是 用传统技术开发的，对人类H7产品免疫原性低的报道。 这种压力带来的高度威胁代表着新技术需要填补的巨大市场缺口。这个 新冠肺炎大流行说明了RNA疫苗作为快速反应平台的潜力，但也 证明了它们的局限性。依赖脂质纳米粒(LNP)递送的当代疫苗有 已知会引发不必要的急性炎症反应，并需要长期超低温 保养点的储存和稳定的冷藏，突出了新的交付方法的必要性。在……里面 第一阶段研究，TIBA Biotech建立了BALB/CJ肌肉免疫的原则证明 小鼠使用一种新的、炎症较少的配方，其中含有专有的递送分子，并高度 H7N9血凝素(HA)、神经氨酸酶(NA)和核蛋白的免疫原性RNA复制 (NP)以1：1：1的质量比诱导针对所有抗原的免疫反应。这一方法预计将 增加疫苗的免疫原性和异型保护潜力，RNABL平台 利用最大限度地安全地提供RNA质量内容，保护RNA不被降解，并使 体内细胞的有效摄取。在第二阶段，Tiba Biotech计划进一步开发H7N9疫苗原型 通过评估不同比例的RNA和TIBA的增强型RNABL文库的交付材料，开发 疫苗的RNA成分的制造、放大和质量控制过程，确定 在小鼠模型中的最佳剂量，在高度相关的雪貂挑战模型中建立保护效力， 并在老鼠身上进行初步的安全性评估和生物分布研究。这些研究将使 申请IND前会议，该会议将用于在IND备案之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和使用的潜力 疫苗储备，以便在H7N9流感大流行情况下做好准备。此外， 这里开发的原型成分将作为一个平台，将任何爆发的抗原序列 可以迅速实施。

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.