Development of a shelf-stable universal mucosal HA-vaccine for the prevention of influenza

项目摘要 TFF制药公司（TFFP）正在开发一种货架稳定的薄膜冷冻（TFF）干粉通用流感 疫苗该产品的商业化将提供第一种疫苗，该疫苗至少有75%的有效性， 症状性流感病毒感染，具有易于递送和在室温下储存的额外益处 以促进广泛的、具有成本效益的分销。与NIAID的流感疫苗创新合作中心 格鲁吉亚大学（UGA）获得了一笔资金，开发出一种针对所有流感病毒的重组疫苗 血凝素（HA）蛋白，并证明了其在小鼠和雪貂模型的疗效。如果证明有效， 它可以为人类提供广泛的保护，防止已知和以前未被识别的流感病毒株 病毒，建立了一个新的标准，防止季节性病毒的出现， 未来的新品种。这种疫苗的传统液体版本将提供巨大的好处， 目前的季节性疫苗，但他们需要冷链处理，增加了成本，并提出了大量的 在不发达地区建立疫苗储备或分发疫苗的障碍。解决这些 为了应对这些挑战，UGA正在与TFFP合作开发通用疫苗的干粉制剂。使用 一种薄膜冷冻（TFF）技术，TFFP可以配制和制造干粉疫苗， 免疫原性，同时耐受无意冷冻。疫苗粉末可以免费储存和运输 冷链处理的扩展存储稳定性。我们的初步研究表明， 重组的TFF配制的UGA HA疫苗引起相同水平的免疫原性， 在BALB/c小鼠中达到与原液体疫苗相同的保护效果。雪貂的随访研究 证实了TFF-HA疫苗在降低鼻拭子中的病毒滴度和预防体重减轻方面的功效。 在这篇直接进入II期SBIR的文章中，TFFP和UGA建议评估用于鼻内和 肺吸入递送，并证实TFF配制的HA的稳定性、免疫原性和功效 在雪貂中接种流感疫苗是流感病毒疫苗测试的金标准（目标1）。Aim 2将扩大制造规模 为随后在大鼠中进行的毒理学研究（目的3），我们还将开发 临床试验用GMP制剂和生产。该项目预计将提供所有需要的IND- 使研究能够准备IND包装并最终推进到人体测试。干粉疫苗 将消除运输和储存方面的挑战，降低疫苗库存的成本和复杂性， 疫苗接种运动。一种货架稳定的通用流感病毒疫苗也将彻底改变公共卫生 这种方法提供了一种低成本，广泛传播的疫苗，对流感至少有75%的有效性， 无论每年出现哪种病毒株，症状性流感病毒感染。

PROJECT SUMMARY TFF Pharmaceuticals (TFFP) is developing a shelf-stable thin-film freeze (TFF) dry powder universal flu vaccine. Commercialization of this product would provide the first vaccine that is at least 75% effective against symptomatic influenza virus infection, with the added benefit of easy delivery and storage at room temperature to facilitate broad, cost-effective distribution. With NIAID’s Collaborative Influenza Vaccine Innovation Center funding, the University of Georgia (UGA) has developed a recombinant vaccine against all influenza virus hemagglutinin (HA) proteins and demonstrated its efficacy in mice and ferret models. If shown to be effective in humans, it could provide broad protection against both known and previously unrecognized strains of influenza virus, establishing a new standard of protection against seasonal viruses while heading off the emergence of novel strains in the future. A traditional liquid version of this vaccine would provide enormous benefits relative to the current seasonal vaccines, but they require cold-chain handling that increases costs and presents substantial barriers to establishing a stockpile or distributing the vaccine in underdeveloped areas. To address these challenges, UGA is collaborating with TFFP to develop a dry powder formulation of the universal vaccine. Using a thin-film freezing (TFF) technique, TFFP can formulate and manufacture dry powder vaccines that maintain immunogenicity while withstanding unintentional freezing. The vaccine powder can be stored and shipped free of cold-chain handling with extended stability for stockpiling. Our preliminary studies demonstrate that a reconstituted TFF-formulated version of UGA’s HA vaccine elicited the same level of immunogenicity and achieved the same protective efficacy as the original liquid vaccine in BALB/c mice. A follow up study in ferrets confirmed the efficacy of the TFF-HA vaccine in reducing viral titers in nasal swabs and preventing weight loss. In this Direct to Phase II SBIR, TFFP and UGA propose to evaluate different adjuvants for intranasal and pulmonary inhalation delivery and confirm the stability, immunogenicity, and efficacy of the TFF-formulated HA vaccine in ferrets, the gold standard for influenza virus vaccine testing (Aim 1). Aim 2 will scale-up manufacturing of the inhaled TFF-HA dry powder vaccine for subsequent toxicology studies in rats (Aim 3); we will also develop GMP formulation and manufacturing for clinical trials. This project is expected to provide all required IND- enabling studies to prepare an IND package and ultimately advance to human testing. A dry powder vaccine would eliminate challenges in shipping and storage, reducing the cost and complexity of vaccine stockpiles and vaccination campaigns. A shelf-stable universal influenza virus vaccine would also revolutionize the public health approach to influenza, providing a low-cost, broadly disseminable vaccine that is at least 75% effective against sympotmatic influenza virus infections regardless of which viral strain emerges each year.