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

开发用于预防流感的储存稳定的通用粘膜HA疫苗

• 批准号: 10600541
• 负责人: Dale J Christensen
• 金额: $ 86.49万
• 依托单位: TFF PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-03 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10600541
• 关键词: Address; Adjuvant; Advanced Development; Antibodies; Antigens; Appearance; Area; Body Temperature; Body Weight; Body Weight decreased; Cessation of life; Clinical Trials; Cold Chains; Collaborations; Development; Dose; Dryness; Ferrets; Film; Follow-Up Studies; Formulation; Freeze Drying; Freezing; Funding; Future; Goals; Guidelines; Hemagglutinin; Human; Hypersensitivity; Immune response; Immunity; Immunologics; Immunology; Impairment; Inbred BALB C Mice; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza A virus; Influenza Hemagglutinin; Influenza prevention; Inhalation; Inhalation Drug Administration; International; Intramuscular; Intramuscular Injections; Liquid substance; Lung; Medically Underserved Area; Methods; Modeling; Mucous Membrane; Mus; National Institute of Allergy and Infectious Disease; No-Observed-Adverse-Effect Level; Pharmacologic Substance; Phase; Powder dose form; Process; Proteins; Public Health; Rattus; Reaction; Recombinant Vaccines; ST14 gene; Safety; Seasons; Shipping; Small Business Innovation Research Grant; Solubility; Structure; Techniques; Temperature; Testing; Thinness; Titrations; Toxic effect; Toxicology; Universities; Vaccination; Vaccine Antigen; Vaccines; Variant; Viral; Virus; Work; commercialization; cost; cost effective; design; efficacy evaluation; first-in-human; immunogenicity; influenza infection; influenza virus strain; influenza virus vaccine; influenzavirus; innovation; manufacture; manufacturing scale-up; nasal swab; novel; pandemic influenza; preservation; prevent; protective efficacy; reconstitution; safety study; scale up; seasonal influenza; success; universal influenza vaccine; universal vaccine; vaccine candidate; vaccine distribution; vaccine evaluation; vaccine failure; vaccine immunogenicity

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.

项目总结 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至少75%有效的疫苗。 有症状的流感病毒感染，加上易于运送和在室温下储存的额外好处 以促进广泛、具有成本效益的分销。与NIAID的流感疫苗合作创新中心 佐治亚大学(UGA)出资研制出了一种针对所有流感病毒的重组疫苗 血凝素(HA)蛋白，并在小鼠和雪貂模型上证明了其有效性。如果被证明在 对人类来说，它可以对已知和以前未识别的流感病毒株提供广泛的保护 病毒，建立了针对季节性病毒的新保护标准，同时防止出现 未来的新菌株。这种疫苗的传统液体版本将提供巨大的好处，相对于 目前的季节性疫苗，但它们需要冷链处理，这增加了成本，并提供了大量 在欠发达地区建立疫苗储备或分发疫苗的障碍。要解决这些问题 为了应对挑战，UGA正在与TFFP合作开发一种通用疫苗的干粉配方。vbl.使用 作为一种薄膜冷冻(TFF)技术，TFFP可以配制和制造干粉疫苗 免疫原性，同时抵御无意冰冻。疫苗粉末可以免费储存和运输 冷链装卸具有更大的储存稳定性。我们的初步研究表明， 重组TFF配方版本的UGA HA疫苗产生了相同水平的免疫原性和 在BALB/c小鼠体内获得了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防止体重下降方面的效果。 在这项直接到第二阶段SBIR，TFFP和UGA建议评估不同的佐剂对鼻腔和 肺吸入给药，并确认TFF配方HA的稳定性、免疫原性和有效性 雪貂疫苗，流感病毒疫苗测试的黄金标准(目标1)。AIM 2将扩大制造规模 吸入型TFF-HA干粉疫苗用于随后的大鼠毒理学研究(目标3)；我们还将开发 用于临床试验的GMP制剂和制造。该项目预计将提供所有需要的IND- 使研究能够准备IND包，并最终推进到人体测试。一种干粉疫苗 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，并 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众健康。 应对流感的方法，提供一种低成本、可广泛传播的疫苗，对预防流感至少75%有效 每年无论出现哪种病毒株，流感病毒感染都是交叉性的。