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.

项目摘要 TFF Pharmaceuticals（TFFP）正在开发架子稳定的薄膜冻结（TFF）干粉末流感 疫苗。该产品的商业化将提供第一种至少有效75％的疫苗 有症状的影响病毒感染，并在室温下易于递送和存储额外的好处 促进广泛的，具有成本效益的分布。 Niaid的合作流感疫苗创新中心 佐治亚大学（UGA）的资助已经开发了针对所有影响力病毒的重组疫苗 血凝素（HA）蛋白质在小鼠和雪貂模型中证明其有效。如果证明是有效的 人类，它可以为已知和以前未被认可的影响力提供广泛的保护 病毒，建立针对季节性病毒的新标准，同时出现 未来的新型压力。该疫苗的传统液体版本将提供相对于 当前的季节性疫苗，但需要冷链处理，以提高成本并提供大量 在欠发达地区建立储存或分配疫苗的障碍。解决这些 挑战，UGA正在与TFFP合作开发通用疫苗的干粉配方。使用 薄膜冷冻（TFF）技术，TFFP可以制造和制造维护的干粉疫苗 免疫原性，同时承受无意的冻结。疫苗粉可以存放并免费运送 冷链处理，具有扩展的储存稳定性。我们的初步研究表明 UGA HA疫苗的重构TFF形成版本引起了相同水平的免疫原性和 雪貂的后续研究 确认了TFF-HA疫苗在减少鼻拭子中病毒滴度并防止体重减轻方面的效率。 在直接直接进行II期SBIR中，TFFP和UGA提案评估了鼻内和 肺吸入输送并确认TFF形成的HA的稳定性，免疫原性和效率 雪貂（雪貂）中的疫苗是影响力病毒疫苗测试的金标准（AIM 1）。 AIM 2将扩大制造 在大鼠的随后毒理学研究的遗传性TFF-HA干粉疫苗中（AIM 3）；我们还将发展 GMP公式和用于临床试验的制造。预计该项目将提供所有必需的ind- 使研究能够准备IND包装，并最终进步进行人体测试。干粉疫苗 将消除运输和存储方面的挑战，降低疫苗库存的成本和复杂性 疫苗接种运动。货架稳定的普遍影响病毒疫苗也将彻底改变公共卫生 影响力的方法，提供一种低成本的，广泛的疫苗，至少有效75％ 病毒感染的精神影响不管每年出现哪些病毒菌株。