Project 1 - Profectus Biosciences, Inc.

项目 1 - Profectus Biosciences, Inc.

• 批准号: 10581498
• 负责人: John Hayward Eldridge
• 金额: $ 86.78万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-20 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10581498
• 关键词: Adjuvant; Aerosols; African Green Monkey; Agonist; Alhydrogel; Animals; Antigens; Area; Australia; Authorization documentation; Award; Bangladesh; Biological; Biological Assay; Biological Products; Biological Sciences; Categories; Cell Culture Techniques; Cell Line; Clinical; Clinical Research; Clinical Trials; Development; Disease; Disease Outbreaks; Documentation; Dose; Dryness; Ebola virus; Emulsions; Encephalitis; Equus caballus; Event; Fatality rate; Ferrets; Formulation; Freeze Drying; Funding; Grant; Health Benefit; Hendra Virus; Henipavirus; Human; Immunity; Immunization; India; Infectious Diseases Research; Liposomes; Liquid substance; Livestock; Malaysia; Mammals; Marketing; Monitor; National Institute of Allergy and Infectious Disease; Nipah Virus; Oryctolagus cuniculus; Paramyxovirus; Performance; Persons; Pesticides; Powder dose form; Process; Prophylactic treatment; Public Health; Qualifying; Recombinants; Reporting; Research Institute; Respiratory Disease; Risk; Safety; Science; Serology; Source; Subunit Vaccines; Suspensions; Testing; Therapeutic; Toxicology; Transportation; Tropism; United States National Institutes of Health; Vaccinated; Vaccination; Vaccines; Variola major virus; Veterinary Medicine; Viral; Virulent; Virus; Virus Diseases; absorption; aluminum sulfate; animal efficacy; arm; authority; biodefense; biothreat; bioweapon; cell bank; clinical development; commercialization; efficacy study; experience; falls; glycoprotein G; human monoclonal antibodies; immunogenicity; improved; manufacture; manufacturing process; nanoparticle; outbreak control; particle; pre-clinical assessment; preclinical development; preclinical study; prevent; product development; reconstitution; research clinical testing; success; transmission process; vaccine delivery; vaccine development; vaccine evaluation; vaccine formulation; virus classification

Project Summary/Abstract Nipah virus (NiV) and Hendra virus (HeV) are classified biological safety level 4 (BSL-4) viruses and are listed in Category C biothreat agents by the NIH and CDC. Nipah and henipaviral (HeV, NiV, Kumasi virus, KV, Cedar virus, CedV, Mojiang virus, MojV, and potentially new viruses in the genus) diseases are included in the 2018 annual review of the WHO Blueprint list of priority diseases. These emerging viruses, unlike other Category A biothreat viral agents such as Smallpox or Ebolavirus, can be isolated from natural reservoirs, grown in cell culture to high titers, and spread and amplified in livestock that are proven sources for transmission to humans, where subsequent person-to-person transmission facilities outbreaks. Transmission via aerosol and a high rate of lethality heighten their potential as biothreat agents. Currently, there is no approved human prophylaxis or therapeutic against NiV disease nor HeV disease. Vaccination may offer a viable strategy to provide significant public health benefit in endemic areas as well as provide an important component in our armamentarium to mitigate an outbreak of these viruses in the event they are used as a bioweapon. Horse anti-HeV vaccine (Equivac® HeV), which subunit is genetically the same as the proposed human subunit vaccine, has been marketed by Zoetis in Australia since November 2012 under the authority of the Australian Pesticides and Veterinary Medicines Authority (APVMA) and is the first commercialized vaccine against any BLS-4 agent. The APVMA granted full registration of Equivac® HeV in August 2015. Profectus BioSciences, Inc. is a vaccine focused company with experience of leading development processes through vaccine manufacturing, regulatory submissions, clinical trials and BLA application. For combating NiV and HeV diseases, the company has received a Partnership for Biodefense R01 award from NIAID for preclinical development of m102.4, an anti-NiV/HeV human MAb, as a post exposure therapeutic for NiV and HeV infection and a similar R01 to develop HeV-sG human vaccine in preclinical studies. Profectus has performed preclinical studies of HeV-sG subunit formulated with alhydrogel to be used in humans as a bivalent vaccine to prevent NiV or HeV infections or break their transmission. A Master Cell Bank (MCB) has been manufactured, GMP vaccine manufacturing process has been developed, toxicology vaccine lot has been produced, GLP tox study has been performed in rabbits, and efficacy after single dose immunization has been confirmed in African Green Monkeys (AGMs). Current formulation is liquid suspension, which although very efficient, is not very convenient for storage and transportation. Our objective here is to further develop the vaccine formulation through lyophilization, which is expected to dramatically improve the vaccine endurance to storage and transportation, also may allow a more convenient intranasal delivery. New more efficient adjuvants to enhance the durability of the immunity will be also explored. We plan to achieve these breakthrough improvements in the human vaccine stability, durability and efficacy through the following 5 Aims: 1) Lyophilization of Alum formulated HeV-sG – nanoparticle formulation; 2) Testing alternate adjuvants for immunogenicity. Lyophilization of HeV-sG formulated with alternate adjuvant – nanoparticle formulation; 3) Perform stability studies to support the animal efficacy studies; 4) Immunogenicity testing of reconstituted vaccine (IM) and nanoparticle formulation through intranasal delivery – duration of immunity and efficacy in ferrets; and 5) Identification of a new product, choice of delivery – intranasal or reconstituted IM, efficacy confirmation and duration of immunity in AGMs.

项目概要/摘要 尼帕病毒 (NiV) 和亨德拉病毒 (HeV) 被列为生物安全 4 级 (BSL-4) 病毒并被列出 NIH 和 CDC 列为 C 类生物威胁病毒和亨尼帕病毒（HeV、NiV、库马西病毒、KV、 雪松病毒、CedV、墨江病毒、MojV 以及该属的潜在新病毒）疾病均包含在 2018 年世界卫生组织重点疾病蓝图清单的年度审查 这些新出现的病毒与其他病毒不同。 A 类生物威胁病毒，例如天花或埃博拉病毒，可以从天然宿主中分离出来， 在细胞培养物中生长至高滴度，并在牲畜中传播和扩增，这些牲畜已被证明是 传播给人类，随后爆发人际传播设施。 通过气溶胶和高致死率增强了它们作为生物威胁剂的潜力。 目前，还没有批准的针对 NiV 疾病或 HeV 疾病的人类预防或治疗方法。 疫苗接种可能提供一种可行的策略，为流行地区以及 为我们的军备库提供重要组成部分，以减轻这些病毒在事件中的爆发 它们被用作生物武器马抗 HeV 疫苗 (Equivac® HeV)，该亚基在基因上是 与拟议的人类亚单位疫苗相同，硕腾自 11 月起已在澳大利亚上市 2012 年在澳大利亚农药和兽药管理局 (APVMA) 的授权下，是 第一个针对任何 BLS-4 药物的商业化疫苗 APVMA 授予 Equivac® HeV 完全注册资格。 2015年8月。 Profectus BioSciences, Inc. 是一家专注于疫苗的公司，拥有领先的开发流程经验 通过疫苗生产、监管提交、临床试验和 BLA 申请来对抗 NiV。 和 HeV 疾病，该公司已获得 NIAID 颁发的生物防御 R01 合作伙伴奖 m102.4（一种抗 NiV/HeV 人 MAb）的临床前开发，作为 NiV 和 HeV 的暴露后治疗剂 与HeV感染类似的R01开发的HeV-sG人类疫苗Profectus已进入临床前研究。 对用酒精凝胶配制的 HeV-sG 亚基进行了临床前研究，以作为二价药物用于人类 预防 NiV 或 HeV 感染或阻止其传播的疫苗已开发出来。 已生产，已开发出GMP疫苗生产工艺，已完成毒理学疫苗批次 生产后，已在兔子身上进行了 GLP 毒性研究，单剂量免疫后的疗效已得到证实 在非洲绿猴 (AGM) 中得到证实，目前的配方是液体悬浮液，但其效果非常差。 效率高，储存运输不太方便，我们这里的目的是进一步发展。 通过冻干法制备疫苗，有望显着提高疫苗的耐受性 储存和运输，也可能让鼻内给药更方便更高效。 我们还将探索增强免疫力持久性的佐剂。 通过以下 5 个目标，突破性提高人类疫苗的稳定性、耐久性和功效： 1) 冻干明矾配制的 HeV-sG – 纳米颗粒制剂；2) 测试替代佐剂 使用替代佐剂 - 纳米颗粒配制的 HeV-sG 的冻干。 配方；3) 进行稳定性研究以支持动物功效研究；4) 免疫原性； 通过鼻内输送测试重组疫苗 (IM) 和纳米颗粒制剂 – 雪貂的免疫力持续时间和功效；以及 5) 新产品的鉴定、交付方式的选择 – 鼻内或重组 IM、AGM 中的功效确认和免疫持续时间。