Project 1 - Profectus Biosciences, Inc.

项目 1 - Profectus Biosciences, Inc.

• 批准号: 10362730
• 负责人: John Hayward Eldridge
• 金额: $ 80.23万
• 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 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10362730
• 关键词: Adjuvant; Aerosols; African Green Monkey; Agonist; Alhydrogel; Animals; Antigens; Area; Australia; Award; Bangladesh; Biological; Biological Assay; Biological Products; Biological Sciences; Categories; Cell Culture Techniques; Cell Line; Centers for Disease Control and Prevention (U.S.); Clinical; Clinical Research; Clinical Trials; Development; Disease; Disease Outbreaks; Documentation; Dose; 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; Monitor; National Institute of Allergy and Infectious Disease; Nipah Virus; Oryctolagus cuniculus; Paramyxovirus; Performance; Persons; Pesticides; Powder dose form; Process; Prophylactic treatment; Public Health; Recombinants; Reporting; Research Institute; Respiratory Disease; Risk; Safety; Science; Serology; Smallpox; Source; Subunit Vaccines; Suspensions; Testing; Therapeutic; Toxicology; Transportation; Tropism; United States National Institutes of Health; Vaccinated; Vaccination; Vaccines; Veterinary Medicine; Viral; Virulent; Virus; Virus Diseases; aluminum sulfate; animal efficacy; arm; authority; biodefense; biothreat; bioweapon; cell bank; clinical development; efficacy study; experience; falls; glycoprotein G; human monoclonal antibodies; immunogenicity; improved; manufacturing process; nanoparticle; 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; Adjuvant; Aerosols; African Green Monkey; Agonist; Alhydrogel; Animals; Antigens; Area; Australia; Award; Bangladesh; Biological; Biological Assay; Biological Products; Biological Sciences; Categories; Cell Culture Techniques; Cell Line; Centers for Disease Control and Prevention (U.S.); Clinical; Clinical Research; Clinical Trials; Development; Disease; Disease Outbreaks; Documentation; Dose; 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; Monitor; National Institute of Allergy and Infectious Disease; Nipah Virus; Oryctolagus cuniculus; Paramyxovirus; Performance; Persons; Pesticides; Powder dose form; Process; Prophylactic treatment; Public Health; Recombinants; Reporting; Research Institute; Respiratory Disease; Risk; Safety; Science; Serology; Smallpox; Source; Subunit Vaccines; Suspensions; Testing; Therapeutic; Toxicology; Transportation; Tropism; United States National Institutes of Health; Vaccinated; Vaccination; Vaccines; Veterinary Medicine; Viral; Virulent; Virus; Virus Diseases; aluminum sulfate; animal efficacy; arm; authority; biodefense; biothreat; bioweapon; cell bank; clinical development; efficacy study; experience; falls; glycoprotein G; human monoclonal antibodies; immunogenicity; improved; manufacturing process; nanoparticle; 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

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.

项目摘要/摘要 NIPAH病毒（NIV）和Hendra病毒（HEV）被分类为生物安全级别4（BSL-4）病毒，并被列为 NIH和CDC中的C类Biothreat剂。 Nipah和Henipaviral（Hev，Niv，Kumasi Virus，KV， 雪松病毒，CEDV，Mojiang病毒，MoJV和属疾病中的潜在新病毒被包括在该属中 2018年WHO蓝图清单的年度评论。这些新兴病毒与其他病毒不同 可以从天然储层中隔离生物托管病毒剂，例如天花或埃博氏病毒。 在细胞培养物中生长到高滴度，并在牲畜中传播和扩展，这些牲畜已被证明是 向人类传播，随后发生人与人之间的传播设施爆发。传播 通过气溶胶和高杀伤力提高了其作为生物治疗剂的潜力。 目前，尚无针对NIV疾病或HEV病的批准的人类预防或治疗性。 疫苗接种可能会提供可行的策略，以在地方性地区以及 在我们的武术中提供重要组成部分，以减轻这些病毒的爆发 它们被用作生物武器。马抗HEV疫苗（Equivac®HEV），亚基通常是 自11月以来，与拟议的人类亚基疫苗相同。 2012年，在澳大利亚农药和兽医药物管理局（APVMA）的授权下，是 首先针对任何BLS-4代理商进行商业化疫苗。 APVMA授予Equivac®HEV的全部注册 2015年8月。 Profectus Biosciences，Inc。是一家以疫苗为中心的公司 通过疫苗制造，监管提交，临床试验和BLA应用。与Niv作战 和HEV疾病，该公司已获得Niaid的Biodefense R01奖的合作伙伴关系 M102.4的临床前开发，一种抗NIV/HEV人物mAB，作为NIV和NIV的暴露后疗法 HEV感染和类似的R01在临床前研究中开发HEV-SG人类疫苗。 Profectus具有 对用alhydrogel配制的HEV-SG亚基进行了临床前研究，以作为人类用作二价 防止NIV或HEV感染或破坏其传播的疫苗。大牢房（MCB）已经 制造的GMP疫苗制造过程已经开发出来，毒理学疫苗已经是 产生的GLP TOX研究已在兔子中进行，单剂量免疫后的效率一直是 在非洲绿猴（AGM）中确认。当前公式是液体悬浮液，尽管非常 高效，对于存储和运输不是很方便。我们的目标是进一步发展 通过冻干的疫苗配方，预计将显着改善疫苗耐力 存储和运输，也可能允许更方便的鼻内输送。新的更有效 还将探索提高免疫力耐用性的调节器。我们计划实现这些 通过以下5个目的，人类疫苗稳定性，耐用性和效率的突破性提高： 1）明矾配方的HEV-SG - 纳米颗粒配方的冻干； 2）测试替代调节器 用于免疫原性。用替代性调整 - 纳米颗粒制成的HEV-SG的冻干 公式; 3）进行稳定研究以支持动物效率研究； 4）免疫原性 通过鼻内递送测试重构疫苗（IM）和纳米颗粒制剂 - 雪貂的免疫力和效率的持续时间； 5）识别新产品，交付的选择 - 鼻内或重组的IM，AGMS中的效率确认和免疫持续时间。