IND-enabling studies of an intranasal, single-replication M2SR influenza vaccine

鼻内单复制 M2SR 流感疫苗的 IND 研究

• 批准号: 10697911
• 负责人: Pamuk Bilsel
• 金额: $ 34.96万
• 依托单位: FLUGEN, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10697911
• 关键词: Acceleration; Address; Adult; Advanced Development; Animal Model; Animals; Antibodies; Antibody titer measurement; Australia; Biological Assay; Birds; Category C pathogen; Cell Line; Cells; Cessation of life; Clinical Research; Clinical Trials; DNA; Development; Distant; Elderly; Evaluation; Ferrets; Growth; Health; Hemagglutinin; Hospitalization; Human; Immune response; Immunity; Inactivated Vaccines; Individual; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza A Virus, H5N1 Subtype; Influenza A virus; Influenza B Virus; Morbidity - disease rate; Mucous Membrane; Mutation; National Institute of Allergy and Infectious Disease; National Security; Pathogenicity; Population; Process; Production; Proteins; Public Health; Qualifying; Reagent; Recommendation; Records; Reporting; Residual state; Respiratory Disease; Respiratory Tract Infections; Running; Safety; Seasons; Serum; Specific qualifier value; T cell response; Testing; Training; Update; Vaccination; Vaccine Antigen; Vaccine Production; Vaccines; Vial device; Virus; aged; analytical method; cell bank; cross immunity; cross reactivity; egg; experimental study; flasks; flu; human old age (65+); immunogenicity; influenza virus strain; influenza virus vaccine; influenzavirus; manufacture; manufacturing process; mortality; multidisciplinary; neutralizing antibody; novel; pandemic influenza; pandemic virus; prototype; research clinical testing; seasonal influenza; seropositive; universal influenza vaccine; vaccine access; vaccine effectiveness; vaccine efficacy; virtual

ABSTRACT Influenza (flu) virus, an NIAID category C priority pathogen, causes a respiratory disease resulting in over 200,000 hospitalizations and ~ 36,000 deaths per year in the US, while global influenza pandemics have resulted in as many as 50-100 million deaths worldwide. To address this threat to public health, annual vaccination is recommended for all individuals aged over 6 months in the US. However, currently available vaccines are lacking in efficacy. CDC’s vaccine effectiveness (VE) estimates for the 2014-2015 influenza season was only 23%. The reduced protection was attributed to the fact that the circulating viruses had drifted from the H3N2 vaccine virus recommended for vaccine production. In fact overall VE from 2005-2016 ranges from 10% to 60% at best. Current influenza vaccines, live or inactivated, offer suboptimal protection when matched and do not provide protection when the vaccine is mismatched. FluGen has developed a novel M2-deficient influenza vaccine (M2SR) that provides effective heterosubtypic protection in animal models. In addition, we have shown that an H1N1 M2SR elicits protection against drifted H1N1 viruses in ferrets. Moreover, H1N1 M2SR provided protection against lethal H5N1 pandemic virus in ferrets. A prototype H3N2 M2SR vaccine, shown to be generally safe and well-tolerated in clinical trials and elicited immune responses in healthy adult subjects who were seronaive, seropositive and seroprotected. The H3N2 M2SR also provided protection against a highly drifted influenza virus in a human challenge trial. In this project, we propose to further develop M2SR as a quadrivalent (Quad) universal influenza vaccine that provides effective protection against drifted influenza viruses in the following specific aims: Aim 1a. Transfer of M2SR and BM2SR production platforms to US-based CMO. Aim 1b. Analytical method transfer, development and qualification at US-based CMO. These activities will accelerate development of the M2SR influenza vaccine toward a quadrivalent vaccine product that can provide broad cross-protection against drifted influenza viruses.

抽象的 流感 (flu) 病毒是 NIAID C 类优先病原体，会引起呼吸道疾病，导致美国每年超过 200,000 人住院，约 36,000 人死亡，而全球流感大流行已导致全球多达 50-1 亿人死亡。为了解决这一对公共健康的威胁，建议美国所有 6 个月以上的人每年接种一次疫苗，但目前可用的疫苗缺乏 CDC 的疫苗有效性 (VE) 估计。 2014-2015年流感季节的保护率仅为23%，原因是流行的病毒偏离了推荐用于疫苗生产的H3N2疫苗病毒。事实上，2005-2016年的总体VE在10%到60%之间。目前的流感疫苗，无论是活的还是灭活的，在匹配时只能提供次优的保护，而在疫苗不匹配时则不能提供保护。 FluGen 开发了一种新型 M2 缺陷型流感疫苗 (M2SR)，可在动物模型中提供有效的异亚型保护。此外，我们还表明，H1N1 M2SR 可以在雪貂中引发针对漂移的 H1N1 病毒的保护，此外，H1N1 M2SR 还可以针对致命的 H5N1 病毒提供保护。雪貂体内的大流行病毒 H3N2 M2SR 疫苗原型在临床试验中显示总体安全且耐受性良好，并已被诱导。在一项人体攻击试验中，H3N2 M2SR 还对血清反应、血清反应呈阳性和血清保护的健康成人受试者的免疫反应提供了针对高度漂移的流感病毒的保护。 在该项目中，我们建议进一步开发 M2SR 作为四价 (Quad) 通用流感疫苗，为以下具体目标提供有效的保护： 目标 1a. 将 M2SR 和 BM2SR 生产平台转移给美国 CMO。 1b. 总部位于美国的 CMO 的分析方法转移、开发和鉴定将加速 M2SR 流感疫苗的开发，开发出可针对漂移流感提供广泛交叉保护的四价疫苗产品。病毒。