权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Development of Influenza Virus-Like Particle (VLP) Vaccines

流感病毒样颗粒（VLP）疫苗的开发

基本信息

批准号：
8132949
负责人：
JOSE M. GALARZA
金额：
$ 115.37万
依托单位：
TECHNOVAX, INC.
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-05-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8132949
关键词：
Adjuvant Advanced Development Antigens Avian Influenza Avian Influenza A Virus Award Baculoviruses Cells Chemicals Chickens Chromatography Contract Services Contracts Cyclic GMP Dependence Development Drug Formulations Elderly Epidemic Epitopes Familiarity Feasibility Studies Ferrets Generations Genetic Materials H7N7 Health Human Immunization Industry Infection Influenza Influenza A Virus, H1N1 Subtype Influenza A Virus, H5N1 Subtype Insecta Intramuscular Intranasal Administration Laboratories Mammalian Cell Methods Molecular Conformation Mus Oryctolagus cuniculus Outcome Performance Pharmaceutical Preparations Phase Phase I Clinical Trials Pilot Projects Principal Investigator Production Protocols documentation Public Health Recombinants Recurrence Regimen Respiratory Tract Infections Risk Rivers Route Safety Small Business Innovation Research Grant Societies Speed Structure System Technology Testing Time TimeLine Toxicology Ultracentrifugation United States Food and Drug Administration Update Vaccine Design Vaccine Production Vaccines Variant Vero Cells Virulent Virus Virus-like particle Work aged base commercialization comparative cost design dosage egg flexibility immunogenic immunogenicity improved influenza virus strain influenza virus vaccine influenzavirus innovation novel vaccines pandemic disease pandemic influenza preclinical study product development programs prophylactic protective efficacy seasonal influenza success technology development vaccine candidate vaccine development vaccine efficacy virus genetics

项目摘要

DESCRIPTION (provided by applicant): Influenza virus-like particles (VLPs) have demonstrated in preclinical studies that they are highly immunogenic and efficacious in protecting against influenza infections. This emerging vaccine technology not only creates new vaccine candidates with alternative routes of administration (intranasal or intramuscular) but also implements a fast, flexible, and dependable cell-based manufacturing system that overcomes many of the burdens associated with the current egg production system. VLPs are structures that morphologically and biochemically mimic a wild type influenza virus, however they lack viral genetic material and are unable to replicate and cause infection; therefore chemical inactivation is not required. This better maintains the native conformation of the antigenic epitopes in the VLP vaccine. The safety of the technology allows for the development of vaccines directed against highly pathogenic influenza virus strains without the risk of disseminating infectious material. The Phase I SBIR award allowed us to create and test in preclinical studies several VLP vaccine candidates designed to protect against highly pathogenic pandemic strains of the influenza virus such as H1N1-1918; H5N1 and H7N7 avian influenza viruses. These studies have shown that VLP vaccines are immunogenic and efficacious, further proving the value of the VLP technology for influenza vaccine development. In the current application, we propose to further advance the development of these vaccine products with additional preclinical studies. We will develop a purification system for large scale manufacturing of VLP vaccines, prior to cGMP manufacturing. We will perform one comparative pilot study between a VLP vaccine produced in the insect cell/baculovirus system and the same VLP vaccine produced in stably transfected recombinant mammalian cells. Further, we aim to perform small scale cGMP vaccine production and toxicology studies for a Pre-Innovation Drug Application (IND) with the FDA. The specific aims of the Phase II SBIR are: A) To produce, characterize, and test in preclinical studies in mice the influenza-virus-like particle (VLP) vaccines designed to protect against 1) H5N1 avian influenza virus, 2) human H1N1-1918 influenza virus and 3) H7N7 avian influenza, and to perform cross protection and enhancement of immunogenicity (including in the elderly) studies as well as to develop a large scale purification method and to compare the immunogenicity of the H5N1 VLP vaccine produced in the insect cell/ baculovirus system and the same vaccine produced in a recently developed stably transformed mammalian which could be developed as a second generation VLP manufacturing system. B) To evaluate vaccine efficacy, dosage and adjuvant formulations for enhancement of vaccine potency and antigen sparing in preclinical studies in ferrets. C) Perform small scale cGMP vaccine production and toxicology studies for a Pre-Innovation Drug Application (IND) with the FDA. Completion of this SBIR Phase II will bring the VLP vaccine technology to the point of a Phase I clinical trial in humans and will advance this new vaccine product and manufacturing system towards commercialization. Although pandemic influenza VLP vaccines are being developed during this project, the outcome will validate the robustness of the technology for development of seasonal influenza vaccine which currently is burdened with prolonged production times, dependence on chicken eggs, insufficient yield with certain strains, inflexibility for accommodating newly emerging variants, and unsuitability when working with highly virulent virus, all issues where the VLP technology is superior. This SBIR Phase II will accelerate the creation of vital prophylactic vaccines (e.g. H5, H7 avian flu and 1918) and will also validate a faster, more flexible, cell-based technology for epidemic influenza vaccine production. PUBLIC HEALTH RELEVANCE: Influenza is a recurrent respiratory infection afflicting humans all over the world. The virus changes constantly generating new epidemic and pandemic viruses, for which vaccines are needed. Although prophylactic vaccines for epidemic strains are available, periodic updates are required to maintain protective efficacy. Vaccines for pandemic viruses are lacking and their development is critical. Here we proposed to further develop the influenza virus-like particle (VLP) technology for the generation of pandemic and epidemic influenza vaccines. This technology is fast, flexible, and reliable for creating highly effective vaccines which are manufactured in a cell-based system. The VLP vaccines system overcomes many of the problems of the egg production system. Successful development of these vaccines will benefit society globally.

描述（由申请人提供）：流感病毒样颗粒（vlp）已在临床前研究中证明，它们具有高度免疫原性，可有效预防流感感染。这种新兴的疫苗技术不仅创造了具有替代给药途径（鼻内或肌肉注射）的新候选疫苗，而且还实现了一种快速、灵活和可靠的基于细胞的制造系统，克服了与当前鸡蛋生产系统相关的许多负担。VLPs是在形态和生化上模仿野生型流感病毒的结构，但它们缺乏病毒遗传物质，不能复制和引起感染；因此不需要化学灭活。这更好地维持了VLP疫苗中抗原表位的天然构象。该技术的安全性允许开发针对高致病性流感病毒株的疫苗，而不会有传播感染性物质的风险。I期SBIR奖使我们能够在临床前研究中创建和测试几种VLP候选疫苗，这些疫苗旨在预防流感病毒的高致病性大流行毒株，如H1N1-1918；H5N1和H7N7禽流感病毒。这些研究表明，VLP疫苗具有免疫原性和有效性，进一步证明了VLP技术在流感疫苗开发中的价值。在目前的申请中，我们建议通过额外的临床前研究进一步推进这些疫苗产品的开发。在cGMP生产之前，我们将开发用于大规模生产VLP疫苗的纯化系统。我们将在昆虫细胞/杆状病毒系统中生产的VLP疫苗和在稳定转染的重组哺乳动物细胞中生产的VLP疫苗之间进行一项比较试点研究。此外，我们的目标是进行小规模的cGMP疫苗生产和毒理学研究，以获得FDA的创新前药物申请（IND）。第二阶段的具体目标是：A)生产、表征和在小鼠临床前研究中测试流感病毒样颗粒（VLP）疫苗，旨在预防1)H5N1禽流感病毒，2)人H1N1-1918流感病毒和3)H7N7禽流感。以及进行免疫原性的交叉保护和增强（包括在老年人中）研究，以及开发大规模纯化方法，并比较在昆虫细胞/杆状病毒系统中生产的H5N1 VLP疫苗和在最近开发的稳定转化的哺乳动物中生产的相同疫苗的免疫原性，该哺乳动物可开发为第二代VLP制造系统。B)在雪貂临床前研究中评估疫苗效力、剂量和佐剂配方，以增强疫苗效力和抗原节约。C)为FDA的创新前药物申请（IND）进行小规模cGMP疫苗生产和毒理学研究。SBIR II期的完成将使VLP疫苗技术进入人体I期临床试验阶段，并将推动这种新疫苗产品和制造系统走向商业化。虽然在本项目期间正在开发大流行性流感VLP疫苗，但结果将验证季节性流感疫苗开发技术的稳稳性，目前季节性流感疫苗的生产时间较长，依赖鸡蛋，某些菌株产量不足，适应新出现的变种缺乏灵活性，以及在处理高毒性病毒时不适合，这些都是VLP技术具有优势的问题。SBIR第二期将加速重要预防性疫苗（如H5、H7禽流感和1918年禽流感）的生产，并将验证一种更快、更灵活的基于细胞的流行性流感疫苗生产技术。公共卫生相关性：流感是一种反复发生的呼吸道感染，影响全世界的人类。病毒不断变化，产生新的流行病和大流行性病毒，需要疫苗。虽然有针对流行毒株的预防性疫苗，但需要定期更新以保持保护效力。目前缺乏针对大流行性病毒的疫苗，研制疫苗至关重要。在此，我们建议进一步开发流感病毒样颗粒（VLP）技术，用于大流行性流感和流行性流感疫苗的生产。这种技术快速、灵活、可靠，可用于生产以细胞为基础的高效疫苗。VLP疫苗系统克服了鸡蛋生产系统的许多问题。这些疫苗的成功开发将使全球社会受益。