GelVac Stable, Dry-Powder Nasal Recombinant VLP-Based Bivalent Norovirus Vaccine

GelVac 稳定干粉鼻重组 VLP 双价诺如病毒疫苗

• 批准号: 8462041
• 负责人: James Forrest Kirk
• 金额: $ 99.7万
• 依托单位: NANOTHERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8462041
• 关键词: 5 year old; Acids; Address; Adjuvant; Agonist; Animal Model; Animals; Antigens; Antiviral Agents; Arizona; Caliciviridae; Centers for Disease Control and Prevention (U.S.); Child; Clinical Research; Clinical Trials; Cyclic GMP; Developing Countries; Development; Disease Outbreaks; Drug Formulations; Epidemic; Family; Gastroenteritis; Gel; Genotype; Human; I-antigen; Immune response; Immunoglobulin A; In Situ; Infection; Inhalators; Intestines; Norovirus; Nose; Oral; Phase; Plants; Polymers; Polysaccharides; Powder dose form; Process; Recombinants; Research Personnel; Safety; Series; Serotyping; Solid; System; Toxicology; Universities; Vaccine Antigen; Vaccines; Viral; Virus; Virus-like particle; base; design; experience; foodborne outbreak; immunogenicity; in vivo; manufacturing process development; nanotherapeutic; novel; phase 2 study; pre-clinical; public health relevance; recombinant virus; residence; response; safety study; vaccine delivery

DESCRIPTION (provided by applicant): Noroviruses are a group of enteropathogenic viruses belonging to the taxonomic family Caliciviridae, which causes approximately 90% of epidemic non-bacterial outbreaks of gastroenteritis around the world and may be responsible for 50% of all foodborne outbreaks of gastroenteritis in the US. In developing countries, according to a 2008 estimate by CDC researchers, up to 200,000 children less than 5 years old die of norovirus infection each year. There is no vaccine against norovirus and no specific antiviral drugs to treat infections. To be safe and effective a vaccine must protect humans against two serotypes of Norovirus currently causing epidemics. Nanotherapeutics and its collaborators propose to conduct BLA-enabling preclinical development of a stable, dry-powder nasal norovirus vaccine that will form the basis for initiation of Phase I clinical studies. The vaccine consists of the GelVac" dry powder formulation in combination with recombinant virus-like particle (rVLP) antigens of two dominant norovirus genotypes (G-III) manufactured in green plants using a transient viral expression system. The powder vaccine is packaged in an established disposable nasal powder inhaler (Valois Monopowder MK IV) ready for nasal administration. The GelVac" dry-powder formulation is a novel in situ gelling nasal powder vaccine delivery platform based on GelSite(R) polymer, a distinct and inert ionic polysaccharide (polygalacturonic acid) that enhances the immune response through (1) prolonged nasal residence, (2) sustained antigen release by an in situ gelation mechanism, and (3) stabilization of vaccine antigens. The GelVac" dry powder approach addresses the storage and administration shortcomings of the current NoV oral approach. The G-I VLP antigen produced using the plant expression system has been successfully formulated with GelVac" dry powder and a series of preclinical immunogenicty studies have been conducted with the vaccine formulation at Arizona State University's (ASU). These studies have demonstrated that the antigen is stable in the GelVac" dry powder and nasal administration of the GelVac" dry powder with G-I antigen induced strong mucosal and humroal responses, including a robust IgA response in intestinal tract. In addition, the response levels generated with GelVac" dry powder was comparable or better than those with formulations containing a variety of TLR agonists as adjuvants. These studies formed a solid basis for the proposed fast-track development of GelVac" dry powder NoV vaccine containing both G-I and G-II antigens that is designed to provide protection against two dominant norovirus genotypes.

描述（由申请人提供）：诺如病毒是一组属于杯状病毒科的肠道病原性病毒，导致全世界约 90% 的流行性非细菌性胃肠炎爆发，并可能导致所有食源性胃肠炎爆发的 50%在美国。根据疾病预防控制中心研究人员 2008 年的估计，在发展中国家，每年有多达 20 万名 5 岁以下儿童死于诺如病毒感染。没有针对诺如病毒的疫苗，也没有治疗感染的特异性抗病毒药物。为了安全有效，疫苗必须保护人类免受目前引起流行病的两种诺如病毒血清型的侵害。 Nanotherapeutics 及其合作者提议对一种稳定的干粉鼻诺如病毒疫苗进行支持 BLA 的临床前开发，这将为启动 I 期临床研究奠定基础。该疫苗由 GelVac” 干粉制剂与使用瞬时病毒表达系统在绿色植物中制造的两种主要诺如病毒基因型 (G-III) 的重组病毒样颗粒 (rVLP) 抗原组合而成。粉末疫苗包装在建立了可用于鼻腔给药的一次性鼻粉吸入器（Valois Monopowder MK IV），GelVac”干粉制剂是一种基于原位胶凝鼻粉疫苗递送平台的新型制剂。 GelSite(R) 聚合物是一种独特的惰性离子多糖（聚半乳糖醛酸），通过以下方式增强免疫反应：(1) 延长鼻腔停留时间，(2) 通过原位凝胶机制持续释放抗原，以及 (3) 稳定疫苗抗原。 GelVac”干粉方法解决了目前NoV口服方法储存和给药的缺点。利用植物表达系统生产的G-I VLP抗原已成功用GelVac”干粉配制，并进行了一系列临床前免疫原性研究。亚利桑那州立大学 (ASU) 的疫苗配方。这些研究表明，该抗原在GelVac“干粉中是稳定的，并且鼻腔施用含有G-I抗原的GelVac”干粉可诱导强烈的粘膜和体液反应，包括肠道中强烈的IgA反应。此外，GelVac”干粉产生的反应水平与含有多种 TLR 激动剂作为佐剂的制剂产生的反应水平相当或更好。这些研究为拟议的 GelVac”干粉 NoV 疫苗的快速开发奠定了坚实的基础。 G-I 和 G-II 抗原旨在提供针对两种主要诺如病毒基因型的保护。