Development of a thermostable rotavirus vaccine for mucosal delivery withoutneed for reconstitution - Phase II

开发用于粘膜递送且无需重构的热稳定轮状病毒疫苗 - 第二阶段

• 批准号: 9348073
• 负责人: Victor Bronshtein
• 金额: $ 45.49万
• 依托单位: UNIVERSAL STABILIZATION TECHNOLOGIES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-10 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9348073
• 关键词: Address; Adverse effects; Age; Animal Model; Antacids; Area; Biological; Biological Assay; Biological Preservation; Buffers; Cell Culture Techniques; Cell Proliferation; Cell Survival; Cessation of life; Characteristics; Cheek structure; Child; Cold Chains; Country; Data; Developing Countries; Development; Diarrhea; Dimensions; Dose; Drops; Evaluation; Film; Formulation; Foundations; Freezing; Future; Gastroenteritis; Ghana; Gnotobiotic; Goals; Hamsters; High temperature of physical object; Human; In Vitro; Individual; Infant; International; Intestines; Intussusception; Lead; Legal patent; Licensing; Life; Liquid substance; Methodology; Methods; Mission; Modeling; Neonatal; Oral; Oral mucous membrane structure; Outcome; Particle Size; Patients; Phase; Phase II Clinical Trials; Placebos; Polymers; Powder dose form; Price; Procedures; Production; Protocols documentation; Rattus; Refrigeration; Research; Rice; Risk; Rotavirus; Rotavirus Vaccines; Rotavirus disease; Safety; Serum; Ships; Surface; Technology; Temperature; Testing; Thick; Time; Tongue; Toxic effect; Transportation; Vaccinated; Vaccination; Vaccines; Vero Cells; Vial device; Viral; Viral Physiology; Water; Weight; Work; burden of illness; cost; cost effective; design; immunogenic; immunogenicity; improved; in vitro testing; in vivo; innovation; irritation; mucosal vaccine; neonate; oral vaccine; particle; phase 1 study; public-private partnership; reconstitution; technology/technique; thermostability; vaccine delivery; vapor; vaporization; wasting

PROJECT SUMMARY/ABSTRACT Rotavirus (RV) is responsible for an estimated 500,000 deaths each year from severe diarrhea, mostly in children in developing countries. Currently only two RV vaccines are broadly available, and are delivered by liquid drops (either directly or after reconstitution) to infants between 6-14 weeks of age. Both vaccines are labile at ambient temperatures and so bound by the cold chain, as well as being sensitive to freezing because of their liquid components. A drawback of liquid delivery to babies is the potential for spitting out the vaccine, which increases the risk of under-vaccination. Also, aside from leaving babies unprotected from RV during the crucial first months of life, the protocol of vaccinating only after 6 weeks old has been found to lead to greater rates of vaccine-associated intussusception – a potentially fatal bowel blockage. Furthermore, the cost of these vaccines is often prohibitively high for introduction in the poorest countries, which have the highest rates and burden of RV gastroenteritis. Thus there is an urgent need to develop a cost-effective thermostable rotavirus vaccine for liquid-free administration during the neonatal time period. International Medica Foundation (IMF) has world-wide license for a low-cost liquid RV vaccine, RRV-TV, and has designed an improved neonatal administration protocol which data indicates will reduce the rate of intussusception. This vaccine was developed as a public-private partnership project and has finished Phase II clinical trials in Ghana, and will seek WHO Prequalification for supply to UN agencies in the near future. UST’s patented Preservation by Vaporization (PBV) stabilization technology and techniques for producing polymeric films containing PBV-dried biologicals enable buccal vaccine delivery in the dry film format. In Phase I studies with RV vaccine, UST has proven that PBV-dried vaccine in polymeric film retains high activity and long-term stability for ≥2 months at 37°C and 5 months at 25°C. The application of these technologies for use with RRV-TV will decreased the cost of vaccine implementation due to the low-priced raw vaccine material, enhanced manufacturing yields possible with PBV, and refrigeration-free distribution and storage. The final product will be a thermostable RV vaccine in a mucoadhesive dissolvable polymeric film for liquid-free administration to the buccal or sublingual surfaces, to provide simpler, more accurate dosing to neonates. The specific objectives of this Phase II project are 1) Application of PBV protocols developed during Phase I to tetravalent RRV-TV vaccine 2) Optimization of film production protocols to incorporate PBV RRV-TV vaccine and antacids, and 3) demonstrate film suitability and safety in vitro as well as in vivo using hamsters and rats, and in vivo vaccine immunogenicity and efficacy against challenge in a gnotobiotic piglet model. The long-term goal is to generate a dissolvable mucoadhesive polymeric film that contains thermostable RRV-TV rotavirus vaccine for simple oral mucosal delivery to neonates which has low cost of manufacture, store and ship and is immunogenic, safe and protective.

项目摘要/摘要 轮状病毒（RV）负责估计每人500,000人死亡，主要是在 发展中国家的儿童目前只有两种RV疫苗 液体滴（直接或重新定态后）到6-14周之间的婴儿。 在环境温度下，受冷链的束缚，并且对冻结敏感 液体成分。 增加疫苗接种量的风险。 生命的头几个月，只有在6周后接种疫苗的方案才能提高到更高的速度 与疫苗相关的肠道震荡 - 可能致命的肠阻塞。 通常是过时的国家，吉奇最高国家，一些最贫穷的国家 RV胃肠炎。 在新生儿期间无液体给药。 国际医疗基金会（IMF）拥有低成本液体RV RV疫苗的全球许可证，RRV-TV 已经设计了改进的新生儿管理协议，数据表明将降低 这种疫苗是作为公共私人合作伙伴项目开发的 加纳的临床试验将在不久的将来寻求谁在联合国机构的资格资格。 UST通过汽化（PBV）稳定技术和生产技术的专利保存 含有PBV干燥的生物学的聚合物膜在干胶片中可以在干胶片中递送 我研究了RV疫苗，UST在聚合物Figh Actititi和 在37°C和25°C下的长期稳定性≥2个月。 使用RV-TV，由于低价的原料材料，将降低疫苗实施成本， 增强的制造可以通过PBV以及无限制的分布和储存。 产品将是粘附性溶解的聚合物膜中的热稳定RV疫苗，无液体 给予颊或舌下表面，以向新生儿提供更简单，更准确的给药。 该阶段项目的具体目标是1）在I期期间开发的PBV协议的应用 到四维尔RRV-TV疫苗2）优化膜生产方案以结合PBV RRV-TV疫苗 和抗酸剂，以及3）展示了使用仓鼠和大鼠的体外膜适用和安全性以及体内 在长期内，体内疫苗不稳定性和有效性 目标是产生不可溶解的粘粘性聚合物膜恒温器恒温RRV-TV轮状病毒 简单口服粘膜粘膜递送到新生儿的疫苗，生产成本较低 免疫原性，安全和保护性。