Development of a thermostable rotavirus vaccine for mucosal delivery without need for reconstitution

 描述（由申请人提供）：轮状病毒是全球儿童严重脱水性腹泻的主要原因，估计每年造成500，000人死亡，主要是发展中国家5岁以下的儿童。最近，两种轮状病毒活疫苗RotaTeq（Merck）和Rotarix（Glaxo Smith Kline）已被批准用于婴儿。重要的是，这些疫苗的运输和储存都需要冷链，并且在其目前的多剂量液体制剂中，这些疫苗的储存空间要求比脊髓灰质炎疫苗高5至20倍。因此，迫切需要开发一种具有成本效益的轮状病毒疫苗，该疫苗是干燥的、环境温度稳定的、有效的并且不需要重构。 巴拉特生物技术公司开发了一种减毒轮状病毒活疫苗（Rotavac），并计划以每剂1美元的价格向全球公开市场出售。该疫苗是作为一个公私伙伴关系项目开发的，预计将于2014年获得印度许可证，并于2015年获得世卫组织资格预审，以供应给联合国机构。Rotavac的临床研究已经证明了印度儿童口服三剂的安全性、免疫原性和有效性;然而，Rotavac必须冷藏以保持稳定性。 Universal Stabilization Technologies，Inc. (UST)已开发并证明了其创新的、正在申请专利的蒸发防腐（PBV）技术的商业价值。UST已经证明，许多生物制品，包括活病毒和细菌，以及抗体，酶，凝血因子和其他蛋白质，在PBV处理后在环境温度下保持高活性和长期稳定性，并且可以在短期（1小时或更长时间）暴露于70°C或更高温度下存活。 拟议的技术开发--一种干燥、热稳定、速溶的Rotavac口腔粘膜制剂--将使疫苗生产更便宜，因为PBV可能提高产量，并降低分销和储存成本，因为PBV制剂不需要冷链。通过将干燥、热稳定的Rotavac疫苗配制成用于口服给药的速溶薄膜，将进一步节省成本。薄膜制剂还将提供比目前市场上的液体制剂更准确的剂量和更容易给婴儿施用。 该I期项目的具体目标是1）开发使用PBV技术生产干燥热稳定轮状病毒疫苗的配方和工艺，以及2）生产适用于口服给药的含有干燥热稳定轮状病毒疫苗的速溶膜。在 在该项目的第二阶段，UST将在动物模型中评估干燥热稳定轮状病毒疫苗的速溶膜制剂的免疫原性和保护效果。该项目的长期目标是生产一种用于口服给婴儿的轮状病毒疫苗的速溶薄膜制剂，该制剂在环境温度下稳定，具有免疫原性，具有保护性，并且生产、储存和运输成本低。

 DESCRIPTION (provided by applicant): Rotavirus is the leading cause of severe dehydrating diarrhea in children worldwide, and is responsible for an estimated 500,000 deaths each year, mostly in children under the age of five years in developing countries. Recently, two live rotavirus vaccines, RotaTeq (Merck) and Rotarix (Glaxo Smith Kline), have been approved for use in infants. Importantly, both transportation and storage of these vaccines require a cold chain, and in their current multi-dose liquid formulations, the storage space requirements for these vaccines are five to twenty times higher than for polio vaccine. Thus there is an urgent need to develop a cost-effective rotavirus vaccine that is dry, ambient temperature-stable, potent, and does not require reconstitution. Bharat Biotech has developed a live attenuated rotavirus vaccine (Rotavac) and plans to sell it to global public markets at a price of US $1.00 per dose. This vaccine was developed as a public-private partnership project and is expected to receive India licensure in 2014 and WHO Prequalification in 2015 for supply to UN agencies. Clinical studies with Rotavac have demonstrated safety, immunogenicity, and efficacy in Indian children when administered orally in three doses; however, Rotavac must be refrigerated to maintain stability. Universal Stabilization Technologies, Inc. (UST) has developed and proven commercial value of its innovative, patent-pending Preservation by Vaporization (PBV) technology. UST has demonstrated that many biologicals, including live viruses and bacteria, as well as antibodies, enzymes, coagulation factors, and other proteins, retain high activity and long-term stability at ambient temperatures after processing by PBV and can survive short-term (1 hour or longer) exposure to 70°C or higher temperatures. The proposed technology development-a dry, thermostable, quick-dissolving oral buccal film formulation of Rotavac-will allow cheaper vaccine production because of the enhanced yields possible with PBV as well as reduced distribution and storage costs because PBV formulations do not require a cold chain. Further cost savings will be achieved by formulating the dry, thermostable Rotavac vaccine as a quick-dissolving film for oral administration. A film formulation will also provide more accurate dosing and easier administration to infants than the current liquid formulations on the market. The specific objectives of this Phase I project are 1) develop a formulation and process for manufacturing dry thermostable rotavirus vaccine using PBV technology, and 2) manufacture quick-dissolving films containing dry thermostable rotavirus vaccine suitable for oral delivery. In Phase II of this project, UST will assess the immunogenicity and protective effects of the quick-dissolving film formulation of dry thermostable rotavirus vaccine in animal models. The long-term goal of this project is to generate a quick-dissolving film formulation of rotavirus vaccine fr oral delivery to infants that is ambient temperature-stable, immunogenic, protective, and low cost to manufacture, store, and ship.