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

点击翻译按钮获取中文摘要

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.