SBIR-STTR Award

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.

Public Health Relevance Statement:


Public Health Relevance:
Rotavirus (RV) is the leading cause of severe dehydrating diarrhea in children worldwide, and although there are currently two licensed vaccines on the market, they must be refrigerated during transportation and storage and are administered as an oral liquid. These vaccines are costly, have short shelf lives at ambient temperatures, and are not easy to administer to infants, all of which are challenges in developing regions of the world where the rotavirus disease burden is highest. We have developed technology for making vaccines stable at ambient temperatures, and we will use this technology to generate a potent, ambient temperature- stable rotavirus vaccine formulation that can be easily administered to infants as a quick-dissolving oral film.

Project Terms:
Address; Age; Age-Months; Aluminum; Animal Model; Antibodies; Attenuated; Attenuated Vaccines; Bacteria; Biological; Biological Preservation; Blood Coagulation Factor; burden of illness; Bypass; Cessation of life; Child; Childhood; Clinical Research; Cold Chains; cost; cost effective; Cost Savings; Country; Data; Developing Countries; Development; Diarrhea; Dose; Drug Formulations; Drug Industry; Effectiveness; Encapsulated; Ensure; Enteral; Enzymes; Evaluation; Excision; Exposure to; Film; Freeze Drying; Glass; Goals; High temperature of physical object; Hospitalization; Hour; Hydroxypropylcellulose; immunogenic; immunogenicity; Incidence; India; Infant; innovation; Legal patent; Licensing; Licensure; Life; liquid formulation; Liquid substance; manufacturing process; Marketing; Measles; Measures; Mortality Vital Statistics; novel; Oral; Oral Administration; Oral mucous membrane structure; Phase; Phase III Clinical Trials; Physical process of vaporization; Poliomyelitis; Powder dose form; Preparation; Price; Probiotics; Process; Production; protective effect; Proteins; public health relevance; public-private partnership; reconstitution; Refrigeration; Risk; Rotavirus; Rotavirus disease; Rotavirus Infections; Rotavirus Vaccines; Rubella virus vaccine; Safety; seal; Shipping; Ships; Solvents; sugar; Techniques; Technology; technology development; Temperature; Testing; thermostability; Time; Transportation; United States; vaccine delivery; vaccine development; Vaccine Production; Vaccines; Vaginal delivery procedure; Virus

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.

Public Health Relevance Statement:
PROJECT NARRATIVE Rotavirus is the leading cause of severe dehydrating diarrhea in children worldwide, and although there are currently two licensed vaccines on the market, they are bound to the cold chain for transportation and storage, are costly, have short shelf lives at ambient temperatures and are not easy to administer to infants who tend to spit out the liquid vaccine- all of which are challenges in developing regions of the world where the rotavirus disease burden is highest. UST has developed technology for making vaccines more stable at ambient temperatures which improve yield and waste, and additionally has designed and successfully validated vaccine film production methods so a mucoadhesive film can be administered to the patient instead of liquid. UST is partnering with International Medica Foundation (IMF) whose mission is to bring a new improved rotavirus vaccine to world-wide markets and through this project will generate a potent, ambient temperature-stable form of the IMF tetravalent rotavirus vaccine that can easily be administered to children under the tongue or in the cheek as a dissolvable polymeric film, allowing a vaccine option for children in developing countries that is low cost, thermostable, and easy to store and administer.

Project Terms:
Address; Adverse effects; Age; Animal Model; Antacids; Area; Biological; Biological Assay; Biological Preservation; Buffers; burden of illness; Cell Culture Techniques; Cell Survival; Cessation of life; Characteristics; Cheek structure; Child; Cold Chains; cost; cost effective; Country; Data; design; Developing Countries; Development; Diarrhea; Dimensions; Dose; Drops; Evaluation; Film; Formulation; Foundations; Freezing; Future; Gastroenteritis; Ghana; Gnotobiotic; Goals; Hamsters; High temperature of physical object; Human; immunogenic; immunogenicity; improved; In Vitro; in vitro testing; in vivo; Individual; Infant; innovation; International; Intestines; Intussusception; irritation; Lead; Legal patent; Licensing; Life; Liquid substance; Methodology; Methods; Mission; Modeling; mucosal vaccine; Neonatal; neonate; Oral; Oral mucous membrane structure; oral vaccine; Outcome; particle; Particle Size; Patients; Phase; phase 1 study; Phase II Clinical Trials; Placebos; Polymers; Powder dose form; Price; Procedures; Process; Production; Protocols documentation; public-private partnership; Rattus; reconstitution; Refrigeration; Research; rhesus rotavirus vaccine; Rice; Risk; Rotavirus; Rotavirus disease; Rotavirus Vaccines; Safety; Serum; Ships; Surface; Technology; technology/technique; Temperature; Testing; thermostability; Thick; Time; Tongue; Toxic effect; Transportation; Vaccinated; Vaccination; vaccine delivery; Vaccines; vapor; vaporization; Vaporizer; Vero Cells; Vial device; Viral; Viral Physiology; wasting; Water; Weight; Work