Development and cGMP Manufacture of a Vitrified Typhoid Vaccine

DESCRIPTION (provided by applicant): Typhoid fever is an infectious disease that annually afflicts an estimated 16 million people worldwide, resulting in 600,000 deaths. The etiologic agent of typhoid fever, Salmonella typhi (S. typhi), is transmitted to humans by the fecal-oral route through contaminated water or food. The use of antibiotics to treat typhoid fever has transformed an often fatal disease into a readily treatable condition. The recent emergence of multidrug-resistant strains of S. typhi found in regions like Southeast Asia has resulted in an increase in the incidence of severe and fatal typhoid fever as well as heightened medical concerns. These concerns may be partially addressed through the use of an effective typhoid fever vaccine that can control morbidity and mortality and limit the spread of drug resistant strains. There are limitations of commercially available vaccines to typhoid fever, which include inconvenient dosing, parenteral administration frequently associated with local reactogenicity and fever, variable protective efficacy, and unpredictable duration of immunity. AVANT Immunotherapeutics, Inc. is developing live, attenuated S. typhi TySOO as an orally administered, single-dose vaccine against typhoid fever. Freshly prepared TySOO was well tolerated and remarkably immunogenic when administered as a single, oral dose to eleven healthy, adult volunteers. A vigorous mucosal response was also detected within seven days of vaccination. Lyophilized TySOO was recently manufactured for evaluation in a Phase I/I I clinical study sponsored by the Division of Microbiology and Infectious Diseases at the NIAID. Lyophilized TySOO requires storage at -20C, requiring a "cold chain" to maintain vaccine potency. AVANT now has technology to preserve bacterial vaccines using a proprietary preservation process that markedly improves vaccine stability at room temperature. The goals of this proposal are to (1) optimize the production methodology to incorporate this innovative drying technology into the production of a thermostable formulation for TySOO; (2) develop multidose and bulk manufacturing techniques that would significantly reduce cost and manufacturing capacity needed for production of large quantities of doses; and (3) perform scale up and GMP production of preserved TySOO. Meeting these goals will facilitate the advance of TySOO as an oral, single-dose vaccine that can be delivered outside of the storage cold chain.