Good Manufacturing Practices Master Cell and Working Cell Banks and Gmp Pilot Lot of Prototype Shigella Flexneri 2a Live Vector Expressing Enterotoxigenic E. Coli Antigens; Cvd 1208s 122

Shigella and enterotoxigenic Escherichia coli (ETEC) are two of the most important diarrheal pathogensworldwide, causing moderate-to-severe diarrheal disease in young children in developing countries andtravelers' diarrhea among U.S. travelers who visit developing countries. We have developed a lead candidateprototype Shigella-enterotoxigenic Escherichia coli (ETEC) vaccine candidate strain, CVD 1208S-122, whichconsists of an attenuated ?guaBA,?set,?sen Shigella flexneri 2a strain engineered to express ETECcolonization factor antigen I (CFA/I) and the B and A2 subunits of heat-labile enterotoxin (LThA2B) from genesintegrated into the chromosome. In animal models this prototype has elicited protective immune responsesagainst these two important human diarrheal pathogens. The overall goal of this proposal is to translate thisprototype Shigella-ETEC vaccine construct from an academic research laboratory vaccine candidate to apotential human vaccine ready to enter Phase 1 clinical trials (under other funding) to evaluate its safety,clinical tolerability, excretion pattern, transmissibility to close contacts, and immunogenicity. We have engagedan industrial partner, PaxVax, Inc. of Redwood City, CA. PaxVax is committed to becoming a futuremanufacturer of our multivalent combination vaccine and will provide overall strategic guidance for thistranslation, including regulatory support (in preparation of the chemistry/manufacture/control (CMC) portion ofthe IND, advice on interaction with contract manufacturing organizations (CMOs), and other industrial know-how. To accomplish this transition from promising research laboratory candidate to potential human trial, wepropose the following activities.Aim 1. Technology transfer, Cell Bank production, process development and pilot scale-up of Shigella-ETECvaccine candidate CVD 1208S-122.Aim 2: Comprehensive cGMP pilot production lot to provide 3000 vials of CVD 1208S-122.Aim 3: Comprehensive pre-clinical studies on the cGMP pilot lot formulation of CVD 1208S-122 to underpinsubmission of an IND to the FDA to prepare for Phase 1 and 2 clinical trials.