Gates Package — page 595

• PATH o May 24, 2012: NIAID/DMID/EHDB (Bill Alexander, Fred Cassels, Melody Mills, Ryan Ranallo, and Shahida Baqar) met with Tom Brewer and other BMGF program staff to discuss specific branch portfolios and potential for collaborative interactions. The same day the same EHDB group met with PATH diagnostics and formulations staff in their Seattle office, also to discuss specific branch portfolios and potential for collaborative interactions. o With EHDB- Enteric Vaccine Initiative (EVI) PATH collaboration on an oral dose escalation clinical trial of double mutant LT (dmLT, LT(R192G/L211A) of Enterotoxigenic E. coli (ETEC) in adults was initiated in 2010 and completed in 2012. dmLT is a component of ETEC vaccines and a viable mucosal adjuvant platform for delivery of enteric and non-enteric vaccines. Primary outcome of the clinical trial is this that dmLT is safe and devoid of any toxicity given orally up to 100μg, whereas, 50 μg is the optimal immunogenic dose (Clin, Vacc. Immunol., In press, 2013). ▪ DMID provided clinical trial and laboratory support. ▪ PATH cGMP manufactured the product, supported all pre-clinical studies, conducted GLP toxicity studies and funds stability studies since the production. PATH maintains/updates CMC and IB as needed. ▪ Based on the results of this trial, PATH is testing this product as an ETEC vaccine component or oral adjuvant for Shigella vaccine in Bangladesh. o Sublingual route of immunization of dmLT clinical trial protocol has been approved by PRA/OCRA, site IRB and all FDA requirements are met. Study was to initiate in the fall of 2013, but due to H7N9 flu studies has been delayed until Jan 2014. ▪ DMID will be providing the support to conduct the clinical study. ▪ EVI-PATH will be providing the product, current stability data and all support to conduct trial related immunological studies. o Intradermal route of immunization clinical trial - concept has been reviewed and approved by DMID;currently protocol is under development. o ETEC antigen to be used in pre-clinical or clinical research. EHDB and EVI has agreed to collaboratively produce (on contract with WRAIR) sufficient amounts of six surface antigens (each organization will fund production cost of three antigens) to be provided to the scientific community to allow direct comparison of various clinical trials and epidemiological studies conducted around the globe. o "Enteric Vaccine Portfolio Holders Workshop" a DMID-EVI PATH jointly funded international meeting was held (Feb 2013) to discuss progress in vaccine development against ETEC and Shigella.Multiple major gaps were identified andways to bridge them are being determined.. o Shahida Baqar, EHDB PO, is a voting member of EVI PATH Scientific Advisory Board. o Future plans ▪ Evaluation/comparison of dmLT for safety and immunogenicity vial oral, sublingual and intradermal routes in adults residing in endemic areas. A safe dose via each route will likely also be tested in children. ▪ Candidate Vaccine-Adjuvant-Route trial in U.S. adults, and adults and children living in endemic areas. NIAID PRECLINICAL RESOURCES FOR PRODUCT DEVELOPMENT