Initial clinical evaluation of attenuated Shigella flexneri 2a live vector expressing enterotoxigenic Escherichia coli antigens, strain CVD 1208S-122.

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Project Summary Shigella and enterotoxigenic Escherichia coli (ETEC) represent two important enteric pathogens. There are no vaccines to prevent both Shigella and ETEC. The Center for Vaccine Development's (CVD) mission to develop vaccines that prevent diarrheal disease in the most vulnerable populations has resulted in construction of a prototype Shigella-ETEC vaccine candidate strain, named CVD 1208S-122. Strain CVD 1208S-122 consists of an attenuated ΔguaBA, Δset, Δsen Shigella flexneri 2a strain that has been engineered to express ETEC colonization factor antigen I (CFA/I) and the B and A2 subunits of heat-labile enterotoxin (LThA2B) from genes integrated into the Shigella chromosome. The overall goal of this proposal is to conduct a proof-of-concept, randomized, double-blinded, placebo-controlled, dose-escalation Phase 1 clinical evaluation on a pilot cGMP lot of strain CVD 1208S-122. Each dose of the live, attenuated vaccine will be administered in the inpatient setting (Research Isolation Ward) and reactogenicity will be assessed over 96 hours (4 days) of direct observation. Stool cultures will be performed, vaccine strains will be isolated from stool, and blood and stool specimens will be analyzed for the immunologic responses to vaccination. This clinical trial is designed to be narrowly focused to provide the preliminary assessment of safety, answer whether the strain is stable, and evaluate the immunogenicity to our Shigella-ETEC combination vaccine approach. Aim1. Assess the safety and tolerability of CVD 1208S-122. Aim 2. Measure the excretion pattern, genetic stability, and transmissibility of CVD 1208S-122. Aim 3. Examine the immune response to CVD 1208S-122. These research aims will assessed within the context of a clinical trial to be conducted according to local legal and regulatory requirements, applicable US federal regulations, ICH guidelines, and Good Clinical Practice (GCP) standards. We have a plan for ensuring clinical monitoring, ongoing quality management with quality assurance and quality control activities, external independent safety oversight, and data management.