Boosting epithelial innate antimicrobial mechanisms.
Recurrent enteric infections in children of low income countries, chronic inflammatory bowel diseases, myelosuppressive/immunosuppressive therapies, are – among others – clinical situations that require strong boosting of mucosal innate defenses to respectively avoid luminal bacterial overgrowth causing malnutrition, chronic inflammation, and deadly translocation. Our challenge is to translate basic findings in the regulation of antimicrobial mechanisms of the epithelium into drugs and interventions boosting their expression. In contract with the high-throughput screening platform of Institut Pasteur Korea, and in collaboration with SANOFI, we aim to identify molecules from the pharmacopoeia inducing strong expression of epithelial antimicrobial molecules, without triggering significant inflammation.
Live oral vaccine candidates. Our group has a tradition in translational research applied to the development of a Shigella vaccine. We started by the rational attenuation of Shigella virulence to develop live-attenuated oral vaccine candidates. A S. flexneri 2a (SC602) and a S. dysenteriae 1 (SC599) vaccine candidates respectively designed against the endemic and epidemic form of shigellosis have undergone phase 1 and 2 clinical trials (30, 31, 32). They yet need validation in the course of phase 3 efficacy trials in endemic areas.
Subunit parenteral vaccine candidates. More recently, we have introduced a switch in paradigm in our approach to Shigella vaccination by developing a program aimed at providing a subunit parenterally-administered vaccine candidate. One option is based on the characterization of cross-reactive proteins preferably surface-exposed and involved in virulence in order to bypass the need to introduce several serotypes in the vaccine preparation, and to combine classical antibacterial immune responses with responses that neutralize the pathogenic potential of Shigella. This project is carried out in collaboration with SANOFI-PASTEUR. The alternative option is serotype-based. In collaboration with the group of Laurence Mulard (Unité de Chimie des Biomolécules, Institut Pasteur), we are developing a series of conjugate “prototypes” in which synthetic oligosaccharides mimicking the protective O-Ag part of the LPS of the most prevalent Shigella serotypes are conjugated to a protein carrier (33). At this stage, the carrier is a classical tetanus toxoid. In the future, it may be replaced by a Shigella-specific protective antigenA large part of the current paradigm switch is achieved in the framework of STOPENTERICS, a European Union-FP7 program coordinated by Philippe Sansonetti (http://stopenterics.bio-med.ch/cms/).