Nanoparticle based Tuberculosis vaccine

Despite the widespread use of Bacille de Calmette et Guérin (BCG) for over50 years, tuberculosis (TB) continues to be a major global health problem, especially in developing countries. Indeed BCG as been shown to reduce infant mortality, but demonstrated very high variability in preventing TB in adults. There is thus an urgent need for the development of an e-cacious novel TB vaccine that confirms long-term protection in both adult and children. A newnanoparticle (NP) delivery technology was recently developed in the laboratories of Prof. Swartz and Prof. Hubbell at the Swiss Federal Institute of Technology in Lausanne (EPFL) which proposes an innovative gene delivery approach for immunotherapy by targeting lymph node-residing dendritic cells (DCs). The NP platform has been shown to be extremely stable, safe, cheap, and able to induce strong T-cell responses and is thus expected to be a potential candidate for BCG replacement or BCG-prime booster. In this context we describe a preclinical testing plan that includes best formulation selection, dosage determination, e--cacy, and safety testing. We also explore regulatory issues, vaccine manufactory and the transition to clinical trials. Parralelly, better characterization of the NP platform itself is needed. The second part of this project is thus devoted to the study of NP surface modifications and their implications in the genera-tion of an immune response. Experiments using methoxylated and hydroxylated NPs suggest that free thiols present at the surface play a role in complement activation, however still poorly understood. In addition, N-terminal modified thiol-containing proteins have been synthesized for coupling on pyridyldisulfide NPs. This strategy greatly broadens the application of the NP platform, since it may be applied to almost any proteins. Finally thiol caging is reported as a method to recover thiols after antigen conjugation