| lühikokkuvõte: |
Enteric infections remain a major cause of morbidity and mortality globally, accounting for an estimated 2 millions deaths each year. Effective preventive and therapeutic interventions are not yet available for many etiological agents of diarrheal diseases. Furthermore, even where vaccines are available, the lag time needed to induce an immune response can be critical in epidemic situations. We have developed a model system in which Lactobacillus, a GRAS microorganism, can be transformed with antibody fragment encoding vectors. This allows the production of functional single-chain antibodies against mucosal pathogens in situ. These antibody fragments retain their biological properties in vivo and may mitigate or prevent disease. The aim of this project is to develop an effective treatment against rotavirus and Clostridium difficile based on lactobacilli producing VHH and scFv antibody fragments. As a proof of principle, a lead VHH fragment against rotavirus will be tested in a human clinical trial in India. In parallel, we will generate, select and express scFv and VHH fragments against the gastrointestinal pathogens rotavirus and C. difficile in lactobacilli. The modified bacteria will be tested for their protective capacity in animal models. The genes encoding the antibody fragments will further be cloned using food grade and biologically contained expression systems and these lactobacilli will be tested for safety in a human clinical trial. Our approach, which falls into the priority "Innovative approaches and interventions" and the work program "Development and production of new generation antibodies" represents a novel system for the induction of passive immunity that can be rapidly applied to populations at risk (for example through the drinking water, rehydrating solution or as a food supplement). If successful, this project could be applied to therapy against a vast number of human/animal pathogens in the gastrointestinal tract. |
