Clostridium difficile infection (CDI) is a major threat to public health in the industrialised world, particularly in Europe. In many EU countries C. difficile now eclipses Methicillin resistant S. aureus (MRSA) with hospital acquired infection mortality exceeding that of MRSA by a factor of four. C. difficile is resistant to a wide range of antibiotics with hypervirulent and multiple drug resistant strains now emerging. Vaccines are under development, but all are injectable and as such will elicit only a systemic immune response whereas growing scientific evidence suggests that to effectively prevent infection mucosal immunity is critical. Further, full protection to CDI (primary infection and recurrence) requires anti-toxin antibody responses as well as decolonisation of C. difficile spores. Our approach will be to use a novel mucosal vaccine delivery system based on the use of inactivated Bacillus subtilis spores that express two different recombinant C. difficile antigens on their surface, a toxoid antigen and a unique spore colonisation factor. In vivo proof of concept studies has provided compelling evidence for their use in a robust oral vaccine to CDI. This project aims to construct and optimise B. subtilis spores expressing these two antigens and to undertake therapeutic development. Our approach will use inactivated, killed, spores and oral delivery addressing any ethical issues that might arise. A patent application has been filed protecting this unique oral spore vaccine approach. A consortium has been built of SMEs with the expertise to optimise the therapeutic product and address its safety and immunogenicity in both preclinical and phase I clinical studies. The project will enable a unique oral vaccine against C. difficile to be clinically validated. The expected outcome will be the implementation of this vaccine in further clinical trials as well as validation of a novel vaccine platform that is applicable to other bacterial and viral infections.