Evaluation of a heat shock protein complex (HspC) approach for vaccination against C.difficile-associated disease.

There are currently heightened public concerns over infection rates in UK hospitals, and in particular those caused by so called ?superbugs? that have become resistant to available antibiotics. One such bug is Clostridium difficile. It causes debilitating diarrhoea, which in extreme cases can kill. It mainly affects the elderly. As this proportion of the population is increasing, the disease is becoming more common. Worryingly, a new, even more deadly variant has now arrived in Europe from North America. Aside from the human suffering, it costs the European health services over 2 billion dollars per year and now is responsible for more deaths per year in the UK than MRSA. Currently there is no vaccine available to prevent C. difficile disease but vaccination has been very successful in preventing other bacterial diseases that were once common. Development of a vaccine for C.difficile would therefore be a very important step forward in fighting this common and potentially deadly infection.

Clostridium difficile is the most frequent cause of nosocomial infection in Europe. The rapid spread of more virulent ribotype 027 strains has resulted in an increase in disease severity and CDAD currently kills more people in the UK than infections caused by MRSA. Management of C.difficile -associated diarrhoea (CDAD) consequently places a huge financial burden on public health services and treatment of infection necessitates combined antibiotic and additional support measures. Currently no vaccine is available to prevent CDAD but clearly a preventative approach which could reduce the incidence of infection would have major benefits in reducing patient mortality and healthcare costs associated with CDAD. This project aims to evaluate a novel approach to generating protective immune responses to C. difficile as the first stage in development of a C. difficile vaccine. A vaccine consisting of C.difficile heat shock protein complexes (HspCs) will be evaluated. HspCs have the potential to generate protective immune responses to a broad range of C. difficile antigens through the inherent ability of heat shock proteins to induce antibody and cell mediated immune responses via interaction with dendritic cells. Using generic technology already established by the Industrial collaborator Immunobiology, C. dificile HspCs will be isolated and their content characterised. Comparison of HspCs generated with C.difficile strains 630 and ribotype 027 R20291 will be made and the potential for use of non-sporulating C.difficile spo0A mutants for generation of HspCs to improve vaccine safety and ease of large scale production will also be evaluated. Immunogenicity of HspCs will be tested initially in mice and functionality of antibodies generated evaluated in vitro in cytotoxicity and adhesion assays. The ability of HspCs to induce a protective response to C.difficile challenge in the hamster infection model will then be evaluated and the breadth of protection assessed using C.difficile strains 630 and R20291. This programme of work will provide proof of principal of the HspC approach for vaccination against CDAD and establish the laboratory process for further vaccine development and evaluation.