Development of an oral spore vaccine to Clostridium difficile infection

Summary 

Clostridium difficile infection (CDI) is one of the leading causes of nosocomial antibiotic-associated diarrhoea. Although CDI is usually considered a disease restricted to HIC, recent data suggests that rates in LMIC are similar to that of Europe or USA. Importantly, the primary method of control is by the use of antibiotics yet this pathogen acquires AMR as well as multidrug resistance and so developing a prophylactic is a priority. Parenteral vaccines have failed. Overarching evidence suggests that to prevent CDI an approach that prevents spore germination of the pathogen and colonization of the host GI-tract is required. Thus, mucosal vaccination that induces secretory IgA responses is a rational approach. Recently, a recombinant spore vaccine expressing the C-terminus of toxin A (TcdA26-39) has been shown to protect against CDI, induce mucosal responses and has been taken to Phase 1 studies. Nevertheless, this vaccine should be improved to ensure higher levels of protection and to overcome downstream regulatory hurdles arising from the use of GMOs. In the current project, we will develop a vaccine candidate using the oral spore (Bacillus subtilis) vaccine approach with a revised vaccine formulation that delivers additional C.difficile antigens constructed utilising a novel cloning system (THY-X-CISE™) that allows the creation of spores that are unable to proliferate in the environment. This latter point is essential for addressing biological containment of genetically modified organisms (GMOs) and ultimately facilitating regulatory approval of the vaccine candidate.