Bacterial diseases are a grave threat for humankind causing approximately six million deaths per year. Antibiotic resistance is increasing. Hygiene measures are failing. Global travel makes disease control increasingly difficult. Enterotoxigenic Escherichia coli (ETEC) and Shigella are enteropathogens that cause significant global mortality and morbidity, particularly in low- and middle-income countries (LMIC). Development of new and improved vaccines against diarrheal infections is a fundamental element of the strategy towards reducing deaths from diarrhea in children under 5 years of age. No vaccines are currently widely available for both residents and travellers to endemic areas.
The aim of the proposed project is to use Generalised Modules for Membrane Antigens (GMMA) as a means to generate a multivalent and low cost vaccine to protect humans against diarrheal diseases caused by Shigella and ETEC. GMMA are outer membrane vesicles naturally shed by Shigella and other Gram-negative bacteria genetically manipulated to increase blebbing and decrease reactogenicity. GMMA present multiple antigens in the context of a membrane and have optimal size for immune stimulation plus self-adjuvanting properties. These vesicles are easy and cheap to produce, are strongly immunogenic and protective. GMMA can also be genetically or chemically modified to present heterologous antigens from other pathogens, supporting the development of multivalent vaccines.
Here, we will test the feasibility of using the GMMA approach for the development of a vaccine covering both Shigella and ETEC. As proof of concept we will use Shigella sonnei GMMA as scaffold and test different strategies for the delivery of LTK63, a not toxic derivative of the Heat-labile enterotoxin (LT) antigen of ETEC, together with the immunodominant O-Antigen (OAg) of Shigella sonnei. LTK63 is a powerful immunogen, non-toxic but maintaining all immunogenic and adjuvant properties of the wild-type LT toxin and is expected to play a Key role as strong mucosal immunogen and adjuvant. S. sonnei GMMA presenting LTK63 will be fully characterized and tested in robust and tractable preclinical animal models to investigate the immunogenicity and protective activity of these multivalent vaccine preparations.
This project will represent a valuable starting point for the development of a low cost and effective multivalent GMMA-based vaccine protecting against both Shigella and ETEC, that have a high incidence worldwide and coexist in many geographical areas, especially LMIC.
Professor Robin Shattock
Professor of Mucosal Infection and Immunity, Imperial College London (UK)
Dr Francesca Micoli, GSK Vaccines Institute for Global Health (Italy)
Dr Anjam Khan, Centre for Bacterial Cell Biology, Institute for Cell and Molecular Biosciences, Newcastle University (UK)
Dr Mariagrazia Pizza, GSK Vaccines (Italy)