Background. Bacterial diseases are a grave threat for humankind causing approximately six million deaths per year. Antibiotic resistance is increasing. Hygiene measures are failing. Urbanization, climate changes and global travel make disease control increasingly difficult. Vaccines remain one of the key tools to combat infections for both residents and travellers to endemic areas, especially in developing countries. Salmonella are bacteria that cause life-threatening diseases in humans and other animal species. Typhoid fever, paratyphoid fever and invasive non-typhoidal Salmonella (iNTS) infections have a high incidence worldwide and these diseases coexist in many geographical areas, especially LMIC.
There is extensive international consensus on the urgent need for better and affordable vaccines against systemic Salmonella infections. Current vaccines against typhoid fever are safe and immunogenic, but require multiple doses and/or show moderate protective ability. No vaccines against iNTS or paratyphoid fever are currently licensed.
The aim of the project is to use Generalised Modules for Membrane Antigens (GMMA) as a means to generate multivalent and low cost vaccines to protect humans against many strains of Salmonella that cause severe infections in endemic areas. GMMA are outer membrane vesicles naturally shed by Salmonella 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.
Work plan. We shall use Salmonella strains, previously optimised to produce large quantities of GMMA. We shall then engineer these strains to express also S. Typhi antigens. GMMA expressing S. Typhi antigens will be fully characterized. We shall then test the immunogenicity and protective activity of these multivalent vaccine preparations in robust and tractable preclinical murine models.
The project has provided innovative proof-of-concept that it is possible to deliver the Vi polysaccharide using General Modules for Membrane Antigens (GMMA). The findings provide the fundamental bases to generate cheap, multivalent, safe vaccines for Low-Middle Income Countries (LMIC) and travellers against typhoid and paratyphoid fever as well as invasive non-typhoid Salmonella infections.