Pietro Mastroeni
University of Cambridge, UK
Title: New approaches for the rational design of safer live attenuated bacterial vaccines.
Biography
Biography: Pietro Mastroeni
Abstract
Typhoid fever and non-typhoidal salmonelloses are responsible for a large disease burden worldwide and can coexist in the same geographical area. Vaccination remains the most feasible means to counteract Salmonella infections. Live attenuated vaccines induce both antibody and protective Th1 responses that are essential to control bacteraemia during a secondary challenge and restrain growth and inter-organ spread of the bacteria in the systemic organs. One of the concerns over the use of live vaccines is their potential residual virulence, especially in areas of the world where comorbidities and immunodeficiences are prevalent and in many cases undiagnosed. We have therefore searched for Salmonella genes that can be deleted to generate live attenuated vaccines with increased safety in situations where the immune system is impaired. We have used a global approach based on Transposon Directed Insertion-site Sequencing (TraDIS) to gain a numerical measure of the extent to which mutants are negatively or positively selected during infection in wild-type mice and in gene-targeted mice representative of common immunodeficiencies that predispose to salmonelloses. We have identified gene candidates that can be deleted to construct live vaccines with reduced and/or delayed reactogenicity in immunodeficient hosts. One of these vaccine strains has been further tested in immunocompromised mice and has shown increased safety as measured by delayed appearance of signs of infection in comparison with other established single mutant vaccine candidates. This mutant colonises mice via the oral and parenteral route and confers protection against lethal oral challenge with virulent Salmonella.