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Investigation of Generalized Modules for Membrane Antigens as a vaccine against invasive non-Typhoidal Salmonella

Invasive non-typhoidal Salmonellosis is a major cause of bloodstream infections in Sub-Saharan Africa, mainly caused by Salmonella enterica serovars Typhimurium and Enteritidis. Naturally shed outer membrane vesicles from Gram-negative bacteria are being explored to generate cost-effective vaccines against many infections, since antigens within vesicles maintain their natural conformation and orientation. Shedding can be enhanced through genetic modification and the resulting vesicles, Generalized Modules for Membrane Antigens (GMMA) offer potential as vaccines. We explored the potential of expressing a known immunogenic antigen of S. Typhimurium, OmpD, in GMMA derived from E. coli as a vaccine. Further, we showed that immunization with GMMA derived from S. Typhimurium (STm-GMMA) induced protection in mice. The response to STm-GMMA immunization included the generation of antibodies to two immunodominant antigens, lipopolysaccharide and porins. Strikingly, the IgG response towards these two antigens was induced with different rates during first week, with a dramatic induction of IgG targeting porins, and not LPS, in a T-cell independent manner. Nevertheless, the antibody response against both antigens persisted for over 200 days in sites including the bone marrow. Results from this thesis shows that STm-GMMA is both attractive as a vaccine and as a tool to facilitate investigations of B-cell responses.