Oral vaccines induce gut immune responses that direct Salmonella into an evolutionary dead-end
Intestinal antibodies (IgA) can exert selective pressure on intestinal bacteria. Via oral vaccines, we can manipulate these selective pressures to force evolution of Salmonella that are impaired in transmitting disease. This new vaccination strategy could be used to prevent disease caused by antibiotic-resistant intestinal bacteria.
The ability of gut bacterial pathogens to escape immunity by antigenic variation, particularly via changing their surface, has been a major barrier to successful vaccine development. However, taken to extremes, this escape process can be turned against the bacteria. A dominant surface antigen of Salmonella Typhimurium is its O-antigen: A long, repetitive glycan that can be rapidly varied. Via repetitive cycles of vaccination and characterization of Salmonella that escaped the immune response, we identified a combination of intestinal antibody specificities that would select for complete loss of long O-antigen. Evolved Salmonella mutants were more susceptible to environmental stressors (detergents, Complement), predation (bacteriophages), and were impaired in gut colonization and virulence. Therefore, a rationally induced cocktail of intestinal antibodies (IgA) can direct an evolutionary trade-off in Salmonella. This lays the foundations for the exploration of mucosal vaccines capable of setting evolutionary traps to eliminate diverse antibiotic resistant gut pathogens, or to edit the intestinal microbiota.
Link to the paper in external page Nature