A rationally designed oral vaccine induces immunoglobulin A in the murine gut that directs the evolution of attenuated Salmonella variants

Médéric Diard, Erik Bakkeren, Verena Lentsch, Andrea Rocker, Nahimi Amare Bekele, Daniel Hoces, Selma Aslani, Markus Arnoldini, Flurina Böhi, Kathrin Schumann-Moor, Jozef Adamcik, Luca Piccoli, Antonio Lanzavecchia, Beth M. Stadtmueller, Nicholas Donohue, Marjan W. van der Woude, Alyson Hockenberry, Patrick H. Viollier, Laurent Falquet, Daniel WüthrichFerdinando Bonfiglio, Claude Loverdo, Adrian Egli, Giorgia Zandomeneghi, Raffaele Mezzenga, Otto Holst, Beat H. Meier, Wolf Dietrich Hardt, Emma Slack

Research output: Contribution to journalArticlepeer-review


The ability of gut bacterial pathogens to escape immunity by antigenic variation—particularly via changes to surface-exposed antigens—is a major barrier to immune clearance1. However, not all variants are equally fit in all environments2,3. It should therefore be possible to exploit such immune escape mechanisms to direct an evolutionary trade-off. Here, we demonstrate this phenomenon using Salmonella enterica subspecies enterica serovar Typhimurium (S.Tm). A dominant surface antigen of S.Tm is its O-antigen: a long, repetitive glycan that can be rapidly varied by mutations in biosynthetic pathways or by phase variation4,5. We quantified the selective advantage of O-antigen variants in the presence and absence of O-antigen-specific immunoglobulin A and identified a set of evolutionary trajectories allowing immune escape without an associated fitness cost in naive mice. Through the use of rationally designed oral vaccines, we induced immunoglobulin A responses blocking all of these trajectories. This selected for Salmonella mutants carrying deletions of the O-antigen polymerase gene wzyB. Due to their short O-antigen, these evolved mutants were more susceptible to environmental stressors (detergents or complement) and predation (bacteriophages) and were impaired in gut colonization and virulence in mice. Therefore, a rationally induced cocktail of intestinal antibodies can direct an evolutionary trade-off in S.Tm. This lays the foundations for the exploration of mucosal vaccines capable of setting evolutionary traps as a prophylactic strategy.

Original languageEnglish (US)
Pages (from-to)830-841
Number of pages12
JournalNature Microbiology
Issue number7
StatePublished - Jul 2021

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Applied Microbiology and Biotechnology
  • Genetics
  • Microbiology (medical)
  • Cell Biology


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