biostudies-literatureDiard MSwiss National Science FoundationEuropean Research CouncilNIAID NIH HHS830-841https://www.ebi.ac.uk/biostudies/studies/S-EPMC7611113biostudies-literatureUnknown6(7)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 environments^2,3. 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 variation^4,5. We quantified the selective advantage of O-antigen variants in the presence and absence of O-antigen-specific immunoglobulin A and idenNature microbiologyA rationally designed oral vaccine induces immunoglobulin A in the murine gut that directs the evolution of attenuated Salmonella variants.PMC7611113200020185128192567R01 AI041239176954173338180953159707310030865730Hockenberry ALentsch Vvan der Woude MWMeier BHHardt WDViollier PHSchumann-Moor KAdamcik JArnoldini MBonfiglio FDiard MAslani SMezzenga RHoces DSlack ERocker AHolst ODonohue NFalquet LLoverdo CZandomeneghi GStadtmueller BMBekele NABohi FWuthrich DPiccoli LLanzavecchia AEgli ABakkeren EfalseA rationally designed oral vaccine induces immunoglobulin A in the murine gut that directs the evolution of attenuated Salmonella variants.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 environments^2,3. 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 variation^4,5. We quantified the selective advantage of O-antigen variants in the presence and absence of O-antigen-specific immunoglobulin A and iden2021-01-01T00:00:00Z2021 Jul2026-05-08T04:36:10.641Z2022-02-11T13:10:37.327ZS-EPMC76111133404571110.1038/s41564-021-00911-1