title: Live attenuated S. Typhimurium vaccine with improved safety in immuno-compromised mice.
abstract: Live attenuated vaccines are of great value for preventing infectious diseases. They represent a delicate compromise between sufficient colonization-mediated adaptive immunity and minimizing the risk for infection by the vaccine strain itself. Immune defects can predispose to vaccine strain infections. It has remained unclear whether vaccine safety could be improved via mutations attenuating a vaccine in immune-deficient individuals without compromising the vaccine's performance in the normal host. We have addressed this hypothesis using a mouse model for Salmonella diarrhea and a live attenuated Salmonella Typhimurium strain (ssaV). Vaccination with this strain elicited protective immunity in wild type mice, but a fatal systemic infection in immune-deficient cybb(-/-)nos2(-/-) animals lacking NADPH oxidase and inducible NO synthase. In cybb(-/-)nos2(-/-) mice, we analyzed the attenuation of 35 ssaV strains carrying one additional mutation each. One strain, Z234 (ssaV SL1344_3093), was >1000-fold attenuated in cybb(-/-)nos2(-/-) mice and ≈100 fold attenuated in tnfr1(-/-) animals. However, in wt mice, Z234 was as efficient as ssaV with respect to host colonization and the elicitation of a protective, O-antigen specific mucosal secretory IgA (sIgA) response. These data suggest that it is possible to engineer live attenuated vaccines which are specifically attenuated in immuno-compromised hosts. This might help to improve vaccine safety.
authors.affiliation: Institute of Microbiology, D-BIOL, ETH Zürich, Zürich, Switzerland.
authors.forename: Balamurugan
authors.initials: B
authors.lastname: Periaswamy
authors.forename: Lisa
authors.initials: L
authors.lastname: Maier
authors.forename: Vikalp
authors.initials: V
authors.lastname: Vishwakarma
authors.forename: Emma
authors.initials: E
authors.lastname: Slack
authors.forename: Marcus
authors.initials: M
authors.lastname: Kremer
authors.forename: Helene L
authors.initials: HL
authors.lastname: Andrews-Polymenis
authors.forename: Michael
authors.initials: M
authors.lastname: McClelland
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Grant
authors.forename: Mrutyunjay
authors.initials: M
authors.lastname: Suar
authors.forename: Wolf-Dietrich
authors.initials: WD
authors.lastname: Hardt
mesh_terms: D000818:Animals; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000172:deficiency / Q000235:genetics; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency / Q000235:genetics; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000235:genetics; D012481:Salmonella Infections, Animal / Q000276:immunology*; D022562:Salmonella Vaccines / Q000009:adverse effects / Q000276:immunology*; D012486:Salmonella typhimurium / Q000276:immunology* / Q000472:pathogenicity*; D014613:Vaccines, Attenuated / Q000009:adverse effects / Q000276:immunology*
chemical_list: D008562:Membrane Glycoproteins; D047888:Receptors, Tumor Necrosis Factor, Type I; D022562:Salmonella Vaccines; C506236:Tnfrsf1a protein, mouse; D014613:Vaccines, Attenuated; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases