Live Attenuated <em>S</em>. Typhimurium Vaccine with Improved Safety in Immuno-Compromised Mice

<div><p>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 <em>Salmonella</em> diarrhea and a live attenuated <em>Salmonella</em> Typhimurium strain (<em>ssaV</em>). Vaccination with this strain elicited protective immunity in wild type mice, but a fatal systemic infection in immune-deficient <em>cybb</em><sup>−/−</sup><em>nos2</em><sup>−/−</sup> animals lacking NADPH oxidase and inducible NO synthase. In <em>cybb</em><sup>−/−</sup><em>nos2</em><sup>−/−</sup> mice, we analyzed the attenuation of 35 <em>ssaV</em> strains carrying one additional mutation each. One strain, Z234 (<em>ssaV SL1344_3093</em>), was >1000-fold attenuated in <em>cybb</em><sup>−/−</sup><em>nos2</em><sup>−/−</sup> mice and ≈100 fold attenuated in <em>tnfr1</em><sup>−/−</sup> animals. However, in wt mice, Z234 was as efficient as <em>ssaV</em> 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.</p> </div>